# projects

application_id: 6944910
project_number: 5R01AR046477-05
project_title: REGULATION OF SODIUM CHANNEL GENE EXPRESSION
administering_ic: NIAMS
award_notice_date: 2005-09-10
application_type: 5
activity_code: R01
ic: AR
serial_number: 046477
program_official: NUCKOLLS, GLEN H
project_start_date: 2001-09-26
project_end_date: 2007-08-31
study_section: Cell Development and Function 5[CDF-5]
contact_pi_person_id: 7875389
contact_pi: KRANER, SUSAN D
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-09-01
project_abstract:
DESCRIPTION (appended verbatim from investigator's abstract): Regulation of Na+     channel gene expression modulates the electrical excitability of muscle cells.      A decrease in muscle Na+ channel expression results in at least one identified      syndrome acute quadriplegic myopathy and may also play a role in other            disease or age-related dysfunction. The mechanisms that control expression of       the skeletal muscle type 1 Na+ channel (SkM1) will be studied to determine how      the transcription factors (TFs) that regulate it work together to modulate          specific temporal and spatial aspects of SkMl expression. Previous work             indicates that the myogenic basic helix-loop-helix (bHLH) proteins myogenin and     MRF4 recruit other novel TFs including both a transrepressor and a                 transactivator in regulating SkM 1 expression. Likely these novel TFs regulate     expression of other genes as well and therefore they will be cloned. Certain        aspects of SkM1 expression such as a preferential expression at neuromuscular      junctions and the relatively late postnatal increase in mRNA levels cannot be      replicated in cultured muscle cells. Therefore several strategies will be used      to study the interaction between the bHLH factors and novel TFs in vivo. The        SkM1 cis-regulatory sequences driving expression of an epitope-tagged Na+           channel will be introduce into transgenic mice and the level temporal and        spatial distribution of the transgene assessed by immunocytochemistry Western      blotting or RNAse protection assays relative to the endogenous SkM1. Mutations      in the binding sites of the novel TFs or the bFILH factors will be tested to        determine what aspect of SkM I expression these sites control. In addition the     role of the bHLH factors will be evaluated by determining what changes in the       temporal or spatial distribution of SkM1 expression occurs in myogenin and MRF4     knockout animals. Future work will utilize recombinant adenovirus to introduce      the bHLH factors novel TFs or dominant/negatives of these factors in vivo.        The effect of these IFs on the spatial and temporal expression of not only SkMI     but also other muscle genes such as the acetyicholine receptor will be studied.     These experiments will validate in vitro findings and in addition will           provide the first temporally integrated analysis of ion channel gene                expression and will yield important insights into how ion channel genes are        regulated in developmental adulthood and perhaps under pathological               conditions.

project_terms:
cholinergic receptors;gene expression;laboratory mouse;molecular cloning;muscle proteins;neuromuscular function;protein structure function;sodium channel;tissue /cell culture;transcription factor;transfection


application_id: 6944802
project_number: 5R01GM041302-17
project_title: Molecular Genetic Analysis of Yeast Sphingolipids
administering_ic: NIGMS
award_notice_date: 2005-08-18
application_type: 5
activity_code: R01
ic: GM
serial_number: 041302
program_official: CHIN, JEAN
project_start_date: 1988-12-01
project_end_date: 2007-08-31
study_section: Microbial Physiology and Genetics Subcommittee 1[MBC-1]
contact_pi_person_id: 1879389
contact_pi: DICKSON, ROBERT C
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-09-01
project_abstract:
DESCRIPTION (provided by applicant): Sphingolipids are emerging as key elements in membrane organization and function and as regulators of signal transduction pathways that mediate stress protection and control growth. Many of these roles seem to be conserved between yeast and mammals. Progress has been made in understanding the functions of sphingolipids in membranes and in signaling but our knowledge remains rudimentary and much effort will be required to achieve a more thorough understanding. Our previous studies demonstrated that sphingolipids are essential for growth of Saccharomyces cerevisiae cells and that they play roles in heat stress. Three Specific Aims will build upon these studies. The first aim is to determine why sphingolipids are necessary for exocytosis during heat stress. Specifically to determine which sphingolipid is necessary which step requires sphingolipids and what the function of the required sphingolipid is. The second aim is to characterize putative protein kinases regulated by sphingoid long chain bases. The protein kinases are Pkh 1p and Pkh2p homologs of mammalian phosphoinositide-dependent kinases (PDKs) and Yck2p a homolog of mammalian casein kinases. These proteins regulate poorly characterized signaling pathways necessary for yeast cell growth and stress protection. In addition the yeast proteome will be screened using a newly developed protein chip technique for proteins that bind specific sphingolipids in order to identify novel signaling pathways and cellular processes that require sphingolipids for function. The third aim is to determine why the very long chain-fatty acid (VLCFA C26) component of sphingolipids is necessary for acidification of vacuoles (lysosomes) by the vacuolar ATPase. VLCFAs are present in all eucaryotes but their functions remain unknown. These studies will reveal new roles for sphingolipids in membrane function such as in lipid rafts and in signaling pathways that are crucial for stress protection growth control and essential physiological processes. The results of the proposed studies should aid in understanding mammalian signaling pathways and help to reveal useful targets for pharmacological intervention in human ailments including cancer atherosclerosis and neurological disorders.

project_terms:
adenosinetriphosphatase;antibody;biological signal transduction;casein kinase;chemical structure function;endoplasmic reticulum;enzyme activity;exocytosis;fungal genetics;heat stimulus;intermolecular interaction;laboratory rabbit;lipid biosynthesis;long chain fatty acid;molecular genetics;phosphorylation;protein binding;protein kinase;protein transport;proteomics;sphingolipids;vesicle /vacuole


application_id: 6944361
project_number: 5R01OH004157-05
project_title: Sustained Work Indicators of Older Farmers
administering_ic: NIOSH
award_notice_date: 2005-06-14
opportunity_number: PA-99-143
application_type: 5
activity_code: R01
ic: OH
serial_number: 004157
program_official: NEWHALL, JIM
project_start_date: 2001-09-30
project_end_date: 2007-09-29
study_section: Safety and Occupational Health Study Section[SOH]
contact_pi_person_id: 8431098
contact_pi: REED, DEBORAH BAKER
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This prospective panel study will focus on     the most rapidly aging workforce in the U.S.: the family farmer. This special       population is known to suffer one of the highest rates of occupational injury       and mortality. Farmers rarely retire from their vocation and work long past         usual retirement age. A longitudinal design to track the sustained work             patterns of aging farmers and to identify factors that influence their decision     to remain in farm work will be used. The specific aims of this study are to: 1.     Identify factors that influence the sustained work of older farmers. 2. Develop     health profiles (including physical and mental indicators) of older male and        female farmers. 3. Develop exposure profiles for tasks related to agricultural      work of older farmers. 4. Explore the sociocultural family and economic            factors that influence the work practices and health of older farmers. The aims     are congruent with the Healthy People 2010 objectives 20.1 and 20.2 to reduce       farm worker fatalities and injuries. This study will enroll a partial sample        from the Kentucky Farm Family Health and Hazard Surveillance Study (data            collected 1994-1996) and their spouses (n=914) and an over sample of African        American farmers and spouses (n=914) for a total of 1828 persons enrolled from     Kentucky and South Carolina. Measures on sociocultural health and behavioral      and work environment factors will be collected through six waves of mailed          surveys over 50 months. Hierarchical regression analysis will provide a             quantitative model of the sustained work of older farmers. Descriptive and          predictive analyses will be conducted by gender and race. Focus groups of male      farmers farmwomen and farm couples will address items not conductive to           survey research. Attachment to farm life and the land farm enterprise              transfer and the meaning of work will be explored in 18 focus group sessions.      Findings from the study will be used to design occupational counseling              appropriate to age gender and race as well as health and safety programs for     aging farmers.

project_terms:
African American;aging;agriculture worker;caucasian American;clinical research;decision making;disease /disorder proneness /risk;family structure /dynamics;female;focus groups;gender difference;human data;human mortality;human old age (65+);injury;longitudinal human study;male;occupational hazard;occupational health /safety;racial /ethnic difference;social behavior


application_id: 6943908
project_number: 5R21DE016477-02
project_title: Oral & Respiratory Status of Retarded/Disabled Persons
administering_ic: NIDCR
award_notice_date: 2005-07-20
opportunity_number: RFA-DE-04-009
application_type: 5
activity_code: R21
ic: DE
serial_number: 016477
program_official: NOWJACK-RAYMER, RUTH
project_start_date: 2004-09-01
project_end_date: 2007-07-31
study_section: ZDE1-RR(53)
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): Respiratory tract infections are the primary causes of death in institutionalized mentally retarded and developmental disabled (MRDD) persons. Aspiration of contaminated oral secretions is a major cause of respiratory infections and oral colonization by pathogenic bacteria resulting from inadequate oral hygiene has been shown to be routine in other high-risk populations. MRDD patients have similar risk factors for oral respiratory pathogen colonization as critically ill and nursing home patients including dry mouth and poor oral hygiene. Poor oral status may be common in institutionalized MRDD patients a significant health disparity and it is not known if their oral cavities become colonized with pathogenic respiratory organisms. We thus propose to conduct exploratory research to fill this gap in knowledge evaluate measures and methodology and provide pilot data for a properly powered clinical trial. This developmental/exploratory research seeks to answer the following questions in institutionalized MRDD patients: 1. What is the oral status of institutionalized MRDD patients? 2. What is the prevalence of oral respiratory pathogen colonization? 3. What species and quantity of respiratory pathogens colonize the oral cavity in this population? 4. Is poor oral status associated with oral respiratory pathogen colonization? 5. Is poor oral status and respiratory pathogen colonization associated with respiratory infection? We will conduct an exploratory study of 220 institutionalized MRDD patients at four facilities. Oral examinations and sample collection will be performed at baseline and then monthly until the end of month six. PCR analysis will be performed on all teeth and tongue samples collected from these 200 subjects. We will also monitor the incidence of respiratory tract infections over the 6-month period. The primary outcomes will be prevalence of respiratory pathogen colonization and the types and quantities of pathogens as determined by PCR analysis of microbiological samples. Explanatory variables will include Plaque Gingivitis and Oral Hygiene Indices co-morbidities and professional and routine oral care. Secondary outcomes will be the association of oral status and respiratory pathogen colonization with respiratory tract infections including pneumonia over the 6-month reporting period. The proposed study will test measures and methodology and will provide pilot data for sample size estimation for a full clinical trial.

project_terms:
clinical research;comorbidity;dental plaque;gingivitis;human subject;mental health facility;mental retardation;microorganism culture;microorganism growth;oral bacteria;oral health;patient oriented research;person with disability;polymerase chain reaction;respiratory infections;sample collection;tongue


application_id: 6943637
project_number: 5R01HD040204-04
project_title: Ovarian failure in LH/hCG receptor knockout animals
administering_ic: NICHD
award_notice_date: 2005-08-11
application_type: 5
activity_code: R01
ic: HD
serial_number: 040204
program_official: TAYMANS, SUSAN
project_start_date: 2002-09-01
project_end_date: 2008-08-31
study_section: Reproductive Endocrinology Study Section[REN]
contact_pi_person_id: 1896238
contact_pi: RAO, CH V
other_pis: Not Applicable
congressional_district: 03
department: OBSTETRICS & GYNECOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-09-01
project_abstract:
Both IIpo Huhtaniemi's and our group recently succeeded in generating LH receptor knockout mice by gene targeting in embryonic stem cells.  Although this gene knockout was not lethal it rendered animals infertile.  While ovaries of wild- type and heterozygous animals contained LH receptors ovaries of homozygous littermates contained none.  Also while ovaries of wild-type and heterozygous animals were normal in size and contained preovulatory follicles and corpora lutea the ovaries of homozygous littermates were small and pale with an arrest of follicular growth at the antral stage.  Preliminary studies indicated this arrest could at least partly be due to a decrease in telomerase levels and a consequent increase in apoptosis.  In homozygous animals LH levels were markedly elevated FSH levels were moderately elevated and estradiol and progesterone levels decreased but were not totally suppressed. Knockout animals can be extremely useful in answering a number of unknowns in LH biology.  For example we could learn: 1) whether LH actions are required for the presence of normal numbers of primordial primary preantral and antral follicles; 2) whether FSH can induce follicular growth and ovulation in the total absence of LH actions; 3) what role LH signaling plays in ovarian development and function from one week after birth through one year of age; 4) what ovarian actions of LH are mediated by estradiol progesterone and testosterone; 5) identify and characterize previously unidentified ovarian genes that are regulated by estradiol progesterone testosterone LH or by their combination; and 6) whether using gene therapy to introduce LH receptors into ovaries of null animals makes them cyclic and ovulate but still not get pregnant because they do not have LH receptors in the uterus.  These are only a few examples of how the use of null animals could advance our current understanding on the role of LH in different ovarian functions.  We propose three specific aims in this application: 1) Investigate structural and functional defects in ovaries of 7-day 25-day 60-day and 1-year old null mice to compare with their age- matched wild-type and heterozygous siblings. 2) Investigate whether estradiol progesterone and testosterone replacement therapy can correct structural and functional defects in ovaries of LH receptor knockout animals. 3) Determine whether retroviral mediated LH receptor gene transfer can correct structural and functional defects in ovaries of null animals so they become cyclic and ovulate even though pregnancy may not occur due to the absence of LH receptors in the uterus.  There are several strengths in this proposal.  Foremost is studying LH biology using knockout technology.  Second is using steroid hormone replacement and gene therapies.  Third is using cDNA expression arrays a powerful technique in gene expression analysis.  All techniques to be used in the proposed studies have already been established to obtain preliminary data presented in the proposal.

project_terms:
aging;biological signal transduction;chorionic gonadotropin;corticosterone;estradiol;follicle stimulating hormone;gene targeting;genetically modified animals;histogenesis;hormone receptor;hormone regulation /control mechanism;hormone therapy;immunocytochemistry;in situ hybridization;laboratory mouse;leptin;luteinizing hormone;morphometry;northern blottings;ovary;ovary disorder;polymerase chain reaction;progesterone;southern blotting;terminal nick end labeling;testosterone;western blottings


application_id: 6943513
project_number: 5R01CA100323-03
project_title: Autoantibodies in NSCLC as Markers for Disease
administering_ic: NCI
award_notice_date: 2005-08-23
application_type: 5
activity_code: R01
ic: CA
serial_number: 100323
program_official: LIVELY, TRACY LUGO
project_start_date: 2003-09-05
project_end_date: 2007-04-30
study_section: Experimental Therapeutics Subcommittee 2[ET-2]
contact_pi_person_id: 7875285
contact_pi: HIRSCHOWITZ, EDWARD A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-09-01
project_abstract:
DESCRIPTION (provided by applicant): A variety of diagnostic and therapeutic strategies are being explored to change poor outcomes in lung cancer. Tumor markers measured in peripheral blood could complement the evolving clinical approach to lung cancer management. Autoantibodies to tumor-associated proteins may effectively expand the number and range of available serologic markers for lung cancer and be translated into a valuable test for lung cancer. Our preliminary data supports this hypothesis. We used phage-display and biopan techniques to identify multiple autoantibodies to known and unknown tumor-associated proteins in the serum of non-small cell lung cancer (NSCLC) patients. Using conventional immunochemical techniques and novel protein microarray we showed that autoantibodies to individual tumor-associated proteins are found in cancer patient sera and not in normals. Because no single antibody response is likely to be a comprehensive marker we intend to build on these exciting data and develop an inclusive blood test for lung cancer by profiling sera for a variety of atuoantibodies. We have already identified 21 proteins recognized by autoantibodies in NSCLC patient sera and using these plus additional proteins identified with these techniques; we will generate a comprehensive a panel of proteins used for antibody measurement. Fluorescent microarray technology applied generally to gene discovery is ideal for this purpose. Thus the primary goal of this proposal is to develop a novel blood test for NSCLC. To begin to expand the clinical relevance of this approach a secondary goal is to show the association of autoantibody responses to tumor protein expression. The data shows feasibility and proof of concept that supports the rationale behind this proposal.

project_terms:
autoantibody;biomarker;blood tests;clinical research;diagnosis design /evaluation;genetic library;high throughput technology;human genetic material tag;human tissue;immunocytochemistry;immunologic assay /test;microarray technology;neoplasm /cancer diagnosis;nonsmall cell lung cancer;oncoproteins;pathologic process;phage display;polymerase chain reaction;tissue resource /registry


application_id: 6942994
project_number: 5R01CA090784-04
project_title: E2F-1 Cancer Gene Therapy
administering_ic: NCI
award_notice_date: 2005-08-29
application_type: 5
activity_code: R01
ic: CA
serial_number: 090784
program_official: WOLPERT, MARY K
project_start_date: 2002-09-01
project_end_date: 2007-08-31
study_section: Experimental Therapeutics Subcommittee 2[ET-2]
contact_pi_person_id: 1972617
contact_pi: MCMASTERS, KELLY M
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: 2005-09-01
project_abstract:
DESCRIPTION (PROVIDED BY APPLICANT): The major reason for the failure ofanticancer drug therapy in most advanced solid tumors is the presence ofchemotherapy-resistant tumor cells. Apoptosis is now considered to be anessential event in antitumor drug induced death. Therefore cells withdeficient apoptotic pathways may be incapable of producing an efficientapoptotic response regardless of the agent to which they are exposed. For thisreason gene therapy using proapoptotic genes that can either trigger apoptosisin chemo-resistant cells or reconstitute the apoptotic pathway to enhancechemotherapy is a potential therapeutic strategy. The transcription factorE2F-1 has recently been identified as a potent tumor suppressor. We and othershave shown that E2F- 1 overexpression efficiently induces apoptosis in avariety of tumor types independent of p53 status both in vitro and in vivo.However the mechanisms by which E2F-1 induces apoptosis remain ill defined.Mechanistically our preliminary data implicate activation of the Fas deathreceptor pathway involving ASK1 JNK p38 and ERK MAP kinases in E2F-1-mediated apoptosis a novel finding. Furthermore NFkappaB activation anddownregulation of inhibitors of apoptosis (IAPs specifically XIAP and cIAP-1)and the antiapoptotic Bcl-2 family member Mcl-1 were seen after E2F-1-overexpression again novel findings. Furthermore our preliminary studiesindicate that topoisomerase I and II agents and the drug temozolomide workcooperatively with E2F-1 to induce apoptosis in colon cancer and melanoma cellsin vitro and in vivo. Based on substantial preliminary data and the existingliterature we have proposed a model of the signal transduction pathwaysinvolved in E2F-1-mediated apoptosis. To evaluate this model and furtherdissect the molecular mechanisms of E2F-1-induced apoptosis SK-MEL-2 melanomaand HT-29 colon cancer cells will be studied. Following adenovirus-mediatedgene transfer we will analyze the role of Fas/FasL interaction JNK p38 andERK activation NFKB activation and XIAP cIAP-1 and Mcl-1 in E2F-1-mediatedapoptosis. Investigation will also be carried out using combinations ofadenovirus E2F-1 and specific chemotheraeutic agents that act cooperativelywith E2F-1 (adriamycin. camptothecin temozolomide) to evaluate the mechanismsby which E2F-1 augments the apoptotic response to chemotherapy. Finally anovel adenoviral vector expressing a truncated E2F-1 mutant that maintainsapoptotic function but lacks E2F-1 transactivation function will be constructedand tested for potential enhancement of tumor death. These studies will enhanceour understanding of E2F-1-mediated cell death and facilitate the design ofimproved treatment strategies.

project_terms:
CD95 molecule;antineoplastics;apoptosis;biological signal transduction;camptothecin;cell growth regulation;cell line;combination therapy;doxorubicin;drug resistance;gene therapy;genetic transduction;mitogen activated protein kinase;neoplasm /cancer chemotherapy;neoplasm /cancer genetics;neoplastic cell;northern blottings;temozolomide;transcription factor;western blottings


application_id: 6942672
project_number: 5U01AG021406-04
project_title: Aging: Effects on Infection Inflammation and Disease
administering_ic: NIA
award_notice_date: 2005-08-26
opportunity_number: RFA-AG-02-002
application_type: 5
activity_code: U01
ic: AG
serial_number: 021406
program_official: FLORES, ROBERTO L
project_start_date: 2002-09-01
project_end_date: 2007-08-31
study_section: ZAG1-ZIJ-5(M4)
contact_pi_person_id: 7875071
contact_pi: NOVAK, MICHAEL JOHN
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  This proposal is a collaborative submission from the University of Kentucky the University of Maryland and the Nutritional and Molecular Physiology Unit of the Laboratory of Neurosciences of the National Institute on Aging. The proposed studies will build on existing data obtained from Rhesus monkeys being maintained on calorie restricted and normal diets by the NIA and will provide a biologic basis for our preliminary observations of altered inflammatory responses in calorie restricted animals. This proposal focuses on utilizing the oral cavity as a model system to examine the impact of aging on host-bacterial interactions as they relate to microbial colonization of mucosal surfaces the induction and regulation of inflammatory/immune responses and the pathologic destruction of host tissues that may result from these interactions. The aims of this study will test the following contrasting scientific hypotheses: (a) that caloric restriction (CR) reduces clinical inflammation by affecting the pathogenicity of microbial plaque and that these changes are due to shifts in the proportions and/or clonal type of the constituent pathogenic and non-pathogenic microorganisms; (b) that CR alters the clinical manifestation of inflammation through an effect on innate immune mechanisms through increased pro-inflammatory molecule release; and/or (c) that CR alters the clinical manifestation of inflammation through an effect on innate immune mechanisms by regulating the release of anti-inflammatory molecules. Aim 1 is a cross-sectional retrospective study to determine the effects of a long-term calorie restricted diet on the progression of naturally occurring inflammatory periodontal disease in CR and non-CR Rhesus monkeys. The effects of CR on clinical inflammation microbial colonization of mucosal surfaces and pro-inflammatory and anti-inflammatory mechanisms will be evaluated. Aim 2 is a longitudinal prospective study to determine the effects of a calorie-restricted diet on the clinical microbiological and host responses observed during experimental ligature-induced periodontitis in the same CR and non-CR Rhesus monkeys. These studies will provide information on the effects of CR on the kinetics of clinical microbiologic and inflammatory changes at mucosal sites. The significance of these studies lies in our capability to use nonhuman primates and the oral cavity to evaluate the efficacy of CR as a means to regulate infection inflammation and inflammatory disease. The long-term implications are that diet control may be considered as an effective public healthcare measure for improving the oral and general health and welfare of the population as a whole.

project_terms:
Macaca mulatta;age difference;aging;bacterial cytopathogenic effect;bacterial disease;caloric dietary content;chemical fingerprinting;cooperative study;dietary restriction;enzyme linked immunosorbent assay;host organism interaction;immature animal;infection;inflammation;longitudinal animal study;mature animal;microorganism population study;molecular film;mucosal immunity;nucleic acid hybridization;nutrition related tag;oral bacteria;pathologic process;periodontium disorder;radiography


application_id: 6942611
project_number: 5R01AG005731-16
project_title: Age Associated Changes in B Lymphocyte Function
administering_ic: NIA
award_notice_date: 2005-08-12
application_type: 5
activity_code: R01
ic: AG
serial_number: 005731
program_official: FLORES, ROBERTO L
project_start_date: 1986-08-01
project_end_date: 2007-07-31
study_section: Immunobiology Study Section[IMB]
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
arra_indicator: N
budget_start_date: 2005-08-15
project_abstract:
DESCRIPTION (provided by applicant): Immune responses to pneumococcal               polysaccharide antigens are important for protection against pneumococcal           infections but are absent in neonates and are reduced in the aged. Using            Pnu-Imune vaccine that is made up of 23 serotypes of pneumococcal                   polysaccharides and TNP-Ficoll two type 2 thymus independent (TI)-2 antigens      we have shown that neonates and the aged have an accessory cell deficiency in       addition to their B-cell defects. This deficiency is overcome by                    supplementation with accessory cell derived cytokines IL-1 and IL-6. The           neonatal macrophages make less IL-l and IL-12 in response to TI stimuli such as     TNP-Ficoll and lipopolysaccharide. This application is directed at testing the      molecular basis of accessory cell defects leading to B-cell unresponsiveness to     polysaccharide antigens in the neonates and the aged. It is hypothesized that       toll-like receptor (TLR) expression and/or TLR signaling pathways may be            defective in neonatal macrophages. Also B-cell macrophage interactions             required for TI responses may involve the macrophage derived cytokine BLyS and      its B-cell receptors TACI and BCMA which may be dysfunctional in the neonate.     Towards this goal five specific aims are proposed. 1. To determine if the           defect in neonatal and the aged macrophages is limited to IL-1 and IL-12 or is      a general property of macrophages in the neonate and the aged. 2. To test the       hypothesis that the molecular nature of the defect in neonatal accessory cells      that contributes to TI-2 unresponsiveness is in TLR expression or in the TLR        signaling pathway. 3. To determine the role of dendritic cells in neonatal and      aged unresponsiveness to polysaccharide antigens. 4. To determine if the            restoration of neonatal B-cell responses to polysaccharides is due to their         ability to signal neonatal B-cells/accessory cells via TLR signaling pathway.       5. To determine the role of monocyte-derived TNF like molecule BLyS and its        receptor (TACI) in B-cell-macrophage interactions and to determine if neonates     or aged have defects in this ligand receptor system. Results from these studies     should in future allow us to design and test agents that can augment accessory      cell function and in turn to develop more effective polysaccharide vaccines for     the neonate and the aged.

project_terms:
B lymphocyte;Streptococcus pneumoniae;Streptococcus pneumoniae vaccine;aging;bacterial antigens;bactericidal immunity;biological signal transduction;cell cell interaction;cytokine;cytokine receptors;dendritic cells;developmental immunology;immune tolerance /unresponsiveness;interleukin 1;interleukin 12;laboratory mouse;macrophage;mature animal;newborn animals;receptor;receptor expression;tissue /cell culture


application_id: 6942601
project_number: 5R01AG020860-05
project_title: AGE AND SPECIFIC MECHANISMS OF VISUAL ATTENTION
administering_ic: NIA
award_notice_date: 2005-08-31
application_type: 5
activity_code: R01
ic: AG
serial_number: 020860
program_official: WAGSTER, MOLLY V
project_start_date: 2001-09-01
project_end_date: 2007-08-31
study_section: Special Emphasis Panel[ZRG1-BBBP-4(01)S]
contact_pi_person_id: 7876930
contact_pi: GOTTLOB, LAWRENCE 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: 2005-09-01
project_abstract:
DESCRIPTION: The goals of this project are to develop two explicit accounts of                              age effects in visual attention: 1) a model of complete RT distributions using      a random walk model and 2) a model of visual encoding functions. The               experiments will involve making measurements of subjects' reaction times and        accuracies under a variety of visual display conditions. Experiments 1-3 will       use long-duration (unmasked) targets and various display and stimulus              variables will be manipulated. Random walks will be fitted to the complete RT       distributions and the best-fit parameters will yield information about             age-group differences in attentional mechanisms. Experiments 4-6 will use           short-duration (masked) targets and accuracy will be measured as a function of     target duration. These encoding functions are expected to allow age-group           comparisons of attentional facilitation by taking sensory factors into explicit     account. Experiments 7-8 will extend the current methods of analysis to a           related attention paradigm. Analyses from the proposed project will allow us to     understand better the mechanisms of age-related change in attentional               facilitation.

project_terms:
age difference;attention;behavioral /social science research tag;clinical research;human middle age (35-64);human old age (65+);human subject;psychological tests;visual perception;visual stimulus;young adult human (21-34)


application_id: 6942575
project_number: 5R01AG016824-25
project_title: Odorant-Receptor Interactions in Olfactory Neurons
administering_ic: NIA
award_notice_date: 2005-08-15
application_type: 5
activity_code: R01
ic: AG
serial_number: 016824
program_official: MONJAN, ANDREW A
project_start_date: 1998-09-15
project_end_date: 2007-08-31
study_section: Integrative, Functional and Cognitive Neuroscience 4[IFCN-4]
contact_pi_person_id: 1879429
contact_pi: GETCHELL, THOMAS V
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-09-01
project_abstract:
DESCRIPTION (provided by applicant): The long-term objective of this project is to investigate intercellular signaling mechanisms that regulate progenitor cell proliferation and neurogenesis in the olfactory epithelium (OE). Short-term using target ablation to induce neuronal apoptosis followed by a synchronous wave of macrophage activation/infiltration and progenitor cell proliferation this project focuses on the role of macrophages as sources of bioactive molecules that regulate intercellular signaling. Innovative use of transgenic mice in pilot studies demonstrated that in the absence of activated macrophages progenitor cell proliferation is substantially reduced following target ablation. The data implicate the chemokine macrophage inflammatory protein (MIP)-1alpha and its receptor CCR1 in macrophage recruitment and suggest that the class A macrophage scavenger receptor (MSR-A) is involved in the clearance of apoptotic neurons thus linking apoptosis phagocytosis cell proliferation and neurogenesis. The proposed in vivo experiments focus on cellular and molecular events that occur at 2 his to 72 hrs after target ablation when macrophage infiltration and subsequent signaling is initiated by addressing three specific aims. The first is to characterize the tune course of mRNA expression for MIP-1alpha and CCR1 following target ablation and to localize their proteins in the OE. The second is to assess the effects of the absence of MIP-1alpha protein in MIP-1alpha-/- mice on macrophage infiltration and progenitor cell proliferation and to determine if the effects can be modulated by exogenous MIP-1alpha protein in knockout mice. The third is to examine the expression of MSR-A as a mediator of phagocytic clearance of apoptotic neurons by macrophages by comparing clearance in wild-type mice and MRS-A-/ mice. Gene profiling methodology will be used in the experiments on knockout mice to examine the involvement of additional chemokine receptors and/or signaling cascades. These studies will elucidate key components of the signaling pathways leading to progenitor cell proliferation and neurogenesis in the OE and establish the use of two new animal models in which to investigate OE cell dynamics in vivo. Understanding the signaling regulating neurogenesis in the OE will yield insights into mechanisms for restoring olfactory function compromised by aging trauma and neurodegenerative diseases.

project_terms:
apoptosis;biological signal transduction;cell proliferation;chemoreceptors;cytokine receptors;electron microscopy;enzyme linked immunosorbent assay;gene expression;genetically modified animals;immunocytochemistry;in situ hybridization;laboratory mouse;macrophage;macrophage inflammatory proteins;microarray technology;neurogenesis;neurons;olfactory lobe;olfactory nerve;phagocytosis;polymerase chain reaction;protein localization;respiratory epithelium;scavenger receptor;stem cells


application_id: 6941615
project_number: 5R44NS040588-03
project_title: Anatomy of the Central Nervous System-Multimedia Course
administering_ic: NINDS
award_notice_date: 2005-06-24
application_type: 5
activity_code: R44
ic: NS
serial_number: 040588
program_official: TALLEY, EDMUND M
project_start_date: 2000-07-01
project_end_date: 2007-06-30
study_section: Special Emphasis Panel[ZRG1-MDCN-L(10)B]
contact_pi_person_id: 1874094
contact_pi: FLEMING, JO E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 79-550-83
duns_number: 79-550-83
fips: US
organization_id: 3012901
organization_name: ORCCA TECHNOLOGY, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405071920
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-07-01
budget_end_date: 2007-06-30
assistance_listing_number: 93.853
project_abstract:
DESCRIPTION (provided by applicant): This project will develop evaluate and distribute an interactive multimedia program to provide interactive instruction about the human nervous system using a programmed learning format. The program will also provide extensive self-testing for the competencies to be acquired through interaction with the software program. The specific aims of the project are: A) to integrate the teaching of the various basic science courses that have a nervous system component including: embryology physiology cell biology histology and pathology and B) to produce an interactive multimedia software package that will provide a simulated in-class experience concerning the nervous system including organization of content interactive tasks built-in testing features and response-based feedback. The final result of the project will be an easily navigated stand-alone self-contained complete and easily distributable program packaged on a CD-ROM that can be used as a premiere ancillary or as a substitution for the neuroscience laboratory or lecture hall. Six specific objectives will be accomplished in Phase II and include: 1) refine modify and enhance the Phase I program architecture based on evaluation feedback 2) develop content for the remainder of the nervous system 3) create multimedia for the remainder of the nervous system tutorial and assessment features of the program 4) integrate multimedia components into the user interface 5) evaluate the program for usability and instructional effectiveness and 6) implement the plan for commercial distribution of the final product.

project_terms:
DVD /CD ROM;Internet;central nervous system;clinical research;computational neuroscience;computer assisted instruction;computer system design /evaluation;curriculum;developmental neurobiology;education evaluation /planning;educational resource design /development;embryology;health care personnel education;human subject;interactive multimedia;neuroanatomy;neurogenesis;neurophysiology


application_id: 6938549
project_number: 5R44GM058987-03
project_title: A NEW SUPPORT FOR THE SYNTHESIS OF BIOACTIVE PEPTIDES
administering_ic: NIGMS
award_notice_date: 2005-08-29
application_type: 5
activity_code: R44
ic: GM
serial_number: 058987
program_official: SCHWAB, JOHN M
project_start_date: 2001-02-15
project_end_date: 2008-02-29
study_section: Special Emphasis Panel[ZRG1-SSS-L(10)B]
contact_pi_person_id: 2475899
contact_pi: LONG, DEANNA W
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 106895766
primary_uei: R2GLRKJGMVP8
duns_number: 106895766
uei: R2GLRKJGMVP8
fips: US
organization_id: 2235101
organization_name: PEPTIDES INTERNATIONAL, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402993861
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-09-01
project_abstract:
DESCRIPTION (provided by applicant):  Many widely used therapeutically important peptide drugs and hormones (annual international sales: $13 billion) are cyclized by means of disulfide bridges. However the production of these peptides is difficult and expensive due to formation of numerous by-products. Current technology requires extensive purification which leads to lower yields and purities and results in high annual production costs. Our Phase I study produced a solid polymer-supported oxidant termed CLEAR-OX(TM) that successfully forms cyclic peptides. These improved synthetic conditions allow rapid purification through simple filtration. Product yields and purities were often better than those obtained by existing strategies. Since this SBIR program was last reviewed additional studies have been carried out on particularly challenging cyclizations; these showed how use of CLEAR-OX(TM) led to increased purities and yields with dramatic decreases in reaction times. Together these improvements will significantly lower annual production costs. Our Phase II prototype will be developed and tested in discrete steps in the following manner: (1) prototype optimization of the polymer-supported oxidant to demonstrate broad applicability; (2) quality control testing measured by the successful synthesis of bioactive drugs; (3) manufacturing process scale-up; and (4) commercial product usage studies of CLEAR-OX(TM). Our successful Phase I study indicates a commercially viable polymer-supported reagent will result from a Phase II project. We envision a successful commercialization plan to produce CLEAR-OX(TM) for leading pharmaceutical and research organizations developing disulfide-bridged peptide drugs. Currently no such commercial product exists. The commercial impact of this product could reach as much as $50 million.

project_terms:
biomedical equipment development;cyclic peptides;disulfide bond;oxidizing agents;peptide chemical synthesis;resin


application_id: 6938237
project_number: 1U60OH008483-01
project_title: Kentucky Occupational Safety and Health Surveillance
administering_ic: NIOSH
award_notice_date: 2005-05-13
opportunity_number: PAR-04-106
application_type: 1
activity_code: U60
ic: OH
serial_number: 008483
program_official: FREDERICK, LINDA J
project_start_date: 2005-07-01
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZOH1 BBK (06)]
contact_pi_person_id: 6608944
contact_pi: MCCOOL, ROBERT
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 927049767
primary_uei: LECJQDCLHVE5
duns_number: 927049767
uei: LECJQDCLHVE5
fips: US
organization_id: 4242701
organization_name: KY ST CABINET/HEALTH/FAMILY SERVICES
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406012321
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by the applicant):   Kentucky's occupational fatality rate is 6.9 deaths/100000 workers (Kentucky Fatality Assessment and Control Evaluation [FACE] program data 2003) 72.5 percent above the national rate of 4/100000 workers. Kentucky's nonfatal worker injury and illness rate is also greater than the national rate (7.1 injuries and illnesses/100 full-time workers compared to 5.3/100 nationally (Bureau of Labor Statistics 2003). The establishment of a fundamental occupational safety and health (OSH) surveillance program in a southeastern state Kentucky will target and unite resources from existing public health surveillance systems and identify and utilize new and existing sources of OSH data. The objectives are to identify worker populations work environments and other factors which contribute to occupational injury and develop state OSH data dissemination strategies to reduce Kentucky occupational injuries. The methodology consists of establishing and conducting comprehensive population-based surveillance of the 13 occupational injury and illness indicators recommended by the Council of State and Territorial  Epidemiologists and the National Institute for Occupational Safety and Health and fatal and nonfatal occupational motor vehicle collisions (MVCs) as another indicator using existing independent data systems: hospital discharge FACE Workers Claims (WC) Poison Control Center (PCC) Vital Statistics Kentucky Adult Blood Lead Epidemiology Surveillance Collision Report Analysis for Safer Highways emergency department (ED) and trauma registry data in addition to online resource data. Extensive analysis of 1) linked hospital discharge and WC datasets to examine occupational falls and: 2) linked CRASH hospital discharge ED and trauma datasets to examine nonfatal occupational motor vehicle collisions will be performed. Narrative data analysis of PCC data will be completed on occupational poisoning incidents. The feasibility of ED data and trauma systems data as independent and linked occupational heath data sources will be explored. We will initiate and expand partnerships with state and local stakeholders to establish a Kentucky state-specific consortium called "Kentucky-Working to SAFE Lives". We will analyze and disseminate surveillance data through the state consortium and other community stakeholders and a process and outcome evaluation of the major activities conducted will be performed.


application_id: 6937265
project_number: 5K01AG000986-06
project_title: Neuroimaging of Complex Motion in Young and Old Adults
administering_ic: NIA
award_notice_date: 2005-08-19
application_type: 5
activity_code: K01
ic: AG
serial_number: 000986
program_official: SUNEJA, SANOJ
project_start_date: 2001-09-30
project_end_date: 2007-08-31
study_section: Basic Neuroscience of Aging Study Section[NIA-N]
contact_pi_person_id: 7875188
contact_pi: JIANG, YANG
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: 2005-09-01
project_abstract:
DESCRIPTION (Provided by applicant):  The long-term career goal of the              candidate is to make significant scientific discoveries in cognitive                neuroscience and to apply research findings to improving the health and             mobility of the aging population. The immediate career objective is to become       an independent researcher involved in cutting-edge research in the                  neuroimaging of human cognitive aging. The candidate has past research              experience in cognitive neuroscience but further training in cognitive aging       theories and neuroimaging methods in aging are necessary to allow her to            attain her career goals.  The candidate will work with a mentor Raja               Parasuraman who has extensive expertise in cognitive neuroscience and aging         and who has a proven record of training students and fellows in these fields.       The training environment will involve a team of top researchers in cognitive        aging neuroscience and neuroimaging. This group will provide training in the      theoretical issues and analysis methods involved in cognitive and neuroimaging      studies in old participants as well as in the issues involved in the               comparison of neuroimaging data between young and old adults. The K01 award         will allow the candidate the time and support necessary to devote to her            research career development as an independent researcher in cognitive aging         and cognitive neuroscience. In her research plan the candidate will examine        how the human brain processes visual information about complex motion (e.g.        shape-from-motion) and what cortical mechanisms mediate age-related changes        in complex motion perception. The topic is important because many everyday          tasks carried out by older adults such as walking driving and playing            sports are critically dependent on the processing of complex visual motion by      the brain. The objective is to identify the human cortical representation of        surfaces and objects defined by motion in young and old adults using both          behavioral methods and functional magnetic resonance imaging (fMRI). The            central hypothesis is that deficits in recognizing objects in relative motion       in old age are due to changes in the functional efficiency of specific              cortical areas in the brain. Additionally complex motion processing is              mediated by cortical regions beyond the simple motion processing areas in the       human visual cortex. Specifically the proposed studies will (1)identify the        human cortical areas associated with the processing of motion-defined flat and      curved surfaces in depth; (2) identify the cortical areas mediating the             processing of shape-from-motion using attention modulation; and (3) determine       the neural basis of age-related decreases in ability to process visual              information about complex motion. Combination of behavioral and neuroimaging        methods will lead to successful establishment of causal relationships between       visual motion processing and cortical function (or dysfunction) in the young        and old. This will provide a foundation for the further development of              diagnostic and therapeutic tools to address important health and mobility           problems in the elderly.

project_terms:
age difference;aging;behavior test;bioimaging /biomedical imaging;brain electrical activity;brain imaging /visualization /scanning;brain mapping;clinical research;cognition;epidemiology;form /pattern perception;functional magnetic resonance imaging;human old age (65+);human subject;motion perception;neural information processing;neurosciences;postdoctoral investigator;visual feedback;young adult human (21-34)


application_id: 6937248
project_number: 5F30MH065055-05
project_title: Dynorphin in Age-related Impairment of Learning/Memory
administering_ic: NIMH
award_notice_date: 2005-08-23
opportunity_number: PA-99-089
application_type: 5
activity_code: F30
ic: MH
serial_number: 065055
program_official: PINARD, COURTNEY ROSE
project_start_date: 2002-09-17
project_end_date: 2006-09-16
study_section: Special Emphasis Panel[ZRG1-BDCN-1(20)L]
contact_pi_person_id: 6840433
contact_pi: NGUYEN, XUAN V
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: (Verbatim from applicant?s abstract): Impairment of learning andmemory is a common phenomenon associated with advancing age although theunderlying mechanisms are not clearly understood. Based on previous reports ofage-correlated increases in dynorphin expression in the brain and on studies ofeffects of dynorphin in vivo and in vitro we are investigating a possible roleof the endogenous opioid neuropeptide dynorphin in age-associated decline inmental health. We have recently found that moderately aged prodynorphinknockout mice perform significantly better than similarly aged wild-type micein a spatial learning and memory task suggesting an important role of thispeptide in causing memory dysfunction. We hypothesize that age-relatedalterations in hippocampal dynorphin levels contribute substantially tofunctional impairment of learning and memory by altering glutamateneurotransmission or other synaptic activities. To test this hypothesis wepropose a set of behavioral assays to assess hippocampal-dependent learning andmemory processes in dynorphin knockout mice and wild-type mice of varying ages.In addition we will supplement the behavioral studies withelectrophysiological analysis and anatomical characterization of specific siteswithin hippocampus where dynorphin is localized. These experiments will allowus to determine the functional role of hippocampal dynorphin in modulatingneuronal activity associated with learning and memory processes which may leadto novel therapeutic strategies for the treatment of learning and memorydysfunction.

project_terms:
aging;behavior test;behavioral /social science research tag;brain electrical activity;disease /disorder onset;dynorphins;genetically modified animals;glutamates;hippocampus;laboratory mouse;learning;memory;memory disorders;neural transmission;neuropeptides;predoctoral investigator;psychological aspect of aging;synapses


application_id: 6936618
project_number: 5K22DE014086-06
project_title: Transcriptional Regulation of Osteoclasts by Mitf
administering_ic: NIDCR
award_notice_date: 2005-07-27
opportunity_number: PAR-00-097
application_type: 5
activity_code: K22
ic: DE
serial_number: 014086
program_official: HARDWICK, KEVIN S
project_start_date: 2001-09-01
project_end_date: 2007-07-31
study_section: ZDE1-WG(02)
contact_pi_person_id: 7875075
contact_pi: LIN, YI-LING
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:
Recent advances in bone biology have revolutionized dentistry. With better understanding of how osteoblasts respond to bone-forming signals dentists now can use a variety of grafting materials to perform bone augmentation procedures and grow bone "de novo". In contrast it is still largely unknown how osteoclasts regulate their activity in response to local factors. This knowledge is of great importance to the dental profession since so many dental diseases are directly or indirectly the result of unwanted osteoclast activation. One critical regulator of osteoclast activity is Microphthalmia transcription factor (Mitt). Mice carrying semidominant Mitf alleles exhibit various degrees of osteopetrosis indicating Mitf is a promising tool for studying gene regulation in osteoclasts. The objective of the proposed study is to gain knowledge of the transcriptional regulation of osteoclasts by Mitf and three other family members TFEB TFEC and TFE3 (the four proteins form the "MiT" family). Since Mitf semidominant mutant mice exhibit an age-dependent phenotype the chronological expression profiles of MiT proteins during osteoclast development will be examined since this would be consistent with functional rescue of Mitf by family members. MAPK and Rsk/PKA have previously been demonstrated to phosphorylate Mitf in melanocytes which resulting in Mitf activation. To examine if similar processes occur in osteoclasts recombinant MiT mutant viruses carrying disrupted MAPK and Rsk/PKA phosphorylation sites will be used and the resulting phenotypic changes will be analyzed. Mitf has been found to regulate cytoskeletal changes in response to maturation signals during fetal osteoclast fusion. Overexpression of the individual MiT protein in fetal mi/mi osteoclasts (which do not fuse or form multinucleated giant cells) will be tested for the ability to rescue the fusion defect. Since Mitf may affect multinucleate giant cell formation by regulating the expression of molecules essential for osteoclast fusion candidates known to be essential for this process (such as vitronectin receptor and osteopontin) will be examined for their relationship with Mitf.

project_terms:
Adenoviridae;Retroviridae;biological signal transduction;cell growth regulation;dimer;embryo /fetus tissue /cell culture;enzyme activity;gene expression;genetic regulation;laboratory mouse;laboratory rat;microphthalmos;mitogen activated protein kinase;monoclonal antibody;mutant;osteoclasts;osteopetrosis;phosphorylation;protein kinase A;protein structure function;transcription factor;transfection /expression vector


application_id: 6935173
project_number: 5F31MH072065-02
project_title: Determinants of Stimulus Preference
administering_ic: NIMH
award_notice_date: 2005-07-15
application_type: 5
activity_code: F31
ic: MH
serial_number: 072065
program_official: PINARD, COURTNEY ROSE
project_start_date: 2004-08-01
project_end_date: 2005-12-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 7893322
contact_pi: DIGIAN, KELLY A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-08-01
project_abstract:
DESCRIPTION (provided by applicant): The proposed experiments will examine the within-trial contrast effect reported by Clement Feltus Kaiser and Zentall (2000) and Clement and Zentall (2002). Clement et al. reported that when given a choice between a stimulus that followed a high effort requirement and a stimulus that followed a low effort requirement pigeons preferred the stimuli that followed greater effort. They attributed the stimulus preference to a within-trial contrast effect in which stimuli that follow effort appear to have more value when compared to the aversive event that preceded it. Clement and Zentall found support for a contrast account by manipulating the expectation of effort. In their experiments pigeons preferred the stimuli that were associated with a high effort initial stimulus. While their design suggests that a contrast effect can produce a stimulus preference it did not rule out a delay reduction account or an effect of effort in Clement et al.'s design. The first set of experiments will determine whether a delay reduction account or an effect of effort could have contributed to the stimulus preference found by Clement et al. The second set of experiments will examine the effects of manipulating reinforcement on the within-trial contrast effect.

project_terms:
animal population study;behavior;behavior test;behavioral /social science research tag;cognition;ethology;learning;memory;pigeons;predoctoral investigator;preference;reinforcer;stimulus /response


application_id: 6934829
project_number: 1R43NS045448-01A3
project_title: Kinematic Biofeedback for Independent Motor Retraining
administering_ic: NINDS
award_notice_date: 2005-04-21
application_type: 1
activity_code: R43
ic: NS
serial_number: 045448
suffix: A3
program_official: CHEN, DAOFEN
project_start_date: 2005-05-01
project_end_date: 2008-04-30
study_section: Special Emphasis Panel[ZRG1 MRS (01)]
contact_pi_person_id: 7771781
contact_pi: HARTMAN, ERIC C
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 129360637
duns_number: 129360637
fips: US
organization_id: 4168101
organization_name: CUSTOMKYNETICS, INC.
organization_city: VERSAILLES
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403401290
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-05-01
budget_end_date: 2008-04-30
project_abstract:
DESCRIPTION (provided by applicant): This project proposes to develop a device that will improve the quality and availability of motor retraining for individuals with neuromotor disorders due to stroke or incomplete spinal cord injury. Biofeedback of postural control variables such as ground reaction force and center of pressure sway has been used effectively however existing devices are not suitable for use by many patients and are not widely available. We propose to develop a therapeutic system that enables patients to practice clinically-relevant closed chain lower-extremity tasks (sit-to-stand transitions and balance shifts) and that uses visual biofeedback of kinematic variables to encourage use of the affected limb(s). We anticipate that use of the proposed device will improve the efficacy of traditional therapy by allowing patients to begin sit-to-stand and balance shift exercises earlier in the rehabilitation process because the proposed mechanical device will reduce the risk of falls.  In Phase I we will: 1} modify an existing exercise device to provide visual biofeedback of measured variables 2) develop clinically relevant biofeedback exercises 3) evaluate the biofeedback displays in a study involving age-matched individuals without a neuromotor deficit and 4) demonstrate feasibility of the approach in a pilot study where patients use the device as one component of their traditional therapy during acute rehabilitation following stroke. The pilot study wilt provide insight into the following objectives: 1) determine if the device can be used safely for this population 2} determine if patients can understand the biofeedback information and complete the specified tasks 3) determine if the device is viewed as a beneficial form of therapeutic exercise by both physical therapists and patients and 4) determine if a rehabilitation program using the device improves the rate of recovery and/or the efficacy of traditional therapy.  In Phase II we will improve the biofeedback interface optimize the protocols to improve transference develop custom electronics to generate the biofeedback displays and test the system in an extensive clinical trial.  The target market for the device is rehabilitation hospitals and clinics that serve patients following stroke or incomplete spinal cord injury.

project_terms:
biofeedback;biomechanics;biomedical equipment development;clinical biomedical equipment;clinical research;exercise;human subject;human therapy evaluation;musculoskeletal disorder therapy;nervous system disorder therapy;neuromuscular disorder;neuromuscular function;patient oriented research;rehabilitation;spinal cord injury;stroke;visual stimulus


application_id: 6934758
project_number: 1R43DK071354-01
project_title: A new ATP delivery system for liver transplantation
administering_ic: NIDDK
award_notice_date: 2005-09-09
application_type: 1
activity_code: R43
ic: DK
serial_number: 071354
program_official: DENSMORE, CHRISTINE L
project_start_date: 2005-09-10
project_end_date: 2007-02-28
study_section: Special Emphasis Panel[ZRG1 SSMI (10)]
contact_pi_person_id: 3148961
contact_pi: EHRINGER, WILLIAM D
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 130225076
duns_number: 130225076
fips: US
organization_id: 10000187
organization_name: VITATECH, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021250
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-09-10
budget_end_date: 2007-02-28
assistance_listing_number: 93.848
project_abstract:
DESCRIPTION (provided by applicant):   
Major limitations in liver transplantation are primary graft failure leading to consumption of the already small donor pool. ATP depletion has been proposed to be involved in graft failure due to both prolonged storage and to transplantation of marginal fatty livers: Our recent developments of a fusogenic lipid vesicles that deliver ATP are therefore a promising therapy to treat primary nonfunction. The goals of the proposed work are to characterize and optimize existing formulations of our lipid vesicles for delivery of ATP to protect against primary graft failure. First the rate of fusion of lipid vesicles to liver cells and delivery of ATP will be determined using cultured primary parenchymal and non-parenchymal (endothelial and Kupffer) cells. We will then determine the effect of delivery of ATP on cell death caused by hypoxia in culture. From these experiments the 3 most promising formulations will be further studied. Next livers will be cold-stored in UW solution (0-48 h) and subsequently perfused on a liver perfusion block as a model of cold storage -induced reperfusion injury; UW solution containing our vesicles (0-5 mg/mL) and Mg-ATP (0-10 mM) will be infused into the organ at the initiation of storage (0-48 h). To mimic primary graft failure due to acute ethanol administration some animals will be pretreated with ethanol (5 g/kg i.g.) 20 h prior to explant surgery.  Primary endpoints include cell death the production of free radicals and indices of metabolic activity and redox states. From these experiments the most effective vesicle preparation will be identified. Taken together the expected results of this proposed work will identify optimal conditions for delivery of ATP to cold-stored livers with lipid vesicles. Such results would not only serve as proof-of-principle of the long-standing hypothesis that ATP pools are critical during liver transplant but also identify a unique therapy that could then be readily applied to the clinical situation where such a therapy is critically needed.

project_terms:
Kupffer&apos;s cell;adenosine triphosphate;aldehydes;apoptosis;high performance liquid chromatography;immunocytochemistry;laboratory rat;liposomes;liver ischemia /hypoxia;liver transplantation;necrosis;oxygen consumption;reperfusion;technology /technique development;tissue /cell culture;transplant rejection;video microscopy


application_id: 6934288
project_number: 1R43AG026168-01
project_title: Characterizing marrow derived cells for neural therapy
administering_ic: NIA
award_notice_date: 2005-05-30
application_type: 1
activity_code: R43
ic: AG
serial_number: 026168
program_official: WISE, BRADLEY C
project_start_date: 2005-06-01
project_end_date: 2005-11-30
study_section: Special Emphasis Panel[ZRG1 BDCN-E (11)]
contact_pi_person_id: 6476481
contact_pi: BOARDMAN, KENDRICK C
other_pis: Not Applicable
congressional_district: 06
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: 2005-06-01
budget_end_date: 2006-05-31
assistance_listing_number: 93.866
project_abstract:
DESCRIPTION (provided by applicant):  Neurodegenerative diseases and injuries of the central nervous system (CMS) - such as Alzheimer's disease Parkinson's desease amytrophic leteral sclerosis (ALS) and stroke - disable and kill millions of American's each year yet there is no cure or even effective treatment for any of these diseases. The discovery of multipotent neural stem cells (NSCs) in adult brain has brought about revolutionary changes in the theory of neurogenesis; however therapies being developed from embryonic stem cells and NSCs directly isolated from brains are fraught with a number of technical (tumor-/teratoma- genesis uncontrolled multipotency sourcing require immune suppression) and ethical hurdles which have hindered rapid progress toward human therapy. This proposal builds upon the innovative discovery that bone marrow-derived cells (MDCs) cultured in the presence of a specific chemical agent leads to the generation of ACT-N(tm) cells that are capable of migrating and differentiating into new neural and glial cells when implanted into the lateral ventricle of rodent brains. Our long-term goal is to develop ACT-N cells as an effective therapy for patients with debilitating conditions of the CNS including but not limited to stroke Alzheimer's disease Parkinson's disease and age-related memory impairment. To achieve this goal we need to explore the potential ability of ACT-N cells to replace and/or augment the native repair mechanisms that are activated in CNS during disease and/or injury and also to develop robust and reproducible manufacturing strategies with the necessary safety quality and process controls. In regards to the latter need this research plan intends to identify unique characteristics of ACT-N cells that differ from the MDCs from which they are derived including immunophenotype DNA methylation levels and differentiation potential. In addition initial considerations pertaining to ACT-N safety will be addressed.

project_terms:
DNA methylation;aging;astrocytes;athymic mouse;biomarker;bone marrow;bromodeoxyuridine;carcinogenesis;cell differentiation;cell line;cell migration;cell population study;cell transplantation;cytogenetics;flow cytometry;hematopoietic stem cells;human tissue;immunocytochemistry;immunogenetics;karyotype;mixed tissue /cell culture;nervous system regeneration;neural degeneration;neurogenesis;neurons;oligodendroglia;therapy design /development


application_id: 6933846
project_number: 5R21CA104230-02
project_title: A Role for Nucleolin in Malignant Transformation?
administering_ic: NCI
award_notice_date: 2005-07-26
opportunity_number: PA-03-041
application_type: 5
activity_code: R21
ic: CA
serial_number: 104230
program_official: SPALHOLZ, BARBARA A
project_start_date: 2004-08-06
project_end_date: 2008-07-31
study_section: Cancer Molecular Pathobiology Study Section[CAMP]
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
project_abstract:
DESCRIPTION (provided by applicant): As a result of our discovery that nucleolin is the likely target of novel aptamer oligonucleotides with strong antitumor activity we have become interested in the role of this protein in cancer biology.  We have proposed that the tumor-selective effects of these aptamers occur because certain nucleolin functions are more critical for the survival of transformed cells than for normal cells.  Elevated levels of nucleolin are already known to be associated with malignant progression and poor clinical prognosis in a variety of cancers.  However because the best characterized functions of nucleolin involve ribosome biogenesis it is commonly supposed that this relationship merely reflects the higher proliferative activity of malignant cells. For this reason the functional role of nucleolin in cancer has not been extensively studied. The central hypothesis of this proposal is that rather than being simply a marker for cancer nucleolin overexpression actively contributes to the process of malignant transformation. This postulate is based in part on a number of recent studies that have identified new functions for nucleolin many of which could potentially promote the development survival or progression of the malignant phenotype.  In addition preliminary data indicate that expression of antisense nucleolin mRNA in Hela tumor cells leads to reduced proliferation and suppression of anchorage-independent growth whereas HeLa cell lines overexpressing nucleolin exhibit a more aggressive phenotype compared to wild type cells. The aim of the proposal is to test the hypothesis that overexpression of nucleolin can cause neoplastic transformation of normal cells in vitro and in vivo This will be achieved by creating NIH3T3-derived cell lines with stable high level expression of nucleolin and generating transgenic mice that have prostate-targeted overexpression of nucleolin. Cell lines will be analyzed for standard features of malignancy such as altered morphology increased proliferation anchorage-independent growth decreased sensitivity to apoptotic stimuli enhanced migration and tumorigenicity in nude mice. Transgenic mice will be examined histologically for malignant or pre-malignant changes of the prostate. Success in demonstrating that nucleolin overexpression functionally contributes to malignant transformation would open up new avenues for exploration in cancer research and firmly establish nucleolin as a novel target for therapeutic intervention.

project_terms:
3T3 cells;HeLa cells;apoptosis;cell morphology;cell proliferation;genetically modified animals;laboratory mouse;messenger RNA;neoplastic transformation;northern blottings;oligonucleotides;prostate neoplasms;protein quantitation /detection;terminal nick end labeling;tissue /cell culture;western blottings


application_id: 6931442
project_number: 1T01OH008437-01
project_title: Occuaptional Safety and Health Program Improvement
administering_ic: NIOSH
award_notice_date: 2005-06-16
opportunity_number: RFA-OH-05-001
application_type: 1
activity_code: T01
ic: OH
serial_number: 008437
program_official: TALTY, JOHN
project_start_date: 2005-07-01
project_end_date: 2010-06-30
study_section: Special Emphasis Panel[ZOH1 SPC (01)]
contact_pi_person_id: 8075543
contact_pi: KRAEMER, DAVID G
other_pis: Not Applicable
congressional_district: 01
department: OTHER HEALTH PROFESSIONS
primary_duns: 041980632
primary_uei: LHC2S92MXG63
duns_number: 041980632
uei: LHC2S92MXG63
fips: US
organization_id: 5591701
organization_name: MURRAY STATE UNIVERSITY
organization_city: MURRAY
organization_state: KY
organization_type: OTHER SPECIALIZED SCHOOLS
organization_zip: 420712393
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION  
Murray State University offers both a BS and MS degree in Occupational Safety and Health. Both programs are accredited by ASAC/ABET. The programs are located within the College of Health Sciences and Human Services. The BS offers options in (1) safety and (2) environmental; the MS offers options in (1) safety management (2) industrial hygiene and (3) environmental. Students who have not worked as a safety professional are required to spend time as a safety intern/co-op. The program has extensive internal support and they are requesting funding primarily for traveling and oversight of the internships improving interdisciplinary courses faculty development and support for students.


application_id: 6931241
project_number: 5R24HS011845-05
project_title: Kentucky HSR Development II
administering_ic: AHRQ
award_notice_date: 2005-07-27
opportunity_number: RFA-HS-03-004
application_type: 5
activity_code: R24
ic: HS
serial_number: 011845
program_official: ANDERSON, KAY
project_start_date: 2001-09-30
project_end_date: 2008-06-30
study_section: ZHS1-HSR-H(03)
contact_pi_person_id: 1860311
contact_pi: FLEMING, STEVEN THOMAS
other_pis: Not Applicable
congressional_district: 06
department: ADMINISTRATION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (PROVIDED BY APPLICANT):  The overall goal of the Kentucky HSR Continuation Project is to sustain a stream of health services research funding from the Agency for Healthcare Research and Quality (AHRQ) the National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC) by improving institutional infrastructure and capacity and promoting collaboration of family physicians with other health services researchers. This is a collaborative research development effort by the University of Kentucky School of Public Health the Center for Health Services Management and Research the Department of Family Practice & Community Medicine and the Martin School of Public Policy and Administration. The aims of the project are (1) To improve faculty capacity to develop research ideas into fundable applications and written publications; (2) To promote the collaboration of physicians with other health services researchers across campus; and (3) To cultivate research ideas from the Kentucky Ambulatory Network (KAN) into research designs and fundable applications. This project includes three Investigator-Initiated Projects.  (1) A two-year project "Designing Support for Colorectal Screening Decisions" proposes to explore how providers make decisions regarding colorectal cancer screening and develop decision aids to inform providers' decisions to deliver and patients' decisions to utilize colorectal cancer screening.  (2) A three-year project "Quality Improvement in Telephone Medicine" proposes to advance the state of knowledge about telephone medicine in the ambulatory practice setting. The project will (a) analyze the telephone medicine systems at the University of Kentucky from a systems perspective looking for potential threats to patient safety and (b) develop and field-test a systems-based method for evaluating and redesigning the handling of telephone calls in a residency setting to maximize patient safety and efficiency.  (3) A one-year project in year three "Participatory Development of a Generic Detailing Program with a Primary Care Research Network" will distribute generic drug samples in an office-based primary care research network and track the effect of generic sampling on physician and patient behavior. Each of these three projects involves the collaboration of academic family physicians with health services research scientists at the University of Kentucky. The three projects address AHRQ research priorities of prevention patient safety/quality and translational research involving costs respectively.

project_terms:
behavioral /social science research tag;clinical research;health care service planning;health science research support;health services research tag


application_id: 6931074
project_number: 5F32AI056970-03
project_title: Manipulation of the host NF-kappa B pathway by Toxopla
administering_ic: NIAID
award_notice_date: 2005-08-09
application_type: 5
activity_code: F32
ic: AI
serial_number: 056970
program_official: WALI, TONU M
project_start_date: 2003-09-01
project_end_date: 2006-08-31
study_section: Special Emphasis Panel[ZRG1-F08(20)L]
contact_pi_person_id: 9248901
contact_pi: MOLESTINA, ROBERT
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-09-01
project_abstract:
DESCRIPTION (provided by applicant): Toxoplasma gondii is an obligate intracellular protozoan parasite which causes opportunistic disease in immunodeficient individuals and congenital disease in newborns. T. gondii is widely regarded as one of the most successful parasites on earth because of its broad host range and capability to establish an asymptomatic life-long chronic infection in immunocompetent populations. One of the strategies used by T. gondii to avoid destruction by the infected host cell is the inhibition of apoptosis. Studies performed by the candidate have shown that T. gondii induces a survival response in infected cells via NF-kappa B-dependent up-regulation of anti-apoptotic genes. Remarkably activation of the NF-kappa B pathway by T. gondii occurs through an unconventional mechanism which is independent of the host I-kappa B kinase (IKK). In addition the evidence suggests the presence of a parasite-derived factor(s) capable of hijacking and phosphorylating I-kappa B. Identification of this factor(s) would provide insight into the modulation of host cell signaling events by Toxoplasma and reveal potential therapeutic targets. The proposed studies in this proposal will apply biochemical and molecular genetic approaches to characterize the putative I-kappa B kinase activity in T. gondii and address the following hypothesis: "Toxoplasma gondii manipulates the NF-kappa B pathway of the host cell by recruiting and phosphorylating I-kappa B via a parasite encoded factor(s) that can function autonomously from host IKK." To fulfill this hypothesis the applicant will: (1) determine the activity of a parasite kinase capable of phosphorylating I-kappa B in subcellular fractions of T. gondii; and (2) identify protein candidates in T. gondii with I-kappa B kinase activity by proteomic and genomic analyses.

project_terms:
I kappa B beta;SDS polyacrylamide gel electrophoresis;Toxoplasma gondii;apoptosis;cytogenetics;enzyme activity;gene expression;high throughput technology;host organism interaction;immunoprecipitation;mass spectrometry;matrix assisted laser desorption ionization;nuclear factor kappa beta;parasite infection mechanism;phosphorylation;postdoctoral investigator;protein kinase;protein protein interaction;proteomics;two dimensional gel electrophoresis


application_id: 6930631
project_number: 5R01DK051656-09
project_title: Regulation of the Steroidogenic Acute Regulatory Protein
administering_ic: NIDDK
award_notice_date: 2005-08-01
application_type: 5
activity_code: R01
ic: DK
serial_number: 051656
program_official: MARGOLIS, RONALD N
project_start_date: 1996-08-15
project_end_date: 2007-01-31
study_section: Reproductive Biology Study Section[REB]
contact_pi_person_id: 1883484
contact_pi: CLARK, BARBARA J
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-08-01
project_abstract:
DESCRIPTION: (provided by applicant) Steroidogenesis in the adrenal and gonads      is acutely controlled by tropic hormones via regulating the synthesis of the        steroidogenic acute regulatory (StAR) protein. StAR synthesis is critical for       cholesterol translocation across the mitochondrial outer membrane to the inner      membrane where the first enzymatic step in steroidogenesis occurs; cholesterol      conversion to pregnenolone by the cholesterol side-chain cleavage enzyme.           Mutation(s) in the StAR gene that lead to the production of a non-functional        protein is the genetic basis for the disorder lipoid congenital adrenal             hyperplasia (LCAH). LCAH patients have markedly impaired adrenal and gonadal        steroidogenesis due to the inability to transport cholesterol into                  mitochondria. Thus understanding the mechanisms that control StAR expression       and function is fundamentally important. Multiple signaling pathways have been      shown to regulate StAR at both the transcriptional and post-transcriptional         level in a cell-specific manner. StAR transcription and protein expression         however appear to be independently regulated by the cAMP-protein kinase a          pathway. The overall objective for this research is to elucidate the molecular      mechanisms for the cAMP-dependent regulation of StAR expression at the              transcriptional and translational and post-translational levels in mouse           Leydig and adrenal cells. The studies outlined in this proposal will determine      whether I) the cAMP-dependent increase in StAR gene activation involves both        loss of repressor and gain of activator functions 2) the level of                 cAMP-dependent protein kinase A activity distinguishes StAR (acute) from CYP1       IA (chronic) gene expression 3) protein kinase A functions at the                  post-transcriptional level to control StAR protein expression and 4) StAR is       translated on polysomes associated with mitochondria. Defining the specific         mechanisms for cAMP-dependent StAR regulation within one cell type is important     in defining the similarities and differences in tropic hormone action on            adrenal ovarin and testicular production of steroids. This will ultimately        lead to a better understanding of potential developmental or disease states         that result from aberrant over- or under-expression of StAR in a cell-specific      manner.

project_terms:
Leydig cells;adrenal glands;adrenocorticotropic hormone;cholesterol;cyclic AMP;enzyme activity;gene expression;genetic promoter element;genetic regulation;genetic transcription;genetic translation;hormone regulation /control mechanism;membrane transport proteins;mitochondria;phosphorylation;polysomes;posttranscriptional RNA processing;posttranslational modifications;pregnenolone;protein biosynthesis;protein kinase A;reporter genes;steroid hormone biosynthesis;tissue /cell culture;transcription factor


application_id: 6930614
project_number: 5R01NS045087-02
project_title: Early Treatment of ALS with Nutrition and NIPPV
administering_ic: NINDS
award_notice_date: 2006-02-28
opportunity_number: PAR-01-119
application_type: 5
activity_code: R01
ic: NS
serial_number: 045087
program_official: CONWIT, ROBIN
project_start_date: 2004-08-01
project_end_date: 2009-11-30
study_section: Neurological Sciences and Disorders K Study Section[NSD-K]
contact_pi_person_id: 1975664
contact_pi: KASARSKIS, EDWARD JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Studies to date indicate that Percutaneous Endoscopic Gastrostomy (PEG) and Non-Invasive Positive Pressure Ventilation (NIPPV) improve survival in Amyotrophic Lateral Sclerosis (ALS) even though introduced late in the disease. We hypothesize that early intervention may improve outcome even further.  However many issues regarding the early use of these treatments preclude the design of a Phase III clinical trial to test this hypothesis. Common to both NIPPV and nutrition is a lack of a reliable indicator of early respiratory or nutritional insufficiency. With respect to nutrition we need reliable and cost effective methods to determine a patient's energy (i.e. caloric) requirements during different stages of the illness and base the recommendation for PEG on the adequacy of energy intake. For NIPPV we need to identify factors that influence acceptance and tolerability of this therapy and measurements of early respiratory dysfunction. Therefore we propose this multicenter Pilot Study to develop methods for a definitive Phase III trial. The Specific Aims of this Pilot Study are: 1) To develop and validate strategies to improve tolerability of NIPPV to identify factors that influence acceptance of this treatment modality and to evaluate measures of early respiratory dysfunction; and 2) To develop and validate methods to determine energy balance in ALS.  In this Pilot Study all 11 sites will enroll patients using a stratified design based on FVC (80-95% vs 50-79%) and offer NIPPV as they decline to the lower limit of this FVC level. Six sites will collect additional detailed information to critically evaluate acceptability of NIPPV devise strategies to improve tolerance and validate this approach as well as collect respiratory measurements that may allow earlier identification of failure. The other 5 sites will use the "gold standard" Doubly Labeled Water method in a longitudinal design to derive empiric equations to reliably predict individual energy needs based on easily performed clinical measures. The results of this Pilot Study will allow us to develop and validate methods so that we can design a multicenter Phase III trial to determine the efficacy of early NIPPV and nutritional intervention. In addition our results will be immediately applicable for use by clinicians in practice and will provide the basis to re-formulate the experimental design of future drug trials in ALS.

project_terms:
amyotrophic lateral sclerosis;bioenergetics;caloric dietary content;clinical research;combination therapy;human subject;human therapy evaluation;nervous system disorder therapy;nutrition;nutrition related tag;patient care management;patient oriented research;quality of life;therapy compliance;therapy design /development


application_id: 6929974
project_number: 5R37AA010762-11
project_title: Tumor Necrosis Factor and Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2005-07-25
application_type: 5
activity_code: R37
ic: AA
serial_number: 010762
program_official: GENTRY, THOMAS
project_start_date: 1996-03-01
project_end_date: 2006-07-31
study_section: Alcohol and Toxicology Subcommittee 4[ALTX-4]
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: 2005-08-01
project_abstract:
DESCRIPTION (Applicant's Abstract): Alcoholic liver disease (ALD) is a major        cause of liver disease and liver related morbidity/mortality in the United          States. One major difficulty in devising specific therapies for ALD has been        our limited understanding of the mechanism(s) for the development and               progression of this liver injury. Cytokines are low molecular weight mediators      of cellular communication that are produced and released by numerous cell types     such as monocytes macrophages and of particular relevance to liver disease       Kupffer cells. Pro-inflammatory cytokines such as tumor necrosis factor a          (TNF) and chemokines such as interleukin-8 have been postulated to play a        role in modulating many of the systemic manifestations of ALD and certain           aspects of the liver injury in ALD. Many factors stimulate cytokine production     including endotoxin (lipopolysaccharide or LPS) and reactive oxygen                 intermediates (ROIs) both of which are of direct relevance to this proposal.       Endotoxin stimulates cytokine production via interaction with LPS binding           protein (LBP); membrane bound CD 14 and ultimately the recently described LPS      receptor Toll-like receptor TLR4. TLR4 then causes activation of the redox         sensitive transcription factor NFkB with subsequent production of cytokines       such as TNF. NFKB also has been identified as a survival factor against TNF         induced apoptosis in multiple cell types. Thus NFKB not only serves as a           transcription factor for several inflammatory cytokines such as TNF and IL-8       but also for several potentially protective factors such as inhibitors of           apoptosis (lAPs). Inhibition of NFkB can initiate fulminant liver injury and        hepatocyte apoptosis at least in part by allowing unregulated signaling via       the TNF "death domain." We postulate that in ALD there is: 1) increased NFkB        activation and TNF production in the major cytokine producing cell in the liver     (Kupffer cell); and 2) decreased NFkB activation and decreased "protective          signaling" in conjunction with increased TNF death signaling in the target cell     (hepatocyte). In this proposal we will use in vitro systems in vivo animal        models of ALD and ultimately will perform translational human studies to            further define mechanisms of liver injury in ALD and potential pathways for         intervention. The specific aims of this proposal are to: 1) Evaluate mechanisms     for increased NFkB activation and TNF production by monocyte/Kupffer cells in       ALD (priming) 2) Evaluate mechanisms of increased susceptibility to                TNF/cytokine hepatotoxicity in ALD (sensitization).

project_terms:
Kupffer&apos;s cell;alcoholic hepatitis;alcoholic liver cirrhosis;alcoholism /alcohol abuse;biological signal transduction;cellular pathology;cytokine;cytotoxicity;ethanol;human tissue;interleukin 8;laboratory mouse;leukocyte activation /transformation;liver cells;monocyte;nuclear factor kappa beta;pathologic process;proteasome;tumor necrosis factor alpha


application_id: 6929947
project_number: 5R21AA014032-03
project_title: Polyamines in neonatal alcohol neurotoxicity
administering_ic: NIAAA
award_notice_date: 2005-07-28
opportunity_number: PA-02-035
application_type: 5
activity_code: R21
ic: AA
serial_number: 014032
program_official: SORENSEN, ROGER
project_start_date: 2003-08-01
project_end_date: 2007-07-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 1865376
contact_pi: BARRON, SUSAN
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    While it is well known that prenatal ethanol (ETOH) exposure has detrimental effects on  the developing CNS there are still numerous questions regarding the mechanisms underlying the  CNS damage observed. The effects of ETOH on the glutamate/NMDA receptor (NMDAR) are  well established. ETOH-induced alterations in NMDAR function during development causes  hippocampal damage by at least two mechanisms; reduced NMDAR function during the presence of ETOH (via apoptosis) and enhanced NMDAR function during ETOH withdrawal (via  excitotoxicity). Which of these mechanisms predominates may be age- dependent with  suppression of NMDAR activity being more damaging at earlier developmental stages and  overexcitation during ETOH WD being a more dominant component in older cultures.  Polyamines are ubiquitous compounds that also play an important trophic role during CNS  development and one of the mechanisms by which polyamines work is by potentiation of the  NMDAR. Since hippocampal NMDAR subtypes and their response to polyamines change during  the first neonatal weeks in rats the timing when ETOH exposure occurs may have significant  influences on response to polyamines NMDAR and outcome. These hypotheses can be tested  directly in vitro using the organotypic cell culture model and comparing cultures obtained from  neonatal rats at PND 2 versus PND 8. The specific aims are 1) to examine how developmental  age affects the response to ETOH as measured by cell damage in our in vitro organotyplc  hippocampal model; 2) to examine how developmental age and ETOH exposure interact with  polyamines as measured by cell damage in the in vitro hippocampal model and 3) To assess  whether in vivo ETOH exposure correlates with the findings from in vitro exposure. The model  proposed in this application will provide an innovative and novel approach for using hippocampal  organotypic cell cultures to address specific developmental questions related to ETOH's effects  and to assess the predictive validity of the model to predict in vivo results. With these findings it  may also be possible to gain a better understanding of some of the mechanisms underlying  neonatal ETOH exposure and the role of polyamines that will provide grounds for pharmacological  interventions that will reduce some of ETOH effects.

project_terms:
NMDA receptors;behavior test;cell age;central nervous system;cytotoxicity;developmental neurobiology;disease /disorder model;drug withdrawal;embryo /fetus toxicology;ethanol;fetal alcohol syndrome;glutamates;hippocampus;laboratory rat;neurotoxicology;newborn animals;organ culture;polyamines;protein structure function


application_id: 6929283
project_number: 5R01AA014185-04
project_title: Oral Antioxidant/Anticytokine Therapy for ALD
administering_ic: NIAAA
award_notice_date: 2005-07-22
application_type: 5
activity_code: R01
ic: AA
serial_number: 014185
program_official: LITTEN, RAYE Z
project_start_date: 2002-08-01
project_end_date: 2007-07-31
study_section: Alcohol and Toxicology Subcommittee 4[ALTX-4]
contact_pi_person_id: 1889113
contact_pi: HILL, DANIELL B
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-08-01
project_abstract:
DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) remains theleading major cause of liver disease and liver related mortality in the UnitedStates. Alcohol metabolism and ALD are associated with lipid peroxidation andoxidative stress with decreased levels of nutritional antioxidants such asreduced glutathione (GSH) and vitamin E. Animal studies have clearly shown thattreatment with GSH precursors such as N-.acetylcysteine (NAC) and S-adenosyl-L-methionine (Adomet or SAMe) ameliorates alcohol/endotoxin liver injury. Wepostulate that chronic alcohol abuse causes increased gut permeability andendotoxemia depletion of nutritional antioxidants (e.g. GSH Vit E)generation of reactive oxygen intermediates activation of NFKB increased TNFproduction increased IL-8 production with neutrophil infiltration Adometdeficiency mitochondrial GSH depletion increased susceptibility to hepaticTNF cytotoxicity and liver injury. We have chosen a combination of twonutritional supplements which inhibit cytokine production in effector cells(e.g. Kupffer cells) and which attenuate liver metabolic abnormalities andenhance cytoprotection in target cells (e.g. hepatocytes). Because there is noideal model system and animal studies to date all support beneficial effects ofAdomet/NAC therapy we are proposing human studies. The two agents to be usedNAC and SAMe are already commercially available as over-the-counternutritional supplements. The specific objectives of this proposal are to: I)Determine an oral dose of Adomet in stable alcoholic cirrhotics that when givenfor 21 days significantly improves methionine clearance increases Adometlevels and attenuates cytokine production; 2) Determine in stable alcoholiccirrhotics an oral dose of NAC that when given for 21 days significantlyincreases whole blood GSH levels and decreases cytokine production; and 3)Determine in stable alcoholic cirrhotics whether giving Adomet and NAC togetherfor a 21 day period provides a degree of improvement in methionine clearancewhole blood GSH values and cytokine levels at least as significant as witheither drug alone and determine that this combination is well tolerated. Thedata from these studies will be useful in designing clinical trials using theseagents in the treatment of acute alcoholic hepatitis.

project_terms:
S adenosylmethionine;acetylcysteine;alcoholic hepatitis;alcoholic liver cirrhosis;antioxidants;clearance rate;combination chemotherapy;diet therapy;drug screening /evaluation;endotoxins;glutathione;human subject;interferon inducers;interleukin 10;interleukin 8;liver disorder chemotherapy;liver function;neutrophil;nuclear factor kappa beta;nutrition related tag;patient oriented research;tumor necrosis factor alpha


application_id: 6929265
project_number: 5R01AG019155-05
project_title: Contingency Learning and Judgment in Older Adults
administering_ic: NIA
award_notice_date: 2005-08-25
opportunity_number: PA-00-052
application_type: 5
activity_code: R01
ic: AG
serial_number: 019155
program_official: SUNEJA, SANOJ
project_start_date: 2001-09-15
project_end_date: 2007-08-31
study_section: Special Emphasis Panel[ZRG1-BBBP-4(01)S]
contact_pi_person_id: 1970612
contact_pi: MUTTER, SHARON A
other_pis: Not Applicable
congressional_district: 02
department: PSYCHOLOGY
primary_duns: 077876258
primary_uei: U5GMACGETKJ1
duns_number: 077876258
uei: U5GMACGETKJ1
fips: US
organization_id: 9186501
organization_name: WESTERN KENTUCKY UNIVERSITY
organization_city: BOWLING GREEN
organization_state: KY
organization_type: SCHOOLS OF EDUCATION
organization_zip: 421011001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The ability to acquire and use knowledge about the relationships or contingencies that exist between events in the environment is the foundation of adaptive behavior enabling us to predict explain and control the events in our lives.  Given the importance of this information for behavioral adaptation even small age-related declines in sensitivity to environmental contingencies could lead to less adjustment in novel situations and to restrictions in everyday activities.  The acquisition and use of contingency information involves fundamental learning and memory processes that are known to change with age.  This research addresses the question of whether these changes produce specific patterns of impaired and intact performance in older adults' contingency learning and judgment.  Three studies are proposed.  The first two studies focus on "data-driven" contingency judgments that follow the acquisition of novel event relationships.  The experiments in Study 1 investigate whether age-related decline in working memory resources affects older adults' ability to acquire and use novel contingency information and whether reducing demands for working memory at encoding and retrieval improves this ability.  The experiments in Study 2 investigate whether age-related changes in explicit learning and memory processes lead older adults to experience greater deficits in the explicit acquisition and recollection of novel contingency information than in the implicit acquisition and use of this information as a basis for improving performance.  The experiments in Study 3 focus on "theory-driven" contingency judgments.  These experiments examine whether an age-related decline in the ability to inhibit the intrusion of pre-existing beliefs and expectancies leads older adults to assign greater weight to their own potentially obsolete or irrelevant contingency knowledge than to novel environmental contingencies. Together the experiments in these three studies will provide a comprehensive view of older adults' ability to acquire retrieve and use contingency information for judgment and prediction.

project_terms:
age difference;behavioral /social science research tag;bias;clinical research;cognition;computer human interaction;decision making;environment;experience;geriatrics;human old age (65+);human subject;interview;judgment;learning;neural information processing;neuropsychological tests;neuropsychology;performance;psychological adaptation;psychological aspect of aging;questionnaires;short term memory;statistics /biometry;young adult human (21-34)


application_id: 6929088
project_number: 7R21DA017885-02
project_title: Integration of the Therapeutic Workplace in Drug Court
administering_ic: NIDA
award_notice_date: 2005-09-12
opportunity_number: PA-03-066
application_type: 7
activity_code: R21
ic: DA
serial_number: 017885
program_official: MCNAMARA-SPITZNAS, CECILIA M
project_start_date: 2004-08-01
project_end_date: 2007-07-31
study_section: HIV and Substance Use Research Study Section [NIDA-E]
contact_pi_person_id: 1892923
contact_pi: WONG, CONRAD J
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):     Incarceration rates of drug-involved offenders have reached staggering proportions and have resulted in the high cost of building and operating prisons. Drug Courts were developed as a therapeutic alternative to incarceration of drug-involved offenders by providing 'judicially supervised' drug abuse treatment and probation for nonviolent offenders in lieu of criminal prosecution and incarceration. Outcome studies have shown that drug courts have modest effects on participation in drug abuse treatment drug use and employment. The Therapeutic Workplace intervention is an effective employment-based treatment that integrates abstinence reinforcement contingencies in a work setting intended to treat individuals with histories of drug addiction and chronic unemployment. Under this intervention drug abuse patients are hired and paid to work. To promote abstinence patients are required to provide drug-free urine samples to gain and maintain daily access in the workplace. In this way patients can work and earn salary but only as long as they remain drug abstinent. Patients using drugs and lacking job skills participate in an initial training phase to initiate abstinence and establish computer data entry skills. Once abstinent and skilled patients are hired into an income-producing Therapeutic Workplace data entry business. Given that many drug court participants suffer from long histories of drug addiction and unemployment the Therapeutic Workplace could be ideal for this population. This grant application proposes research to integrate the Therapeutic Workplace intervention into the Baltimore City Drug Treatment Court. We are proposing to develop procedures to integrate the Therapeutic Workplace into the Drug Court program and to conduct a pilot study (N=70) in which Drug Court participants will be randomly assigned to either a 'Usual Care' group or 'Therapeutic Workplace' group. All participants will receive standard drug court services. Therapeutic Workplace group participants will be invited to attend the Therapeutic Workplace for 12 weeks. Overall the proposed project will allow for the development and evaluation of procedures to integrate the Therapeutic Workplace intervention in the drug court. Outcome data will provide the empirical basis for the design and implementation of future studies evaluating the effectiveness of the Therapeutic Workplace in drug courts.

project_terms:
behavioral /social science research tag;clinical research;clinical trials;computers;court;data collection methodology /evaluation;drug /alcohol abstinence;drug abuse therapy;employment /unemployment;human subject;human therapy evaluation;legal /correctional;longitudinal human study;outcomes research;patient care management;reinforcer;social adjustment;therapy design /development;training;urinalysis;vocational guidance;work site


application_id: 6928034
project_number: 5K01AA013099-05
project_title: Hypoxia and free radicals in alcoholic pancreatitis
administering_ic: NIAAA
award_notice_date: 2005-07-26
opportunity_number: PA-00-019
application_type: 5
activity_code: K01
ic: AA
serial_number: 013099
program_official: PUROHIT, VISHNU
project_start_date: 2001-08-01
project_end_date: 2007-07-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 2047731
contact_pi: ARTEEL, GAVIN E
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
APPLICANT'S ABSTRACT:                                                                                                   We hypothesize that ethanol-induced chronic pancreatitis is triggered by            hypoxia/reoxygenation injury leading to stimulation of inflammatory cell           recruitment and activation of these cells by circulating endotoxins. We             recently showed pancreatic injury characteristic of chronic pancreatitis in         humans in an enteral model modified to deliver higher amounts of ethanol. Our       first goal is to characterize this new model. Wistar rats will receive alcohol      internally using our modified protocol for up to 6 months. Pancreatic function      and injury will be determined and compared to changes in key molecular events.      We expect that alcohol will cause progressive irreversible changes in              pancreatic morphology and function similar to clinical observations. We will       next test the hypothesis that alcohol causes hypoxia in pancreas in vivo.           Initially we will determine if the hypoxia marker pimonidazole can be used to      index pancreatic hypoxia in rats. We will then determine the effect of alcohol      on pancreatic hypoxia in our enteral model. We expect that chronic ethanol          will cause early increases in hypoxia suggesting that hypoxia might play a         key early role in the initiation of damage. The effect of removing endotoxin        by lactobacillus treatment to displace Gram-negative bacteria or killing           macrophages with silica will next be studied. We expect pancreatic damage will      be blunted by these treatments suggesting a role of endotoxin and macrophages      in chronic alcoholic pancreatitis. Next the hypothesis that free radicals          play a causative role in chronic alcoholic pancreatitis will be tested. This        question will be addressed using adeno-associated virus (RAAV) to deliver           superoxide dismutase (SOD) and cause stable long-term pancreatic expression.        First optimal conditions to confer pancreatic transgene expression will be         determined. The effect of RAAV containing superoxide dismutase (SOD) on             pancreatic injury will be determined. Free radical formation and oxidative          stress will also be quantitated. We expect that preventing oxidative stress         with SOD will protect against chronic alcoholic pancreatitis indicating that       free radicals play an important role in the progression of chronic alcoholic        pancreatitis. This work will lay the mechanistic foundation for future studies      of targeted therapies to prevent alcoholic pancreatitis that can applied in         the clinic where such therapy is desperately needed. Further through              didactic training and interactions with his mentor and key faculty in the           enteral model of alcohol exposure molecular biology and viral vector gene         therapy the applicant will acquire new skills that will greatly enhance his        career development and bridge the gap to becoming a successful member of the        academic and scientific community.

project_terms:
alcoholism /alcohol abuse;antioxidants;biomarker;cell proliferation;electron spin resonance spectroscopy;endotoxins;ethanol;free radicals;gene expression;gene therapy;histology;hypoxia;laboratory rat;leukocyte activation /transformation;morphology;nonhuman therapy evaluation;nuclear factor kappa beta;oxidative stress;pancreas;pancreatitis;pathologic process;postdoctoral investigator;serology /serodiagnosis;superoxide dismutase;toxicology;transfection;tumor necrosis factor alpha


application_id: 6927166
project_number: 5R01GM064606-03
project_title: Regulation of HSF1 and HSF2 by SUMO-1 Modification
administering_ic: NIGMS
award_notice_date: 2006-08-02
application_type: 5
activity_code: R01
ic: GM
serial_number: 064606
program_official: ANDERSON, JAMES J
project_start_date: 2003-08-01
project_end_date: 2008-07-31
study_section: Physiological Chemistry Study Section[PC]
contact_pi_person_id: 7875217
contact_pi: SARGE, KEVIN D
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2006-08-01
project_abstract:
DESCRIPTION (provided by applicant):   The long-term goal of this application is to elucidate the mechanism(s) that regulate stress-induced and constitutive expression of heat shock proteins (hsps) which are critical not only for the cell's ability to survive exposure to stress conditions but also for normal protein folding in non-stressed cells. The stress-inducible vs. constitutive activities of the transcriptional regulatory proteins HSF1 and HSF2 are critical for this stress-activated and basal hsp gene expression but how their differentially-regulated activities are controlled is unknown. In the search for this mechanism we have identified differential regulation of SUMO-1 modification of HSF 1 and HSF2 leading to stress-induced and constitutive activation respectively. We propose that SUMO-1 modification of HSFs is pre-requisite for their transcriptional activities at the levels of their ability to interact with promoters of hsp genes (DNA-binding activities) for assembly of transcription complexes with other factors on these promoters (transactivation potential) and for their protection against degradation. In this application we will 1) determine the functional consequences of SUMO-1 modification for the DNA-binding and transactivation activities of HSF 1 and HSF2 2) characterize the role of this modification in regulating the turnover of HSF1 and HSF2 and 3) identify the mechanism(s) which mediate the differential regulation of stress-induced vs. constitutive SUMO-1 modification of HSF1 and HSF2 determine the significance of HSF sumoylation for protein misfolding in vivo and determine whether sumoylation of HSFs is altered by cellular aging. Results from the proposed studies will define the basis of the differential regulation of HSF 1 and HSF2 leading to stress-induced and constitutive expression of heat shock proteins and may provide a strategy for manipulating cellular heat shock protein expression a promising potential treatment of diseases caused by protein misfolding/aggregation such as Parkinson's Huntington's and Alzheimer's Disease.

project_terms:
DNA binding protein;cell age;chemical conjugate;flow cytometry;gene expression;heat shock proteins;high performance liquid chromatography;immunoprecipitation;posttranslational modifications;protein degradation;protein folding;protein kinase;protein protein interaction;protein sequence;site directed mutagenesis;transcription factor;transfection;ubiquitin;yeast two hybrid system


application_id: 6925456
project_number: 5R01HD042674-04
project_title: FAILURE TO MODULATE T & NK CELL ZETA EXPRESSION IN RSA
administering_ic: NICHD
award_notice_date: 2005-06-08
application_type: 5
activity_code: R01
ic: HD
serial_number: 042674
program_official: YOSHINAGA, KOJI
project_start_date: 2002-07-01
project_end_date: 2008-06-30
study_section: Human Embryology and Development Subcommittee 1[HED-1]
contact_pi_person_id: 1867564
contact_pi: TAYLOR, DOUGLAS DILLON
other_pis: Not Applicable
congressional_district: 03
department: OBSTETRICS & GYNECOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-07-01
project_abstract:
DESCRIPTION (provided by applicant):  Escape of the fetus from the maternal immune system is essential for fetal development and successful pregnancy. Evidence has accumulated suggesting that the deletion or selective inactivation of reactive lymphocytes or the production of suppressor factors by cells of fetal origin may contribute to maternal immune dysfunction. Impairment to complete failure to induce NK and T cell dysfunction in some pregnant women could be for poor pregnancy outcomes from pre-term labor to fetal death. Understanding the mechanisms of pregnancy-associated T and NK cell dysfunction will provide the greatest impact on clinical improvements in the prevention of negative pregnancy outcomes. Recent evidence indicates that the loss of signal-transducing zeta chain associated with CD3 and CD16 represents one of the mechanisms responsible for T and NK cell dysfunction. The absence of zeta chain results in defects in the assembly and function of the antigen reactive receptors and the affected leukocytes exhibit diminished proliferation and production of specific cytokines. We have demonstrated reduced expression of CD3 and CD 16-zeta chain in peripheral blood T and NK cells respectively of women developing normal pregnancies. Our recent studies have demonstrated that the sera from women with normal term pregnancies suppressed the level of zeta chain expression in T and NK cells while sera from women with histories of recurrent pregnancy loss failed to significantly inhibit CD3 and CD16-zeta chain expression. Subsequently we have isolated a 14kappaD protein from the plasma of a normal pregnant woman at 34 weeks gestation. A similar inhibitory protein could be demonstrated in the sera of five other normal term pregnant women. However this factor could not be demonstrated in the sera obtained from pregnant women who spontaneously aborted. This protein specifically suppresses zeta chain levels; however it does not modulate the levels of the kinases lck and zeta-associated protein (ZAP)-70. This proposal will address the biochemical molecular and functional characterization of the pregnancy-derived 14kappaD zeta-inhibiting protein (ZIP). Initially this investigation will identify differences in the l4kD proteins associated with uncomplicated pregnancies and recurrent aborters. We will further isolate and characterize its gene to define ZIP's expression during normal pregnancy and RSA. Using proteomic analysis we will identify cellular events associated with T and NK cell activation that are altered by ZIP from normal and RSA pregnancies using multiple activation pathways and timing of ZIP exposure to determine the specific events affected. Since the loss of T-cell zeta chain has been correlated with successful pregnancy while impairments in this normal suppression of CD3 and CD16-zeta appear to be associated with recurrent spontaneous abortions we will develop an ELISA for ZIP to define its biologic and clinical importance by correlating its level in patients' sera experiencing recurrent pregnancy loss. The inability to effectively modulate CD3 and CD 16-zeta chain during pregnancy might allow the generation of an effective cellular response against the fetus directly resulting in spontaneous abortions.

project_terms:
CD16 molecule;CD3 molecule;T cell receptor;T lymphocyte;biological signal transduction;blood chemistry;blood proteins;chronic spontaneous abortion;clinical research;embryo /fetus;enzyme linked immunosorbent assay;gel electrophoresis;gene expression;gestational age;high performance liquid chromatography;human subject;inhibitor /antagonist;matrix assisted laser desorption ionization;natural killer cells;placenta;pregnancy circulation;pregnancy immunology;protein protein interaction;proteomics;tissue /cell culture


application_id: 6923590
project_number: 5R01GM066072-04
project_title: Optimizing dosing to prevent antibiotic resistance
administering_ic: NIGMS
award_notice_date: 2005-09-01
opportunity_number: PA-99-147
application_type: 5
activity_code: R01
ic: GM
serial_number: 066072
program_official: OKITA, RICHARD T
project_start_date: 2002-09-01
project_end_date: 2007-08-31
study_section: Pharmacology A Study Section[PHRA]
contact_pi_person_id: 7875280
contact_pi: EVANS, MARTIN E
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Antibiotic resistance among bacteria is a major problem in medicine. There have been repeated calls for the prudent use of antibiotics but little is known about optimizing use to conserve efficacy. A better understanding of the relationship between dosing and the selection of resistance mechanisms may be useful. We have taken an approach that integrates pharmacokinetic bacteriological and molecular data into a pharmacodynamic model that examines the emergence of resistance when Staphylococcus aureus is exposed to ciprofloxacin in an in vitro system. This system allows accurate simulations of human pharmacokinetics and monitoring of the pharmacodynamic effect on bacteria. We found that antibiotic "sensitive" (S) cultures often harbor subpopulations with low-level resistance (RL); regimens providing low antibiotic concentrations may kill S but allow RL to survive without evolving into bacteria with high-level resistance (Ru); regimens producing moderate concentrations may eradicate S but cause RL to evolve into RH through a variety of mechanisms; and regimens producing high concentrations may eradicate S and RL strains before they evolve into RH Thus the evolution of RL to RH and ultimately treatment success or failure appears to be dependent. in part upon antibiotic dosing. A preliminary pharmacodynamic model described the experimental data well. Based on these findings we hypothesize that novel regimens may prevent the emergence of resistance and these regimens can be rationally designed by understanding the effect of antibiotic concentrations on the selection of antibiotic resistance mechanisms. To test this hypothesis we will expose bacteria to constant and fluctuating ciprofloxacin concentrations in the in vitro system and monitor the incidence and prevalence of bacteria with up-regulated efflux and/or mutations in the quinolone resistance determining regions of topoisomerase genes with conventional assays and real-time PCR. Correlations between phannacokinetic parameters and resistance mechanisms will be used to develop alternative pharmacodynamic models that more accurately characterize the relationship between dosing and resistance. The ability of the pharmacodynamic models to predict the outcome of regimens designed to prevent (or allow) the emergence of resistance will be tested using artificially constructed cultures comprised of varying proportions of S RL and RH bacteria. We believe understanding the mechanisms underlying resistance will enhance our ability to design alternative dosing strategies to effect clinical cure.

project_terms:
DNA topoisomerases;Staphylococcus aureus;antibacterial agents;antibiotics;bacteria infection mechanism;bacterial genetics;disease /disorder prevention /control;dosage;drug resistance;drug screening /evaluation;fluorescence spectrometry;high performance liquid chromatography;pharmacokinetics;polymerase chain reaction;quinoline


application_id: 6922194
project_number: 2R01HL034579-19A1
project_title: Adenosine and Pyruvate Protection During Heart Surgery
administering_ic: NHLBI
award_notice_date: 2005-06-10
application_type: 2
activity_code: R01
ic: HL
serial_number: 034579
suffix: A1
program_official: LIANG, ISABELLA Y
project_start_date: 1996-06-01
project_end_date: 2006-03-15
study_section: Bioengineering, Technology and Surgical Sciences Study Section[BTSS]
contact_pi_person_id: 1891192
contact_pi: MENTZER, ROBERT M
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
The complication rates of severe ventricular dysfunction myocardial infarction (MI) heart failure and death after heart surgery including certain subsets of high-risk CABG surgery patients may exceed 10-15%. While there are many causes of myocardial injury after heart surgery ischemia/reperfusion injury and the lack of optimal myocardial protection are important contributing factors that are amenable to improvement. New findings from our laboratory indicate that the cardioprotective effects of adenosine and pyruvate may be mediated via the modulation of mitogen activated protein kinases (MAPK). The purpose of the proposed research is to further elucidate the mechanisms underlying ischemia/reperfusion injury and evaluate the relationship between MAPKs and the cardioprotective effects of acute and delayed adenosine receptor activation and the intermediary metabolite pyruvate. Specific Aim 1 will test the hypothesis that acute and delayed A1receptor preconditioning of the cardiac myocyte during ischemia-reperfusion is mediated via MAPK modulation of mitochondrial function and intracellular Ca++ homeostasis. Specific Aim 2 will determine how adenosine receptor-mediated acute and delayed reduction of infarct size in vivo is mediated via signaling through one or more of the MAPKs. Specific Aim 3 will determine the relationship between adenosine receptor-mediated acute and delayed attenuation of myocardial stunning in vivo and activation of one or more of the MAPK families (p38 ERK JNK). Specific Aim 4 will determine whether the beneficial effects of pyruvate in reversibly and irreversibly injured myocardium are due to redox modulation of MAPK signaling. Experiments will be performed in isolated rat ventricular myocytes under conditions of simulated ischemia and in in vivo rat infarct and in vivo porcine stunning preparations. In the isolated myocyte studies fluorescence imaging and confocal microscopy will be used to simultaneously measure changes in myocyte oxidative stress intramitochondrial free [Ca++] the mitochondria] permeability transition pore (MPTP) mitochondrial membrane potential and changes in mitochondrial redox status. In the in vivo studies changes in infarct size and myocardial function will be correlated with the expression and activity of the MAPKs in subcellular fractions. It is anticipated the results of these studies will provide new insights regarding mechanisms underlying the salutary effects of adenosine and pyruvate. Ultimately the findings should lead to strategies that will allow for the amplification of the cardioprotective effects of these endogenous agents and/or the development of new and specific therapeutic regimens designed to improve patient outcomes after heart surgery.

project_terms:
adenosine;apoptosis;cardiac myocytes;confocal scanning microscopy;cytoprotection;free radical oxygen;free radical scavengers;heart imaging /visualization /scanning;heart surgery;immunoprecipitation;laboratory rat;mitogen activated protein kinase;myocardial ischemia /hypoxia;oxidative stress;postoperative state;purinergic receptor;pyruvates;receptor expression;reperfusion;swine;tissue /cell culture;western blottings


application_id: 6920337
project_number: 2R01OH007650-03A1
project_title: Health Effects of Occupational Exposures in PGDP Workers
administering_ic: NIOSH
award_notice_date: 2005-07-12
application_type: 2
activity_code: R01
ic: OH
serial_number: 007650
suffix: A1
program_official: KARR, JOAN
project_start_date: 2005-07-01
project_end_date: 2008-06-30
study_section: Special Emphasis Panel[ZOH1 SPC (12)]
contact_pi_person_id: 1871961
contact_pi: TOLLERUD, DAVID J
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV 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 PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION: The Paducah Gaseous Diffusion Plant (PGDP) is located in Western Kentucky about 10 miles west of the City of Paducah. It currently employs approximately 1700 workers; some 8000 individuals have worked at the plant since it was opened in 1952. The plant is located in a rural area adjacent to protected conservation wildlife and recreation areas. The primary function of the PGDP has been to produce enriched uranium for use by commercial reactors or as feed material for other plants that further enrich the uranium. Workers government officials and the surrounding community have raised concerns about potential health effects from current and past exposures at the plant. The studies proposed here will complete an ongoing mortality investigation to help address those concerns by combining work histories with historical exposure data to create an exposure metric for each worker at the plant throughout the history of the facility. In Specific Aim 1 we will validate the worker roster against other existing name lists and source documents. In Specific Aim 2 we will develop a comprehensive list of jobs and job histories for the workforce from paper records and electronic files. In Specific Aim 3 we will create a Job Exposure Matrix for chemical and radiation exposures throughout the history of the plant. In Specific Aim 4 we will link the Work History data with the Job Exposure Matrix to estimate individual worker exposure metrics. In Specific Aim 5 we will evaluate worker mortality for relationships with workplace exposures using standardized mortality ratios and risk assessment approaches. In Specific Aim 6 we will communicate the study results to employees and management.  
  
The overarching goal of these investigations is to evaluate the impact of historical exposures on worker mortality. The PGDP is the only remaining gaseous diffusion plant in the US that has not undergone a comprehensive occupational health study. The data generated by the PGDP investigations will be available to merge with the two prior studies at the Portsmouth and Oak Ridge gaseous diffusion plant facilities. The Paducah data will add substantially to the statistical power of the combined database to address the pressing health concerns of uranium enrichment workers.

project_terms:
biomarker;blood chemistry;chromosome aberrations;clinical research;electron spin resonance spectroscopy;environmental exposure;environmental radiation;epidemiology;fluorescent in situ hybridization;gene mutation;genetic markers;glycophorin;hazardous substances;hemoglobin;human subject;hypoxanthine phosphoribosyltransferase;interview;mass spectrometry;occupational hazard;occupational health /safety;radiation dosage;radiation hazard;rural area;transportation /recreation safety;uranium


application_id: 6919921
project_number: 5R01HL065618-04
project_title: Endothelial Metabolism of Atherogenic Aldehydes
administering_ic: NHLBI
award_notice_date: 2005-07-26
application_type: 5
activity_code: R01
ic: HL
serial_number: 065618
program_official: SRINIVAS, POTHUR R
project_start_date: 2002-08-01
project_end_date: 2008-07-31
study_section: Pharmacology A Study Section[PHRA]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-08-01
project_abstract:
DESCRIPTION (provided by applicant):  The long-term goal of this project is to assess the contribution of lipid peroxidation to atherogenesis and to understand the mechanisms by which the products of lipid peroxidation contribute to the formation of atherosclerotic lesions. Previous studies have shown that the oxidation of low-density lipoprotein (LDL) generates toxic aldehydes which could trigger and sustain the formation of atherosclerotic lesions. However the contribution of these aldehydes to atherogenesis is unclear and the mechanism by which they are metabolized and detoxified in the endothelium have not been examined. The intent of this project is to examine the endothelial metabolism of the LDL-derived aldehydes and to delineate their contribution to the initiation and the development of atherosclerotic lesions. To examine the biochemical processes that metabolize these aldehydes we will use 1-palmitoyl-2-(-5-oxovaleryl)-3-glycero phosphocholine (POVPC) and 4-hydroxy-trans-2-nonenal (HNE) as model aldehydes. These aldehydes respresent the most abundant esterified and non-esterified aldehydes generated during the oxidation of LDL. Our central hypothesis is that the polyol pathway enzyme aldose reductase (AR) catalyzes the major reductive pathway common to the detoxification of both the esterified and non-esterifled aldehydes and the AR-catalyzed pathway protects against the atherogenic effects of oxidized LDL. To test this hypothesis in Aim 1 we will identify quantify and characterize the major products of POVPC and HNE in human endothelial cells in culture. To delineate the contribution of AR in Aim 2 we will examine changes in the rate and extent of formaiton of the major metabolites in the presence of aldose reductase inhibitors and investigate the relationship between aldose reductase and other pathways of aldehyde metabolism due to phospholipases platelet activating factor-acetylhydrolase and aldehyde dehydrogenase. To assess the toxicological significance of the aldose reductase-catalyzed pathway we will examine whether inhibition of this enzyme enhances the extent of induction of the adhesion molecules ICAM-1 and VCAM in endothelial cells and increases the adhesion of monocytes to endothelial cells in culture. In Aim 3 we will examine the development of atherosclerotic lesions in apoE and LDL-receptor null mice and determine whether inhibition of aldose reductase exacerbates pre-atherosclerotic changes and increases the arterial abunbance of ICAM-1 and VCAM and whether this accelerates the formation of atherosclerotic lesions. The results of these studies will provide a better understanding of the mechanisms by which phospholipid oxidation promotes atherosclerosis amd may lead to the identification of a novel pathway regulating the extent and the severity of arterial lesions. These studies could also form the basis of future assessments of individual risk for atherosclerosis due to differences in the vascular metabolism of aldehydes.

project_terms:
aldehyde dehydrogenases;aldehyde reductase;aldehydes;atherosclerosis;atherosclerotic plaque;biochemistry;cell adhesion molecules;chemical synthesis;enzyme activity;enzyme inhibitors;gene targeting;genetically modified animals;immunocytochemistry;laboratory mouse;lipid metabolism;low density lipoprotein;monocyte;pathologic process;peroxidation;phosphatidylcholines;tissue /cell culture;vascular endothelium


application_id: 6917950
project_number: 5R03ES013193-02
project_title: Identifying Proteins Involved in DNA Damage Response
administering_ic: NIEHS
award_notice_date: 2005-07-01
opportunity_number: PA-03-108
application_type: 5
activity_code: R03
ic: ES
serial_number: 013193
program_official: BALSHAW, DAVID M
project_start_date: 2004-07-05
project_end_date: 2006-06-30
study_section: Special Emphasis Panel[ZRG1-CDF-2(90)S]
contact_pi_person_id: 7875365
contact_pi: LI, GUO-MIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  DNA mismatch repair (MMR) plays an important role in maintaining genomic stability as defects in MMR lead to the development of cancer. In the past the genome maintenance function of MMR had been attributed to its ability to correct mismatches. However increasing evidence suggests that the MMR system also maintains genomic stability by promoting apoptosis in response to DNA damage induced by physical and chemical agents including environmental chemical carcinogens. This response is known to be dependent on MutS and MutL homologs and eliminates potentially carcinogenic cells from growing. The MMR-dependent apoptosis appears to involve a signaling network which transmits a DNA damage signal to the apoptotic machinery to kill damaged cells. However how the network works and what proteins are involved in this network are poorly understood. This study aims to identify and characterize proteins that participate in MMR-dependent apoptosis induced by environmental chemical carcinogens using a prote0mic approach. First MMR-proficient and deficient cells will be treated with chemical carcinogens and protein expression profiles before and after treatments from these cells will be analyzed by 2-dimensional gel electrophoresis. Proteins with differential expression will be subjected to mass spectromic analysis and the resulting peptides will be used for database homology searching to reveal their identities. Second given the involvement of protein phosphorylation or dephosphorylation in many signaling networks we hypothesize that many proteins participating in MMR-dependent apoptosis may be phosphorylated or dephosphorylated. To test this hypothesis proteins that are identified in this study and known previously to be involved in MMR-dependent apoptosis will be analyzed for their phosphorylation status by 1-dimensional or 2-dimensional gels combined with Western blot analysis followed by mass spectrometry analysis. Data resulting from this project will formulate the basis for more detailed investigations (R01 applications) to fully understand the molecular mechanism by which the MMR system maintains genomic stability by promoting apoptosis induced by environmental chemical carcinogens. Because certain cancer chemotherapeutics e.g. cisplatin and alkylating agents can signal apoptosis in an MMR-dependent fashion this study will also impact cancer treatment particularly cancers caused by MMR defects.

project_terms:
DNA damage;DNA repair;adduct;apoptosis;benzopyrenes;biological signal transduction;cell growth regulation;chemical carcinogen;environment related neoplasm /cancer;environmental contamination;gene expression;hydrocarbons;mass spectrometry;molecular biology information system;phenanthrene;phosphorylation;protein quantitation /detection;protein structure function;two dimensional gel electrophoresis;western blottings


application_id: 6915603
project_number: 5R01MH063022-05
project_title: Brain endothelial cell TNF and Tat-induced cell injury
administering_ic: NIMH
award_notice_date: 2005-07-29
application_type: 5
activity_code: R01
ic: MH
serial_number: 063022
program_official: RAO, VASUDEV RAMACHANDRA
project_start_date: 2001-08-01
project_end_date: 2006-07-31
study_section: Special Emphasis Panel[ZRG1-AARR-6(01)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
budget_start_date: 2005-08-01
project_abstract:
Impaired function of the brain vasculature might be a critical factor in mechanisms of HIV-1 virus trafficking in the central nervous system (CNS).  We hypothesize that the viral gene product the protein Tat at least in part is responsible for this effect.  We have evidence that exposure to Tat can induce activation and injury to brain microvascular endothelial cells (BMEC) with subsequent breakdown of the blood-brain barrier (BBB).  Disrupted BBB may allow accelerated entry of the HIV-1 into the CNS.  In addition Tat-induced activation of BMEC can lead to upregulation of adhesion molecules and inflammatory cytokines and thus facilitate adherence of infected monocytes to the brain endothelium and their migration to underlying tissues. Our preliminary data indicate that Tat is a strong inducer of the tumor necrosis factor-alpha (TNF) gene in BMEC.  TNF is one of the most potent inducers of inflammatory responses in endothelial cells.  Based on these facts we developed a leading hypothesis of the current proposal that endogenous production of TNF can induce oxidative stress and markedly enhance Tat-mediated injury to BMEC.  In support of this hypothesis we demonstrated that neutralization of endogenous TNF produced by BMEC can markedly protect against Tat-induced endothelial injury.  The present research application is designed to study the effects of BMEC endogenous TNF on oxidative-type cellular injury.  We hypothesize that Tat-induced endogenous TNF can exacerbate cellular oxidative stress and inflammatory responses of BMEC induced by Tat.  These hypotheses will be studied using both in vitro and in vivo experimental settings.  The long term goals of the current proposal are to determine mechanisms which may prevent Tat- induced injury to BMEC.  Thus data arising from this proposal will be critical for a better understanding of disruption of the BBB during HIV-1 infection and for the possible development of therapeutic interventions to prevent HIV-1 entry into the CNS.

project_terms:
AP1 protein;binding sites;biological signal transduction;blood brain barrier;cellular pathology;clinical research;cytotoxicity;gene expression;gene mutation;genetic regulation;host organism interaction;human immunodeficiency virus 1;human tissue;inflammation;laboratory mouse;macrophage;nuclear factor kappa beta;oxidative stress;posttranslational modifications;tissue /cell culture;transcription factor;tumor necrosis factor alpha;vascular endothelium;vascular endothelium permeability;virus infection mechanism;virus protein


application_id: 6913629
project_number: 5R01CA105152-02
project_title: Transcriptional repression in leukemia
administering_ic: NCI
award_notice_date: 2005-07-15
application_type: 5
activity_code: R01
ic: CA
serial_number: 105152
program_official: MUFSON, R ALLAN
project_start_date: 2004-07-01
project_end_date: 2005-09-30
study_section: Cancer Molecular Pathobiology Study Section[CAMP]
contact_pi_person_id: 1868623
contact_pi: GRIMES, H LEIGHTON
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-07-01
project_abstract:
DESCRIPTION (provided by applicant): The cloning and characterization of leukemia oncoproteins over the last 25 years has resulted in a greater understanding of the central role of transcription factors in hematopoiesis and leukemogenesis. Human acute myeloid leukemias are characterized by the presence of chromosomal translocations which result in the fusion of coding sequences from one gene to coding sequences of transcription factors. Overexpression of these fusion transcription factors often inhibits myeloid differentiation and such fusion transcription factors may play an important role in the development of the leukemic phenotype. Though much is known about the expression of human transcription-factor oncoproteins in clinical disease their transcriptional targets are not as clear. Growth factor independence-1 (GFI1) is a transcription factor that is essential for normal lymphoid and myeloid development. GFI1 was originally identified as a frequent target of Moloney murine leukemia virus insertion in rat and mouse genomes. Transgenic expression of GFI1 is oncogenic and potently accelerates leukemogenesis induced by the Moloney murine leukemia virus; confirming the role of GFI1 in Moloney oncogenesis. Mutation of GFl1 leads to a human neutropenia syndrome that predisposes to acute myeloid leukemia. Our preliminary evidence indicates that GFl1 is targeted by a chimeric transcription factor found in human acute myeloid leukemia and that GFI1 targets key myeloid lineage transcription factors. We hypothesize that GFI1 tethers a multiprotein transcription complex to DNA to control the expression of lineage-specific transcription factors and that abnormal GFl1  expression predisposes to acute myeloid leukemia. We will molecularly characterize GFI1 target genes in myelopoiesis and biologically test suggested genetic interactions. Moreover we will dissect GFl1 as a target of a human chimeric transcription factor oncoprotein and determine whether loss of GFl1 is predisposing to leukemia.

project_terms:
acute myelogenous leukemia;cancer risk;chromatin immunoprecipitation;flow cytometry;gel mobility shift assay;gene expression;gene induction /repression;genetic transcription;growth factor;human tissue;laboratory mouse;molecular oncology;neoplasm /cancer genetics;oncoproteins;phosphorylation;protein structure function;transcription factor


application_id: 6912690
project_number: 5R01EY009532-13
project_title: Regulation of transport mechanisms in lens cells
administering_ic: NEI
award_notice_date: 2005-07-01
application_type: 5
activity_code: R01
ic: EY
serial_number: 009532
program_official: LIBERMAN, ELLEN S
project_start_date: 1993-01-01
project_end_date: 2007-06-30
study_section: Visual Sciences A Study Section[VISA]
contact_pi_person_id: 1872319
contact_pi: DELAMERE, NICHOLAS A
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-07-01
project_abstract:
DESCRIPTION (provided by applicant): Lens cells utilize Na K-ATPase topreserve stable cytoplasmic composition and thus transparency. In order toovercome the difficulty of ion regulation in such a large mass of tightlypacked cells the lens is specialized such that epithelial cells particularlyat the lens equator maintain a high activity of Na K-ATPase while fiber cellshave low Na K-ATPase activity. This unequal distribution of Na K-ATPaseactivity is important because it provides the driving force for circulatingionic currents that flow outward at the posterior pole inward at the anteriorpole. However there is a gap in our knowledge of how the unequal spatiallocalization of Na K-ATPase activity is established because all lens cellsepithelium and fibers have a similar abundance of Na K-ATPase protein. Thelevel of Na K-ATPase protein expression in lens cells does not tally with NaK-ATPase activity. Other factors seem to be involved. Here we plan to study howthe epithelial cells achieve and maintain high Na K-ATPase activity. Studieswill be conducted to examine the link between activity of Na K-ATPase and theability of lens epithelial cells to synthesize new Na K-ATPase protein (AimI); determine whether oxidative posttranslational modification of Na K-ATPaseprotein contributes to reduction of Na K-ATPase activity (Aim II); and todetermine whether tyrosine phosphorylation of the a subunit can bring aboutchanges in Na K-ATPase activity (Aim III). Results from these studies willgive us a better understanding of lens ion regulation and lens cellspecializations that underpin long term maintenance of lens transparency.

project_terms:
RNase protection assay;SDS polyacrylamide gel electrophoresis;cell differentiation;electrolyte balance;enzyme activity;enzyme biosynthesis;epithelium;fibroblast growth factor;ion transport;laboratory mouse;laboratory rat;lens;mass spectrometry;matrix assisted laser desorption ionization;membrane permeability;oxidative phosphorylation;protein biosynthesis;sodium potassium exchanging ATPase;western blottings


application_id: 6908910
project_number: 5R01DK053525-07
project_title: TGF-Beta Signaling Pathways in Prostate Tumorigenesis
administering_ic: NIDDK
award_notice_date: 2005-07-12
application_type: 5
activity_code: R01
ic: DK
serial_number: 053525
program_official: MULLINS, CHRISTOPHER V
project_start_date: 1997-09-01
project_end_date: 2008-06-30
study_section: Reproductive Endocrinology Study Section[REN]
contact_pi_person_id: 7875447
contact_pi: KYPRIANOU, NATASHA
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-07-01
project_abstract:
DESCRIPTION (provided by applicant):Transforming growth factor-b (TGF-beta) isa negative regulator of prostate growth via its ability to inhibit cellproliferation and induce apoptosis in epithelial cells. Evidence indicates thatin prostate cancer an increase in epithelial TGF-beta expression is paralleledby loss of expression of its membrane receptors TbetaRI and TbetaRII. Thelong-term goal of the proposed studies is to identify the interplay between theandrogen axis and TGF-beta signaling pathways during prostate tumorigenesis.Our recent studies demonstrated that restoration of expression of thefunctional TbetaRII receptor in human prostate cancer cells LNCaP that areresistant to TGF-beta leads to TGF-beta sensitivity and suppression oftumorigenic growth via cell cycle arrest and apoptosis induction. In thisproposal we will use this model of hormone-sensitive TGF-beta responsiveprostate cancer cells to explore the molecular mechanism underlying thedysfunctional TGF-beta signaling pathway in prostate tumorigenesis. In SpecificAim 1 we will determine the ability of androgens to affect the action ofTGF-beta on prostate cancer cell growth as linked to deregulation of cell cycle(cdk inhibitors) and apoptosis induction (caspases bcl-2). The effect ofandrogens on TGF-beta mediated suppression of in vivo tumorigenic growth ofLNCaP TbetaRII cells will be determined using orthotopic injections. InSpecific Aim 2 using transfections and co-immunoprecipitation approaches wewill investigate the functional involvement of the Smad intracellular effectorsof TGF-beta in transducing the apoptotic signals to the nucleus. In SpecificAim 3 the interaction between the androgen receptor (AR) and TGF-beta signalingpathways in LNCaP TbetaRII prostate cells will be characterized usingimmunoprecipitation assays. These studies will establish: a) that androgenscontribute to the impairment of TGF-beta signaling in prostate cancer cells;and b) the significance of defects in post-receptor intracellular mediators ofTGF-beta signal the Smads in the development of hormone-resistance inprostate cancer.

project_terms:
SCID mouse;androgen receptor;androgens;apoptosis;biological signal transduction;carcinogenesis;carcinogenesis inhibitor;cell cycle;cell growth regulation;cell line;clinical research;cysteine endopeptidases;enzyme inhibitors;growth factor receptors;hormone regulation /control mechanism;human tissue;immunoprecipitation;neoplasm /cancer genetics;neoplastic growth;neoplastic process;prostate neoplasms;protein kinase;receptor expression;transfection;transforming growth factors


application_id: 6908908
project_number: 5R21CA104258-02
project_title: Tumor FDG Kinetics in a 3-D Tissue Culture System
administering_ic: NCI
award_notice_date: 2005-05-24
opportunity_number: PA-01-030
application_type: 5
activity_code: R21
ic: CA
serial_number: 104258
program_official: NORDSTROM, ROBERT J
project_start_date: 2004-07-01
project_end_date: 2007-06-30
study_section: Diagnostic Radiology and Nuclear Medicine Study Section[RNM]
contact_pi_person_id: 7606517
contact_pi: NG, CHIN K
other_pis: Not Applicable
congressional_district: 03
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   Positron Emission Tomography (PET) offers the uniqueness of non-invasive in vivo quantification for a variety of biological diseases. PET imaging with F-18 labeled fluorodeoxyglucose (FDG) has shown great promises to be a powerful unique clinical tool for the diagnosis and the staging of many carcinomas especially when it is used simultaneously with Computed Tomography (CT). Nonetheless the validity of FDG as a radiotracer for glucose metabolism in cancer cells is still not well understood. In order to explore this further four human non-small cell lung cancer (NSCLC) lines (squamous adenocarcinoma large cell and bronchioalveolar) will be immobilized with microcarriers in suspension. This 3-D tissue culture system where cells are isolated from other control factors is analogous to an isolated perfused heart system. Time activity curves (TAC) will be obtained in high temporal resolution by on-line dynamic measurement of FDG uptake into cells with two external gamma probes. The TAC will be further analyzed by a compartmental model for kinetic parameters associated with both the transport and phosphorylation steps. Three specific aims for this proposal are: 1. To determine the growth conditions to obtain a steady state of immobilized cells per gram microcarrier for four common types of NSCLCs 2. To characterize the metabolic and hemodynamic parameters (oxygen glucose lactate CO2 pH temperature) for all four cell types in the 3-D tissue culture system 3. To investigate FDG kinetics and the lumped constant behaviour in all four cell types. Since the overexpression of glucose transporter and hexokinase isoforms are not expected to be the same for all carcinomas FDG kinetics in these four NSCLCs should demonstrate certain degree of differential uptakes. Results obtained from the proposed research will provide a basis for the understanding of FDG kinetics in cancer cells and the identification of new non-invasive means to probe biological diseases. The same experimental setup can also be used with many other types of cells to probe biological diseases with either PET or SPECT ligands. FDG kinetics in NSCLCs was chosen only to demonstrate its potential utility by relating problems to a well-established clinical procedure in PET imaging. Therefore the long-term objective is to develop a versatile experimental setup that combines a 3-D tissue culture system with external gamma probes for the development and the evaluation of radiopharmaceuticals.

project_terms:
adenocarcinoma;bioimaging /biomedical imaging;cell population study;deoxyglucose;glucose metabolism;glucose transport;hexokinase;neoplastic growth;nonsmall cell lung cancer;positron emission tomography;radionuclides;squamous cell carcinoma;three dimensional imaging /topography;tissue /cell culture


application_id: 6905519
project_number: 5R01CA091901-05
project_title: NOVEL AUREOLIC ACID TYPE ANTITUMOR AGENTS
administering_ic: NCI
award_notice_date: 2005-05-02
application_type: 5
activity_code: R01
ic: CA
serial_number: 091901
program_official: FU, YALI
project_start_date: 2001-06-01
project_end_date: 2008-05-31
study_section: Bio-Organic and Natural Products Chemistry Study Section[BNP]
contact_pi_person_id: 2257319
contact_pi: ROHR, JURGEN T
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-06-01
project_abstract:
DESCRIPTION: (provided by applicant):Mithramycin (MTM) is an aureolic acid                                                   antimicrobial and antitumor agent produced by various Streptomyces species          including S. argillaceus which has been used e.g. for the treatment of           testicular carcinoma. In addition MTM is unique among anticancer agents in         that it also has been used clinically to treat cancer-caused malignant              hypercalcemia and Paget's bone disease. However MTM's bone marrow hepatic        and renal toxicity limit its widespread clinical use. It is proposed to             investigate various aspects of the biosynthesis of the antitumor and                osteoclast-inhibiting agent mithramycin in order to develop analogs with            increased therapeutic indices which also may allow the separation of the two       principal effects of MTM (i) on cancer growth and (ii) on osteoclasts. This        will lead to novel antitumor agents and/or to therapeutics against osteoporosis     and other diseases related to bone growth disorders and bears the potential        for a novel gene therapy concept in future. Combinatorial biosynthetic methods      will be used to provide an array of MTM analogs. For this the biosynthetic         pathway to MTM which is dominated by a type II polyketide synthase (PKS)          needs to be further characterized. Especially genes encoding enzymes                responsible for the late biosynthetic steps the post-PKS tailoring enzymes        particularly oxidoreductases and group transferases will be modified Resulting      mutant strains will help to determine the series of events within the               biosynthetic pathway and will characterize substrates and function of important     enzymes in the MTM pathway. This information will be used to design novel           compounds with specific activity-increasing functionality. In context with the      mechanism of action of MTM on osteoclasts we want to explore whether MTM           derivatives can effect the expression of c-src a proto-oncogene necessary for      the osteoclastic bone resorption following the novel hypothesis that MTM and       its derivatives inhibit osteoclast bone resorption by blocking Sp 1 binding to      the promoter region of the c-src proto-oncogene.                                                                                                                        The following three specific aims will be addressed:                                                                                                                    (1) To further characterize the biosynthetic pathway of mithramycin and to          develop new niithramycin derivatives through selective gene inactivation and        product identification. Various group transferases and oxidoreductases will be      investigated. In addition the mtm genes will be recombined with promising          deoxysugar biosynthesis glycosyltransferase and oxygenase encoding genes from      other pathways to develop novel niithramycin analogs modified in their              saccharide and/or 0-atom pattern.                                                                                                                                       (2) The two oxygenases of the MTM pathway MtmOII and MtmOIV will be               investigated. The work on MtmOII an early-acting oxygenase will help to           identify the missing link between the final PKS product and                         4-demethylpremithramycinone the earliest mithramycin precursor documented to       date. Tetracyclic niithramycin analogs will be converted into their tricycic        and expected more active counterparts by overexpressing oxygenase MtmOIV in the     various glycosyltransferase deletion mutants.                                                                                  (3) To assay the binding properties of MTM and its novel analogs to the GC-rich     elements in the c-myc and c-src promoters and their ability to prevent Sp 1         binding. Testing the high-affinity c-myc will follow thisand c-src binding          compounds for inhibition of gene expression in human cancer cells and for their     effects on growth and viability of normal and cancer cells. Finally promising      c-src inhibiting analogs will be analyzed for activity against                      osteoclastmediated bone resorption.

project_terms:
analog;biosynthesis;clinical research;enzyme activity;genetic promoter element;human subject;interferon gamma;mithramycin;osteoclasts;osteopetrosis;oxidoreductase;pathologic bone resorption;polyketide synthase;protooncogene;skeletal pharmacology;transcription factor;transferase


application_id: 6902536
project_number: 5T32DC000065-05
project_title: CELLULAR AND MOLECULAR NEUROSCIENCE OF SENSORY SYSTEMS
administering_ic: NIDCD
award_notice_date: 2005-06-27
application_type: 5
activity_code: T32
ic: DC
serial_number: 000065
program_official: SKLARE, DAN
project_start_date: 2001-07-01
project_end_date: 2006-06-30
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 1879429
contact_pi: GETCHELL, THOMAS V
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-07-01
project_abstract:
DESCRIPTION (from applicant's abstract): The goal of this training program is to prepare promising graduate and medical students postdoctoral and medical resident fellows for successful careers in Cellular and Molecular Neuroscience of Sensory Systems. This program arises from the perceived benefits of integrated training in the fundamental principles which shape the function of all of our senses and is guided by the following conceptual framework:  (I) The sensory systems of the human body are fundamental contributors to the health and well-being of people and are critical substrates for disease processes.  (II) These neural systems share many core mechanisms of organization and function which are especially apparent at the cellular molecular and genetic levels. (III) Common mechanisms are also reflected in sensory pathologies- specific disease processes often impact multiple sensory systems.  (IV) Graduate and postdoctoral research training which integrates cellular molecular and genetic aspects over a range of sensory systems will enhance the ability of trainees to conduct innovative health-related research.  Core mechanisms span multiple sensory systems as do disease processes (e.g. Charcot-Marie-Tooth disease Norrie disease Retinitis pigmentosa Usher's syndrome Aging and sensory senescence).  Thus there is a need for research training which integrates across the traditional boundaries of each special-sense tissue.  The proposed training faculty consists of 12 members with expertise in the auditory chemosensory mechanosensory and visual systems.  Faculty research approaches range from mutagenesis and molecular genetics through cell and molecular biology to intact animal physiology behavioral analysis and clinical research. The institutional resources level of extramural support and training histories of the training faculty engender a superb training environment.


application_id: 6901848
project_number: 5R21AI061432-02
project_title: Surface proteins in pneumonic plague
administering_ic: NIAID
award_notice_date: 2005-06-24
opportunity_number: PA-03-080
application_type: 5
activity_code: R21
ic: AI
serial_number: 061432
program_official: SCHAEFER, MICHAEL R
project_start_date: 2004-07-01
project_end_date: 2007-06-30
study_section: Special Emphasis Panel[ZRG1-IDM-A(90)S]
contact_pi_person_id: 1864206
contact_pi: STRALEY, SUSAN C
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Yersinia pestis is the most highly virulent extracellular pathogen known and poses an ominous threat as an agent of bioterrorism. The bacteria are highly infectious by aerosol and cause pneumonic plague which can kill in as little as two days after exposure. There is no vaccine available for plague. Vaccines under development for prevention of plague contain two proteins called LcrV and FI. They provide moderate protection against pneumonic plague but not if the infecting strain lacks the F1 capsular protein. F1 is not required for virulence by the aerogenic route and its gene is easily deleted posing the potential of a weaponized Fl-lacking strain against which these candidate vaccines do not protect effectively. To find alternative vaccine candidates we will develop a novel proteomics approach to identify Y. pestis surface proteins that are expressed during pneumonic plague. These studies will provide the technical base for a more detailed screen for new plague vaccine candidates. Further we hope that one or more of the proteins we identify in the proposed pilot studies will prove in the future to be protective against pneumonic plague caused by a non-encapsulated strain against which vaccines currently under development will not protect adequately. Our aims are: 1. Develop a biotinylation-MS approach for identification of surface-exposed proteins on Y. pestis recovered from lungs of mice with pneumonic plague. 2. Identify up to 10 surface proteins and evaluate them for conditions that optimize expression.

project_terms:
Yersinia pestis;Yersinia pestis disease;bacterial capsules;bacterial genetics;bioinformatics;biotechnology;bioterrorism /chemical warfare;gene expression;laboratory mouse;lung;mass spectrometry;membrane proteins;molecular probes;protein quantitation /detection;proteomics;technology /technique development;vaccine development


application_id: 6898211
project_number: 5R01AI051930-06
project_title: Mycobacterium tuberculosis in vivo gene expression
administering_ic: NIAID
award_notice_date: 2005-05-27
application_type: 5
activity_code: R01
ic: AI
serial_number: 051930
program_official: SIZEMORE, CHRISTINE F
project_start_date: 2001-09-17
project_end_date: 2007-05-31
study_section: ZHL1-CSR-L(M4)
contact_pi_person_id: 6484029
contact_pi: GRAHAM, JAMES ERIC
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: 2005-06-01
project_abstract:
DESCRIPTION   (provided by applicant)                                               Mycobacterium tuberculosis is a pathogen that is able to adapt to a variety of      different environments encountered during the progressive course of human           infection.  An ability to inhibit maturation of the macrophage phagosome            initially created an ideal environment for bacterial growth allowing               colonization of the body.  when deprived of this favorable environment by the       hosts's own tissue-damaging immune response infection often fails to               progress and bacilli enter an nonreplicating latent state having reached a        degree of equilibrium with the host.  Changes in the host over time may then        allow bacteria to resume replication leading to further tissue destruction         and extracellular growth to high titers.  This project will identify bacterial      genes that are specifically expressed by M.  tuberculosis during adaptation to      these in vivo environments.  A new method developed specifically for                examination of mycobacterial mRNAs expressed in infected host cells and             tissues (SCOTS) has so far identified 9 M.  tuberculosis genes which are            expressed in response to growth within cultured human macrophage phagosomes.        The first aim of the proposed work is to make bacterial strains specifically        inhibited in expression of these genes and evaluate their ability to survive        and grow in cultured human macrophages.  The second aim is to identify              additional M.  tuberculosis genes that are differently expressed by tubercle        bacilli in another environment that bacilli normally encounter during the           natural course of human infection.  Bacterial genomic array hybridization with      cDNAs obtained by SCOTS will be used to analyze global mRNA expression              patterns in bacilli recovered from patient sputum samples providing insight        into the physiology and metabolism of the microbe during active growth in the       human lung.  Our third aim is to extend analysis of differential bacterial          gene expression to a C57BL/6 mouse model of host interaction facilitating          studies of both active and latent types of infection in a genetically defined       host.  Bacterial cDNA already obtained by SCOTS from tubercle bacilli growing       in cultured mouse macrophages and from infected mouse lung tissues will be          compared by array hybridization to cDNA from tubercle bacilla growing in human      macrophages and lung tissues.  A limited number of M.  tuberculosis genes           commonly expressed in response to these mammalian host interactions will then       be evaluated for their contributions to virulence in this animal model.             Understanding the roles of such differentially expressed genes will further         define host-pathogen interactions in human disease and allow development of        new tools to reduce the enormous global impact of tuberculosis on mankind.

project_terms:
Mycobacterium tuberculosis;antisense nucleic acid;bacteria infection mechanism;bacterial genetics;cell death;complementary DNA;gene expression;host organism interaction;human genetic material tag;human tissue;laboratory mouse;macrophage;messenger RNA;microarray technology;molecular pathology;nucleic acid hybridization;phagocytosis;polymerase chain reaction;tissue /cell culture;virulence


application_id: 6897896
project_number: 5R01NS042089-04
project_title: Controlling Apoptosis in Oligondendrocytes
administering_ic: NINDS
award_notice_date: 2005-05-12
application_type: 5
activity_code: R01
ic: NS
serial_number: 042089
program_official: KLEITMAN, NAOMI
project_start_date: 2002-07-01
project_end_date: 2007-05-31
study_section: Special Emphasis Panel[ZRG1-MDCN-2(01)S]
contact_pi_person_id: 1958914
contact_pi: KNAPP, PAMELA E
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-06-01
project_abstract:
DESCRIPTION (provided by applicant): Myelination is necessary for proper CNS function. Neurological deficits occur in spinal cord injury (SCI) and other conditions where oligodendrocyte (OL) death results in demyelination. It is not clear how the loss of OLs is initiated in SCI but several factors known to induce OL apoptosis are elevated in the extracellular environment. This suggests that OLs may be the target of multiple toxic agents. OLs which die in SCI show activation of post-mitochondrial events typical of apoptosis including caspase-3 activation. The goal of this proposal is to define events which occur earlier in OL apoptosis and to apply intervention strategies so that OLs survive and myelinating function is maintained. Our overall goal is to devise a therapeutic strategy to interrupt OL apoptosis regardless of the initiating agent so that it can be used effectively in many demyelinating conditions. The proposed studies use in vivo and culture methods to test the following hypotheses: 1) that soluble factors which induce OL apoptosis after SCI cause activation of the proapoptotic molecule BAD; 2) that OL apoptosis can be ameliorated by inactivating BAD either by upregulating the enzymes which phosphorylate it (Akt PI 3-kinase) or by using drugs which inhibiting its dephosphorylation (FK506); 3) that caspase-independent effectors such as endonuclease-G play an important role in cell loss after SCI. Specific Aim 1: Immunohistochemistry and immunoblots are used to show that soluble apoptotic agents result in BAD dephosphorylation and related biochemical events in OLs. Specific Aim 2: Adenoviral transfection and pharmacological approaches are used to test whether increasing levels of P-BAD through overexpression of Akt1 and PI 3-kinase or inhibition of calcineurin activity can promote survival and myelinating function in cultured OLs. Specific Aim 3: Unbiased stereology is used to test whether mice with deletions in the genes for PTEN (an Akt inhibitor) and caspase-3 show an increase in tissue sparing and OL survival after SCI. Specific Aim 4: Biochemical and histological techniques are used to determine whether pathways which are independent of caspase-3 play a significant role in cell loss after SCI.

project_terms:
Bax gene /protein;FK506;apoptosis;biological signal transduction;calcineurin;cysteine endopeptidases;endodeoxyribonuclease;enzyme activity;gene deletion mutation;gene expression;genetically modified animals;immunocytochemistry;laboratory mouse;myelination;myelinopathy;oligodendroglia;pharmacokinetics;phosphatidylinositol 3 kinase;phosphorylation;protein kinase;protooncogene;spinal cord injury;tissue /cell culture;transfection /expression vector;western blottings


application_id: 6897859
project_number: 5R01AA013388-03
project_title: Hippocampal neurotoxicity induced by ethanol withdrawal
administering_ic: NIAAA
award_notice_date: 2005-05-26
application_type: 5
activity_code: R01
ic: AA
serial_number: 013388
program_official: SORENSEN, ROGER
project_start_date: 2003-06-01
project_end_date: 2007-05-31
study_section: Alcohol and Toxicology Subcommittee 3[ALTX-3]
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-06-01
project_abstract:
DESCRIPTION (provided by applicant): A model system has been developed utilizing organotypic cultures of rat hippocampus in which a single cycle of ethanol exposure and removal results in significant "spontaneous" neuronal death mainly in the pyramidal cells of the CA1 region. This in vitro model is potentially valuable for understanding the mechanisms underlying alcoholic brain damage arguably the most important preventable cause of dementia in the USA. The data obtained thus far suggest that in this model neuronal damage is mostly excitotoxic and occurs during ethanol withdrawal. The primary hypothesis is that ethanol-induced adaptations in the glutamatergic system lead on withdrawal of ethanol to a cascade of changes including synaptic hyperactivity network excitation and excess release of endogenous glutamate and polyamines. These mediators then co-activate glutamate/NMDA receptors (NMDARs) that may be "supersensitive" to both agents and which cause toxic Ca2+ entry. The primary specific aim is test these hypotheses and to elucidate the pre-synaptic and post-synaptic mechanisms that lead to withdrawal-induced toxicity in this model. Selective antagonists for ionotropic and metabotropic glutamate receptors and calcium channels will be used to probe mechanisms for initial synaptic excitation (calcium orange fluorescence microscopy) release of glutamate and polyamines (HPLC) distribution and sensitivity of NMDARs ([125I]MK801 autoradiography) and the relation between cumulative Ca2+ uptake (radiotracer 45Ca2+) and neurotoxicity (propidium iodide fluorescence microscopy). A second major aim is to investigate the role of network excitation in these changes by studying effects of transecting neural pathways within the culture on these parameters. Mechanisms that rely on transsynaptic activation should be prevented by this procedure. All studies in the project will focus on the regional distribution of toxicity within the slice culture and the mechanisms that contribute to this distribution. In addition to testing the hypotheses these experiments should suggest novel therapeutic interventions into alcohol-induced neurodegenerative disease and elucidate why specific neuronal phenotypes are susceptible to alcohol withdrawal. Both are research priorities in the recent NIAAA Review of Neuroscience and Behavioral Science Portfolio.

project_terms:
NMDA receptors;autoradiography;calcium channel blockers;calcium flux;drug withdrawal;ethanol;fluorescence microscopy;glutamate receptor;glutamates;high performance liquid chromatography;hippocampus;laboratory rat;neurotoxicology;neurotransmitter antagonist;neurotransmitter transport;polyamines;protein localization;protein structure function;radiotracer;receptor sensitivity;tissue /cell culture


application_id: 6896806
project_number: 5R01GM055343-24
project_title: Hepatic Drug Elimination in Pregnancy
administering_ic: NIGMS
award_notice_date: 2005-06-10
application_type: 5
activity_code: R01
ic: GM
serial_number: 055343
program_official: OKITA, RICHARD T
project_start_date: 1979-09-30
project_end_date: 2006-12-04
study_section: Pharmacology A Study Section[PHRA]
contact_pi_person_id: 1862358
contact_pi: VORE, MARY
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-06-01
project_abstract:
DESCRIPTION (provided by applicant):  This proposal focuses on the effects of estradiol and its metabolites on the function and expression of Mrp2 (ABCC2) the ABC transporter that mediates the biliary excretion of glucuronide and glutathione conjugates from the hepatocyte into bile. The proposal builds on our findings that 1) Mrp2-mediated transport of estradiol-17Beta-(Beta-D-glucuronide) (E217G) is essential for its cholestatic activity 2) E217G causes endocytic retrieval of Mrp2 from the canalicular membrane that coincides with decreased bile flow and 3) expression of Mrp2 protein but not Mrp2 mRNA is decreased in pregnancy. Aim 1 will test the hypothesis that transport of cholestatic E217G and the choleretic estradiol-3-glucuronide (E23G) by rat Mrp2 and human MRP2 is mediated by overlapping but non-identical substrate binding sites. We will use an Mrp2/MRP2 baculovirus expression system in Sf9 cells and probe the substrate binding sites of E217G vs E23G. We will also determine if women with intrahepatic cholestasis of pregnancy have polymorphisms in MRP2 that alter their transport of E217G vs E23G. Aim 2 will test the hypotheses that A) E217G causes endocytic retrieval of Mrp2 and other transporters critical to bile formation from the canalicular membrane leading to inhibition of flow and B) agents that protect against cholestasis do so by either inhibiting Mrp2 transport of E217G or prevention of transporter retrieval. We will use confocal immunomicroscopy to monitor endocytic retrieval of transporters from and their exocytic insertion into the canalicular membrane. Aim 3 will characterize the changes in Mrp2 expression in pregnancy and test the hypotheses that A) estrogens mediate the decreased hepatic Mrp2 expression in pregnancy B) Mrp2 is subject to transcript-specific translational control conferred by regulatory elements in the 5' or 3' untranslated regions of Mrp2 mRNA and C) pregnancy and estrogens increase the degradation of Mpr2 protein. We will use polysomal distribution analysis of Mrp2 mRNA translation assays in HepG2 cells and determine the degradation half-life of Mrp2 protein in control pregnant and estrogen-treated rats. Significance: Characterization of the mechanisms by which estrogens decrease Mrp2/MRP2 function and expression can lead to 1) improved drug therapy for women in pregnancy 2) development of therapeutic measures to increase MRP2 function in cholestatic liver disease and 3) methods to screen for cholestatic toxicity in drugs under development.

project_terms:
alanine transaminase;antipyrine;bilirubin glucuronide;binding sites;cholestasis;clinical research;colchicine;daunorubicin;drug metabolism;estradiol;estrogen analog;female;genetic polymorphism;genetic regulation;glutathione;hormone regulation /control mechanism;human subject;intracellular transport;laboratory rat;liver metabolism;liver pharmacology;membrane transport proteins;messenger RNA;methotrexate;paclitaxel;patient oriented research;pregnancy disorder;protein degradation;protein glutamine gamma glutamyltransferase;protein isoforms;protein transport


application_id: 6896766
project_number: 5R01DA013930-03
project_title: Redesign of Butyrylcholinesterase for Cocaine Metabolism
administering_ic: NIDA
award_notice_date: 2005-06-02
application_type: 5
activity_code: R01
ic: DA
serial_number: 013930
program_official: SHIH, MING L
project_start_date: 2003-08-20
project_end_date: 2006-09-09
study_section: Medication Development Research Study Section[NIDA-L]
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-07-01
project_abstract:
DESCRIPTION (provided by applicant):  This project focuses on the rational redesign of human butyrylcholinesterase (BChE) in order to accelerate cocaine metabolism in man. Enhancing cocaine metabolism by administration of BChE has been recognized as a possible treatment strategy for cocaine overdose and addiction. However the catalytic activity of this plasma enzyme is three orders-of-magnitude lower against the naturally occurring (-)-cocaine than that against the relatively biologically inactive (+)-cocaine isomer. (+)-cocaine can be cleared from plasma in seconds prior to partitioning into the central nervous system. The long-term goal of this project is to guide the construction of a BChE mutant using site-directed mutagenesis by our collaborators so that the mutant can be used as an exogenous enzyme in human body with a catalytic activity for (-)-cocaine comparable to that of wild-type BChE for (+)-cocaine. For this purpose state-of-the-art computational techniques will be used to uncover the mechanistic difference of the enzymatic reaction between (-)-cocaine and (+)-cocaine and to establish a rational basis for theoretical design of BChE mutants with an improved activity for (-)-cocaine. The specific aims of the investigation involved in the present proposal include: 1. To determine structures and dynamics of the BChE binding with (-)-cocaine and (+)-cocaine including the non-prereactive and prereactive BChE-substrate complexes. 2. To uncover fundamental reaction pathways for BChE-catalyzed hydrolysis of (-)-cocaine and (+)-cocaine at the benzoyl ester by performing reaction coordinate calculations on properly chosen model systems; 3. To investigate dynamics and changes of BChE binding with (-)-cocaine and (+)-cocaine during the enzymatic hydrolysis by carrying out MD simulations on the enzyme-reactant transition state intermediate and product complexes; 4. To evaluate free energy profiles and kinetics of the enzymatic hydrolysis by performing combined quantum mechanical and free energy perturbation calculations (QM-FE); 5. To design BChE mutants expected to have higher activity for (-)-cocaine based on the binding information obtained from Specific Aim 2 and the energetic information from Specific Aim 3.

project_terms:
bioenergetics;biotechnology;chemical kinetics;cholinesterases;cocaine;computer simulation;drug design /synthesis /production;drug metabolism;enzyme activity;enzyme substrate complex;hydrolysis;molecular dynamics;mutant;protein engineering;quantum chemistry;site directed mutagenesis


application_id: 6896414
project_number: 5R21NS046426-02
project_title: Oxidative Stress and the Ketogenic Diet
administering_ic: NINDS
award_notice_date: 2005-04-22
opportunity_number: PAR-01-111
application_type: 5
activity_code: R21
ic: NS
serial_number: 046426
program_official: FUREMAN, BRANDY E
project_start_date: 2004-07-01
project_end_date: 2007-04-30
study_section: ZNS1-SRB-A(17)
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This application is for a bi-institutional collaborative Exploratory/Developmental Award in Epilepsy Research for Junior Investigators. The PI is an Assistant Professor at the University of Kentucky and although published extensively in the field of mitochondrial bioenergetics and mitochondria-mediated cellular injury and death he is relatively new to the field of epilepsy research. During a post-doctoral fellowship the PI initiated an innovative collaboration with an established epilepsy researcher at the University of California at Irvine. The co-PI is an expert on mechanisms underlying the anticonvulsant actions of the ketogenic diet (KD) an effective non-pharmacological treatment for medically refractory epilepsy. The KD is a high-fat low-carbohydrate/low-protein diet designed to reproduce the early biochemical changes seen upon fasting. Despite decades of successful clinical experience with the KD the mechanisms underlying its anticonvulsant actions remain poorly understood. It is well known that fasting increases peripheral mitochondrial uncoupling protein (UCP) activity. However there are no data addressing the effects of a KD on brain mitochondrial uncoupling. In preliminary studies we have found that a KD enhances mitochondrial uncoupling and decreases reactive oxygen species (ROS) production in normal mouse cortex. The fundamental goal of the proposed studies is to determine whether a KD decreases mitochondrial oxidative damage in the hippocampus of developing epileptic mice (i.e. the Kcnal-null mutant) and following acute excitotoxic insult in normal mice. Specifically we hypothesize that a KD increases UCP-mediated mitochondrial uncoupling and reduces subsequent ROS formation in epileptic hippocampus. Additionally we hypothesize that the KD reduces mitochondrial dysfunction lipid peroxidation and protein oxidation following kainic acid-induced seizures. Our preliminary data in the kainic acid model strongly suggest a direct neuroprotective effect of the KD not related to seizure severity between groups of control diet- vs. KD-treated animals. The results of these studies will shed light on whether a KD reduces oxidative stress in a genetic model of developmental epilepsy as well as in a well-established excitotoxic model. The clinical importance of such findings is that this therapy may ameliorate the epileptic condition itself and not merely halt spontaneous recurrent seizure activity.

project_terms:
cell component structure /function;cell death;diet therapy;dietary lipid;epilepsy;free fatty acids;free radical oxygen;genetically modified animals;hippocampus;kainate;ketone body;laboratory mouse;membrane potentials;membrane transport proteins;mitochondria;nervous system disorder therapy;neurotoxins;nutrition related tag;oxidative stress;peroxidation


application_id: 6896378
project_number: 5R01EY014623-03
project_title: Complement System and Choroidal Neovascularization
administering_ic: NEI
award_notice_date: 2005-06-16
application_type: 5
activity_code: R01
ic: EY
serial_number: 014623
program_official: DUDLEY, PETER A
project_start_date: 2003-08-01
project_end_date: 2006-01-04
study_section: Special Emphasis Panel[ZRG1-VISC(01)Q]
contact_pi_person_id: 1867228
contact_pi: BORA, PURAN S
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-07-01
project_abstract:
DESCRIPTION (provided by applicant): The complement system plays a critical role in the host defense against microorganisms and in the modulation of inflammatory responses. Recently it has been suggested that there may be a link between complement activation and vascular proliferation. Age-related macular degeneration (ARMD) is the leading cause of blindness in the Western world in individuals over 55 years of age. Although the nonexudative (dry) form of ARMD is more prevalent catastrophic vision loss is more frequently associated with the exudative (wet) form specifically from the complications of neovascularization of the choroid. The pathogenesis of new choroidal vessel formation (CNV) in exudative ARMD is poorly understood. Although inflammation has been implicated in the development of CNV the role of complement has not been explored. In the current proposal we wish to explore the role of complement in choroidal neovascularization using the mouse model of laser-induced CNV. Using this model our recent results suggest that the complement system is central to the development of laser-induced choroidal angiogenesis. Thus we propose to explore the role of complement and complement regulatory proteins in the development of experimental CNV as well as the treatment effect of complement inhibition using soluble complement regulatory proteins. The specific aims of this proposal are:  1. To study the complement system in the mouse model of laser-induced CNV.  2. To study complement regulatory proteins (CRPs) in the mouse model of laser-induced CNV.  3. To establish the complement (i.e. MAC) dependence and temporal expression of angiogenic growth  factors in laser-induced CNV. We believe that these studies will lead to a better understanding of an important underlying molecular mechanism in the development of CNV (i.e. complement activation) and will help to identify new molecular targets for novel therapeutic approaches.

project_terms:
acute phase protein;angiogenesis;blood vessels;cell proliferation;choroid uvea;complement;complement pathway;confocal scanning microscopy;eye circulation;eye surgery;genetically modified animals;growth factor;inflammation;laboratory mouse;macular degeneration;polymerase chain reaction;western blottings


application_id: 6896228
project_number: 5R01AA010496-09
project_title: ALCOHOL LIVER DISEASE AND S-ADENOSYLMETHIONINE
administering_ic: NIAAA
award_notice_date: 2005-05-16
application_type: 5
activity_code: R01
ic: AA
serial_number: 010496
program_official: GENTRY, THOMAS
project_start_date: 1996-03-01
project_end_date: 2007-05-31
study_section: Alcohol and Toxicology Subcommittee 4[ALTX-4]
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: 2005-06-01
project_abstract:
EXCEEDTHE SPACE PROVIDED.  Alcoholic liver disease (ALD) is a major cause of liver disease and liver related morbidity/mortality in the United States. One major difficulty in devising specific therapies for ALD has been our limited understanding of the mechanism(s) for the development andprogression of this liver injury. Cytokines are low molecular weight mediators of cellular communication that are produced and released by numerouscell types such as monocytes macrophages and of particular relevance to liver disease Kupffer cells. Pro-inflammatory cytokines such as tumor necrosis factor a (TNF) and chemokines such as interleukin-8 have been postulated to play a role in modulating many of the systemic manifestations of ALD and certain aspects of the liver injury in ALD. Many factors stimulate cytokine production including endotoxin (lipopolysaccharide orLPS) and reactive oxygen intermediates (ROIs) both ofwhich are of direct relevance to this proposal. Endotoxin stimulates cytokine production via interaction with LPS binding protein (LBP) membranebound CD14 and ultimately the recently described LPS receptor Toll-like receptor TLR4.  TLR4then causes activation ofthe redox sensitive transcription factor NFicB with subsequent production of cytokines such as TNF. NFicB also has been identified as a survival factor against TNF induced apoptosis in multiple cell types  Thus NFicB not only serves as a transcription factor for several inflammatory cytokines such as TNF andTL-8 but also for several potentially protective factors such as inhibitors of apoptosis (lAPs). Inhibition of NFicB can initiate fulminant liver injury and hepatocyte apoptosis at least in part by allowing unregulated signaling via the TNF "death domain". We postulate that in ALD there is: 1)increased NFicB activation and TNF production in the major cytokine producing cell in the liver (Kupffer cell); and 2) decreased NFicBactivation and decreased "protective signaling" in conjunction with increased TNF death signaling in the target cell (hepatocyte). In this proposal we will use in vitro systems in vivo animal models of ALD and ultimately will perform translational human studies to further define mechanisms of liver injury in ALD and potential pathways for intervention. The specific aims of this proposal are to: 1) Evaluate mechanisms for increased NFicB activation and TNF production by monocyte/Kupffer cells in ALD (priming) 2) Evaluate mechanisms of increased susceptibility to TNF/cytokinehepatotoxicity in ALD (sensitization). PERFORMANCE SITE ========================================Section End===========================================

project_terms:
AIDS therapy;HIV infections;S adenosylmethionine;alcoholic hepatitis;choline deficiency;clinical research;clinical trials;diet therapy;dietary supplements;hepatotoxin;human subject;human therapy evaluation;hypoxia;intravenous administration;laboratory rat;liver disorder chemotherapy;malnutrition;nutrition related tag;protein deficiency;tumor necrosis factor alpha


application_id: 6895535
project_number: 5K01MH067123-03
project_title: Study of novel REST/NRSF-Interacting LIM domain Protein
administering_ic: NIMH
award_notice_date: 2005-08-05
application_type: 5
activity_code: K01
ic: MH
serial_number: 067123
program_official: VAN'T VEER, ASHLEE VICTORIA
project_start_date: 2003-07-01
project_end_date: 2007-06-30
study_section: Special Emphasis Panel[ZRG1-MDCN-1(01)S]
contact_pi_person_id: 7875223
contact_pi: SHIMOJO, MASAHITO
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-07-01
project_abstract:
DESCRIPTION (provided by applicant):   
Previous studies by the applicant have focused on the regulation of the cholinergic gene locus. This locus is composed of two proteins choline acetyltransferase (CHAT) which synthesizes acetylcholine and the vesicular acetylcholine transporter (VAChT) which transports acetylcholine into synaptic vesicles. It was found that ChAT and VAChT are coordinately regulated through a protein kinase All dependent pathway. This regulation involves repression of the locus by the zinc finger transcription factor REST/NRSF and de-repression by a neuron specific isoform of REST/NRSF called REST4. REST4 is formed through alternative splicing of the REST/NRSF gene in a process regulated by protein kinase All. REST4 was found to be localized to the nucleus with the nuclear localization signal mapped within zinc finger domains 2-5. This domain contained signals that not only localized REST4 to the nucleus but also translocated REST4 into the nucleus. These findings lead to a study of the nuclear trafficking of REST4 as well as REST/NRSF. A yeast-two hybrid screen using zinc finger domains 2-5 as bait resulted in the cloning of a novel cDNA. The deduced amino acid sequence of this cDNA showed the presence of three LIM domains a domain reported to act as a protein-protein interaction domain. This protein was named the REST/NRSF-Interacting LIM domain Protein (RILP). The long-term goal of this proposal is to reveal the physiological function of RILP using molecular genetic biochemical and structural approaches. To achieve this goal three specific aims are proposed. The first specific aim is to characterize the importance of LIM domains C-terminal prenylation phosphorylation and nuclear localization signals (NLSs) for RILP function. The second specific aim is to study the effect of RILP on REST/NRSF regulated neuronal gene expression. The third specific aim is to identify RILP interacting protein. These would be either other proteins in which RILP is involved in their translocation to the nucleus or nuclear envelope proteins that RILP interacts with. These studies mentored by Drs. Louis Hersh and Brett Spear will permit the candidate to expand his expertise into new areas and to develop a research program that should lead to independent research funding. Dr. Shimojo will have access to shared-use equipment laboratory space and faculty and staff which will enhance the likelihood that the proposed objectives will be successfully accomplished.

project_terms:
acetylcholine;cell line;choline acetyltransferase;gene expression;genetic transcription;isoprenoid;membrane proteins;nuclear membrane;phosphorylation;postdoctoral investigator;posttranslational modifications;protein localization;protein protein interaction;protein structure;protein structure function;protein transport;transcription factor;yeast two hybrid system


application_id: 6893402
project_number: 5R21NS047635-02
project_title: Novel calpain inhibitors based on phage display
administering_ic: NINDS
award_notice_date: 2005-05-02
opportunity_number: PAR-02-138
application_type: 5
activity_code: R21
ic: NS
serial_number: 047635
program_official: HICKS, RAMONA R
project_start_date: 2004-05-15
project_end_date: 2007-04-30
study_section: Neurological Sciences and Disorders A Study Section[NSD-A]
contact_pi_person_id: 3079616
contact_pi: GUTTMANN, RODNEY P
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   Many researchers have shown that over activation of the calcium-dependent proteases the calpains likely contributes to the cell death that occurs following brain injury. Therefore it is critical to develop therapeutic agents to stem this over activation and reduce or prevent the subsequent cellular and tissue destruction. In preliminary work we have used phage peptide display to identify a class of peptides that bind to calpain in a calcium-dependent manner. Interestingly the representative peptide LSEAL has homology to conserved repetitive sequence found in calpastatin. Hence we hypothesize that we have identified a novel class of calpastatin peptide mimetic. The goal of this proposal is to confirm and extend our initial observation that we have identified a novel family of calpain inhibitor for potential clinical use in the treatment of brain injury by carrying out the following specific aims: Specific Aim 1" Use phage peptide display to identify peptides that bind calpain in a calcium-dependent manner. We have already identified a candidate peptide LSEAL. Additional libraries of increased stringency are to be used to find potentially more effective sequences. Specific Aim 2: To test the hypothesis that phage peptide display-derived peptides are novel and specific inhibitors of calpain activity with a mechanism similar to calpastatin. In preliminary work we have found that a representative peptide from the initial library (LSEAL) is a potent inhibitor of calpain's actions on proteolysis of the microtubule-associated protein tau a known calpain substrate. BIAcore technology will be used in addition to Elisa based assays to assay for calcium-dependent competitive binding between calpastatin tau and LSEAL. We will also test additional calpain substrates. Specific Aim 3: To evaluate the hypothesis that LSEAL and related peptides act as novel calpain inhibitors in a cellular setting. In preliminary work we have used cultured cortical neurons to demonstrate that cell death caused by increased cytosolic calcium mediated by either ionomycin or UV light is prevented by treatment with LSEAL and not by a scrambled sequence negative control peptide ELLAS. These studies will evaluate key aspects of LSEAL actions and provide important evidence to support the future development of this potentially new class of calpain inhibitor for use in the treatment of brain injury.

project_terms:
biomimetics;biotechnology;brain injury;calpain;drug discovery /isolation;enzyme inhibitors;enzyme linked immunosorbent assay;fluorescence microscopy;laboratory rat;peptide chemical synthesis;phage display;protein binding;statistics /biometry;stroke therapy;tissue /cell culture


application_id: 6893297
project_number: 5R01HL068088-05
project_title: MOLECULAR BASIS OF PRECONDITIONING
administering_ic: NHLBI
award_notice_date: 2005-05-26
application_type: 5
activity_code: R01
ic: HL
serial_number: 068088
program_official: LIANG, ISABELLA Y
project_start_date: 2001-07-20
project_end_date: 2008-05-31
study_section: Cardiovascular and Pulmonary Research B Study Section[CVB]
contact_pi_person_id: 8251726
contact_pi: GUO, YIRU
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-06-01
project_abstract:
DESCRIPTION (provided by applicant): Recent data demonstrate that the               cardioprotective effects of late preconditioning (PC) are mediated by COX-2 an     enzyme that is generally thought to be detrimental. These findings reveal a         novel unsuspected function of COX-2. At present the regulation of this            protein in intact heart and its actions during myocardial ischemia/reperfusion      are essentially unknown. The objective of this proposal is to elucidate the         molecular mechanisms underlying the newly discovered cardioprotective role of       COX-2. The applicant will test the hypothesis that diverse PC stimuli               upregulate COX-2 through a complex signal transduction cascade that includes        PKC-epsilon Src/Lck and multiple transcription factors. Three different forms     of late PC elicited by a pathological (ischemia) physiological (exercise) and      pharmacological (NO donor) stimulus will be interrogated in an effort to            develop a comprehensive pathophysiologic paradigm. A broad multidisciplinary        approach will be used that will combine diverse techniques (integrative             physiology protein chemistry mass spectrometry biochemistry cell biology       molecular biology gene targeting and transgenesis) and will integrate genetic     and biochemical information at the molecular level with the physiological           information at the whole animal level. Twenty-three genetically engineered          mouse lines will be studied. Unequivocal evidence for or against an obligatory      role of three specific kinases (PKC-epsilon Src Lck) in COX-2 upregulation        will be provided by the use of two novel PKC-epsilon transgenic mouse lines and     Src and Lck knockout mice. The role of PKC-epsilon in recruiting COX-2 will be      conclusively established by determining the effects of specific transgenic          inhibition of this isozyme. The role of Src PTKs in the transcriptional versus      posttranslational modulation of COX-2 will be discerned by comparing inhibition     of these kinases during the PC stimulus (on day 1) versus 24 hours after the PC     stimulus (on day 2). targeted disruption of the Src and Lck genes will be           employed to conclusively establish the specific function of individual PTKs.        The role of NF-kappaB in COX-2 regulation will be unequivocally determined by       targeted disruption of three specific NF-kappaB subunits (p50 RelB c-Rel) and     by the use of a novel transdominant IkappaBa mutant mouse with cardiac-specific     repression of NF-kappaB activity. The specific modulatory proteins that govern      COX-2 gene expression will be systematically identified by targeted genetic         ablation of the main factors known to bind to the COX-2 promoter (AP-1 STAT5a     STAT5b CREB NF-IL-6 CEBPd and Ets-1). The Src PTK-dependent                     posttranslational modulation of COX-2 24 hours after PC will be elucidated by       identifying the precise phosphorylation site(s) on COX-2 with HPLC                  coupled-electrospray ionization mass spectrometry. Finally the specific            prostanoid receptor subtype(s) responsible for COX-2-dependent protection will      be systematically interrogated by targeted genetic disruption of all known          prostaglandin receptors (DP EP1 EP2 EP3 EP4 F and IP receptors). this         project should produce important new insights into the molecular mechanisms         that underlie COX-2-dependent cytoprotection late PC and the role of COX-2 in     cardiac pathophysiology in general.

project_terms:
cytoprotection;electrospray ionization mass spectrometry;enzyme activity;exercise;gene targeting;genetically modified animals;heart pharmacology;isozymes;laboratory mouse;myocardial ischemia /hypoxia;myocardium;nuclear factor kappa beta;prostaglandin endoperoxide synthase;prostaglandin receptor;protein binding;protein kinase;protein tyrosine kinase;reperfusion;transcription factor


application_id: 6892350
project_number: 5K02DE014765-04
project_title: Endothelin A Signaling in Craniofacial Development
administering_ic: NIDCR
award_notice_date: 2005-05-13
opportunity_number: PA-00-020
application_type: 5
activity_code: K02
ic: DE
serial_number: 014765
program_official: HARDWICK, KEVIN S
project_start_date: 2002-08-01
project_end_date: 2005-11-30
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 3063608
contact_pi: CLOUTHIER, DAVID E.
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):  Most bone and cartilage structures of the jaw and throat are derived from cephalic neural crest cells. These cells arising from the hindbrain migrate to the pharyngeal arches where they undergo a proliferation and differentiation program culminating in the formation of craniofacial structures. While numerous signaling cascades regulate this developmental program the effectors of these cascades are poorly defined. This Independent Scientist Award application requests salary support for the candidate to elucidate the downstream effectors of endothelin-A receptor signaling that control development of cephalic neural crest cells and their derivatives. The candidate will use a variety of techniques to accomplish this aim including analysis of genomic changes using custom cDNA microarrays and analysis of proteomic changes using 2D-gel electrophoresis and mass spectroscopy. Career goals of the candidate are centered on developing an active research laboratory dedicated to understanding the molecular and cellular basis of normal and abnormal craniofacial development. This lab will serve the additional goal of training pre- and post-doctoral students in craniofacial research. An ISA will enhance the candidate's development as an independent investigator by enabling specific expansion of expertise and research activities. Immediate plans include traveling to an external laboratory to develop expertise in the production and analysis of large-scale custom cDNA microarrays as well as learning modern techniques in protein profiling and identification at the Core Proteomics Laboratory and the Biomolecular Mass Spectroscopy Core Laboratory both at the University of Louisville. To take full advantage of the array and proteomic data the candidate will also attend a bioinformatics course designed to enable researchers to write programs to manage genomic and proteomic research data. The Institution's development plans include: provision of significant start-up funds; guaranteed salary support beyond the period of time requested for K02 support; permission for the candidate to spend essentially full-time conducting research: minimal departmental duties; funds to travel to laboratories as outlined in the candidate's plans; provision of funds to hire a post-doctoral fellow to contribute to the growing research program in the candidate's laboratory: participation in monthly inter- and intra-departmental discussion groups designed to facilitate the development of the candidate's research program. The research environment offers excellent opportunities for scientific interactions that foster scientific growth and development. Many senior investigators direct active research programs at the University of Louisville offering many potential interactions. Importantly the candidate's chairman is a well-established investigator studying the molecular and cellular basis of facial birth defects. Both his personal interaction as well as his continuing efforts to recruit individuals with active research programs in the areas of craniofacial development and genetics underscores the commitment to build a strong research group further helping the candidate build his own research program.

project_terms:
biological signal transduction;bone development;cartilage development;cell differentiation;cell migration;cell proliferation;craniofacial;embryo /fetus;endothelin;gene expression;genetically modified animals;growth /development;histochemistry /cytochemistry;in situ hybridization;laboratory mouse;mass spectrometry;microarray technology;neural crest;polymerase chain reaction;receptor expression;transcription factor


application_id: 6892172
project_number: 5R01HL068440-04
project_title: Factor Xlll Activation and Substrate Specificity
administering_ic: NHLBI
award_notice_date: 2005-05-11
application_type: 5
activity_code: R01
ic: HL
serial_number: 068440
program_official: LINK, REBECCA P
project_start_date: 2002-07-08
project_end_date: 2006-05-31
study_section: Hematology Subcommittee 2[HEM-2]
contact_pi_person_id: 1912066
contact_pi: MAURER, MURIEL C.
other_pis: Not Applicable
congressional_district: 03
department: CHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_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: 2005-06-01
project_abstract:
In blood coagulation the enzyme thrombin cleaves fibrinogen sites for fibrin polymerization are revealed and fibrin clot formation begins.  Activated Factor XIII a transglutaminase is responsible for catalyzing the formation of covalent crosslinks between fibrin molecules and in fibrin-enzyme complexes.  Thrombin activates Factor XIII by cleaving a peptide sequence that lies across the Factor XIII catalytic site.  The thrust of this research project will be to examine in solution the structural features that govern the activation and substrate specificity of Factor XIII.  The specific aims are designed to prove the following hypotheses: 1) There is no obvious consensus sequence for defining the substrate specificity of Factor XIII for glutamine donating groups.  The glutamine containing substrates are hypothesized to interact with the Factor XIII enzyme surface using similar bound conformations with defined flexible and/or solvent exposed regions.  Peptides based on natural and synthetic substrates will be examined. 2) The Factor XIII activation peptide segment has components that resemble the fibrinogen Aalpha chain the thrombin receptor and PPACK all of which interact with thrombin.  The Factor XIII activation peptide segment is hypothesized to adopt a bound conformation that allows for the most effective interactions with the thrombin surface. An understanding of how unique amino acid positions within this segment participate in binding may lead to the design of Factor XIII enzymes whose degree of activation and optimal target site can be controlled.  A model system for these studies is Factor XIII V34L a common polymorphism that has been correlated with protection against myocardial infarction and is more susceptible to thrombin cleavage than the native sequence.  To address these specific aims a combination of kinetic studies hydrogen/deuterium exchange followed by MALDI-TOF mass spectrometry 1D proton line broadening NMR 2D TOCSY 2D transferred NOESY and molecular modeling will be used. Understanding the molecular details of how Factor XIII is activated and how its substrate specificity is regulated is critical considering the role this enzyme plays in increasing the risk of heart disease stroke and arteriosclerosis.

project_terms:
SDS polyacrylamide gel electrophoresis;activation product;active sites;antifibrinolytic agents;binding sites;blood coagulation;caseins;computer simulation;conformation;crosslink;deuterium;enzyme substrate;fibrin;fibrin stabilizing factor;fibronectins;high performance liquid chromatography;hydrogen;hydrolysis;mass spectrometry;matrix assisted laser desorption ionization;membrane transport proteins;molecular dynamics;nuclear magnetic resonance spectroscopy;protein glutamine gamma glutamyltransferase;protein structure function;thrombin


application_id: 6892034
project_number: 5F30DA014596-05
project_title: SUBSTRATE AND INHIBITOR SPECIFICITY IN NEUROPEPTIDASES
administering_ic: NIDA
award_notice_date: 2005-05-13
opportunity_number: PA-99-089
application_type: 5
activity_code: F30
ic: DA
serial_number: 014596
program_official: BABECKI, BETH
project_start_date: 2002-05-01
project_end_date: 2005-09-30
study_section: Special Emphasis Panel[ZRG1-MDCN-5(01)L]
contact_pi_person_id: 6579838
contact_pi: HINES, CHRISTINA S
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION(Adapted from applicant's abstract): We are investigating the molecular basis for substrate recognition and inhibitor action in neuropeptidases. These enzymes play key roles in the generation and inactivation of peptide neurotransmitters and hormones. A better understanding of these enzymes and the development of specific inhibitors may permit novel therapies for psychotic disorders pain and drug and alcohol addiction. We study one enzyme neurolysin as a model system. Like a number of the neuropeptidases it is active only on short peptides and it is able to recognize a diverse but specific set of cleavage sites. This enzyme is known to control the levels of neurotensin which is one of the most potent analgesics known and is thought to play a role in schizophrenia and depression. Our group has determined a crystal structure of neurolysin which is a 78kDa zinc metallopeptidase. We now plan to determine crystal structures of the enzyme complexed with peptides and inhibitors to determine the basis for the unusual aspects of its substrate recognition. This structural work will be complemented by a series of functional studies aimed at better defining the features of a good substrate. And finally we will compare the mechanisms of substrate recognition and inhibitor binding with those of a neuropeptidase from a different enzyme family

project_terms:
X ray crystallography;bradykinin;enzyme activity;enzyme inhibitors;enzyme substrate;high performance liquid chromatography;hormone regulation /control mechanism;metalloendopeptidases;neprilysin;neurotensin


application_id: 6891790
project_number: 5R21NS047129-02
project_title: Role of Olig3 gene in gliogenesis
administering_ic: NINDS
award_notice_date: 2005-06-20
application_type: 5
activity_code: R21
ic: NS
serial_number: 047129
program_official: UTZ, URSULA
project_start_date: 2004-07-01
project_end_date: 2007-06-30
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
contact_pi_person_id: 1906514
contact_pi: QIU, MENGSHENG
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-07-01
project_abstract:
DESCRIPTION (provided by applicant):   
Astrocytes constitute more than half the number of cells in the central nervous system and play numerous important roles in supporting the function of the CNS including regulating the concentration of extracellular ions and neurotransmitters forming brain blood barrier regulating synapse formation and efficacy inducing neurogenesis in the adult brain and etc. In the injured CNS astrocytes also have profound effects on the success or failure of reinnervation by regrowth of severed axons as astrocytes participate in the formation of glial scars to impede axon regeneration. Despite the importance of astrocytes in the function and repairing of the CNS the origin and molecular specification of astrocytes have remained mysterious. The long-term goal of this study is to understand the molecular mechanisms that control the specification and differentiation of astrocytes. Specifically we plan to study the regulation and function of a candidate regulatory gene (Olig3) that may participate in the regulation of astrocyte development during embryogenesis. This regulatory gene is specifically expressed in subventricular cells outside the oligodendrogenic domain of embryonic spinal cord and is hypothesized to promote astrocyte fate but inhibits oligodendrocyte development. Two specific aims are proposed to test this hypothesis and to further investigate the molecular mechanisms underlying the specification and differentiation of astrocytes. Specific aim 1 will investigate the role of Olig3 transcription factors in regulating astrocyte and oligodendrocyte development. Specific aim 2 will study the regulation of Olig3 gene expression in the developing spinal cord. Results derived from the proposed studies will significantly enhance our understanding of the genetic circuitry governing the early specification and differentiation of astrocytes and may provide theoretic basis for design of novel therapeutic approaches for prevention of glial scar formation in the injured spinal cord and promote regeneration of oligodendrocytes.

project_terms:
astrocytes;cell differentiation;chick embryo;developmental genetics;electroporation;gene induction /repression;genetic regulation;laboratory rat;nerve stem cell;neurogenesis;oligodendroglia;protein structure function;regulatory gene;tissue /cell culture;tissue /cell preparation;transcription factor;vertebrate embryology


application_id: 6890914
project_number: 5R03AA014578-02
project_title: IMPROVING POSTTREATMENT ALCOHOLICS ANONYMOUS UTILIZATION
administering_ic: NIAAA
award_notice_date: 2005-05-16
opportunity_number: PA-02-174
application_type: 5
activity_code: R03
ic: AA
serial_number: 014578
program_official: CHIAPELLA, PAGE
project_start_date: 2004-05-01
project_end_date: 2008-04-30
study_section: ZAA1-BB(37)
contact_pi_person_id: 7599645
contact_pi: CLOUD, RICHARD N
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 SOCIAL WELFARE/WORK
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Substance abuse is widely recognized as one of the top healthcare problems in the US and alcohol dependence is the by far the most prevalent addictive disorder. While psychosocial treatments have been shown to be beneficial the majority of clients treated in abstinence based treatments relapse in the year following treatment. A growing body of research suggests that aftercare services and post-treatment Alcoholics Anonymous (AA) involvement improve drinking outcomes. Despite this optimism two problems stand as barriers to improved outcomes relying on these two strategies: (1) regarding the former strategy the US DHHS Reports shortages in treatment capacity and it is unlikely that substantial professionally led aftercare services can be expanded at this time and (2) regarding the latter research suggests that involvement in AA following twelve-step facilitative treatment is minimal or nonexistent in the most  cases.    This study seeks to improve treatment outcomes by improving post-treatment AA involvement using a newly developed intervention. The grant team relies on the Rounsaville and colleagues (2001) model for new intervention development and proposes to conduct a small stage lb randomly controlled pilot study (N=60) of this newly developed intervention. Alcohol dependent subjects meeting inclusion / exclusion will be recruited from a large inpatient treatment facility in the Louisville KY area and randomly assigned to an experimental condition (N=30) or a treatment as usual control group (N=30) and followed up at three- and six-months post-treatment. The intervention consists of two motivational sessions that will be delivered by the PI at or near the end of treatment. During the second motivational session the subject will be introduced to a randomly-assigned and gender-matched AA mentor and agree to meet at six meetings in the three weeks following treatment with an express goal of advancing AA socialization processes.  Primary aims are to advance knowledge on how to increase post-treatment AA utilization by (1) pilot testing the intervention in a small randomly controlled trial to establish benefits if any; (2) advance a theoretical model that identifies causes and mechanisms of long-term AA affiliation and or disaffiliation; and (3) publish treatment training and research compliance guides to assist with future research and knowledge transfer. A secondary aim of the application involves increasing knowledge of how to utilize the AA recovery community by evaluating methods used to recruit screen train and engage the recovering community for provision of mentoring services.

project_terms:
alcoholism /alcohol abuse;behavior therapy;behavioral /social science research tag;clinical research;health care service utilization;health services research tag;human subject;human therapy evaluation;mentoring /mentor;motivation;patient oriented research;psychosocial service;role model;self help organization


application_id: 6890381
project_number: 5R01NS036350-08
project_title: Schwann cells neurotrophins and spinal cord regrowth
administering_ic: NINDS
award_notice_date: 2005-06-02
application_type: 5
activity_code: R01
ic: NS
serial_number: 036350
program_official: MAMOUNAS, LAURA
project_start_date: 1998-05-15
project_end_date: 2007-04-30
study_section: Special Emphasis Panel[ZRG1-BDCN-4(03)M]
contact_pi_person_id: 7378367
contact_pi: XU, XIAO-MING
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-05-01
project_abstract:
DESCRIPTION (provided by applicant):  Glial cell line-derived neurotrophic factor (GDNF) a distant member of the transforming growth factor-beta (TGF-beta) family is widely expressed in the developing and adult central nervous system (CNS). Limited knowledge is available for its role in the repair of spinal cord injury (SCI). Preliminary results demonstrate that 1) distinct CNS regions that compose descending motor pathways expressed GFR(I and c-Ret the two co-receptors that are required for GDNF signaling; 2) both GDNF and its co-receptors were increasingly expressed in these regions after SCI; 3) GDNF significantly enhanced axonal regeneration and myelination within mini-guidance channels implanted into a spinal hemisection gap when it was delivered either alone or in combination with Schwann cells (SCs); and 4) intrathecal delivery of GDNF demonstrated a protective/regenerative effect on distinct supraspinal axons following a contusive SCI. Thus GDNF may play a novel therapeutic role in the regeneration and myelinogenesis of the injured spinal cord. We have previously also demonstrated that neurotrophins BDNF and NT-3 promoted robust axonal outgrowth from SC-bridge transplants into the distal host spinal cord; some of these axons formed bouton-like endings on host spinal neuronal cell bodies. The goal of the present proposal is to investigate whether a preformed growth-promoting pathway of GDNF (used individually or in combination with BDNF and NT-3) extending from the site of injury to the lumbar central pattern generator (CPG) promotes axons of responsive tracts to regenerate across the lesion and more importantly grow back into the host spinal cord to re-establish connections with appropriate distal neuronal targets. This may lead to improved recovery of hind limb locomotor function following SCI. Using a low-thoracic spinal cord hemisection and SC-seeded mini-channel implantation mode we will test the central hypotheses that 1) regeneration of injured spinal and brainstem neurons across a SC-bridge transplant and into the distal spinal cord is regulated by the supply of neurotrophic factors (GDNF BDNF and NT-3) along the growth promoting pathway and 2) recovery of hind limb locomotion is proportional to the number of spinal- and brainstem-derived axons that re-innervate neuronal targets within the central pattern generator. In addition we will also investigate mechanisms underlying GDNF induced axonal regeneration and myelination by studying its direct or indirect effect on SCs both in vitro and in vivo. Finally a combinatory repair strategy involving GDNF SCs guidance channels neurotrophins gene transfer and dural repair will be employed to provide the best possible environment for observation of effective axonal regeneration and meaningful functional recovery.

project_terms:
Schwann cells;axon;behavior test;biological signal transduction;electrophysiology;enzyme linked immunosorbent assay;immunocytochemistry;in situ hybridization;laboratory rat;myelination;nervous system regeneration;neurons;neurotrophic factors;spinal cord injury;spinal ganglion;tissue /cell culture;transforming growth factors;western blottings


application_id: 6890020
project_number: 5T32AI049795-05
project_title: Training Program in Microbial Pathogenesis
administering_ic: NIAID
award_notice_date: 2005-07-27
application_type: 5
activity_code: T32
ic: AI
serial_number: 049795
program_official: MCSWEEGAN, EDWARD
project_start_date: 2001-08-01
project_end_date: 2007-07-31
study_section: Microbiology and Infectious Diseases Advisory Committee[MID]
contact_pi_person_id: 1864206
contact_pi: STRALEY, SUSAN C
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-08-01
project_abstract:
DESCRIPTION (provided by applicant): This is a request to support threepredoctoral students and three postdoctoral fellows in a new Training Programin Microbial Pathogenesis with the goal of preparing trainees for productivecareers as scientists in academic industrial or government positions. Theproposed program builds upon the existing strong research training programthat offers diverse research opportunities in basic mechanisms of bacterialviral prion protozoa! and fungal host-parasite interactions in a medicalcenter setting. The proposed training faculty have their primary appointmentsin 6 Medical Center basic science and clinical Departments: the Department ofMicrobiology and Immunology (which will administer the program) and theDepartments of Biochemistry Internal Medicine Neurology Oral HealthScience and Pathology. Cohesion in the graduate training experience comesfrom a common collaboratively taught new Integrated Biomedical Sciencescurriculum for the first year of predoctoral training that develops a strongdidactic foundation in basic biochemistry cell biology and signalinggenetics and molecular biology. The research training faculty have excitingwell-funded research programs and strong track records in predoctoral andpostdoctoral training. They provide a multidisciplinary approach to trainingand research in the context of a collegial interactive scientificenvironment. Program trainees also benefit from the larger scientificcommunity that includes several new faculty appointees in microbialpathogenesis. In addition to formal instruction there is a rich program ofseminars and minisymposia by visiting scientists; and both pre- andpost-doctoral trainees gain experience and breadth by giving mentored seminarsin weekly well-attended programs and by participating in journal clubs anddiscussions with visiting scientists. They present their work and refine theirthinking through regularly scheduled laboratory research conferences dataclubs and local regional and national scientific meetings. In summary thespecial character of this program derives from the high concentration ofoutstanding basic science and clinical faculty with research expertise inmicrobial pathogenesis and a strong commitment to the development ofsuccessful young scientists.


application_id: 6889530
project_number: 5R01GM066152-04
project_title: Synthetic Probes of Protein Prenylation
administering_ic: NIGMS
award_notice_date: 2005-04-11
application_type: 5
activity_code: R01
ic: GM
serial_number: 066152
program_official: FABIAN, MILES
project_start_date: 2002-05-01
project_end_date: 2008-04-30
study_section: Bio-Organic and Natural Products Chemistry Study Section[BNP]
contact_pi_person_id: 7875230
contact_pi: SPIELMANN, H PETER
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-05-01
project_abstract:
DESCRIPTION (provided by applicant): Synthetic Probes of Protein Prenylation:       Covalent modification by isoprenoid lipids prenyIation) is a critical               post-translational event for many proteins involved in cellular signaling. The      discovery that the members of the Ras family of protooncogenes are modified by      the farnesyl isoprenoid (farnesylation) and that prenylation is required for       the oncogenic forms of these proteins to express their transforming potential      has led to intense investigation of protein-farnesyltransferase (FTase)             inhibitors (FTIs) as promising cancer chemotherapeutic agents. However recent      developments have made it clear that the mechanism of FTI action is                 unexpectedly complex although it involves inhibition of FTase. In addition        the contribution of isoprenoid lipids to the overall biology of Ras is              incompletely understood. Therefore a key to applying FTase-based                   pharmacological intervention is a thorough understanding of the in vivo             farnesylation pathways. Knowledge of the substrate specificity for FTase and       the cellular function of the prenyl moiety are critical to improving the design     of future FTIs. The central hypothesis of this study is that the prenyl group       plays an active role in directing both post-translational processing and          cellular membrane localization of prenylated proteins. An important corollary       to this hypothesis is that modifications to the prenyl structure may lead to        significant biologically relevant effects on the activity of the unnaturally       prenylated protein. We have synthesized FPP analogs that are transferred to         oncogenic Ras but fail to support transformation. These molecules are leads for     a unique class of potential anti-cancer: therapeutics we term RFIs (Ras             function inhibitors). The specific aims of this project are: 1) specifically       substituted unnatural analogs of farnesyl pyrophosphate and the homologous          isoprenoid geranylgeranyl pyrophosphate will be synthesized in a combinatorial      scheme; 2) these compounds will be screened as substrates or inhibitors of          FTase and the closely related enzyme geranylgeranyltransferase I; 3) building       upon promising preliminary results in this area an in vivo isoprenoid              structure-function relationship will be established by replacing the H-Ras          farnesyl group with a select subset of the analogs available from the studies       described in specific aim 1 and 2 and analyzing their biological functions         following microinjection into Xenopus oocytes. The  results of these               experiments will provide further insight into the mechanisms of Ras processing      transformation a greater understanding of the specific functions of the H-Ras      farnesyl group in vivo and fruitful directions for improvements in FTIs as         well as novel transferable analogs which might act as RFIs.

project_terms:
Xenopus oocyte;alkyltransferase;analog;antineoplastics;chemical structure function;combinatorial chemistry;drug design /synthesis /production;enzyme inhibitors;farnesyl compound;geranyl compound;isoprenoid;posttranslational modifications;protein localization;pyrophosphates


application_id: 6889181
project_number: 5R01ES004849-15
project_title: MOLECULAR MECHANISMS OF CHEMICAL ATHEROGENESIS
administering_ic: NIEHS
award_notice_date: 2005-05-02
application_type: 5
activity_code: R01
ic: ES
serial_number: 004849
program_official: MASTIN, PATRICK
project_start_date: 1989-09-03
project_end_date: 2008-04-30
study_section: Alcohol and Toxicology Subcommittee 1[ALTX-1]
contact_pi_person_id: 6221833
contact_pi: RAMOS, KENNETH S
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-05-01
project_abstract:
Environmental chemicals are significant risk factors for atherosclerotic vascular disease but molecular mechanisms of atherogenesis have not been elucidated with certainty. Research in this laboratory during the previous funding cycle established that transcriptional deregulation of gene expression by aromatic hydrocarbons is a critical event in the induction of proliferative (i.e. atherogenic) phenotypes in vascular smooth muscle cells (vSMCs). Challenge with atherogenic hydrocarbons was shown to alter redox status and trigger a complex cellular response that culminates in modulation of vascular gene expression. Of particular relevance was the finding that functional interactions between aryl hydrocarbon receptor (AhR) and proteins that bind the antioxidant/electrophile response element (AREBpRE) are central to the loss of transcriptional control in hydrocarbon-treated cells. On the basis of these findings our unifying hypothesis is that deregulation of gene expression in vSMCs by aromatic hydrocarbons involves complex interactions between activated ARE/EpRE binding proteins AhR and co-regulators of transcription during the course of the atherogenic response. To test this hypothesis experiments are proposed to purify and clone AREJEpRE binding proteins from vascular tissue following chemical injury evaluate the role of HMG-1 (Y) as a co-regulator of ARFJEpRE-regulated gene transcription in vSMCs and characterize promoter-specific patterns of trans-regulation in vSMCs. These studies will enable us to define the role of ARE/EpRE binding proteins in oxidant-induced atherogenesis and identify critical transacting factors involved in the atherogenic response to environmental injury.

project_terms:
affinity chromatography;antioxidants;aromatic hydrocarbon receptor;atherosclerosis;benzopyrenes;binding proteins;complementary DNA;crosslink;environmental toxicology;gel mobility shift assay;gene expression;genetic promoter element;genetic regulation;genetic transcription;glutarates;immunoprecipitation;laboratory mouse;oncogenes;pathologic process;polymerase chain reaction;protein protein interaction;site directed mutagenesis;tissue /cell culture;vascular smooth muscle;western blottings


application_id: 6887738
project_number: 5R01AG017963-05
project_title: AGING AND 6 HYDROXYDOPAMINE NEUROTOXICITY
administering_ic: NIA
award_notice_date: 2005-04-27
application_type: 5
activity_code: R01
ic: AG
serial_number: 017963
program_official: CHEN, WEN G
project_start_date: 2001-05-01
project_end_date: 2008-04-30
study_section: Special Emphasis Panel[ZRG1-BDCN-2(01)S]
contact_pi_person_id: 1863805
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
budget_start_date: 2005-05-01
project_abstract:
DESCRIPTION: (Verbatim from the Applicant's Abstract) The nigrostriatal             dopamine (DA) system of the brain plays a major role in the control of              movement. A gradual loss of nigrostriatal DA neurons occurs during normal aging     in humans and many elderly persons display one or more of the signs of             Parkingson's disease without having the disease. This may indicate that these       people have a greater than normal loss of nigrostriatal DA. An animal model of      aging with a partial loss of DA neurons (ICV injection of 6-hydroxydopamine        6-OHDA) is currently being developed by the applicant. The experiments in the       present proposal will use this model to determine the extent of spontaneous         recovery of presynaptic dopaminergic functioning in young middle-aged and aged     rats. In addition the effects of the potent dopaminergic factor glial cell         line-derived neurotrophic factor (GDNF) will also be examined in this model. It     is hypothesized that the nigrostriatal DA system in aged rats will have a           reduced capacity to recover from the neurotoxic effects of 6-OHDA compared to       young rats. It is further hypothesized that GDNF will be less effective in aged     animals compared to young animals both in its ability to protect against 6-OHDA     and to promote recovery after the lesion. The first specific aim will examine       spontaneous recovery in young (4 months old) middle-aged (14 months old) and       aged (24 months old) male and female Fischer-344 rats following partial             bilateral lesions with 6-OHDA. Locomotor activity basal levels and evoked          overflow of DA and its metabolites in the striata (as measured with                 microdialysis) and tyrosine hydroxylase immunohistochemistry studies will be       carried out at several time points after the lesion to determine extent of          recovery. Post-mortem measurements of tissue monoamines will be analyzed as         well. The second specific aim will evaluate the ability of GDNF to prevent or       reduce 6-OHDA-induced changes in locomotor activity and presynaptic                 dopaminergic function in the three age groups while the third specific aim         will examine the ability of GDNF to promote behavioral and neurochemical            recovery from the lesion in the three age groups. The results of these              experiments will help determine if the nigrostriatal DA system of the aging         brain has the same capacity to recover from a neurotoxic insult as that of          younger animals and will begin to evaluate age-related differences in response     of nigrostriatal DA neurons to neurotrophic factors.

project_terms:
6 hydroxydopamine;Parkinson&apos;s disease;aging;amphetamines;chordate locomotion;corpus striatum;disease /disorder model;dopamine;high performance liquid chromatography;immunocytochemistry;laboratory rat;microdialysis;neuropharmacology;neurotoxicology;neurotrophic factors;potassium ion;substantia nigra;tyrosine 3 monooxygenase


application_id: 6887447
project_number: 5R21CA091624-02
project_title: Autologous Dendritic Cell Vaccines in NSCLC
administering_ic: NCI
award_notice_date: 2005-03-15
opportunity_number: PAR-03-005
application_type: 5
activity_code: R21
ic: CA
serial_number: 091624
program_official: ULLMANN, CLAUDIO A
project_start_date: 2004-04-19
project_end_date: 2007-03-31
study_section: Clinical Oncology Study Section[CONC]
contact_pi_person_id: 7875285
contact_pi: HIRSCHOWITZ, EDWARD A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Clinical outcomes of unresectable stage III NSCLC are universally poor. Survival with combination chemo-radiotherapy is 11-18 months. Investigation of additional therapies is warranted. Immunotherapies specifically cancer vaccines have therapeutic potential. Preliminary data indicate that autologous dendritic cells pulsed with allogeneic tumor antigens can induce measurable immune responses in individuals with NSCLC. Responses have been seen irrespective of stage or prior therapy and the spectrum includes responders and nonresponders. The host environment appears to play a significant role in regulating T cell responses to vaccines. We postulate that physiologic (inducible) and pathologic (constitutive expression by NSCLC tumor cells) COX-2 activity can mediate immune regulation. COX-2 is the enzyme responsible for PGE-2 production a prominent immunosuppressive cytokine with numerous direct and indirect effects that polarize the immune response towards suppression or tolerance. Specifically PGE-2 and monocyte-derived IL 10 induced by PGE2 may significantly suppress antigen presentation and proliferation of NSCLC specific T cells as well as lead to premature death of DCs. Modifying the host environment with COX-2 inhibitors is feasible and a rational strategy to enhance T cell responses to DC vaccines. Literature and preliminary data support these precepts. Thus studies are designed to test the routine effectiveness of DC vaccines in unresectable stage III NSCLC and further evaluate the immune modulating effects of COX-2 inhibitors used in concert with tumor vaccines. Postulating an inverse relationship between COX-2 activity and immunologic response to vaccines biomarkers of COX-2 activity will be evaluated as correlative markers of immune reactivity. Markers will also be used to track biologic effects of the COX-2 inhibitor Celebrex in NSCLC.

project_terms:
T lymphocyte;biomarker;clinical research;combination cancer therapy;cyclooxygenase inhibitors;dendritic cells;enzyme activity;enzyme linked immunosorbent assay;human subject;human therapy evaluation;immune response;immunomodulators;interferon gamma;interleukin 10;interleukin 4;neoplasm /cancer immunotherapy;neoplasm /cancer vaccine;neoplastic process;nonsmall cell lung cancer;oxidoreductase inhibitor;patient oriented research;prognosis;prostaglandin endoperoxide synthase;tumor antigens;tumor infiltrating lymphocyte


application_id: 6884164
project_number: 1R41HL079855-01
project_title: New anti-complement therapy to reduce reperfusion injury
administering_ic: NHLBI
award_notice_date: 2005-04-27
application_type: 1
activity_code: R41
ic: HL
serial_number: 079855
program_official: LIANG, ISABELLA Y
project_start_date: 2005-05-01
project_end_date: 2006-10-31
study_section: Special Emphasis Panel[ZRG1 GDD (01)]
contact_pi_person_id: 2129782
contact_pi: MALDONADO, CLAUDIO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 144667602
primary_uei: TGWXNHCYTTR3
duns_number: 144667602
uei: TGWXNHCYTTR3
fips: US
organization_id: 10004330
organization_name: ENDOPROTECH, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402041019
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-05-01
project_abstract:
DESCRIPTION (provided by applicant):   The purpose of this proposal is to provide proof-of-concept that a novel therapy that prevents complement activation could be effective in reducing ischemia reperfusion injury (IRI) in transplanted organs. Complement activation after IRI in transplanted organs is a well-known phenomenon that may be responsible for delayed graft function and the hastening of acute rejection. The proposed therapy to reduce IRI is based on novel fusogenic lipid vesicles (FLVs) that rapidly incorporate into cell membranes. Our FLVs allow the rapid display of protective exogenous proteins on the surface of endothelial cells. The goal of this proposal is to optimize the display of a modified complement blocking protein named vaccinia virus complement control protein (VCP) on the surface of endothelial cells and show that it can reduce complement induced damage after cells are exposed to hypoxia and reoxygenation. We hypothesize that the VCP displayed on the surface of endothelial cells will bind complement fragments early in the complement cascade and prevent cell injury. To test this hypothesis we will perform the following specific aims. In Aim I the formulation and concentration of biotinylated lipid vesicles will be optimized for optimal biotin coverage of cells. Aim II will assess on the surface of endothelial cells the biotin binding capacity of the streptavidin domain on our recently developed streptavidin-VCP (SA-VCP) chimeric protein. Aim III will assess the ability of SA-VCP to inhibit complement derived damage after hypoxia and reoxygenation of endothelial cells.     If this proposal is successful it will demonstrate the effectiveness of both our novel cell membrane biotinylation platform technology and our newly developed anti-complement chimeric protein. In a Phase II proposal we plan to test our technology in a transplantation animal model. We believe that our technology will make it possible to rapidly modify the functional characteristics of endothelial cell membranes without the use of gene therapy. If SA-VCP ex-vivo therapy is highly effective in preventing complement activation after IRI this will be extremely valuable for organ transplantation. The economic implications of our technologies for clinical application are vast.


application_id: 6884057
project_number: 5R01HD042245-03
project_title: Female mate choice and cultural transmission
administering_ic: NICHD
award_notice_date: 2005-03-28
application_type: 5
activity_code: R01
ic: HD
serial_number: 042245
program_official: FREUND, LISA S
project_start_date: 2003-07-01
project_end_date: 2007-04-30
study_section: Biobehavioral and Behavioral Processes 1[BBBP-1]
contact_pi_person_id: 1890522
contact_pi: DUGATKIN, LEE ALAN
other_pis: Not Applicable
congressional_district: 03
department: BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-05-01
project_abstract:
DESCRIPTION (provided by applicant): Social/cultural factors such as copying behavior may have considerable effects on a female's decision regarding with whom to mate.  The strongest evidence for female mate copying comes from work on the guppy Poecilia reticulata.  In addition to providing the first controlled experimental work on mate copying subsequent work on female mate copying in the guppy has found that young females are more likely to copy the mate choice of old females than vice versa females will switch their initial preference if they observe another female choose a male which they did not themselves choose and mate copying can under some conditions override genetic predispositions for certain male traits.    Despite prior work on mate copying many of the most fundamental and conceptually intriguing questions on copying and mate choice have yet to be investigated experimentally in this system or any other. To date my work on cultural transmission and mate choice in guppies has focused on the behavior of individual females. Demonstrating the power of cultural transmission via the behavior of individuals is a critical first step but it is truly just a first step in understanding the cultural transmission of social behavior. One of the most potent elements in how cultural transmission shapes behavior focuses on how individual decisions ripple through groups and change the distribution of behavioral choices within a group in a single (or a very few) generations. It is this component of cultural transmission in animals that I propose to work on over the next few years.    The studies proposed here have implications for developmental and social psychology as well as evolutionary and behavioral ecology. Although psychologists have studied copying behavior in many contexts it has been difficult to assess the relative contribution that genetic and social factors (such as copying) may have on the manifestation of a particular behavior. The guppy system allows one to overcome this hurdle as well and has the added benefit of examining the dynamics of cultural transmission with respect to a behavior - mate choice - that is of significant interest to numerous different fields in psychology. In fact my initial work on mate copying in guppies has facilitated collaboration with Dr. Michael Cunningham a social psychologist.  Based on the questions developed in the guppy research we examined human mate copying behavior. We have found some evidence of mate copying in a study using written surveys. Here I propose to continue my work with Dr. Cunningham and examine mate copying in an experimental scenario that moves away from a written survey and provides a more realistic evaluation of human mate copying.

project_terms:
behavior test;behavioral /social science research tag;behavioral genetics;choice;clinical research;culture;decision making;developmental psychology;ethology;female;fish;growth /development;human subject;imitative behavior;interpersonal relations;peer group;questionnaires;sex behavior;social behavior;social psychology


application_id: 6883346
project_number: 1R43RR021289-01
project_title: L1 mutagenesis for mammalian models of human diseases
administering_ic: NCRR
award_notice_date: 2005-02-11
application_type: 1
activity_code: R43
ic: RR
serial_number: 021289
program_official: RALL, WILLIAM F
project_start_date: 2005-02-14
project_end_date: 2006-01-31
study_section: Special Emphasis Panel[ZRG1 SSS-Y (10)]
contact_pi_person_id: 3075176
contact_pi: OSTERTAG, ERIC M
other_pis: Not Applicable
congressional_district: 02
department: Unavailable
primary_duns: 145182338
duns_number: 145182338
fips: US
organization_id: 10004431
organization_name: TRANSPOSAGEN BIOPHARMACEUTICALS, INC.
organization_city: Lexington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405071112
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-02-14
budget_end_date: 2006-01-31
assistance_listing_number: 93.389
project_abstract:
DESCRIPTION (provided by applicant):  Transposagen is developing an innovative mammalian random mutagenesis system that uses an L1 retrotransposon for direct germ-line mutagenesis. Transposagen's goal is to produce "mutator rats". In these rats mutagensis will occur in sperm and some offspring will contain single gene disruptions. We will use the mouse to optimize and validate our system because of the much higher cost in producing transgenic rats. We have developed "mutator mice" containing a marked L1 transgene capable of germ-line insertional mutagenesis. The focus of this proposal is to validate the Transposagen random mutagenesis system as a tool for functional genomics. Phase I of this project includes characterization of the mutator mice. Specific aim 1 is to determine the frequency of insertional mutagenesis in the sperm of mutator mice. Specific aim 2 is to determine the percentage of insertions that insert into genes. Specific aim 3 is to determine the efficiency of gene disruption. Phase II of the project will use the information gained from the Phase I mouse studies to create mutator rats. L1 elements are present in all mammals and a human L1 element is capable of high-level retrotransposition in human mouse hamster feline and even quail cells. Therefore our findings in mice from this study should extrapolate directly to rats. Transposagen's random mutagenesis system could utlimately be adapted for use in any mammal. Mutator mice and rats will substantially aid drug discovery programs by producing animal models for new drug targets.

project_terms:
animal breeding;biomedical resource;biotechnology;cryopreservation;disease /disorder model;functional /structural genomics;gene frequency;gene mutation;gene targeting;genetic manipulation;genetic mapping;genetic transcription;genetically modified animals;laboratory mouse;model design /development;polymerase chain reaction;sperm;tissue resource /registry;transfection;transposon /insertion element


application_id: 6882813
project_number: 4R37HL055757-11
project_title: OXYGEN RADICALS AND CARDIAC ADAPTATIONS TO ISCHEMIA
administering_ic: NHLBI
award_notice_date: 2005-06-20
application_type: 4
activity_code: R37
ic: HL
serial_number: 055757
program_official: LIANG, ISABELLA Y
project_start_date: 1995-05-01
project_end_date: 2010-06-30
study_section: NSS-H
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-07-01
project_abstract:
EXCEED THE SPACE PROVIDED. During the current funding period we have discovered a number of m olecular mechanisms that underlie exercise- induced late PC. During the next funding period we will build upon our previous work and address the following five specific Aims: 1. To establish the role of the JAK-STAT signaling pathway in exercise-induced late P C. Using our well-  established murine model we will dptermine whether exercise PC is abrogated in mice with constitutive targeted  deletion of the STAT1 gene (STATI") constitutive cardiac-specific targeted deletiop of the STAT3 gene (STAT3")  and conditional cardiac-specific targeted deletion of the STAT3 gene (cond-STAT3"). 2. To determine the mechanism whereby STAT3 is activated by exercise. We will use two genetically-  engineered mice: a transgeni_._puse expressing a dominant negative STAT3 in which Tyr-705 has been replaced  by phenylalanine (DN-STAT3 ''wr) and a mutant mouse in W_ Ser-727 of STAT3 has been replaced by alanine  (STAT3 SALSA). We will determine whether the DN-STAT3 ..... and STAT3 SALSA mutations abrogate protection  and STAT3 activation after exercise whether the JAK and o_hePKCs-Raf-1-MEK-1/2-p44/42 MAPK cascades are  activated by exercise and whether inhibition of PKCs (PKC6" mice) blocks Ser-727 phosphorylation of STAT3. 3. To determine the relative roles of apoptosis and necrosis in the protection afforded by exercise-induced  late PC. We will utilize state-of-the-art confocal microscopy techniques to identify apoptosis and necrosis with  hairpin-l/caspase-3 and hairpin-2/caspase-3 dual-labeling assays respectively. 4. To decipher the molecular mechanism by which exercise suppresses cardiac apoptosis. We will assess the  effect of exercise on the expression of the major pro-apoptotic (Bak Bax Bid and Bad) and anti-apoptotic (Bcl-2  Bcl-xL Mcl-1 c-FLIPL c-FLIPs ARC XIAP clAP-l and clAP-2) proteins in the heart. We will also assess the  influence of exercise on the extrinsic and intrinsic pathways of apoptosiso 5. To determine the role of ecSOD in exercise-induced late PC and the mechanism of ecSOD upregulation.  We will determine whether exercise upregulates ecSOD expression in cardiac myocytes. We will then determine  whether the cardioprotective effects of exercise PC are abrogated by genetic deletion of ecSOD (ecSOD" mice)  and conversely whether they can be mimicked by cardiac-specific overexpression of ecSOD (ecSOD transgenic  mice). We will also investigate whether exercise activates cardiac Nrf2. Then we will use Nrf2_ mice to  conclusively establish the role of this transactivating protein in the upregulation of ecSOD by exercise. The studies outlined above will extend and complete our current analysis of the mechanism of exercise-induced late PC. Together they will furnish novel insights into the molecular mechanisms whereby exercise promotes the shift of the heart to a defensive (preconditioned) phenotype that confers tolerance to ischemia/reperfusion injury. Besides ischemja/reperfusion injury these data will also have broad conceptual implications for our understanding of the mechanism whereby the heart adapts to stress in general. PERFORMANCE SiTE ========================================Section End===========================================


application_id: 6881509
project_number: 5R03DC004939-03
project_title: The Efficacy of Group Aural Rehabilitation Program
administering_ic: NIDCD
award_notice_date: 2005-05-12
opportunity_number: PA-01-126
application_type: 5
activity_code: R03
ic: DC
serial_number: 004939
program_official: DONAHUE, AMY
project_start_date: 2003-06-01
project_end_date: 2008-05-31
study_section: ZDC1-SRB-O(26)
contact_pi_person_id: 1920229
contact_pi: PREMINGER, JILL E
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 proposed research will examine the efficacy of adult group aural rehabilitation training for adults with hearing loss offered in a classroom environment. Group aural rehabilitation classes may include training in speech reading auditory perception and communication strategies. Group classes offer an opportunity to teach general information about hearing loss and provide a forum in which adults with hearing loss can share information and emotional support. It is not known if group training in speech reading auditory perception and/or communication strategies will lead to improved performance. It is not clear what component or components of the group aural rehabilitation class specifically lead to reduced hearing handicap. In Experiment 1 48 adults with hearing loss will participate in a 6-week group aural rehabilitation class in which the content is limited to speech reading and auditory perception exercises. Half of the subjects will attend classes that encourage group interaction; the other half will attend classes that provide no opportunity for interaction. The results of Experiment 1 will determine: 1) whether listeners with hearing loss who receive speech reading and auditory perception training over a 6-week period actually improve these abilities as measured by tests of visual and auditory speech perception; and 2) whether group interaction within an aural rehabilitation class effects hearing handicap. In Experiment 2 48 new subjects will participate in 3 types of group classes: 1) training in communication strategies with limited group interaction; 2) training in communication strategies with time devoted to group interaction; and 3) no training lectures only class with time devoted to group interaction. This data will be analyzed with the data from Experiment 1. The results of Experiment 2 will determine which aspect(s) of group aural rehabilitation classes provide benefit.

project_terms:
behavior test;behavioral /social science research tag;clinical research;communication behavior;group therapy;hearing aids;hearing disorders;human subject;human therapy evaluation;interpersonal relations;interview;nervous system disorder therapy;patient oriented research;quality of life;questionnaires;rehabilitation;social support network;sound perception;speechreading;visual perception


application_id: 6879739
project_number: 5R01HL067379-04
project_title: PULMONARY C-NEURON HYPERSENSITIVITY:CELLULAR MECHANISMS
administering_ic: NHLBI
award_notice_date: 2005-03-21
application_type: 5
activity_code: R01
ic: HL
serial_number: 067379
program_official: NOEL, PATRICIA
project_start_date: 2002-04-01
project_end_date: 2007-08-16
study_section: Respiratory Physiology Study Section[RESP]
contact_pi_person_id: 1857989
contact_pi: LEE, LU-YUAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-04-01
project_abstract:
DESCRIPTION (provided by applicant): The long-range goal of this research           project is to understand the neurogenic mechanisms underlying the bronchial         hyperreactivity caused by inflammation of airway mucosa. Increasing evidence        suggests an involvement of hypersensitivity of bronchopulmonary C-fiber             afferents in the manifestation of bronchial hyper-reactivity induced by airway      epithelial injury. The primary objective of this proposal is to investigate the     role of endogenous prostaglandin E2 (PGE2) a potent autacoid in the               sensitization of bronchopulmonary C fibers caused by airway mucosal                 inflammation and to elucidate the cellular mechanisms involved in this action.     PGE2 is locally synthesized and releases from airway epithelium during various      inflammatory reactions and our recent studies have demonstrated a sensitizing      effect of exogenous PGE2 on the pulmonary C fibers. The central hypothesis of       this study is that endogenous PGE2 increases the sensitivity of the pulmonary       C-fiber endings by activating EP2 and/or EP4 prostanoid receptors; activation       of these EP receptors enhances the neuronal excitability by activating the          cyclic AMP/protein kinase A signaling pathway that leads to modulation of the       function of tetrodotoxin-resistant sodium channel. Proposed experiments will be     carried out to test these hypotheses in rats using both in vivo (single-fiber       recording) and in vitro (whole-cell patch-clamp recording) preparations; the        latter will be performed in isolated nodose and jugular ganglion neurons            innervating the lung and airways. The results obtained from this study should       provide crucial information for gaining new insight into the signaling              transduction mechanisms underlying the PGE2-induced sensitization of pulmonary      C neurons. This information may therefore help to develop new therapeutic         strategies for alleviating the symptoms of bronchial hyperreactivity associated     with airway mucosal inflammation.

project_terms:
C fiber;biological signal transduction;capsaicin;chemical structure function;cyclic AMP;delayed hypersensitivity;electrophysiology;inflammation;laboratory rat;mucosa;neurons;ozone;prostaglandin E;prostaglandin endoperoxide synthase;prostaglandin receptor;protein kinase A;protein metabolism;protein structure function;respiratory airway pressure;respiratory epithelium;respiratory hypersensitivity;sodium channel;tissue /cell culture;voltage /patch clamp


application_id: 6879708
project_number: 5G11HD038435-06
project_title: Research Development at Kentucky State University
administering_ic: NICHD
award_notice_date: 2005-03-30
opportunity_number: RFA-HD-02-102
application_type: 5
activity_code: G11
ic: HD
serial_number: 038435
project_start_date: 2000-06-01
project_end_date: 2008-03-31
study_section: ZHD1-DSR-W(06)
contact_pi_person_id: 1885382
contact_pi: KOCHHAR, TEJINDER S
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 071317788
primary_uei: HT6FA2BL8JG7
duns_number: 071317788
uei: HT6FA2BL8JG7
fips: US
organization_id: 4240801
organization_name: KENTUCKY STATE UNIVERSITY
organization_city: FRANKFORT
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 406012334
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-04-01
project_abstract:
DESCRIPTION (provided by applicant): In Phase II of the SRIP the Office of the Research and Development (ORD) at Kentucky State University will continue to provide faculty and students an opportunity to participate in research and training programs in health related sciences funded by NIH and other agencies. The program will be directed by Extramural Associate (EA) Dr. Kochhar who participated in NIH's EA program in Spring 2000.  In Phase I ORD played a key role in submission of six grant proposals of which five have been funded. Two grant writing workshops conducted for faculty members greatly helped to achieve this. The PI sponsored four undergraduate science majors for summer research experience at outstanding research-intensive institutions. The main goal of Phase ll will be to continue to enhance the research infrastructure at KSU through active participation of university faculty and students in biomedical and behavioral science research. The proposed goal will be achieved by : 1) providing seed monies for faculty pilot projects; 2) organizing grant writing workshops; 3) assisting faculty on one-to-one basis in initiating and completing grant proposals; 4) disseminating information on opportunities to faculty members; and 5) motivating science majors to pursue careers in health-related areas by assisting them to acquire on campus and extramural laboratory experience.


application_id: 6878067
project_number: 5R01AI051517-04
project_title: SV5 and Hendra virus F protein promoted membrane fusion
administering_ic: NIAID
award_notice_date: 2005-05-05
application_type: 5
activity_code: R01
ic: AI
serial_number: 051517
program_official: CASSETTI, CRISTINA
project_start_date: 2002-05-15
project_end_date: 2007-04-30
study_section: Experimental Virology Study Section[EVR]
contact_pi_person_id: 8106840
contact_pi: DUTCH, REBECCA E.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-05-01
project_abstract:
EXCEED THE SPACE PROVIDED. The paramyxovirus family contains both established major human pathogens including measles virus and respiratory syncytial virus and newly emerged human pathogens the Hendra and Nipah viruses. The fusion  (F) proteins from paramyxoviruses promote fusion of viral and cellular membranes an event that is both an essential step mediating entry of enveloped viruses into the host cell and an excellent model system for  investigating the basic molecular events in membrane fusion processes. The long-term objective of this  proposed research is to understand the precise mechanism(s) of the paramyxovirus F proteins in promotion of membrane fusion. The central hypothesis of this research proposal is that regions of the paramxyovirus F  proteins that are critical for promotion of membrane fusion will be conserved between disparate members of the family and that analysis of these regions will aid in understandingthe precise mechanisms of the F proteins in promotion of membrane fusion. The experiments in Specific Aim 1 will utilize transient  expression systems and site-directed mutagencsis to analyzethe synthesis and processing of the F protein  from Hendra virus a recently discovered human pathogen. The research proposed in Specific Aim 2 will characterize the membrane fusion event promoted by the Hendra virus F protein using several different membrane fusion assays which allow for examination of various stages of the reaction. Finally the  experiments in Specific Aim 3 will examine the effect of mutations in the SV5 F and Hendra F proteins in  regions that show amino acid conservation throughout the paramyxovirusfamily to determine whether these changes effect folding protein processing or promotion of membrane fusion. Accomplishing these goals will provide crucial information on the processing and fusion-promotion activity of a paramyxovirus F protein from a newly emerged virus. In addition conserved regions of the F proteins that are important in function will be identified. The results of all of these studies will provide significant new information relevant to understanding specific molecular events involved in membrane fusion processes. PERFORMANCE S1TE(S) (organization city state) University of Kentucky. Lexineton. KY KEY PERSONNEL ========================================Section End===========================================

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


application_id: 6877950
project_number: 5T35HL007832-10
project_title: Short-Term Training for Minority Students Program
administering_ic: NHLBI
award_notice_date: 2005-03-10
opportunity_number: RFA-HL-00-019
application_type: 5
activity_code: T35
ic: HL
serial_number: 007832
program_official: COMMARATO, MICHAEL
project_start_date: 1995-05-19
project_end_date: 2006-04-30
study_section: ZHL1-CSR-K(F1)
contact_pi_person_id: 1917399
contact_pi: JOSHUA, IRVING G
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION(Applicant's abstract) The goal of this program is to continue to provideminority undergradaute students with an initial exposure to basic scienceresearchers and their areas of cardiovascular research at the University ofLouisville School of Medicine. The program will continue emphasis 1) thedevelopment of an appreciation for the scientific method of investigation thatemphasizes exposing students to literature based hypothesis generationintroduction to experimental design and data analysis 2) exposure toclinically relevant biomedical research that emphasizes collaboration betweenbasic scientist and clinical researchers and 3) providing an accurateperception of the importance of animal research with emphasis on proper use ofanimals and exposure to the ethics issues associated conducting research.Research projects in laboratories of eighteen cardiovascular faculty in theDepartments of Physiology and Biophysics and Biochemistry and MolecularBiology have been identified for the proposed program. These projects willallow students to choose from a wide variety of research approaches thatinclude whole animal/whole organ studies as well as biochemical cellularand molecular research approaches to the investigation of cardiovascularphenomenon. Students will be involved in ongoing basic science research thatexplores cardiovascular mechanisms involved in hypertension diabetesmellitus atherosclerosis heart failure and aging.The research experience for each trainee will last for 10 weeks during theSummer (late May thru August). Each research project will be developed fromgrant funded research currently being pursued in the laboratories of theselected mentors. The majority of the time spent during the 10 weekexperience will be in the form of bench research. Students will also beencouraged to visit other active cardiovascular research laboratories at thehealth Science Center. Students will be required to write a one page abstractof their research experience at the end of the 10-week program and a poster oftheir research will be presented at a special trainee session at the end ofthe program that will be attended by trainees and mentors. In addition toparticipating in laboratory research projects each trainee will be required toattend a special seminar series that will address research related issues thatinclude scientific ethics research design proper animal care and careerpreparation and opportunities available in cardiovascular research. We planto support 8 students per year with the program with an additional 2 studentsbeing supported by minority supplements to funded NIH researchers and by fundsfrom the School of Medicine.


application_id: 6877008
project_number: 5T35ES010951-05
project_title: Environmental Toxicology
administering_ic: NIEHS
award_notice_date: 2005-03-23
application_type: 5
activity_code: T35
ic: ES
serial_number: 010951
program_official: SHREFFLER, CAROL A
project_start_date: 2001-04-01
project_end_date: 2006-03-31
study_section: Environmental Health Sciences Review Committee[EHS]
contact_pi_person_id: 1862358
contact_pi: VORE, MARY
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-04-01
project_abstract:
EXCEED THE SPACE PROVIDED. The primary objective of the Minority Summer Research Experience in Environmental Toxicology is to provide five students with an opportunity to participate actively in an ongoing research project. Students will have "hands- on" responsibilities in research projects in which reasonable conclusions can be obtained in a 9-week period and will spend 85% of their time in the laboratory. Research opportunities in Environmental Toxicology are available in the specialty areas of metabolism and transport of xenobiotics mechanisms of toxicity of halogenated hydrocarbons mechanisms of oxidative stress-induced toxicity DNA repair and mutagenesis neurotoxicology and immunotoxicology. Students will work with faculty who are Core and Joint Faculty in the Graduate Center for Toxicology who are also Training Grant Faculty on the T32 Environmental Toxicology NIEHS Training Grant (a total of 30 faculty). Students will be recruited from the University of Puerto Rico (UPR) as the continuation of a program for students from UPR which has been cosponsored by the University of Kentucky (UK) and UPR for the last three summers. We will continue to work with Dr. Braulio Jimenez the Director of the Center for Environmental and Toxicological Research at the Medical Sciences Campus of UPR to identify and recruit students for the summer program. Applicants will be asked to provide their student transcripts and will be interviewed by Dr. Jimenez; the best candidates will send their transcripts an essay describing their research interests and why they wish to work in Toxicology and one letter of recommendation. Dr. Vore and 3 additional members of the Training Grant Faculty will review the candidates and select the top five. This group will also match the interests of the applicants with those faculty who are able to work with the students in any given summer. Dr. Vore will closely monitor the satisfaction of the students and mentors during and at the end of the program. Students will attend a seminar series in which they discuss their research and hear presentations on the use of animals and ethics in research and how to prepare for Graduate School. Finally students will make a 15 minute presentation and discussion of their research results. PERFORMANCE SITE ========================================Section End===========================================


application_id: 6876390
project_number: 1S10RR019118-01A1
project_title: Analytical Ultracentrifuge
administering_ic: NCRR
award_notice_date: 2005-04-01
opportunity_number: PAR-04-029
application_type: 1
activity_code: S10
ic: RR
serial_number: 019118
suffix: A1
program_official: TINGLE, MARJORIE
project_start_date: 2005-04-01
project_end_date: 2006-03-31
study_section: Special Emphasis Panel[ZRG1 BST-A (30)]
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The University of Louisville is promoting structural biology and cancer research as part of its core mission. Under the aegis of the JG Brown Cancer Center and the Department of Chemistry a number of core facilities and major collaborative programs are being established. This currently includes NMR spectroscopy X-ray crystallography Molecular Modeling and protein expression. To enable the functional analysis of macromolecules and their interactions in the solution state we are now building a biophysics core to be headed by a senior scientist. We have identified analytical ultracentrifugation as an integral component of this core. An essential part of any functional analysis is the determination of the physical state of the isolated components (including molecular weight shape hydration and homogeneity) as well as measuring the stoichiometry of the complexes and the interaction strength. This is difficult to achieve by other nonequilibrium methods because of the dependent of the parameters on both shape and size. The analytical ultracentrifuge is one of the few techniques that can independently and rigorously determine mass of a functional component in a non-denaturing state in solution as well as provide information about homogeneity and frictional properties. Furthermore it is generally necessary to know the stoichiometry and preferably the symmetry of an oligomer or complex before a complete NMR structure determination can be contemplated. The analytical ultracentrifuge is an ideal shared instrument as it can readily accommodate several research groups whose primary methodologies are not in the hydrodynamics of macromolecules but who need the specific data it provides in order to further their research and solve problems that cannot be tackled by other techniques. Hydrodynamic analysis of macromolecules can be seen as an integral part of the overall biophysics program at the Cancer Center. The combination of structural and biophysical techniques is central to understanding regulatory processes inside cells and for providing the basic information about basic drug targets during the drug discovery and development process. There are numerous NIH-funded investigators who need access to this instrumentation and who would be major users. There are many other groups who will need less frequent access. All of the researchers are actively involved in protein expression and analysis of complex interactions related to disease states.

project_terms:
analytical ultracentrifugation;biomedical equipment purchase;cancer registry /resource;intermolecular interaction;macromolecule;structural biology


application_id: 6876162
project_number: 5K22AI052252-02
project_title: Identification of the chlamydial adhesin and receptor
administering_ic: NIAID
award_notice_date: 2005-04-06
opportunity_number: PAR-98-072
application_type: 5
activity_code: K22
ic: AI
serial_number: 052252
program_official: HILTKE, THOMAS J
project_start_date: 2004-04-01
project_end_date: 2005-06-30
study_section: Microbiology and Infectious Diseases Advisory Committee[MID]
contact_pi_person_id: 1941640
contact_pi: CARABEO, REYNALDO A
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Chlamydiae are obligate intracellular bacteria that cause a wide spectrum of disease in humans such as trachoma infertility pneumonia and possibly atherosclerosis. Entry of chlamydia into a favorable intracellular niche is an absolute requirement for its survival and thus it has been speculated that this organism has developed a very efficient means of entering a host cell. How chlamydia enters the host cell is unknown and this glaring lack of knowledge of the mechanisms involved in chlamydial invasion stems from its undeveloped genetic system. A recently isolated Chinese hamster ovary (CHO) mutant clone that arose from random chemical mutagenesis of the CHO-K1 cell line and selection of resistance to infection by the lyric serovar L2 indicate the requirement for a secondary receptor. Engagement of this receptor by chlamydial elementary bodies is downstream of binding of heparan sulfate. This grant proposal will focus on two areas of research that takes advantage of this novel cell line and relies on experimental approaches that are designed to preserve the surface structures of both pathogen and host. Firstly this cell line will be used to identify the chlamydial receptor using cDNA complementation functional binding assays and mass spectrometry. Verification of candidates will involve the introduction of the wild type copy of the gene to restore the susceptibility phenotype. In addition knockout alleles of the gene will be created in susceptible cells to recapitulate the resistance phenotype. The second research aim will focus on the identification of chlamydial ligands by mass spectrometry. Assays will take advantage of the natural affinity of the receptor for the chlamydial adhesin. Existence of homologs of the lympogranuloma venereum (LGV) serovar L2 adhesin in other serovars will be determined and the presence of genetic polymorphisms that may contribute to the biological differences such as tissue tropism will be investigated. Findings from the two research aims will be correlated with the biological differences between LGV and non-LGV serovars. Knowledge gained from these research areas should contribute to our understanding of chlamydial pathogenesis and lead to rationally sound strategies in combating infection by this clinically relevant organism.

project_terms:
Chlamydia trachomatis;Chlamydiaceae;adhesin;bacteria infection mechanism;bacterial genetics;chlamydial disease;complementary DNA;crosslink;genetic polymorphism;heparan sulfate;ligands;lymphogranuloma venereum;mass spectrometry;polymerase chain reaction;receptor;two dimensional gel electrophoresis;western blottings;yeast two hybrid system


application_id: 6874410
project_number: 5R01HD018702-30
project_title: Interaction and Activation of the LH Receptor
administering_ic: NICHD
award_notice_date: 2005-05-19
application_type: 5
activity_code: R01
ic: HD
serial_number: 018702
program_official: YOSHINAGA, KOJI
project_start_date: 1992-02-01
project_end_date: 2008-05-31
study_section: Biochemical Endocrinology Study Section[BCE]
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: 2005-06-01
project_abstract:
Luteinizing hormone(LH) and human chorionic gonadotropin (hCG) bind to the same receptor (LHR).  These hormones and LHR play crucial roles in reproduction women's health and some ovarian and prostate cancers.  LHR and hormone derivatives have been used or are tested for diagnosis and therapeutics.  Our long term goal is to understand the molecular mechanism of LHR's interaction with hCG and generation of differential signals for second messengers cAMP and inositol phosphates (IP). LHR and other glycoprotein hormone receptors belong to a structurally unique subfamily of G-protein-coupled receptors. Each receptor consist of the extracellular N-terminal half with approximately 350 amino acids (exodomain) and the membrane associated C-terminal half with an equal number of amino acids (endodomain).  The exodomain is generally thought to form a 1/3 donut structure by 7-9 leu Rich Repeats (LRR) and to bind hCG via the LRRs.  Yet little experimental evidence is available to support the LRRs.  Since we and others reported nearly ten years ago that the exodomain is capable of high affinity binding site for hCG that the hCG/exodomain complex undergoes a conformational adjustment upon hormone binding and that the endodomain is the site for signal generation.  Based on these observations we proposed that the initial hormone/exodomain complex interacts with the endodomain and this secondary interaction is responsible for signal generation.  Lately many of these propositions have been demonstrated and adopted by others.  During the current grant period we have made a number of significant new observations furthering the current understanding models and hypotheses as well as introducing new concepts: The LRRs are active in LHR and LRR4 interacts hCG the N  and C-flanking regions of the LRRs appear to reach the back of hCG and wrap around it (which may be key factor in the high binding affinity) and the C-terminal region of the LRRs seems to activate the endodomain to generate signal whereas LRR4 suppresses the endodomain.  On the other hand the 3 exoloops share common and distinct functions.  The exoloop 3 is involved in differentially generating signals for cAMP and Ips the exoloop 2 appears to be the primary site for contacting the exodomain while the exoloop 1 may be involved in inter-exoloop interaction and signal generation.  This is a mini-breakthrough. In addition we have observed that the hCG/exodomain complex of one LHR may contact and activate the endodomain of another LHR which has a far reaching implication on signal transduction in general. We propose to extend our observations (Specific Aim 1) to determine the interaction of the exodomain with hCG and (Specific Aim 2) to determine the interactions and function of the three exoloops.  When successfully carried out these studies will provide new insights on the hormone binding and intra- and inter- molecular differential signal generation for LHR and other receptors and therefore clinical and industrial applications.

project_terms:
G protein;affinity labeling;autoradiography;biological signal transduction;chorionic gonadotropin;computer simulation;cyclic AMP;high performance liquid chromatography;hormone receptor;hormone regulation /control mechanism;inositol;intermolecular interaction;luteinizing hormone;mass spectrometry;model design /development;molecular dynamics;molecular site;peptide chemical synthesis;physical model;radioimmunoassay;radiotracer;receptor binding;site directed mutagenesis;structural biology;tissue /cell culture;transfection


application_id: 6874256
project_number: 1T15HL075759-01A1
project_title: Cardiovascular Disease Research Ethics ("CADRE") Program
administering_ic: NHLBI
award_notice_date: 2005-06-13
opportunity_number: PAR-01-143
application_type: 1
activity_code: T15
ic: HL
serial_number: 075759
suffix: A1
program_official: FRIEDMAN, LAWERENCE
project_start_date: 2005-06-13
project_end_date: 2006-05-31
study_section: Special Emphasis Panel[ZRG1 HOP-E (50)]
contact_pi_person_id: 2306205
contact_pi: STONE, T HOWARD
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The PI and collaborators propose a 3-year collaborative cross-disciplinary project titled "Cardiovascular Disease Research Ethics ("CADRE") Program" consisting of short-term courses with a goal of improving the skills of biomedical researchers at identifying and addressing the ethical legal and social implications of cardiovascular research involving human research participants; course content will be based upon a national needs assessment. The CADRE Program brings together a team of expert and experienced investigators and includes a curriculum advisory committee and community-based organizations to help guide project development implementation and evaluation. Both one-day on-site and online courses will be offered. On-site courses will be held three times annually at different sites across the U.S. including one course held concurrently with a national scientific society (e.g. the American Heart Association) a second course held on the campus of the Morehouse School of Medicine and a third course held at the Texas Heart Institute in Houston Texas; each course is intended to draw participants from across the U.S. Special recruitment and travel assistance will be used to draw historically underserved course participants. The online course will be web-based asynchronous and interactive. Participants will be asked to complete course evaluations and continuing education credit will be provided. The project consists of four specific aims and related research methods: 1) develop a modular transportable ethics training program in cardiovascular research that includes both traditional onsite and computer-mediated instruction; 2) deliver annually three needs-driven one-day onsite courses tailored to scientific and institutional constituents one of which is tailored to community non-scientific constituents; 3) deliver a skill-based case-centered online course with user-defined feedback-driven instructional content; and 4) assess instructional effectiveness through participant and user evaluations pre- and post-course knowledge tests and long-term surveys.


application_id: 6872942
project_number: 5R01NS043415-04
project_title: Regulation of B Cell Development by Neuropeptides
administering_ic: NINDS
award_notice_date: 2005-03-25
application_type: 5
activity_code: R01
ic: NS
serial_number: 043415
program_official: UTZ, URSULA
project_start_date: 2002-04-01
project_end_date: 2007-03-31
study_section: Special Emphasis Panel[ZRG1-IFCN-2(01)S]
contact_pi_person_id: 1901005
contact_pi: MCGILLIS, JOSEPH P.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-04-01
project_abstract:
The objective of this project is to understand how the nervous system influences the production of new B cells in the bone marrow. B cells produce antibodies following vaccination or exposure to a pathogen. The function of the immune system requires that new white blood cells (leukocytes) including B cells be produced at controlled rates. Under or overproduction of leukocytes could lead to a reduced capacity to fight infectious disease or to leukemia autoimmunity or other disease states. For this reason it is critical that the rate of production of leukoctyes is maintained at levels that insure sufficient numbers for their proscribed protective functions without risk of overproduction. The focus of this project is on the role of the neuropeptide calcitonin- gene related peptide (CGRP) in regulating early B cell differentiation. Cells in the immune system have CGRP receptors and CGRP influences the activity of mature lymphocytes macrophages and granulocytes. CGRP and another sensory neuropeptide substance P play a role in regulating the differentiation of distinct leukocyte populations. CGRP is found in nerve endings in bone marrow hematopoietic cells have CGRP receptors CGRP induces production of B cell regulatory cytokines and inhibits B cell progenitor responses to IL-7. The specific aims of this project are to show that administration of CGRP reduces the number of B cell progenitors to identify CGRP receptor expressing cells in the B cell lineage to examine how specific stages in early B cell development are influenced by CGRP and to study the cellular mechanisms by which CGRP blocks B cell differentiation. The in vivo studies will determine the number of pre-B CFUs following CGRP treatment. CGRP receptor expressing cell populations will be identified by CGRP receptor mRNA analysis and by functional responses to CGRP. The role of CGRP in B cell differentiation will be studied using short term in vitro studies with cells derived from bone marrow. These studies will examine the effect of CGRP on proliferation and differentiation of distinct populations of B cell precursors present in bone marrow. Preliminary studies suggest that CGRP inhibits early B cell differentiation by cellular mechanisms involving events influenced by IL-7 and by activation of NFkappa-B. Studies will determine how CGRP inhibits NFkappa-B activation in a pre-B cell line and will examine how CGRP inhibits IL-7 responses in normal B cell progenitors. A better understanding of CGRP's role in B cell development may offer new avenues for new therapeutic approaches.

project_terms:
B lymphocyte;G protein;bone marrow;calcitonin gene related peptide;cell differentiation;cell line;cytokine;flow cytometry;gel mobility shift assay;immunoprecipitation;injection /infusion;interleukin 7;laboratory mouse;leukocytes;leukopoiesis;nervous system;nuclear factor kappa beta;phosphorylation;radioimmunoassay;receptor expression;transforming growth factors;western blottings


application_id: 6872860
project_number: 5R01NS042196-04
project_title: Cognitive Dysfunction after TBI: Role of alpha7 nAChrs
administering_ic: NINDS
award_notice_date: 2005-04-06
application_type: 5
activity_code: R01
ic: NS
serial_number: 042196
program_official: HICKS, RAMONA R
project_start_date: 2002-04-01
project_end_date: 2008-03-31
study_section: Special Emphasis Panel[ZRG1-BDCN-1(01)]
contact_pi_person_id: 1883820
contact_pi: PAULY, JAMES R
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-04-01
project_abstract:
Trauma to the CNS initiates acute and secondary cascades of biochemical and metabolic changes often results in a state of persistent neurological dysfunction.  Understanding the neurochemical alterations that occur following damage to the CNS is critical for the development of therapeutic strategies that can prevent and/or remediate the detrimental effects of trauma. The neurobiological basis for the protracted memory deficit that commonly occurs following traumatic brain injury (TBI) is not clearly understood although a number of studies have suggested that deficits in the CNS cholinergic system play a prominent role.  However most of the previous studies have focused on muscarinic rather than nicotinic cholinergic receptor mechanisms.  This is surprising since deficits in the nicotinic receptor system have been repeatedly associated with the cognitive deficit that occurs to neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease.  Our initial studies clearly demonstrate that a cortical contusion injury (CCI) causes significant and widespread defects in hippocampal and cortical alpha 7 nicotinic receptor (nAChr) expression.  The working hypothesis of the proposed studies is that changes in the CNS alpha7 nAChr's contribute significantly to head trauma- induced cognitive dysfunction.  Furthermore we predict that pharmacological modulation of alpha7 neuronal nicotinic receptors will have neuroprotective and cognitive-enhancing properties in head-injured rats.  The Specific Aims of this proposal will evaluate: 1) the time course of changes in alpha7 protein and message expression following TBI 2) neuroprotective actions of nicotinic receptor antagonists administered in the acute phase of TBI 3) cognitive enhancing properties of nicotine and selective alpha7 agonists administered acutely (or chronically) in the delayed phase of TBI 4) the effects of TBI on deficits in auditory sensory gating and 5) restoration of sensory gating following treatment with nicotine and other selective alpha7 agonists.

project_terms:
auditory feedback;autoradiography;behavior test;brain injury;chemoprevention;cognition disorders;disease /disorder model;histochemistry /cytochemistry;in situ hybridization;inhibitor /antagonist;laboratory rat;mental disorder prevention;messenger RNA;neurochemistry;neuropharmacology;neuroprotectants;nicotinic receptors;protein structure function;receptor binding;receptor expression;sensory feedback;stereotaxic techniques;trauma


application_id: 6870245
project_number: 5R01HL070239-04
project_title: Role of MMPs in AngII induced abdominal aortic aneurysms
administering_ic: NHLBI
award_notice_date: 2005-03-25
application_type: 5
activity_code: R01
ic: HL
serial_number: 070239
program_official: WASSEF, MOMTAZ K
project_start_date: 2002-04-01
project_end_date: 2007-03-31
study_section: Pathology A Study Section[PTHA]
contact_pi_person_id: 8378256
contact_pi: DAUGHERTY, ALAN
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-04-01
project_abstract:
The central hypothesis to be tested is that the initiation and maturation of angiotensin II (AngII)-induced abdominal aortic aneurysms (AAAs is mediated by a specific matrix metalloproteinase (MMP) that is secreted and/or activated via a leukocyte-specific mechanism. To test this hypothesis we propose the following aims: Aim 1. Determine whether a specific MMP is responsible for AngII- induced AAA.. To identify the action of a specific MMP we will use mice with genetically engineered deficiencies of specific MMPs. We will focus our efforts on MMP-2 -9 and -12 based on the demonstration of their presence in aneurysmal tissue and their previous inferred roles in the disease process. Further we will define the temporal sequence of elaboration of MMPs and their endogenous inhibitors in evolving and mature aneurysmal tissue. Aim 2. Determine whether AngII induces the release of MMPs from leukocytes and/or enhances the activation of MMPs secreted by neighboring vascular cells. To determine the direct contribution of AngII on MMP mediated AAA formation we will perform bone marrow transplantation studies in which bone marrow cells from MMP+/+ or -/- mice will be used to repopulate MMP+/+ recipient mice. Aim 3. Determine the mechanism of AngII on leukocyte-dependent regulation of MMP activity. We will determine whether AngII exerts a direct effect on the synthesis and secretion of specific MMPs in cultured cells. Further we will define whether AngII results in increased activation of MMPs. Aim 4. Determine the effects of MMP inhibition when selective inhibitors are administrated after the formation of AAAs. In preliminary studies we demonstrated that inhibition of MMPs prevented the initiation of AngII-induced AAA. However in the human disease ultrasound is used to detect an already formed AAA and thus an effective pharmacologic treatment would have to either reduce the progression or reverse the pathology of an established AAA. It is conceivable that MMPs play a different role in the remodeling process in established AAAs as compared to their role in the initiation of the disease. Therefore initial studies will determine the effects of broad specificity MMP inhibitors on the maturation process of an already formed AAA. Subsequent studies will use more selective inhibitors of MMPs based on data obtained in Specific Aims 1-3. The significance of this research relates to delineation of mechanism for AA formation and maturation with emphasis on potential development of pharmacological treatments of the disease.

project_terms:
ACE inhibitors;SDS polyacrylamide gel electrophoresis;angiotensin II;angiotensin receptor;aorta aneurysm;apolipoproteins;biological signal transduction;bone marrow transplantation;cell population study;disease /disorder etiology;enzyme activity;enzyme biosynthesis;enzyme induction /repression;enzyme mechanism;genetically modified animals;hyperlipidemia;immunocytochemistry;laboratory mouse;low density lipoprotein receptor;metalloendopeptidases;tissue /cell culture;tissue /cell preparation;tissue inhibitor of metalloproteinases;vascular endothelium;western blottings


application_id: 6870229
project_number: 5R01DA014079-05
project_title: Cognitive Processes in Cocaine and Polydrug Abuse
administering_ic: NIDA
award_notice_date: 2005-04-01
opportunity_number: RFA-DA-01-001
application_type: 5
activity_code: R01
ic: DA
serial_number: 014079
program_official: SCHNUR, PAUL
project_start_date: 2001-04-01
project_end_date: 2007-03-31
study_section: ZDA1-MXV-P(04)
contact_pi_person_id: 6368360
contact_pi: FILLMORE, MARK T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION: (provided by applicant)                                                Cocaine abuse remains a serious public-health concern in the United States. The     propensity to binge use cocaine and to combine it with other abused drugs         such as alcohol heighten the health risks associated with cocaine use. Cocaine     can impair several cognitive and mental processes including those that control     behavior. Thus it is important to understand how such disturbances also can        reduce control over cocaine intake once cocaine use has begun. The proposed         project aims to determine how an inability to control cocaine consumption is        linked to cocaine-induced impairment of inhibitory and activiational processes      involved in the self-control and regulation of behavior. The project will test      acute and chronic cocaine effects in adult cocaine abusers. The research            combines measures of cocaine effects on cognitive inhibitory processes with         conventional indices of abuse potential based on subjective rewarding effects      of the drug and its ability to reinforce self-administration. Initial studies       will determine dose-response functions of cocaine on inhibitory control and        compare effects of different routes of administration. Subsequent studies will      determine how inhibitory processes contribute to abuse potential by testing the     degree to which acute cocaine-induced impairment of inhibitory control              contributes to cocaine self-administration. The research also will determine        how alcohol contributes to cocaine abuse potential by testing the degree to         which its concomitant administration exacerbates cocaine-induced impairments of     inhibitory control. Finally the research will provide information on how           long-term cocaine use could contribute to cognitive deficits that resemble          attentional disorders by producing a chronic deficit in basal levels of            inhibitory control. The research has several long-term objectives. First the       findings and research strategies used to examine the role of cognitive              mechanisms in cocaine abuse will allow the investigators to further develop and     refine drug-testing protocols that measure the ability of medications to block      the cognitive-impairing effects of cocaine which could play a role in its abuse     potential. Second the proposed research strategies and measures will provide       initial methods and protocols for studying the combination of cocaine with          other drugs of abuse that might also disrupt cognitive functions such as           opiates which are also commonly co-administered with cocaine. Finally the         procedures for assessing inhibitory processes can be used to assess drug-free      basal levels of cognitive inhibitory functioning in drug abusers. Such studies      would provide information on the degree to which these basic cognitive              mechanisms play a role in the etiology of a general disinhibitory                   psychopathology which is considered to be a common phenotypic characteristic        among drug abusers.

project_terms:
alcoholism /alcohol abuse;clinical research;cocaine;cognition disorders;drug abuse;drug administration routes;drug interactions;ethanol;human subject;locus of control;psychopharmacology;self medication;substance abuse related behavior


application_id: 6869539
project_number: 5R21MH066682-04
project_title: Promoting HIV Risk Reduction in African-American Men
administering_ic: NIMH
award_notice_date: 2005-03-18
opportunity_number: PA-99-134
application_type: 5
activity_code: R21
ic: MH
serial_number: 066682
program_official: CAMPBELL-ROSEN, HOLLY RENEE
project_start_date: 2003-04-01
project_end_date: 2007-03-31
study_section: AIDS and Related Research 7[AARR-7]
contact_pi_person_id: 8234905
contact_pi: CROSBY, RICHARD A
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Young African American adults attending STD clinics are a population at increased risk for HIV infection. Thus the search for effective clinic-based interventions tailored to youth at risk for HIV infection remains a national priority. One commonly understudied aspect of HIV prevention is the promotion of correct condom use; a behavior that males typically control in the context of heterosexual relationships. The proposed project will enroll 180 young African American men (ages 18 - 29) in a pilot study that will assess the feasibility and efficacy of a brief (30 to 60 minute) interactive one-on-one intervention designed to motivate men to use condoms and provide them with the skills needed to use them correctly. The initial phase of this study will involve focus group work and pre-testing of the instruments and intervention. Subsequently men will be recruited from an urban STD clinic located in Atlanta GA. Men diagnosed with any STD will be eligible for participation in the study. After a brief assessment men will be randomized to receive standard-of- care treatment only or standard-of-care plus an experimental brief counseling program. All participants will be contacted and asked to return for a follow-up assessment occurring three months after the initial assessment. The study has three specific aims: 1) to identify areas of information motivation and skills training that deserve specific emphasis in a brief program designed to promote consistent and correct use of condoms among high-risk young African American men 2) to establish the feasibility of a brief clinic-based method to provide high-risk young African American men with information motivation and behavioral skills that will protect them from acquiring and subsequently transmitting HIV/STD and 3) to provide preliminary evidence for the efficacy of a brief intervention designed to reduce HIV/STD risk behavior among high-risk young African American men. In addition the study will detect trends in differential rates of STD re-infection between the two study groups based on a clinical records review conducted 12 months after study enrollment. The findings from this study will provide guidance for the further development and refinement of brief clinic-based interventions designed to prevent HIV and STD infection among young African American men.

project_terms:
AIDS education /prevention;African American;HIV infections;behavior therapy;behavioral /social science research tag;clinical research;condoms;counseling;disease /disorder proneness /risk;human subject;human therapy evaluation;information systems;longitudinal human study;male;motivation;sex behavior;sexually transmitted diseases;training;young adult human (21-34)


application_id: 6869522
project_number: 5R03AI060468-02
project_title: Evaluating Control of HIV Infection by Engineered Virus
administering_ic: NIAID
award_notice_date: 2005-04-10
opportunity_number: PA-03-108
application_type: 5
activity_code: R03
ic: AI
serial_number: 060468
program_official: VOULGAROPOULOU, FROSSO
project_start_date: 2004-04-01
project_end_date: 2006-03-31
study_section: AIDS Clinical Studies and Epidemiology Study Section[ACE]
contact_pi_person_id: 10583564
contact_pi: GARCIA, GISELA RAMOS
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): We propose to construct a mathematical model for evaluation of a potential therapy that uses genetically modified viruses to control HIV infection. Current anti-viral drug therapies may reduce HIV load below detection but do not cure the infection due to a persistent latent cellular reservoir. Moreover drugs have significant drawbacks such as cost toxicity and evolution of resistance. An alternative therapy is the use of engineered viruses designed to kill cells infected by HIV. These viruses considerably decrease the HIV-1 load in vitro (Schnell et al. 1997) but the potential effectiveness for reducing the viral load of AIDS patients is unknown. This therapeutic virus is expected to have two main effects in vivo. First it will kill HIV-infected cells thus compensating for the dysfunction of the immune system associated with AIDS. This will reduce the HIV-1 load and aid in the recovery of the activated CD4+ T cells (Revilla & Garcia-Ramos 2003). These cells are the main target of HIV-1 and are essential to activate an immune response. Second this recovery of cells will improve the immune system thus providing further control on the HIV population. A mathematical model based on coupled ordinary differential equations will study the interactions among HIV-1 the CD4+ T cell an immune response and an engineered virus in an in vivo context. This model will examine the complex dynamics of the therapeutic infection. The main objective is to determine the efficiency of a therapeutic virus in concert with a strengthened immune response for controlling HIV load. In particular our analysis will determine if the therapeutic virus will survive in a system with a depleted HIV load; establish the potential effect of the virus on the long-term reservoir of resting HIV-infected CD4+ T-cells; and evaluate the impact of attacking this reservoir on the control of HIV infection.

project_terms:
AIDS therapy;Rhabdoviridae;biotechnology;genetic manipulation;helper T lymphocyte;host organism interaction;human immunodeficiency virus 1;human therapy evaluation;immune response;immune system;leukocyte activation /transformation;mathematical model;microorganism immunology;model design /development;recombinant virus;virus load


application_id: 6866412
project_number: 5R01AG017237-05
project_title: SR-BI MEDIATED SELECTIVE CHOLESTEROL ESTER UPTAKE
administering_ic: NIA
award_notice_date: 2005-02-07
application_type: 5
activity_code: R01
ic: AG
serial_number: 017237
program_official: KOHANSKI, RONALD A
project_start_date: 2001-03-01
project_end_date: 2006-02-28
study_section: Special Emphasis Panel[ZRG1-SSS-T(02)F]
contact_pi_person_id: 1884301
contact_pi: DE BEER, FREDERICK C.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-03-01
project_abstract:
DESCRIPTION: There is interest in understanding the factors that regulate HDL       and apoA-I levels in humans as these are inversely correlated with the risk for     atherosclerotic vascular disease. Plasma levels of HDL and apoA-I are related       to the rate of apoA-I catabolism rather than apoA-I production. Neither the         mechanisms underlying accelerated catabolism nor the site(s) of apoA-I removal      from plasma have been clearly delineated. This proposal focuses on the role of      the HDL receptor SR-B1 in regulating apoA-I catabolic rate. SR-B1 delivers        cholesteryl ester to cells via a process that is fundamentally distinct from        receptor-mediated endocytosis. During this process HDL binds to SR-B1 on the       cell surface and transfers cholesteryl ester from the core of the particle to       the cell without internalization of the apolipoprotein moiety. Despite the          absence of apolipoprotein uptake increased selective lipid uptake in the liver     mediated by SR-B1 is associated with increased catabolism of apoA-I and at         least some of this catabolism occurs in the kidney. Thus a central hypothesis      of this proposal is that SR-B1 interaction with HDL initiates changes in the        lipoprotein particle that promotes subsequent catabolism by a mechanism that is     independent of SR-B1. SR-B1 binds with high affinity a number of different          lipoprotein particles in addition to HDL including VLDL LDL and oxidized         LDL. The important metabolic event subsequent to lipoprotein binding by SR-B1       is the selective delivery of CE from the core of particles to cells. We propose     that apoA-I is a critical ligand for SR-B1-mediated selective uptake and that      apoA-I conformation on the HDL particle can influence its interaction with          SR-B1 to impede or promote receptor binding and/or selective uptake. The            efficiency of selective uptake mediated by SR-B1:apoA-I interaction can be          modulated by properties of the HDL particle (lipid composition apolipoprotein      content or the structure of apoA-I itself). These hypotheses will be tested by     defining: 1) the sub-population of HDL particles that are the preferred             substrate for SR-B1-mediated lipid transfer; 2) the structure and composition       of HDL particles after processing by SR-B1 (including the potential for apoA-I      proteolysis); and 3) the metabolic fate of HDL particles after SR-B1                processing. Understanding the role of SR-B1 in HDL metabolism could define new      areas for potential therapeutic assault.

project_terms:
biotransformation;cholesterol esters;high density lipoproteins;human tissue;laboratory mouse;lipid metabolism;lipid transport;phosphatidylcholine sterol acyltransferase;protein metabolism;protein structure;receptor binding;transfection /expression vector


application_id: 6865409
project_number: 5R01CA090892-05
project_title: Breast Cancer Etiology
administering_ic: NCI
award_notice_date: 2004-12-07
application_type: 5
activity_code: R01
ic: CA
serial_number: 090892
program_official: POLAND, ALAN P
project_start_date: 2001-12-06
project_end_date: 2008-11-30
study_section: Chemical Pathology Study Section[CPA]
contact_pi_person_id: 8240457
contact_pi: GUPTA, RAMESH C
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: 2004-12-01
project_abstract:
DESCRIPTION:(PROVIDED BY APPLICANT) A number of risk factors including dietary     fat intake family history and exposure to exogenous and endogenous chemicals     have been implicated in the etiology of breast cancer incidence.                    Epidemiological studies have identified an association of elevated levels of        estrogens with breast cancer development. In particular the natural hormone       17B-estradiol (E2) and its major metabolite 4-hydroxyestradiol (4-E2) which       are known animal carcinogens have been implicated in human breast cancer and       it is believed that these substances cause free radical-mediated direct and/or     indirect DNA damage.                                                                                                                                                    Novel polar DNA adducts have been detected in the mammary tissues of both rats     and humans by devising new systems to employ 32P-postlabeling/TLC. Adduct           spectra between rat and human mammary DNA exhibited strong similarities.            Further the polar adducts were significantly enhanced in estrogen-sensitive        tissues particularly mammary after treatment of S/D rats with estradiol. In       light of the known redox-cycling activity of 4-E2 a major metabolite of            estradiol these results suggest a link between polar DNA adduct formation and      metabolic processing of E2. We hypothesize that the polar DNA adducts detected      in the mammary tissues originate from free radical mediation. We also               hypothesize that significant inter-subject differences occur in the                 accumulation of pre-mutational DNA lesions and these differences could in part     explain the wide range of susceptibility seen in the induction of some cancers.     Specific studies will be as follows: (1) To analyze DNA damage in mammary           epithelium of rats treated with the endogenous estrogen and its metabolites as     well as the equine estrogen equilin and equilenin. Blood lymphocytes will be       included as surrogates for comparison. Antioxidant intervention experiments         will be performed to support the hypothesis. Also measured will be the tissue       and plasma levels of E2 and its metabolites by sensitive HPLC-CoulArray for         correlating with oxidative DNA adduct burden. (2) To analyze DNA damage in          epithelial cells of breast tissues of cancer-free women and breast cancer           patients and surrogate blood lymphocytes and blood lymphocytes of women            receiving hormone replacement therapy. Tissue levels of E2 and its metabolites      will be correlated with oxidative DNA adduct burden and breast cancer               incidence. (3) To develop and apply LC-MS/MS and CE-MS/MS technology in             conjunction with 32P-postlabeling for identifying DNA adducts in human breast       tissues.                                                                                                                                                                Data resulting from this highly sensitive approach will reveal the etiological      nature of exposure and will determine inter-subject differences in mammary DNA      damage that may be associated with susceptibility differences. Furthermore if      tissue levels of estradiol metabolite(s) and/or oxidative burden are found to       correlate positively with breast cancer incidence then future clinical studies     to reduce breast cancer risks can be planned with antioxidant intervention.

project_terms:
DNA damage;breast neoplasms;chemical carcinogenesis;clinical research;disease /disorder etiology;estrogens;female;free radicals;genetic susceptibility;high performance liquid chromatography;hormone regulation /control mechanism;hormone related neoplasm /cancer;hormone therapy;human subject;laboratory rat;liquid chromatography mass spectrometry;mammary epithelium;mass spectrometry;neoplasm /cancer genetics;women&apos;s health


application_id: 6863744
project_number: 5R01HL056652-09
project_title: Molecular Mechanisms of Platelet Exocytosis
administering_ic: NHLBI
award_notice_date: 2005-03-15
application_type: 5
activity_code: R01
ic: HL
serial_number: 056652
program_official: SARKAR, RITA
project_start_date: 1996-07-01
project_end_date: 2007-03-31
study_section: Hematology Subcommittee 1[HEM-1]
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: 2005-04-01
project_abstract:
DESCRIPTION (provided by applicant): Platelet exocytosis is integral to             hemostasis and vascular integrity. Conversely inhibiting exocytosis is an          important target for preventing improper thrombosis which can ultimately lead      to strokes and heart attacks. Understanding the molecular events required for       platelet exocytosis will broaden our ability to control platelet activity. In       the initial funding period it was proposed that membrane proteins in granule        and open canalicular system membranes (OCS) mediate platelet secretion. From        that work it is now clear that specific Soluble NSF Attachment Protein             Receptors (v- and t-SNAREs) are required for membrane fusion in each of the         three platelet exocytosis events. The original hypothesis is now expanded to       address how this platelet exocytosis machinery is regulated. The hypothesis of      this proposal is that exocytosis by stimulated platelets is governed by             specific proteins that control SNARE-SNARE interactions. Several potential          SNARE regulators have been identified in platelets. Using the in vitro platelet     exocytosis assay (developed during the previous period). it is now possible to      determine how these potential regulators function during platelet activation.       Two specific aims are proposed:                                                                                                                                         1. To determine the role that v-SNARE proteins play in platelet exocytosis. The     ultimate goal is to produce a complete description of the SNARE proteins            required for platelet exocytosis. While several platelet t-SNAREs have been         identified and functionally defined the platelet v-SNAREs are yet to be            characterized. This aim focuses on the role of platelet v-SNAREs. These studies     together with previous work will yield a comprehensive picture of all the           molecular machinery required for the final step of the release reaction.                                                                                                2. To determine the role of t-SNARE regulatory proteins in the platelet release     reaction. The goal is to determine how SNARE interactions are controlled during     platelet exocytosis. The in vitro release assay will be used to determine which     t-SNARE regulators are functional in platelets and how their activity affects       SNARE complex formation and function. The studies of this aim will begin to         elucidate the proteins and molecular interactions that are required to promote      membrane fusion in activated platelets.

project_terms:
antibody;chimeric proteins;exocytosis;granule;immunoelectron microscopy;immunofluorescence technique;immunoprecipitation;intracellular transport;laboratory rabbit;lysosomes;membrane fusion;membrane proteins;platelet activation;platelets;protein protein interaction;protein structure function;secretion;synaptic vesicles;syntaxin


application_id: 6862780
project_number: 5R01MH047386-09
project_title: DEVELOPMENT OF ATTENTION AND COMPREHENSION IN ADHD
administering_ic: NIMH
award_notice_date: 2005-03-04
application_type: 5
activity_code: R01
ic: MH
serial_number: 047386
program_official: RUMSEY, JUDITH M
project_start_date: 2001-03-20
project_end_date: 2007-08-31
study_section: Special Emphasis Panel[ZRG1-BBBP-6(01)S]
contact_pi_person_id: 7876936
contact_pi: LORCH, ELIZABETH P
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-03-01
project_abstract:
EXCEED THE SPACE PROVIDED.  The proposed studies are designed to extend work initiated by the present investigators examining story comprehension and its relation to attention in children with attention deficit hyperactivity disorder (ADHD). The results of earlier studies suggest important differences between the two groups of children in the development of story comprehension and its relation to attention. Early on children with ADHD have a general deficit in understanding causal relations and they lose factual information only when their attention is disrupted. As they develop their skills at acquiring factual informationbecomes indistinguishable from those of the comparison childrenbut their understandingof causal connections is deficient when their attention is reduced. Although these results suggest important developmental changes in story comprehension for children with ADHD they are based on cross-sectional comparisons that preclude definitiveconclusions. This issue is particularly important when studying ADHD where referral patterns change across ages.  To address these limitationsa cohort-sequential longitudinal study is proposed in which story comprehension of children with ADHD can be examined from the preschool through the school-age years. In addition the proposed project will allow for a systematic investigation of attentions! and story structure factors that influence specific components of story comprehension and how these may differ developmentally for comparison children and childrenwith ADHD. Another emphasis of the proposed project is to examine factors (e.g. allocation of attention story structure) that influencethe components (e.g. encoding representation retrieval) of story comprehension and how these may differ developmentally for the two groups of children.  FORMANCE SITE(S) (organization city state) University of Kentucky Lexington KY KEY PERSONNEL ========================================Section End===========================================

project_terms:
attention;attention deficit disorder;cognition;hearing;human subject;impulsive behavior;intelligence tests;mental disorder diagnosis;middle childhood (6-11);neural information processing;neuropsychological tests;performance;play;problem solving;psychomotor reaction time;stimulus /response;television;videotape /videodisc;visual perception


application_id: 6862632
project_number: 5R21EB003485-02
project_title: Immuno Biosensor for Real-Time Factor V Leiden Diagnosis
administering_ic: NIBIB
award_notice_date: 2005-01-25
application_type: 5
activity_code: R21
ic: EB
serial_number: 003485
program_official: KORTE, BRENDA
project_start_date: 2004-03-01
project_end_date: 2007-02-28
study_section: Hemostasis and Thrombosis Study Section. Committee was terminated on 11/30/2020. [HT]
contact_pi_person_id: 1895231
contact_pi: KANG, KYUNG AIH
other_pis: Not Applicable
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: 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
budget_start_date: 2005-03-01
project_abstract:
DESCRIPTION (provided by applicant): The Global Goal of the project is to develop a rapid accurate and inexpensive diagnostic immuno-optical biosensor for Factor V Leiden (FVL) diagnosis. FVL is the most common hereditary blood coagulation disorder comprising 3 - 7 percent of the general population and 20-40 percent of individuals with thrombosis. The sensor will be composed of an array of two optical fibers with each immobilized monoclonal antibodies against normal Factor V (FVN) or FVL. After FVN/FVL in the sample reacts with the corresponding antibodies they will be probed with a fluorophore tagged another antibody to specifically quantify the amount of these two molecules in the sample. This sensor will diagnose the FVL with high specificity (vs. clotting assays) faster (vs. DNA analysis) and less expensive and also provide the information on the degree of thrombophilia by having the amount of both FVN and FVL. This early diagnosis method prevents patients from having traumatic thromboembolic complications by allowing them to receive immediate treatments when needed. The specific aims to initiate the research goal are: Aim 1. Purification of FVL from homozygous FVL patients (months 0-2 4). FVL molecules will be purified from the plasma of homozygous FVL patients. Aim 2. Identification and Production of Antibodies against FVN/FV L (months 4-12). Monoclonal antibodies against either FVN or FVL have been generated. The affinity to the native form of FVN or FVL will be identified. Hybridoma cells producing proper antibodies wiII be cultured in bioreactors and purified. Aim 3. Development of Sensors for FVN and FVL (months 7-24). Protocols developed for the Protein C biosensor will be used to detect FVN and FVL on two individual fiber optic sensors and a prototype of dual sensor will be developed.

project_terms:
antibody specificity;biomedical equipment development;biosensor device;biotechnology;blood coagulation disorders;blood disorder diagnosis;clinical research;coagulation factor V;cost effectiveness;diagnosis design /evaluation;early diagnosis;fluorescent dye /probe;gene mutation;human subject;immunoaffinity chromatography;immunologic assay /test;immunologic substance development /preparation;ionophores;monoclonal antibody;portable biomedical equipment;prognosis;protein purification;protein sequence;rapid diagnosis;time resolved data


application_id: 6861732
project_number: 5R01EY006915-17
project_title: Solute transport mechanisms in the ciliary body.
administering_ic: NEI
award_notice_date: 2005-02-03
application_type: 5
activity_code: R01
ic: EY
serial_number: 006915
program_official: LIBERMAN, ELLEN S
project_start_date: 1986-07-01
project_end_date: 2008-02-28
study_section: Special Emphasis Panel[ZRG1-VISA(01)Q]
contact_pi_person_id: 1872319
contact_pi: DELAMERE, NICHOLAS A
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-03-01
project_abstract:
DESCRIPTION (provided by applicant): Our goal is to develop a better understanding of cellular mechanisms that regulate aqueous humor secretion and an improved understanding of NaK-ATPase function. The application focuses on the idea that function of Na K-ATPase and other transport proteins can be modulated by changes in cytoplasmic pH (pHi). In recent studies we discovered that carbonic anhydrase inhibitors (CAIs) lower phi in cultured nonpigrnented ciliary epithelial (NPE) cells. In Aim I we propose studies to examine how cytoplasmic acidification alters Na K-ATPase function. Experiments will be conducted to determine whether cytoplasmic acidification inhibits Na K-ATPase activity via a tyrosine kinase mechanism. Studies will also be done to determine whether the pattern of changes in aqueous humor composition in rabbits treated with CAIs is consistent with altered Na K-ATPase function in ciliary epithelium. Preliminary Studies also show sodium orthovanadate reduces pHi in NPE and experiments will be carried out to explore whether the pH change could be linked to the ability of sodium orthovanadate to reduce lOP. Since we propose changes of pHi could change the activity of Na K-ATPase and other transport proteins we consider H+-ATPase a proton export pump to be important to NPE function. Indeed lOP is reduced by the selective H+-ATPase inhibitor bafilomycin A1. Results from recent studies with angiotensin II and calcium channel blockers indicate the existence of cellular mechanisms that control H+-ATPase. In Aim II we propose experiments to learn more about Hv-ATPase and its control mechanisms. Studies will be conducted to examine the effects of cAMP and protein kinase A activation on Hv-ATPase and also to determine whether nitric oxide and vanadate cause inhibition of H+-ATPase. In summary we propose to examine how ion transport mechanisms in the NPE are set up to respond to cytoplasmic pH changes and to study how pHi is controlled in the NPE. Improved basic science knowledge in this area might lead to the future development of lOP-lowering drugs that work by interfering with cell pH balance.

project_terms:
acidity /alkalinity;biological transport;carbonate dehydratase;carbonic anhydrase inhibitors;cytoplasm;epithelium;fluorescent dye /probe;immunoprecipitation;inhibitor /antagonist;intraocular aqueous flow;ion transport;laboratory rabbit;potassium channel;protein kinase A;protein kinase C;second messengers;secretion;sodium potassium exchanging ATPase;solute;swine;tissue /cell culture;uvea ciliary body;western blottings


application_id: 6859226
project_number: 1R01CA112405-01
project_title: A Molecular Basis for Neuroendocrine Carcinogenesis
administering_ic: NCI
award_notice_date: 2004-12-13
application_type: 1
activity_code: R01
ic: CA
serial_number: 112405
program_official: MIETZ, JUDY
project_start_date: 2005-02-01
project_end_date: 2005-09-30
study_section: Special Emphasis Panel[ZRG1 CG (01)]
contact_pi_person_id: 1868623
contact_pi: GRIMES, H LEIGHTON
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-02-01
project_abstract:
DESCRIPTION (provided by applicant): The cloning of oncogenes and tumor suppressor genes over the last twenty years has allowed profound insight into the molecular basis of cancer and subsequently provided molecular targets for clinical intervention. However the molecular basis of neuroendocrine lung tumors such as small cell lung carcinoma (SCLC) is still not understood. We hypothesize that the Growth factor independence-1 (GFI1) transcriptional repressor oncoprotein and the basic helix-loop-helix (bHLH) transcription factor human achaete and scute homolog- 1 (ASH1) are modifiers of SCLC because they control neuroendocrine differentiation of lung epithelium. Striking parallels can be drawn between the activity of Drosophila orthologs of GFI 1 and ASH 1 in fly neurogenesis and the development of pulmonary neuroendocrine cells and SCLC. Using conditional knockout and transgenic mouse models we will determine the requirement for GFI1 and ASH1 in SCLC oncogenesis acute lung airway injury repair and pulmonary neuroendocrine cell development. Finally a molecular dissection of GFI1 target gene regulation will link transcription effects to lung phenotypes. The proposed experiments should critically determine how key participants in a newly discovered Drosophila developmental cascade are relevant to the induction of SCLC in vivo.

project_terms:
cell differentiation;genetic regulation;genetically modified animals;growth factor;histology;hormone related neoplasm /cancer;immunocytochemistry;in situ hybridization;laboratory mouse;neoplasm /cancer genetics;neuroendocrine system;oncogenes;oncoproteins;phenotype;polymerase chain reaction;protein structure;respiratory epithelium;small cell lung cancer;transcription factor


application_id: 6857212
project_number: 1R01EY016205-01
project_title: Idiopathic Anterior Uveitis and Type I Collagen
administering_ic: NEI
award_notice_date: 2005-01-17
application_type: 1
activity_code: R01
ic: EY
serial_number: 016205
program_official: SHEN, GRACE L
project_start_date: 2005-02-01
project_end_date: 2006-01-04
study_section: Special Emphasis Panel[ZRG1 AED (01)]
contact_pi_person_id: 1859398
contact_pi: BORA, NALINI S.
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-02-01
project_abstract:
DESCRIPTION (provided by applicant):  Idiopathic acute anterior uveitis (AAU) is the most common form of intraocular inflammation in humans. The recurrent nature of the disease can lead to permanent visual loss from the secondary complications of cystoid macular edema posterior subcapsular cataract and glaucoma. Experimental autoimmune anterior uveitis (EAAU) is an organ specific autoimmune disease of the eye and serves as a model of idiopathic human AAU. It is produced in Lewis rats by an antigen specific CD4+ T cell response to an antigen derived from bovine iris and ciliary body. We have purified the uveitogenic antigen to homogeneity and recent results from our laboratory suggest that the uveitogenic antigen is a 22 kDa fragment of bovine type I collagen alpha-2 chain and we refer it to as CI-alpha2 (22 kDa). Our results further suggest that the pathogenic antigen in EAAU is tissue specific being localized solely to the eye. Although human AAU has been historically characterized as a collagen disease this is the strongest evidence to date that collagen is the target autoantigen in uveitis. The specific aims of this proposal are:  1. Expression and localization of CI-alpha2 (22 kDa) within the rat and human eye - expression within the ocular tissue. 2. Presence of CI-alpha2 (22 kDa) in intraocular fluid.  3. Induction of tolerance to CI-alpha2 (22 kDa) to inhibit EAAU.  4. Identification of CI-alpha2 (22 kDa) as the target antigen in idiopathic human AAU - i.e. correlation of idiopathic AAU with the immune response to bovine CI-alpha2 (22 kDa).  We believe that these studies are essential to definitely prove that EAAU is an autoimmune response to ocular CI-alpha2 (22 kDa) and that it is the autoantigen responsible for idiopathic human AAU. These observations should also allow the development of effective therapy based on selective antigen specific modulation of the immune response in the treatment of this disease.

project_terms:
autoantigens;clinical research;collagen;human subject;immune response;immune tolerance /unresponsiveness;laboratory rat;protein localization;protein quantitation /detection;uveitis


application_id: 6855771
project_number: 5R21AT001490-03
project_title: Green Tea Polyphenols: A Novel Approach to IBD
administering_ic: NCCIH
award_notice_date: 2005-05-06
application_type: 5
activity_code: R21
ic: AT
serial_number: 001490
program_official: SORKIN, BARBARA C
project_start_date: 2004-02-15
project_end_date: 2008-02-28
study_section: ZAT1-DB(09)
contact_pi_person_id: 7130705
contact_pi: OZ, HELIEH S
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-03-01
project_abstract:
DESCRIPTION (provided by applicant): Crohn's disease and Ulcerative Colitis are chronic idiopathic inflammatory disease of the gastrointestinal tract (IBD). Current medical intervention of IBD consists of anti-inflammatory and immunosuppressive agents. Despite medical intervention many patients remain refractory. Clearly new therapeutic modalities are needed to minimize the destructive nature of IBD. Use of alternative medicine is widespread and on the rise in the United States. Patients with IBD frequently use alternative medicine and consider it an important form of therapy. There are a number of alternative medicine therapies that may prove beneficial. These include therapies that have anti-inflammatory properties or alter the bacterial flora in the bowel. However the scientific evidence for the use of alternative medicines is often lacking or weak and safety generally has not been assessed. Thus there is a great need to establish the effectiveness and safety of alternative medicines used in patients. Green tea has potent anti-inflammatory properties. We present evidence that green tea polyphenols decrease the disease activity in interleuken-2 mice model of autoimmunity and IBD. The transcription factor NF-KappaB and NF-KappaB-inducible inflammatory mediators (e.g. TNF-alpha interleukin-1) play a critical role in the intestinal injury and the clinical/biochemical abnormalities observed in IBD. We recently showed that polyphenols extracted from green tea are potent inhibitors of NF-KappaB. We have compelling preliminary data showing that the green tea polyphenol and its extract (-)-epigallocatechin-3-gallate (EGCG) inhibit the activity of I-KB kinase (IKK) a pivotal enzyme in the NF-KappaB activation pathway. The overall objectives of this project are to determine whether green tea polyphenols (in doses ranging from functional foods to pharmacological) and/or EGCG modulate intestinal injury and immune cell responses in the Dextran Sulfate Sodium (DSS) model of Ulcerative Colitis. We will also confirm our findings using another IBD model the interleukin-10 (IL-10) deficient mice that develop spontaneous enterocolitis (similar to Crohn's disease). These studies should provide evidence supporting green tea polyphenols/EGCG as potent anti-inflammatory therapy and provide the basis for a green tea polyphenols/EGCG intervention trials in patients with Inflammatory Bowel Disease.

project_terms:
Crohn&apos;s disease;alternative medicine;antiinflammatory agents;antioxidants;autoimmune disorder;blood chemistry;colitis;diet therapy;dosage;enzyme inhibitors;flavonoids;gel mobility shift assay;high performance liquid chromatography;histology;inflammatory bowel diseases;laboratory mouse;nonhuman therapy evaluation;nuclear factor kappa beta;nutrition related tag;plant extracts;polymerase chain reaction;protein kinase;statistics /biometry;tea;ulcerative colitis;western blottings


application_id: 6855095
project_number: 5R44CA085023-03
project_title: Preclinical Development of PEG-TNF
administering_ic: NCI
award_notice_date: 2005-02-04
application_type: 5
activity_code: R44
ic: CA
serial_number: 085023
program_official: MUSZYNSKI, KAREN
project_start_date: 1999-11-01
project_end_date: 2006-01-31
study_section: Special Emphasis Panel[ZRG1-SSS-1(10)]
contact_pi_person_id: 8187374
contact_pi: BOMALASKI, JOHN S
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
fips: US
organization_id: 3656401
organization_name: PHOENIX PHARMACOLOGICS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-02-04
budget_end_date: 2006-01-31
assistance_listing_number: 93.395
funding_mechanism: SBIR/STTR
project_abstract:
DESCRIPTION (provided by applicant):  Unformulated human tumor necrosis factor( (huTNF() has anti-tumor activity in mice but there is little difference between the effective and lethal doses. Systemic administration of unformulated huTNFalpha has been tested in humans. All studies indicated the dose limiting toxicity was usually hypotension the circulating half life was < 20 min and little anti-tumor activity was seen. Recent results from isolated limb perfusions with huTNFalpha for prolonged times indicated this cytokine to have marked anti-tumor activity in humans with melanoma. This suggests huTNFalpha may be therapeutically useful provided the toxicity and short circulating half-life can be overcome.    Formulation of other biologically active cytokines and proteins with polyethylene glycol (PEG) has significantly improved their safety and increases their circulating half-life. Examples include PEG-alpha interferon and PEG-GCSF which are now approved by the FDA.    The Phase 1 SBIR grant application proposed formulating huTNFalpha with PEG to increase its circulating half-life and increase its safety. An optimal formulation of huTNFalpha was found (termed huTNFalpha-SS PEG 20000 mw). The circulating half-life safety and efficacy of this formulation have been substantially increased compared with unformulated huTNFalpha in mice.    In a Pre IND meeting with the FDA the final preclinical studies were identified and are the focus of this Phase 2 SBIR application. The specific aims are to: 1) produce cGMP huTNFalpha-SS PEG 20000 mw; 2) finalize its pharmacological characterization; and 3) test the immunogenicity and its safety in animals according to GLP (Good Laboratory Practice).    The data from these studies will provide the final information enabling the filing of an IND with the FDA to support human Phase I clinical testing.

project_terms:
SDS polyacrylamide gel electrophoresis;biotherapeutic agent;cell mediated lymphocytolysis test;cytokine;drug design /synthesis /production;enzyme linked immunosorbent assay;gel electrophoresis;high performance liquid chromatography;laboratory mouse;laboratory rabbit;melanoma;perfusion;pharmacokinetics;pharmacology;polyethylene glycols;skin disorder chemotherapy;skin pharmacology;tumor necrosis factor alpha


application_id: 6850788
project_number: 5R21CA098166-02
project_title: Tumor-reactive IgG in the diagnosis of ovarian cancer
administering_ic: NCI
award_notice_date: 2005-02-02
opportunity_number: PA-03-003
application_type: 5
activity_code: R21
ic: CA
serial_number: 098166
program_official: LIVELY, TRACY LUGO
project_start_date: 2004-02-05
project_end_date: 2007-01-31
study_section: Clinical Oncology Study Section[CONC]
contact_pi_person_id: 1867564
contact_pi: TAYLOR, DOUGLAS DILLON
other_pis: Not Applicable
congressional_district: 03
department: OBSTETRICS & GYNECOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_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): Ovarian cancer is the fourth leading cause of cancer-related deaths in women. Although significant progress has been made in its treatment long-term survival has not changed significantly due to inadequate early diagnostic approaches. The objective of this project is to develop a diagnostic assay for the early detection of ovarian cancer based on the identification and quantitation of tumor-reactive IgG specifically against transformation-linked aberrant gene products. In human and experimental animal tumors tumor-reactive antibodies can be demonstrated prior to the appearance of discernable tumors or the detection of circulating tumor antigens. The presence of circulating tumor-reactive IgG has been correlated with poor prognosis. Molecular biologic techniques have shown promise in detecting early gene mutations associated with the development of lung cancer; however these techniques rely on the acquisition of transformed cells for analysis. Our studies have shown that since immune recognition appears to be a direct consequence of cancer-linked genetic changes resulting in alterations within these proteins the presence of reactive IgG provides an early marker of cancer-associated gene aberrations. This diagnostic assay is based on our patented diagnostic use of reactive antibodies combined with recognition of specific gene products which have  been demonstrated to be altered in ovarian cancer patients. Genetic alterations resulting in altered proteins have been demonstrated in tumor suppressor and growth regulatory genes. This study will analyze the recognition of specific intracellular proteins by autoantibodies from ovarian cancer patients and correlating this recognition with stage of disease. This project will also combine proteomics and autoreactivity to ovarian cancer-derived cellular proteins to identify novel components to provide additional tumor specificity. Since autoreactive IgGs are markers of gene alterations the timing of their appearance will also provide information on specific genetic changes in cancer development and progression. Ultimately antigenic proteins linked with histologic type and stage of disease will be combined into the development of protein arrays to screen for circulating reactive IgG as an early diagnostic test.

project_terms:
autoantibody;biomarker;cell cycle proteins;clinical research;diagnosis design /evaluation;early diagnosis;gene mutation;human subject;humoral immunity;immunoglobulin G;immunoprecipitation;molecular shape;neoplasm /cancer classification /staging;neoplasm /cancer diagnosis;neoplastic transformation;oncoproteins;ovary neoplasms;patient oriented research;protein sequence;proteomics;statistics /biometry;tissue /cell culture;tumor antigens;two dimensional gel electrophoresis;western blottings;women&apos;s health


application_id: 6850644
project_number: 5R43GM070193-02
project_title: Bypassing fluidics in proteomic screening
administering_ic: NIGMS
award_notice_date: 2005-06-02
opportunity_number: PA-02-125
application_type: 5
activity_code: R43
ic: GM
serial_number: 070193
program_official: EDMONDS, CHARLES G
project_start_date: 2004-02-10
project_end_date: 2007-05-31
study_section: Special Emphasis Panel[ZRG1-SSS-2(10)B]
contact_pi_person_id: 8498806
contact_pi: DESCHATELETS, PASCAL
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 144375263
duns_number: 144375263
fips: US
organization_id: 10002039
organization_name: POTENTIA PHARMACEUTICALS, INC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-06-01
budget_end_date: 2007-05-31
project_abstract:
DESCRIPTION (provided by applicant): The goal of this proposal is to develop a new groundbreaking technology for the rapid identification of ligands for proteins. Every year the pharmaceuticals industry loses about $3 billion by targeting genes/proteins wrongfully identified as the cause of disease. In the past decade thousands of new genes/proteins with a potential role in disease have been identified. Simultaneously millions of small molecule ligands have been generated in pharmaceutical libraries with little knowledge on their binding potential to these novel gene/protein targets. Potentia has developed a technology that will pave the way towards the matching of these ligands with new potential drug targets. Intelligent access to these libraries of ligands will generate a wealth of knowledge on disease mechanisms that is deemed to revolutionize the process of gene/protein validation in the drug industry. Potentia's technology is unique in its capacity to circumvent the inherent 'slowness' of analyzing molecules in solution. Proteins are immobilized on the tip of an atomic force microscope and then exposed to arrays of biosensors. Each biosensor is individually functionalized with a different small molecule ligand resulting in Potentia's groundbreaking screening platform. The first aim of this proposal will be to eliminate background noise when functionalizing specialized biosensors with ligands in order to generate sensors for protein binding. The second aim will be to show that an atomic force microscope tip can be used as a bias electrode to gate our specialized biosensors. The third aim will be to determine whether it is possible to retrieve quantitative information from a binding event when using an atomic force microscope tip as a 'robotic arm' to bring a protein in contact with a ligand-coated biosensor. The success of this proposal will generate intelligence on millions of small molecule-protein interactions generating unprecedented insight in the various gene/protein pathways and their role in disease.

project_terms:
atomic force microscopy;bioengineering /biomedical engineering;biomedical equipment development;biosensor device;biotechnology;chemical genetics;chemical structure function;chemical synthesis;computer data analysis;electrical measurement;high throughput technology;intermolecular interaction;ligands;molecular biology information system;molecular film;polyethylene glycols;protein binding;proteomics;robotics;silanes;surface coating;surface property


application_id: 6844315
project_number: 5R21DK065730-02
project_title: Role of O-GlcNAc transferase in insulin gene expression
administering_ic: NIDDK
award_notice_date: 2004-12-13
opportunity_number: PA-02-008
application_type: 5
activity_code: R21
ic: DK
serial_number: 065730
program_official: APPEL, MICHAEL C
project_start_date: 2004-01-15
project_end_date: 2007-05-31
study_section: Metabolism Study Section[MET]
contact_pi_person_id: 7875121
contact_pi: OZCAN, SABIRE
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Although several lines of evidence suggest that increased levels of O-GIcNAc modification interferes with normal glucose homeostasis the exact functional consequences of this modification remain to determined. Recent data indicate that O-linked GIcNAc transferase (OGT1) in a complex with the co-repressors Hdac1 and mSin3A mediates repression of gene expression in the HepG2 liver cell line. However the target genes and the conditions under which this repressor complex is active in vivo are not known. Insulin gene expression in the pancreatic beta cells is induced by high blood glucose levels and is decreased when blood glucose levels are low. Using the deacetylase inhibitor trichostatin A we have recently discovered that insulin gene expression is inhibited at low concentrations of glucose by the recruitment of deacetylases to the insulin promoter in the mouse insulinoma (MIN6) cell line. Furthermore we found that OGT1 and Hdac1/2 are recruited to the insulin gene promoter and interact with each other only at low levels of glucose in the MIN6 beta cells. Based on these data we hypothesize that OGT1 and Hdac1/2 are in a complex and repress insulin gene expression at low levels of glucose. We will test this hypothesis as described in the following three specific aims. 1) To analyze the role of OGT1 in repression of insulin gene expression in MIN6 beta cells. 2) To identify the transcription factor(s) that recruits the OGT1-Hdac1/2 repressor complex to the insulin gene promoter. 3) To identify genes with altered transcription in response to increased O-GIcNAc modification. Understanding the role of OGT1 in regulating insulin gene transcription will provide new insights into the mechanisms by which defects in O-GIcNAc modification lead to symptoms associated with diabetes. In addition the obtained data will be instrumental in the design of novel strategies for the treatment and prevention of type I and type II diabetes and the secondary complications associated with diabetes.

project_terms:
blood glucose;diabetes mellitus;diabetes mellitus genetics;enzyme activity;enzyme complex;gene expression;gene induction /repression;genetic transcription;hexosyltransferase;human genetic material tag;hyperglycemia;immunoprecipitation;insulin;microarray technology;pancreatic islets;posttranslational modifications;tissue /cell culture;transcription factor


application_id: 6843156
project_number: 5R01CA035635-20
project_title: Specificity of Intercalation Reactions
administering_ic: NCI
award_notice_date: 2004-12-20
application_type: 5
activity_code: R01
ic: CA
serial_number: 035635
program_official: FU, YALI
project_start_date: 1984-03-01
project_end_date: 2007-12-31
study_section: Biophysics and Biophysical Chemistry A Study Section[BBCA]
contact_pi_person_id: 1863983
contact_pi: CHAIRES, JONATHAN B.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-01-01
project_abstract:
EXCEED THE SPACE PROVIDED.  DNA is an underrepresented target for small molecule therapeutic agents. One reason for the dearth of DNA-targeted drugs is that the fundamental molecular mechanisms that govern sequence- and structural-selective ligand binding to DNA are poorly understood. The rational design of new DNA-targeted drugs requires a thorough understanding of the binding mechanisms of existing compounds that bind to DNA with unique types of specificity. The long-range goal of the proposed research is to understand the molecular mechanism of intercalation reactions with emphasis on the energetic basis of their sequence and structural selective binding. Renewal is sought for a successful and highly productive basic science program that has produced several promising avenues for DNA-targeted drug development. Research in the next funding period will focus on innovative studies designed to clarify the mechanisms that govern structural and sequence selective ligand binding to nucleic acids. Specific aims include: 1. Use and refinement of a high- throughput competition dialysis assay for the identification and characterization of structural selective ligand binding to nucleic acids. 2. Characterization of ligand binding to DNA:RNA hybrid structures. 3. Characterization of regional-selective drug binding by a novel calorimetric "bootprinting" method. The results of these studies will: 1. Provide a definitive taxonomy of structural selective ligand binding to nucleic acids along with a description of the energetic basis of that structural selectivity 2. Provide fundamental information to guide the rational design of compounds targeted to DNA:RNA hybrid structures a target of enormous biological significance. 3. Provide a new tool for the quantitative study of drug-DNA interaction in long (genomic) pieces of DNA. PERFORMANCE SITE ========================================Section End===========================================


application_id: 6843117
project_number: 5K08DE014845-03
project_title: Nuclear Co-Activators in Developing Craniofacial Tissue
administering_ic: NIDCR
award_notice_date: 2004-12-22
opportunity_number: PA-00-003
application_type: 5
activity_code: K08
ic: DE
serial_number: 014845
program_official: HARDWICK, KEVIN S
project_start_date: 2003-01-01
project_end_date: 2007-12-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 7031215
contact_pi: PHILIPOSE, JOHN T
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
EXCEED THE SPACE PROVIDED. The purpose of this application is to seek training support for a well-defined period of specialized study that will enable the applicant to develop into an outstanding clinician and research scientist. The applicant's commitment to a career in laboratory research is substantial and in the judgement of the candidate's mentors his potential to develop into an independent investigator is excellent. A comprehensive six year plan for the applicant's training program is presented in the current application. The training program includes didactic coursework and supervised basic science research experiences that will culminate in attainment of the Ph.D. degree in Pharmacology &Toxicology as well as completion of specialized postgraduate residency training in Orthodontics. A senior well-funded and experienced basic science research mentor and a clinical mentor with substantial research experience have been identified to provide cohesion and integration of the scientific growth and development of the applicant. A detailed research thesis proposal is presented in the current application that integrates the applicant's research training area (molecular mechanisms of craniofacial growth) with his orthodontic clinical training and future interests in academic dentistry. One hundred percent of the applicant's full-time professional effort as outlined in the training program proposed in the current application will be devoted to the goals of this K-08 award. PERFORMANCE SITE ========================================Section End===========================================


application_id: 6842220
project_number: 5F32HL075998-02
project_title: Cardiac Opioid Receptor Activation and Protein Kinase C
administering_ic: NHLBI
award_notice_date: 2004-12-15
opportunity_number: PA-03-067
application_type: 5
activity_code: F32
ic: HL
serial_number: 075998
program_official: MEADOWS, TAWANNA
project_start_date: 2004-01-01
project_end_date: 2005-04-30
study_section: Special Emphasis Panel[ZRG1-F10(20)L]
contact_pi_person_id: 8190333
contact_pi: REID, EASTON A.
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):  Opioid receptors belong to the family of G-protein coupled receptors (GPCRs) with seven transmembrane regions spanning the sarcolemmal membrane and are coupled to inhibitory G-proteins which activate hospholipase C (PKC) and protein kinase C (PKC). One or multiple PKC isoforms translocate from the cytosol to target membranes where phosphorylation of serine/threonine residues cause a cascade of myocyte protective events. To date the effects of cardiac opiate receptor subtype activation and their intracellular signaling mechanisms in normal and ischemic myocardium have been conflicting. This training proposal will determine opioid receptor subtype modulation of cardiac myocyte excitation-contraction coupling via specific PKC isoforms. Specific aims will: 1) determine delta- and kappa-opioid receptor modulation of cardiac excitation-contraction coupling in intact myocardium and 2) determine opioid receptor mediated PKC isoform signaling and modulation of intracellular calcium.

project_terms:
biological signal transduction;calcium;cardiac myocytes;confocal scanning microscopy;heart contraction;immunocytochemistry;immunofluorescence technique;laboratory rat;myocardium;opioid receptor;postdoctoral investigator;protein isoforms;protein kinase C;protein transport;receptor coupling;receptor expression;western blottings


application_id: 6841603
project_number: 5R01DA013144-05
project_title: METHAMPHETAMINE AND HIV PROTEIN-INDUCED NEUROTOXICITY
administering_ic: NIDA
award_notice_date: 2005-01-03
application_type: 5
activity_code: R01
ic: DA
serial_number: 013144
program_official: LAWRENCE, DIANE M
project_start_date: 2001-02-15
project_end_date: 2007-12-31
study_section: Special Emphasis Panel[ZRG1-AARR-5(01)S]
contact_pi_person_id: 7875434
contact_pi: MARAGOS, WILLIAM F
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-01-01
project_abstract:
DESCRIPTION: Several lines of evidence indicate that the basal ganglia are          highly susceptible to infection with the human immunodeficiency virus (HIV).        However the pathogenesis of basal ganglia dysfunction is not well understood.      Patients with HIV infection often abuse drugs such as methamphetamine a drug       that is well known to also cause long-term structural and functional changes to     the basal ganglia. There is now mounting evidence that "virotoxins" (viral          products released from infected cells) and methamphetamine share a common           mechanism which leads to neuronal damage. Two such products are the HIV            proteins gp120 and Tat. In this proposal we will examine the degree of synergy     between these virotoxins and methamphetamine by determining the severity of         damage they cause to the dopaminergic system in vivo and to human cortical          neurons in vitro. To identify common mechanisms that lead to neuronal               dysfunction and ultimately to cell death we will also examine two                 pathophysiological processes that contribute independently to virotoxin and MA      toxicity namely reactive oxygen species and the cytokine TNF-alpha. In             studying these two processes we will 2) measure production of compounds of         interest (e.g. reactive oxygen species and TNF-alpha) and determine the             efficacy of a variety of inhibitors on neurotoxicity. To accomplish these           goals we will assess the effects of intrastriatal injections of virotoxins in      animals treated with methamphetamine and in vitro in human cortical neurons         where cell types can be manipulated.

project_terms:
HIV envelope protein gp120;HIV infections;clinical research;free radical oxygen;genetically modified animals;human fetus tissue;human immunodeficiency virus;laboratory mouse;laboratory rat;methamphetamine;neurons;neurotoxins;tissue /cell culture;tumor necrosis factor alpha;virus protein


application_id: 6839529
project_number: 5R01AI025098-17
project_title: Characterization of the Hms phenotype of Yersinia pestis
administering_ic: NIAID
award_notice_date: 2005-02-18
opportunity_number: PA-03-080
application_type: 5
activity_code: R01
ic: AI
serial_number: 025098
program_official: SCHAEFER, MICHAEL R
project_start_date: 1993-09-30
project_end_date: 2008-01-31
study_section: Bacteriology and Mycology Subcommittee 2[BM-2]
contact_pi_person_id: 1864186
contact_pi: PERRY, ROBERT DONALD
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
EXCEED THE SPACE PROVIDED.  Yersiniapestis primarily causes a zoonotic disease - plague. Although humans are an accidental dead- end host bubonic and pneumonic plague has caused widespread loss of human life during recurrent pandemics. Nearly 2000 human plague cases occur yearly and small epidemics in South America and Southeast Asia are common. In nature the bacterium has an obligate flea-mammal (primarily rodent) life cycle. Survival of plague in nature is dependent upon its ability to propagate in fleas and upon its transmission from fleas to mammals.  In this proposal we will focus on the hemin-storage (Hms +) phenotype of Y. pestis that is required for Y. vestis to cause blockage of the proventricular valve of fleas. Blockage of this valve between the esophagus and stomach of the flea is required for transmission of the disease from fleas to mammals. In vitro the Hms + phenotype is characterized by binding of enormous quantities of exogenous hemin or Congo red (CR) dye to cells grown at 26-34C (forming red colonies) but not at higher temperatures. We now have evidence that the Hms phenotype of Y. pestis produce an extraceUular matrix (ECM; possibly a biofilm) and that the levels or activities of HmsP and HmsT regulate formation of this ECM. HmsT and HmsP likely synthesize and degrade cyclic-di-GMP which may control the activities ofECM-synthesizing Hms protein(s). The mechanisms ofproventricular blockage roles of rims proteins in biofilm formation and mechanisms of temperature regulation of the phenotype remain to be elucidated. We propose to continue 1) identifying and genetically analyzing essential hms genes; 2) analyzing the regulation of rims-dependent ECM expression; 3) biochemically analyzing the ECM and Hms proteins; and 4) analyzing the physiological role(s) of the Hms  system.  These studies will enhance our understanding of bacterial features that are required for Y. pestis to block the flea which is essential for the transmission of plague from fleas to mammals. This will facilitate measures to control or eliminate natural reservoirs of plague and control disease transmission. In addition elucidation of the enzymatic activities of rims proteins and regulatory mechanisms controlling the synthesis of the ECM produced by Hms proteins may have relevance for biofilm formation by other pathogenic bacteria. PERFORMANCE SITE ========================================Section End===========================================


application_id: 6838697
project_number: 5R01NS036660-06
project_title: Detection of presymptomatic Alzheimer's disease by fMRI
administering_ic: NINDS
award_notice_date: 2004-12-24
application_type: 5
activity_code: R01
ic: NS
serial_number: 036660
program_official: REFOLO, LORENZO
project_start_date: 1997-09-30
project_end_date: 2007-12-31
study_section: Special Emphasis Panel[ZRG1-BDCN-1(01)S]
contact_pi_person_id: 8364843
contact_pi: SMITH, CHARLES DENNIS
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-01-01
project_abstract:
EXCEED THE SPACE PROVIDED.  Alzhimer's disease (AD) is preceded by a period when detectable changes in brain function occur without warning symptoms. This period may be twenty years or longer. Activation measured by functional magnetic resonance imaging is reduced during confi_ntation naming in normal women who have increased risk of late-onset Alzbeimer's disease at an average age of only 53 years. These same individuals have reduced activation in the posterior cingulat cortex during a memorization task among other disparities. Our hypothesis is that the altered functional MRI responses in naming working memory and memorization will quantifiably worsen with age due to progressive underlying Alzheimcr's disease pathology. Disease-modifying treatments applied in this early pre-symptomatic stage of AD could have profound impact by preventing the onset of cognitive symptoms. Millions are currently being spent on large-scale prevention trials with AD symptoms as end-points. By providing a biomarker ofpre-symptomatic AD progression fMRI could potentially reduce the duration and costs of such trials. This continuation proposal is designed to detect changes in brain function in high-AD risk individuals over time. We will study normal education-matched groups of high- and low-AD risk subjects in the age ranges 40-65 and 65-90 years using fMRI stimulus tasks which have previously demonstrated regional disparities in high-AD risk individuals. In addition we will repeat the naming and fluency fMRI studies performed previously in high- and low-AD risk individuals after an interval of five years in order to detect longitudinal changes in activation. The convergence of evidence from these cross-sectional and longitudinal studies could provide powerful evidence for a model of Alzheimer's disease as a relentless slowly progressive brain pathology that begins early in adult life but remains compensated until it produces clinical symptoms in its late stages. PERFORMANCE SITE ========================================Section End===========================================


application_id: 6837682
project_number: 5R01MH061531-05
project_title: ANXIETY DEPRESSION OPTIMISM AND CELLULAR IMMUNITY
administering_ic: NIMH
award_notice_date: 2005-01-21
application_type: 5
activity_code: R01
ic: MH
serial_number: 061531
program_official: MUEHRER, PETER R
project_start_date: 2001-02-16
project_end_date: 2007-01-31
study_section: Special Emphasis Panel[ZRG1-BBBP-2(01)S]
contact_pi_person_id: 1886687
contact_pi: SEGERSTROM, SUZANNE C
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-02-01
project_abstract:
DESCRIPTION: Optimism or positive outcome expectancies has been associated        with better psychological and physical health including changes in the immune      system. Under moderately severe stress optimists have more lymphocytes             associated with cell-mediated immunity and natural killer cell cytotoxicity.        The proposed research is intended to test whether optimism is beneficial during     different sorts of stressors and using and in vivo measure of immune function.      In a group of first year law students optimism will be related to                  cell-mediated immunity as measured by skin test over five time points:             baseline (before school starts) a moderately severe stressor (mid-semester) a     more sever stressor (final examinations) recovery (beginning of second             semester) and feedback (return of first semester grades). The various time          points allow for a test of the adaptiveness of optimism under different levels      of stress and after confirmation or discontinuation of optimistic beliefs.          Potential moderators and mediators of an optimism-immunity relationship will        also be investigated. First social network integration may provide a buffer;       in its absence optimism may be more important. Second the degree to which         optimism effects are independent of those of negative affectivity will be           tested. Third state positive and negative and cognitive appraisal processes        may be psychosocial mediators by which optimism affects the immune system. The      amount and rhythm of cortisol release is a potential physiological mediator.        The results will have the potential to clarify the circumstances under which        optimism is beneficial differentiate optimisms effects from those of negative      affectivity and examine the role of mood cognitive processes and cortisol in     stressor-related immune change. Given that interventions to increase optimism       are being developed it is becoming increasingly important to understand when       and why optimism leads to better psychological health less distress and           better immune function during stressors.

project_terms:
belief;cellular immunity;circadian rhythms;clinical research;coping;cortisol;expectancy;fear;grief;hormone regulation /control mechanism;human subject;psychological stressor;psychoneuroimmunology;social support network;university student


application_id: 6836519
project_number: 5R01AI051592-03
project_title: Cis-acting RNA elements in hepatitis C virus replication
administering_ic: NIAID
award_notice_date: 2005-01-10
application_type: 5
activity_code: R01
ic: AI
serial_number: 051592
program_official: KOSHY, RAJEN
project_start_date: 2003-01-01
project_end_date: 2007-12-31
study_section: Experimental Virology Study Section[EVR]
contact_pi_person_id: 6801917
contact_pi: LUO, GUANGXIANG GEORGE
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-01-01
project_abstract:
EXCEED THE SPACE PROVIDED. Hepatitis C virus (HCV) is the major etiologic agent of non-A non-B (NANB) viral hepatitis infecting approximately 4 million people in the U.S. HCV has a positive-stranded RNA genome consisting of a single open reading frame (ORF) flanked by the untranslated regions (UTR) at the 5' and 3' ends. The ORF encodes a large polypeptide that is processed to structural and nonstructural viral proteins. The roles of viral proteins and conserved RNA sequences/structures in HCV replication are poorly understood. The overall goal of this research proposal is to determine the sequence and structural requirements of cis-acting RNA elements in the 5' and 3' UTRs in viral RNA replication. Both the 5' and 3' UTR sequences are highly conserved among various HCV isolates. Genetic studies have demonstrated that both 5' and 3' UTRs are essential for HCV RNA replication. We hypothesize that the conserved 5' and 3' UTRs contain cis-acting RNA elements important for control of HCV RNA replication. The highly conserved 5'UTR harbors two distinct RNA elements a short 5'-proximal RNA element with a stern-loop structure and a longer element of internal ribosomal entry site (IRES). To determine cis-acting RNA elements in the 5'UTR and to define their roles in HCV RNA replication we will perform systematic mutagenesis analyses of the conserved sequences/structures by nucleotide deletions substitutions and replacement with non-HCV IRES. The 3'UTR consists of three distinct regions a highly conserved 98 nucleotides that form three stern-loop structures a poly(U/C) tract of variable length and a variable region at immediate downstream of the ORF. Cis-acting RNA elements in the 3'UTR for HCV RNA replication will be defined by nucleotide deletions and substitutions. The effects of mutations in the 5' and 3' UTRs on HCV RNA replication will be determined by using reverse genetics systems. We have developed a DNA-based HCV replicon replication system. We have also demonstrated that a DNA-based HCV 'minigenome' RNA was replicated when active replicase complex was provided in trans. These reverse genetics systems for HCV RNA replication will be used to determine cis-acting RNA elements in the 5' and 3' UTRs and their roles in HCV RNA replication. Information gained from these studies will immediately contribute to our understanding of the molecular mechanism of HCV RNA replication and provide meaningful insights to the design of effective strategies for controlling HCV infection. PERFORMANCE SITE ========================================Section End===========================================


application_id: 6835669
project_number: 5R01EY014060-03
project_title: Tolerance and autoimmunity in the eye
administering_ic: NEI
award_notice_date: 2005-01-17
application_type: 5
activity_code: R01
ic: EY
serial_number: 014060
program_official: SHEN, GRACE L
project_start_date: 2003-01-01
project_end_date: 2006-12-31
study_section: Visual Sciences A Study Section[VISA]
contact_pi_person_id: 1863468
contact_pi: WOODWARD, JEROLD G
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2005-01-01
project_abstract:
EXCEED THE SPACE PROVIDED. Autoimmune uveitis is a sight threatening autoimmune disease affecting some 20/100000 people per year. Like other autoimmune diseases uveitis appears to result form the aberrant activation of T cells toward self antigen present within the eye. How the T cells become activated and the mechanism of autoimmune tissue destruction is poorly understood. In mice experimental autoimmune uveitis (EAU) can be induced by immunization with the retinal antigen interphotoreceptor retinol binding protein (IRBP). This laboratory has optimized the production of human recombinant IRBP and will use this to probe the nature of the IRBP specific T cells which mediate EAU. One of the fundamental processes in T cell activation is the interaction of the T cell with the antigen presenting cell yet nothing is known about how this interaction affects EAU in vivo. In the first aim the role of the antigen presenting cell in the priming and effector function of the IRBP specific T cell will be studied. This will be accomplished through in vivo modulation of APC function and adoptive transfer studies. These experiments will answer important questions regarding how the autoreactive T cell becomes activated and the nature of the antigen presenting cel within the eye itself which is responsible for T cell effector function. While the transfer of EAU into na'='vemice with IRBP specific T cells has been demonstrated the nature of the T cell that is capable of inducing disease is not known. In the second aim a panel of IRBP specific T cell clones will be characterized for a variety of functional properties as well as their ability to transfer EAU to normal mice. In the third aim T cell receptor genes from select clones will be isolated and used to produce transgenic mice. These mice will provide a valuable new model system in which to further study the mechanism of EAU. Toward this aim we will also further develop a transgenic model system in which ovalbumin is expressed in the retina. This will involve the production of new transgenic mice which express a form of ovalbumin which will be retained within the retina rather than being secreted. Together these studies will provide important new informtion as well as produce a new model system resulting in much greater understanding of the mechanisms of autoimmune uveitis. PERFORMANCE SITE ========================================Section End===========================================


