# projects

application_id: 7494311
project_number: 3UC6AI066844-01S1
project_title: Center of Predictive Medicine for Biodefense
administering_ic: NIAID
award_notice_date: 2007-09-28
opportunity_number: RFA-AI-04-032
application_type: 3
activity_code: UC6
ic: AI
serial_number: 066844
suffix: S1
program_official: LEWIS, AMBROSE B
project_start_date: 2005-09-01
project_end_date: 2010-08-31
study_section: ZAI1-JB-M(M2)
contact_pi_person_id: 9085131
contact_pi: MARTINEZ, MANUAL MALDONADO
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: UNIVERSITY-WIDE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
The University of Louisville proposes to establish a Center for Predictive Medicine for Biodefenseand Emerging Infectious Diseases (CPMBEID). Our long-term objective is to support the development ofgene-based countermeasures and diagnostic approaches based on system changes that occur during host-pathogen interactions. Focusing on host-based biothreat and emerging infectious disease research shouldallow the development of broad-spectrum interventions to infectious agents rather than the currentparadigm of "one bug/one vaccine" approach so prevalent today. Our specific aims are to 1) meet theexpanding needs of current researchers who work with Category A B or C priority pathogens at theUniversity of Louisville; 2) expand facilities so that we can add an additional six faculty investigators whowork with these agents; 3) assemble a unique mix of technologies in a free standing BSL3 facility so thatthe instrumentation and expertise is available on site to manipulate experimental materials and avoid theneed for shipping material off site; and 4) to serve as a resource for investigators from other institutions inour region who can benefit from the unique mix of technologies we will assemble in the facility as well as beprepared to bring those technologies to bear in the event of a bioterrorism emergency. The Universitycreated a superb team of investigators and administrators to shepherd this project from application tooperation. We are committed to working with NIAID and believe our missions can be mutually reinforced bybuilding a RBL in Louisville.Principal Investigator: Martin Nancy C.5. Budget (Supporting Documents)5.a. Source of Nonfederal Funding: The University of Louisville proposes to establish a stand alone RBL facility called the Center ofPredictive Medicine for Biothreat and Emerging Infectious Disease. This facility will be strategically locatedon the 180-plus acre Shelby campus the location of a Science and Technology park with a developingemphasis on Homeland Security related activities. The building itself will be a single-story building of brickCMU construction. The facility building will include a penthouse that will be limited to facility mechanicaland heating ventilation and air-conditioning (HVAC) components. The +/- 4 acre site is topographicallylocated atop a bluff that is surrounded by steep gradients to the north west and south and is furtherprotected from surrounding development due to the presence of a regional storm water detention basin.Further details regarding the site and its location are provided in Section 7a. of this application. The rationale for the proposed center is based on unmet needs of current and future researchersat UofL who focus on biothreat and emerging infectious diseases at U of L and will also serve other universities inthe region through the Ohio Valley Affiliates for Life Sciences (OVALS) an organization dedicated toleveraging resources at member institutions for the benefit of all members. In planning the project weconsidered three aspects in detail: 1. the construction costs necessary to build a stand-alone 30000square foot facility; 2. the architectural requirements to satisfy threat-risk evaluations; and 3. the specificneeds of electric ventilation and other structural support for housing heavy research equipment such asmass spectroscopic instruments for proteomic studies Fluorescence Activated Cell Sorters etc as well ascomputer server equipment for datamining the voluminous data that will be generated. Thus the finalbudget will support the construction and equipping of a facility that will meet the overall goal of developinggene-based countermeasures and diagnostic approaches based on system changes that occur during host-pathogen interactions. The architectural and operations plan envisions a shared lab approach to maximizethe use of the proposed unique state-of-the art biomedical research capability by U of L and OVALscientists as well as their colleagues from elsewhere in the nation. With full institutional support the current budget is based on the continuous interaction anddiscussions of a working team composed of users i.e. the researchers and administrators responsible foranimal care biosafety and construction and an outside construction consulting firm CUH2A as well as anoutside threat-risk consultant Tetra Tech Inc. The final budget for the entire proposed facility is$34629950.00 with the total Non-Allowable Costs of $5369700 and the total Allowable Costs of$29260250. In this proposal we are seeking funding for 75% of the total Allowable-Costs for a total of$21945187.00. The University will cost share $7315063 in Allowable-Costs. This amount plus the Non-Allowable Costs total $12684763; the plan for the source of this non-federal funding is: i. Commitment of $3 million in cash from the funds available in the offices of Vice President for Health Affairs and Senior Vice President for Research; $1.5 million respectively. ii. Commitment of $12684763 to be covered by bonding.This funding commitment is described in a letter from the President of the University of Louisville Dr. JamesRamsey to the Principal Investigator Dr. Nancy Martin (see next page).5.b. Composition of Funds:Federal Funding: $2194518750;Non-Federal Funding: $12684763: Allowable: $7315063; Non-Allowable:$5369.700. i. Cash: $3000000 ii. Bond: $9684763 (An additional $3000000 Contingency Fund will also be generated by bonding.)

project_terms:
Administrator;Air Conditioning;Arts;Biological Sciences;Biomedical Research;Bioterrorism;Budgets;Categories;Commit;Communicable Diseases Emerging;Computers;Consult;Contingency Fund;Cost Sharing;Data;Development;Diagnostic;Emergency Situation;Environmental air flow;Equipment;Evaluation;Event;Facility Construction Funding Category;Faculty;Funding;Future;Genes;Goals;Health;Heating;Infectious Agent;Infectious Diseases Research;Institution;Intervention;Letters;Location;Mechanics;Medicine;Mission;National Institute of Allergy and Infectious Disease;Object Attachment;Ohio;Operative Surgical Procedures;Pes;Principal Investigator;Proteomics;Research;Research Personnel;Resources;Risk;Science;Scientist;Security;Shipping;Ships;Site;Source;System;Technology;Today;Universities;Ursidae Family;Vaccines;Water;Work;animal care;base;biodefense;biosafety level 3 facility;biothreat;cost;data mining;fluorescence activated cell sorter device;instrument;instrumentation;member;pathogen;supported housing


application_id: 7494269
project_number: 1R01AI076169-01A2
project_title: Antiviral lectins as microbicides
administering_ic: NIAID
award_notice_date: 2008-04-09
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: AI
serial_number: 076169
suffix: A2
program_official: TURPIN, JIM A
project_start_date: 2008-04-15
project_end_date: 2012-03-31
study_section: AIDS Discovery and Development of Therapeutics Study Section[ADDT]
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH E
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Administration Intravaginal;Agriculture;Animals;Antibodies;Antiviral Agents;Attention;Binding (Molecular Function);Binding Sites;Biological;Biological Assay;Biological Markers;Blood specimen;Cells;Chemotaxis Leukocyte;Chlamydia trachomatis;Clinical;Collaborations;Complex;Data;Data Set;Depth;Development;Dose;Drug Kinetics;Economics;End Point;Epithelial;Epithelium;Evaluation;Exhibits;Fermentation;Gel;Genetic;Genital system;Goals;HIV;HIV-1;Herpesvirus 2 Human;Histology;Histopathology;Homologous Gene;Human;Immune;Immune response;In Vitro;Infection;Infiltration;Inflammation;Inflammatory Response;Lectin;Leukocytes;Mannose;Measurement;Measures;Modeling;Molecular;Mus;Mutagenesis Site-Directed;Mutate;Oryctolagus cuniculus;Pathology;Peptides;Pharmaceutical Preparations;Pharmacology and Toxicology;Phenotype;Placebo Control;Plant Leaves;Play;Predisposition;Production;Proteins;Recombinant Proteins;Recombinants;Recruitment Activity;Research;Resistance;Risk Factors;Role;Safety;Series;Sexually Transmitted Diseases;Simplexvirus;Solutions;Structure;Sum;Surface;System;Testing;Tissues;Tobacco;Toxic effect;Toxicology;Transmission Sexual;Vaccines;Vagina;Vaginal Douching;Vertebrates;Virus;base;chemokine;cost;cytokine;hydroxyethylcellulose;immunogenic;immunogenicity;in vivo;inhibitor/antagonist;insight;irritation;lymphocyte proliferation;microbicide;mutant;pathogen;practical application;prevent;public health medicine (field);rectal microbicide;research study;resistance mechanism;response;sugar;transmission process


application_id: 7494049
project_number: 5K23DK073750-04
project_title: Evaluation of the Effect of Green Tea Polyphenols on IBD
administering_ic: NIDDK
award_notice_date: 2008-09-08
opportunity_number: PA-00-004
application_type: 5
activity_code: K23
ic: DK
serial_number: 073750
program_official: PODSKALNY, JUDITH M,
project_start_date: 2005-09-15
project_end_date: 2010-08-31
study_section: Clinical Research Review Committee[RIRG-G]
contact_pi_person_id: 7368605
contact_pi: DRYDEN, GERALD W
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   Interest in green tea as an agent for improving health and treating disease has increased in both the lay and scientific literature. Green tea consists of several components with most research focusing on the  polyphenol fraction. The green tea polyphenols (GrTP) include (-)-epicatechin (EC) (-)-epigallocatechin  (EGC) (-)- epicatechin-3-gatlate (ECG) and (-)-epigallocatechin-3-gallate (EGCG). Of these EGCG  accounts for greater than 40% of the total polyphenol content. Therapeutic and prophylactic benefits have been attributed to the potent anti-oxidant effects of the polyphenols including reducing the risk of cancer. GrTP also have potent anti-inflammatory properties. GrTP have proven to be potent inhibitors of nuclear factor-kappa B (NF-kB) a key regutatory factor in the control of intestinal inflammation. Activation of NF-kB can be induced by a variety of stimulatory factors such as the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-a) or interleukin-1 (IL-1) bacterial endotoxin or oxidative stress. In unstimulated cells NF-kB exists as a heterodimer comprised of p65 and p50 subunits bound to a member of the inhibitor-kB (IkB) family of inhibitory proteins. NF-kB activators induce degradation of IkB by the 26s proteosome by phosphorylation of two serines in the N-terminal regulatory domain of IkB by IkB kinase (IKK). The liberated NF-kB translocates to the nucleus binds specific promoter sequences and induces expression of proinflammatory cytokines. These cytokines are expressed at high levels in chronic inflammatory bowel disease (IBD). IL-1 and TNF-a also activate NF-kB in a positive regulatory loop. This may lead to amplification of the inflammatory response. NF-kB appears to play a significant role in inflammation and is a likely target for anti-inflammatory therapies. Animal models of inflammation improved with GrTP administration. The scientific portion of this proposal intends to evaluate the use of GrTP in humans. Specific aim 1 will confirm that GrTP inhibit NF-kB activation in human peripheral blood monocytes. Specific aim 2 will evaluate the safety and tolerability of GrTP in volunteers with quiescent IBD while defining the pharmacokinetics and pharmacodynamics of GrTP. Specific aim 3 will further evaluate the safety of GrTP in subjects with IBD while providing preliminary data on the efficacy of this therapy in patients with active ulcerative colitis.

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


application_id: 7493649
project_number: 5R01DK074816-02
project_title: Albumin-AFP Gene Family Regulation in Fetal and Adult Liver
administering_ic: NIDDK
award_notice_date: 2008-06-25
application_type: 5
activity_code: R01
ic: DK
serial_number: 074816
program_official: SERRANO, JOSE
project_start_date: 2007-09-01
project_end_date: 2011-06-30
study_section: Gastrointestinal Cell and Molecular Biology Study Section[GCMB]
contact_pi_person_id: 1879406
contact_pi: SPEAR, BRETT
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
DESCRIPTION (provided by applicant): Mammalian liver development requires the sequential activation of genes in a highly ordered manner. Once activated levels of gene expression in the liver must continually be responsive to extracellular signals in order for organisms to maintain physiological homeostasis. We have been studying the mouse alpha- fetoprotein (AFP) gene as a model of liver-specific gene regulation. These studies have focused on the AFP enhancer region. More recently we have become increasingly interested regulation of all genes in the albumin-AFP gene family. One main goal of this proposal is to investigate the role of the AFP enhancers in the control of this gene family in the liver. Since AFP is activated in the fetal liver shut-off at birth and reactivated in models of liver damage and liver cancer these studies should help elucidate the basis of transcriptional changes that occur during liver damage and hepatocarcinogenesis. We are also interested in studying the process of zonal regulation in the adult liver. Zonal gene expression is a mechanism that allows different subpopulations of hepatocyte in the liver to carry out distinct metabolic activities. The zonal gene regulation can be disrupted in damaged liver and in neoplastic liver cells. Since zonal gene regulation is essential for the liver to carry out its normal function it is important to understand the basis for this control in the normal and diseased liver.

project_terms:
Activation Gene;Adult;Albumins;Binding (Molecular Function);Binding Proteins;Birth;Chromosomes;Complement 3c;Development;Elements;Enhancers;Family;Fetal Liver;Gene Expression;Gene Expression Regulation;Gene Family;Genes;Genomics;Glutamate-Ammonia Ligase;Goals;Hepatocarcinogenesis;Hepatocyte;Homeostasis;Human;Indium;Link;Liver;Malignant neoplasm of liver;Mammals;Mediating;Metabolic;Methods;Modeling;Molecular;Molecular Conformation;Mus;Neoplastic liver;Organism;Positioning Attribute;Process;Promoter Regions (Genetics);Promotor (Genetics);Rattus;Regulation;Regulatory Element;Regulatory Sequences Nucleic Acid;Repression;Role;Signal Transduction;Testing;Time;Transgenic Organisms;Vitamin D-Binding Protein;alpha-Fetoproteins;base;comparative;extracellular;fetal;interest;member;postnatal;research study


application_id: 7493409
project_number: 5K12DA014040-09
project_title: BUILDING INTERDISCIPLINARY RESEARCH CAREERS IN WOMEN'S HEALTH IN KENTUCKY
administering_ic: NIDA
award_notice_date: 2008-08-18
opportunity_number: RFA-OD-05-002
application_type: 5
activity_code: K12
ic: DA
serial_number: 014040
program_official: FRANKENHEIM, JERRY
project_start_date: 2000-09-30
project_end_date: 2010-08-31
study_section: Special Emphasis Panel[ZRG1-EMNR-J(50)R]
contact_pi_person_id: 7875362
contact_pi: FERGUSON, JAMES E.
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The primary goal of the proposed BIRCWH Program is to continue to provide Interdisciplinary Women's Health Research (IWHR) scholars with state-of-the-art multidisciplinary training in women's health research that will ensure that they successfully establish independent research careers in academic medicine. To achieve this goal we have refined and adapted our already successful organizational structure to provide scholars with in-depth training in 4 focused and interacting areas of women's health: 1) drug abuse and its relationship to sex and gender differences 2) cancer as it relates to women's health 3) hormonal regulation across a woman's lifespan and 4) oral health and its impact on cardiovascular and endocrine health and pregnancy outcomes. The 4 current focus areas were chosen as an extension of our previous research areas because research in these areas is of fundamental importance to improving the health of women. Also these 4 focus areas address the 4 overarching themes identified by NIH and ORWH as important for this proposal (interdisciplinary research sex/gender determinants lifespan and health disparities/differences and diversity). We will establish an innovative Shared Resource Laboratory called Advancing Research Through Support (ARTS) that will provide Scholars with skilled technical services that are unavailable elsewhere in the UK research environment. Finally we will establish an innovative program whereby former BIRCWH Scholars ("graduates") will act as Coaches by serving as members of research teams and providing an extensive and interactive support network for the IWRH Scholars. A unique feature and an important strength of our BIRCWH Program is its multidisciplinary cross departmental and interactive nature. This multidisciplinary structure allows us to address a broad range of issues related to public health including addictive behaviors aging cancer diabetes hormone action obesity oral health and pregnancy. During the previous funding period we used this interactive structure with considerable success. Therefore we propose to expand the opportunities afforded to each IWHR Scholar for rich concentrated and multidisciplinary experiences with a primary mentor a former BIRCWH Scholar (Coach) and many other faculty members that will enrich the IWHR Scholar's research experience and provide multiple role models to enhance the Scholar's career development.

project_terms:
Addictive Behavior;Address;Aging;Area;Arts;Cardiovascular system;Depth;Development;Diabetes Mellitus;Drug abuse;Endocrine;Ensure;Environment;Faculty;Funding;Gender;Goals;Health;Hormones;Kentucky;Laboratories;Longevity;Malignant Neoplasms;Medicine;Mentors;Nature;Obesity;Oral health;Pregnancy;Pregnancy Outcome;Range;Research;Resource Sharing;Services;Sex Characteristics;Structure;Study Interdisciplinary;Training;United States National Institutes of Health;Woman;Women's Health;career;experience;health disparity;hormone regulation;improved;innovation;member;multidisciplinary;organizational structure;programs;public health medicine (field);role model;sex;success


application_id: 7493386
project_number: 5P20RR020145-05
project_title: Center for Biologic Basis of Oral/Systemic Diseases (CB*
administering_ic: NCRR
award_notice_date: 2008-08-25
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
program_official: DOUTHARD, REGINE
project_start_date: 2004-09-23
project_end_date: 2009-09-29
study_section: ZRR1-RI-5(02)
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    The objectives of the Center for the Biologic Basis of Oral/Systemic Diseases (CBBOSD) are: RESEARCH: To develop a better understanding of the biologic principles that underpin the observed linkages of chronic oral infections and inflammation with systemic disease sequelae; and TRAINING: To use this research focus as a platform to develop promising young investigators in oral health sciences and enhance their competitiveness for external funding including NIH grant support. We will accomplish these objectives by: Organizing a cadre of established funded scientists to examine crucial questions related to oral and systemic health linkages Providing young research faculty with opportunities for interdisciplinary training in oral health sciences and systemic disease Mentoring young faculty in research projects focused on oral infections host responses and systemic disease that will lead to success as independent NIH-funded researchers Developing and supporting core facilities and resources to optimize the research enterprise of the CBBOSD faculty Facilitating pilot projects as well as intra- and inter-university collaborations among CBBOSD faculty and other researchers at the University of Kentucky Strategic hiring of new faculty to complement existing strengths to contribute to a critical mass of funded investigators in the biology of oral-systemic diseases. To address this need we have organized the research activities and leadership of the CBBOSD into 2 broad thematic areas. These thematic areas will incorporate 6 research projects that are integrated with respect to underlying concepts methodologies and availability of biological specimens. THEMATIC AREA 1: Oral infections: Translational studies of hostparasite interactions; Project 1: Oral Infections and HIV Recrudescence; Project 2: Oral Infections: Inflammation Lipid Metabolism and Atherosclerosis; Project 3: Oral Infections: Genomic Analysis of Host Responses to Polyrnicrobial Infections;. THEMATIC AREA 2: Oral infections: Clinical implications for systemic disease; Project 4: Oral Infections: Impact on Gestational Diabetes; Project 5: Oral Infections: Dietary Regulation of Local and Systemic Inflammatory Responses; Project 6: Oral Infections: Viral/Bacterial Interactions in Chronic Diseases. These research projects are integral to the goals of the CBBOSD because they focus on critical questions of the biology of chronic oral infections and contribution to alterations in systemic health. The overall focus of the CBBOSD is diverse to enable this interdisciplinary research team to: (i) address the myriad of challenges in understanding critical parameters of the interplay between infections and disease in the oral cavity and (ii) use the available expertise of senior faculty at UK with experience in mentoring young investigators. Thus junior investigators will be integrated into research projects with established funded faculty who use state-of-the-art cellular and molecular approaches to explore the biologic basis of this relationship. The breadth of science and varied senior research expertise assures that the CBBOSD will provide opportunities for many junior investigators who will have the capability to interact within this nurturing environment. The outcomes of this mentored nurturing structure will enhance the maturation of oral health research at UK through the College of Dentistry and synergize in expanding NIH-funded research in the Commonwealth of Kentucky.


application_id: 7492669
project_number: 5R01MH072567-04
project_title: Tat amyloid beta and brain endothelial barrier function
administering_ic: NIMH
award_notice_date: 2008-08-11
opportunity_number: PAS-04-072
application_type: 5
activity_code: R01
ic: MH
serial_number: 072567
program_official: RAO, VASUDEV RAMACHANDRA
project_start_date: 2005-09-20
project_end_date: 2010-08-31
study_section: Special Emphasis Panel[ZRG1-AARR-A(05)M]
contact_pi_person_id: 8260644
contact_pi: TOBOREK, MICHAL
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): One (1) of the emerging problems in HIV/AIDS is an increase in an older population affected by HIV infection. This phenomenon is of significant concern because aging is a predictor of rate of progression of HIV infection. Elderly patients develop AIDS more rapidly and have higher morbidity and mortality rates. Older patients are also more likely to develop AIDS-associated dementia. The present research application is focused on the mechanisms that may contribute to the development of dementia in elderly HIV-infected patients. Specifically we propose to study the mechanisms related to the injury to the vascular endothelium and dysfunction of the blood brain barrier (BBB). Our research has concentrated on the hypothesis that the viral gene product HIV Tat protein can be responsible for brain microvascular endothelial cells (BMEC) injury and impaired normal function of the BBB. Furthermore aging is associated with increased deposits of amyloid P-peptide (AP) which also can induce dysfunction of BMEC. Therefore it is striking to notice that AB and HIV Tat protein may work in concert in older HIV patients to induce impaired function of the brain vascular endothelium and contribute to the development of neuroAIDS. In the present grant application we hypothesize that AB and Tat can cross-amplify their cytotoxic effects and exacerbate the disruption of the BBB. Thus a combined exposure to Ap and Tat can lead to accelerated entry of HIV-1 into the CNS. To study these hypotheses this research proposal is focused on the pathways related to AP and/or Tat-induced cellular oxidative stress monocyte transendothelial passage disruption of expression of cell junction proteins and decreased barrier function of the BBB. The main in vitro experimental system will consist of the unique and innovative co-cultures of human BMEC with astrocytes which endogenously produce and release Tat. Part of our studies will also employ an animal model of amyloid angiopathy exposed to Tat. The long term goals of the current proposal are to determine mechanisms which may prevent Ap and Tat-induced injury to BMEC. Data arising from this proposal will be critical for a better understanding of mechanisms responsible for disruption of the BBB during HIV-1 infection associated with aging. In a broader aspect this proposal will contribute to better knowledge of how aging can contribute to the development of neurological complications of HIV/AIDS.

project_terms:
AIDS Dementia Complex;AIDS neuropathy;AIDS/HIV problem;Abbreviations;Acquired Immunodeficiency Syndrome;Adherence (attribute);Adhesions;Affect;Age;Aging;Alzheimer's Disease;Amyloid;Amyloid beta-Protein;Amyloid beta-Protein Precursor;Animal Model;Anti-HIV Therapy;Apoptotic;Area;Astrocytes;Biological Models;Blood;Blood - brain barrier anatomy;Blood Vessels;Brain;Brain Death;CCL2 gene;CREB1 gene;Calcium;Cell Adhesion Molecules;Cell Death;Cell Line;Cells;Cerebrum;Chemosensitization;Coculture Techniques;Cyclic AMP-Responsive DNA-Binding Protein;Data;Dementia;Deposition;Development;Disease;Disruption;Elderly;Endothelial Cells;Endothelium;Endothelium Vascular;Event;Exposure to;Functional disorder;Genes;Glycine dehydrogenase (decarboxylating);Goals;Grants Applications;HIV;HIV Infections;HIV-1;Human;In Vitro;Infection;Inflammatory;Inflammatory Response;Injury;Intercellular Junctions;Intercellular adhesion molecule 1;Interleukins;Knowledge;Lead;Life Expectancy;Mediating;Metabolism;Mice Transgenic;Mitochondria;Monocyte Chemoattractant Protein-1;Morbidity - disease rate;Mortality Vital Statistics;Mus;NIH Program Announcements;Nerve Degeneration;Neuraxis;Neuroglia;Neurologic;Neurons;Nuclear;Numbers;Older Population;Oxidation-Reduction;Oxidative Stress;Oxidative Stress Induction;Pathogenesis;Pathology;Pathway interactions;Patients;Peptides;Process;Proteins;Rate;Reaction;Research;Research Personnel;Research Proposals;STAT protein;STAT1 gene;Stress;Strikes Employee;Structure;Survival Rate;System;TNF protein human;Tg2576;Tight Junctions;Tissues;Toxic effect;Transcription Factor AP-1;Tumor Necrosis Factor-alpha;Tumor Necrosis Factors;Up-Regulation (Physiology);Vascular Cell Adhesion Molecule-1;Viral Proteins;Work;age related;amyloid peptide;base;brain metabolism;cell injury;cell type;chemokine;cytokine;cytotoxic;design;in vivo;innovation;interest;macrophage;migration;monocyte;mouse model;mutant;neglect;novel;older patient;peptide P;prevent;programs;protein expression;response;tat Protein;tat Protein HIV;trafficking;transcription factor;transcytosis


application_id: 7492539
project_number: 1R24MD002757-01
project_title: Faith Moves Mountains: A CBPR Appalachian Wellness & Cancer Prevention Program
administering_ic: NIMHD
award_notice_date: 2008-05-22
opportunity_number: RFA-MD-07-003
application_type: 1
activity_code: R24
ic: MD
serial_number: 002757
program_official: STINSON, NATHANIEL
project_start_date: 2008-05-22
project_end_date: 2013-01-31
study_section: Special Emphasis Panel[ZMD1 RN (01)]
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Abstinence;Address;Affect;Cancer Control;Cancer Prevention Secondary;Cervical;Chronic Disease;Collaborations;Colorectal Cancer;Communities;Diet;Diet Modification;Effectiveness of Interventions;Ensure;Evaluation;Event;Fostering;Goals;Health;Health Fairs;Incidence;Institution;Intervention;Intervention Studies;Interview;Kentucky;Malignant Neoplasms;Malignant neoplasm of breast;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Mammography;Methods;Modeling;Monoclonal Antibody R24;Morbidity - disease rate;Mortality Vital Statistics;National Center on Minority Health and Health Disparities;Ohio;Outcome;Pap smear;Participant;Phase;Physical activity;Population;Prevention;Prevention program;Process;Protocols Treatment;Randomized;Rate;Research;Research Design;Risk Appraisals Health;Risk Factors;Rural;Rural Health;Screening for Colorectal Cancer;Screening for cancer;Secondary Prevention;Smoking;Testing;Training;Trust;Universities;Work;base;cancer health disparity;cancer prevention;cancer risk;community based participatory research;design;diet and exercise;energy balance;health disparity;medically underserved;member;preference;prevent;programs;response;smoking cessation;therapy design


application_id: 7492464
project_number: 3R01AA015970-03S2
project_title: S-adenosylhomocysteine and S-adenosylmethionine in Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2007-08-31
application_type: 3
activity_code: R01
ic: AA
serial_number: 015970
suffix: S2
program_official: RADAEVA, SVETLANA
project_start_date: 2005-09-30
project_end_date: 2010-06-30
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This proposal will evaluate critical-interactions of cytokines and nutritional/ metabolicabnormalities of the hepatic transmethylation/transsulfuration pathways in the developmentof ALD using novel human animal and in vitro models with the ultimate goal of developingspecific therapy for ALD. Abnormal metabolism of tumor necrosis factor-a (TNF) is welldocumented in both experimental models of ALD and human ALD anchTNF plays a critical role inthe development of experimental ALD. Abnormal methionine metabolism also is well documented inALD with patients frequently having elevated plasma methionine concentrations which correlatewith prognosis. MAT1 A the enzyme responsible for the initial conversion of methionine to S-adenosylmethionine (SAMe) is decreased in ALD. Depressed SAMe levels are observed in mostforms of experimental liver injury including ALD and SAMe therapy is an effective hepatoprotectiveagent in experimental liver injury. Data from our group show that one potential beneficial effect ofSAMe is its ability to inhibit endotoxin stimulated TNF production in monocytes/Kupffer cells.Moreover MAT1A "knockout" mice have recently been generated and these SAMe deficient micedevelop spontaneous steatohepatitis and are much more sensitive to a second insult. While SAMelevels are depleted in ALD both S-adenosylhomocysteine(SAH) and homocysteine levels areelevated. The SAMe:SAH ratio and the cellular concentration of SAH critically control mostmethyltransferase reactions in the body and we recently reported that increased SAH sensitized toTNF induced hepatotoxicity. It is our working hypothesis that increased TNF in conjunctionwith altered SAMe/SAH metabolism play an etiologic role in the development/progression ofliver injury in ALD. The specific objectives of this proposal are to: 1. Document thatSAHsensitizes to TNFhepatotoxicity in vitro and in vivo. 2. Evaluate the effects of alcohol/SAH oninduction of mitochondria) dysfunction and hepatocyte death. 3. Determine mechanismswhereby SAMe and SAH modulate LPS-stimulated cytokine production. 4. Evaluate beneficialeffects of SAMe therapy on critical metabolic functions in patients with alcoholic cirrhosis.These studies utilize state-of-the-art models/techniques in a translational approach to develop anenhanced understanding of mechanisms involved in ALD and potential new therapy for ALD.

project_terms:
Alcohol abuse;Alcoholic Liver Diseases;Animals;Antioxidants;Arts;Cessation of life;Choline Deficiency;Chronic;Communication;Data;Depressed mood;Development;Elevation;Endotoxemia;Endotoxins;Enzymes;Evolution;Fatty Liver;Fatty Liver Alcoholic;Forecast of outcome;Functional disorder;Gel;Generations;Goals;Grants Applications;Health;Hepatic;Hepatocyte;Hepatoprotective Agent;Hepatotoxicity;Homocysteine;Homocystine;Human;In Vitro;Inflammation;Inflammatory;Injury;Killings;Knowledge;Kupffer Cells;Laboratories;Liver;Liver Cirrhosis Alcoholic;Liver diseases;Malignant neoplasm of liver;Mediating;Mediator of activation protein;Metabolic;Metabolism;Methionine;Methionine Metabolism Pathway;Methylation;Methyltransferase;Mice Knockout;Mitochondria;Modeling;Models Experimental;Molecular Weight;Mus;Nutritional;Oxidative Stress;Pathway interactions;Patients;Permeability;Personal Satisfaction;Plasma;Play;Predisposition;Production;Property;Reaction;Reporting;Research;Research Personnel;Role;S-Adenosylmethionine;Simulate;Steatohepatitis;TNF protein human;Techniques;Therapeutic;Therapeutic Agents;Transferase;Tumor Necrosis Factor-alpha;Tumor Necrosis Factors;United States;Vitamin E;Work;alcohol effect;base;cell type;cytokine;cytotoxicity;in vitro Model;in vivo;macrophage;methionine adenosyltransferase;mitochondrial dysfunction;monocyte;multicatalytic endopeptidase complex;novel;reactive oxygen intermediate;translational approach;transmethylation


application_id: 7492043
project_number: 5R01GM036065-22
project_title: Regulation of Protein N-Glycosylation in the CNS
administering_ic: NIGMS
award_notice_date: 2008-08-29
application_type: 5
activity_code: R01
ic: GM
serial_number: 036065
program_official: MARINO, PAMELA
project_start_date: 1981-06-01
project_end_date: 2010-08-31
study_section: Biochemistry and Biophysics of Membranes Study Section[BBM]
contact_pi_person_id: 7875239
contact_pi: WAECHTER, CHARLES J
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-09-01
project_abstract:
DESCRIPTION (provided by applicant):  The co-translational N-glycosylation of many important cell surface receptors ion channels and lysosomal enzymes is essential for their correct folding intracellular routing and function in the CNS and other mammalian cells. The vital importance of protein N-glycosylation in humans is emphasized by the clinical consequences of a series of inherited genetic defects in this pathway classified as Congenital Disorders of Glycosylation (CDG). While the enzymology and topology of the biosynthesis of Glc3Man9GlcNAc2-P-P-Dol the oligosaccharyl donor in the endoplasmic reticulum (ER) have been studied extensively many gaps remain in the understanding of how the enzymes in this pathway are organized and regulated. This proposal describes further studies to learn more about the role of ER-associated proteins in the regulation of dolichyl phosphate (Dol-P) biosynthesis and recycling and the transbilayer movement of Man-P-Dol.      
  
Three Specific Aims are planned using biochemical genetic and immunochemical approaches designed: 1) To utilize a recently cloned cDNA to learn more about the long-chain c/s-isoprenyltransferase (c/s-IPTase) catalyzing the elongation stage in Dol-P biosynthesis by investigating its regulation and the nature of its association with potential binding partners in the ER; 2) To utilize cloned cDNAs encoding dolichol kinase (DK) and Dol-P-P phosphatase an ER enzyme with a lumenally-oriented active site in in vivo and in vitro experiments aimed at elucidating their precise roles in the ote novo synthesis of Dol-P and the recycling of the glycosyl carrier lipid and 3) To purify identify and characterize the ER protein(s) mediating the transverse diffusion of Man-P-Dol in mammalian cells ("flippase"). The information gained on the structure of the Man-P-Dol flippase will be relevant to related membrane proteins mediating the transbilayer movement of other dolichyl-P-(P)-saccharide intermediates in protein O- C- and N-glycosylation glycerophospholipids glucosylceramide and glycosylphosphatidylinositol (GPI) anchor precursors and potential defects in patients with Congenital Disorders of Glycosylation (CDG).

project_terms:
Affect;Affinity;Anabolism;Antibody Formation;Back;Benzophenones;Binding (Molecular Function);Binding Sites;Biochemical;Biochemical Genetics;Cells;Chinese Hamster Ovary Cell;Clinical;DNA Complementary;Defect;Diffuse;Diffusion;Disorders Congenital;Dolichol;Dolichol kinase;Endoplasmic Reticulum;Enzymatic Biochemistry;Enzymes;GPI Membrane Anchors;Genes;Glucosylceramides;Glycerophospholipids;Human;In Vitro;Inherited;Ion Channel;Learning;Length;Lipids;Mammalian Cell;Mediating;Membrane Proteins;Modeling;Movement;Mutagenesis Site-Directed;Mutation;Nature;Numbers;Pathway interactions;Patients;Phosphoric Monoester Hydrolases;Phosphotransferases;Principal Investigator;Procedures;Protein Dephosphorylation;Protein Overexpression;Proteins;Reaction;Receptors Cell Surface;Recycling;Regulation;Role;Route;Sepharose;Series;Sites Active;Staging;Structure;System;Tissues;Water;analog;base;benzophenone;design;dolichol monophosphate;glycosylation;in vivo;mannose-phosphate-citronellol;monolayer;novel;programs;reconstitution;research study


application_id: 7491419
project_number: 5R01EY016155-02
project_title: Signal Transfer in the Tectothalamic Pathway
administering_ic: NEI
award_notice_date: 2008-08-21
application_type: 5
activity_code: R01
ic: EY
serial_number: 016155
program_official: OBERDORFER, MICHAEL
project_start_date: 2007-09-01
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZRG1-IFCN-B(02)M]
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: PETRY, HEYWOOD M
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-09-01
project_terms:
Autistic Disorder;Axon;Cell Nucleus;Cells;Code;Complex;Corpora quadrigemina superior colliculus;Diffuse;Disease;Dorsal;Dyslexia;Electron Microscopy;Electrons;Excitatory Postsynaptic Potentials;Frequencies (time pattern);GABA Agonists;Human;Image;In Vitro;Injection of therapeutic agent;Label;Lateral Geniculate Body;Light;Location;Mediating;Membrane;Methods;Microelectrodes;Microscopic;Motion;Movement;Neurons;Pathway interactions;Patients;Pattern;Physiology;Preparation;Primates;Process;Property;Pulvinar structure;Research Personnel;Retina;Schizophrenia;Signal Transduction;Slice;Speed (motion);Stimulus;System;Techniques;Tectum Mesencephali;Temporal Lobe;Testing;Thalamic structure;Tracer;Trees;Tupaiidae;Visual;Visual Motion;Visual Pathways;Visual Perception;Whole-Cell Recordings;Williams Syndrome;area MT;computer generated;design;extracellular;immunocytochemistry;in vivo;insight;optic imaging;programs;receptive field;response;segregation;visual stimulus


application_id: 7491146
project_number: 5R01GM070662-06
project_title: COOPERATIVE INTERACTIONS IN DNA REPAIR
administering_ic: NIGMS
award_notice_date: 2008-09-08
application_type: 5
activity_code: R01
ic: GM
serial_number: 070662
program_official: PREUSCH, PETER
project_start_date: 2004-04-01
project_end_date: 2012-08-31
study_section: Biophysics and Biophysical Chemistry A Study Section[BBCA]
contact_pi_person_id: 8344857
contact_pi: FRIED, MICHAEL G.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-09-01
project_abstract:
DESCRIPTION (provided by applicant): Our goal is to elucidate mechanisms by which DNA-repair proteins perform their essential biological functions. As immediate objectives we will investigate the interactions of human 0 6- alkylguanine-DNA alkyltransferase (AGT) with O6-alkylguanine (lesion)-containing and lesion-free DNAs. AGT repairs pro-mutagenic O -alkylguanine residues in DNA. It binds DNA with substantial cooperativity but little sequence or base composition dependence. These results argue against mechanisms of target recognition that depend strongly on sequence. An alternate possibility which comprises the central hypothesis of this application is that cooperative DNA binding and access to DNA modulate the binding distributions of AGT and its rate of DNA-repair. To test this hypothesis we will pursue three specific aims. These are: 1. To determine how binding cooperativity supercoiling and the presence of nucleosomes affect the equilibrium distribution of AGT among available DNA sites and between O6-alkylguanine - containing and lesion-free sequences. 2. To identify amino acids that are present at the protein-protein interface in the cooperative AGT-DNA complex. To test the consequences of mutation of these residues on DNA binding in vitro and on DNA repair in vitro and in vivo. 3. To identify the roles played by cooperative binding supercoiling and nucleosomes in the kinetic mechanisms of lesion-search by AGT and on its rate of DNA repatr. At the conclusion of this research we will have identified the role played by cooperative binding in lesion-search -binding and -repair and we will have tested the notion that the rate of lesion-search depends on the structure of the DNA template. Together these results will test the hypothesis that differences in DNA structure and accessibility determine the mechanism(s) by which AGT scans the genome for lesions and repairs them.

project_terms:
Affect;Affinity;Amino Acids;Appendix;Base Composition;Binding (Molecular Function);Biological Process;Biology;Complex;DNA;DNA Binding;DNA Repair;DNA Structure;DNA alkyltransferase;DNA repair protein;DNA-Binding Proteins;Dependence;Equilibrium;Genome Scan;Goals;Homologous Gene;Human;In Vitro;Kinetics;Lesion;Modeling;Molecular;Mutation;Nucleosomes;O(6)-Methylguanine-DNA Methyltransferase;Positioning Attribute;Protein Binding;Proteins;Rate;Research;Role playing therapy;Site;Sites Active;Testing;Work;experience;in vivo;mutant;protein protein interaction;repaired


application_id: 7491008
project_number: 5R01MH063705-08
project_title: Targeting Mass Media Campaigns for HIV STD and Pregnancy Prevention
administering_ic: NIMH
award_notice_date: 2008-09-04
application_type: 5
activity_code: R01
ic: MH
serial_number: 063705
program_official: SCOTT-SHELDON, LORI ANN JENNIFER
project_start_date: 2001-06-28
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZRG1-AARR-G(02)M]
contact_pi_person_id: 7876977
contact_pi: PALMGREEN, PHILIP C
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-09-05
project_abstract:
DESCRIPTION (provided by applicant): The proposed study represents a continuation of a successful NIH-funded research program on improving the effectiveness of mass media campaigns targeted toward individuals predisposed to high levels of sexual risk-taking. Our current project assessed the impact of a televised PSA intervention campaign designed specifically to reduce high-risk sexual behavior in young adults. Results have been impressive with 4-6 month effects on condom use and critical mediators of condom use for high-sensation-seeking (HSS) and impulsive decision-making (IDM) young adults in an interrupted time-series 2-city field experiment. The proposed continuation study will examine the effectiveness of intensive television campaigns in persuading young adolescents to delay initiation of sexual activity in 2 comparable top 125 Nielsen markets (Charleston SC and Augusta GA) employing a controlled time-series design similar to that in the current project. It will involve 3 high-saturation 3-month TV PSA campaigns (2 in 1 community and 1 in the other) focusing on delay of initiation of sexual activity employing theory-based age-appropriate gender-targeted and culturally sensitive messages. Over the 27-month assessment period the study will monitor PSA exposure sexual norms about waiting to have sex refusal self-efficacy involvement in a relationship intentions to have sex and delay having sex placing oneself in potentially sexual situations as well as individual difference variables (particularly sensation-seeking and impulsive decision-making) through interviews with monthly random samples from a cohort of students in public schools in the 2 communities. An accompanying process study will provide insight into the individual and social processes through which the campaign has its effects on behavior. The principal objectives of the study are to: 1) test the ability of a targeted televised PSA campaign to reach at-risk adolescents with messages to reduce HIV-related risky behavior by delaying initiation of sexual activity 2) provide a controlled test of the ability of such a campaign to produce significant changes over time in initiation of sexual activity and related mediating variables 3) explore the roles of sensation-seeking and impulsive decision-making in moderating such effects 4) explore how the processes through which the campaign affects the above mediating and outcome variables are similar or different for African-American and Caucasian adolescents 5) explore the ability of a booster campaign to enhance or sustain the impact of a previous campaign and 6) enhance understanding of the individual and social processes related to campaign effects. The potential public health significance of this project includes delaying sexual activity for hundreds of early adolescents resulting in significant reductions in rates of unwanted teen pregnancy and STDs (including HIV) over an extended period of time. The televised public service announcements will also be made available to other communities for airing there with potentially significant public health outcomes.

project_terms:
AIDS prevention;Adolescent;Affect;Affective;African American;Age;Air;Alcohol or Other Drugs use;Arousal;Attention;Attitude;Behavior;Behavioral;Caucasians;Caucasoid Race;Cities;Clinical;Communities;Computers;Condoms Unspecified;Decision Making;Development;Diffuse;Educational Curriculum;Effectiveness;Environment;Esthesia;Funding;Gender;HIV;Individual;Individual Differences;Intervention;Intervention Studies;Interview;Laboratories;Laboratory Study;Learning;Marketing;Mass Media;Measures;Media Campaign;Mediating;Mediator of activation protein;Monitor;Numbers;Outcome;Penetration;Placement;Population;Pregnancy in Adolescence;Prevention;Prevention intervention;Procedures;Process;Radio;Rate;Research;Research Personnel;Risk;Risk Behaviors;Risk-Taking;Role;Running;Sampling;Schools;Self Efficacy;Sensory;Series;Services;Sex Behavior;Students;Television;Testing;Time;Work;aged;base;cohort;delay sex;delay sexual debut;design;high risk sexual behavior;improved;innovation;insight;novel;preference;pregnancy prevention;programs;public health medicine (field);research study;response;sex;size;social;social cognitive theory;theories;young adult


application_id: 7489885
project_number: 5R01DK077632-03
project_title: Protective Effects of Stearic Acid on Gestational and Acquired Diabetes Mellitus
administering_ic: NIDDK
award_notice_date: 2008-09-05
opportunity_number: RFA-DK-05-014
application_type: 5
activity_code: R01
ic: DK
serial_number: 077632
program_official: CASTLE, ARTHUR
project_start_date: 2006-09-15
project_end_date: 2010-09-14
study_section: ZDK1-GRB-N(O1)S
contact_pi_person_id: 1896984
contact_pi: SMART, ERIC J
other_pis: GRAF, GREGORY A
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Hypothesis. The central hypothesis of this proposal is that CD36 ABCD2 and mitoNEET mediate the protective effects of stearic acid on gestational diabetes and on the acquired diabetes of the progeny. Rationale. The goal of this proposal is to test the novel hypothesis that stearic acid ameliorates gestational diabetes mellitus (GDM) and subsequent diabetes in the progeny of GDM mothers through a triad of CD36 ABCD2 and mitoNEET proteins. We will use the CSTBLKS/J-Lep/*'* mouse that develops GDM around day 16 of gestation. We will examine the mechanisms of stearic acid on CD36 ABCD2 and mitoNEET expression and function in both GDM and on long-term metabolic and cardiovascular outcomes in the progeny of the db/+ dams. Finally we will use individual genetic knockout models for each protein to determine the extent to which each protein mediates the action of stearic acid in both GDM and diabetes of the progeny. The uniqueness and potential clinical relevance of this approach is the mechanistic analysis of a possible means for treatment of both GDM and pursuant diabetes mellitus acquired by the offspring. We propose in vivo studies that can be further dissected by in vitro studies with isolated tissues and cells which will enable us to thoroughly explore the protective mechanism of action of stearic acid. 1. To determine the impact of stearic acid on the development and extent of GDM. Db/+ dams will be used to examine whether stearic acid affects the development of GDM by measuring oral glucose tolerance vascular responsiveness and adipocyte function. The expression and subcellular localization of CD36 ABCD2 and mitoNEET in adipose will be quantified and functionality of the proteins assessed through measurements of fatty acid biochemistry (p-oxidation fatty acid composition and angiotensin II secretion). Similarly we will also examine the effect of stearic acid treatment fed exclusively to the db/+ dams on the extent of diabetes in the offspring. Finally we will thoroughly examine the mechanism of action of stearic acid on fatty acid biochemistry in insulin resistant 3T3-L1 adipocytes. This aim is important because we will mechanistically evaluate a potential palliative intervention for both GDM and the accompanying diabetes of the offspring. 2. To determine the duration which stearic acid improves the diabetic phenotype in db/db mice. Db/db progeny will be treated with stearic acid and the duration and extent of the protective effect investigated. The effect of withdrawal of stearic acid on the lasting benefit of the intervention will also be examined. We will measure blood pressure vascular responsiveness weight and glucose. We will examine the mechanisms of stearic acid action by determining the expression and subcellular location of CD36 ABCD2 and mitoNEET in adipose and assessing function of each protein through measurements of adipose fatty acid biochemistry. This aim is important because it will provide data on the cardiovascular benefit and sustainability of stearic acid intervention. 3. To determine whether the beneficial effects of stearic acid are mediated by CD36 ABCD2 and/or mitoNEET. We will cross mice null for CD36 ABCD2 or mitoNEET with db/+ mice and assess the efficacious effects of stearic acid in ameliorating GDM and the ensuing diabetic phenotype of the double crossed db/db progeny lacking each individual gene. We will measure OGTT vascular responsiveness and adipose fatty acid biochemistry in db/+ dams. Furthermore we will assess the effect of individual gene knockout on the ability of stearic acid to affect the development of diabetes in the db/db mice. This will be accomplished through measurements of weight glucose insulin blood pressure and vascular responsiveness. Mechanistically the effects of gene ablation will be dissected through comprehensive analyses of isolated primary adipose biochemistry. This aim is critical because each double crossed mouse line will provide the definitive mechanistic data regarding the role of each protein in mediating the beneficial effects of stearic acid.

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


application_id: 7488881
project_number: 5R01DK069766-04
project_title: Tolerance Induction to Islet Transplants
administering_ic: NIDDK
award_notice_date: 2008-08-12
application_type: 5
activity_code: R01
ic: DK
serial_number: 069766
program_official: APPEL, MICHAEL C
project_start_date: 2005-09-01
project_end_date: 2010-08-31
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 1878929
contact_pi: ILDSTAD, SUZANNE T
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-09-01
project_abstract:
DESCRIPTION (provided by applicant): The focus of this proposal is to develop a novel "conditioning" approach that will replace myelotoxic agents to establish chimerism in NOD mice. We will induce immune deviation to promote host-versus-graft hyporesponsiveness thereby giving the hematopoietic stem cell (HSC) an opportunity to engraft and establish subsequent self-perpetuating deletional tolerance to islet allografts. Our recent studies in a mouse model suggest that the primary role for conditioning for HSC transplantation is to suppress host-versus-graft alloreactivity rather than to prepare vacant niches in the recipient's bone marrow compartment. This observation suggests that one could replace myelotoxic agents with antigen-specific approaches to induce host-versus-graft hyporeactivity or anergy at the time of HSC transplantation. As the mechanisms underlying T cell activation are defined highly specific approaches to suppress this alloreactivity have emerged. In AIM I. we will ESTABLISH CHIMERISM THROUGH IMMUNE DEVIATION OF THE RECIPIENT. We will immunomodulate the recipient: (a) targeting alloreactive cells in the host microenvironment; (b) inducing anergy and/or antigen-specific apoptosis of alloreactive host cells; and (c) through generation of regulatory T cells (Treg) and develop a novel nonmyeloablative conditioning regimen to induce antigen-specific hyporesponsiveness to the HSC and islet allografts. Cell-based therapies have great potential for inducing transplantation tolerance. Of greatest interest are the new subpopulations of bone marrow-derived dendritic cells (DC) that have recently been shown to be potently tolerogenic in vitro under certain circumstances. We are the first to demonstrate an in vivo engraftment-enhancing effect for precursor plasmacytoid DC (p-preDC). The exploitation of this discovery in vivo and its potential to reduce the need for myelotoxic conditioning has not yet been tested. Hematopoietic growth factors have also been used to drive the immune response to a tolerogenic T helper 2 (Th2) phenotype through production of p-preDC or other tolerance-promoting cells (graft facilitating cells {FC}) that in turn generate Treg. In AIM II we will USE PRE-TRANSPLANT IMMUNOMODULATION OF THE DONOR WITH HEMATOPOIETIC GROWTH FACTORS TO GENERATE TOLEROGENIC CELLS IN THE HSC ALLOGRAFT. We will use these factors and the cells they generate to modulate the tolerogenicity of the donor marrow inoculum in vivo to tip the immune milieu in favor of graft acceptance enhancing bone marrow chimerism without myelotoxic conditioning. We will examine the mechanism by which this occurs and identify which cell types in the graft are critical to tolerance induction. P-preDC exposed to apoptotic donor antigens are potently tolerizing in vitro through generation of Treg. The therapeutic application of this approach has not been tested in vivo. In AIM III we will USE EX VIVO IMMUNOMODULATION OF THE MARROW to expand p-preDC and FC and induce a tolerogenic inoculum for HSC transplantation.

project_terms:
Acute;Address;Adverse effects;Allogenic;Allografting;Antigens;Apoptosis;Apoptotic;Appendix;Autoimmune Diseases;Autoimmune Process;Autoimmunity;Bone Marrow;Bone Marrow Transplantation;Cells;Cessation of life;Chimerism;Clinical Treatment;Clinical Trials;Condition;Data;Dendritic Cells;Diabetes Mellitus;Diabetes Mellitus Insulin-Dependent;Doctor of Medicine;Engraftment;Generations;Goals;Graft-vs-Host Disease;Hematopoietic Cell Growth Factors;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Immune;Immune response;Immunization;In Vitro;Infusion procedures;Insulin;Interleukin-3;Islets of Langerhans Transplantation;Journals;Maintenance;Marrow;Medicine;Methods;Mice Inbred NOD;Morbidity - disease rate;Phenotype;Population;Principal Investigator;Production;Productivity;Protocols Treatment;Role;Staging;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;Therapy Cell;Time;Transplantation;Transplantation Immunology;Transplantation Tolerance;anergy;blood glucose regulation;cell type;clinical application;conditioning;disorder prevention;immunoregulation;in vivo;interest;islet;islet allograft;mouse model;novel;prevent;programs;research study;reverse tolerance


application_id: 7488873
project_number: 5R01DA013519-08
project_title: Development of Novel Therapies or Methamphetamine Abuse
administering_ic: NIDA
award_notice_date: 2008-08-20
application_type: 5
activity_code: R01
ic: DA
serial_number: 013519
program_official: APPEL, NATHAN M
project_start_date: 2000-08-15
project_end_date: 2010-08-31
study_section: Medication Development Research Study Section[NIDA-L]
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-09-01
project_abstract:
DESCRIPTION (provided by applicant):  Methamphetamine (METH) abuse continues to escalate and effective treatments are not yet available. METH interacts with the vesicular monoamine transporter (VMAT2) promoting both dopamine (DA) release into the cytosol and reversal of the DA transporter (DAT) to increase extracellular DA concentrations which is thought to be associated with its abuse liability. Importantly progress on the current project has shown that alpha-lobeline (LOB) has high affinity for the [3H]dihydrotetrabenazine binding site on VMAT2 and potently inhibits [3H]DA uptake into synaptic vesicles. We have also shown that LOB inhibits METH-evoked DA release in vitro and METH self-administration in rats. Thus LOB has potential as a new therapeutic agent for the treatment of METH abuse and has recently successfully completed Phase 1 a clinical trials. However LOB has been shown to interact with many different CMS targets (i.e. it is a relatively nonselective or "dirty" drug) including alpha4beta2* alpha6abeta2* and alpha3beta4* nicotinic acetylcholine receptors. In the current proposal we aim to develop LOB analogs with high affinity and selectivity for VMAT2 which we believe will have increased benefits over LOB as therapeutic candidates for the treatment of METH abuse. We chose VMAT2 as the target as it is a key point of regulation in DA synaptic transmission due to the high affinity of LOB for VMAT2 and due to METH's interaction with VMAT2 which results in increased extracellular DA that is associated with its reward and abuse. Thus our hypothesis focuses on VMAT2 as a novel therapeutic target for the treatment of METH abuse. Development of selective high affinity VMAT2 inhibitors will allow us to test the hypothesis that selective inhibition of VMAT2 decreases METH reward. We have identified lobelane as our lead compound due to its high affinity and relative selectivity for VMAT2 its ability to inhibit METH-evoked DA release and its ability to decrease METH self-administration. Thus the long-term goal of this research is to develop novel lobelane analogs as treatments for METH abuse pioneering the development of a novel class of therapeutic agents that selectively target VMAT2 and have potential as efficacious treatments for METH abuse.

project_terms:
3-Dimensional;Affinity;Binding (Molecular Function);Binding Sites;Biological Assay;Characteristics;Class;Clinical Trials;Corpus striatum structure;Cytosol;Development;Dopamine;Dose;Drug Kinetics;Electronics;Evaluation;Exhibits;Goals;In Vitro;Kinetics;Lead;Length;Link;Lobeline;Metabolism;Methamphetamine;Modeling;Modification;Molecular Conformation;Nicotinic Receptors;Pharmaceutical Preparations;Pharmacodynamics;Phase;Pliability;Property;Rattus;Regulation;Relative (related person);Research;Research Personnel;Rewards;Self Administration;Series;Site;Slice;Specificity;Sucrose;Synaptic Transmission;Synaptic Vesicles;System;Testing;Therapeutic;Therapeutic Agents;Thinking function;Time;Vesicle;analog;dihydrotetrabenazine;dopamine transporter;extracellular;inhibitor/antagonist;lipophilicity;methyllycaconitine;molecular modeling;novel;novel therapeutics;pharmacophore;piperidine;presynaptic;programs;stereochemistry;therapeutic target;uptake;vesicular monoamine transporter


application_id: 7488507
project_number: 5K23HD050581-03
project_title: Cervical (Neck) Auscultation and Developmental Outcomes
administering_ic: NICHD
award_notice_date: 2008-09-10
opportunity_number: PA-00-004
application_type: 5
activity_code: K23
ic: HD
serial_number: 050581
program_official: RAJU, TONSE N
project_start_date: 2006-09-27
project_end_date: 2011-08-31
study_section: Pediatrics Study Section[CHHD-A]
contact_pi_person_id: 7584915
contact_pi: REYNOLDS, ERIC W
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): Feeding is arguably the most complex skill a newborn infant must master in order to achieve independent survival. The integration of suck-swallow-breath rhythms is essential for development of effective feeding behavior. Patterns of suck-swallow-breath rhythms during feeding become more uniform as preterm infants grow and these rhythms are disrupted in infants with bronchopulmonary dysplasia (BPD). Inability to coordinate these rhythms may be a marker of poor neurologic outcome. Cervical auscultation (CA) with an accelerometer with digital signal processing (DSP) technology can be used to quantitatively compare the sounds of infant feeding by calculating the Variance Index (VI) of swallow-associated sounds. This method has been used to show that the swallow-associated sounds of low-risk preterm infants become more uniform with increasing post-menstrual age. As with other feeding rhythms this progression is not seen in infants with BPD. No studies have correlated CA/DSP data with developmental outcomes. The objectives of this project are: 1) to identify factors inherent in the development of stability and sources of variability of swallow-associated sounds in infant feeding 2) to correlate CA/DSP measurements of swallow-associated sounds during early rhythmic suckle feeding with long-term neurologic/developmental outcomes 3) to identify differences in rhythmic suckle feeding of infants with various pathologic conditions and 4) to measure the effects of therapeutic interventions such as speech therapy on swallow-associated sounds. Objectives 1 2 and 3 will be met with a prospective cohort study following 6 groups of infants healthy term cohort HIE term cohort drug-exposed cohort low-risk preterm cohort BPD cohort and a Grade III/IVIVH cohort (n = 25 per group). The infants will be followed from the beginning of oral feeding to two years of life. CA/DSP and biometric data will be collected during feeding. Vis will be compared between groups at various time points and within each group over time. CA/DSP data will be correlated with neurobehavioral and developmental outcome data. By correlating the VI and other DSP parameters with behavioral and developmental data CA/DSP data may be used to identify infants who are at higher risk of a poor long-term outcome thus allowing earlier developmental intervention to take place. For objective 4 we will enroll an additional 25 infants with BPD and randomize the total group so that half of the infants (25) receive speech therapy and the other half do not. CA/DSP results will be compared before and after feeding therapy. We hypothesize that if therapy is successful the VI for the intervention group will approximate the VI for the low-risk preterm infants. By successfully completing these projects we will increase our understanding of the development of successful feeding behavior and make CA/DSP technology more available as a non-invasive diagnostic technique.

project_terms:
Age;Auscultation;Behavioral;Biometry;Bronchopulmonary Dysplasia;Cervical;Characteristics;Cohort Studies;Complex;Condition;Data;Deglutition;Development;Development Infant;Diagnostic Procedure;Digital Signal Processing;Enrollment;Feeding behaviors;Forecast of outcome;Infant;Infant Newborn;Infant Premature;Intervention;Invasive;Life;Link;Measurable;Measurement;Measures;Methods;Neck;Neonatal;Neurologic;Neurological outcome;Oral;Outcome;Pathogenesis;Pathologic;Pattern;Pharmaceutical Preparations;Randomized;Recording of previous events;Research;Risk;Services;Signal Transduction;Site;Sound - physical agent;Source;Speech Therapy;Technology;Testing;Therapeutic Intervention;Time;cohort;drug exposure in utero;feeding;indexing;intraventricular hemorrhage;neonatal hypoxic-ischemic brain injury;neurobehavioral;prospective;skills;sucking


application_id: 7488074
project_number: 1F31ES016719-01
project_title: Curcumin inhbits BPDE-induced damage by lowering the threshold of p53 activation
administering_ic: NIEHS
award_notice_date: 2008-04-21
opportunity_number: PA-07-106
application_type: 1
activity_code: F31
ic: ES
serial_number: 016719
program_official: HUMBLE, MICHAEL C
project_start_date: 2008-05-01
project_end_date: 2011-03-31
study_section: Special Emphasis Panel[ZRG1 IMM-L (29)]
contact_pi_person_id: 8797117
contact_pi: ROGERS, ERICA NICOLE
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Lung cancer the leading cause of cancer-related deaths in America is most commonly caused by long-term exposure to tobacco smoke carcinogens such as benzo[a]pyrene (BaP) which is metabolized into the ultimate metabolite benoz[a]pyrene-78-dihyrodiol-910-epoxide (BPDE). Despite improvements in the treatment and management of lung cancer these methods fail to reduce the overall mortality rate of this disease. While dietary components such as curcumin (turmic spice) show promising effects against BPDEinduced carinogenesis its exact mode of action is not fully understood. The objective of this project is to elucidate whether pretreatment with curcumin inhibits BPDE-induced DMA damage by activating p53. We hypothesize that curcumin may reduce the mutagenic activity of low dose BPDE by lowering the threshold of p53 activation thereby inducing DNA repair and cell cycle arrest at lower BPDE exposures. In Specific aim 1 the expression of p53 and p53-regulated proteins as well as cell cycle progression will be monitored by Western blot and flow cytometric analysis respectively to determine whether curcumin influences cell cycle arrest in response to BPDE exposure. Because global genomic repair (GGR) removes most BPDE-DNA  
adducts in a p53-dependent manner Specific aim 2 will use immunoslot blot [32P]-postlabeling and  
UvrABC mediated gene and strand-specific southern blot assays to analyze whether curcumin affects p53 activation and thus the relative extent of BPDE-DNA adducts formed and removed in genomic DNA. In Specific aim 3 Northern and Western blot assays will be used to investigate the role of curcumin in the induction of damage recognition proteins of the GGR pathway (XPC DDB2) which are p53-dependent. Furthermore it is believed that conjugation of glutathione (GSH) to BPDE by glutathione-S-transferase (GST) interacts with the expression of p53 to inactivate BPDE. In Specific aim 4 Western blot and GST colorimetric assays will be used to monitor the expression of proteins involved in the GSH detoxification system as well as the overall activity of GST respectively. This aim will provide a better understanding of potential alternative routes that may inactivate BPDE and how curcumin may influence this activity. By investigating the effects of curcumin on p53-mediated responses to DNA damage a better understanding of the potential role of curcumin in preventing tobacco carcinogen-induced mutagenesis and carcinogenesis will be gained. In addition the results from this project will benefit the public by providing easy and inexpensive alternative methods in preventing initial and continuing signs of lung cancer.

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


application_id: 7487773
project_number: 5R01HL056652-11
project_title: Molecular Mechanisms of Platelet Exocytosis
administering_ic: NHLBI
award_notice_date: 2008-06-19
application_type: 5
activity_code: R01
ic: HL
serial_number: 056652
program_official: SARKAR, RITA
project_start_date: 1996-08-20
project_end_date: 2011-05-31
study_section: Hemostasis and Thrombosis Study Section. Committee was terminated on 11/30/2020. [HT]
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-06-01
project_abstract:
DESCRIPTION (provided by applicant): Platelet exocytosis is integral to hemostasis and vascular integrity. Conversely inhibiting exocytosis is an important target for clinically managing improper thrombosis. Thus understanding the molecular events required for platelet exocytosis will broaden our ability to control platelet function. From previously funded work it is clear that specific Soluble NSF Attachment Protein Receptors (v- and t-SNAREs) are required for platelet secretion. With this established our goals have now expanded to address how this exocytosis machinery is regulated. We hypothesize that platelet exocytosis is governed by proteins that control SNARE- SNARE interactions. Three specific aims are proposed: Aim 1) To determine which v-SNARE proteins are required for platelet granule release. Our work demonstrates that VAMP-8/endobrevin is required for platelet exocytosis. The goals of Aim 1 are to complete the characterization of VAMP-8's role to identify which VAMP (2 or 3) serves as the secondary v-SNARE and to determine when this mechanism is used. Aim 2) To define the pathway of interactions required for t-SNARE function in platelet exocytosis. Previous work assigned roles for SNAP-23 syntaxin 2 and 4. This aim focuses on proteins that regulate these t-SNAREs to promote granule release. The syntaxin chaperones of the Munc18 family and their effectors Munc13S and Doc2s will be examined using a combination of immunological and biochemical techniques to determine how these proteins interact during exocytosis. These data will expand our understanding of how the syntaxin t-SNAREs are regulated to pair with appropriate SNAREs and to mediate membrane fusion. Aim 3) To determine how the small GTP-binding protein ADP-ribosylation factor 6 (Arf6) participates in platelet activation. Members of the Arf family are associated with membrane trafficking specifically exocytosis. Our work shows that Arf6 is critical to platelet activation secretion and actin dynamics. This aim will directly address how changes in Arf6-nucleotide state affect actin cytoskeleton and secretion and will identify the Arf6 effectors required for those functions. These data will yield insight into the central role of this small GTP- binding protein in activated platelets. Overall the information gained from this proposal will help to identify new therapeutic targets that will be useful for modulating hyperactive platelets and to provide diagnostic reagents for determining how hypoactive platelets are defective.

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


application_id: 7487711
project_number: 1F31GM084665-01
project_title: Skeletal muscle adaptation to hypoxia
administering_ic: NIGMS
award_notice_date: 2008-06-16
opportunity_number: PA-07-106
application_type: 1
activity_code: F31
ic: GM
serial_number: 084665
program_official: TOLIVER, ADOLPHUS
project_start_date: 2008-07-01
project_end_date: 2011-06-30
study_section: Special Emphasis Panel[ZRG1 HOP-T (29)]
contact_pi_person_id: 9092972
contact_pi: GAMBOA, JORGE LUIS
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): It has been shown that hypoxia could be detrimental for skeletal muscle mitochondria function. For instance high altitude mountaineers present a reduction in subsarcolemmal rnitochondrial content; however the exact mechanism that underlies this phenomenon has not been described. The same pattern of nitochondrial reduction has also been in muscle biopsies of patients with diabetes mellitus type 2 and a recent gene expression study in diabetic patients concluded that hypoxia may be a possible trigger for the development of metabolic syndrome. Mitochondrial abnormalities are also observed in patients with chronic obstructive pulmonary disease (COPD) a condition where hypoxia is prominent feature. Thus the study of mitochondria! changes under hypoxic conditions is not only relevant to high altitude adaptation but to diseases states where hypoxia may play a pathogenic role. The overall objective of the study is to define the mechanisms that underlie the reduction of mitochondria) oxidative capacity in skeletal muscles under hypoxic conditions. We will use sedentary mice exposed to steady level of normobaric hypoxia to avoid confounding factors such as the hypoxia level and the physical activity. We will test the hypothesis that hypoxia will reduce the expression and protein levels of mitochondrial biogenic factors particularly PGC-1a. In specific aim 1 we will evaluate the gene expression and protein level of the mitochondria! biogenic factor under hypoxic conditions using the standard molecular biology techniques. Specific Aim 2 will evaluate the changes of mitochondrial oxidative capacity under hypoxic conditions. Mitochondrial respiration and enzymes activities will be measured for this purpose. In Specific Aim 3 we will test that the pharmacological activation of PGC-1a with resveratrol will reverse the hypoxic-induced mitochondrial changes in skeletal muscle. The comprehension of the mitochondria) changes that occur during hypoxia will help us to elucidate its potential role on the pathogenesis of diseases such as diabetes mellitus type 2 and COPD in order to develop new therapeutic strategies.

project_terms:
Affect;Altitude;Biochemical;Biogenesis;Biopsy;Blood flow;Blotting Western;Brain;Cell Hypoxia;Chronic;Chronic Obstructive Airway Disease;Citric Acid Cycle;Comprehension;Condition;Cultured Cells;DNA;Development;Diabetes Mellitus Non-Insulin-Dependent;Disease;Electrons;Environment;Enzymes;Exercise;Gene Expression;Genes;Health;Heart;Hematocrit procedure;Human;Hyperventilation;Hypoxia;Kidney;Limb structure;Lung diseases;Malignant neoplasm of kidney;Measures;Metabolic;Metabolic syndrome;Mitochondria;Mitochondria Muscle;Molecular Biology Techniques;Mus;Muscle;Nuclear;Numbers;Oxidative Phosphorylation;Oxygen;Partial Pressure;Pathogenesis;Pathway interactions;Patients;Pattern;Peroxisome Proliferators;Phosphorylation;Physical activity;Play;Proteins;Purpose;RNA Messenger;Rate;Renal carcinoma;Respiration;Resveratrol;Role;Sea;Skeletal muscle structure;Standards of Weights and Measures;Techniques;Testing;Tissues;Transcription Genetic;cancer cell;cofactor;density;diabetic;enzyme activity;factor A;hypoxia inducible factor 1;insight;mRNA Expression;novel therapeutics;nuclear respiratory factor;prevent;protein expression;receptor;research study;sedentary;transcription factor


application_id: 7487518
project_number: 5R13LM009315-03
project_title: Annual UT-ORNL-KBRIN Bioinformatics Summit
administering_ic: NLM
award_notice_date: 2008-09-08
opportunity_number: PA-06-041
application_type: 5
activity_code: R13
ic: LM
serial_number: 009315
program_official: YE, JANE
project_start_date: 2006-09-01
project_end_date: 2009-08-31
study_section: ZLM1-AP-C(M3)
contact_pi_person_id: 7948398
contact_pi: ROUCHKA, ERIC C
other_pis: Not Applicable
congressional_district: 03
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): In response to PAR-06-041 NIH SUPPORT FOR CONFERENCES AND SCIENTIFIC MEETINGS the UTORNL-KBRIN Bioinformatics Summit is proposed as an annual event held through a collaborative effort between the state of Tennessee and the commonwealth of Kentucky specifically the University of Tennessee system Oak Ridge National Labs and the Kentucky Biomedical Research Infrastructure Network. There are four specific aims for creating such a summit: 1) plan and organize an annual conference to discuss current bioinformatics research; 2) create an environment conductive to increasing collaborative efforts across disciplines and institutions within Tennessee and Kentucky; 3) provide introductory tutorials and workshops for  
bioinformatics topics; and 4) enhance bioinformatics education and research by providing opportunities for undergraduate and graduate participation. In order to achieve these aims the meeting will be held annually each spring and will be composed of scientific research symposia in three or four topic areas. Each of these scientific sessions will be led by a seminar from a leading national or international researcher in the field along with talks from Tennessee and/or Kentucky researchers with interests in the area. In addition a number of tutorials will be held on various topics such as microarray data analysis; sequence similarity searching; protein folding prediction; transcriptome analysis; proteomics analysis; and scientific databases. Posters sessions will be held as well to encourage the participation of students both at the undergraduate and graduate levels to present their work in a formal yet friendly environment. At the end of the funding period researchers throughout both Kentucky and Tennessee should have gained a much better appreciation for the multidisciplinary field of bioinformatics. In addition it is expected that a number of cross institutional and cross discipline collaborative relationships will be fostered due to overlapping research interests which would go unnoticed without the summit. The summit should have a significant impact on making researchers within Tennessee and Kentucky more competitive for future funding opportunities due to the synergy created from cross-discipline and cross-institutional collaborations.

project_terms:
Area;Bioinformatics;Biomedical Research;Collaborations;Data Analyses;Databases;Discipline;Educational aspects;Educational workshop;Environment;Event;Fostering;Funding;Funding Opportunities;Future;Gene Expression Profile;Institution;International;Kentucky;Numbers;Proteomics;Research;Research Infrastructure;Research Personnel;Sequence Analysis;Students;System;Tennessee;United States National Institutes of Health;Universities;Work;interest;multidisciplinary;posters;protein folding;response;symposium


application_id: 7487050
project_number: 5F30MH079531-02
project_title: Pre- and Post-operative Differences in Brain and Sleep-related Events in Children
administering_ic: NIMH
award_notice_date: 2008-08-25
opportunity_number: PA-05-151
application_type: 5
activity_code: F30
ic: MH
serial_number: 079531
program_official: CHURCHILL, JAMES D
project_start_date: 2007-08-15
project_end_date: 2011-08-14
study_section: Special Emphasis Panel[ZRG1-F12A-D(20)L]
contact_pi_person_id: 8193534
contact_pi: BARNES-DAVIS, MARIA E
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): In an estimated 1-3% of the pediatric population Obstructive Sleep Apnea (OSA) is likely responsible for many behavioral and neurocognitive dysfunctions. Recently the American Academy of Pediatrics highlighted the need to study the progression of pediatric OSA after surgical intervention. In previous studies measures of neurocognitive function were based on behavioral tasks or questionnaires completed by the caregiver. A more objective and reliable measure of the efficacy of adenotonsillectomy (AT) for OSA is needed. I hypothesize that children diagnosed with OSA by overnight polysomnography (PSG) will exhibit differences in event-related potentials (ERPs) when presented with auditory and visual tasks that tap the cognitive functions of the brain's frontal lobes. High-density ERP techniques are safe and effective in children and they provide insight into the electrical activity of the brain at the millisecond level. These time- locked waveforms can also be used to form spatial models which help localize electrical activity in the brain. ERP differences in childhood have been linked to behaviorally observed cognitive impairment and learning disorders. Differences such as decreased peak amplitudes and increased latencies of specific waveforms discussed later in the proposal might serve as markers for the cognitive deficits associated with sleep- disordered breathing. After AT these measures should normalize. I propose to contribute to the current research by accomplishing three aims: (1) measuring cognitive and electrophysiological changes in children with OSA before and after surgery using ERPs; (2) examining the postoperative changes in clinical symptoms with behavioral tasks standard neuropsychological assessments and physiological measures such as PSG; (3) obtaining the experience instruction and writing skills needed to become a functioning member of the scientific community. This proposal relates to the goals of NIH and NIMH in that it seeks to further understanding of the processes of neurobehavioral development with a focus on childhood (a period of rapid change during which the brain is particularly sensitive) and to employ several techniques to assess the severity of OSA and accompanying behavioral or psychological pathology. The proposed study will have a positive impact on public health by testing the extent to which sleep disorders like OSA affect the functioning of our children and assessing whether the commonly performed surgery actually resolves cognitive and behavioral problems. Increased awareness of the importance of sleep and treatment of sleep disorders in childhood is greatly needed. This study will further inform the scientific community and the public on the protection of sleep hygiene and the consequences and treatment of pediatric sleep disorders.

project_terms:
Academy;Address;Adult;Affect;Aftercare;Aggressive behavior;American;Apnea;Area;Arousal;Attention;Attention deficit hyperactivity disorder;Auditory;Awareness;Behavior;Behavioral;Brain;Caregivers;Child;Childhood;Chronic;Clinical;Cognition;Cognitive;Cognitive deficits;Communities;Condition;Development;Diagnosis;Discrimination Speech;Disruption;EP300 gene;Event;Event-Related Potentials;Exhibits;Functional disorder;Goals;Hygiene;Hyperactive behavior;Hypoxia;Impaired cognition;Individual;Instruction;Intervention;Knowledge;Laboratories;Language;Learning;Learning Disorders;Link;Localized;Measures;Medical;Medicine;Memory;Modeling;National Institute of Mental Health (U.S.);Neurocognitive;Operative Surgical Procedures;Outcome;Oxygen;Pathology;Pediatrics;Performance;Physiological;Polysomnography;Population;Postoperative Period;Problem behavior;Process;Quality of life;Questionnaires;Relative (related person);Reporting;Research;Schedule;Schools;Science;Severities;Sleep;Sleep Apnea Syndromes;Sleep Apnea Obstructive;Sleep Disorders;Sleep Fragmentations;Sleep disturbances;Standards of Weights and Measures;Symptoms;Techniques;Testing;Theoretical model;Time;Training;Treatment outcome;United States National Institutes of Health;Visual;Visuospatial;Work;Writing;base;behavior measurement;brain electrical activity;cognitive function;density;executive function;experience;frontal lobe;frontal lobe function;improved;inattention;indexing;insight;language processing;member;millisecond;neurobehavioral;neuropsychological;psychologic;public health medicine (field);respiratory;response;skills;vigilance


application_id: 7485582
project_number: 5R01HD050571-02
project_title: ROLE OF PACAP IN THE MALE FETAL PITUITARY
administering_ic: NICHD
award_notice_date: 2008-05-09
application_type: 5
activity_code: R01
ic: HD
serial_number: 050571
program_official: LAMAR, CHARISEE A
project_start_date: 2007-08-15
project_end_date: 2012-05-31
study_section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER]
contact_pi_person_id: 2050006
contact_pi: MOORE, JOSEPH P
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-06-01
project_terms:
Activins;Adult;Affect;Appearance;Birth;Cell Line;Cells;Complex;Contraceptive Agents Male;Couples;Data;Development;Early Diagnosis;Embryo;Embryonic Development;Endocrine;Event;Fetal development of the mammalian embryo or fetus;Follicle Stimulating Hormone;Follicle Stimulating Hormone beta Subunit;Follistatin;Gene Expression;Gonadotropins;Growth;Half-Life;Hormones;Hypothalamic structure;In Vitro;Infertility;Laboratories;Lead;Life;Luteinizing Hormone beta Subunit;Molecular;Mus;Neonatal;Organ;Physiological;Pituitary Gland;Pituitary Gland Anterior;Pituitary Gonadotropins;Play;Prevention;Process;Production;RNA Messenger;Rattus;Regulation;Role;Sexual Development;Sexual Maturation;System;Testis;Time;Transcription Genetic;falls;fetal;human male;infancy;mRNA Expression;male;pituitary adenylate cyclase activating polypeptide;receptor;reproductive function


application_id: 7485398
project_number: 1R13NS062643-01
project_title: Second International Brainstorming Meeting on Parkinson Disease: Nosology
administering_ic: NINDS
award_notice_date: 2008-03-18
opportunity_number: PA-06-041
application_type: 1
activity_code: R13
ic: NS
serial_number: 062643
program_official: SIEBER, BETH-ANNE
project_start_date: 2008-04-01
project_end_date: 2008-08-31
study_section: Special Emphasis Panel[ZNS1 SRB-W (29)]
contact_pi_person_id: 2452926
contact_pi: LITVAN, IRENE
other_pis: Not Applicable
congressional_district: 03
department: NEUROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This application seeks support for the "Second International Brainstorming Meeting on Parkinson disease: Nosology" scheduled for May 16th and 17th in Louisville KY. The main goal of this conference is to bring together world-known clinical and basic scientist experts from various research backgrounds to brainstorm on the nosology of idiopathic Parkinson's disease (PD) and refine its diagnostic criteria. There are no biological markers for the pre-mortem diagnosis of PD. PD misdiagnosis is frequent particularly at early stages. Recent understanding of the non-motor aspects of PD and degeneration outside the substantia nigra has increased the understanding of the disorder but these findings have also challenged current clinical diagnostic criteria. Moreover in view of recent advances in PD genetics (i.e. alpha-synuclein triplications and duplications) it needs to be clarified if dementia is part of the spectrum of PD. Further since some genetically determined Parkinson syndromes sometimes closely resemble PD but differ from it neuropathologically; it needs to be elucidated if Lewy bodies are required for the neuropathologic PD definition. It is clear that PD is diverse clinically pathologically and etiologically diverse but the various entities have not been fully agreed upon. Since only well defined populations lead to firm conclusions in genetic epidemiologic or clinical drug trials it is crucial and timely in view of current scientific advances to reflect on the PD nosology and to redefine the set of clinical and pathologic diagnostic criteria for this disorder. International experts will cover the fields of pathology genetics molecular biology movement disorders neuroimaging neuropsychology neurobehavior and neuroepidemiology. This conference will also engage junior investigators to present ongoing research at poster sessions and will provide an excellent opportunity for them to interact with senior scientists. Discussions will center on current knowledge caveats of current studies and future research needs providing opportunities for new collaborations and new study proposals as well as revisions of clinical and neuropathologic diagnostic criteria for PD. The results of this conference will be published in a peer-reviewed journal and it is anticipated that this will allow gaining a greater insight and understanding of PD that will help move the field forward. The PI has extensive experience in organizing this type of meetings that have led to highly cited publications in peer-review journals. This conference has the support of the Movement Disorder Society and the University of Louisville and NINDS support is critical to its success and dissemination there are no recent or future conferences on this topic. PUBLIC HEALTH RELEVANCE: The main goal of this conference is to bring together clinical and basic scientist experts from various research backgrounds to brainstorm on the nosology of idiopathic Parkinson's disease (PD) and refine its diagnostic criteria.

project_terms:
Biological Markers;Clinical;Collaborations;Dementia;Diagnosis;Diagnostic;Disease;Future;Genetic;Goals;International;Journals;Knowledge;Lead;Lewy Bodies;Molecular Biology;Motor;Movement Disorders;Neuropsychology;Parkinson Disease;Pathologic;Pathology;Peer Review;Pharmaceutical Preparations;Population;Publications;Publishing;Research;Research Personnel;Schedule;Scientific Advances and Accomplishments;Scientist;Senior Scientist;Societies;Staging;Substantia nigra structure;Syndrome;Universities;alpha synuclein;disease/disorder classification;experience;insight;neurobehavior;neuroimaging;posters;public health medicine (field);success;symposium


application_id: 7485109
project_number: 5R01AI067434-03
project_title: Eradication of a Primary Filariasis Vector Population at an Endemic Field Site
administering_ic: NIAID
award_notice_date: 2008-07-25
application_type: 5
activity_code: R01
ic: AI
serial_number: 067434
program_official: COSTERO-SAINT DENIS, ADRIANA
project_start_date: 2006-08-15
project_end_date: 2011-07-31
study_section: Special Emphasis Panel[ZRG1-VB-P(01)Q]
contact_pi_person_id: 7876895
contact_pi: DOBSON, STEPHEN LEONARD
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
project_abstract:
DESCRIPTION (provided by applicant): Lymphatic filariasis (Elephantiasis) affects over 120 million people in 80 countries with 1.2 billion people at risk worldwide. Over 90% of infections are caused by Wuchereria bancrofti for which humans are the exclusive host. The absence of a nonhuman reservoir suggests that transmission can be interrupted by elimination of the microfilariae reservoir via community-wide treatment (Mass Drug Administration MDA) which is the current focus of the Global Programme for the Elimination of Lymphatic Filariasis. While MDA strategies can be effective history suggests that elimination of lymphatic filariasis in Polynesia is unachievable without vector control. An example is provided by Maupiti in French Polynesia where filariasis persists despite five decades of constant MDA. The biology of the primary mosquito vector Aedes polynesiensis has been blamed for MDA failure. Since mosquitoes are obligate vectors of W. bancrofti this suggests an additional approach for filariasis elimination: eradication of the mosquito vectors will break the disease transmission cycle. Unfortunately Ae. polynesiensis currently cannot be controlled much less eradicated. Here we propose a novel strategy in which releases of male Ae. polynesiensis mosquitoes infected with Wolbachia bacteria result in the sterilization of female mosquitoes at a field site endemic for filariasis transmission. Repeated male releases will permit the eradication of the targeted Ae. polynesiensis population. We emphasize that male mosquitoes do not blood feed and therefore are not disease vectors. Furthermore the proposed strategy employs a naturally occurring bacteria infection and does NOT include genetically modified organisms. The preliminary studies section describes how a l/Vo/bac/7/a-infected Ae. polynesiensis strain has been generated and shown to sterilize female mosquitoes from Maupiti. The research plan describes laboratory and field cage tests of the eradication strategy followed by field trials in which the Ae. polynesiensis population is eradicated from an endemic focus of filariasis. Additional experiments describe the characterization of the targeted field site (an uninhabited islet in Maupiti) prior to during and following the field trial. Prior to the field trial experiments will compare the release strain and field population in their fitness population dynamics and genetic structure mating competitiveness and vector competency. Recently developed techniques for generating new Wolbachia infection types in mosquitoes via microinjection will be used to generate additional mosquito strains for use in vector eradication strategies. We discuss the development of a model for the transitioning from field trials to a vector eradication campaign. We emphasize that a vector eradication strategy is more feasible economically relative to ongoing vector control in Polynesia. Furthermore the geography of Polynesia will simplify an eradication approach by reducing problems of vector reinfestation via immigration. Relevance: History demonstrates that the current global effort to eliminate lymphatic filariasis can fail in the Pacific if it continues to rely solely upon a mass drug administration (MDA) strategy. The proposed research will demonstrate a strategy for eradicating the primary mosquito vector of filariasis at an endemic field site. Integration of the vector eradication strategy and the MDA approach will facilitate filariasis elimination in areas where MDA alone has failed.

project_terms:
Address;Adult;Aedes (genus);Affect;Area;Attitude;Bacteria;Biology;Blood;Communities;Compatible;Condition;Country;Culicidae;Data;Decision Making;Development;Disease Transmission Horizontal;Disease Vectors;Elephantiasis;Embryo;Environmental Risk Factor;Event;Failure (biologic function);Female;Filaria bancrofti;Filarial Elephantiases;Filariasis;French Polynesia;Frequencies (time pattern);Genetic Structures;Geography;Human;In-Migration;Infection;Island;Laboratories;Measures;Microfilaria;Microinjections;Microsatellite Repeats;Modeling;Monitor;Organisms Genetically Modified;Ownership;Partner in relationship;Pharmaceutical Preparations;Polynesia;Population;Population Dynamics;Population Sizes;Populations at Risk;Rate;Recording of previous events;Relative (related person);Research;Research Personnel;Risk;Risk Assessment;Sampling;Site;Sterilization Female;Study Section;Techniques;Testing;Transfection;Variation (Genetics);Wolbachia;cost;design;disability;disease transmission;feeding;filaria;fitness;improved;islet;male;novel strategies;programs;research study;transmission process;vector;vector control;vector mosquito


application_id: 7484002
project_number: 7R03CA115864-03
project_title: Adjuvant Treatment Decision Making for Lung Cancer
administering_ic: NCI
award_notice_date: 2007-12-17
opportunity_number: PAR-04-117
application_type: 7
activity_code: R03
ic: CA
serial_number: 115864
program_official: NELSON, WENDY
project_start_date: 2005-08-01
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZRG1-RPHB-J(50)R]
contact_pi_person_id: 1909539
contact_pi: STUDTS, JAMIE L
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Approximately 173770 people are expected to be diagnosed with lung cancer in the United States in 2004 and another 160440 are expected to die from the disease. Kentucky leads the nation in both lung cancer incidence and mortality providing an unfortunate but unique laboratory to study this disease and its treatment. Chemotherapy has not historically played a role in adjuvant care for surgically resectable non-small cell lung cancer (NSCLC). However recent data on platinum-based chemotherapy showed significantly increased 5-year survival from NSCLC influencing the standard of care. While more individuals diagnosed with NSCLC will be offered adjuvant chemotherapy experts caution that the modest benefits of chemotherapy should be weighed against the short and long-term treatment sequelae and that the data should be used to help patients make informed choices based on their own values and preferences. Yet it is not clear that NSCLC patients have the capacity to interpret quantitative treatment benefit information. Among 120 individuals diagnosed with stages T-TTTA NSCLC the proposed study will explore factors which may influence treatment decision-making regarding adjuvant chemotherapy. The primary aim is to examine the effects of different methods of communicating quantitative estimates of treatment benefit on adjuvant chemotherapy decisions among individuals diagnosed with NSCLC. Using an experimental design based on a hypothetical clinical scenario this study will test the hypothesis that individuals diagnosed with NSCLC randomly assigned to receive relative risk reduction estimates will be more likely to choose adjuvant chemotherapy than individuals randomly assigned to receive absolute risk reduction information. This hypothesis is based on previous research which suggests that the method of describing treatment benefits plays an important role in treatment decisions regarding adjuvant chemotherapy. The secondary aim is to examine sociodemographic psychological social and health factors which influence adjuvant chemotherapy decisions among individuals diagnosed with NSCLC. It is hypothesized that individuals who are older more distressed have less social support and have poorer health status are more likely to decline adjuvant chemotherapy. With the expanding role of chemotherapy in NSCLC it becomes even more important to understand the factors which influence treatment decisions and to identify the best methods of describing treatment benefits to patients. Only when patients understand the necessary information about the risks and benefits of each treatment option will they be able to make informed treatment decisions that are consistent with their values.

project_terms:
behavioral /social science research tag;clinical research;decision making;health services research tag;human subject;informed consent;medical records;neoplasm /cancer chemotherapy;nonsmall cell lung cancer;patient care management;patient care personnel relations;patient oriented research;psychological aspect of aging;questionnaires


application_id: 7483855
project_number: 1F31DA023853-01A1
project_title: Reinforcing and neurochemical effects of cocaine in a rodent model of ADHD
administering_ic: NIDA
award_notice_date: 2008-03-06
opportunity_number: PA-07-002
application_type: 1
activity_code: F31
ic: DA
serial_number: 023853
suffix: A1
program_official: AVILA, ALBERT
project_start_date: 2008-03-24
project_end_date: 2010-03-23
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 8780703
contact_pi: WOOTERS, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):   The use of methylphenidate (MPH) for the treatment of attention-deficit/hyperactivity disorder (ADHD) has increased in recent years. However MPH has abuse potential and is typically administered during early development prompting some concern that early MPH exposure may increase the risk for substance abuse later in life. Despite of this there is a notable lack of experimental data directly examining the influence of oral MPH exposure on subsequent cocaine (COC) abuse. This is critical because MPH and COC produce similar behavioral and neurochemical effects and because COC abuse is prevalent in the ADHD population. In the present application experiments are proposed to examine the role of developmental exposure to oral MPH on vulnerability for COC abuse in early adulthood in the spontaneously-hypertensive rat (SHR) model of ADHD; Sprague-Dawley rats will be used as controls. Specific Aim 1 will determine whether repeated oral MPH administration during postnatal days (PND) 28-42 (i.e. periadolescence) alters the locomotor effect of COC on PND 75 (i.e. early adulthood). Specific Aim 2 will test for MPH-induced alterations in COC self administration. MPH-treated rats will be trained to self-administer COC under a fixed ratio (FR) 1 schedule during a single training session on PND 75. Then over the next 14 days COC infusions will be available under a progressive ratio (PR) schedule to assess motivational aspects of COC self-administration following developmental MPH exposure. This protocol has been shown previously to produce progressive increases ('sensitization') of PR breakpoints and should therefore be more sensitive than FR schedules for detecting potential enduring MPH-induced alterations in the reinforcing efficacy of COC. Food-maintained responding will also be assessed to determine whether MPH selectively alters motivation for COC reinforcement. Specific Aim 3 will assess the effect of COC on dopamine transporter (DAT) function in the nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC) of MPH-treated rats in early adulthood. The NAcc and mPFC are implicated in COC abuse as well as ADHD; thus the effect of systemic COC on clearance of locally-applied dopamine in these regions will be monitored with in vivo voltammetry (high-speed chronoamperometry) in order to determine whether DAT is a substrate for potential MPH-induced alterations n COC self-administration. Collectively these preclinical results should provide clinically-relevant information on the association between oral MPH exposure during adolescence and subsequent COC abuse in early adulthood.   
  
PUBLIC HEALTH RELEVANCE:  These results may also aid the development of safer ADHD medications and should enhance our understanding of the etiology of COC abuse in the vulnerable ADHD population.

project_terms:
Abuse Cocaine;Administration Oral;Adolescence;Amphetamines;Attention deficit hyperactivity disorder;Behavioral;Brain region;Catheters;Clinical;Cocaine;Condition;Data;Development;Dopamine;Dose;Drug abuser;Etiology;Exhibits;Exposure to;Food;Human;Implant;Infusion procedures;Life;Medial;Methylphenidate;Modeling;Monitor;Motivation;Nucleus Accumbens;Oral;Pharmaceutical Preparations;Population;Prefrontal Cortex;Protocols documentation;Psychological reinforcement;Range;Rat Strains;Rats Inbred SHR;Rats Sprague-Dawley;Rattus;Relative (related person);Risk;Rodent Model;Role;Route;Schedule;Science of neurochemistry;Self Administration;Self-Administered;Specificity;Speed (motion);Substance abuse problem;Techniques;Testing;Therapeutic;Time;Training;Work;clinically relevant;day;density;dopamine transporter;in vivo;postnatal;pre-clinical;public health medicine (field);reinforced behavior;reinforcer;relating to nervous system;research study;response


application_id: 7483270
project_number: 5R21AI074783-02
project_title: HMPV Fusion protein-host cell interactions
administering_ic: NIAID
award_notice_date: 2008-07-24
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: AI
serial_number: 074783
program_official: KIM, SONNIE
project_start_date: 2007-08-15
project_end_date: 2010-07-31
study_section: Special Emphasis Panel[ZRG1-IDM-G(91)S]
contact_pi_person_id: 8106840
contact_pi: DUTCH, REBECCA
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): Human metapneumovirus (HMPV) is a recently identified paramyxovirus associated with severe respiratory disease particularly in infants with symptoms that closely resemble those seen with respiratory syncytial virus. We have established efficient assays for the study of membrane fusion promoted by the HMPV fusion (F) glycoprotein. Interestingly HMPV F protein-mediated cell-cell fusion only occurs when transfected cells are both treated with trypsin (to proteolytically process the HMPV F protein) and exposed to low pH. As previously studied paramyxovirus F proteins promote fusion at neutral pH at the plasma membrane the triggering of HMPV F protein fusion activity by low pH suggests that this protein functions in a manner unique among the paramyxoviruses. Our results also demonstrate that HMPV F is competent to promote fusion in the absence of the attachment (G) protein consistent with reports that recombinant HMPV viruses lacking the HMPV G protein replicate efficiently both in cell culture and in hamster and non-human primate animal model. Our long-term goal is to understand the attachment and entry of paramyxoviruses. Our specific hypothesis is that HMPV F interacts with one or more defined cellular receptors and that this interaction is necessary to prime the F protein for low-pH induced promotion of membrane fusion. To address this hypothesis we will pursue three research aims. First we will utilize our recently developed efficient reporter gene assay to systematically define the target cell components required for HMPV F protein-promoted membrane fusion. Second we will analyze the effect of treatments to the HMPV F protein on promotion of membrane fusion including effects of prior low pH treatment proteolytic processing of the F protein or addition of soluble glycosaminoglycans. Finally we will utilize a soluble form of the HMPV F protein to analyze binding and identify the specific cellular receptor(s) for HMPV F. Accomplishing these goals will provide crucial information on the cellular components that interact with the HMPV F protein and may well lead to identification of the first receptor for a paramyxovirus fusion protein. In addition these studies will further clarify the mechanism by which the HMPV F protein promotes critical early steps in infection and set the stage for future analysis of inhibitors of this important viral protein. Human metapneumovirus (HMPV) is a recently identified human pathogen responsible for significant levels of severe respiratory disease particularly in infants. This research will address significant questions concerning the cellular factors which interact with the HMPV fusion protein to facilitate attachment of the virus and entry into cells.

project_terms:
Acute;Address;Age;Animal Model;Binding (Molecular Function);Biological Assay;Carbohydrates;Cell Communication;Cell Line;Cell fusion;Cell membrane;Cell surface;Cells;Cellular Structures;Chemicals;Child;Chimeric Proteins;Cultured Cells;Enzymes;Family;Fusion Protein Paramyxovirus;Future;GTP-Binding Proteins;Genes;Genes Reporter;Glycoproteins;Glycosaminoglycans;Goals;Hamsters;Human;Human Metapneumovirus;Human respiratory syncytial virus;Individual;Infant;Infection;Infectious Agent;Lead;Location;Lung diseases;Mediating;Membrane Fusion;Metapneumovirus;Modification;Paramyxovirus;Process;Production;Proteins;Proteins Cell Surface;Proteoglycan;Proteolytic Processing;Reagent;Recombinants;Reporting;Research;Respiratory Tract Diseases;Respiratory syncytial virus;Sampling;Sequence Analysis;Staging;Symptoms;Trypsin;Viral;Viral Proteins;Virus;attachment protein G;cell type;crosslink;experience;inhibitor/antagonist;nonhuman primate;pathogen;protein function;receptor;treatment effect


application_id: 7483182
project_number: 5R01AG029493-02
project_title: Targeting CNTF to increase adult forebrain neurogenesis
administering_ic: NIA
award_notice_date: 2008-05-22
opportunity_number: PAS-05-092
application_type: 5
activity_code: R01
ic: AG
serial_number: 029493
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 2007-09-01
project_end_date: 2012-06-30
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 6902570
contact_pi: HAGG, THEO
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
8-Hydroxy-2-(di-n-propylamino)tetralin;Adult;Adverse effects;Affect;Agonist;Antibodies;Astrocytes;Brain;Cells;Ciliary Neurotrophic Factor;Clinical Trials;Corpus striatum structure;Cyclic AMP;Data;Denervation;Dopamine Agonists;Dopamine D2 Receptor;Dose;Drug Delivery Systems;Failure (biologic function);Glial Fibrillary Acidic Protein;Human;Injection of therapeutic agent;Intervention;Invasive;Ischemia;Ischemic Stroke;Lateral;Mediating;Mediator of activation protein;Midbrain structure;Modeling;Mus;Neostriatum;Nervous system structure;Neurons;Numbers;Occlusion Middle Cerebral Artery;Oral;Pathway interactions;Peripheral Nerves;Pharmaceutical Preparations;Production;Proliferating;Prosencephalon;Quinpirole;Regulation;Replacement Therapy;Rest;Rodent;Schwann Cells;Serotonin;Testing;Thinking function;Time;Transplantation;cytokine;injured;nerve stem cell;nerve supply;nervous system disorder;neuroblast;neurogenesis;novel;receptor;relating to nervous system;repaired;research study;stroke;therapy development


application_id: 7483151
project_number: 5R21AI070769-02
project_title: Hepatitis C virus infection and lipoproteins
administering_ic: NIAID
award_notice_date: 2008-07-23
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: AI
serial_number: 070769
program_official: KOSHY, RAJEN
project_start_date: 2007-08-15
project_end_date: 2010-07-31
study_section: Special Emphasis Panel[ZRG1-IDM-G(91)S]
contact_pi_person_id: 6801917
contact_pi: LUO, GUANGXIANG GEORGE
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infection poses a major global health problem infecting approximately 4 million people in the United States and 170 million people worldwide. The properties and biochemical composition of HCV virions have not been determined due largely to the lack of a robust culture system for HCV infection and propagation. Recently we have successfully established a stable culture system for robust production of infectious HCV. The characterization of HCV RNA-containing particles revealed that the low-density HCV particles were of the highest infectivity in sharp contrast to the higher-density particles which contained the highest level of HCV RNA genome but were not infectious. Additionally apolipoproteins B and E were detected in the low- density fractions of HCV particles and HCV infection was potently inhibited by human lipoproteins LDL and VLDL. Therefore we hypothesize that HCV virion is assembled with lipoproteins which play important roles in the mediation of HCV infection through specific interactions with cell surface receptors/co-receptors. HCV virion assembly with lipoproteins represents a novel concept that warrants exploratory investigation and holds promise for discovering novel antiviral drugs. The overall goal of this application is to determine the properties and biochemical composition of HCV RNA-containing particles and to define the role of lipoproteins in HCV assembly and infection. Our specific aims are: 1) to determine the nature and biochemical composition of HCV RNA-containing particles and the structural determinants of HCV infectivity using structural cell biological biochemical immunological and proteomic approaches; 2) to define the role of lipoproteins in HCV virion production and infection by altering the levels of lipoprotein production in stable HCV-producing cells as well as by using antibodies against specific apolipoproteins. The levels of lipoproteins will be either up regulated by apolipoprotein-expression vectors and chemical inducers or down regulated by specific siRNAs and small molecular inhibitors. Additionally we will determine the underlying mechanisms for the inhibition of HCV infection by human lipoproteins. Findings derived from these studies will not only determine the molecular basis underlying HCV infectivity but also provide novel targets for antiviral intervention. Furthermore information gained from our studies will provide a foundation towards a thorough understanding of the molecular mechanisms of HCV virion assembly and infection. Hepatitis C virus (HCV) infection poses a major global health problem infecting about 4 million people in the United States and 170 million people worldwide. This application is to determine the properties and biochemical composition of HCV particles and to define the role of lipoproteins in HCV production and infection. Findings derived from these studies will provide novel targets and therapies for antiviral intervention of HCV infection.

project_terms:
Accounting;Antibodies;Antibodies Blocking;Antiviral Agents;Antiviral Therapy;Apolipoproteins;Apolipoproteins B;Appendix;Biochemical;Biological;Cell Culture System;Cells;Centrifugation Density Gradient;Chemicals;Culture Media;Detection;Foundations;Genome;Goals;Health;Hepatitis C;Hepatitis C virus;High Density Lipoproteins;Human;Infection;Infectious hepatitides;Intervention;Investigation;Lipoproteins;Low-Density Lipoproteins;Mediation;Molecular;Nature;Numbers;Pharmaceutical Preparations;Play;Production;Property;Proteomics;RNA;RNA Viral;Range;Receptors Cell Surface;Role;System;Time;United States;Very low density lipoprotein;Virion;Virus;Virus Assembly;Virus Replication;anti-hepatitis C;base;concept;density;drug discovery;expression vector;inhibitor/antagonist;novel;particle;receptor;research study;virus culture


application_id: 7483107
project_number: 5R01AA011691-10
project_title: Individual Differences in Alcohol-Related Aggression
administering_ic: NIAAA
award_notice_date: 2008-08-07
application_type: 5
activity_code: R01
ic: AA
serial_number: 011691
program_official: GRAKALIC, IVANA
project_start_date: 1998-09-15
project_end_date: 2011-08-31
study_section: Social Psychology, Personality and Interpersonal Processes Study Section[SPIP]
contact_pi_person_id: 7876958
contact_pi: GIANCOLA, PETER R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-09-01
project_abstract:
DESCRIPTION (provided by applicant): The purpose of this revised application is to support an ongoing program of research aimed at determining in whom and in what contexts acute alcohol consumption facilitates aggressive behavior. The overarching aim of this 2-study laboratory project is to elucidate the influence of 3 individual difference variables [1) beliefs about aggression 2) beliefs about alcohol and 3) dispositional empathy] and 2 contextual variables [1) induced empathy and 2) provocation] on the alcohol-aggression relation in men-and women. STUDY 1 will examine the impact of 3 individual difference variables (i.e. beliefs about aggression beliefs about alcohol and dispositional empathy) on intoxicated aggression under varying levels of contextual provocation (low and high). Subjects will be 230 adult male and female social drinkers randomly assigned to either an Alcohol or a Placebo group. Beliefs about aggression beliefs about alcohol and dispositional empathy will be measured using a battery of validated self-report inventories. Aggression will be measured using a modified version of the well-established Taylor Aggression Paradigm (TAP; Taylor 1967) in which subjects administer and receive mild electric shocks to/from a fictitious opponent (actually a computer program) under the guise of a competitive reaction-time task. Aggression is operationalized as the intensity of shock administered by the subject to the fictitious opponent. STUDY 2 will examine the impact of dispositional (individual difference) and induced (contextual) empathy on the alcohol-aggression relation under varying levels of provocation (low and high). Subjects will be 320 adult male and female social drinkers randomly assigned to 1 of 4 groups" 1) Alcohol/Empathy-Induction 2) Alcohol/No Empathy-Induction 3) Placebo/Empathy-Induction or 4) Placebo/No Empathy- Induction. Empathy will be induced using well-validated empathy-induction techniques. Aggression will be measured using the TAP.

project_terms:
Acute;Adult;Aggressive behavior;Alcohol consumption;Alcohols;Belief;Beverages;Computer Programs and Programming;Condition;Empathy;Equipment and supply inventories;Female;Individual Differences;Laboratory Study;Measures;Patient Self-Report;Persons;Placebos;Purpose;Randomized;Reaction Time;Research;Shock;Techniques;Woman;alcohol effect;male;men;programs;social


application_id: 7482727
project_number: 2R44HD050006-02
project_title: Stimulation-Augmented Exercise and Neuromotor Therapy
administering_ic: NICHD
award_notice_date: 2008-06-24
opportunity_number: PA-07-280
application_type: 2
activity_code: R44
ic: HD
serial_number: 050006
program_official: SHINOWARA, NANCY
project_start_date: 2006-05-01
project_end_date: 2011-03-31
study_section: Special Emphasis Panel[ZRG1 MOSS-L (02)]
contact_pi_person_id: 7771781
contact_pi: HARTMAN, ERIC C
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 129360637
duns_number: 129360637
fips: US
organization_id: 4168101
organization_name: CUSTOMKYNETICS, INC.
organization_city: NICHOLASVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403401290
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
project_abstract:
DESCRIPTION (provided by applicant):  This Phase II SBIR project proposes to develop an electrical stimulation augmented exercise device for individuals with incomplete spinal cord injury (iSCI).  The device will provide a closed-chain load bearing lower extremity exercise that has the potential to condition muscles and reverse or slow the rate of loss of bone mineral density.  Users will be encouraged to voluntarily perform the exercise.  Client volitional efforts will be augmented by electrical stimulation and a servomotor drive such that the prescribed exercise range of motion is fulfilled with each movement cycle.  The adaptive stimulation controller will continuously adjust the stimulation profile based on movement errors and servomotor activity to provide only the stimulation that is necessary to complete the exercise while encouraging clients to contribute their best volitional effort on each exercise cycle.  A visual feedback infrastructure will be developed that encourages client participation emphasizes clinically relevant therapeutic exercise goals and rewards client achievements.  The visual environment will require clients to generate a series of appropriately timed and executed volitional trigger events (ranging from 'trace levels of applied force' to 'unassisted movements') which will be rewarded with a full range of motion movement cycle and success in a game.  We hypothesize that long-term use of the device in a comprehensive motor rehabilitation program may lead to functional improvements in addition to the localized and systemic benefits of exercise.  Phase I feasibility milestones were achieved including demonstration that: 1) client volitional effort could be synchronized with the stimulation controller; 2) functional stimulation levels could be well tolerated in this population where cutaneous sensation is in-tact (potentially hypersensitive); and 3) the stimulation controller could accommodate client volitional effort and generate only the stimulation that was needed to elicit the desired exercise movement.  We propose to build upon Phase I results through the following Phase II aims: 1) develop a servomotor drive that will improve exercise quality provide a wider range and better control of bodyweight loading allow use by individuals with advanced osteoporosis who are most in need of the exercise and accomplish the goal of coordinating volitional and stimulation-augmented efforts via haptic feedback rather than a real-time visual display; 2) develop intellectually engaging visual display environments that encourage and reward clinically relevant client volitional efforts; and 3) improve reliability and manufacturability.  We will demonstrate efficacy via a two-site clinical trial in which twenty (20) individuals with chronic incomplete spinal cord injury participate in a 12-week exercise paradigm using the device. Outcome measures will include assessment of functional improvements (i.e. FIM gait analysis) and a dynamometer test to assess improvements in volitional control independent of exercise-related improvements in torque generating capability. The target market for the device is clinics who serve individuals with neuromotor disabilities such as incomplete SCI traumatic brain injury or stroke.  The device will be competitively priced within the electrical stimulation-based exercise equipment market.  PUBLIC HEALTH RELEVENCE: The proposed work may benefit public health through development of a clinically viable electrical stimulation based therapeutic exercise device for use in motor rehabilitation following spinal cord injury or stroke. Compared to existing devices and techniques the adaptively controlled electrical stimulation servomotor assist and video game components and tight integration of instrumentation control stimulation visualization and reporting features may improve efficacy and availability of the therapeutic intervention for many affected individuals.

project_terms:
Achievement;Affect;Bone Density;Cardiovascular Diseases;Chronic;Client;Clinic;Clinical Trials;Clinical Trials Phase II;Condition;Craniocerebral Trauma;Cutaneous;Development;Devices;Diabetes Mellitus;Electric Stimulation;Electronics;Environment;Equipment;Esthesia;Event;Examination of gait;Exercise;Feedback;Generations;Goals;Imagery;Individual;Joints;Lead;Leg;Localized;Lower Extremity;Marketing;Mechanics;Motor;Movement;Muscle;Osteoporosis;Outcome Measure;Paralysed;Pattern;Personal Satisfaction;Pes;Phase;Physical Fitness;Population;Positioning Attribute;Price;Range;Range of Motion Articular;Range of motion exercise;Rate;Rehabilitation therapy;Reporting;Research Infrastructure;Rewards;Series;Site;Sledding;Small Business Funding Mechanisms;Small Business Innovation Research Grant;Spinal cord injury;Structure;System;Techniques;Testing;Therapeutic;Therapeutic Intervention;Time;Torque;Traumatic Brain Injury;Video Games;Visual;Week;Weight-Bearing state;Work;base;clinically relevant;design;desire;disability;functional improvement;haptics;improved;instrumentation;motor control;nervous system disorder;programs;prototype;public health medicine (field);respiratory;sensor;stroke;success;tool;visual feedback


application_id: 7482269
project_number: 5R37HD029957-16
project_title: Early Development with Williams or Down Syndrome
administering_ic: NICHD
award_notice_date: 2008-09-03
application_type: 5
activity_code: R37
ic: HD
serial_number: 029957
program_official: OSTER-GRANITE, MARY LOU
project_start_date: 2004-09-15
project_end_date: 2009-07-31
study_section: Child Psychopathology and Developmental Disabilities Study Section[CPDD]
contact_pi_person_id: 1901361
contact_pi: MERVIS, CAROLYN B.
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
project_abstract:
DESCRIPTION (provided by applicant): The overall objective of the proposed research is to delineate and make sense of the process of lexical development and its relations to communicative development grammatical development and both general and specific aspects of nonlinguistic cognitive development.  The research will focus on the language and cognitive development of three groups: children with Williams syndrome children with Down syndrome and typically developing children.  Out research during the current grant period indicates that the language skills of children with Williams syndrome are more advanced than their nonverbal cognitive skills; children with Down syndrome show the opposite pattern.  Children who are typically developing tend to have equivalent levels of language and cognitive skills.  Because of these differences in the general nature of the relations between language and nonlinguistic cognition inclusion of all three groups in the same studies provides a unique opportunity to identify factors that are universal and necessary to lexical communicative or grammatical development versus those that are specific to particular rates or paths to language acquisitions.  The proposed research consists of a 5-year longitudinal study beginning in late infancy and both longitudinal and cross-sectional studies involving preschool-and school-age children.  Both observational and experimental methods will be used.  There are four specific aims.  The first is to delineate the nature of early lexical growth curves.  The second is to further examine the role of lexical operating principles (heuristics) and foundational social cognitive abilities in the acquisition and extension of new words.  The third is to begin to delineate the development of communicative abilities by toddlers and young children who have Williams syndrome.  The fourth is to determine longitudinally the developmental trajectories of language and cognitive abilities for children with Williams syndrome.  The research will have implications both for theoretical models of the relations between language and cognition and for the design of cognitive and language intervention strategies for children with developmental disabilities.

project_terms:
2 year old;Affect;Affective;Age;Appendix;Behavior;Behavioral;Birth;Caregivers;Child;Child Behavior;Child Development;Cognition;Cognitive;Cross-Sectional Studies;Data Analyses;Daughter;Development;Developmental Delay Disorders;Developmental Disabilities;Distress;Down Syndrome;Emotional;Emotions;Exhibits;Gender;Goals;Grant;Growth;Individual;Infant;Infant Very Low Birth Weight;Intervention;Joints;Language;Language Development;Life;Literature;Longitudinal Studies;Maintenance;Measures;Mediating;Mediation;Medical;Methods;Modeling;Mothers;Motor;Nature;Outcome;Parents;Pattern;Play;Population;Problem behavior;Process;Range;Rate;Regulation;Relative (related person);Research;Risk;Risk Factors;Role;Sampling;School-Age Population;Schools Nursery;Score;Social Impacts;Social Interaction;Son;Survival Rate;System;Technology;Theoretical model;Time;Toddler;Toy;Williams Syndrome;age related;base;boys;caregiving;cohort;design;heuristics;improved;infancy;lexical;lexical processing;male;protective effect;response;skills;social


application_id: 7482233
project_number: 5P20RR020171-05
project_title: Center of Biomedical Research Excellence in Molecular Basis of Human Disease
administering_ic: NCRR
award_notice_date: 2008-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
program_official: CANTO, MARIA TERESA
project_start_date: 2004-09-01
project_end_date: 2009-08-31
study_section: ZRR1-RI-5(01)
contact_pi_person_id: 7875201
contact_pi: LOUIS HERSH, LOUIS HERSH LOUIS HERSH
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    The objective of the Center of Biomedical Research Excellence in the Molecular Basis of Human Disease (COBREMBHD) is to enhance the success of promising junior investigators at the University of Kentucky for competing for NIH grant support through the development of a research center focusing on understanding human disease at the molecular level. We will achieve this objective by:  (1) assembling a group of established extramurally funded scientists who will serve as mentors for junior faculty serving as principal investigators on research projects. (2) providing these junior faculty with state-of-the-art training in concepts and techniques relevant to studying human disease with an emphasis on the application of structural biology to these projects (3) establishing mentoring plans including milestones as the basis of the development program (4) developing and supporting shared core facilities (5) providing pilot grants for projects that will complement those of the junior faculty (6) providing a seminar program stressing the latest advances in studying human diseases at the molecular level and techniques of structural biology and their application to biomedical research (6) holding an annual retreat to evaluate and critique the progress of the junior faculty and (7) hiring promising new faculty to develop a critical mass of productive investigators in studying molecular aspects of human disease.     Five tenure track Assistant Professors will serve as PIs on research projects that overlap in concepts and methodology. The junior investigators participating in the COBRE came from excellent postdoctoral experiences and are likely to benefit from the training program. Their projects apply one or more of the techniques of structural biology to studies related to human disease and have a high likelihood of developing into successful RO1 type research grants.


application_id: 7481709
project_number: 1R41NS062531-01
project_title: Small Molecule Drug Therapy for Parkinson's Disease
administering_ic: NINDS
award_notice_date: 2008-08-27
opportunity_number: PA-07-281
application_type: 1
activity_code: R41
ic: NS
serial_number: 062531
program_official: SIEBER, BETH-ANNE
project_start_date: 2008-09-01
project_end_date: 2009-08-31
study_section: Special Emphasis Panel[ZRG1 BDCN-A (11)]
contact_pi_person_id: 6808256
contact_pi: SUGAYA, KIMINOBU
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 803410831
duns_number: 803410831
fips: US
organization_id: 10010204
organization_name: NEOCYTEX BIOPHARMA, INC.
organization_city: COVINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 410112312
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-09-01
budget_end_date: 2009-08-31
project_abstract:
DESCRIPTION (provided by applicant): The total cost of caring for Parkinson's disease is about $25 billion per year in the United States. There is an urgent and unmet need for an effective treatment for the patients who have suffered debilitating loss of neurons and motor function. Development of neuroregeneration therapy is an important goal because neurdegenerative diseases disable and kill millions of people worldwide each year yet a viable therapeutic option is not available. Discovery of neural stem cells in the aging and diseased brain has sparked interest in the development of new approaches to boost the body's natural ability to create healthy new cells from endogenous stem cells. Recently we made the serendipitous discovery that a small molecule heterocyclic pyrimidine derivative can speed up the growth of human neural stem cells grown in culture. Subsequent preliminary analysis in rodents suggested that the molecule also accelerate neurogenesis in aged brain and improve motor function in dopaminergic lesion mouse a Parkinson's disease model apparently without any side effects. Based on these preliminary observations we are hypothesizing that administration of the heterocyclic pyrimidine derivative will stimulate new brain cell formation leading to improved motor function. To establish proof of concept we are proposing to conduct a series of studies with a mouse model of Parkinson's disease. We investigate whether the heterocyclic pyrimidine derivative has a potential to protect and/or regenerate neurons by stimulating proliferation migration and differentiation of endogenous neural stem cells using Immunohistological assays Western blot and behavioral tests. Upon the completion of these experiments we expect to confirm the feasibility of using the heterocyclic pyrimidine derivative to promote dose dependent improvement in motor function associate with neurogenesis in animal model for Parkinson's disease without inducing obviously deleterious effects. In Phase II we will conduct detailed safety distribution and efficacy studies on the molecule with non-human primate Perkinson's disease model in preparation for carrying out IND enabling studies during Phase III. This project is innovative because our test compound offers a novel approach for inducing new brain cell growth in patients with neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: We are proposing to test a new small molecule drug candidate that can boost the body's natural ability to regenerate brain cells from endogenous stem cells. When successful our drug candidate will offer a new treatment alternative for patients with neurodegenerative diseases such as Parkinson's disease Alzheimer's disease and ALS.

project_terms:
Abnormal Cell;Acute;Adult;Adverse effects;Affect;Age;Aging;Alzheimer's Disease;American;Amyotrophic Lateral Sclerosis;Animal Model;Animals;Behavioral;Biological Assay;Blotting Western;Brain;Brain Stem;Bromodeoxyuridine;Caring;Cell Count;Cell Nucleus;Cell Proliferation;Cell Transplantation;Cells;Cellular biology;Cercopithecus pygerythrus;Chronic;Clinical;Clinical Trials;Clinical Trials Phase I;Corpus striatum structure;Daily;Data;Deep Brain Stimulation;Defect;Development;Diagnosis;Diathermy;Disease;Disease model;Dopamine;Dopaminergic Cell;Dose;Drug Industry;Drug Monitoring;Electrodes;Electrodes Implanted;Equilibrium;Exploratory Behavior;Forelimb;Formulations Drug;Funding;Globus Pallidus;Goals;Grant;Growth;Healed;Human;Hyperactive behavior;Impaired cognition;Injection of therapeutic agent;Injury;Killings;Lead;Lesion;Licensing;MPTP Poisoning;Macaca mulatta;Magnetic Resonance Imaging;Maleates;Marketing;Measurable;Measures;Medicine;Methods;Microscopy;Modeling;Monitor;Morphology;Motor;Motor Activity;Motor Neurons;Movements Involuntary;Mus;Muscle Rigidity;Natural regeneration;Nerve Tissue;Nervous system structure;Neurodegenerative Disorders;Neurons;Neurophysiology - biologic function;Operative Surgical Procedures;Other Resources;Parkinson Disease;Pathology;Patients;Pattern;Performance;Persons;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacotherapy;Phase;Placement;Preparation;Procedures;Process;Proliferating;Property;Pyrimidine;Pyrimidines;Recovery;Research;Risk;Rodent;Rods (Retina);Safety;Science of Chemistry;Series;Small Business Technology Transfer Research;Speech;Speed (motion);Staging;Stem cells;Strikes Employee;Structure of subthalamic nucleus;Substantia nigra structure;Testing;Therapeutic;Tissues;Toxic effect;Tremor;Tyrosine 3-Monooxygenase;United States;Universities;Visual;Week;aged;aging brain;base;behavior test;brain cell;cell growth;cell type;clinical application;commercialization;concept;cost;day;design;disabling disease;dopamine transporter;dopaminergic neuron;experience;healing;improved;in vivo;innovation;interest;migration;mouse model;nerve stem cell;nervous system disorder;neurogenesis;neuron loss;neuroprotection;nonhuman primate;novel;novel strategies;professor;public health medicine (field);relating to nervous system;research study;small molecule;success;tool


application_id: 7480977
project_number: 5R01HD052724-02
project_title: Functional neuroanatomy of developmental changes in face processing
administering_ic: NICHD
award_notice_date: 2008-05-09
application_type: 5
activity_code: R01
ic: HD
serial_number: 052724
program_official: FREUND, LISA S
project_start_date: 2007-08-10
project_end_date: 2012-05-31
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 1911365
contact_pi: JOSEPH, JANE E
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-06-01
project_terms:
Adolescence;Adult;Affect;Age;Attention;Autistic Disorder;Base of the Brain;Behavioral;Brain;Brain imaging;Brain region;Child;Cognitive;Data;Development;Event-Related Potentials;Exposure to;Face;Face Processing;Human;Imaging Device;Imaging Techniques;Individual;Infant Newborn;Intervention;Invasive;Lead;Literature;Magnetic Resonance Imaging;Magnetic Resonance Imaging Functional;Nature;Neuroanatomy;Neurobiology;Numbers;Pattern;Personal Satisfaction;Persons;Process;Property;Prosopagnosia;Range;Rate;Research;Research Personnel;Risk;School-Age Population;Scientist;Shapes;Social Behavior;Techniques;Volunteers Human;cognitive function;developmental disease/disorder;experience;improved;infancy;interest


application_id: 7480381
project_number: 5R42GM075628-03
project_title: Enhancement of the baculovirus expression vector system
administering_ic: NIGMS
award_notice_date: 2008-07-25
opportunity_number: PA-06-121
application_type: 5
activity_code: R42
ic: GM
serial_number: 075628
program_official: JONES, WARREN
project_start_date: 2005-08-29
project_end_date: 2010-07-31
study_section: Special Emphasis Panel[ZRG1-GGG-J(10)B]
contact_pi_person_id: 1857794
contact_pi: WEBB, BRUCE A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The baculovirus expression vector system (BEVS) is one of the most powerful and versatile eukaryotic expression systems. The BEVS is being used to produce antigens for vaccine development to manufacture human therapeutics to develop faster acting biological insecticides and as a protein expression system for a multitude of research projects. However a limitation of any lytic viral expression system including BEVS is that lysis of the infected cells interrupts protein expression and requires repetitive infections which results in decreased productivity levels and high production costs. ParaTechs and the Webb laboratory at the University of Kentucky have identified a gene family from an insect virus that delays death and lysis of baculovirus infected cells and significantly enhances recombinant protein production. This enhanced protein production presents a significant commercial opportunity that was the focus of ParaTechs' 'proof-of- concept' Phase I proposal. During Phase I ParaTechs demonstrated utility and estimated the commercial value of its enhanced BEVS technology by quantifying the level of enhanced protein production and developing alternative methods of delivering the protein of interest to virus-infected cells. In this proposal we seek support to optimize enhancement of the technology in insect cell lines (objective 1) engineered baculovirus transfer viruses (objective 2) and in selectively modified baculovirus DNA (objective 3). We will quantify the effect of these modifications to ParaTechs' enhanced BEVS technology by measuring the expression of reporter membrane-bound and secreted proteins. We have proven that ParaTechs' enhanced BEVS is more efficacious in the synthesis of some secreted proteins as the integrity of the cells infected with the enhanced BEVS is prolonged. A critical element for many modern medical treatments and research applications entails the ability to produce biologically active proteins with a high degree of safety. Baculovirus expression vectors have proven to have multiple advantages for protein production in a variety of applications such as production of proteins for vaccine development and human therapeutics for a number of diseases. The enhanced BEVS technology to be developed with this award has potential to significantly improve efficacy of protein production in all such medical applications.

project_terms:
Antigens;Award;Baculoviruses;Binding (Molecular Function);Biological;Biological Assay;Cathepsins;Cell Line;Cell Line Transformed;Cells;Cessation of life;Chitinase;Clinical Trials Phase II;Clinical Trials Phase III;Compatible;Complement;Condition;Cytolysis;DNA;DNA Viral;Data;Development;Disease;Effectiveness;Elements;Engineering;Funding;Gene Expression;Gene Family;Genes;Genomics;Human;Infection;Insect Viruses;Insecta;Insecticides;Kentucky;Laboratories;Licensing;Lytic;Marketing;Measures;Medical;Membrane;Methods;Modification;Numbers;Phase;Positioning Attribute;Production;Productivity;Promotor (Genetics);Proteins;Protocols documentation;Recombinant Proteins;Recombinants;Recombination Genetic;Reporter;Research;Research Project Grants;Safety;System;Techniques;Technology;Technology Enhancement;Testing;Therapeutic;Time;TimeLine;Universities;Vendor;Viral;Virus;base;cellular engineering;commercialization;concept;cost;day;experience;expression vector;improved;interest;protein expression;prototype;vaccine development;vector


application_id: 7480219
project_number: 5R21RR022864-03
project_title: NOVEL UV OPTICAL WAVEGUIDES FOR SENSITIVE SPECTROSCOPY OF BIOMOLECULAR FILMS
administering_ic: NCRR
award_notice_date: 2008-08-26
opportunity_number: RFA-RR-05-001
application_type: 5
activity_code: R21
ic: RR
serial_number: 022864
program_official: FRIEDMAN, FRED K
project_start_date: 2006-09-01
project_end_date: 2011-08-31
study_section: ZRR1-BT-6(01)
contact_pi_person_id: 7844807
contact_pi: MENDES, SERGIO B
other_pis: Not Applicable
congressional_district: 03
department: PHYSICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
We propose here the development of an optical waveguide-based spectroscopic instrumentation in theultra-violet (UV) region for research of unprecedented sensitivity in biomolecular thin-film assemblies.Single-mode integrated optical waveguides (IOW) have shown to provide the ultimate sensitivity to performattenuated total reflection (ATR) absorption spectroscopy of molecular films and has been successfullydemonstrated in protein films at the visible spectral region. However the lack of adequate optical waveguidematerials has limited the extension of the technique into the UV region which represents a serious limitationas most important spectroscopic fingerprints of biomolecular species are located in the deep UV (300 -190nm) region e.g. the aromatic groups of the protein amino acids tryptophan tyrosine and phenylalanine. Thesuccessful development of UV-compatible optical waveguides will allow us to implement a highly sensitivesingle-mode IOW ATR spectrometer at the UV spectral region (450 -190nm). In this project we will focuson the critical and enabling developments of i) optical materials and process that can produce single-modelOWs with low propagation loss in the UV spectral range and ii) a novel architecture for the single-modeIOW-ATR spectrometer that will greatly simplify its use for the investigation of molecular assemblies at thesolid-liquid and solid-gas interfaces. To validate the capabilities of the novel technology we will apply it toseveral case studies including specific investigations of protein behavior at interfaces. Immobilization and adsorption of proteins and other biomolecules to solid surfaces is critical in thedevelopment of solid-phase-based bioanalytical techniques biocompatible materials and biosensors.Gaining a more detailed and accurate understanding of how proteins adsorb in what amount andconformation and establishing a systematic correlation between the physical/chemical environment and theirbioactivity is an essential knowledge for designing novel biointerfacial processes and biomaterials forimplants and for creating new biomedical diagnostics and drug delivery systems.

project_terms:
Adsorption;Amino Acids;Architecture;Arizona;Attenuated;Behavior;Biocompatible Materials;Biological;Biosensor;Case Study;Chemicals;Classification;Compatible;Condition;Coupling;Depth;Development;Diagnostic;Drug Delivery Systems;Environment;Film;Fingerprint;Formulations Drug;Gases;Gel;Glass;Housing;Immobilization;Implant;In Situ;Investigation;Knowledge;Laboratories;Light;Liquid substance;Molecular;Molecular Conformation;Monitor;Optics;Oxidation-Reduction;Phase;Phenylalanine;Process;Process of absorption;Proteins;Range;Research;Research Personnel;Science;Solid;Source;Spectrum Analysis;Surface;Techniques;Technology;Time;Today;Tryptophan;Tyrosine;Universities;Viola;base;biomolecular film;chemical property;college;density;design;detector;instrumentation;molecular assembly/self assembly;molecular film;monolayer;new technology;novel;programs;stoichiometry;tool;transmission process


application_id: 7479374
project_number: 5R01GM075248-04
project_title: Role of USP Ligand Binding Pocket During Development
administering_ic: NIGMS
award_notice_date: 2008-07-24
application_type: 5
activity_code: R01
ic: GM
serial_number: 075248
program_official: ANDERSON, RICHARD A
project_start_date: 2005-08-01
project_end_date: 2011-07-31
study_section: Special Emphasis Panel[ZRG1-VB(01)Q]
contact_pi_person_id: 1898656
contact_pi: JONES, GRACE M
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
project_abstract:
DESCRIPTION (provided by applicant): A major unresolved question in insect endocrinology is whether the nuclear receptor ultraspiracle (USP) has an active ligand-binding function or alternatively is a non-liganded even passive heterodimer partner. Our previous NIH-funded protein biochemical studies emphasized screening of many point mutants to the ligand-binding domain of the Drosophila USP. The specific aims were to identify optimal mutant USPs for future testing of an in vivo USP ligand binding function of 2 transgenic fly assays. Our studies  supported by recent studies by others were successful in demonstrating in cultured cell assays that the USP of Drosophila (flies) and Aedes (mosquitoes) can transduce transcriptional signaling by methyl epoxyfarnesoate a natural juvenile hormone (JH) in flies and mosquitoes. The studies also show that this intracellular JH signaling requires a surface region on USP corresponding to a ligand-activated co-activator binding surface of the vertebrate counterpart RXR. Using the cultured cell functional assay we were successful in preparing point mutants to the USP ligand-binding pocket and co-activator binding surface that act as dominant negatives to block USP-dependent JH signaling in the cultured cells. On this basis the recent NIH study section panel summary directed that our next proposal move past the protein biochemical studies by using "the mutants already in hand rather than looking for more mutants" and to now orient the studies "into a direct biological context". Therefore in this new proposal we take these Drosophila USP mutants (and corresponding Aedes USP mutants) will be used in the transgenic fly assays in order to ask the following questions: 1) Is the USP ligand-binding pocket needed for USP function in JH/ecdysone-driven larval-to-larval molting? 2) Does the USP ligand-binding pocket transduce JH effects on pupal-adult metamorphosis? These in vivo studies are the next logical step building upon protein biochemical and cultured-cell assays and are insect endocirinology's first direct in vivo tests of a ligand-binding function for any USP. The outcome will have broad implications for insect endocrinology enabling specific tests on the Aedes USP the results of which will yield new insights on hormonal signaling in the technically more difficult mosquito.

project_terms:
Adult;Aedes (genus);Binding (Molecular Function);Biochemical;Biological;Biological Assay;Culicidae;Cultured Cells;Development;Dominant-Negative Mutation;Drosophila genus;Ecdysone;Endocrinology;Funding;Future;Hand;Hormonal;Insecta;Juvenile Hormones;Ligand Binding;Ligand Binding Domain;Ligands;Metamorphosis Biological;Molting;Nuclear Receptors;Outcome;Proteins;RXR;Role;Screening procedure;Signal Transduction;Study Section;Surface;Testing;Transgenic Organisms;United States National Institutes of Health;base;fly;in vivo;insight;mutant


application_id: 7479103
project_number: 5R01GM074101-04
project_title: Intermolecular Activation of G Protein Coupled Receptors
administering_ic: NIGMS
award_notice_date: 2008-07-28
application_type: 5
activity_code: R01
ic: GM
serial_number: 074101
program_official: DUNSMORE, SARAH
project_start_date: 2005-08-01
project_end_date: 2009-07-31
study_section: Physiological Chemistry Study Section[PC]
contact_pi_person_id: 8257380
contact_pi: JI, TAE H.
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
project_abstract:
DESCRIPTION (provided by applicant): G protein coupled receptors (GPCRs) are the major hormone receptors constituting approximately 3 percent of the human genome. It has been a dogma that when a hormone1 binds to a GPCR the liganded receptor activates itself to generate hormone signals (cis-activation). In contrast to this dogmatic cis-activation the evidence is emerging that a liganded receptor molecule can intermolecularly activate nonliganded receptor molecules (trans-activation). There are only several reports on trans-activation of GPCRs: two on the thrombin receptors and our reports on the LH receptor (LHR). LHR consists of two equal halves the extracellular N-terminal exo-domain and the membrane associated heptahelical endo-domain. Hormone binds to the exo-domain whereas the endo-domain generates two distinct hormone signals: one for adenylyl cyclase to produce cAMP (cAMP signal) and the other for phospholipase cbeta to produce diacylglycerol and inositol phosphate (IP signal).    Trans-activation is difficult to test because it has to be differentiated from cis-activation and hormone binding needs to be distinguished from signal generation. LHR meets these requirements and offers a unique model to test trans-activation. We have established a large library of two mutant groups one deficient in hormone binding and the other deficient in signal generation. Co-expression of a binding deficient mutant and a signal deficient mutant in a cell rescues signal generation. Our preliminary data show that the trans-activation generates either the cAMP signal or IP signal but not both. Aim 1 will test the hypotheses that trans-activation occurs not only to the mutant receptor pairs but also to the wild type receptor and that the signal selection is specific. Aim 2 will define the mechanistics of the trans-activation and signal selection. These new paradigms will have broad implications on the mechanisms of GPCR signal generation and development of new receptor therapeutics particularly to control a specific signal without invoking other signals. Receptors generate multiple signals which is a source of undesirable/toxic side effects of hormone therapeutics.

project_terms:
12-diacylglycerol;Adenylate Cyclase;Adverse effects;Binding (Molecular Function);Blood Pressure;Cells;Complex;Cyclic AMP;Data;Development;Diglycerides;Disease;Feeling;Figs - dietary;G Protein-Coupled Receptor Signaling;G-Protein-Coupled Receptors;Generations;Genetic Complementation Test;Genome Human;Glycoproteins;Heart;Hormone Receptor;Hormones;Human Chorionic Gonadotropin;Inositol Phosphates;Length;Libraries;Ligand Binding;Ligands;Malignant Neoplasms;Membrane;Memory;Modeling;N-terminal;Pain;Phospholipase;Process;Receptor Signaling;Receptors LH;Reporting;Role;Signal Transduction;Smell Perception;Source;Taste Perception;Temperature Sense;Testing;Therapeutic;Thinking function;Thrombin Receptor;daily functioning;extracellular;human disease;mutant;neurotransmission;peptide hormone;pleasure;receptor;size


application_id: 7478816
project_number: 5R21DE018332-02
project_title: Effects of ART on Oral Epithelial Cell Biology
administering_ic: NIDCR
award_notice_date: 2008-07-07
opportunity_number: RFA-DE-07-001
application_type: 5
activity_code: R21
ic: DE
serial_number: 018332
program_official: RODRIGUEZ-CHAVEZ, ISAAC R
project_start_date: 2007-08-02
project_end_date: 2011-07-31
study_section: ZDE1-PZ(19)
contact_pi_person_id: 1883677
contact_pi: MILLER, CRAIG 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:
DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) infects millions of humans annually and is a leading cause of death worldwide. In the absence of medical therapy death usually results within 10 years of infection. The introduction of antiretroviral (ART) drugs has significantly diminished morbidity and mortality. However ART must be taken throughout life and the several long term effects (e.g. dyslipidemia mitochondrial dysfunction exocrine pathology) have only recently been appreciated. Studies that address the adverse effects of ART on the oral mucosa are lacking. Our goal is to elucidate the effects of ART on the function of oral soft tissues focusing on epithelial cell biology. This knowledge is a requisite for understanding the long-term implications of ART on the critical importance of the mucosa and epithelium in controlling oral opportunistic infections in HIV infected individuals. The GENERAL HYPOTHESIS of the proposed research is select ART drugs dysregulate oral epithelial cell biology impacting on normal proteasome pathways epithelial cell homeostasis and parameters of innate immunity resulting in deleterious alternations of the oral mucosa and the epithelial cell's ability to respond to microbial pathogens. Our specific aims are to 1) examine the effect of ART on the proteasome-proteolytic pathway in oral epithelial cells 2) determine the effects of ART on toll-like receptor (TLR) signaling pathways in oral epithelial cells and 3) determine the effects of ART on oral epithelial cell differentiation.  
  
Specific biochemical and molecular methodologies are described that will allow us to systematically determine if ART adversely effects the proteasome function TLR signaling and ability of epithelial cells to differentiate. These processes are key to maintaining oral mucosal health in patients who are infected with HIV and for understanding how opportunistic infections develop despite the presence of ART.

project_terms:
Address;Adverse effects;Affect;Anti-Retroviral Agents;Basic Science;Biochemical;Cause of Death;Cell Differentiation process;Cells;Cellular biology;Cessation of life;Class;Communicable Diseases;Communication;Disease;Dyslipidemias;Environment;Enzyme-Linked Immunosorbent Assay;Epithelial;Epithelial Cells;Epithelium;Figs - dietary;Functional disorder;Goals;HIV;Health;Homeostasis;Human;Immune;Immune response;Immune system;Immunity Mucosal;Immunity Natural;Individual;Infection;Inflammatory;Knowledge;Life;Ligands;Liquid substance;Long-Term Effects;Measures;Medical;Methodology;Mitochondria;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Mouth Diseases;Mucous Membrane;Opportunistic Infections;Oral;Oral Medicine;Oral cavity;Oral health;Oral mucous membrane structure;Papillomavirus Human;Pathology;Pathology Oral;Pathway interactions;Patients;Pattern recognition receptor;Peptide Hydrolases;Pharmaceutical Preparations;Population;Positioning Attribute;Process;Production;Receptor Signaling;Recycling;Research;Research Design;Risk;Saliva;Science of Anatomy;Scientist;Signal Pathway;Signal Transduction;Structure;TGFB1 protein human;TLR2 gene;TLR3 gene;TLR4 gene;Testing;Tissues;Toll-like receptors;Ubiquitin;Viral;Virus Diseases;antiretroviral therapy;base;chemokine;cytokine;fighting;immune function;immunocytochemistry;insight;microbial;mitochondrial dysfunction;monolayer;multicatalytic endopeptidase complex;oral cavity epithelium;oral pathogen;pathogen;protein degradation;response;soft tissue


application_id: 7478583
project_number: 5R01CA115801-02
project_title: Redox Modulation of Prostate Cancer
administering_ic: NCI
award_notice_date: 2008-06-30
application_type: 5
activity_code: R01
ic: CA
serial_number: 115801
program_official: BERNHARD, ERIC J
project_start_date: 2007-08-01
project_end_date: 2012-05-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 1941793
contact_pi: ST CLAIR, WILLIAM H
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-06-30
project_terms:
AEOL10113;Androgens;Animals;Antibodies;Antioxidants;Area;Basic Science;Binding (Molecular Function);Binding Sites;Cancer Etiology;Cell Death;Cell Line;Cell Proliferation;Cell Survival;Cells;Cessation of life;Characteristics;Clinical;Clinical Treatment;Clone Cells;Code;Complement;Complication;Coupled;Critiques;Daily;Data;Development;Diarrhea;Disadvantaged;Dominant-Negative Mutation;Dose;Effects of radiation;Electron Microscopy;Enhancer Elements (Genetics);Ensure;Enzymes;Epitopes;Evaluation;Family;Fecal Incontinence;Figs - dietary;Free Radicals;Funding;Gene Expression;Gene Targeting;Generations;Genes;Genes Regulator;Gleason Grade for Prostate Cancer;Goals;Grant;Growth;Hemorrhage;Heterogeneity;Hormones;Human;Image Analysis;Immune response;Immunity;Immunology;Implant;In Vitro;Injection of therapeutic agent;Injections Subcutaneous;Injury;Interruption;Intervention;Intestines;Investigation;Ionizing radiation;Kinetics;LNCaP;Lead;Light;Link;Localized;Location;Malignant Neoplasms;Malignant neoplasm of prostate;Manganese Superoxide Dismutase;Manuscripts;Measures;Mediating;Methodology;Methods;Mice Nude;Microscope;Modeling;Monitor;Mus;Mutate;NF-kappa B;Nature;Normal Cell;Normal tissue morphology;Nuclear;Nuclear Translocation;Numbers;Outcome;Oxidation-Reduction;Oxidative Stress;PC3 cell line;Pathologist;Pathway interactions;Patients;Pattern;Pelvis;Peptides;Personal Satisfaction;Physicians;Play;Polymerase Chain Reaction;Population;Postdoctoral Fellow;Preservation Biological;Process;Proctitis;Production;Promoter Regions (Genetics);Promotor (Genetics);Prostate;Protein Overexpression;Proteins;Publications;Publishing;RNA Small Interfering;Radiation;Radiation Tolerance;Radiation therapy;Radiobiology;Range;Rapid Access to Intervention Development;Rate;Reactive Oxygen Species;Rectum;Regulation;Relative (related person);Reporting;Research;Research Personnel;Resistance;Resources;Reverse Transcriptase Polymerase Chain Reaction;Role;SN50 peptide;Saline;Sampling;Schedule;Scientist;Serum;Signal Transduction;Skin Neoplasms;Staining method;Stains;Standards of Weights and Measures;Stream;Subcellular Fractions;TNFRSF5 gene;TP53 gene;Testing;Tetanus Helper Peptide;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Time;Tissues;Topical application;Toxicology;Transcription Genetic;Translating;Universities;Variant;Week;Wisconsin;aminoacid sequence of protein;androgen independent prostate cancer;animal tissue;anticancer research;balsalazide;base;cancer cell;cancer therapy;concept;day;design;direct application;immunogenic;implantation;improved;in vitro Model;in vivo;in vivo Model;inhibitor/antagonist;insight;interest;intracellular protein transport;irradiation;knock-down;male;member;men;mimetics;mutant;neoplastic cell;novel strategies;p65;prevent;programs;protein localization location;radiation resistance;rectal;reproductive;research study;response;stable cell line;survivin;synthetic peptide;transcription factor;tumor;vector


application_id: 7478263
project_number: 3R01AG019241-05S2
project_title: PREVENTION OF ALZHEIMER'S BY VITAMIN E AND SELENIUM
administering_ic: NIA
award_notice_date: 2007-08-07
application_type: 3
activity_code: R01
ic: AG
serial_number: 019241
suffix: S2
program_official: RYAN, LAURIE M
project_start_date: 2001-09-30
project_end_date: 2008-03-31
study_section: Epidemiology and Disease Control Subcommittee 1[EDC-1]
contact_pi_person_id: 1894359
contact_pi: MARKESBERY, WILLIAM R
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This application is for a five-year renewal of the study entitled "Prevention of Alzheimer's Disease by VitaminE and Selenium" (PREADVISE). PREADVISE is an add-on study to the Selenium and Vitamin E ProstateCancer Prevention Trial (SELECT) a National Cancer Institute funded phase III double blind 2x2 factorialrandomized control trial to assess the effect of Se or vitamin E or the combination of both on the reduction ofthe incidence of prostate cancer in 35534 healthy men. The study duration is 12 years.Prevention is the key to eliminating Alzheimer's disease (AD). Multiple studies have demonstrated thatoxidative damage to lipids proteins DMA and RNA plays a role in the pathogenesis of neurodegeneration inAD. Recent studies have shown that marked oxidative damage is present in mild cognitive impairment theearliest detectable form of the disease. Population studies also suggest using antioxidants for AD preventionand underscore the need for large scale long term randomized controlled trials of antioxidants in AD. Thusthe rationale for diminishing oxidative stress/damage as a means of slowing the onset or preventing AD is ona solid basis. The aims of PREADVISE are to define the effect of Se and/or vitamin E on the reduction of theincidence of AD and other neurodegenerative diseases and to assess the effect of Se and vitamin E onnormal cognitive aging in a sub-sample of participants. Also during this five year phase emphasis will beplaced on retention of subjects in PREADVISE and SELECT.PREADVISE has recruited 5100 participants and 18% of these are ethnic minorities. Another 1300 menare eligible for enrollment in PREADVISE. PREADVISE subjects are randomized to one of four arms:vitaminE plus Se vitamin E plus Se placebo Se plus vitamin E placebo and Se placebo plus vitamin E placebo.Participants undergo a memory impairment screening examination as part of the initial evaluation andannuallly thereafter. Those that fall below the cut off point undergo a more thorough cognitive evaluationusing the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery of cognitive tests.Subjects who fail the CERAD battery receive a thorough dementia evaluation that is reviewed by aconsensus conference. DNA is available for APOE genotype testing and future study of other genetic factorsin AD. This is the largest national and international prevention trial of AD and is based on an innovative andinter-institute collaborative sub-study model that is uniquely cost effective

project_terms:
Affect;African American;Age;Aging-Related Process;Alzheimer disease prevention;Alzheimer's Disease;Antioxidants;Apolipoprotein E;Appendix;Clinical Trials;Cognitive;Cognitive aging;Consensus;Country;DNA;Data;Dementia;Dementia Vascular;Diagnostic Procedure;Disease;Double-Blind Method;Early treatment;Elderly;Enrollment;Etiology;Evaluation;Event;Frontotemporal Dementia;Funding;Future;Genetics Other;Genotype;Incidence;Individual;Institutes;International;Lewy Body Disease;Lipid Peroxidation;Lipids;Malignant neoplasm of prostate;Measures;Memory impairment;Minority;Monitor;National Cancer Institute;Nerve Degeneration;Neurodegenerative Disorders;Oxidative Stress;Participant;Pathogenesis;Phase;Placebos;Play;Population;Population Study;Prevalence;Prevention;Preventive;Process;Prostate Cancer Prevention Trial;Proteins;RNA;Randomized;Randomized Controlled Trials;Range;Recruitment Activity;Registries;Research Personnel;Role;Sampling;Screening procedure;Selenium;Selenium and Vitamin E Efficacy Trial;Selenium/vitamin E;Solid;Staging;Study models;Supranuclear Palsy Progressive;Testing;United States;Upper arm;Vitamin E;Vitamins;age effect;base;cognitive function;corticobasal degeneration;cost;cost effective;disorder prevention;ethnic minority population;experience;falls;innovation;men;men's group;mild cognitive impairment;normal aging;oxidation;prevent;research clinical testing;symposium;treatment duration


application_id: 7478044
project_number: 5R01NS053470-02
project_title: Designer Proteoglycans for Central Nervous System Injury
administering_ic: NINDS
award_notice_date: 2008-06-30
application_type: 5
activity_code: R01
ic: NS
serial_number: 053470
program_official: KLEITMAN, NAOMI
project_start_date: 2007-08-01
project_end_date: 2012-07-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 7875161
contact_pi: SNOW, DIANE M
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
project_terms:
Adult;Astrocytes;Behavior;Binding (Molecular Function);Biological Assay;Brain;Chondroitin Sulfate Proteoglycan;Cicatrix;Core Protein;Cues;Data;Engineering;Family member;Goals;Growth;Image;In Vitro;Injury;Injury of central nervous system;Knowledge;Lesion;Link;Measures;Methods;Modeling;Modification;Natural regeneration;Nerve;Nervous system structure;Neurites;Neuronal Injury;Neuronal Plasticity;Neurons;Patients;Pattern;Protein Family;Protein Isoforms;Protein Processing Post-Translational;Proteoglycan;Regulation;Relative (related person);Reporting;Site;Spinal Cord;Spinal cord injury;Structure;Tertiary Protein Structure;Testing;Therapeutic;Transcriptional Activation;Trauma Nervous System;Up-Regulation (Physiology);axon growth;clinical application;glycosylation;in vivo;injured;innovation;mutant;novel;progesterone 11-hemisuccinate-(2-iodohistamine);proteoglycan core protein;response;restoration;sulfation


application_id: 7477393
project_number: 1R21DA021178-01A2
project_title: A Web-based Employment Intervention for Drug Court Participants
administering_ic: NIDA
award_notice_date: 2008-09-14
opportunity_number: PA-07-331
application_type: 1
activity_code: R21
ic: DA
serial_number: 021178
suffix: A2
program_official: FLETCHER, BENNETT
project_start_date: 2008-09-15
project_end_date: 2010-08-31
study_section: Health Services Research Study Section[NIDA-F]
contact_pi_person_id: 8335129
contact_pi: WEBSTER, JOHN MATTHEW
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This twice amended R21 application is submitted by a new investigator and an established research team to conduct a study of a computerized Web-based employment intervention for female and male drug court participants. The innovative project tailors an employment intervention developed for drug court participants and adapts it for use on the Internet. The project places special emphasis on collecting data to identify and examine important gender differences in employment barriers to employment and perceptions of work as well as to understand gender differences in experiences with the Web-based intervention. Although drug treatment is related to desirable employment outcomes women have not fared as well as men on traditional measures of employment success such as employment status and earnings. The majority of employment interventions for drug abusers have not measured or even considered employment barriers and employment needs separately for females and males. After adapting the intervention for the Internet this project will collect data from both female and male drug abusers and identify differences and commonalities between women and men in employment barriers employment needs and other work-related measures. Over the project's two years a sample of 180 unemployed drug court participants will be recruited during a 15 month period (approximately 12 per month) from a drug court with which the investigators have a strong collaborative relationship. Participants who consent to participate will be interviewed about their employment experiences drug use and criminal history. Upon completing the baseline interview participants will be randomized to a control group (drug court as usual) or to the intervention group (Web-based employment intervention in addition to drug court as usual). Participants in the intervention group will complete a five module intervention grounded in a completed randomized controlled trial of an employment intervention which focused on obtaining maintaining and upgrading employment. Follow-up interviews will be conducted at 3 months. The overall aim of this project is to use the findings from a promising randomized controlled trial adapt it for use on the Internet and test its effectiveness on unemployed female and male drug abusers. The specific aims are to: (1) Adapt an existing efficacious employment intervention for unemployed drug court participants for Internet delivery as a Web-based intervention; (2) Evaluate the Web-based intervention's effect on employment outcomes (employment status days worked and earnings) and secondary outcomes (drug use and crime); and (3) Test the moderating effects of gender on the intervention's effect on employment and secondary outcomes.

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


application_id: 7477255
project_number: 5R01NS039774-07
project_title: Sympathetic Function in Diabetes
administering_ic: NINDS
award_notice_date: 2008-07-24
application_type: 5
activity_code: R01
ic: NS
serial_number: 039774
program_official: MITLER, MERRILL
project_start_date: 2000-09-30
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZRG1-CICS(01)Q]
contact_pi_person_id: 1887495
contact_pi: RANDALL, DAVID C
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-09-01
project_abstract:
DESCRIPTION (provided by applicant): Autonomic neuropathy is a serious complication of both Types 1 and 2 diabetes mellitus. We identified 2 promising indices of sympathetic neuropathy during the initial years of this grant. The first is a cross- correlation between arterial blood pressure (BP) and heart rate; the second is a mathematical (wavelet) analysis sensitive to a specific rhythm in arterial BP that is uniquely driven by the sympathetic nervous system. We now propose in Aim 1 to analyze changes in our indices as diabetic dysautonomia develops in the diabetes prone (DP) rat and to identify characteristics of the indices that coincide with the development of moderate (Stage 1) and severe (Stage 2) autonomic neuropathy. We will accomplish this by recording BP via telemetry for >10 months in the DP rat vs. a non-diabetic control; recording commences before the DP rat converts to the diabetic state allowing us to follow progressive changes in function during the development of AN. Objective features of the indices will be assessed relative to quantitative histological characteristics of the autonomic nerves harvested from the rats at each of the stages. In Aim 2 we compare in human diabetic patients our new indices to standard clinical tests of autonomic neuropathy. We will assess our indices in our patients against state-of-the-art evaluations of the autonomic control of cardiovascular function. Tests will be conducted during rest and during a passive tilt intended to challenge sympathetic and parasympathetic systems. Our ultimate goal is to develop a practical assessment of autonomic neuropathy that relative to those currently in use is more sensitive (detect and track the initial stages of the disease process more reliably) more selective (distinguish between sympathetic vs. parasympathetic dysfunction) and easier and less expensive to obtain. The results of these experiments will thereby help develop better clinical approaches to the control and management of diabetic autonomic neuropathy.

project_terms:
Age;Appearance;Area;Arts;Autonomic Dysfunction;Autonomic nerve structure;Blood Glucose;Blood Pressure;Breathing;Cardiovascular Physiology;Cardiovascular system;Characteristics;Clinical;Complication;Data;Depth;Development;Diabetes Mellitus;Disease;Disease Progression;Dysautonomias;Evaluation;Frequencies (time pattern);Functional disorder;Goals;Grant;Harvest;Head;Heart Rate;Human;Hyperglycemia;Individual;Invasive;Measures;Methods;Nerve;Neural Conduction;Neurons;Neuropathy;Neuropathy Diabetic Autonomic;Pathway interactions;Patients;Peripheral Nerves;Persons;Process;Property;Rattus;Records Controls;Relative (related person);Research Personnel;Rest;Science of Anatomy;Signal Transduction;Specific qualifier value;Staging;Standards of Weights and Measures;Statistically Significant;Sympathetic Nervous System;System;Telemetry;Testing;Time;Work;autonomic neuropathy;blood pressure regulation;day;diabetic;digital;indexing;nerve supply;non-diabetic;programs;research study;response;type I and type II diabetes;visceral afferent nerve


application_id: 7477241
project_number: 5R01DK071765-04
project_title: Mechanisms of S-adenosylmethionine in NASH
administering_ic: NIDDK
award_notice_date: 2008-07-22
application_type: 5
activity_code: R01
ic: DK
serial_number: 071765
program_official: DOO, EDWARD
project_start_date: 2005-09-15
project_end_date: 2010-07-31
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
project_abstract:
DESCRIPTION (provided by applicant): S-adenosylmethionine (SAMe) is an important methyl donor and antioxidant. Depressed SAMe levels are observed in multiple forms of experimental liver injury and SAMe therapy is an effective hepatoprotective agent in diverse forms of experimental liver injury. SAMe is available as a complementary and alternative medicine and is widely used to treat several forms of liver disease as well as depression. Likely therapeutic properties of SAMe include its effects on methylation antioxidant status mitochondrial function hepatocyte differentiation cytokine metabolism and/or antidepressive functions. In this proposal we will evaluate potential benefits of SAMe in an emerging major health problem in the U.S. non-alcoholic steatohepatitis (NASH). While the etiology of NASH still remains unclear most investigators agree that a baseline of steatosis requires a second "hit" capable of inducing inflammation fibrosis or necrosis in order to develop NASH. The focus of our research group has been the interactions of cytokines oxidative stress with lipid peroxidation and mitochondrial dysfunction in the induction of steatohepatitis both alcoholic and nonalcoholic in origin. Recent research from other laboratories also supports increased cytokine activity oxidative stress and mitochondrial dysfunction in the pathogenesis of NASH. Our long-term goal is to further understand mechanism(s) of action of SAMe in liver disease. In this proposal we will evaluate specific mechanisms of action of SAMe in the human liver disease NASH. This is not a clinical trial but a mechanistic translational study. The specific objectives for this proposal are: 1 .Evaluate mechanisms for dysregulated TNF/cytokine production in patients with NASH and determine whether or not SAMe in vitro/ex vivo favorably modulates this abnormal cytokine metabolism; 2. Evaluate in vivo mechanisms of action of SAMe in NASH patients including antioxidant status cytokine metabolism liver function and quality of life issues; 3. Determine whether or not hepatic methyltransferases are decreased in NASH and improve with SAMe therapy; and 4. Determine by proteomic analysis of serum and liver biopsies the proteins (esp. oxidative stress oxidized and mitochondrial proteins) that may play a role in the diagnosis or etiology of NASH and which may be modified by SAMe therapy

project_terms:
Alcohol consumption;Antioxidants;Body Weight decreased;Choline Deficiency;Clinical;Clinical Trials;Coin;Complementary and alternative medicine;Depressed mood;Development;Diabetes Mellitus;Diagnosis;Enzymes;Etiology;Evolution;Female;Fibrosis;Goals;Grants Applications;Health;Hepatic;Hepatitis Alcoholic;Hepatocyte;Hepatoprotective Agent;Human;Hyperlipidemia;Hypertension;In Vitro;Inflammation;Injury;Insulin Resistance;Knowledge;Laboratories;Lipid Peroxidation;Liver;Liver diseases;Liver neoplasms;Mental Depression;Metabolic;Metabolic syndrome;Metabolism;Methionine;Methylation;Methyltransferase;Mice Knockout;Mitochondria;Mitochondrial Proteins;Mus;Necrosis;Obesity;Organ;Oxidative Stress;Pathogenesis;Patients;Pharmaceutical Preparations;Pharmacotherapy;Play;Polycystic Ovary Syndrome;Predisposition;Production;Property;Proteins;Proteomics;Protocols documentation;Quality of life;Research;Research Personnel;Role;S-Adenosylmethionine;Serum;Simulate;Steatohepatitis;Syndrome;TNF protein human;Tamoxifen;Therapeutic;Therapeutic Agents;Toxin;Translational Research;Tumor Necrosis Factor-alpha;Tumor Necrosis Factors;base;biopsy of liver;cytokine;diabetic;improved;in vivo;liver function;methionine adenosyltransferase;mitochondrial dysfunction;non-alcoholic;nonalcoholic steatohepatitis;problem drinker;translational study


application_id: 7476062
project_number: 3R01AA012895-05S1
project_title: Mechanisms of Alcohol Tolerance and Priming in Humans
administering_ic: NIAAA
award_notice_date: 2007-07-26
application_type: 3
activity_code: R01
ic: AA
serial_number: 012895
suffix: S1
program_official: MATOCHIK, JOHN A
project_start_date: 2000-12-01
project_end_date: 2010-08-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 6368360
contact_pi: FILMORE, MARK T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Excessive alcohol use (i.e. a binge) contributes to many adverse health consequences (e.g. alcoholpoisoning acute alcoholic hepatitis and live cirrhosis). Alcohol is well-known for its acute impairing effectson neurocognitive processes involved in the regulation of behavior and attention. Yet little research hasexamined how such disturbances might reduce self-control over actual alcohol use leading to patternsofabusive drinking (e.g. binge drinking). Given that even mild doses of alcohol impair control of behavior andattention it is important to understand how acute intoxication can reduce control over alcohol intake once adrinking episode has begun. The proposed project is basedon the hypothesis that abuse potential ofalcohol is determined by its reward-enhancing effects and its disruptive effects on control mechanisms.Experiments will examine non-dependent adults and will test the disruptive effects of alcohol onneurocognitive control mechanisms in relation to two characteristics associated with increased alcoholabuse: 1) alcohol-induced priming of self-administration; 2) the development of alcohol tolerance. Studiesexamine the effects of controlled doses of alcohol on neurocognitive performance tasks that measureinhibitory and activational aspects of control. The measures will be studied in relation to alcohol-inducedpriming of self-administration and in the development of learned alcohol tolerance. The findings will providean understanding of how drinkers' susceptibility to alcohol's acute behavioral-impairing effects can pose anearly-onset risk factor for later alcohol dependence by promoting a continued pattern of abusive bingedrinking. The research strategies also will provide methods for testing the role of neurocognitivemechanisms in the treatment efficacy of existing pharmacotherapies such as naltrexone and acamprosateas well as some investigational medications that might operate via neurocognitive control mechanisms:

project_terms:
Accounting;Acute;Acute Alcoholic Hepatitis;Adult;Affect;Alcohol abuse;Alcohol consumption;Alcohol dependence;Alcohols;American;Attention;Behavior;Behavior Control;Behavioral;Behavioral Model;Characteristics;Cirrhosis;Consumption;Dependence;Development;Dose;Euphoria;Eye;Eye Movements;Funding;Goals;Health;Human;Impairment;Individual;Intoxication;Laboratories;Learning;Life;Measures;Methods;Modeling;Naltrexone;Neurocognitive;Pattern;Personal Satisfaction;Pharmaceutical Preparations;Pharmacotherapy;Play;Predisposition;Principal Investigator;Procedures;Process;Rate;Recovery;Regulation;Research;Research Personnel;Rewards;Risk;Risk Factors;Role;Self Administration;Self-control as a personality trait;Series;Staging;Stimulus;Task Performances;Technology;Testing;Training;Treatment Efficacy;Withdrawal;Work;acamprosate;alcohol effect;alcohol poisoning;alcohol sensitivity;base;behavioral pharmacology;binge drinking;craving;drinking;early onset;programs;psychologic;research study;response;selective attention


application_id: 7476032
project_number: 2R56EY014821-05
project_title: Mechanisms of Intermediate Distance Space Perception
administering_ic: NEI
award_notice_date: 2007-07-30
application_type: 2
activity_code: R56
ic: EY
serial_number: 014821
program_official: OBERDORFER, MICHAEL
project_start_date: 2003-04-01
project_end_date: 2008-07-31
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 1965646
contact_pi: HE, ZIJIANG
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2007-08-01
project_abstract:
Visual space perception in the intermediate distance range (2-25 meters) serves a multi-faceted function. Itallows the observer to perceive the 3D shapes sizes and locations of objects orient in space and guide ouractions. Yet despite its importance in enabling the observer to interact in the natural environmentknowledge of the mechanisms underlying space perception in the intermediate distance is incomplete.Pertaining to the ability to locate an object on the ground previous work found that the visual systemachieves this by constructing a representation of the ground surface and then uses it as a reference frame tolocalize the object. To localize a suspended object requires determining the relative position between thesuspended object and the ground reference frame. Recent empirical studies have provided critical evidencefor the notion of a ground-based space perception and led to the discovery of several fundamentalmechanisms for representing the ground surface. This progress has motivated the formulation of a morecomprehensive theoretical framework for understanding how the visual system forms the ground-basedperceptual space. The goal of the current proposal is to seek quantifiable empirical proofs to substantiateand advance the framework. The following three broadly defined issues will be investigated:A. The Perceptual Mechanisms for Representing the Ground Surface and Ceiling SurfaceB. The Selection Hypothesis and Attention Operation in Space PerceptionC. Locating an Object that Does Not Have a Direct Surface Contact with the GroundThe knowledge gained from the proposed project will advance the science of human space perception in theintermediate distance range. It will also improve understanding of the space perception and action problemsencountered by patients with visual deficits (e.g. those with strabismus and amblyopia) as well as problemsencountered by ordinary people in non-optimal visual environments. Furthermore to complement theresearch in the real environment the proposed project will investigate space perception in the virtualenvironment by capitalizing on the virtual reality technology. This approach is not only useful for controllingthe experimental stimulation but will also yield insights into how one can improve the immersive quality ofvirtual scenes.

project_terms:
Affect;Amblyopia;Attention;Characteristics;Complement;Conceptions;Cues;Depth;Depth Perception;Effectiveness;Environment;Eye;Figs - dietary;Financial compensation;Formulations Drug;Funding;Goals;Human;Investigation;Knowledge;Learning;Localized;Location;Measures;Modeling;Motion;Operative Surgical Procedures;Patients;Positioning Attribute;Process;Range;Relative (related person);Research;Resources;Role;Science;Shapes;Space Perception;Stimulus;Strabismus;Surface;Technology;Testing;Texture;Vision Disparity;Vision Binocular;Visual;Visual system structure;Work;base;directed attention;improved;insight;meter;monocular;research study;size;spatial relationship;virtual;virtual reality


application_id: 7475793
project_number: 5R03CA125782-02
project_title: Defining the role of MC1R in UV-induced oxidative damage and DNA repair
administering_ic: NCI
award_notice_date: 2008-07-15
opportunity_number: PAR-06-313
application_type: 5
activity_code: R03
ic: CA
serial_number: 125782
program_official: PERLOFF, MARJORIE
project_start_date: 2007-08-01
project_end_date: 2009-07-31
study_section: ZCA1-SRRB-F(M1)
contact_pi_person_id: 8508402
contact_pi: D'ORAZIO, JOHN A
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):   
  
We are interested in deciphering the molecular basis of UV injury and carcinogenesis in the skin with the long- term research objective of designing chemoprotective strategies against skin cancer. Fair skin correlates with enhanced expression of pheomelanin a pigment with poor UV-blocking abilities and reduced expression of eumelanin a pigment with excellent UV-blocking properties. Logically pheomelanotic individuals endure the highest incidence of UV-mediated damage including skin cancer. Pigmentation is regulated by the binding of melanocortin stimulating hormone (MSH) to its cognate receptor the melanocortin-1 receptor (MC1R) which in turn mediates adenylyl cyclase activation and subsequent production of cyclic AMP (cAMP). High functioning MC1R variants result in high levels of cAMP and eumelaninization whereas low functioning MC1R variants lead to low levels of cAMP and pheomelanization. We have developed a novel mouse model that mimics human skin of different pigmentation (eumelanotic pheomelanotic and albino). We found that by topically applying a small molecule (forskolin) to the fair-skinned animals eumelanin production was induced and the animals were UV-protected. Such forskolin-mediated eumelanin production likely occurs by directly activating adenylyl cyclase in melanocytes thereby "by-passing" the defective MC1R signaling that causes fair skin in our model. We hypothesize that MC1R dysfunction leads to UV-dependent oxidative damage in the skin and defective repair of UV-mediated DNA damage. Further we propose that topical forskolin protects against UV injury through eumelanin induction and rescue of DNA repair. Taking advantage of our unique murine model we will determine the effect of pheomelanin on UV damage in the skin (Specific Aim aim 1) and define the contribution of MC1R function in the repair of UV-mediated damage (Specific Aim aim 2). In our studies we will measure different types of UV-induced oxidative damage analyze repair of this damage and determine whether topical forskolin can modify these damage and repair profiles. Our findings will have significant health relatedness as they will clarify longstanding questions regarding pheomelanin in oxidative damage and MC1R function in the repair of UV-induced damage. Most importantly we anticipate that our resulting data will provide clear insight into effective topical approaches to repairing UV-mediated skin damage and preventing skin cancer.

project_terms:
Address;Adenylate Cyclase;Affect;Animal Model;Animals;Binding (Molecular Function);Bypass;Chemicals;Chemoprotective Agent;Cyclic AMP;Cyclobutanes;DNA Damage;DNA Repair;Data;Defect;Event;Exposure to;Failure (biologic function);Figs - dietary;Forskolin;Functional disorder;Generations;Genetic;Goals;Health;Hormones;Human;Incidence;Individual;Injury;Lead;Link;Measures;Mediating;Melanins;Melanocyte stimulating hormone;Methods;Modeling;Molecular;Mus;Nucleotide Excision Repair;Phenotype;Pigmentation physiologic function;Pigments;Predisposition;Prevention of Skin Cancer;Prevention strategy;Process;Production;Property;Proteins;Receptor Signaling;Receptor Melanocortin Type 1;Reporting;Research;Risk Factors;Role;Signal Transduction;Skin;Skin Cancer;Sulfates Inorganic;Sulfates Unspecified or Sulfate Ion;Testing;Tissues;Topical application;Transgenic Animals;UV Radiation Exposure;UV induced;UV sensitive;Ultraviolet Rays;Variant;alpha-Melanocyte stimulating hormone;base;carcinogenesis;congenic;defined contribution;design;dimer;eumelanin;insight;interest;melanocyte;melanoma;mouse model;novel;oxidative DNA damage;pheomelanin;receptor;receptor function;repaired;simulation;small molecule;tool;ultraviolet damage


application_id: 7475778
project_number: 5R03CA125788-02
project_title: Prevention of Cigarette Smoke-Induced Lung Cancer by Dietary Selenium
administering_ic: NCI
award_notice_date: 2008-06-27
opportunity_number: PAR-06-313
application_type: 5
activity_code: R03
ic: CA
serial_number: 125788
program_official: DAVIS, CINDY D
project_start_date: 2007-08-01
project_end_date: 2011-07-31
study_section: ZCA1-SRRB-F(M1)
contact_pi_person_id: 6221724
contact_pi: GLAUERT, HOWARD P
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
  
Lung cancer is the leading cause of death from cancer in the United States. The major risk factor for lung cancer development is cigarette smoking. One strategy for preventing lung cancer development is to increase the consumption of nutrients which have chemopreventive potential. Dietary selenium has been found to inhibit the development of several types of cancer in epidemiological and experimental studies. A 1996 intervention study found that individuals who consumed selenium supplements developed a lower incidence of several types of cancer including lung cancer. However no animal model has ever been established showing that dietary selenium inhibits cigarette smoke-induced lung cancer. In these studies we propose to test the hypothesis that dietary selenium inhibits lung cancer induced by cigarette smoke in the A/J mouse model. Mice will be fed diets containing the recommended level of selenium as well as two higher levels to determine if supplemental selenium will inhibit lung tumorigenesis. In other studies mice will be exposed to cigarette smoke for shorter periods of time to determine if dietary selenium inhibits the induction of cytochrome P-450 activity oxidative DNA damage and cell proliferation by cigarette smoke. These studies will determine if the A/J mouse model is valid for studying the effects of dietary selenium. If successful the model can then be further studied to determine the molecular mechanisms by which selenium is inhibitory and thus provide a mechanistic basis for possible dietary recommendations for the prevention of lung cancer.

project_terms:
8-hydroxy-2'-deoxyguanosine;A/J Mouse;Animal Model;Antioxidants;Bromodeoxyuridine;Cause of Death;Cell Proliferation;Cells;Chemopreventive Agent;Consumption;Cytochrome P-450 CYP1A1;Cytochrome P450;Development;Diet;Dietary Selenium;Human;Incidence;Individual;Intervention Studies;Label;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Modeling;Molecular;Mus;Nutrient;Oxidative Stress;Prevention;Prevention of Lung Cancer;Principal Investigator;Proteins;Rate;Recommendation;Risk Factors;Selenium;Smoke;Testing;Time;United States;Week;base;cancer type;cigarette smoke;cigarette smoke-induced;cigarette smoking;enzyme activity;feeding;glutathione peroxidase;indexing;lung tumorigenesis;mouse model;oxidative DNA damage;prevent;programs;research study;selenoenzyme;tumor;urinary


application_id: 7475549
project_number: 2R56HL067379-05A1
project_title: Pulmonary C-Neuron Hypersensitivity: Cellular Mechanisms
administering_ic: NHLBI
award_notice_date: 2007-08-31
application_type: 2
activity_code: R56
ic: HL
serial_number: 067379
suffix: A1
program_official: NOEL, PATRICIA
project_start_date: 2001-04-01
project_end_date: 2009-07-31
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 1857989
contact_pi: LEE, LU-YUAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Allergens;Appendix;Asthma;Body Temperature;Breathing;Bronchial Hyperreactivity;C Fiber;Cardiopulmonary;Chemicals;Chronic;Data;Development;Disease;Electric Stimulation;Fever;Goals;Hypersensitivity;Individual;Induced Hyperthermia;Inflammation;Inflammatory;Investigation;Ion Channel;Laboratories;Lead;Light;Local Hyperthermia;Lung;Mediating;Membrane;Neurons;Neurons Afferent;Ovalbumin;Ovum;Personal Satisfaction;Phase;Physiological;Play;Property;Range;Rattus;Regulation;Relative (related person);Reporting;Research Project Grants;Role;Stimulus;Strenuous Exercise;Temperature;Testing;Tissues;Up-Regulation (Physiology);Vanilloid;afferent nerve;airway hyperresponsiveness;airway inflammation;asthmatic patient;hyperthermia treatment;improved;insight;neuromechanism;receptor;response


application_id: 7475287
project_number: 5R01ES015375-04
project_title: Apple Peel Extract Protects UV-Induced Carcinogenesis
administering_ic: NIEHS
award_notice_date: 2008-07-16
application_type: 5
activity_code: R01
ic: ES
serial_number: 015375
program_official: HUMBLE, MICHAEL C
project_start_date: 2006-09-28
project_end_date: 2011-07-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
project_abstract:
DESCRIPTION (provided by applicant): Environmental exposure to UV light is a major etiologic factor in the development of human skin cancers. Experimentally UV acts both as tumor initiator and a tumor promoter in animal models. It is recognized that certain nutritional factors and phytochemicals play an important role in an individual's susceptibility to environmental carcinogens. Understanding of the underlying mechanisms will enhance the effectiveness of prevention and therapeutic efforts. Our preliminary studies indicate that apple peel extract has antioxidant activities. It inhibits ultraviolet (UVB 280-320 nm) radiation-induced AP-1 activation both in vitro and in vivo possibly by interfering with signal transduction events involving MAP kinase ERKs and JNK. Cell transformation studies show that apple peel extract inhibited TPA-induced cell transformation. We hypothesize that apple peel extract may function as an antioxidant and as a chemopreventive agent against oxidative stress-induced carcinogenesis. We will use UVB-induced skin carcinoma as a model to test this hypothesis. Four specific aims are proposed. Specific Aim 1 will identify the active antioxidant components of apple peel extract. We will study the antioxidant properties of various chromatographic fractions derived from apple peel extract and examine the phenolic compounds identified previously for their reaction rates toward oxygen free radicals. Specific Aim 2 will investigate antioxidant properties of apple peel extract individual fraction and previously identified phenolic compounds in JB6 cells and in living animals. Specific Aim 3 will investigate the effects of apple peel extract on UVB-induced activation of AP-1 NF-DB and NAFT in vitro and in vivo. Specific Aim 4 will evaluate the effects of apple peel extract individual fraction and previously identified phenolic compounds on UVB-induced lipid peroxidation protein oxidation oxidative DMA damage and carcinogenesis in SKH-1 hairless mice exposed to UVB. This Aim will also investigate the effects of apple peel preparations on proliferative and/or cell deletion activities by measuring proliferation and apoptosis. This application can be used as a preclinical study for nutritional intervention against cancer resulting from environmental exposure to UV light. This study is related to the priority areas of the Public Health Service program "Healthy People 2010" which is committed to achieving the promotion of health and prevention of disease. Thus the results may have an important impact on public health.

project_terms:
Acetates;Administration Oral;Animal Model;Animals;Antioxidants;Apoptosis;Apple;Area;Benz(a)Anthracenes;Carcinogens Environmental;Cell Line;Cell Proliferation;Cells;Chemicals;Chemoprevention;Chemopreventive Agent;Chromatography High Pressure Liquid;Chronic Disease;Commit;Consumption;Detection;Diet;Dietary Intervention;Effectiveness;Electron Spin Resonance Spectroscopy;Environmental Exposure;Epidemiologic Studies;Epigallocatechin Gallate;Equilibrium;Event;Exhibits;Exposure to;Extracellular Signal Regulated Kinases;Free Radicals;Fruit;Goals;Green tea (dietary);Health Promotion;Healthy People 2010;Human;Human Development;Hydrogen Peroxide;Hydroxyl Radical;In Vitro;Incidence;Individual;Initiators Tumor;Investigation;Life;Light;Lipid Peroxidation;MAPK8 gene;MEKs;Malignant Neoplasms;Measures;Methods;Mice Inbred HRS;Mice Transgenic;Micronutrients;Microscope;Minerals;Modeling;Molecular;Mus;NF-AT;Non-Malignant;Numbers;Nutritional;Oxidative Stress;Phytochemical;Plants;Play;Podophyllum peltatum;Predisposition;Preparation;Prevention;Promoters Tumor;Property;Proteins;Radiation;Reactive Oxygen Species;Research Personnel;Risk;Role;Signal Transduction;Skin;Skin Cancer;Skin Carcinogenesis;Skin Carcinoma;Source;Spin Trapping;Sunlight;Superoxides;Testing;Therapeutic;Topical application;Trans-Activation (Genetics);UV carcinogenesis;UVB induced;Ultraviolet B Radiation;United States Public Health Service;Vitamins;Xanthine Oxidase;Xanthines;ascorbate;base;benzanthracene;cancer type;carcinogenesis;cell injury;cell transformation;disorder prevention;free radical oxygen;fruits and vegetables;functional food;in vivo;irradiation;neoplastic cell;nuclear factor 1;nuclear factors of activated T-cells;oxidation;oxidative DNA damage;preclinical study;programs;public health medicine (field);reaction rate;tumorigenesis;ultraviolet;xanthine


application_id: 7475036
project_number: 5R01EY016782-02
project_title: Molecular Targets of Corneal Anti-angiogenesis
administering_ic: NEI
award_notice_date: 2008-07-15
application_type: 5
activity_code: R01
ic: EY
serial_number: 016782
program_official: SHEN, GRACE L
project_start_date: 2007-08-01
project_end_date: 2012-07-31
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 1881039
contact_pi: MOHAN, ROYCE
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
project_abstract:
DESCRIPTION (provided by applicant):  The leading cause of corneal blindness world wide is from angiogenesis which is the pathogenic growth of new blood vessels from an existing vasculature. Normal wound healing in the cornea does not involve angiogenesis. Therefore identifying the molecular mechanisms that are responsible for preventing self- destructive angiogenic processes have important bearing on corneal homeostasis regeneration and transplantation. A novel biochemical feature preventing corneal stromal cells from participating in pathogenic fibrotic repair processes has recently been linked to the evolutionary conserved ubiquitin proteasome pathway (UPP). The UPP regulates protein quality control inflammatory transcription factor NF-kappa B activation cell cycle differentiation and antigen presentation. We have investigated the hypothesis that a DPP-mediated genetic program controls the angiogenic phenotype of the cornea. We show that the UPP is upregulated in vascular endothelial cells when activated by angiogenic stimulators and during injury healing in vascularized corneas in vivo. This pattern of UPP activation is attenuated by the potent small molecule angiogenesis inhibitor withaferin A. To demonstrate that a protein binding target(s) of withaferin A mediates this drug's anti-angiogenic mechanism we generated a biotinylated analog of withaferin A. We have successfully exploited this affinity reagent and isolated the withaferin binding target. In this R01 proposal we plan to exploit angiogenic and nonangiogenic models of wound healing to define the UPP-driven healing mechanism(s) of the cornea and validate newly identified molecular targets for anti-angiogenesis. For these investigations withaferin A will serve both as a pharmacological agent and a cell permeable probe of its binding-protein target's function. Specifically we will (1) characterize the drug's inhibitory mode of action on targeting the angiogenic activation of the UPP (2) investigate key components of the UPP as mediators of the drugs activity and (3) investigate withaferin-protein target-deficient mouse models to validate the requirement for drug-protein interaction in the corneal anti-angiogenic mechanism of WFA. We believe these investigations focused on the UPP and the target of withaferin A will enable us to reach our long-term objectives of discovering new therapeutic approaches to control angiogenesis and promote its homeostasis.

project_terms:
Affinity;Alkalies;Angiogenesis Inhibitors;Antigen Presentation;Attenuated;Binding (Molecular Function);Binding Proteins;Biochemical;Biochemical Pathway;Biological Factors;Blindness;Blood Vessels;Burn injury;Cell Cycle;Cell Cycle Arrest;Cells;Chemicals;Collagen;Competence;Cornea;Corneal Neovascularization;Cultured Cells;Cytostatics;Data;Dose;Drug Design;Endothelial Cells;Fibroblasts;Genetic Programming;Healed;Homeostasis;Inflammation;Inflammatory;Injury;Investigation;Lactones;Lead;Link;Mediating;Mediator of activation protein;Modeling;Molecular;Molecular Target;Mus;NF-kappa B;Natural regeneration;Pathway interactions;Pattern;Pharmaceutical Preparations;Phenotype;Process;Production;Protein Binding;Protein Inhibition;Proteins;Quality Control;Reaction Time;Reagent;Regulation;Research Personnel;Role;Rolfing;Signal Transduction;Signaling Protein;Stromal Cells;Testing;Tissues;Translational Research;Transplantation;Ubiquitin;Ubiquitination;Vascular Endothelial Cell;Vimentin;Wound Healing;analog;angiogenesis;antiangiogenesis therapy;cooking;healing;in vivo;inhibitor/antagonist;injured;mouse model;multicatalytic endopeptidase complex;neovascularization;new growth;novel;novel therapeutics;prevent;programs;repaired;research study;small molecule;transcription factor;ubiquitin isopeptidase;withaferin A


application_id: 7475035
project_number: 5R01EY018350-02
project_title: Pro-and anti-angiogenic effects of vascular endothelial growth factor-A
administering_ic: NEI
award_notice_date: 2008-07-16
application_type: 5
activity_code: R01
ic: EY
serial_number: 018350
program_official: SHEN, GRACE L
project_start_date: 2007-08-01
project_end_date: 2012-07-31
study_section: Biology and Diseases of the Posterior Eye Study Section[BDPE]
contact_pi_person_id: 2446639
contact_pi: AMBATI, JAYAKRISHNA
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
project_terms:
Acute;Affect;Age related macular degeneration;Animal Model;Binding (Molecular Function);Biochemical;Biology;Blindness;Blood Vessels;Bone Marrow;Bone and Bones;Breast;Cells;Choroid;Choroidal Neovascularization;Clinical;Complex;Condition;Data;Development;Disease;Elderly;Endothelial Cells;Environment;Epidemic;Extracellular Matrix;Extracellular Protein;Genes;Goals;Growth;Human;In Situ;In Vitro;Incidence;Inflammation;Inflammatory;Injury;Laser injury;Lasers;Leukocytes;Ligands;Link;Malignant neoplasm of prostate;Mediating;Mediator of activation protein;Membrane;Methods;Modality;Modeling;Molecular;Monkeys;Monocyte Chemoattractant Protein-1;Operative Surgical Procedures;Osteonectin;PTPN6 gene;Pathologic Neovascularization;Pathway interactions;Patients;Phase;Prevalence;Process;Promotor (Genetics);Protein Dephosphorylation;Proteins;Receptor Activation;Receptor Protein-Tyrosine Kinases;Receptor Signaling;Relative (related person);Reporting;Research Personnel;Retina;Role;Route;Signal Transduction;Specimen;Stem cells;Structure of retinal pigment epithelium;Testing;Therapeutic;Tissues;United States;United States Food and Drug Administration;Vascular Endothelial Growth Factor A;Vascular Endothelial Growth Factor Receptor;Vascular Endothelial Growth Factor Receptor-1;angiogenesis;base;cytokine;driving force;drug development;in vivo;injured;insight;macula;mouse model;neovascularization;nonhuman primate;novel;prevent;programs;public health medicine (field);receptor;receptor binding;response;size;stem;therapy development;vasculogenesis


application_id: 7474721
project_number: 5R01HL079583-05
project_title: Ribosomal Function and Diamond-Blackfan Anemia
administering_ic: NHLBI
award_notice_date: 2008-07-16
opportunity_number: RFA-HL-04-008
application_type: 5
activity_code: R01
ic: HL
serial_number: 079583
program_official: QASBA, PANKAJ
project_start_date: 2004-09-30
project_end_date: 2010-07-31
study_section: ZHL1-CSR-D(S1)
contact_pi_person_id: 1922324
contact_pi: ELLIS, STEVEN R
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    Diamond-Blackfan anemia (DBA) is a rare pure red-cell aplasia that presents early in infancy. Virtually every aspect of DBA is heterogeneous posing considerable challenges to efforts to understand and treat this disease. Approximately 25% of DBA cases are linked to mutations in the ribosomal protein $19 gene whereas the remaining cases are of unknown etiology. A goal of this application is to address the molecular basis of DBA focusing on the role of Rps19 in ribosome synthesis. Our studies in yeast have shown that Rps19 is required for the maturation of 40S ribosomal subunits. We plan to extend these studies and examine ribosome synthesis in cell lines from DBA patients. We have also identified several other yeast ribosomal proteins that appear to cooperate with Rps19 in the maturation of 40S subunits. If patients with normal Rps19 were defective in ribosome synthesis genes encoding proteins that cooperate with Rps19 would become candidate genes for disease-causing mutations. Our studies in yeast have also pointed to a need for functional testing of putative disease-causing mutations identified in Rps19 genes from DBA patients. Finally we will study the relationship between ribosome synthesis and bone marrow failure in a transgenic mouse model.  The specific aims of this application are to:  1. continue studies characterizing the effect of DBA missense mutations on the function of the Rps19 protein in yeast.  2. determine if there are defects in the protein synthetic machinery in cell lines from DBA patients.  3. determine which ribosomal proteins depend on Rps19 for their assembly into 40S ribosomal subunits.  4. characterize the phenotype of mice hemizygous for LAMR1 including hematological analysis cancer incidence and the presence of other congenital abnormalities.

project_terms:
Address;Cell Line;Classification;Clinical;Code;Congenital Abnormality;Defect;Diamond-Blackfan anemia;Disease;Etiology;Eye;Fibroblasts;Genes;Goals;Heterogeneity;Incidence;LAMR1 gene;Link;Lymphocyte;Malignant Neoplasms;Mice Transgenic;Molecular;Mus;Mutate;Mutation;Mutation Missense;Outcome;Pancytopenia;Patients;Phenotype;Predisposition;Proteins;RNA Processing;RPS19 gene;Red-Cell Aplasia Pure;Resources;Ribosomal Proteins;Ribosomal RNA;Ribosomes;Role;Staging;Testing;Therapeutic;Transgenic Organisms;Yeasts;base;disease-causing mutation;gene synthesis;infancy;mouse model;ribosomal protein S19;synthetic protein


application_id: 7474633
project_number: 5R01CA122383-03
project_title: Tumor-Targeting Oligonucleotides
administering_ic: NCI
award_notice_date: 2008-07-18
application_type: 5
activity_code: R01
ic: CA
serial_number: 122383
program_official: LEES, ROBERT G
project_start_date: 2006-08-01
project_end_date: 2011-07-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 6663799
contact_pi: BATES, PAULA J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
project_abstract:
DESCRIPTION (provided by applicant): A major goal of translational cancer research is to develop targeted therapies that can specifically inhibit the expression or function of proteins that play an essential role in oncogenesis. There is considerable interest in using synthetic DNA or RNA oligonucleotides to achieve this goal because of their ability to recognize specified nucleic acid sequences or protein structures with high affinity. Several oligonucleotide-based strategies including antisense small interfering RNAs (siRNAs) protein-binding aptamers and immunostimulatory oligonucleotides have produced potent anti-cancer effects in pre-clinical studies. However clinical trials of therapeutic (antisense) oligonucleotides have been generally disappointing and this has been attributed in part to their inefficient uptake by cancer cells. The Principal Investigator and her collaborators have developed a novel antiproliferative oligonucleotide named AGRO100. This molecule has recently been tested in a clinical trial involving patients with advanced cancer and has demonstrated a remarkable lack of toxicity combined with promising clinical activity. Unlike most other oligonucleotides AGRO100 is taken up efficiently and selectively by cancer cells in culture and in vivo. We hypothesize that these extraordinary properties are related to the unusual G-quadruplex structure of AGR0100 and its ability to bind specifically to a protein that is expressed at high levels on the surface of cancer cells. The long-term goal of this project is to develop oligonucleotides that are avidly and selectively taken up by cancers in vivo. Such tumor-targeting sequences could be incorporated into oligonucleotide-based therapeutics or conjugated to chemotherapy drugs in order to enhance their efficacy and reduce unpleasant side effects. In this application we propose to elucidate the mechanism involved in the preferential uptake of AGRO100 by tumors and to identify sequence or structural motifs that lead to efficient oligonucleotide internalization by cancer cells. The first specific aim is to characterize the cellular internalization of AGRO100 and confirm the role of nucleolin in this process. The second aim is to use a SELEX approach to identify oligonucleotides (from combinatorial libraries) that have efficient and selective uptake by cancer cells. The third aim is to incorporate the optimal tumor-targeting sequences into antisense siRNA and immunomodulatory oligonucleotides in order to determine if this leads to superior uptake and activity.

project_terms:
Adopted;Advanced Malignant Neoplasm;Adverse effects;Affinity;Base Sequence;Binding (Molecular Function);Cancer Detection;Cancer Patient;Cancer cell line;Cell Death;Cell Nucleolus;Cell surface;Cells;Chemicals;Classification;Clinical;Clinical Trials;Clinical Trials Phase I;Development;Disease;Endothelial Cells;Evolution;G-Quartets;Goals;Hand;Image;In complete remission;Individual;Lead;Libraries;Ligands;Malignant Neoplasms;Malignant neoplasm of breast;Mediating;Methods;Modification;Monoclonal Antibodies;Mus;Names;Normal Cell;Nucleic acid sequencing;Oligonucleotides;Oligonucleotides Antisense;Patients;Peptides;Pharmaceutical Preparations;Play;Polymerase Chain Reaction;Principal Investigator;Procedures;Process;Proliferating;Property;Protein Binding;Proteins;Purpose;RNA;RNA Small Interfering;Radioisotopes;Recombinants;Reporting;Research Personnel;Resistance;Role;Serum;Specific qualifier value;Structure;Surface;Techniques;Testing;Therapeutic;Therapeutic Clinical Trial;Toxic effect;Tumor Tissue;Vertebral column;Xenograft procedure;anticancer activity;anticancer research;aptamer;base;cancer cell;cancer therapy;cell type;chemotherapy;combinatorial;design;improved;in vivo;insight;interest;nanoparticle;neoplastic cell;novel;novel strategies;nuclease;nucleolin;phosphodiester;phosphorothioate;preclinical study;programs;protein function;protein structure;synthetic construct;tumor;tumorigenesis;uptake


application_id: 7474632
project_number: 5R21DA022314-02
project_title: Calcitriol and Methamphetamine Neurotoxicity
administering_ic: NIDA
award_notice_date: 2008-07-24
opportunity_number: PA-03-107
application_type: 5
activity_code: R21
ic: DA
serial_number: 022314
program_official: FRANKENHEIM, JERRY
project_start_date: 2007-08-01
project_end_date: 2011-07-31
study_section: Molecular Neuropharmacology and Signaling Study Section[MNPS]
contact_pi_person_id: 7875148
contact_pi: CASS, WAYNE A
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Methamphetamine (METH) is a potent psychomotor stimulant that has high potential for abuse in humans. METH is also a neurotoxin affecting primarily central dopamine (DA) and serotonin (5-HT) neurons. The abuse potential of METH together with its neurotoxic effects make METH an important drug from the standpoint that chronic use by humans may lead to long-term or permanent changes in brain neurochemistry and function. The experiments in this R21 exploratory grant proposal will focus on the ability of calcitriol the active metabolite of vitamin D to prevent the neurotoxic effects of METH on brain monoamine neurons and to restore function to damaged neurons. Several reports have indicated that calcitriol provides signification neuroprotection against various lesions possibly by upregulating trophic factors such as GDNF. GDNF has been shown to have protective and restorative effects for brain DA neurons. Thus it is possible that systemic administration of calcitriol may be able to prevent or reduce METH-induced damage to monoamine neurons and help restore function to neurons previously damaged by METH. It is hypothesized that calcitriol will protect against the neurotoxic effects of METH on striatal DA and 5-HT terminals and the calcitriol will be effective in reversing METH-induced damage to striatal DA and 5-HT terminals. This hypothesis will be tested by addressing the following two specific aims: 1) Does pretreatment with calcitriol prevent or reduce METH-induced reductions in striatal monoamine release and content? And 2) Can calcitriol treatment accelerate recovery of striatal monoamine release and content in animals previously administered neurotoxic doses of METH? For these experiments rats will be treated with calcitriol before or after administration of saline or neurotoxic doses of METH. Microdialysis studies and post-mortem monoamine analyses will be carried out to investigate protective and restorative effects. Calcitriol induced upregulation of GDNF will be examined as an initial investigation into the mechanism of any neuroprotective or restorative effects observed.   
  
Relevance to Public Health: METH abuse and addiction is a major public health issue in the United States.  The results of the experiments in the proposal will help determine the extent to which calcitriol can protect against the neurotoxic effects of METH and if calcitriol can restore damage resulting from neurotoxic doses of METH.  IF calcitriol proves effective the results of the proposal studies could lead to novel therapeutic strategies for treating individuals who chronically abuse METH.  Furthermore if calcitriol is effective it could have therapeutic applications in other disease processes where there is a loss of monoamine neurons such as in Parkinson's disease.

project_terms:
Address;Affect;Animals;Attenuated;Behavioral;Brain;Calcitriol;Chronic;Corpus striatum structure;Daily;Disease;Dopamine;Dose;Grants Applications;Human;In Vitro;Individual;Injection of therapeutic agent;Investigation;Lead;Lesion;Measures;Mediating;Methamphetamine;Microdialysis;Moods;Nerve;Neuraxis;Neurons;Neurotoxins;Parkinson Disease;Pharmaceutical Preparations;Process;Rattus;Recovery;Reporting;Saline;Science of neurochemistry;Serotonin;Severities;Testing;Therapeutic;Time;United States;Up-Regulation (Physiology);Vitamin D;Week;addiction;day;dopaminergic neuron;functional restoration;glial cell-line derived neurotrophic factor;in vivo;monoamine;neuroprotection;neurotoxic;neurotoxicity;novel therapeutics;prevent;protective effect;public health medicine (field);research study;treatment duration


application_id: 7474585
project_number: 5R01EY013813-06
project_title: TNF-alpha in Cell Death & Neuroprotection in Glaucoma
administering_ic: NEI
award_notice_date: 2008-07-15
application_type: 5
activity_code: R01
ic: EY
serial_number: 013813
program_official: AGARWAL, NEERAJ
project_start_date: 2003-08-01
project_end_date: 2012-07-31
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 6803489
contact_pi: TEZEL, GULGUN
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
project_terms:
Address;Adult;Axon;Blindness;Cell Death;Cell Death Signaling Process;Cell Survival;Cells;Cessation of life;Complement;Complex;Cultured Cells;Data Set;Elevation;Eye;Glaucoma;Grant;Immunohistochemistry;In Vitro;Incubated;Injection of therapeutic agent;Injury;Intervention;Mediating;Microglia;Mitogen-Activated Protein Kinases;Modeling;Nerve Degeneration;Neuroglia;Nuclear;Ocular Hypertension;Pathway interactions;Physiologic Intraocular Pressure;Predisposition;Proteins;Proteome;Proteomics;Rattus;Relative (related person);Research Personnel;Retina;Retinal;Retinal Ganglion Cells;Saline;Sampling;Signal Transduction;TNF protein human;Technology;Time;Tissues;Tumor Necrosis Factor Receptor;Tumor Necrosis Factor-alpha;Veins;Week;base;comparative;follow-up;improved;in vivo;innovation;limbal;macroglia;neuronal survival;neuroprotection;prevent;programs;protein expression;receptor binding;research study;response;tandem mass spectrometry


application_id: 7474307
project_number: 1R01DK080418-01A1
project_title: Adiponectin and Regulation of Triglyceride Metabolism
administering_ic: NIDDK
award_notice_date: 2008-03-13
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: DK
serial_number: 080418
suffix: A1
program_official: LAUGHLIN, MAREN R
project_start_date: 2008-04-01
project_end_date: 2013-01-31
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 8333955
contact_pi: SHAO, JIANHUA
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Adiponectin is an adipose-derived hormone that promotes insulin sensitization and plays an important role in energy metabolism. However adiponectin gene expression and plasma adiponectin concentrations are paradoxically reduced in obesity. Hypertriglyceridemia usually accompanies adiposity. Previous human and animal studies have clearly shown that circulating adiponectin protein levels correlate inversely with triglyceride concentrations indicating that adiponectin regulates triglyceride metabolism. However the mechanism by which adiponectin regulates triglyceride metabolism is largely unknown. Our long term goal is to elucidate the underlying mechanisms of obesity-induced dyslipidemia. Using adenovirus-mediated in vivo gene transduction we have shown that elevated plasma adiponectin reduces serum triglyceride levels without significantly changing hepatic very low density lipoprotein (VLDL)-triglyceride production. Interestingly post-heparin plasma lipoprotein lipase (LPL) activities as well as LPL and VLDL receptor gene expression in skeletal muscle were significantly increased in mice with elevated plasma adiponectin. LPL is a rate-limiting enzyme for VLDL- triglyceride hydrolysis and the VLDL receptor enhances LPL activity. Our studies have also found that the expression of PPAR3 co-activator-11 (PGC-11) was robustly increased by adiponectin in both skeletal muscle and cultured myotubes. PGC-11 plays a pivotal role in skeletal muscle mitochondrial biogenesis and fatty acids oxidation. Therefore we hypothesize that adiponectin reduces plasma triglyceride concentration by increasing VLDL-triglyceride catabolism in skeletal muscle and that PGC-11 mediates the regulatory effects of adiponectin by increasing LPL and VLDLr gene expression. This project will address two main specific aims. In specific aim 1 we will investigate the mechanism by which adiponectin stimulates VLDL-triglyceride catabolism and the roles of skeletal muscle LPL and the VLDLr in this regulation. This will be accomplished in part using skeletal muscle tissue-specific LPL-deficient or VLDLr-deficient mice. In addition the role of the LKB1/AMPK pathway in adiponectin-stimulated VLDL-TG catabolism in skeletal muscle will be investigated using skeletal muscle-specific LKB1-deficient mice. In specific aim 2 we will use the PGC-11-deficient mice and molecular techniques to determine the mechanisms by which PGC-11 mediates adiponectin-induced VLDL-triglyceride catabolism in skeletal muscle. This study is expected to reveal a new mechanism and concept about how an adipose-derived hormone adiponectin regulates lipid and lipoprotein metabolism. It will also shed light on a novel mechanism that integrates adipose and skeletal muscle tissues in the context of lipoprotein metabolism. These studies may lead to new prevention or therapeutic strategies for obesity and the metabolic syndrome which impose a serious health problem world wide. PUBLIC HEALTH RELEVANCE: This study is expected to reveal a new mechanism and concept about how an adipose-derived hormone adiponectin regulates lipid and lipoprotein metabolism. It will also shed light on a novel mechanism that integrates adipose and skeletal muscle tissues in the context of lipoprotein metabolism. These studies may lead to new prevention or therapeutic strategies for obesity and the metabolic syndrome which impose a serious health problem world wide.

project_terms:
5'-AMP-activated protein kinase;Address;Adenoviruses;Adipocytes;Adipose tissue;Animals;Biogenesis;Catabolism;Couples;Diet;Dyslipidemias;Elevation;Energy Metabolism;Enhancers;Enzymes;Fatty Acids Nonesterified;Fatty acid glycerol esters;Gene Expression;Genes;Glucose;Goals;Health;Heart;Heparin;Hepatic;Hormones;Human;Hydrolysis;Hypertriglyceridemia;Insulin;Lead;Light;Lipids;Lipoproteins;Mediating;Metabolic syndrome;Metabolism;Mice Transgenic;Mitochondria;Modeling;Molecular;Mus;Muscle Cells;Muscle Fibers;Numbers;Obesity;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Plasma;Play;Prevention;Production;Proteins;RNA Small Interfering;Rate;Receptor Gene;Regulation;Reporting;Role;STK11 gene;Serum;Skeletal muscle structure;Techniques;Therapeutic;Tissues;Transcriptional Activation;Transduction Gene;Transgenic Organisms;Triglyceride Metabolism;Triglycerides;Up-Regulation (Physiology);VLDL receptor;Very low density lipoprotein;adiponectin;base;concept;fatty acid oxidation;in vivo;insulin signaling;lipid metabolism;lipoprotein lipase;mouse model;novel;public health medicine (field);receptor expression;very low density lipoprotein triglyceride


application_id: 7473893
project_number: 5R01AG025403-05
project_title: Mitochondrial Proteome Changes in Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2008-08-01
opportunity_number: RFA-AG-04-006
application_type: 5
activity_code: R01
ic: AG
serial_number: 025403
program_official: SUNEJA, SANOJ
project_start_date: 2004-09-30
project_end_date: 2010-08-31
study_section: ZAG1-ZIJ-5(O1)
contact_pi_person_id: 7947546
contact_pi: LYNN, BERT C
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The major barrier to treating or preventing Alzheimer's disease (AD) is its unknown etiology/pathogenesis. However increasing evidence supports a role for mitochondrial dysfunction in the pathogenesis of AD. Most information on mitochondrial dysfunction has been obtained one protein at a time. It is the hypothesis of this proposal that changes in the mitochonrial proteome are an early event in the pathogenesis of neuron degeneration in AD and that these changes may be evaluated using quantitative proteomics. In preliminary studies we applied 2-dimensional liquid chromatography coupled with tandem mass spectrometry (2D-LC/MS/MS) and the isotope coded affinity tag (ICAT) method to identify and quantify protein levels in mitochondria isolated from early AD late stage AD and age-matched control subjects. 2D-HPLC/MS/MS analysis of ICAT-labeled mitochondrial samples identified and quantified 22 unique proteins. Our results show that for early AD subjects ATP synthase and pyruvate kinase (essential for ATP production) and VDAC (part of the permeability transition pore) are significantly depleted. In late stage AD subjects our results show that most proteins involved in ATP production are significantly depleted along with VDAC while uracil DNA glycosylase (base excision repair) and guanine nucleotide-binding protein (extra-matrix signal modulation) are significantly increased. To test the hypothesis that changes in mitochondrial proteome are an early event in the pathogenesis of neuron degeneration in AD we will a) quantitatively evaluate mitochondrial protein expression in the hippocampus temporal pole superior and middle temporal gyrus and cerebellum of control early AD and late-stage AD subjects b) immunohistochemically examine tissue sections from the same subjects to determine if proteins with altered expression correlate with neuropathologic features and c) quantitatively evaluate changes in mitochondrial protein expression in primary rat cortical neuron cultures resulting from AD relevant insults including AB iron/hydrogen peroxide glucose deprivation and glutamate.

project_terms:
Address;Affinity;Age;Aging;Alzheimer's Disease;Amyloid;Amyloid beta-Protein;Apoptosis;Atrophic;Brain;Cerebellum;Cerebrum;Code;Complex;Coupled;DNA;Data;Deposition;Disease;Enzymes;Etiology;Event;Glucose;Glutamates;Hippocampus (Brain);Hydrogen Peroxide;Immunohistochemistry;Individual;Iron;Isocitrate Dehydrogenase (NAD+);Isotopes;Isotopically-Coded Affinity Tagging;Label;Lead;Liquid Chromatography;Metabolic;Methods;Mitochondria;Mitochondrial Matrix;Mitochondrial Proteins;Nerve Degeneration;Neurites;Neurofibrillary Tangles;Neurons;Neuropsychological Tests;Oxidoreductase;Pathogenesis;Pathologic;Permeability;Play;Population;Production;Proteins;Proteome;Proteomics;Psyche structure;Pyruvate Kinase;Rattus;Repairs Base Excision;Role;Sampling;Score;Senile Plaques;Signal Transduction;Specimen;Staging;Structure of middle temporal gyrus;Study Section;Testing;Thinking function;Time;Tissues;Uracil;Voltage-Dependent Anion Channel;base;cell type;cytochrome c oxidase;deprivation;disorder control;glucose metabolism;guanine nucleotide binding protein;hexokinase;in vivo;ketoglutarate dehydrogenase;mitochondrial dysfunction;prevent;protein expression;pyruvate dehydrogenase;tandem mass spectrometry;trend;two-dimensional;uracil-DNA glycosylase


application_id: 7473266
project_number: 5R01CA086412-25
project_title: Ligation of CR3 by Glucan and iC3b Links Innate and Adaptive Anti-tumor Immunity
administering_ic: NCI
award_notice_date: 2008-08-13
application_type: 5
activity_code: R01
ic: CA
serial_number: 086412
program_official: MCCARTHY, SUSAN A
project_start_date: 2000-02-23
project_end_date: 2010-07-31
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: Not Applicable
congressional_district: 03
department: PATHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
project_abstract:
DESCRIPTION (provided by applicant): Our strong preliminary data demonstrate a novel therapeutic strategy for tumor therapy by engaging leukocyte complement receptor 3 (CR3 CD11b/CD18 alphaMbeta2-integrin) to kill tumor cells opsonized with iC3b. Therapeutic efficacy is achieved by using yeast beta-glucan in combination with anti-tumor mAbs in multiple mouse syngeneic tumor models. The long-term goal has been to understand the molecular and cellular mechanisms of action within yeast beta-glucan mediated tumor immunotherapy and then promote it for clinical utilization with humanized anti-tumor mAbs or tumor vaccines eliciting a sufficient humoral response for activation of complement. We further demonstrate that yeast particulate beta-glucan stimulates dendritic cells for up-regulation of surface co-stimulatory molecules and MHC class II expression and secretion of IL-12 and TNF-alpha. Moreover combined therapy of beta-glucan and MUC1 vaccine exhibits a synergistic effect on tumor regression. The central hypotheses to be tested in this proposal are: 1) yeast particulate beta-glucan enhances the adaptive immunity via secretion of cytokines and the enhanced dendritic cell antigen presentation; and 2) yeast beta-glucan has a synergistically therapeutic effect on a B cell-mediated MUC1 vaccine in MUC1/MT double Tg mice developing spontaneous mammary carcinoma. Aim 1 determines whether beta-glucan mediated tumor immunotherapy promotes the adaptive T and B cell responses by using adoptively transferred OVA TCR transgenic OT-I (CDS) and/or OT-II T cells (CD4). The enhanced dendritic cell antigen presentation and subsequent enhanced antigen-specific T cell responses by beta-glucan will be determined. Aim 2 uses a B cell-mediated MUC1 vaccine in combination with beta-glucan to investigate the therapeutic efficacy in MUC1/MT double Tg mice developing spontaneous mammary carcinoma. Targeting tumor-associated antigen MUC1 to B cells breaks T and B cell tolerance in MUC1 Tg mice. The enhancing effect of beta-glucan on anti-MUd T and B cell responses will be determined. Beta-glucan mediated immunotherapy demonstrates promising results in the therapeutic setting and is potentially remedial for cancer patients.

project_terms:
Address;Antibodies;Antibody -dependent cell cytotoxicity;Antigen Presentation;Antigens;Asians;Award;B-Lymphocytes;Binding (Molecular Function);Biological Response Modifiers;Breast Carcinoma;C3bi;CD4 Positive T Lymphocytes;Cancer Patient;Cancer Vaccines;Carcinoma Lewis Lung;Cells;Centers for Disease Control and Prevention (U.S.);Clinical;Complement;Complement Activation;Complement Receptor;Data;Dendritic Cells;Disease regression;Effector Cell;Exhibits;Family;Glucans;Goals;Growth Factor Inhibition;Histocompatibility Antigens Class II;Human;ITGAM gene;Immune;Immunity;Immunoconjugates;Immunotherapy;Inflammatory;Integrins;Interleukin-12;Japan;Killings;Lectin;Leukocytes;Ligands;Ligation;Link;Macrophage-1 Antigen;Malignant Neoplasms;Mediating;Medicine Traditional;Modeling;Molecular;Monoclonal Antibodies;Mucin-1 Staining Method;Mus;Natural Killer Cells;Ovalbumin;Particulate;Patients;Radioisotopes;Surface;T-Lymphocyte;TNF protein human;Testing;Therapeutic;Therapeutic Effect;Toxin;Transcriptional Activation;Transgenic Organisms;Treatment Efficacy;Tumor Antigens;Tumor Immunity;Tumor Necrosis Factor-alpha;United States Food and Drug Administration;Up-Regulation (Physiology);Vaccines;Yeasts;beta-Glucans;cancer care;cancer therapy;clinically relevant;cytokine;cytotoxic;cytotoxicity;insight;macrophage;neoplastic cell;neutrophil;novel;novel strategies;novel therapeutics;prophylactic;response;success;tumor


application_id: 7472507
project_number: 5R01DA022191-03
project_title: Evaluation of Atomoxetine for Cocaine Dependence: A Pilot Trial
administering_ic: NIDA
award_notice_date: 2008-07-11
opportunity_number: RFA-DA-06-002
application_type: 5
activity_code: R01
ic: DA
serial_number: 022191
program_official: BOUGH, KRISTOPHER J
project_start_date: 2006-09-26
project_end_date: 2011-07-31
study_section: ZDA1-MXS-M(02)
contact_pi_person_id: 1877426
contact_pi: WALSH, SHARON L.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This application is written in response to Request for Applications DA-06-002 entitled "Pilot Clinical Trials of Pharmacotherapies for Substance Related Disorders." Cocaine abuse and dependence has been recognized as a significant public health problem and no broadly effective medications are available. Recent promising results have been obtained from studies employing the agonist substitution or replacement approach including studies of d-amphetamine and modafinil. This pilot project proposes to evaluate atomoxetine (Strattera) a compound presently marketed for the treatment of ADHD in adolescents and adults for the treatment of cocaine dependence. Atomoxetine is a norepinephrine reuptake blocker which has relatively low affinity for the dopamine and serotonin transport sites. It has been safely tolerated in clinical practice and is associated with low abuse potential. Preliminary data suggest that its pharmacodynamic effects overlap partially with prototypic stimulants and that maintenance on atomoxetine can reduce the subjective response to cocaine and self-reported ratings of desire for cocaine in cocaine abusing volunteers. This application proposes to conduct a single placebo-controlled double blind randomized pilot clinical trial to evaluate atomoxetine (Stattera) for the treatment of cocaine dependence. Cocaine-dependent healthy individuals who are seeking treatment for their substance abuse will be enrolled after careful medical and psychiatric screening to ensure their suitability for the study over a two- week period. Patients will be stratified on variables known to impact cocaine abuse treatment outcomes prior to randomization to one of two groups (n=25/group). Patients will be randomized to receive either atomoxetine (80 mg/day with a brief lead-in) or a matched-placebo during a trial lasting 12 weeks. All patients will participate in weekly cognitive behavioral counseling sessions. A contingency management procedure will be employed to reinforce attendance and decrease attrition from the trial. A broad array of measures including measures of drug use safety mood psychosocial functioning and medication compliance (including riboflavin testing and pill counts) and cocaine craving will be collected throughout the course of the trial. The primary outcome measures will be urine toxicology results for benzoylecgonine over time and achievement of three consecutive weeks of abstinence. Secondary outcome measures will include clinic attendance medication adherence psychosocial functioning and other drug use. Data will be analyzed using PROC Mix General Estimating Equations and parametric ANOVA approaches. The group size was based upon power analyses derived from other trials in which positive medications signals were obtained in this population. This study will provide preliminary safety and efficacy data on the potential utility of atomoxetine and determine whether a larger-scale evaluation is warranted.

project_terms:
Abstinence;Abuse Cocaine;Achievement;Adolescent;Adult;Affinity;Agonist;Analysis of Variance;Attention deficit hyperactivity disorder;Behavioral;Cardiovascular system;Chronic;Clinic;Clinical;Clinical Research;Clinical Trials;Cocaine;Cognitive;Cognitive Therapy;Counseling;Count;Crack Cocaine;Data;Dependence;Dependences Cocaine;Dextroamphetamine;Dopamine;Dose;Double-Blind Method;Drug usage;Enrollment;Ensure;Equation;Evaluation;Funding Mechanisms;In Vitro;Individual;Maintenance;Marketing;Measures;Mediating;Medical;Methadone;Methylphenidate;Modafinil;Moods;National Institute of Drug Abuse;Neuro-Oncological Ventral Antigen 2;Norepinephrine;Outcome Measure;Patient Self-Report;Patients;Pharmaceutical Preparations;Pharmacodynamics;Pharmacotherapy;Pilot Projects;Placebo Control;Placebos;Population;Prevalence;Procedures;Program Development;Randomized;Rate;Request for Applications;Research Personnel;Riboflavin;Role;Safety;Screening procedure;Serotonin;Signal Transduction;Site;Specific qualifier value;Strattera;Substance abuse problem;Substance-Related Disorders;Testing;Time;Toxicology;Treatment outcome;Urine;Week;Withdrawal;Writing;atomoxetine;base;benzoylecgonine;contingency management;craving;day;desire;dopamine system;in vivo;interest;medication compliance;nicotine replacement;pill (pharmacologic);pilot trial;pre-clinical;programs;psychosocial;public health medicine (field);response;reuptake;size;volunteer


application_id: 7472497
project_number: 5R01DA020429-04
project_title: Preventing Cocaine Relapse: Developing Pharmacotherapies
administering_ic: NIDA
award_notice_date: 2008-06-30
opportunity_number: RFA-DA-05-004
application_type: 5
activity_code: R01
ic: DA
serial_number: 020429
program_official: BOUGH, KRISTOPHER J
project_start_date: 2005-09-27
project_end_date: 2010-07-31
study_section: ZDA1-RXL-E(15)
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Cocaine abuse continues to be a significant public health concern. Relapse rates to cocaine use after treatment remain discouragingly high even with the advent of sophisticated behavioral and cognitive relapse prevention therapies. Identifying an effective pharmacological adjunct will likely be necessary to further reduce cocaine relapse rates. The specific aim of this proposal is to demonstrate that aripiprazole is an effective "anti-relapse" medication for cocaine and possibly determine the behavioral mechanism by which it exerts this effect (i.e. aripiprazole attenuates the discriminative effects of priming doses of cocaine thereby reducing subsequent drug self-administration). To accomplish this aim we will first determine the safety and tolerability of cocaine-aripiprazole combinations by administering ascending doses of oral and intranasal cocaine doses during aripiprazole maintenance and monitoring physiological and behavioral responses (Exp. 1). We will then demonstrate that chronic aripiprazole treatment attenuates the discriminative-stimulus effects of cocaine (Exp. 2). The discriminative-stimulus effects of drugs may be involved in relapse to drug taking behavior in that the initial or priming dose (i.e. a lapse) functions as a discriminative stimulus that signals the availability of more cocaine. Finally Exp. 3 will demonstrate that a priming dose of cocaine (i.e. a lapse) increases subsequent cocaine taking using a novel self-administration procedure designed to model relapse and that aripiprazole attenuates this effect. Aripiprazole was chosen for study because it is a potent partial agonist at the dopamine (DA) D2 and serotonin (5-HT) 5-HT1A receptors. Cocaine is thought to exert its effects by blocking monoamine transporters (e.g. DA and 5-HT). Partial agonists may represent a novel and effective means to prevent relapse to cocaine use because theoretically they should have the therapeutic advantages of both an agonist and an antagonist. Consistent with this notion the results of a recent experiment conducted in our laboratory suggest that acutely administered aripiprazole significantly attenuates the discriminative-stimulus and subjective effects of d-amphetamine in humans. We are unaware of any published reports in which the effects of cocaine were assessed in humans following pretreatment with aripiprazole. The proposed research will provide the initial clinical information regarding the efficacy of aripiprazole as a putative "anti-relapse" medication for cocaine dependence. The conduct of the proposed controlled laboratory studies will provide important information (e.g. appropriate doses) that will guide the design of a subsequent clinical trial. Reducing relapse to drug use is important because intravenous abuse of cocaine may be associated with increased risk of acquired immunodeficiency syndrome (A.I.D.S.).

project_terms:
Abuse Cocaine;Accident and Emergency department;Acquired Immunodeficiency Syndrome;Admission activity;Aftercare;Agonist;American;Amphetamines;Animals Laboratory;Attenuated;Basic Science;Behavior;Behavioral;Behavioral Mechanisms;Buprenorphine;Chronic;Clinical;Clinical Trials;Cocaine;Cognitive;Dependence;Dependences Cocaine;Development Computer Systems;Dextroamphetamine;Dopamine;Dose;Drug usage;Human;Individual;Institution;Intravenous;Kentucky;Laboratories;Laboratory Study;Location;Maintenance;Measures;Mediating;Modeling;Monitoring Physiologic;Opioid;Oral;Patient Self-Report;Patients;Pharmaceutical Preparations;Pharmacotherapy;Prevention therapy;Procedures;Process;Publishing;Questionnaire Designs;Rate;Receptor Serotonin 5-HT1A;Recording of previous events;Relapse;Relative (related person);Reporting;Research;Research Personnel;Risk;Role;Safety;Self Administration;Serotonin;Signal Transduction;Stimulus;Therapeutic;Thinking function;Time;United States;aripiprazole;concept;craving;design;drug discrimination;monoamine;novel;prevent;prevention of later incidences of a disorder;programs;public health medicine (field);receptor;research study;response;stimulant abuse


application_id: 7472466
project_number: 5R01CA116784-02
project_title: Abl kinases in growth factor signaling motility and invasion
administering_ic: NCI
award_notice_date: 2008-07-10
application_type: 5
activity_code: R01
ic: CA
serial_number: 116784
program_official: AULT, GRACE S
project_start_date: 2007-08-01
project_end_date: 2012-07-31
study_section: Intercellular Interactions Study Section[ICI]
contact_pi_person_id: 1918859
contact_pi: PLATTNER, RINA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
project_terms:
ABL1 gene;Adhesions;Affect;Animals;Basement membrane;Biochemical;Biological;Biological Assay;Blood;Blood Vessels;Breast Cancer Cell;Cancer Etiology;Cancer cell line;Cell Line;Cell Proliferation;Cells;Cessation of life;Chemotaxis;Condition;Cytoskeletal Modeling;Data;Development;Distant;Dominant-Negative Mutation;Drug Combinations;Epidermal Growth Factor Receptor;Family;Fatty acid glycerol esters;Fibroblasts;Figs - dietary;Goals;Growth Factor;Growth Factor Receptors;Immune;In Vitro;In-Migration;Invaded;Invasive;Label;Location;Malignant Neoplasms;Malignant neoplasm of breast;Mammary Gland Parenchyma;Mammary Neoplasms;Mammary gland;Matrix Metalloproteinases;Mediating;Metalloproteases;Metastatic Lesion;Molecular;Mortality Vital Statistics;Mus;Neoplasm Metastasis;Normal tissue morphology;Organ;PTK2 gene;PTPN11 gene;Pathway interactions;Pharmaceutical Preparations;Phosphotransferases;Platelet-Derived Growth Factor Receptor;Play;Primary Neoplasm;Process;Proliferating;Protein Tyrosine Kinase;Proteins;RNA Interference;Regulation;Resistance development;Role;Signal Transduction;Site;Solid Neoplasm;Stream;Tail;Testing;Translating;Tumor Cell Invasion;Tumor Cells Cultured;Veins;base;c-abl Proto-Oncogenes;cell motility;fluorescence imaging;in vivo;inhibitor/antagonist;insight;kinase inhibitor;leukemia;migration;neoplastic cell;prevent;research study;rho;src-Family Kinases;tumor;tumor progression


application_id: 7472417
project_number: 5R13CA124224-03
project_title: Louisville Breast Cancer Update
administering_ic: NCI
award_notice_date: 2008-07-23
opportunity_number: PA-06-041
application_type: 5
activity_code: R13
ic: CA
serial_number: 124224
program_official: XIE, HENG
project_start_date: 2006-09-01
project_end_date: 2011-07-31
study_section: ZCA1-GRB-T(M1)
contact_pi_person_id: 7874100
contact_pi: CHAGPAR, ANEES B
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The purpose of the Louisville Breast Cancer Update is to provide a high quality forum for the dissemination of advances in the state-of-the-art multidisciplinary management of breast cancer and to allow for an exchange of ideas regarding controversial issues regarding care of breast cancer patients. Lectures from some of the most prominent breast cancer researchers and clinicians will be presented covering all aspects of breast cancer care. This year topics to be covered will include: Indications utility and challenges of MRI; minimally invasive mastectomy; Innovations in reconstruction; Advances in systemic chemotherapy; Hormones in breast cancer: to replace or inhibit?; Targeted therapy for breast cancer; Genomics in the management of breast cancer; Advances in radiation therapy: should we be doing more or less?; Prevention genetics and high risk breast cancer and Supportive Care Issues. In addition this meeting will be expanded to facilitate the interaction between basic scientists and clinicians with a scientific poster session that will promote fruitful collaborations and a common understanding of progress in the breast cancer arena from bench to bedside. The meeting will therefore further the NCI's mission for the alleviation of suffering and death due to cancer by providing a forum for the dissemination of advances in the multidisciplinary care of patients with breast cancer and the building of collaborations that will promote further research in this area. This annual event is the only one of its kind in Kentucky and provides an important resource for education of clinicians scientists and advocates.

project_terms:
Advocate;Area;Arts;Cancer Patient;Caring;Cessation of life;Collaborations;Educational aspects;Event;Genetic;Genomics;Hormones;Invasive;Kentucky;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of breast;Mastectomy;Mission;Patient Care;Prevention;Purpose;Radiation therapy;Research;Research Personnel;Resources;Risk;Scientist;Supportive care;Update;bench to bedside;cancer care;chemotherapy;innovation;lectures;multidisciplinary;posters;reconstruction


application_id: 7472332
project_number: 5R01CA083237-08
project_title: Molecular Mechanisms of Metastasis Suppression by NM23
administering_ic: NCI
award_notice_date: 2008-06-26
application_type: 5
activity_code: R01
ic: CA
serial_number: 083237
program_official: WOODHOUSE, ELIZABETH
project_start_date: 1999-08-01
project_end_date: 2011-07-31
study_section: Cancer Genetics Study Section[CG]
contact_pi_person_id: 7875382
contact_pi: KAETZEL, DAVID M
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
project_abstract:
DESCRIPTION (provided by applicant): While mechanisms regulating oncogenesis have been elucidated substantially in recent years comparatively little is yet known about the mechanisms that underlie metastasis of tumor cells the ultimate cause of death in cancer. Metastasis suppressor genes play pivotal roles in controlling this process but only a handful have been identified. NM23 ("negative in metastasis") genes represent the first described metastasis suppressors and are recognized for their antimetastatic activity in melanoma breast and gastric carcinoma. The overall goal of this project to systematically dissect the molecular mechanisms and genomic pathways underlying the metastasis suppressor activity of NM23. We recently found that the NM23-H1 isoform is a 3'-5' exonuclease (3'5' EXO) an activity often associated with genome integrity apoptosis and chromatin remodeling. Although there is clear potential relevance of these processes to malignant progression we will also measure the extent to which the nucleoside diphosphate kinase (NDPK) and histidine kinase (hisK) activities of NM23-H1 contribute to its metastasis suppressor properties. In Specific Aim 1 we will complete a detailed structure-function analysis to delineate the active site of the 3'5 EXO and characterize a panel of mutants harboring lesions that selectively disrupt the 3'5' EXO NDPK and hisK functions of the NM23-H1 molecule. The mutants will be used as molecular tools to determine the relative contributions of each to suppression of the metastatic phenotype (Specific Aim 2) in human melanoma cells using cell culture and in vivo models to measure tumorigenic and metastatic potential. Gene expression changes elicited by expression of NM23-H1 variants will be determined by microarray analysis and real-time PCR (Specific Aim 3). Correlational analysis will identify NM23-regulated genes whose expression tracks with metastatic phenotype and metastatic progression. Functional relevance of identified genes will be validated by viral-mediated overexpression and knockdown approaches. In Specific Aim 4 we will directly test the DMA repair activity of NM23-H1 in mammalian and yeast cell models and identify the relevant enzymatic function. These studies should provide the first systematic analysis of pathways through which NM23 proteins oppose metastasis in multiple cancer types and therefore could suggest novel strategies to combat this final and intractable stage of the disease.

project_terms:
Amino Acids;Apoptosis;Biochemical;Biological Models;Breast Melanoma;Carcinoma;Cause of Death;Cell Line;Cell model;Cells;Chromatography Gel;Chromatography High Pressure Liquid;Classification;Clinical;Condition;Cultured Cells;Data;Development;Disease;Dominant-Negative Mutation;Embryo;End Point;Enzymes;Fibroblasts;Gene Expression;Genes;Genes Metastasis Suppressor;Genome;Genomics;Goals;Green Fluorescent Proteins;Homologous Gene;Human;Image;Individual;Induced Mutation;Intervention;Knock-out;Laboratories;Learning;Lesion;Link;Liver;Malignant - descriptor;Malignant Neoplasms;Measures;Mediating;Melanoma Cell;Metastasis Suppression;Metastatic Melanoma;Metastatic to;Microarray Analysis;Modeling;Molecular;Molecular Profiling;Mouse Strains;Mus;Mutation;NME1 gene;Neoplasm Metastasis;Nucleoside Diphosphate Kinase A;Nucleoside-Diphosphate Kinase;Nucleotides;Pathway Analysis;Pathway interactions;Phenotype;Phosphodiesterase I;Play;Polymerase Chain Reaction;Process;Property;Protein Isoforms;Protein Overexpression;Proteins;RNA Small Interfering;Rate;Relative (related person);Research Personnel;Role;Saccharomyces cerevisiae;Sites Active;Staging;Stomach;Stomach Carcinoma;Structure;T-Lymphocytes Cytotoxic;Testing;Time;Transcriptional Regulation;Tumor Suppression;Variant;Viral;Yeasts;cancer cell;cancer type;cell motility;chromatin remodeling;in vitro Model;in vivo;in vivo Model;insight;malignant phenotype;molecular modeling;mutant;neoplastic cell;novel strategies;nuclease;programs;protein expression;protein-histidine kinase;repaired;research study;tool;tumor progression;tumorigenesis;tumorigenic


application_id: 7472143
project_number: 1R21ES015812-01A1
project_title: Transplacental Arsenic Induced Hepatic Dysfunction and Vascular Disease
administering_ic: NIEHS
award_notice_date: 2008-02-09
opportunity_number: PA-06-181
application_type: 1
activity_code: R21
ic: ES
serial_number: 015812
suffix: A1
program_official: NADADUR, SRIKANTH
project_start_date: 2008-04-01
project_end_date: 2010-03-31
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Cardiovascular disease is the major cause of death in the U.S. Chronic arsenic ingestion causes atherosclerosis and is associated with increased mortality from myocardial infarction and stroke. Early life arsenic exposure may play a significant role in development of atherosclerosis in adult life as suggested by reports of infant deaths from myocardial infarction caused by advanced arteriosclerosis in regions where mothers consumed water with high levels of arsenic. Transplacental arsenic exposure can disrupt liver DNA methylation patterns and thus alter liver gene expression. Underlying liver disease is an independent risk factor for atherosclerosis. Hence arsenic exposure induced liver disease may predispose to atherogenesis and widespread exposure to arsenic in drinking water in the U.S. likely contributes to atherogenesis and death from cardiovascular disease. Our working hypothesis is that arsenic exposure disrupts epigenetic control of hepatic gene expression predisposing the liver to inflammation that is an atherogenic trigger resulting in accelerated atherosclerosis in susceptible animals. Preliminary data indicate that atherosclerosis-prone apolipoprotein E knockout (ApoE -/-) mice transplacentally exposed to arsenic in drinking water develop overt vascular disease by 10 weeks of age without high lipid diet and that liver gene expression suggests a pro-inflammatory state. The aims of this exploratory grant application are 1) to refine and to optimize this newly developed model of transplacental arsenic induced atherogenesis by determining arsenic exposure response of arsenic blood levels in pregnant females and fetuses determining exposure/time dependence of atherosclerotic lesion formation (rate and extent of lesion formation) assessing arsenic exposure-response of changes in vascular reactivity and characterizing the nature of arterial lesions (lesion cellularity fibrosis and inflammation) in arsenic exposed mice; 2) explore transplacental arsenic-induced hepatic changes by characterizing liver pathology determining circulating biomarkers of liver dysfunction and test the hypothesis that there is a temporal correlation between hepatic changes and vascular changes. Tissues will be examined at birth and at 10 16 and 24 weeks of age to determine the course of disease and stability of molecular changes induced by in utero arsenic exposure. The goal of the proposed studies is to determine whether there is a threshold level of arsenic exposure necessary to accelerate atherogenesis using the ApoE model. The relevance of this model to human atherosclerosis is that people prenatally exposed to arsenic are likely more susceptible to dietary influences later in life. These studies will provide important information on the mechanisms of arsenic induced atherosclerosis and the role that fetal arsenic exposure plays in disease progression. This model also will be a rich resource for future research on the mechanism of arsenic induced atherosclerosis including determination of the critical stages of development for the arsenic effect and molecular studies of arsenic exposure induced changes in DNA methylation chromatin structure gene expression and genetic imprinting. PUBLIC HEALTH RELEVANCE: Exposure to arsenic drinking water is a major concern in the United States. The effect of early life arsenic exposure on adult disease progression is unknown but potentially very important. This project uses a mouse model of fetal arsenic exposure induced vascular disease to investigate effects of fetal arsenic exposure on liver development that likely cause vascular disease by young adulthood.

project_terms:
Adult;Age;Animal Model;Animals;ApoE knockout mouse;Apolipoprotein E;Arsenic;Arterial Fatty Streak;Arteriosclerosis;Atherosclerosis;Biological Markers;Birth;Blood;Blood Vessels;Cardiovascular Diseases;Cause of Death;Cellular Stress;Cellularity;Cessation of life;Cholesterol;Chromatin Structure;Chronic;Condition;DNA Methylation;Data;Dependence;Development;Diet;Digit structure;Disease;Disease Progression;Dysfunction Liver;Elderly;Epidemiologic Studies;Epigenetic Process;Exposure to;Fatty acid glycerol esters;Female;Fetus;Fibrosis;Functional disorder;Future;Gangrene;Gene Expression;Genetic;Genomic Imprinting;Goals;Grants Applications;Hepatic;Hepatic Tissue;Human;Hyperlipidemia;Infant;Inflammation;Inflammatory;Inflammatory Response;Ingestion;Lesion;Life;Link;Lipids;Liver;Liver diseases;Modeling;Molecular;Mortality Vital Statistics;Mothers;Mus;Myocardial Infarction;Nature;Pathology;Patient currently pregnant;Pattern;Phenocopy;Play;Process;Rate;Reporting;Research;Resources;Risk Factors;Role;Staging;Testing;Time;Tissues;United States;Vascular Diseases;Water;Week;Work;arterial lesion;atherogenesis;drinking water;fetal;in utero;interest;mouse model;prenatal;prenatal exposure;programs;public health medicine (field);response;stroke


application_id: 7472005
project_number: 1R21HL089737-01A1
project_title: Isolation of novel mesenchymal stem cell subpopulations
administering_ic: NHLBI
award_notice_date: 2008-03-15
opportunity_number: PA-06-407
application_type: 1
activity_code: R21
ic: HL
serial_number: 089737
suffix: A1
program_official: ADHIKARI, BISHOW B
project_start_date: 2008-03-15
project_end_date: 2010-02-28
study_section: Special Emphasis Panel[ZRG1 CVS-Q (90)]
contact_pi_person_id: 7035773
contact_pi: DAWN, BUDDHADEB
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Although therapy with adult bone marrow (BM)-derived unfractionated mesenchymal stem cells (MSCs) improves cardiac function remodeling and perfusion after MI the extents of MSC-induced angiogenesis myogenesis and antiapoptotic and `paracrine effects' have been inconsistent in studies from different laboratories. These apparent discrepancies might have stemmed from the heterogeneous nature of unfractionated `MSCs' and the use of dissimilar expansion protocols in different laboratories. Our fundamental hypothesis is that a primitive and homogenous MSC subpopulation isolated on the basis of surface antigen expression will exhibit greater endothelial and cardiomyogenic differentiation potential and secrete greater amounts of cardioprotective growth factors/cytokines; and that optimization of medium is critical for the expansion of MSC subpopulation specifically intended for cardiac repair without significant changes in antigenic phenotype gene expression differentiation potential and secretory profile. Accordingly Aim 1 will thoroughly examine whether compared with unfractionated MSCs an antigenically-defined MSC subpopulation exhibits a more primitive phenotype expresses endothelial/cardiomyogenic lineage markers and undergoes greater endothelial/cardiomyogenic differentiation. Expression of markers of pluripotency and lineage commitment will be compared using real-time RT-PCR in unfractionated MSCs and MSC subpopulations isolated by flow cytometry based on the expression of CD45 c-kit Flk-1 Sca-1 CD90 and CD105. Endothelial and cardiomyogenic differentiation will be rigorously quantitated (morphology immunocytochemistry confocal microscopy). To predict in vivo efficacy differentiation (and secretory profile in Aim 2) will be assessed in culture conditions that simulate the in vivo milieu. Aim 2 will examine whether an antigenically-defined MSC subpopulation secretes greater amounts of cardioprotective growth factors/cytokines and whether gene expression profiles correlate with secretory profiles. Aim 3 will conclusively establish the optimal medium composition for the expansion of select MSC subpopulation(s) with no or minimal alterations in surface antigen expression gene expression differentiation potential and secretory abilities. Four primary media (DMEM IMDM 1-MEM and Mesencult) and five factors (LIF IGF-1 FGF-2 PDGF-B and Wnt3a) will be examined. Antigen and gene expression differentiation and secreted factors will be examined during serial passages. In summary this exploratory/developmental proposal aims to identify a novel MSC subpopulation most suitable for cardiac repair and to establish the optimal medium that will expand these cells without significant changes in surface antigen expression/gene expression/differentiation potential/secretory attributes for future cardiac repair in vivo. The results of the proposed investigations will not only provide novel insights into MSC biology but may also identify a cellular population ideally-suited for cardiac repair in patients with ischemic heart disease and post-MI heart failure. PUBLIC HEALTH RELEVANCE: Ischemic heart disease is the single most prevalent cause of death and morbidity in all Western countries. Despite significant advances in medical treatments the prognosis for patients with large heart attacks is poor with eventual progression to end-stage heart failure and death. Although recent studies indicate that therapy with adult primitive cells can repair dead heart muscle the results have been variable and the mechanisms remain unclear. Thus the identification of an ideal cell for heart repair a major goal of this exploratory proposal would have enormous therapeutic implications for patients with ischemic heart disease and heart failure. The optimization of culture medium for expansion of this cell population will help generate a large number of cells for potential use in vivo. The results of the proposed studies will therefore be highly relevant for improving public health and improving the length and quality of life of millions of patients with ischemic heart disease and heart failure.

project_terms:
Adherence (attribute);Adult;Antigens;Arts;Bone Marrow;Cardiac;Cause of Death;Cell Count;Cells;Cellular biology;Cessation of life;Clinical Trials;Condition;Country;Culture Media;Cultured Cells;Development;Developmental Biology;Diffuse;Discipline;ENG gene;Enzyme-Linked Immunosorbent Assay;Exhibits;Fibroblast Growth Factor 2;Flow Cytometry;Forecast of outcome;Foundations;Future;Gene Expression;Gene Proteins;Genetic;Goals;Growth Factor;Heart failure;In Vitro;Infarction;Insulin-Like Growth Factor I;Investigation;LIF gene;Laboratories;Length;Maintenance;Mediating;Medical;Mesenchymal Stem Cells;Microscopy Confocal;Modeling;Molecular Biology;Molecular Profiling;Morbidity - disease rate;Morphology;Myocardial Infarction;Myocardial Ischemia;Myocardium;Nature;PTPRC gene;Patients;Perfusion;Phenotype;Plastics;Population;Property;Protein Chemistry;Proto-Oncogene Protein c-kit;Protocols documentation;Quality of life;Reverse Transcriptase Polymerase Chain Reaction;Role;Serial Passage;Simulate;Staging;Stromal Cell-Derived Factor 1;Surface Antigens;Techniques;Testing;Therapeutic;Time;Vascular Endothelial Growth Factors;Ventricular Function Left;angiogenesis;base;combinatorial;cytokine;heart cell;immunocytochemistry;improved;in vivo;insight;interdisciplinary approach;leukemia inhibitory factor;myogenesis;novel;pluripotency;prevent;primitive cell;protein expression;public health medicine (field);relating to nervous system;repaired;stem;stem cell therapy;stemness


application_id: 7471953
project_number: 1K01NR010239-01A1
project_title: Older Mothers and Adult Daughters: High Blood Pressure Self Management Behaviors
administering_ic: NINR
award_notice_date: 2008-03-24
opportunity_number: PA-06-001
application_type: 1
activity_code: K01
ic: NR
serial_number: 010239
suffix: A1
program_official: HUSS, KAREN
project_start_date: 2008-05-01
project_end_date: 2011-04-30
study_section: National Institute of Nursing Research Initial Review Group[NRRC (40)]
contact_pi_person_id: 8639560
contact_pi: SHAWLER, CELESTE
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Heart disease is the leading cause of death in American women. Kentucky ranks as the 6 highest state in the nation for heart disease among women. This program of research will advance the initiatives of Healthy People 2010 by assisting women to develop self management behaviors to reduce and moderate hypertension a major risk factor for heart disease. The long-term aim of this program of research is to determine the causal relationships of inner strength perceived control and quality of the relationship of older mothers and their adult daughters so that nursing interventions can be developed to improve cardiovascular self management behaviors and health related quality of life. The specific aim of this longitudinal predictive study is to determine the impact of inner strength perceived control and the quality of the relationship of older mothers and their adult daughters on blood pressure self management behaviors and health related quality of life. To achieve these goals the candidate has designed a comprehensive training program with experienced nurse researchers who will facilitate the development of the candidate's expertise in the theoretical perspectives of chronic illness management specifically blood pressure self management and health related quality of life. The candidate will complete formal coursework and planned interactions and meetings with mentors and consultants. In addition the candidate will participate in on-going research seminars prepare and submit scientific publications and present at scientific sessions. Mentors will be Dr. Debra Moser Professor U. of Kentucky and Dr. Neville Strumpf Professor U. of Pennsylvania. The proposed training and research environments are: the College of Nursing and Sanders Brown Center on Aging at the U. of Kentucky Lexington Kentucky; Hartford Center for Geriatric Nursing Excellence: U. of Pennsylvania Philadelphia Pennsylvania; and U. of Louisville School of Nursing Louisville Kentucky. The candidate will apply the knowledge gained from the training program to develop a program of research designed to enhance blood pressure self management behaviors of older women with hypertension. The aims of the proposed study are to: (1) Use dyadic analysis to examine the direct (i.e. 'actor') and indirect (i.e. 'partner') effects of mothers' and daughters' inner strength on the outcomes of self management strategies for blood pressure and health related quality of life in both mothers and daughters measured at baseline and 6 months later and to determine whether there are significant changes over time in the outcomes; (2) To determine using dyadic analysis whether perceived control mediates the relationship between inner strength and outcomes in mothers and daughters; (3) To determine using dyadic analysis whether the mother-daughter relationship mediates the relationship between inner strength and outcomes in mothers and daughters; (4) To determine using dyadic analysis if there is a significant relationship between perceived control and quality of the mother-daughter relationship. The findings from this study will be used to support a program of theory-based nursing intervention studies designed to increase blood pressure self management behaviors of mother-daughter dyads when the older woman is diagnosed with hypertension. The adult daughter may or may not be diagnosed with hypertension and the study is designed to compare relationships whether or not daughters are diagnosed with hypertension. Previous work by the candidate demonstrated that inner strength was a key concept for older women and their adult daughters in managing health crisis. The candidate plans to further examine the significance of inner strength and modifiable health behaviors of older women with hypertension.

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


application_id: 7471782
project_number: 1R21AI076956-01A1
project_title: Importance of CD5 for the function of regulatory T cells
administering_ic: NIAID
award_notice_date: 2008-06-17
opportunity_number: PA-06-181
application_type: 1
activity_code: R21
ic: AI
serial_number: 076956
suffix: A1
program_official: LAPHAM, CHERYL K
project_start_date: 2008-06-17
project_end_date: 2010-05-31
study_section: Gastrointestinal Mucosal Pathobiology Study Section[GMPB]
contact_pi_person_id: 7739669
contact_pi: BONDADA, SUBBARAO
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Studies in animal models have shown that both the adaptive and the innate immune system have a definite role in inducing intestinal inflammation a hallmark of inflammatory bowel diseases (IBD). The Th-1 and Th-17 type T cells have a dominant role in Crohn's disease while the Th-2 type T cells appear to be more important for ulcerative colitis. Studies in the past decade have established the unequivocal role of regulatory T cells (T-Reg) in controlling the development of IBD. The T-regs are a recently discovered subset of CD4+ T cells that have a profound ability to suppress the effector function of helper T cells. They are characterized by expression of a transcription factor Foxp3 and CD25 while being quiescent. In cell transfer models T-Regs have been shown to potently suppress IBD. Yet there have not been any methods to augment the function of regulatory T cells in vivo which could have therapeutic potential. T-Regs express CD5 a cell surface marker present primarily on T cells and a minor subset of B- cells called B-1 cells. Based on our previous work about the negative signaling role of CD5 in B-1 cells we hypothesized that CD5 might negatively regulate TCR signaling in T-reg cells. This predicted that the regulatory function of T-Regs can be augmented in the absence of CD5. Accordingly we have shown that T-Regs from CD5 knockout mice are more effective in suppressing proliferation of CD4+CD25- effector T cells. Moreover our preliminary studies showed that in the dextran sulfate (DSS) induced model of colitis CD5 knockout mice have a milder form of the disease which we hypothesize is due to more effective nTreg function. Our specific aims are:  1. Our goal is to first to demonstrate the increased effectiveness of CD5 deficient T- Regs in an adoptive transfer model that consists in transferring CD45RB+ CD4+ CD25- T-cells into Rag1-/- mice with wild type or CD5 knockout T-Regs. 2. To develop a wild type animal model in which nTreg function can be enhanced. Here we will determine if development of IBD is reduced by inhibiting interaction of CD5 with its ligand using a CD5-Ig fusion protein and/or anti-CD5 antibodies. Since dendritic cells (DC) are known to modulate the development and function of T-Regs and since CD5 has been shown by us to regulate TCR mediated calcium signaling we will test the hypothesis that interaction of DC with T-Regs via CD5 and its ligand CD5L affects T-reg function. 3. To develop an alternate model of colitis to evaluate the role of non T cells in the inreased resistance of CD5-/- mice to colitis induction. PUBLIC HEALTH RELEVACE We have found that CD5 a molecule generally expressed on all T cells decreases regulatory T cell (T-reg) function and that T-Regs from mice in which CD5 is genetically deleted are more potent regulators of immune response. Here we plan to demonstrate that in an in vivo animal model of colitis induced by disease causing T cells the function of T-Regs is regulated by CD5 expression.

project_terms:
5-(6)-carboxyfluorescein diacetate succinimidyl ester;Adoptive Transfer;Affect;Animal Model;Antibodies;Antigen-Presenting Cells;B-Lymphocyte Subsets;B-Lymphocytes;CD4 Positive T Lymphocytes;Calcium Signaling;Cell physiology;Cell surface;Cells;Characteristics;Chimeric Proteins;Colitis;Colon;Crohn's disease;Dendritic Cells;Development;Dextran Sulfate;Disease;Effectiveness;Genus Cola;Goals;Helper-Inducer T-Lymphocyte;Human;IL2RA gene;Immune;Immune response;Immune system;Inflammatory;Inflammatory Bowel Diseases;Inflammatory disease of the intestine;Investigation;Knock-out;Label;Ligands;Mediating;Methods;Mice Knockout;Minor;Modeling;Molecular Target;Mus;Rag1 Mouse;Receptor Signaling;Resistance;Role;Signal Transduction;Sulfonic Acids;T-Cell Receptor;T-Lymphocyte;TCR Activation;Testing;Therapeutic;Trinitrobenzenes;Ulcerative Colitis;Work;base;day;in vivo;novel therapeutics;public health medicine (field);transcription factor


application_id: 7471729
project_number: 3R01HL071010-05A1S1
project_title: Mechanism of Vascular Remodeling in Hyperhomocysteinemia
administering_ic: NHLBI
award_notice_date: 2007-07-19
application_type: 3
activity_code: R01
ic: HL
serial_number: 071010
suffix: A1S1
program_official: SRINIVAS, POTHUR R
project_start_date: 2002-06-01
project_end_date: 2011-03-31
study_section: Vascular Cell and Molecular Biology Study Section[VCMB]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Elevated plasma levels of homocysteine (Hey) known as hyperhomocysteinemia (HHcy) cause vasculardisease. The long-term objective of this project is to understand the mechanism of vascular remodeling inHHcy. Studies from the previous funding period showed that there is an inverse relationship between plasmaHey and levels of peroxisome proliferators activated receptor (PPAR) a nuclear receptor which amelioratesvascular endothelial dysfunction. The central hypothesis of this competitive renewal application is thatHey decreases thioredoxin peroxiredoxin increases NADH oxidase mtNOS activity and reactive oxygenspecies (ROS) in mitochondria in a gene dose-dependent manner. ROS transduces metalloproteinaseactivation causing thickening (fibrosis) of the basement membrane rendering ineffective endothelial nitricoxide synthase (eNOS) and promotes endothelial-smooth muscle disconnection/uncoupling by antagonizingPPARy activity. The specific aims to address the central hypothesis are as following: Specific Aim #1: Todetermine whether by rendering ineffective PPARy Hey decreases mitochondrial thioredoxin peroxiredoxinincreases NADH oxidase mtNOS activity and ROS. The PPARy agonist ciglitazone will be administered towild type (WT) cystathione (3 synthase (CBS) knockout heterozygote and homozygote (i.e. CBS +/+ CBS -/+ and CBS -/-)PPARy-/+ iNOS-/- p47-/- MMP-9-/- and double knockout mice. Aortic PPARy activity willbe measured by EMSA. Levels of mitochondrial ROS will be measured using 2 7-dichlorofluorescein incontinuous assay. Peroxiredoxin thioredoxin and NADH oxidase will be measured in situ by Western blotand RT-PCR analyses. Specific Aim #2: To determine whether Hey increases metalloproteinase activitydecreases the elastin/collagen ratio and causes fibrosis by antagonizing PPARy. Metalloproteinase TIMPelastin and collagen will be measured in situ by novel 2-D zymography reverse-zymography real-time RT-PCR and Western blot analysis. Specific Aim #3: To determine whether Hey attenuates vascular function byincreasing iNOS and rendering eNOS ineffective by antagonizing PPARy. Aortic contractile response will bemeasured. The novelty of this proposal is that it elucidates the mitochondrial mechanism of oxidative stressand vascular remodeling by Hey. This study will provide new insights into the mechanism of arterialremodeling and will have therapeutic ramifications for vessel wall disease.

project_terms:
3-nitrotyrosine;9-deoxy-delta-9-prostaglandin D2;AKAP13 protein human;Abbreviations;Acetylcholine;Address;Agonist;Aorta;Arachidonic Acids;Attenuated;Basement membrane;Biological Assay;Blood Vessels;Blood flow;Blotting Western;Bradykinin;Breeding;Caliber;Collagen;Cystathionine;Disease;Disintegrins;Dose;EMSA;Eicosatrienoic Acid;Elastin;Electrodes;Endothelin-1;Extracellular Matrix;Fibrosis;Fluorescein;Fluoresceins;Functional disorder;Funding;Gelatin;Gelatinase A;Gelatinase B;Genes;Genetic;Goals;Heterozygote;Homo;Homocysteine;Homocystine;Homozygote;Hydroxyeicosatetraenoic Acids;Hyperhomocysteinemia;In Situ;Knock-out;Leukotriene B4;Matrix Metalloproteinases;Measures;Mediating;Metalloproteases;Mice Knockout;Mitochondria;Mus;Myocytes Smooth Muscle;NADH;NADH oxidase;NF-kappa B;NG-Nitroarginine Methyl Ester;NOS3 protein human;Nicotinamide adenine dinucleotide;Nitric Oxide;Nitroprusside;Nuclear;Nuclear Receptors;Oxidation-Reduction;Oxidative Stress;Peroxisome Proliferator-Activated Receptors;Plasma;Polymerase Chain Reaction;Pressure- physical agent;Proteomics;Purpose;RXR;Reactive Oxygen Species;Research Personnel;Reverse Transcriptase Polymerase Chain Reaction;Role;Smc1l1 protein mouse;Smc1l2 protein mouse;Smooth muscle (tissue);Stress;Structure;Superoxide Dismutase;Therapeutic;Thick;Thioredoxin;Time;Tissue Inhibitor of Metalloproteinase-1;Tissue Inhibitor of Metalloproteinases;Tissues;Vascular Diseases;Vascular remodeling;arginine methyl ester;arterial remodeling;ciglitazone;ciprofibrate;in vivo;insight;mouse model;novel;peroxiredoxin;response;tetrahydrobiopterin;tissue inhibitor of metalloproteinase 4;vascular endothelial dysfunction;vasoactive agent


application_id: 7471366
project_number: 5R01HL063763-08
project_title: SR-BI and SR-BII recycling and selective lipid uptake
administering_ic: NHLBI
award_notice_date: 2008-07-03
application_type: 5
activity_code: R01
ic: HL
serial_number: 063763
program_official: SRINIVAS, POTHUR R
project_start_date: 2000-09-15
project_end_date: 2009-07-31
study_section: Integrative Nutrition and Metabolic Processes Study Section[INMP]
contact_pi_person_id: 7875298
contact_pi: VAN DER WESTHUYZEN, DENEYS REM
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: 2008-08-01
project_abstract:
DESCRIPTION (provided by applicant): HDL levels are inversely related to coronary artery disease. The HDL receptor SR-BI plays a key role in HDL metabolism. SR-BI binds HDL and mediates the process known as selective lipid uptake the mechanism of which is not understood. Various studies have indicated that selective uptake by SR-BI in certain cells occurs at the cell surface by a non-endocytic process. However recent studies have reported that in hepatocytes SR-BI mediates the internalization of intact HDL particles and suggest that selective lipid uptake involves HDL internalization and recycling in cells. We have shown that SR-BII a variant of SR-BI differs markedly from SR-BI in its cellular trafficking and endocytosis of HDL. The central hypothesis of this proposal is that the functions of SR-BI and SR-BII in intracellular cholesterol trafficking are coupled to receptor/ligand recycling in cells and that SR-BI and SR-BII follow different internalization and recycling routes and differentially affect cellular cholesterol trafficking and regulation. The specific aims are: 1) determine the contribution of HDL internalization and intracellular recycling to the selective lipid uptake process mediated by SR-BI and SR-BII. HDL recycling by each of the two receptors will be quantified in hepatocytes and other cells 2) elucidate the mechanisms responsible for HDL internalization and recycling by SR-BI and SR-BII. Endocytic and recycling pathway(s) used by SR-BI and SR-BII will be studied and protein motifs in the C-terminal tails of SR-BI and SR-BII that are responsible for receptor targeting will be identified 3) determine how differences in the intracellular targeting of HDL by SR-BI and SR-BII influence cellular cholesterol regulation and trafficking. We will determine the effects of selective lipid uptake via SR-BI and SR-BII on the pool of regulatory sterols in cells and on cholesterol efflux and 4) assess the roles of SR-BI and SR-BII in HDL metabolism and atherogenesis in vivo using isoform-specific knock-in mice. Isoform-specific knock-in mice will be generated and the effects of each receptor on plasma lipoproteins HDL metabolism and atherogenesis studied.

project_terms:
Accounting;Affect;Amino Acid Motifs;Atherosclerosis;Binding (Molecular Function);C-terminal;Catabolism;Caveolae;Cell surface;Cells;Cholesterol;Cholesterol Esters;Cholesterol Homeostasis;Coronary Arteriosclerosis;Coupled;Cytoplasmic Tail;Development;Endocytosis;Epidemiologic Studies;Extrahepatic;HDL receptor;Hepatic;Hepatocyte;High Density Lipoprotein Cholesterol;High Density Lipoproteins;Incidence;Knock-in Mouse;Ligands;Lipids;Lipoproteins;Liver;Localized;Low Density Lipoprotein oxidation;Mediating;Metabolism;Microscopy Fluorescence;Not Defined;Pathway interactions;Plasma;Play;Process;Protein Isoforms;Proteins;Rate;Recycling;Regulation;Reporting;Research Personnel;Role;Route;SR-B proteins;Sterols;Tail;Tissues;Variant;atherogenesis;cholesterol trafficking;in vivo;particle;polarized cell;programs;protective effect;receptor;receptor internalization;reverse cholesterol transport;trafficking;uptake


application_id: 7470388
project_number: 1R21EY018112-01A1
project_title: Temporal and Spatial patterns of structural proteins in extraocular muscles
administering_ic: NEI
award_notice_date: 2008-09-18
opportunity_number: PA-06-181
application_type: 1
activity_code: R21
ic: EY
serial_number: 018112
suffix: A1
program_official: ARAJ, HOUMAM H
project_start_date: 2008-09-30
project_end_date: 2010-07-31
study_section: Special Emphasis Panel[ZRG1 MOSS-L (07)]
contact_pi_person_id: 7875119
contact_pi: MONCMAN, CAROLE L.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Extraocular muscles (EOM) although classified as skeletal muscle are unique in their developmental origin developmental pattern of myosin heavy chain (MyHC) protein isoform expression and patterns of innervation. Interestingly EOM are spared in many of the devastating muscular dystrophies that affect the peripheral skeletal muscle such as Duchenne's and limb girdle muscular dystrophies and on the other hand are specifically targeted in oculopharyngeal muscular dystrophy and myasthenia gravis. The hypothesis driving this proposal is that the unique nature of the myogenesis myofibrillogenesis and maturation of the EOM provide the mechanisms for enhanced plasticity and regenerative properties. The EOM undergo a different developmental path than the somite derived skeletal muscles and therefore are affected by different signaling pathsways. Gene expression profiling of EOM have implicated the presence of both cardiac and skeletal muscle isoforms of myofibrillar and cytoskeletal mRNAs; however with the notable exceptions of MyHC and myomesin there is little biochemical data to substantiate these data. A major goal of this exploratory project as outlined in the specific aims is to evaluate the end products in these signaling pathways in the form of the cytoskeletal myofibrillar and ECM proteins expressed in the developing and adult EOM and compare these protein distributions to prototypic fast muscle (both adult and developing) such as the EDL. We will use biochemical and immunological tools to examine the expression patterns of the myofibrillar cytoskeletal and extracellular matrix of EOMs. This new information on the proteins that integrate the structural support and contractile elements of the developing and mature EOMs will yield insights into how this novel adult phenotype is established and should add to our understanding of how it is disrupted in strabismus.  PUBLIC HEALTH RELEVENCE: The selective sparing of the extraocular muscle in Duchenne's muscular dystrophy demonstrates the unique nature of the extraocular muscle and suggests that important insights into devastating muscular disease can be learned by studying this muscle. Information gained in this analysis may pave the road for the development of new therapeutic treatments for both eye muscle diseases and peripheral skeletal muscle diseases.

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


application_id: 7470333
project_number: 1R21DE017378-01A2
project_title: Oral H. pylori Prevalence in Intellectually/Developmentally Disabled Adults
administering_ic: NIDCR
award_notice_date: 2008-06-28
opportunity_number: PAR-06-246
application_type: 1
activity_code: R21
ic: DE
serial_number: 017378
suffix: A2
program_official: NOWJACK-RAYMER, RUTH
project_start_date: 2008-07-01
project_end_date: 2010-06-30
study_section: Special Emphasis Panel[ZDE1 SK (07)]
contact_pi_person_id: 7034912
contact_pi: BINKLEY, CATHERINE J
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Helicobacter pylori (H. pylori) bacteria play a significant role in the etiology of gastric and duodenal ulcers gastro-esophageal reflux disease and gastric adenocarcinoma. Intellectually disabled/developmentally disabled (ID/DD) adults are reported to have H. pylori infection at approximately twice the rate of the general population and experience recurrence at a seven-fold higher rate contributing to increased mortality due to gastric cancer. The oral cavity may serve as a reservoir for H. pylori and subsequently contribute to the recurrence of gastric infection. Numerous studies have identified H. pylori in dental plaque an environment that is relatively resistant to systemic antibiotics. Systemic antibiotics are used to treat H. pylori infections but do not appear to eradicate H. pylori in the mouth. The oral status of ID/DD adults is reported to be poor due to inadequate oral hygiene leading to increased plaque caries and periodontal disease. Furthermore poor oral status (periodontal disease) has been associated with H. pylori seropositivity. While ID/DD adults have elevated rates of H. pylori gastric infections nothing is known about the prevalence of H. pylori in their oral cavities. The proposed exploratory research will address the following questions in this disadvantaged population: 1) What is the prevalence of H. pylori in the dental plaque in ID/DD adults? 2) Is poor oral status associated with H. pylori gastric infection? and 3) Does H. pylori persist in the dental plaque of ID/DD adults after systemic antibiotic treatment and if so is it associated with recurrence of gastric infection? This epidemiological study of 112 institutionalized ID/DD and 112 control subjects will involve oral examinations indices dental plaque sampling and C13 Urea Breath Tests at baseline to determine prevalence. Nested Polymerase Chain Reaction (PCR) analyses will be used to detect H. pylori in the dental plaque. For those ID/DD subjects who have a positive gastric H. pylori test at baseline repeated oral sampling and gastric tests will be performed over 1 year to determine persistence. If poor oral health status and oral H. pylori prevalence are correlated with gastric H. pylori infections a future pilot clinical trial will be conducted to investigate the concordance between genetic strains of H. pylori in the mouth and stomach the effect of various interventions on oral health oral H. pylori prevalence and H. pylori gastric infections in ID/DD adults. The proposed research responds to the Surgeon General's National Call to Action to conduct studies to elucidate underlying mechanisms and determine any causal associations between oral infections and systemic conditions. The proposed research also addresses the need to reduce health disparities improve quality of life and reduce morbidity and mortality in vulnerable populations. Project Narrative: Helicobacter pylori infections are a significant cause of morbidity in institutionalized intellectually and developmentally disabled (ID/DD) persons in the United States. There is reason to investigate whether there is an association between oral health and H. pylori infection and recurrence of H. pylori infection in ID/DD individuals. The proposed study would provide pilot data for a clinical trial and add to the knowledge concerning oral status and H. pylori infection. Our results may demonstrate that professional oral care is medically necessary for the reduction of morbidity and mortality caused by H. pylori infection in ID/DD persons. This research is consistent with the Healthy People 2010 overarching goal of eliminating health disparities. It is also consistent with the Surgeon General's National Call to Action to determine oral health care needs refine protocols of care for special needs patients and to conduct studies to determine associations between oral infections and systemic conditions.

project_terms:
Accounting;Address;Adult;Aftercare;Antibiotic Therapy;Antibiotics;Bacteria;Biological Assay;Breath Tests;Caregivers;Caring;Cessation of life;Clinical Research;Clinical Trials;Condition;Data;Dental Clinics;Dental Hygiene;Dental Plaque;Dental Plaque Index;Dental caries;Development;Disabled Persons;Disadvantaged;Disease;Duodenal Ulcer;Environment;Epidemiologic Studies;Etiology;Exploratory/Developmental Grant;Foundations;Frequencies (time pattern);Future;Gastric Adenocarcinoma;Gastroesophageal reflux disease;General Population;Genotype;Goals;Habits;Health Policy;Health Status;Healthy People 2010;Helicobacter Infections;Helicobacter pylori;Incidence;Individual;Infection;Intervention;Intestinal Diseases;Knowledge;Malignant Neoplasms;Malignant neoplasm of stomach;Morbidity - disease rate;Mortality Vital Statistics;Nested PCR;Oral;Oral Examination;Oral Hygiene Index;Oral cavity;Oral health;Patients;Pattern;Periodontal Diseases;Play;Polymerase Chain Reaction;Population;Prevalence;Preventive;Protocols documentation;Pylorus;Quality of life;Rate;Recurrence;Reporting;Research;Resistance;Risk;Risk Factors;Role;Route;Sampling;Site;Standards of Weights and Measures;Stomach;Stomach Carcinoma;Stomach Diseases;Surgeon;Testing;Tooth structure;United States;Urea;Vulnerable Populations;Week;day;developmentally disabled;experience;genetic strain;health disparity;improved;medically necessary care;oral care;oral infection;oral status


application_id: 7469962
project_number: 5R01MH074865-02
project_title: BE-ACTIV: Treating Depression in Nursing Homes
administering_ic: NIMH
award_notice_date: 2008-06-18
application_type: 5
activity_code: R01
ic: MH
serial_number: 074865
program_official: ROWLAND, LAURA
project_start_date: 2007-07-14
project_end_date: 2012-06-30
study_section: Interventions Committee for Disorders Related to Schizophrenia, Late Life, or Personality[ITSP]
contact_pi_person_id: 1908020
contact_pi: MEEKS, SUZANNE
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_terms:
Affect;Attention;Behavior Therapy;Behavioral;Cognitive;Collaborations;Communities;Comorbidity;Condition;Data;Dementia;Depressed mood;Depressive disorder;Diagnosis;Diagnostic;Discipline of Nursing;Elderly;Epidemiology;Evaluation;Event;Face;Foundations;Goals;Health;Individual;Institution;Intervention;Interview;Interviewer;Link;Manuals;Measures;Mediating;Mental Depression;Mental Health;Modeling;Moods;Nursing Homes;Outcome;Outcome Measure;Outpatients;Participant;Patient Self-Report;Phase;Population;Problem behavior;Process;Process Measure;Purpose;Randomized;Rate;Recovery;Reinforcements Positive;Research;Research Personnel;Risk;Score;Social Functioning;Structure;Symptoms;Testing;Theoretical model;base;blind;depressive symptoms;design;follow-up;health practice;intervention program;member;minor depressive disorder;programs;public health medicine (field);response;satisfaction;social;theories


application_id: 7469422
project_number: 5K01DA021309-02
project_title: Rural Drug Abuse Treatment: Organizations Counselors and Client Outcomes
administering_ic: NIDA
award_notice_date: 2008-06-18
opportunity_number: PA-06-001
application_type: 5
activity_code: K01
ic: DA
serial_number: 021309
program_official: JONES, DIONNE
project_start_date: 2007-07-15
project_end_date: 2012-06-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 6264981
contact_pi: OSER, CARRIE BETH
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Administrator;Adoption;Age;Alcohol or Other Drugs use;Area;Attention;Belief;Censuses;Characteristics;Client;Climate;Clinical;Commit;Communities;County;Development;Drug abuse;Education Professional;Educational aspects;Emotional;Employment;Environment;Evaluation Studies;Funding;Future;Goals;Grants Applications;Institutes;Instruction;Intention;Justice Criminal;Knowledge;Lateral;Linear Models;Literature;Mental Health;Methodology Research;Modeling;Motivation;National Institute of Drug Abuse;Organizational Change;Outcome;Patient Self-Report;Perception;Pharmaceutical Preparations;Pharmacological Treatment;Pressure- physical agent;Principal Investigator;Professional counselor;Qualitative Research;Recording of previous events;Recovery;Reporting;Research;Research Personnel;Resources;Rural;Rural Community;Services;Site;Status Employment;Structure;Substance abuse problem;Substance of Abuse;System;Techniques;Therapeutic;Training;Training Activity;Training and Education;Treatment outcome;Work;base;career;contextual factors;data collection methodology;demographics;exhaustion;experience;follow-up;health care service utilization;improved;innovation;metropolitan;organizational structure;practical application;programs;psychologic;rural area;size;skills;treatment organization;treatment program;urban area


application_id: 7468350
project_number: 5K23NR010011-03
project_title: Impact of Family Distress and Burden on Patients Outcomes in Heart Failure
administering_ic: NINR
award_notice_date: 2008-07-29
opportunity_number: PA-05-143
application_type: 5
activity_code: K23
ic: NR
serial_number: 010011
program_official: HUSS, KAREN
project_start_date: 2006-08-09
project_end_date: 2009-07-31
study_section: Nursing Science Review Committee[NRRC(35)]
contact_pi_person_id: 8446344
contact_pi: CHUNG, MISOOK LEE
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
project_abstract:
DESCRIPTION (provided by applicant): In the 1990s heart failure (HF) emerged as a significant public health threat and reached epidemic proportions. As the population of patients with HF increases millions of family members will become informal caregivers for these patients and provide a central source of support in patients' self-care. Researchers have suggested that support from family or significant others can have a positive impact on patients' outcomes including quality of life morbidity and mortality. However family members can suffer significant stress related to their caregiving and support roles. As a consequence family members often experience emotional distress (i.e. depression and anxiety). In the inevitable interactions between patients and family caregivers in the HF self-care process a family caregiver's emotional distress and perceived burden may be transmitted to the patient. It has been reported that HF patients and family caregivers have similar levels of emotional distress. However it is not known whether family caregiver distress and perceptions of burden. Contribute to patients' poor emotional well-being quality of life morbidity and mortality. In the very limited cross-sectional studies in this area family caregiver emotional distress was associated with patient quality of life. However the longitudinal effects of family caregivers' perceived burden and emotional distress on patients' clinical mortality and morbidity outcomes are unknown. The purpose of this longitudinal study is to examine the impact of family caregivers' psychological distress on quality of life and physical health outcomes of adults with HF. A total of 180 HF patient-family dyads will complete questionnaires about emotional distress caregiver burden and quality of life. Patients will be followed for one year to collect rehospitalization and mortality data. The candidate has an interest in (1) understanding the relationship between family caregiver patient psychological factors (i.e. depression and anxiety) and HF patient outcomes; (2) and developing family-based interventions to improve outcomes in patients with chronic cardiovascular illnesses. This grant will allow the candidate to obtain advanced knowledge about patient-family dynamics and psychological distress and receive the training necessary for the longitudinal clinical outcome study and the training to develop family intervention programs.

project_terms:
Acute;Adult;Age;Anxiety;Area;Cardiac;Cardiovascular system;Caregiver Burden;Caregivers;Caring;Cessation of life;Characteristics;Chronic;Chronic Disease;Class;Clinical;Cohort Studies;Comorbidity;Condition;Cross-Sectional Studies;Data;Disease Management;Distress;EFRAC;Emotional;End Point;Epidemic;Event;Exhibits;Factors Psychological;Family;Family Caregiver;Family dynamics;Family member;Gender;Grant;Health;Heart Diseases;Heart failure;Hospitalization;Hospitals;Housing;Incidence;Individual;Intervention;Investigation;Knowledge;Living Wills;Longitudinal Studies;Measures;Mental Depression;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Numbers;Outcome;Patients;Perception;Persons;Pharmaceutical Preparations;Population;Prevalence;Process;Purpose;Quality of life;Questionnaires;Rate;Recovery;Reporting;Research;Research Personnel;Risk;Risk Factors;Role;Score;Self Care;Services;Source;Stress;Study Outcome;Subgroup;Symptoms;Time;Training;Well in self;base;care giving burden;caregiving;cost;depressive symptoms;emotional distress;experience;follow-up;functional status;improved;instrument;instrumental activity of daily living;interest;intervention program;programs;psychological distress;psychological outcomes;public health medicine (field)


application_id: 7468277
project_number: 3R01AA014371-04S1
project_title: Mechanisms of Alcohol-Induced Immunosuppression
administering_ic: NIAAA
award_notice_date: 2007-07-13
application_type: 3
activity_code: R01
ic: AA
serial_number: 014371
suffix: S1
program_official: JUNG, KATHY
project_start_date: 2004-09-01
project_end_date: 2009-06-30
study_section: Special Emphasis Panel[ZRG1-DIG-F(02)M]
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Alcohol abuse imposes a heavy burden on the U.S. health care system. Immune dysfunction associated with chronic alcohol abuse is linked to increased clinical morbidity such as infectious diseases and neoplasia. A critical factor in the alcohol abuse associated immune impairment is the loss of CD4+ T lymphocytes. Based on our substantial preliminary data we hypothesize that a decrease in S-adenosylmethionine (SAMe) caused by ethanol-induced inhibition of methionine adenosyl transferase (MAT2A) enhances the susceptibilityof CD4+ T-cells to Fas- and activation (T cell receptor - TCR) - mediated apoptotic death. To test this hypothesis we will examine the effect of ethanol on PBMCs/CD4+ T-cells obtained from alcoholic patients and abstinent healthy control subjects. The overall goals of this proposal are: (i) to elucidate the molecular mechanisms underlying ethanol mediated depletion of CD4+ T lymphocytes and ensuing immune dysfunction and (ii) to provide a basis for clinically relevant paradigms for the development of potential therapeutic intervention(s) using S-adenosylmethionine (SAMe) in alcoholic patients. Accordingly the effects of ethanol on Fas- and TCR-induced apototic signaling components will be determined. We will perform systematic analyses of the effects of ethanol on MAT2A gene expression and activity and SAMe levels in CD4+ T-cells in order to determine the relevance of MAT2A and SAMe asmolecular targets of ethanol-induced CD4+ T-cell toxicity. We will also determine the efficacy of exogenousSAMe supplementation in attenuating CD4+ T-cell death induced by ethanol. Overall we expect our studiesto elucidate critical molecular mechanisms underlying CD4+ T-cell depletion associated with chronic atcohol abuse. Moreover the data from these studies would support our future goals by providing a basis for relevant clinical paradigms for the development of potential therapeutic intervention(s) for alcoholic patients.

project_terms:
Activities of Daily Living;Alcohol abuse;Alcohols;Apoptosis;Apoptotic;Attenuated;CD4 Positive T Lymphocytes;Cell Death;Cells;Cessation of life;Chronic;Classification;Clinical;Clinical Research;Communicable Diseases;Data;Development;Dose;Ethanol;Figs - dietary;Functional disorder;Future;Gene Expression;Goals;Healthcare Systems;Hepatic;Immune;Immune System Diseases;Immune system;Immunity;Impairment;Infection;Investigation;Link;Malignant Neoplasms;Mediating;Metabolism;Methionine;Molecular;Molecular Target;Morbidity - disease rate;Natural immunosuppression;Neoplasms;Numbers;Patients;Play;Population;Predisposing Factor;Predisposition;Signal Transduction;Supplementation;T-Cell Activation;T-Cell Depletion;T-Cell Receptor;T-Lymphocyte;Testing;Therapeutic Intervention;Therapeutic immunosuppression;Time;Toxic effect;Transferase;Upper arm;alcohol effect;base;caspase-3;clinically relevant;immunotoxicity;peripheral blood;prevent;problem drinker


application_id: 7468129
project_number: 1R01HL089939-01A1
project_title: Organ protection during cardiopulmonary arrest
administering_ic: NHLBI
award_notice_date: 2008-04-17
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: HL
serial_number: 089939
suffix: A1
program_official: LIANG, ISABELLA Y
project_start_date: 2008-05-01
project_end_date: 2012-03-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 7035773
contact_pi: DAWN, BUDDHADEB
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  No intervention is currently available to prevent the consequences of organ damage associated with cardiopulmonary arrest. While the protective effects of preconditioning (PC) during regional ischemic injury to several organs have been well-documented it remains unknown whether this phenomenon can be utilized to improve the outcome following cardiac arrest. The overall objective of this proposal is to evaluate the efficacy of physiologic and pharmacologic late PC-mimetic interventions in preventing cardiac and neuronal injury during cardiopulmonary arrest. Our fundamental hypothesis is that the heart and brain can be preconditioned to tolerate the ischemic injury during cardiac arrest by using clinically-feasible PC-mimetic interventions that can be given prophylactically to patients at risk for cardiopulmonary arrest. Specifically we will test the hypothesis that exposure to exercise adenosine A1 receptor agonists opioid ?1 receptor agonists and NO donors induces delayed antistunning and antiapoptotic effects that result in improved outcome following cardiopulmonary arrest and that these salubrious effects are mediated by a coordinated upregulation of iNOS COX-2 and HO-1. This study will utilize a broad multidisciplinary approach that will involve integrative physiology protein chemistry molecular biology and gene targeting. All studies will be carried out in a well-characterized mouse model of cardiac arrest using genetically-engineered animals which will provide conclusive information. In Aim 1 the efficacy of exercise CCPA TAN-67 and DETA/NO in conferring protection during cardiac arrest will be carefully characterized and the mechanism of the antiapoptotic effects will be elucidated. Aim 2 will investigate the role of iNOS in organ protection during cardiopulmonary arrest. Both iNOS-/- and iNOS transgenic mice will be used to determine whether iNOS is necessary and sufficient to confer protection. In Aim 3 the beneficial role of COX-2 will be conclusively established by genetic ablation and pharmacologic inhibition. Aim 4 will elucidate the role of HO-1 as a co-mediator of protection using HO-1-/- mice and HO-1 transgenic mice. Aim 5 will determine the utility of adenovirus-mediated gene transfer of iNOS COX-2 and HO-1 in recapitulating the beneficial effects. This proposal will yield new and important information regarding the role of clinically-relevant agents in inducing protection against a devastating and common health problem. This information may eventually lead to the development of novel therapeutic strategies to save human lives.  PUBLIC HEALTH RELEVANCE Approximately 500000 Americans are affected by cardiopulmonary arrest every year. Despite decades of research the survival and prognosis after cardiac arrest remain dismal. Although the phenomenon of preconditioning (PC) has been shown to protect various organs during ischemic injury its role in cardiac arrest remains unclear. The primary goal of this proposal is to examine whether PC-mimetic physiologic and pharmacologic interventions can protect against cardiac and neurologic injury sustained during cardiac arrest. These results would have enormous therapeutic implications for patients with cardiac arrest. The results of the proposed studies will therefore be highly relevant for improving public health and improving the length and quality of life of thousands of patients with cardiac arrest.

project_terms:
Abbreviations;Ablation;Adenosine;Adenosine A1 Receptor;Adenoviruses;Affect;Agonist;American;Animals;Apoptosis;Arrest Cardiopulmonary;Blood Circulation;Brain;Cardiac;Cardiopulmonary;Clinical Research;Development;Dose;Effectiveness of Interventions;Endothelial Cells;Engineering;Exercise;Exposure to;Female;Forecast of outcome;Gene Targeting;Gene Transfer;Genetic;Goals;Health;Heart;Heart Arrest;Heart Failure Congestive;Heme Oxygenase (Decyclizing);Human;Inhibition of Apoptosis;Injury;Intervention;Intestines;Ischemia;Ischemic Preconditioning;Kidney;Lead;Left;Length;Life;Mediating;Mediator of activation protein;Mice Transgenic;Molecular Biology;Mortality Vital Statistics;Mus;Muscle;Myocardial;Myocardial Ischemia;Myocardium;Myocytes Cardiac;NOS2A protein human;NS-398;Neurologic;Neuronal Injury;Nitric Oxide;Opioid;Organ;Outcome;PTGS2 gene;Pathology;Patients;Personal Satisfaction;Phase;Physiological;Physiology;Pressure- physical agent;Protein Chemistry;Protein Overexpression;Quality of life;Reactive Oxygen Species;Recovery;Research;Risk;Role;Stress;Testing;Therapeutic;Time;Transgenic Organisms;Up-Regulation (Physiology);Ventricular;Ventricular Fibrillation;celecoxib;clinically relevant;cyclooxygenase 2;experience;gene therapy;improved;inhibitor/antagonist;interdisciplinary approach;mimetics;mouse model;neuron apoptosis;novel;novel therapeutics;preconditioning;prevent;protective effect;public health medicine (field);receptor;response


application_id: 7468128
project_number: 1R01HL087039-01A2
project_title: Delayed Rectifier K Channel Biogenesis is Unveiled in Models of Long QT Syndrome
administering_ic: NHLBI
award_notice_date: 2008-04-11
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: HL
serial_number: 087039
suffix: A2
program_official: WANG, LAN-HSIANG
project_start_date: 2008-04-15
project_end_date: 2013-03-31
study_section: Electrical Signaling, Ion Transport, and Arrhythmias Study Section[ESTA]
contact_pi_person_id: 7001509
contact_pi: DELISLE, BRIAN P
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Action Potentials;Affect;Arrhythmia;Biochemical;Biogenesis;Cardiac;Cell surface;Cells;Complex;Data;Death Sudden Cardiac;Degradation Pathway;Depth;Disease;Endoplasmic Reticulum;Environment;Ether Ethyl;Ethers;Gene-Modified;Genes;Genetic;Genotype;Goals;Health;Heart;Heart Diseases;Human;Imaging Techniques;Inherited;Intracellular Transport;Link;Long QT Syndrome;Mammalian Cell;Membrane;Modeling;Molecular;Molecular Chaperones;Mutation;Mutation Missense;Numbers;Palpitations;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Phenotype;Potassium Channel;Property;Purpose;Quality Control;Rare Diseases;Research;Seizures;Syncope;Syndrome;Testing;Therapeutic;Transport Vesicles;Voltage-Gated Potassium Channel;cytotoxic;intracellular protein transport;loss of function;novel;novel therapeutics;prevent;protein folding;protein misfolding;public health medicine (field);therapeutic target;trafficking


application_id: 7467389
project_number: 5R21DE017706-02
project_title: Oral Chlorhexidine effect on ICU mortality and ventilator-associated pneumonia
administering_ic: NIDCR
award_notice_date: 2008-05-29
opportunity_number: PAR-06-245
application_type: 5
activity_code: R21
ic: DE
serial_number: 017706
program_official: ATKINSON, JANE C
project_start_date: 2007-07-10
project_end_date: 2010-06-30
study_section: ZDE1-LK(28)
contact_pi_person_id: 7034912
contact_pi: BINKLEY, CATHERINE J
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Nosocomial pneumonia is the second most common hospital-acquired infection and most common intensive care unit infection. It is associated with significant morbidity and mortality. Aspiration of oropharyngeal contents is considered a major risk factor for pneumonia especially in mechanically ventilated patients. Whether application of oral antimicrobial agents such as chlorhexidine reduces the risk of pneumonia in the general intensive care unit patient population remains controversial. The proposed Phase III clinical trial will be a five-year four-center placebo-controlled randomized clinical trial with a chlorhexidine oral application as the intervention. The research will extend previous findings in a general ICU population study sample by using well-validated clinical and scoring criteria for major outcomes. The proposed trial will be powered to evaluate a composite primary outcome of ventilator-associated pneumonia (VAP) and/or mortality with 535 patients in the control group and 535 patients in the intervention group. A 2 year planning grant is requested to refine the study design and methodology develop a Manual of Operating Procedures refine patient recruitment approaches organize potential study centers for standardization of approach and diagnostic criteria and establish administrative and monitoring committees. Personnel from the four clinical sites and the data coordinating center will participate in these activities as part of the Clinical Trial Planning Committee. The Phase III clinical trial would be the first outcome study properly powered to evaluate the effect of chlorhexidine oral application on pneumonia and/or mortality and associated morbidity outcomes in mechanically ventilated patients with various indications for ICU admission (including surgical medical and neurological). It may provide evidence for changing health care policy by showing that a simple inexpensive oral care preventive intervention reduces the morbidity mortality and costs associated with nosocomial pneumonia.

project_terms:
Accounting;Address;Admission activity;Alcohols;Aspirate substance;Bacteria;Chlorhexidine;Clinical;Clinical Data;Clinical Trials;Clinical Trials Phase III;Condition;Control Groups;Controlled Clinical Trials;Critical Care;Critical Illness;Data Coordinating Center;Databases;Development;Diagnosis;Diagnostic;Double-Blind Method;Economics;Enrollment;Environmental air flow;General Population;Goals;Grant;Health Care Costs;Health Policy;Health Professional;Hearing;Hospitals;Hour;Human Resources;Incidence;Infection;Intensive Care Units;Intervention;Irrigation;Laboratories;Lead;Legal;Length;Length of Stay;Logistics;Lung;Manuals;Measures;Mechanical ventilation;Medical;Medical center;Methodology;Microscopy;Monitor;Morbidity - disease rate;Mortality Vital Statistics;Mouthwash;Multi-Drug Resistance;Multi-Institutional Clinical Trial;Neurologic;Nosocomial Infections;Nosocomial pneumonia;Operative Surgical Procedures;Oral;Oral cavity;Oropharyngeal;Outcome;Patients;Pharmaceutical Preparations;Physicians;Placebo Control;Placebos;Pneumonia;Population;Population Study;Preventive;Preventive Intervention;Procedures;Randomized;Rates Case Fatality;Recruitment Activity;Recruitments Patient;Regression Analysis;Research;Research Career Programs K-Series;Research Design;Research Institute;Research Personnel;Risk;Risk Factors;Sampling;Score;Solutions;Specimen;Sputum;Standardization;Stratification;Structure of parenchyma of lung;Study Outcome;Swab;Testing;Time;Tooth structure;Toothbrushing;Trials Randomized Clinical;United States;United States National Institutes of Health;Upper arm;Ventilator;antimicrobial;antimicrobial drug;chlorhexidine gluconate;clinical research site;cost;cost effectiveness;day;design;disorder control;experience;human disease;oral care;pathogen;prevent;public health medicine (field);respiratory;toothbrush;treatment effect


application_id: 7467343
project_number: 5R01AI069321-02
project_title: Modulation of apoptosis by Legionella Pneumophila
administering_ic: NIAID
award_notice_date: 2008-06-25
application_type: 5
activity_code: R01
ic: AI
serial_number: 069321
program_official: KORPELA, JUKKA K
project_start_date: 2007-07-15
project_end_date: 2012-06-30
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 1877865
contact_pi: ABU KWAIK, YOUSEF A
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_terms:
Abbreviations;Adenylate Cyclase;Apoptosis;Apoptotic;Biochemical;Biogenesis;Biological Models;Biology;Caspase Inhibitor;Cell physiology;Cells;Cellular biology;Co-Immunoprecipitations;Disease;Early Endosome;Endoplasmic Reticulum;Ensure;Golgi Apparatus;Human;Infection;Knowledge;Lead;Legionella;Legionella pneumophila;Life Style;Light;Mediating;Molecular;Nuclear;Organism;Pan Genus;Pathway interactions;Peptides;Phagolysosome;Phagosomes;Preservation Biological;Prevention therapy;Process;Proteins;RNA Interference;RNA Small Interfering;Role;Staging;Testing;Type IV Secretion System Pathway;Vesicle;caspase-3;clinical application;disorder prevention;inhibitor/antagonist;macrophage;monocyte;mutant;novel;pathogen;programs;trafficking


application_id: 7467297
project_number: 5R01DK072032-04
project_title: Podocytes and oxidative stress in diabetic kidney
administering_ic: NIDDK
award_notice_date: 2008-07-16
application_type: 5
activity_code: R01
ic: DK
serial_number: 072032
program_official: NIHALANI, DEEPAK
project_start_date: 2005-09-01
project_end_date: 2010-07-31
study_section: Pathobiology of Kidney Disease Study Section[PBKD]
contact_pi_person_id: 1927079
contact_pi: EPSTEIN, PAUL N
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
project_abstract:
DESCRIPTION (provided by applicant): The single largest cause of end stage renal disease in the United States is diabetic nephropathy (DN). We have recently characterized the progression of DN in a transgenic mouse model of Type I diabetes called OVE26. This model is a significant improvement over previous DN models in that 9 month old OVE26 mice exhibit many characteristics of advanced DN. They show a 100 fold increase in albuminuria extensive interstitial fibrosis and a modest reduction in GFR. We will use this model to assess the role of reactive oxygen species (ROS) in the glomerular podocyte for development of DN. OVE26 mice will also allow us to assess changes in glomerular gene expression by laser capture and Affymetrix gene array analysis during the progression from early DN at two months of age to severe DN at fourteen months of age in OVE26 mice. In addition the severe DN in OVE26 animals will allow us to make the first test of the ability of oral antioxidant therapy to block advance DN.    ROS have been shown to be a critical component of DN. Systemic treatment with antioxidants or ubiquitously expressed antioxidant transgenes protect diabetic animals from early stage DN. However by systemic treatment it is not possible to identify which cells in the glomerulus are injured by ROS or protected by antioxidant treatment. Podocytes are an important candidate cell. They make up a critical component of the selective glomerular filtration membrane and many podocytes are lost during the progression of DN. In addition they have been shown to produce ROS. We developed transgenic mice that use the podocyte selective nephrin promoter to overexpress a transgene for the potent antioxidant protein metaliothionein. We demonstrated elevated podocyte expression of the metaliothionein transgene by immunohistochemistry and western blotting. Mice that overexpress metaliothionein in podocytes were bred to OVE26 Type I diabetic mice. Our initial results demonstrate that podocyte overexpression of metaliothionein dramatically reduces diabetes-induced macroalbuminuria and significantly reduces glomerular hypertrophy. These mice will be used to assess the role of ROS damage to the podocyte in the changing gene expression and deteriorating structure and function that lead to diabetic end stage renal disease.

project_terms:
2266-tetramethyl-4-piperidinol-N-oxyl;Age-Months;Albuminuria;Animals;Antioxidants;Ascorbic Acid;Biological Markers;Blotting Western;Breeding;Cells;Characteristics;Chronic;Clinical;Data;Deterioration;Development;Diabetes Mellitus;Diabetes Mellitus Insulin-Dependent;Diabetic Nephropathy;Diabetic mouse;End stage renal failure;Event;Exhibits;Failure (biologic function);Fibrosis;Gene Expression;Genes;Glomerular Filtration Rate;Human;Hypertrophy;Immunohistochemistry;Inflammation;Injury;Kidney;Lasers;Lead;Light;Lipid Peroxidation;Malondialdehyde;Membrane;Metallothionein;Mice Transgenic;Modeling;Morphology;Mus;Myocytes Cardiac;Nephrons;Numbers;Oligonucleotide Microarrays;Oral;Oxidative Stress;Pancreas;Production;Promotor (Genetics);Protein Overexpression;Proteins;Protocols Treatment;Publishing;RNA;Reactive Oxygen Species;Renal function;Research Personnel;Rodent Model;Role;Source;Staging;Structure;Superoxide Dismutase;Testing;Therapeutic;Thioctic Acid;Transgenes;Transgenic Organisms;Tubular formation;United States;Urine;Weaning;antioxidant therapy;cell injury;cell type;diabetic;glomerular filtration;injured;interstitial;kidney cell;macroalbuminuria;mouse model;nephrin;podocyte;prevent;programs;type I diabetic


application_id: 7466262
project_number: 1R01HL089380-01A1
project_title: Cardioprotective Mechanisms of Glutathione S-transferase P
administering_ic: NHLBI
award_notice_date: 2008-04-11
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: HL
serial_number: 089380
suffix: A1
program_official: SCHWARTZ, LISA
project_start_date: 2008-04-11
project_end_date: 2013-03-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 8767000
contact_pi: CONKLIN, DANIEL JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Ablation;Accounting;Acrolein;Acute;Affect;Affinity;Aldehydes;Antioxidants;Attenuated;Biochemical Pathway;Cardiac;Cardiovascular Physiology;Cardiovascular system;Coronary heart disease;Doctor of Philosophy;Drug resistance;Enzymes;Excision;Foundations;Future;Gender;Genes;Genetic;Glutathione;Glutathione S-Transferase;Glutathione Reduced;Heart;Human;In Situ;Individual;Infarction;Injury;Intervention;Ischemia;Kinetics;Lead;Link;Lipid Peroxidation;MAPK8 gene;Measures;Mediating;Metabolic;Metabolic Detoxication Drug;Metabolic Pathway;Metabolism;Mice Knockout;Mice Transgenic;Modeling;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocytes Cardiac;Natural regeneration;Occlusions Coronary;Oxidative Stress;Pathology;Pathway interactions;Peroxidase;Peroxidases;Peroxides;Phenotype;Physiological reperfusion;Polymorphism Genetic;Population;Predisposition;Principal Investigator;Production;Protein Isoforms;Protein Overexpression;Protein Processing Post-Translational;Proteins;Race;Rate;Reactive Oxygen Species;Relative (related person);Reperfusion Injury;Reperfusion Therapy;Research;Role;Signal Pathway;Signal Transduction;Stress;Sulfenic Acids;Testing;Tissues;Tracer;Transgenic Organisms;Translations;adduct;base;carcinogenesis;cardiovascular disorder risk;detoxication;enzyme substrate;gain of function;heart metabolism;insight;loss of function;novel;oxidized lipid;prevent;programs;protein protein interaction;public health medicine (field);translational study


application_id: 7465567
project_number: 5R01DE017384-02
project_title: Epithelial Cell TLRs in Disease Susceptibility
administering_ic: NIDCR
award_notice_date: 2008-04-25
application_type: 5
activity_code: R01
ic: DE
serial_number: 017384
program_official: LUNSFORD, DWAYNE
project_start_date: 2007-07-09
project_end_date: 2012-05-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7301447
contact_pi: KINANE, DENIS F
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: 2008-06-01
project_abstract:
DESCRIPTION (provided by applicant):  Humans develop gingivitis and periodontitis in response to the challenges produced by microbial dental plaque. Individuals vary in their susceptibility to both gingivitis (superficial inflammation) and periodontitis (extensive inflammation causing bone and tooth loss). The etiology of periodontal disease is not fully understood; however it is accepted that variance in the human host response to microbial plaque will relate to the host's innate inflammatory or immune defense systems. Single nucleotide polymorphisms (SNPs) exist in the human genes encoding many molecules pertinent to the host-microbe interaction. Periodontal inflammation (gingivitis and periodontitis) begins with the perturbation of the epithelial cells by bacteria via receptors including Toll-like Receptors (TLRs). Our preliminary data indicates that the pro-inflammatory cytokines and chemokines produced in response to bacterial and cytokine perturbations differ between individuals and these differences may relate to carriage of a specific TLR4 polymorphism. Our general hypothesis is that individual response characteristics of gingival epithelial cells to foreign challenges relate to their cellular TLR genotype which influences susceptibility to gingivitis and periodontitis. Thus we will address the following aims utilizing multiple primary human gingival epithelial cells (HGECs) clinical studies and genotype and phenotype analyses. The first aim is to characterize molecularly the inter-patient differences in TLR expression in HGECs using qPCR gene expression profiling protein assays and immunoreactivity and to correlate this to the TLR genotype. Secondly functional analysis of genetically- modified HGECs (using siRNA knock-downs and over-expression) will elucidate the role of TLR4 and the Asp299Gly and other SNPs in epithelial LPS hypo-responsiveness. Thirdly we aim to translate this work by determining clinically if TLR4 polymorphisms and hypo-responsiveness correlate with the severity of experimental gingivitis and if they can differentiate periodontitis cases and controls. Finally we aim to challenge HGECs and other cell types monocytes gut epithelia and endothelial cells to assess LPS responsiveness relevant to the etiopathology of TLR4 associated diseases such as inflammatory bowel disease atheroma and asthma. Characterization of response differences and determination of related SNPs may lead to new therapeutics or diagnostics in a range of infectious and inflammatory diseases.

project_terms:
Address;Age;Arterial Fatty Streak;Asthma;Bacteria;Biological Assay;Bone and Bones;CD14 gene;Cells;Characteristics;Chronic;Clinical Research;Complex;DNA;Data;Dental;Dental Plaque;Development;Diagnostic;Disease;Disease susceptibility;Endothelial Cells;Epithelial;Epithelial Cells;Epithelial Receptor Cell;Epithelium;Etiology;Experimental Genetics;Fibroblasts;Gene Expression Profiling;Genes;Genomics;Genotype;Gingiva;Gingivitis;Host Defense;Human;Immune;Immune response;Immune system;Individual;Individual Differences;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Intestines;Lead;Leukocytes;Lipopolysaccharides;Microbe;Molecular;Outcome;Patients;Periodontal Diseases;Periodontitis;Phenotype;Play;Polymorphism Genetic;Porphyromonas gingivalis;Predisposition;Primary Cell Cultures;Proteins;RNA Interference;RNA Messenger;RNA Small Interfering;Range;Reporting;Research Personnel;Resistance;Risk;Role;Severities;Signaling Molecule;Single Nucleotide Polymorphism;System;Systemic disease;TLR4 gene;Testing;Therapeutic;Toll-like receptors;Tooth Loss;Transfection;Translating;Variant;Vascular Endothelial Cell;Work;case control;cell type;chemokine;cytokine;gastrointestinal epithelium;immunoreactivity;knock-down;microbial;monocyte;novel therapeutics;pathogen;programs;receptor;receptor expression;receptor function;response;sex


application_id: 7465455
project_number: 5R01CA116428-04
project_title: Targeting of 6-Phosphofructo-2 kinase in Cancer
administering_ic: NCI
award_notice_date: 2008-05-09
application_type: 5
activity_code: R01
ic: CA
serial_number: 116428
program_official: FORRY, SUZANNE L
project_start_date: 2005-08-19
project_end_date: 2009-08-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 1923745
contact_pi: CHESNEY, JASON A.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-05-09
project_abstract:
DESCRIPTION (provided by applicant): The ability of neoplastic cells to survive and grow in a hypoxic environment requires a global shift that involves large increases in the use of glucose not only for energetic but also for anabolic activities.  Glycolytic flux in neoplastic cells is activated by Hypoxia Inducible Factor 1 (HIF-1) and the oncogenic proteins c-myc and ras. HIF-1 and ras independently induce the synthesis of fructose-26-bisphosphate (F26BP) a potent allosteric activator of 6-phosphofructo-1-kinase (PFK-1) the rate-limiting enzyme of glycolysis. The steady-state concentration of F26BP depends on the activity of the enzyme 6-phosphofructo-2-kinase (PFK-2) which is expressed in several tissue-specific isoforms (PFKFB1-4). The only isoform expressed in epithelial cells inducible PFK-2 (iPFK-2; PFKFB3) also has been found to be: (I) over-expressed by human solid tumors in situ (ii) induced by hypoxic exposure via HIF-1a; and (iii) required for K562 leukemia tumor growth in vivo. The long-term objectives of this application are to validate iPFK-2 as a molecular target for the development of anti-neoplastic agents. We developed a computational model of the tertiary structure of iPFK-2 based on the crystal structures of two homologous PFK-2 isozymes and screened virtual combinatorial libraries for pharmacophore fits of the fructose-6-phosphate (F6P) binding site of iPFK-2. We examined 81 highly scored compounds for cytotoxic activity against Jurkat T cell leukemia cells and identified a lead compound designated F6P33 that suppresses glycolytic flux to lactate and induces apoptosis selectively in transformed cells (100 nM-1M). We now propose to both silence and  
ectopically enhance iPFK-2 in transformed cells in vitro and in vivo and examine the consequences on the anti-neoplastic effects of F6P33. We expect that these studies will support the role of iPFK-2 as the molecular target of F6P33 and thus validate the development of small molecule inhibitors of iPFK-2 as antineoplastic agents.

project_terms:
6-Phosphofructo-2-kinase;6-Phosphofructokinase;Adenocarcinoma;Anabolism;Anchorage-Independent Growth;Antineoplastic Agents;Apoptosis;Attenuated;Binding Sites;CD3 Antigens;Carbon;Carcinoma Lewis Lung;Cell Line Transformed;Cell Transformation Neoplastic;Cells;Computer Simulation;Condition;Cytostatics;Daily;Data;Development;Dose;Ectopic Expression;Environment;Enzymes;Epithelial Cells;Exposure to;Fibroblasts;Fructose;Genomics;Glucose;Glycolysis;Growth;HRAS gene;Heterozygote;Human;Hypoxia;Hypoxia Inducible Factor;In Situ;In Vitro;Indole-3-Carbinol;Isoenzymes;Jurkat Cells;K-562;Label;Lead;Leukemia T-Cell;Libraries;Lung;Lung Adenocarcinoma;Malignant Neoplasms;Mammary gland;Metabolic;Metabolism;Mice Nude;Mice Transgenic;Molecular Target;Mus;Normal Cell;Normal tissue morphology;Oncogenic;Pathway interactions;Phosphotransferases;Production;Property;Protein Isoforms;Proteins;Proto-Oncogene Proteins c-myc;Purines;Pyrimidine;Pyrimidines;RNA Small Interfering;Range;Rate;Resistance;Ribose;Role;Score;Solid Neoplasm;Structure;T-Lymphocyte;Telomerase;Testing;Tissues;Toxic effect;Transgenic Organisms;Urethane;Vascularization;Viral Tumor Antigens;Week;base;c-myc Genes;cell transformation;combinatorial;cytotoxic;enzyme activity;fructose-6-phosphate;glucose transport;glucose uptake;hypoxia inducible factor 1;in vivo;inhibitor/antagonist;leukemia;neoplastic;neoplastic cell;pharmacophore;protein expression;purine;sialosyl-T antigen;small molecule;tumor;tumor growth;virtual


application_id: 7465073
project_number: 2R01EY014821-05A1
project_title: Mechanisms of Intermediate Distance Space Perception
administering_ic: NEI
award_notice_date: 2008-07-28
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: EY
serial_number: 014821
suffix: A1
program_official: OBERDORFER, MICHAEL
project_start_date: 2003-04-01
project_end_date: 2012-07-31
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 1965646
contact_pi: HE, ZIJIANG
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Address;Affect;Amblyopia;Attention;Characteristics;Complement;Cues;Daily;Depth;Depth Perception;Distance Perception;Effectiveness;Environment;Eye;Figs - dietary;Financial compensation;Formulations Drug;Funding;Goals;Human;Investigation;Knowledge;Learning;Link;Literature;Localized;Location;Locomotion;Measures;Mediating;Methods;Motion;Operative Surgical Procedures;Patients;Positioning Attribute;Process;Psychophysiology;Range;Relative (related person);Research;Role;Sampling;Scanning;Science;Shapes;Source;Space Perception;Specific qualifier value;Strabismus;Surface;Technology;Testing;Texture;Upper arm;Vision;Vision Disparity;Vision Binocular;Visual;Visual system structure;Work;base;improved;insight;meter;monocular;novel;public health medicine (field);size;tool;virtual;virtual reality


application_id: 7464979
project_number: 1R01AI071047-01A2
project_title: Adjuvant Functions of Detoxified LPS
administering_ic: NIAID
award_notice_date: 2008-01-25
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: AI
serial_number: 071047
suffix: A2
program_official: LEITNER, WOLFGANG W
project_start_date: 2008-02-01
project_end_date: 2013-01-31
study_section: Immunity and Host Defense Study Section[IHD]
contact_pi_person_id: 1941645
contact_pi: MITCHELL, THOMAS C.
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Adjuvant;Adoptive Transfer;Agonist;Antibody Formation;Antigens;Appendix;B-Lymphocytes;Bioterrorism;CD4 Positive T Lymphocytes;CD8B1 gene;Clinical;Clonal Expansion;Communicable Diseases;Data;Detection;Development;End Point;Endotoxins;Europe;Event;Glycogen Synthase Kinase 3;Human;Immune response;Immune system;Inflammatory;Knowledge;Lymphoid Cell;Maintenance;Mediating;Memory;Memory B-Lymphocyte;Modeling;Molecular;Mus;Parents;Pathway interactions;Poxviridae;Property;Publishing;Range;Relative (related person);Research Personnel;Role;Safety;Science;Signal Pathway;Signal Transduction;Standards of Weights and Measures;Structure;T memory cell;T-Lymphocyte;TLR4 gene;Testing;Toxic effect;Transgenic Model;United States;Vaccination;Vaccine Adjuvant;Vaccines;Vaccines Subunit;Variant;Work;aluminum sulfate;base;cytokine;design;diphosphoryl lipid A;improved;in vivo;interest;macrophage;monocyte;monophosphoryl lipid A;next generation;novel vaccines;prophylactic;public health medicine (field);response;success


application_id: 7464106
project_number: 1R01AR055246-01A1
project_title: Circadian rhythms and skeletal muscle
administering_ic: NIAMS
award_notice_date: 2008-02-29
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: AR
serial_number: 055246
suffix: A1
program_official: BOYCE, AMANDA T
project_start_date: 2008-03-01
project_end_date: 2013-02-28
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 8263548
contact_pi: ESSER, KARYN A
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Actinin;Actins;Aging;Bed rest;Behavior;Binding (Molecular Function);Biological;Biological Clocks;Biological Process;Brain;Cachexia;Cell physiology;Cells;Chronic Disease;Circadian Rhythms;Clinical;Complement;Development;Diabetes Mellitus;Disease;Disruption;Down-Regulation;Electron Microscopy;Enhancers;Feedback;Feeding behaviors;Fiber;Functional disorder;Gel;Gene Expression;Gene Proteins;Gene Targeting;Genes;Genetic;Hour;Hypothalamic structure;In Situ Hybridization;Insulin Resistance;Intrinsic drive;Knock-out;Laboratories;Lesion;Link;Liver;Maintenance;Malignant Neoplasms;Mammals;Measures;Mechanics;Mental Health;Metabolic Diseases;Mice Mutant Strains;Microfilaments;Microscopy Confocal;Microscopy Fluorescence;Molecular;Molecular Profiling;Mus;Muscle;Muscle Fibers;Muscle function;Mutation;Myosin ATPase;Myosin Heavy Chains;Normal Cell;Operative Surgical Procedures;Pattern;Peripheral;Physical activity;Physiology;Polymerase Chain Reaction;Promotor (Genetics);Protein Isoforms;Proteins;Regulation;Rehabilitation therapy;Role;Skeletal muscle structure;Skeletal system;Spinal cord injury patients;Structure;Structure of suprachiasmatic nucleus;System;Time;Tissues;Transcription Genetic;Translations;Work;behavior influence;circadian pacemaker;connectin;cryptochrome;day;design;intracellular protein transport;mutant;nebulin;nerve supply;novel;protein localization location;public health medicine (field);rehabilitation strategy;research study;sarcopenia;stoichiometry;transcription factor;wasting


application_id: 7464059
project_number: 1R01HD056002-01A1
project_title: Sensory-driven motor recovery in poorly recovered subacute stroke patients
administering_ic: NICHD
award_notice_date: 2008-09-01
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: HD
serial_number: 056002
suffix: A1
program_official: ANSEL, BETH
project_start_date: 2008-09-01
project_end_date: 2013-06-30
study_section: Musculoskeletal Rehabilitation Sciences Study Section[MRS]
contact_pi_person_id: 7375465
contact_pi: SAWAKI-ADAMS, LUMY
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Activities of Daily Living;Acute;Address;Adult;Affect;Animals;Area;Behavioral;Brain;Brain Injuries;Chronic;Complex;Control Groups;Controlled Clinical Trials Randomized;Coupled;Data;Disease;Effectiveness;Future;Goals;Hand;Human;Intervention;Lead;Learning;Maps;Measures;Metacarpophalangeal joint structure;Modeling;Motor;Motor Cortex;Motor Skills;Motor output;Muscle;Nerve;Neurologic;Neurorehabilitation;Patients;Peripheral Nerve Stimulation;Persons;Phase;Plastics;Play;Quality of life;Range;Recovery;Recovery of Function;Rehabilitation therapy;Research;Research Project Grants;Risk;Role;Science of neurophysiology;Score;Sensory;Solid;Testing;Therapeutic;Therapeutic Intervention;Thinking function;Time;Tissues;Training;Transcranial magnetic stimulation;United States;Upper Extremity;Wolves;Work;Wrist;acute stroke;animal data;chronic stroke;constraint induced therapy;day;disability;experience;improved;memory process;motor deficit;motor impairment;post stroke;public health medicine (field);restoration;sensory cortex;skill acquisition;stroke;stroke rehabilitation


application_id: 7463879
project_number: 5R01CA034627-23
project_title: Pharmacogenetics of drug and carcinogen metabolism
administering_ic: NCI
award_notice_date: 2008-06-10
application_type: 5
activity_code: R01
ic: CA
serial_number: 034627
program_official: POLAND, ALAN P
project_start_date: 1989-09-01
project_end_date: 2010-12-01
study_section: Chemical Pathology Study Section[CPA]
contact_pi_person_id: 1924912
contact_pi: HEIN, DAVID W
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
project_abstract:
DESCRIPTION (provided by applicant): Genetic susceptibility to breast cancer is determined by an interaction of genes and environment but remains poorly understood. In this revised competing renewal of our investigation into the role of pharmacogenetic polymorphisms in carcinogen metabolism on genetic predisposition to cancer we hypothesize that aromatic amine carcinogens such as 4-aminobiphenyl (ABP) present in tobacco smoke and heterocyclic amine carcinogens such as 2-amino-3-methylimidazo [45-f]pyridine (IQ) present in deep-fried well-done meats are more likely to initiate breast cancer in those individuals with rapid and/or slow acetylator N-acetyltransferase- 1 (NAT1) and - 2 (NAT2) acetylator genotypes. We hypothesize that breast cancer frequency will be higher in tobacco smokers with very slow NAT2 acetylator / rapid NAT1 acetylator genotypes and in individuals who eat deep-fried well-done meats and are rapid for both NAT1 and NAT2 acetylator genotypes. To test this hypothesis we propose to determine the effect of single nucleotide polymorphisms (SNPs) in human NAT1 and NAT2 on ABP and IQ genotoxicity through stable transfection of human NAT1 or NAT2 variant alleles into Chinese hamster ovary cells transfected with human CYP1A1 or CYP1B1; determine the relative level of NAT1 and NAT2 expression in normal human mammary tissue as a function of genotype; construct and characterize rapid and slow acetylator rat strains congenic at the NAT2 locus to determine the frequency of breast tumors in female rapid and slow acetylator congenic rats administered ABP or IQ; determine quantity stability and regulatory effects of ABP or IQ on NAT1- and NAT2-specific mRNA protein and catalytic activity; and determine the metabolism and genotoxicity of ABP and IQ in primary mammary cell cultures derived from rapid and slow acetylator congenic rats. We also will assess the effect of NAT1 and NAT2 genotypes in breast cancer risk through participation in ongoing molecular epidemiology investigations of breast cancer in Shanghai China and in Nashville Tennessee.

project_terms:
2-Amino-1-Methyl-6-Phenylimidazo[45-b]pyridine;4-biphenylamine;Acetylation;Affinity;Alleles;Aromatic Amines;Breast;CYP1A1 gene;Carcinogen Metabolism;Carcinogens;China;Chinese Hamster Ovary Cell;Cultured Cells;DNA;DNA Adducts;DNA Repair;DNA Repair Gene;Data;Depth;Eating;Environmental Exposure;Enzymes;Epidemiology Molecular;Epithelial Cells;Female;Frequencies (time pattern);Genes;Genetic;Genetic Predisposition to Disease;Genotype;Health;Heterocyclic Amines;Human;Individual;Investigation;Malignant Neoplasms;Malignant neoplasm of breast;Mammary Neoplasms;Mammary gland;Meat;Metabolism;N-acetyltransferase 1;NADPH-Ferrihemoprotein Reductase;NAT1 protein human;NAT2 protein human;Pharmaceutical Preparations;Pharmacogenetics;Phase;Polymorphism Genetic;Population;Predisposition;Proteins;RNA Messenger;Rat Strains;Rattus;Relative (related person);Role;Sampling;Single Nucleotide Polymorphism;Smoker;Tennessee;Testing;Tissue Sample;Tissues;Tobacco;Tobacco smoke;Transfection;Variant;cancer risk;carcinogenicity;chemical carcinogen;congenic;cytochrome P-450 CYP1B1;cytotoxicity;gene environment interaction;genotoxicity;heterocyclic aromatic amines;protein expression;pyridine


application_id: 7463846
project_number: 5K01AG024190-05
project_title: Calcineurin and Biobehavioral Markers of Brain Aging
administering_ic: NIA
award_notice_date: 2008-07-21
application_type: 5
activity_code: K01
ic: AG
serial_number: 024190
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 2004-09-30
project_end_date: 2009-07-31
study_section: Basic Neuroscience of Aging Study Section[NIA-N]
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
project_abstract:
DESCRIPTION (provided by applicant):   Our previous work indicates that protein phosphatase activity is increased in hippocampus of aged rats and contributes to age-related alterations in synaptic strength and cognition. The proposed studies investigate whether the protein phosphatase calcineurin interacts significantly with several other brain aging biomarkers including increased Ca2+ channel function and altered gene expression. In each aim of this project calcineurin activity in hippocampal cultures and in hippocampus of intact rats is manipulated using recombinant viruses (adeno- and lentivirus). The first specific aim tests whether constitutively active calcineurin causes aging-like changes in voltage sensitive Ca2+ channels (VSCC) (i.e. an increase in L-type VSCC currents and a decrease in N-type VSCC mRNA levels). Molecular interactions of calcineurin with VSCCs also will be explored. The second aim tests whether increased calcineurin activity leads to aging-like changes in global gene expression as assessed using gene microarrays. The specific role of the calcineurin/NF-AT transcriptional pathway will be explored using recombinant virus containing a potent NFAT inhibitor VIVIT. The third aim uses recombinant viruses to test whether the calcineurin/NF-AT pathway contributes to age-related memory deficits on the Morris swim task. After completion of behavioral training intact and partially dissociated hippocampal slices will be prepared from these rats to determine whether the calcineurin/NF-AT pathway also is responsible in part for age-related alterations in synaptic strength plasticity (i.e. long-term potentiation and long-term depression) and L-type VSCC activity. Furthermore individual neurons and glia will be harvested from zipper slices to examine single cell gene expression profiles using gene microarray technology.

project_terms:
Adenoviruses;Age;Aging;Animals;Behavior;Behavioral;Binding (Molecular Function);Biochemical;Biological Markers;Calcineurin;Cells;Cognition;Electrophysiology (science);Facility Construction Funding Category;Gene Expression;Gene Expression Profile;Genes;Harvest;Hippocampus (Brain);Impaired cognition;Individual;Kentucky;Laboratories;Long-Term Depression (Physiology);Long-Term Potentiation;Membrane;Memory impairment;Microarray Analysis;Modeling;Molecular;Molecular Profiling;NF-AT;Neuroglia;Neurons;Pathway interactions;Pharmacology;Physiological;Protein phosphatase;RNA Messenger;Rattus;Role;Signal Transduction;Slice;Subfamily lentivirinae;Swimming;Synapses;Techniques;Testing;Training;Transgenes;Universities;Work;age related;aging brain;aging hippocampus;biobehavior;inhibitor/antagonist;recombinant virus;synaptic function;voltage


application_id: 7463788
project_number: 5R01HL063760-06
project_title: Oxidative Stress and Heart Failure by Copper Restriction
administering_ic: NHLBI
award_notice_date: 2008-07-09
opportunity_number: PA-05-089
application_type: 5
activity_code: R01
ic: HL
serial_number: 063760
program_official: ERSHOW, ABBY
project_start_date: 2001-06-15
project_end_date: 2011-06-30
study_section: Integrative Nutrition and Metabolic Processes Study Section[INMP]
contact_pi_person_id: 1877629
contact_pi: KANG, Y JAMES
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Sustained pressure overload causes cardiac hypertrophy and the transition to heart failure. The aortic banding mouse model leads to hypertrophic cardiomyopathy and heart failure through the mechanism of sustained pressure overload but we have evidence that mineral imbalance may be involved. We have observed that increasing dietary copper (Cu) intake from 6 mg Cu/kg diet to 20 mg/kg diet can reverse the established hypertrophic cardiomyopathy in the aortic banding mouse model even in the presence of sustained pressure overload. Decreased cytochrome c oxidase (CCO) activity and mitochondriopathy are associated with heart failure in humans. The same CCO defect and mitochondriopathy are also found in the mouse model of pressure overload-induced cardiomyopathy and increasing dietary Cu intake recovered CCO activity and reversed mitochondriopathy. We propose this study to carry out the following aims: Aim 1 is to explore molecular mechanism by which sustained pressure overload causes Cu restriction to CCO in the heart. We will test the hypothesis that Cu mobilization and redistribution or efflux in response to oxidative stress generated by sustained pressure overload leads to Cu restriction to CCO resulting in altered CCO assembly and suppressed CCO activity. Aim 2 is to determine the essential role of recovery of suppressed CCO activity in Cu supplementation-induced regression of cardiomyopathy by sustained pressure overload. A cardiac COX10 conditional knockout mouse model in which cardiac CCO activity can be reduced by 50- 70% under the treatment with tamoxifen will be used. We hypothesize that Cu supplementation would not rescue the failing heart in the cardiac COX10-knockout or CCO-deficient mice if the recovery of CCO activity is essential even Cu supplementation can reverse alterations in other events including calcineurin/NFAT PI3K/Akt and ERK1/2 pathways or can activate other cardiomyopathy regression mechanisms. Aim 3 is to define potential application of Cu therapy to appropriate populations of heart failure patients by testing the hypothesis that Cu supplementation should be limited to pressure overload cardiomyopathy not applied to diabetic cardiomyopathy because diabetes causes liver dysfunction which in turn causes Cu retention in the system increasing the risk of Cu toxicity to the heart and other organs. Therefore Cu supplementation is not an appropriate approach to rescue diabetic cardiomyopathy.

project_terms:
Address;Adverse effects;Binding (Molecular Function);Binding Sites;Calcineurin;Cardiac;Cardiomyopathies;Chelation Therapy;Chromatography Gel;Chromatography High Pressure Liquid;Copper;Defect;Depressed mood;Detection;Diabetes Mellitus;Diet;Dietary Copper;Disease regression;Dysfunction Liver;Estrogen Receptors;Event;Functional disorder;Heart;Heart Hypertrophy;Heart failure;Histidine;Human;Hypertrophic Cardiomyopathy;Intake;Intervention;Knock-out;Liver;Metabolic Diseases;Metabolism;Metallothionein;Mice Transgenic;Minerals;Molecular;Molecular Chaperones;Mus;Mutation;Organ;Oxidative Stress;Pathway interactions;Patients;Population;Pressure- physical agent;Prevention;Promotor (Genetics);Proteins;Recovery;Research Personnel;Risk;Role;Stress;Supplementation;System;Tamoxifen;Testing;Toxic effect;Zinc;chelation;clinical application;clinically relevant;cytochrome c oxidase;diabetic cardiomyopathy;human study;insight;mouse model;mutant;novel;programs;recombinase;response


application_id: 7462898
project_number: 1R21CA129881-01A1
project_title: Increasing Colorectal Cancer Screening for Patients with Multiple Morbidities
administering_ic: NCI
award_notice_date: 2008-05-20
opportunity_number: PA-06-351
application_type: 1
activity_code: R21
ic: CA
serial_number: 129881
suffix: A1
program_official: BRESLAU, ERICA S
project_start_date: 2008-05-21
project_end_date: 2010-04-30
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Appalachian and rural underserved residents in general experience higher rates of multiple morbidities (MM) with fewer resources to prevent and manage disease. Some researchers have speculated that the well-documented cancer health disparities affecting Appalachians may be attributable to multiple morbidity management demands which may deprioritize essential and efficacious cancer screenings. In this pilot study we examine whether and how multiple morbidities affect colorectal cancer screening rates. Our long-term goal is to turn this disadvantageous situation of competing time and resource pressure into an advantage by increasing cancer screening services during the more frequent medical interactions of those with multiple morbidities. Addressing the nearly three-quarters of middle aged and older adults with MM is essential due to skyrocketing rates of MM higher rates of cancer mortality among those with MM and competing demands of disease prevention and management. We aim to expand our limited understanding of the association between MM and colorectal cancer (CRC) screening through three research activities. First to obtain rich insights into the factors and circumstances that affect patterns of CRC screening behavior among those with multiple morbidities in-depth interviews will be conducted with 5 health care providers representing diverse practices in Appalachia and with 40 patients who have two or more chronic diseases. These interviews will provide locally grounded perspectives from the two most salient health decision makers providers and patients. Second to insure generalizability we will assess the impact of factors germane to both MM and CRC screening behavior by conducting a stratified representative survey of Appalachians. Finally after identifying factors circumstances and patterns that prevent CRC screening in the context of multiple morbidities we will hold focus groups to validate our findings and discuss optimal direction for interventions. Ultimately these findings will lead to the development of a community-based participatory intervention R01 that will capitalize on the relatively frequent medical care visits of those with multiple morbidities and ultimately will increase CRC screening improve practice coordination and decrease cancer-associated deaths. PUBLIC HEALTH RELEVANCE: In the US the majority of the ever-growing middle aged and older population has multiple morbidities or several chronic diseases. Having multiple morbidities generally decreases the likelihood of receiving highly effective cancer prevention like colorectal cancer screening. This project uses innovative methods to determine the reasons why those with multiple morbidities may be less likely to get colorectal cancer screening and will eventually develop a culturally consistent intervention for the underserved rural health disparities population of Appalachia to increase early detection of this deadly cancer.

project_terms:
Address;Affect;Age;Appalachian Region;Area;Attention;Behavior;Cancer Prevention Secondary;Caring;Cessation of life;Chronic;Chronic Disease;Colorectal Cancer;Communities;Computers;Condition;Consultations;Data;Depth;Development;Disease;Early Diagnosis;Elderly;Evaluation;Focus Groups;Foundations;Future;Gender;Goals;Health;Health Personnel;Healthcare;Home environment;Incidence;Intervention;Interview;Investigation;Lead;Malignant Neoplasms;Mass Media;Media Campaign;Medical;Methods;Morbidity - disease rate;Mortality Vital Statistics;Office Visits;Older Population;Outcome;Patients;Pattern;Persons;Physicians;Pilot Projects;Population;Pressure- physical agent;Preventive;Primary Health Care;Provider;Rate;Research;Research Activity;Research Personnel;Resources;Rural;Rural Community;Screening for Colorectal Cancer;Screening for cancer;Screening procedure;Services;Status Socioeconomic;Surveys;Testing;Time;Underserved Rural Health;Visit;Work;base;cancer diagnosis;cancer health disparity;cancer prevention;design;disorder prevention;experience;health disparity;improved;indexing;innovation;insight;middle age;outreach;prevent;public health medicine (field);therapy development;underserved rural area


application_id: 7462860
project_number: 1R01HL086662-01A2
project_title: Oxidative stress in a murine model of sleep apnea
administering_ic: NHLBI
award_notice_date: 2008-06-16
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: HL
serial_number: 086662
suffix: A2
program_official: TWERY, MICHAEL
project_start_date: 2008-07-01
project_end_date: 2009-02-01
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 1896463
contact_pi: GOZAL, DAVID
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Obstructive sleep apnea syndrome (OSAS) the most severe form of sleep disordered breathing (SDB) is a condition characterized by repeated episodes of intermittent hypoxia (IH) that frequently imposes substantial neurocognitive morbidities in humans. Rodent models have demonstrated that IH is associated with behavioral learning and memory deficits that are preceded by neurodegenerative changes in the hippocampus and cortex. Activation of the enzyme NADPH oxidase a major source of superoxide radicals may underlie many of the IH-induced oxidative modifications and contribute to the behavioral and neuronal consequences of IH. Recent evidence also indicates that consumptions of a diet high in fat and sugar a major cause of obesity not only enhances susceptibility to neuronal injury but increases activation of NADPH oxidase suggesting that diet and IH may increase oxidative stress through a common pathway. Given that the obesity is a major risk factor for OSAS it is imperative to identify the underlying factors that contribute to the neurocognitive morbidities associated with the disease implications. To test the hypothesis that IH and diet a primary environmental cause of obesity modulate neuronal susceptibility to IH three major specific aims will be examined in an adult mouse model using as using Morris water maze task paradigms changes in NADPH oxidase gene and protein expression markers of oxidative stress and apoptosis as follows: (1) The effect of genetic absence of NADPH oxidase activity (gp91phox-/- mice) on the behavioral and neuronal susceptibility to 14 days of intermittent daytime hypoxia (IH); (2) The effect of administration of apocynin an inhibitor of assembly of the NADPH oxidase complex on the behavioral and neuronal susceptibility to 14 days of intermittent daytime hypoxia (IH); (3) To determine if a long-term high fat/refined carbohydrate (HFRC) diet increases the behavioral and neuronal susceptibility of adult male mice to IH and whether these deficits are prevented by the absence of NADPH activity (gp91phox-/- mice) and/or apocynin an inhibitor of assembly of the NADPH oxidase complex. These studies will provide insight into the potential mechanisms which underlie the effects of IH on neuronal function as well as the manner whereby environmental factors influence the pathogenesis of OSAS-associated cognitive deficits. PUBLIC HEALTH RELEVANCE:Obstructive sleep apnea syndrome (OSAS) the most severe form of sleep disordered breathing (SDB) is frequently associated with cognitive deficits in humans and is currently estimated to affect as many as 18 million individuals in the United States alone. Substantial variability in the neurobehavioral outcomes of patients with sleep apnea suggest that both intrinsic (i.e. genetically-determined) or extrinsic (i.e. environmentally acquired) elements modify the behavioral susceptibility to sleep apnea. The studies in the present application will utilize a mouse model of the nocturnal breathing patterns of OSAS patients to not only provide information as to the potential cellular and molecular mechanisms underlying such dysfunction but also the manner in which a primary extrinsic factor for OSAS obesity may modify such responses. Given the increasing prevalence of both OSAS and obesity in our society it is therefore imperative to identify the underlying factors that contribute to the adverse behavioral outcomes associated with the disease.

project_terms:
Address;Adult;Affect;Airway Obstruction;Animal Model;Apoptosis;Arousal;Behavioral;Breathing;CREB1 gene;Carbohydrates;Cardiovascular system;Chronic;Cognitive;Cognitive deficits;Complex;Condition;Consumption;Development;Diet;Dinoprostone;Disease;Elements;Environmental Risk Factor;Enzyme Activation;Exhibits;Exposure to;F2-Isoprostanes;Fatty acid glycerol esters;Functional disorder;Gene Proteins;Genetic;Hippocampus (Brain);Human;Hypoxia;Impaired cognition;Individual;Inflammation;Learning;Light;Malondialdehyde;Medical;Memory;Memory impairment;Modeling;Modification;Molecular;Morbidity - disease rate;Mus;NAD(P)H oxidase;NADP;NADPH Oxidase;Nerve Degeneration;Neurocognitive;Neurodegenerative Disorders;Neuronal Injury;Neurons;Numbers;OSA;Obesity;Outcome;Oxidative Stress;PTGS2 gene;Pathogenesis;Pathway interactions;Patients;Pattern;Phosphorylation;Predictive Value;Predisposition;Prevalence;Production;Recurrence;Risk Factors;Rodent;Rodent Model;Role;Severity of illness;Sleep;Sleep Apnea Syndromes;Sleep Apnea Obstructive;Sleep Fragmentations;Societies;Source;Structure of dentate gyrus;Superoxides;Testing;United States;Variant;Water;acetovanillone;basal forebrain;day;functional loss;gray matter;immunocytochemistry;inhibitor/antagonist;insight;male;morris water maze;mouse model;neurobehavioral;neutrophil cytosol factor 67K;prevent;protein expression;public health medicine (field);response;sugar


application_id: 7462330
project_number: 5R01DA016718-05
project_title: Licit & Illicit Opioids: Comparative Studies in Humans
administering_ic: NIDA
award_notice_date: 2008-07-15
opportunity_number: PA-01-048
application_type: 5
activity_code: R01
ic: DA
serial_number: 016718
program_official: WETHERINGTON, CORA LEE
project_start_date: 2004-07-10
project_end_date: 2010-05-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 1877426
contact_pi: WALSH, SHARON L.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Epidemiological studies report increasing non-medical use and diversion of prescription opioid analgesics. Oxycodone is marketed in an array of formulations and used for the treatment of acute and chronic pain. Oxycontin(r) is a sustained-release formulation which is marketed in higher dosage formulations compared to immediate release products; both formulations have received substantial negative publicity due to reports of increased frequency of unintentional addiction fatal overdose and criminal diversion. Hydrocodone a related semi-synthetic opioid is the most widely prescribed opioid analgesic in the United States and the most frequently mentioned prescription opioid in emergency room admissions. Despite their widespread clinical use few studies have evaluated the abuse liability and clinical pharmacology of these commonly used opioids. This project will employ controlled laboratory procedures to evaluate and characterize the effects of oxycodone and hydrocodone in volunteers with histories of opioid abuse under an array of conditions. Each of the studies will use randomized placebo-controlled double blind within-subject designs. Dose rising pilot evaluations will precede randomized testing for safety purposes. Experiment 1 will compare the effects of oral oxycodone and hydrocodone to those of hydromorphone a mud opioid agonist with known high abuse potential and placebo over a broad range of doses. Experiment 2 will focus on the sustained-release Oxycontin(r) product and will compare its pharmacokinetic and pharmacodynamic properties when administered intact or after tampering (pulverizing to by-pass the sustained release features) to immediate release oxycodone and placebo; pharmacokinetic analyses will yield bioavailability data in this study. Experiment 3 will evaluate the pharmacodynamic effects of IVoxycodone and hydrocodone compared to morphine heroin and placebo. In all studies data will be collected across multiple domains. Physiological and subjective measures will be collected to assess safety and abuse liability respectively and a battery of psychomotor and cognitive tasks will assess the impairing effects of these agents. These studies will contribute substantial new knowledge about the relative abuse potential and safety of these widely available agents at therapeutic and supratherapeutic doses in a population of subjects who are likely to abuse them. Information relevant to the public health will include the relative potency and tolerability of these compounds the consequences of tampering with marketed formulations and empirical information relevant to safety scheduling and marketing of these agents.

project_terms:
Absence of pain sensation;Accident and Emergency department;Accounting;Acute;Addiction Opiate;Admission activity;Age;Agonist;Analgesics;Analgesics Opioid;Attention;Biological Availability;Bolus Infusion;Bypass;Categories;Cessation of life;Clinical;Cognitive;Collection;Comparative Study;Condition;Data;Deltastab;Dose;Double-Blind Method;Drug Evaluation;Drug Kinetics;Drug abuse;Enrollment;Epidemiologic Studies;Evaluation;Formulations Drug;Frequencies (time pattern);Heroin;Hospitals;Household;Human;Hydrocodone;Hydromorphone;Individual;Inpatients;Intravenous;Knowledge;Laboratories;Laboratory Procedures;Law Enforcement;Marketing;Measures;Medical;Morphine;Numbers;Opioid;Oral;Overdose;Oxycodone;Patient Self-Report;Performance;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology Clinical;Physiological;Placebo Control;Placebos;Population;Preparation;Prevalence;Procedures;Property;Purpose;Randomized;Range;Rate;Recording of previous events;Relative (related person);Reporting;Risk;Risks Relative;Safety;Schedule;Surveys;Testing;Therapeutic;Time;United States;addiction;base;chronic pain;design;dosage;drug development;novel;opioid abuse;prescription document;prescription drug abuse;prescription procedure;public health medicine (field);research study;response;time use;volunteer


