# projects

application_id: 7942792
project_number: 5R21NS066117-02
project_title: PYCNOGENOL AND TRAUMATIC BRAIN INJURY
administering_ic: NINDS
award_notice_date: 2010-07-23
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: NS
serial_number: 066117
program_official: HICKS, RAMONA R
project_start_date: 2009-09-30
project_end_date: 2011-08-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 1884283
contact_pi: SCHEFF, STEPHEN W
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a global health problem that is financially crippling for many families because of both specialized care and lost financial income. TBI involves at least two separate injury cascades that lead to neuronal and cognitive dysfunction. The secondary injury cascade may be amenable to pharmacologic intervention but the mechanisms are complicated requiring a multi-faceted approach. Oxidative stress loss of mitochondrial function and neuroinflammation appear to play major roles. Naturally occurring flavonoids are unique in possessing not only tremendous free radical scavenging properties but also the ability to modulate cellular homeostasis leading to a reduction in inflammation and cell toxicity. The proposed studies will investigate the idea that Pycnogenol(r) (PYC) a combination of bioflavonoids can significantly reduce the secondary injury cascade following TBI. This is an extremely novel approach to TBI therapy since it utilizes a family of very closely related biologically active polyphenols derived from tree bark. The first series of studies will explore the best possible dosing of PYC to maximally reduce oxidative stress and neuroinflammation following experimental TBI in rodents. The second set of studies will explore the protective qualities of PYC on mitochondrial bioenergetics and cell survival in the hippocampus following experimental TBI. Successful completion of the studies will pave the way for using PYC in more involved experimental TBI studies and contribute to the development of a rational therapy leading to a more favorable outcome.   
   
PUBLIC HEALTH RELEVANCE: The proposed studies investigate a specialized compound called a bioflavonoid to determine if it can help protect cells in the brain following injury. Using a well characterized animal model of traumatic brain injury subjects are treated with the compound Pycnogenol(r) and tested for a variety of outcome measures. Bioflavonoids are known to manifest multiple different helpful properties such as reducing oxidative stress. If the studies work then more complex and longer term studies can be proposed hopefully leading to a more rational therapy for brain injury.

project_terms:
Age;Animal Model;Animals;Antioxidants;Apoptosis;Bioenergetics;Bioflavonoid;Brain;Brain Injuries;Caring;Cause of Death;Cell Death;Cell Survival;Cells;Cessation of life;Complex;Development;Dose;Early treatment;Elements;Experimental Models;Family;Flavonoids;Free Radical Scavengers;Free Radical Scavenging;Hippocampus (Brain);Homeostasis;Impaired cognition;Income;Individual;Inflammation;Injury;Intervention;Lead;Legal patent;Length;Longitudinal Studies;Membrane;Methods;Mitochondria;Monitor;Neurocognition;Neuronal Dysfunction;Neurons;Outcome;Outcome Measure;Oxidants;Oxidative Stress;Pathogenesis;Pharmaceutical Preparations;Pinus maritima;Play;Population;Property;Proteins;Pycnogenol;Reactive Nitrogen Species;Reactive Oxygen Species;Recovery;Rehabilitation therapy;Research;Rodent;Role;Series;Staining method;Stains;Stress;Synapses;Testing;Therapeutic;Time;Toxic effect;Trauma;Traumatic Brain Injury;Tree Bark;United States;Work;clinical care;cohort;cytokine;disability;fluoro jade;global health;long term hospitalization;macrophage;neurobehavioral;neuroinflammation;novel strategies;polyphenol;public health relevance;research study;response

public_health_relevance:
The proposed studies investigate a specialized compound called a bioflavonoid todetermine if it can help protect cells in the brain following injury. Using a wellcharacterized animal model of traumatic brain injury subjects are treated with thecompound Pycnogenol(R) and tested for a variety of outcome measures. Bioflavonoids areknown to manifest multiple different helpful properties such as reducing oxidative stress. Ifthe studies work then more complex and longer term studies can be proposed hopefullyleading to a more rational therapy for brain injury.


application_id: 7942730
project_number: 5RC2AA019385-02
project_title: Biomarkers for Steatohepatitis
administering_ic: NIAAA
award_notice_date: 2010-08-19
opportunity_number: RFA-OD-09-004
application_type: 5
activity_code: RC2
ic: AA
serial_number: 019385
program_official: RADAEVA, SVETLANA
project_start_date: 2009-09-30
project_end_date: 2012-08-31
study_section: ZAA1-GG(02)R
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: Y
project_abstract:
DESCRIPTION (provided by applicant): Alcoholic Liver Disease (ALD) remains a major cause of alcohol-related morbidity and mortality. 15-30% of heavy drinkers develop advanced ALD over 25000 deaths occur annually related to liver disease and over 40% of those are attributed to alcoholic cirrhosis. Major advances have been made in our understanding of mechanisms of ALD especially related to oxidative stress cytokines mitochondrial dysfunction and adduct formation. However there is no FDA-approved therapy for alcoholic hepatitis or cirrhosis and our understanding concerning disease pathogenesis remains incomplete. The emergence of the obesity epidemic (non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) as the hepatic manifestations of the metabolic syndrome) has provided new insights into mechanisms of liver injury. The "two-hit" theory for NASH that a baseline of fatty liver plus one of multiple second "hits" initiates the progression from steatosis to more serious liver injury steatohepatitis. Similarly most patients who drink heavily develop steatosis but only a few develop steatohepatitis and similar mechanisms or "hits" for disease progression to alcoholic steatohepatitis (ASH) have been postulated. Lastly we have recently reported that environmental toxicants (TASH) can produce steatohepatitis indistinguishable histologically from that produced by obesity or alcohol. We are in a unique situation to utilize a proteomics/ metabolomics approach for discovery of biomarkers for alcoholic liver disease and specifically alcoholic steatohepatitis. We have a one-of-a-kind database/repository in which we have a large number of serum/plasma specimens from well-characterized patients with severe alcoholic hepatitis well-characterized NASH and a highly-novel patient population of well-characterized TASH. Thus we will be able to compare/ contrast the proteomics/metabolomics signatures in specimens from well-characterized patients with diverse steatohepatitis. We will also compare the results from the human ASH studies with experimental ASH samples from our ULARC rodent repository. Specific Aims of this proposal address the following 3 questions: 1) Are there biomarkers determined by proteomics/metabolomics that are common to ASH NASH and TASH that indicate mechanistic commonalities in steatohepatitis?; 2) Are there unique biomarkers for ASH compared with NASH/TASH?; and 3) Are there biomarkers for ASH that predict prognosis/outcomes?  
  
PUBLIC HEALTH RELEVANCE: The Research Area explored in this proposal is "Molecular Markers of Alcohol Exposure and Alcohol-Induced Tissue Injury". We postulate that there are metabolic pathways and biomarkers that can be defined by proteomics and metabolomics that are common to Alcoholic Steatohepatitis (ASH) Non-Alcoholic Steatohepatitis (NASH) and Toxicant Associated Steatohepatitis (TASH). Furthermore we predict that ASH may have unique biomarkers/metabolic pathways and differences may be seen in patients who resolve their disease compared to those who are having ongoing injury or die.

project_terms:
Address;Alcoholic Hepatitis;Alcoholic Liver Cirrhosis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Animal Model;Area;Arts;Cessation of life;Cirrhosis;Classification;Clinical;Databases;Disease;Disease Progression;Epidemic;Ethanol;FDA approved;Family;Fatty Liver;Funding;Heavy Drinking;Hepatic;Histologic;Human;Hyperlipidemia;Hypertension;Individual;Injury;Institutes;Insulin Resistance;Interdisciplinary Study;Knowledge;Label;Lead;Liver;Liver diseases;Metabolic Pathway;Metabolic syndrome;Morbidity - disease rate;Mortality Vital Statistics;National Institute on Alcohol Abuse and Alcoholism;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Operative Surgical Procedures;Outcome;Oxidative Stress;Pathogenesis;Patients;Pharmaceutical Preparations;Plasma;Proteomics;Reporting;Research;Rodent;Sampling;Specimen;Steatohepatitis;Stigmata;Tamoxifen;Techniques;Tissues;Toxic Environmental Substances;Translational Research;United States National Institutes of Health;Universities;Vinyl Chloride;adduct;alcohol exposure;alcohol research;biobank;biomarker;cytokine;insight;metabolomics;mitochondrial dysfunction;molecular marker;multidisciplinary;non-alcoholic fatty liver;nonalcoholic steatohepatitis;novel;nutrition;outcome forecast;patient population;problem drinker;public health relevance;repository;social stigma;theories;toxicant

public_health_relevance:
The Research Area explored in this proposal is "Molecular Markers of Alcohol Exposureand Alcohol-Induced Tissue Injury". We postulate that there are metabolic pathwaysand biomarkers that can be defined by proteomics and metabolomics that are commonto Alcoholic Steatohepatitis (ASH) Non-Alcoholic Steatohepatitis (NASH) and ToxicantAssociated Steatohepatitis (TASH). Furthermore we predict that ASH may have uniquebiomarkers/metabolic pathways and differences may be seen in patients who resolvetheir disease compared to those who are having ongoing injury or die.


application_id: 7941974
project_number: 5R01AI078756-04
project_title: IFN-gamma production by microglia for prevention of toxoplasmic encephalitis
administering_ic: NIAID
award_notice_date: 2010-06-03
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AI
serial_number: 078756
program_official: WALI, TONU M
project_start_date: 2008-07-03
project_end_date: 2013-06-30
study_section: AIDS-associated Opportunistic Infections and Cancer Study Section[AOIC]
contact_pi_person_id: 1882071
contact_pi: SUZUKI, YASUHIRO
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): Reactivation of chronic Toxoplasma gondii infection in the brains of immunocompromised individuals results in the development of life-threatening toxoplasmic encephalitis (TE). To improve prevention and management of TE it is important to understand the immunopathogenesis of the disease. The murine models of TE that we developed provide an excellent opportunity to critically analyze the mechanisms of host defense in the brain. It is well documented that T cells recruited into the brain are an essential source of IFN-3 for prevention of TE. However it is not known how the host defense functions during the early stage of reactivation of infection before large numbers of T cells enter the brain. This early defense system could be crucial for limiting tachyzoite growth and initiating T cell immunity to prevent TE. We recently found that microglia which are resident macrophages in the brain parenchyma produce IFN-3 during the early stage of reactivation. Our studies also suggest that production of IFN-3 by brain-specific cells in addition to T cells is required for prevention of TE. Therefore IFN-3 production by microglia appears to be a novel early defense mechanism essential for prevention of the disease. The specific aims in this proposal are designed to define the role of IFN-3 produced by microglia in inhibition of tachyzoites growth induction of T cell immunity and prevention of TE. In the first aim we will examine the inhibitory effects of IFN-3 produced by microglia on tachyzoite proliferation in the brain after reactivation of infection using mice that have IFN-3 production only by microglia. The second aim is to determine if IFN-3 production by microglia induces expression of mediators that recruit T cells into the brain. We will examine whether IFN-3 production by microglia induces expression of chemokines in brain cells and adhesion molecules on cerebrovascular endothelial cells. We will then use in vivo T cell migration assays to determine whether IFN-3 production by microglia facilitates infiltration of immune T cells into the brain. The third aim is to determine if IFN-3 production by microglia induces expression of MHC molecules for activation of T cells in the brain. In the fourth aim we will determine the requirement of IFN-3 production by microglia and T cells for prevention of TE. For this purpose we will purify immune T cells from infected wild-type or IFN-3-deficient mice and transfer these T cells into infected mice that express IFN-3 only by microglia or lack expression of this cytokine. Host mice will be followed for development of TE. We will also examine the role of IFN-3-dependent mediators of T cell recruitment determined in Specific Aim 2 for prevention of TE. The studies in these four specific aims will provide novel and crucial information that allows us to understand how IFN-3-production by microglia enables the host defense system in the brain to prevent TE. PUBLIC HEALTH RELEVANCE Reactivation of chronic Toxoplasma gondii infection in the brains of immunocompromised individuals results in the development of life-threatening toxoplasmic encephalitis (TE). The proposed studies are to analyze how brain cells (microglia) inhibit parasite growth and induce the immune responses to prevent TE. This information will contribute to better understanding of the immunopathogenesis of TE and to improved prevention and management of the disease.

project_terms:
Acquired Immunodeficiency Syndrome;Address;Antigen Presentation;Brain;Cell Adhesion Molecules;Cells;Chronic;Defense Mechanisms;Development;Disease;Disease Management;Encephalitis;Endothelial Cells;Goals;Growth;Host Defense;Host Defense Mechanism;Immune;Immune response;Immunity;Immunocompromised Host;Individual;Infection;Infiltration;Interferon Type II;Life;MHC Class I Genes;Mediator of activation protein;Microglia;Migration Assay;Modeling;Molecular;Mus;Neuroglia;Neurons;Organ;Parasites;Play;Prevention;Production;Recruitment Activity;Role;Source;Staging;System;T cell response;T-Cell Activation;T-Lymphocyte;Toxoplasma gondii;Toxoplasmosis;brain cell;cerebrovascular;chemokine;cytokine;design;disorder prevention;immune activation;improved;in vivo;macrophage;novel;prevent;public health relevance;response


application_id: 7941893
project_number: 5R01CA150947-02
project_title: Mechanisms of Immune Modulation Mediated by Yeast-derived Particulate Beta-Glucan
administering_ic: NCI
award_notice_date: 2010-07-08
opportunity_number: RFA-AT-08-003
application_type: 5
activity_code: R01
ic: CA
serial_number: 150947
program_official: KIM, YOUNG S
project_start_date: 2009-09-28
project_end_date: 2013-07-31
study_section: ZAT1-SM(13)
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The use of -glucans in complementary and alternative medicine (CAM) has prevailed for centuries in traditional Asian medicine. However their clinical use against malignancies in Western medicine has experienced an oscillating success due to a lack of understanding in their exact mechanisms of action. We have previously demonstrated that soluble yeast -glucan of low molecular weight is capable of binding to the lectin site of complement receptor 3 (CR3 CD11b/CD18) and priming CR3+ effector cells for cytotoxicity of iC3b-opsonized tumor cells. The work presented here shows that particulate yeast -glucan has more unique features than soluble -glucan. The objective of the proposed study is to elucidate the cellular and molecular mechanisms of action for particulate -glucan in tumor immunotherapy.   
Preliminary studies demonstrated that particulate -glucan not soluble -glucan stimulated macrophages and dendritic cells (DCs) for activation and proinflammatory cytokine production. Furthermore orally administered particulate -glucan stimulated DCs that captured apoptotic tumor cells for activation and maturation leading to the enhanced anti-tumor CD4 and CD8 T cell responses. Strikingly oral particulate -glucan treatment altered the tumor microenvironment toward Th1 response. Particulate -glucan was also shown to activate the complement system via an alternative pathway leading to C5a deposition on tumors. These preliminary data provide a strong basis for the current study.   
Aim 1 will dissect which signaling pathway(s) may be critical for particulate -glucan-mediated DC activation and cytokine release. Toll-like receptor pathway MyD-88- and TRIF-deficient mice CR3-deficient mice and dectin-1 pathway dectin-1- and CARD9-deficient mice will be used to address this issue. In addition T cell differentiation (Th1 Th2 and Th17) in the presence of particulate yeast -glucan stimulated DCs will be examined both in vitro and in vivo. Aim 2 will test the hypothesis that particulate -glucan modulates suppressive cells existing in the tumor microenvironment thereby promoting Th1 response. The function of myeloid-derived suppressive cells (MDSCs) dynamic interaction between regulatory T cells (Treg) and Th17 cells cross-talk between MDSCs and tumor-infiltrating macrophages will be examined. Lewis lung carcinoma transfected with surrogate antigen ovalbumin and tumor-associated antigen MUC1 will be used as the model systems to address those issues. Aim 3 will test the hypothesis that particulate -glucan stimulated complement activation may be partially contributed to the enhanced anti-tumor T cell responses. Furthermore the requirement for C3a and/or C5a and their receptors C3aR and C5aR as modulators of anti-tumor T cell responses will be determined. Further knowledge of the mechanisms involved in these effects of particulate -glucan will be of great value in the design of effective clinical applications.  
  
Public Health Relevance: This study will elucidate the cellular and molecular mechanisms of action of particulate yeast -glucan in tumor immunotherapy. The data generated in this study will allow for the rational design of immunotherapeutic protocols usable in clinical trials.

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

public_health_relevance:
Project NarrativeThis study will elucidate the cellular and molecular mechanisms of action of particulate yeast -glucan in tumor immunotherapy. The data generated in this study will allow for the rationaldesign of immunotherapeutic protocols usable in clinical trials.


application_id: 7941835
project_number: 5P20RR020145-07
project_title: Center for the Biologic Basis of Oral/Systemic Disease (CBBOSD)
administering_ic: NCRR
award_notice_date: 2010-09-10
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
program_official: DOUTHARD, REGINE
project_start_date: 2004-09-23
project_end_date: 2014-07-31
study_section: ZRR1-RI-B(01)
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute Disease;Address;Advanced Glycosylation End Products;Aging;Aging-Related Process;Bacterial Infections;Biochemical;Bioinformatics;Biological;Biometry;Cardiovascular system;Cells;Chronic;Clinical;Clinical Research;Clinical Trials;Communication;Complex;Coupled;Culture Techniques;Data;Dental;Dental Plaque;Dental caries;Dentistry;Development;Diabetes Mellitus;Diagnosis;Diagnostic;Discipline;Discipline of Nursing;Disease;Disease Progression;Documentation;Early Diagnosis;Ecology;Ensure;Epidemiologic Studies;Event;Faculty;Fibromyalgia;Focal Infection;Food Webs;Funding;Gene Expression Profile;Genetic;Genetic Structures;Genome;Goals;Grant;Growth;Health;Health Sciences;Immune response;Immunology;Individual;Infant;Inflammation;Inflammatory Bowel Diseases;Inflammatory Response;Institutes;Internet;Intervention;Intervention Studies;Intestines;Investigation;Investments;Kentucky;Link;Literature;Low Birth Weight Infant;Mediating;Medicine;Mentors;Methods;Microbial Biofilms;Microbiology;Molecular;Mouth Diseases;Mucous Membrane;National Institute of Dental and Craniofacial Research;Nature;Oral;Oral cavity;Oral health;Orofacial Pain;Osteoporosis;Pathogenesis;Patients;Periodontal Diseases;Periodontitis;Periodontium;Physiological;Physiology;Population;Population Group;Preventive;Process;Property;Proteome;Research;Research Design;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Research Training;Risk;Science;Scientist;Signal Transduction;Site;Specificity;Strategic Planning;Streptococcus mutans;Surface;System;Systemic disease;Temporomandibular Joint Disorders;Tissues;Translational Research;Underserved Population;Universities;Vagina;Validation;Viral;Virulence;Virus Diseases;Woman;base;biological adaptation to stress;biomarker;cerebrovascular;clinical practice;college;craniofacial;diabetes management;gene therapy;health disparity;improved;information gathering;infrastructure development;microbial;microorganism;new technology;novel strategies;novel therapeutic intervention;oral infection;oral tissue;prevent;programs;prospective;research clinical testing;response;success;tool;type I and type II diabetes


application_id: 7941739
project_number: 5R03CA144721-02
project_title: The Impact of Smoke-Free Policy on Quitline Utilization and Smoking Outcomes
administering_ic: NCI
award_notice_date: 2010-08-13
opportunity_number: PAR-09-003
application_type: 5
activity_code: R03
ic: CA
serial_number: 144721
program_official: DJORDJEVIC, MIRJANA V
project_start_date: 2009-09-30
project_end_date: 2011-08-31
study_section: ZCA1-SRLB-Y(O1)B
contact_pi_person_id: 2049426
contact_pi: FERNANDER, ANITA F.
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): Cigarette smoking produces substantial and staggering health and health-related economic costs to society. The Commonwealth of Kentucky (location of the applicant institution) ranks first in the nation in adult smoking prevalence (28.2%) and subsequently has one of the highest smoking attributable cancer incidence and death rates in the U.S. One of the Healthy People 2010 objectives is to reduce tobacco use among adults to 12% or less. Evidence demonstrates that telephone QuitLines are effective in helping tobacco users quit. The CDC as part of its Comprehensive Tobacco Control Initiative has suggested in addition to enacting smoke-free policies every state implement a publicly-accessible telephone QuitLine for tobacco users who want to quit. Since July 2005 Kentucky has implemented a free statewide evidence-based telephone QuitLine. To date no documented research has examined the efficacy of the telephone QuitLine in Kentucky nor examined the impact of enacting smoke-free policies on telephone QuitLine utilization reductions in smoking and smoking cessation rates. The proposed study is a quasi-experimental time-series design involving secondary data analyses on a large data set collected as part of the publicly-funded state-wide telephone QuitLine in Kentucky. The primary objective of the proposed investigation is to test the effects of the enactment of municipal smoke-free legislation/regulation on telephone QuitLine utilization rates average daily cigarette consumption and cessation rates among cigarette smokers in Kentucky who initiated state telephone QuitLine contact between July 2005 and June 2009. The analysis utilized will not only allow for comparisons between communities with and without these laws but also comparisons from pre- to post-law in communities that enacted laws during the study period. Implementation of comprehensive tobacco control programs including enacting policy change and providing cessation resources can reduce the prevalence of smoking and its associated cancer mortality and mortality. What is less clear is whether the enactment of smoke-free legislation influences state telephone QuitLine utilization and smoking behavior (including reductions in smoking and smoking cessation). Furthermore it is unclear whether the strength and extent of smoke-free policy law/regulation impacts smoking cessation efforts within particular communities. The proposed data set provides a unique opportunity to examine telephone QuitLine usage and cessation rates in communities that have enacted various strengths of smoke-free legislation/regulation and those that have not. Results of the proposed project will provide novel information about the impact of smoke free laws/regulations on telephone QuitLine utilization and smoking related outcomes. This information will assist in understanding how to guide the successful application promotion and dissemination of this evidence-based treatment with the goal of refining treatment and informing policy to ultimately reduce smoking-attributable cancer morbidity and mortality.  
  
PUBLIC HEALTH RELEVANCE: One of the Healthy People 2010 objectives is to reduce smoking among adults to 12% or less. Because evidence demonstrates that telephone QuitLines are effective in helping tobacco users quit the CDC as part of its Comprehensive Tobacco Control Initiative has suggested in addition to enacting smoke-free policies every state implement a publicly-accessible telephone QuitLine for tobacco users who want to quit. The proposed study provides a unique opportunity to test the effects of municipal smoke-free laws and regulations on telephone QuitLine utilization average daily cigarette consumption and cessation rates of smokers who utilize Kentucky's publicly-funded telephone QuitLine. The analysis utilized will not only allow for for comparisons between communities with and without these laws but also comparisons from pre- to post-law in communities that enacted laws during the study period. Results of the proposed project will provide novel information about the impact of smoke-free laws and regulations on telephone QuitLine utilization and smoking related outcomes. This information will assist in understanding how to guide the successful application promotion and dissemination of this evidence-based treatment with the goal of refining treatment and informing policy and ultimately decreasing smoking-attributable cancer morbidity and mortality.

project_terms:
Adult;Centers for Disease Control and Prevention (U.S.);Cigarette;Cigarette Smoker;Communities;Consumption;County;Data Analyses;Data Set;Death Rate;Evidence based treatment;Funding;Goals;Health;Healthy People 2010;Incidence;Institution;Intake;Intervention;Interview;Investigation;Kentucky;Laws;Life;Location;Malignant Neoplasms;Morbidity - disease rate;Mortality Vital Statistics;Outcome;Policies;Regulation;Research;Resources;Series;Smoke;Smoker;Smoking;Smoking Behavior;Societies;Statutes and Laws;Telephone;Testing;Time;Tobacco;cigarette smoking;design;economic cost;evidence base;novel;programs;public health relevance;quitline;reduce tobacco use;smoking cessation;smoking prevalence;tobacco control

public_health_relevance:
PROJECT NARRATIVE One of the Healthy People 2010 objectives is to reduce smoking among adults to 12% or less. Becauseevidence demonstrates that telephone QuitLines are effective in helping tobacco users quit the CDC as partof its Comprehensive Tobacco Control Initiative has suggested in addition to enacting smoke-free policiesevery state implement a publicly-accessible telephone QuitLine for tobacco users who want to quit. Theproposed study provides a unique opportunity to test the effects of municipal smoke-free laws and regulationson telephone QuitLine utilization average daily cigarette consumption and cessation rates of smokers whoutilize Kentucky's publicly-funded telephone QuitLine. The analysis utilized will not only allow for forcomparisons between communities with and without these laws but also comparisons from pre- to post-law incommunities that enacted laws during the study period. Results of the proposed project will provide novelinformation about the impact of smoke-free laws and regulations on telephone QuitLine utilization and smokingrelated outcomes. This information will assist in understanding how to guide the successful applicationpromotion and dissemination of this evidence-based treatment with the goal of refining treatment andinforming policy and ultimately decreasing smoking-attributable cancer morbidity and mortality.


application_id: 7941604
project_number: 1R01GM094155-01
project_title: Mechanism of Neuropilin Dependent Angiogenesis
administering_ic: NIGMS
award_notice_date: 2010-09-06
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: GM
serial_number: 094155
program_official: DUNSMORE, SARAH
project_start_date: 2010-09-06
project_end_date: 2015-06-30
study_section: Macromolecular Structure and Function C Study Section[MSFC]
contact_pi_person_id: 9627039
contact_pi: VANDER KOOI, CRAIG
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Angiogenesis the production of new blood vessels from existing vasculature is required for normal development wound repair and vascular homeostasis. Neuropilin is an essential mammalian cell surface receptor for one of the most potent pro-angiogenic molecules vascular endothelial growth factor (VEGF) and functions in synchrony with VEGFR receptor tyrosine kinases. Neuropilin is of particular medical importance because it is critical to the pathology of VEGF dependent hyper-vascularization in tumor angiogenesis.  We propose a series of parallel and complementary structural and functional studies to understand the physical interactions and receptor coupling at the heart of the VEGF signaling complex. Unlike many other kinase systems VEGF binding to VEGFR in the absence of neuropilin is insufficient to induce angiogenesis. We seek to first understand the molecular mechanism(s) underlying neuropilin's unique role in VEGF dependant angiogenesis. In Aim 1 we will determine the basis for competitive binding of ligands to neuropilin and the role that this competition plays in regulating angiogenesis. In Aim 2 we will explore the structural and conformational changes that neuropilin undergoes in its transition from inactive monomer to activated dimer. More globally we seek to define the physical basis for the coordinated action of VEGF neuropilin and VEGFR. Aim 3 is focused on utilizing multiple structural and biochemical tools coupled with endothelial cell signaling assays to determine the physical interactions and conformational changes necessary to couple extracellular ligand binding to receptor activation. Taken together these studies will provide a molecular understanding of the physical mechanisms underlying the critical first step connecting VEGF ligand binding to receptor activation.  
  
PUBLIC HEALTH RELEVANCE: Neuropilin is an essential receptor needed for the formation of new blood vessels. New blood vessels are critical during normal development and wound repair but also provide a tumor with critical nutrients for its growth. Understanding how neuropilin works in the formation of new blood vessels will help us understand how this pathway normally functions and how we can block its activity in tumors and related diseases.

project_terms:
Angiogenesis Inhibitors;Arginine;Binding (Molecular Function);Biochemical;Biological Assay;Blood Vessels;Breast;C-terminal;Cardiovascular system;Cell Surface Receptors;Competitive Binding;Complex;Coupled;Coupling;Development;Dimerization;Disease;Electron Microscopy;Endothelial Cells;Extracellular Structure;Family;Genus Cola;Goals;Growth;Growth Factor;Growth Factor Interaction;Heparin;Homeostasis;Ligand Binding;Ligands;Mammalian Cell;Mediating;Medical;Membrane;Molecular;Nature;Neuropilins;Nutrient;Pathology;Pathway interactions;Peptide Hydrolases;Phosphotransferases;Pituitary Gland;Play;Production;Prostate;Proteolytic Processing;Publishing;Receptor Activation;Receptor Protein-Tyrosine Kinases;Resolution;Role;Series;Signal Pathway;Signal Transduction;Solid Neoplasm;Structure;System;Techniques;Tumor Angiogenesis;Vascular Endothelial Growth Factor Receptor;Vascular Endothelial Growth Factors;Vascularization;Work;Wound Healing;angiogenesis;antiangiogenesis therapy;axon guidance;base;cytokine;dimer;extracellular;glucosaminoglycans;member;monomer;novel;public health relevance;receptor;receptor coupling;tool;tumor

public_health_relevance:
Neuropilin is an essential receptor needed for the formation of new blood vessels. New blood vessels arecritical during normal development and wound repair but also provide a tumor with critical nutrients for itsgrowth. Understanding how neuropilin works in the formation of new blood vessels will help us understandhow this pathway normally functions and how we can block its activity in tumors and related diseases.


application_id: 7940986
project_number: 5R01HD065279-02
project_title: Gross morphological correlates to the minicolumnopathy of autism
administering_ic: NICHD
award_notice_date: 2010-08-23
opportunity_number: RFA-MH-09-170
application_type: 5
activity_code: R01
ic: HD
serial_number: 065279
program_official: KAU, ALICE S
project_start_date: 2009-09-30
project_end_date: 2011-11-30
study_section: ZMH1-ERB-B(A1)
contact_pi_person_id: 1905047
contact_pi: CASANOVA, MANUEL F
other_pis: Not Applicable
congressional_district: 03
department: PSYCHIATRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): The minicolumn is a basic anatomical and physiological element of the mammalian cerebral cortex comprising a linear array of pyramidal cell bodies their projections and accompanying GABAergic interneurons. Postmortem studies of the organization of pyramidal cell arrays in autism have revealed that minicolumns in the brains of autistic patients are narrower. Since the minicolumn re-iterates itself millions of times throughout the brain variations in the total number and width of minicolumns may result in macroscopic changes to the brain's surface area folding (gyrification) and white matter pathways linking regional networks of minicolumns. In effect data derived from comparative anatomy studies indicates that minicolumnar findings if generalized have specific gross correlates that can be detected by MRI. These changes include alterations in the gyral window gray/white matter ratio parcellation of the white matter and size of the corpus callosum.  This grant proposes studying a unique series of cases (n = 58) derived from the Autism Tissue Program (ATP). All of the cases included in this study had clinical documentation and a postmortem MRI. Autism was diagnosed according to DSM-IV-TR and ADI-R criteria. There are three specific aims to our study: 1) To quantify and compare the radial structure of dendritic bundles in the cerebral cortex of postmortem autistic patients and controls 2) To determine the correlation between minicolumnar structure defined by fiber bundles and white matter distribution in the brains of postmortem autistic patients and controls and 3) To perform a cluster analysis of autism diagnostic criteria and morphometric measurements. Specific aim 3 is an exploratory study that will attempt to provide construct validity to a current diagnostic scheme (ADI-R) by correlating clinical parameters to obtained neuropathological/neuroimaging data. All of the aims are in-keeping with the research objectives of the applied request for applications (RFA-MH-09-170).  In order to achieve our specific aims the proposed study will correlate anthropometric indices (MRI) to specific minicolumnar parameters. Postmortem data will be derived from the analysis of apical dendritic bundles in nine cortical areas that display varying degrees of cytoarchitectural differentiation: paralimbic high- order (hetermodal) association modality-specific (unimodal) association and idiotypic areas (primary sensory/motor cortices) (BA 4 9 10 17 21 22 33 39 and 40). Other areas i.e. corticoid and all cortical formations were not included in our sampling scheme due to their lack of minicolumnar organization. The analysis of specific minicolumnar compartments will allow us to screen a series of anatomical elements incriminated in previous studies i.e. minicolumnar narrowing most prominently in the peripheral neuropil space. Preliminary findings suggest: 1) high predictive ability between macro- and microscopic parameters and 2) a high degree of diagnostic (autism) selectivity when combining the different anthropometric indices espoused in this grant proposal.  
  
PUBLIC HEALTH RELEVANCE: This project attempts to establish a correlation between autopsy and neuroimaging findings in autism. The intent is to develop markers of the condition that can be detected while the patient is alive. Another innovative aspect of the proposal is an attempt to validate current diagnostic screening techniques against autopsy findings.

project_terms:
Accounting;Adrenal Cortex Hormones;Affect;Age;Algorithms;Apical;Applications Grants;Area;Autistic Disorder;Autopsy;Award;Behavior;Body Image;Body Size;Brain;Case Series;Celloidin;Cells;Cerebral cortex;Clinical;Cluster Analysis;Code;Cognitive;Comparative Anatomy;Controlled Study;Corpus Callosum;Data;Development;Diagnosis;Diagnostic;Disease;Documentation;Electroencephalography;Elements;Evolution;Fiber;Grant;Gray unit of radiation dose;Homologous Gene;Image;Interneurons;Interview;Left;Link;Magnetic Resonance Imaging;Measurement;Measures;Microscopic;Modality;Morphologic artifacts;Morphology;Motor Cortex;Neocortex;Neurons;Neuropil;Pathology;Pathway interactions;Patients;Peripheral;Physiological;Primates;Process;Pyramidal Cells;Radial;Reporting;Request for Applications;Research;Research Personnel;Rodent;Sampling;Scheme;Screening procedure;Sensory;Series;Severities;Shapes;Specimen;Staining method;Stains;Structure;Surface;Symptoms;Synapses;Syndrome;Techniques;Testing;Time;Tissues;Trees;Variant;Width;Wit;area striata;base;brain size;cell body (neuron);comparative;endophenotype;falls;imaging modality;in vivo;indexing;innovation;morphometry;neuroimaging;programs;public health relevance;sex;white matter

public_health_relevance:
This project attempts to establish a correlation between autopsy and neuroimaging findings in autism. Theintent is to develop markers of the condition that can be detected while the patient is alive. Another innovativeaspect of the proposal is an attempt to validate current diagnostic screening techniques against autopsyfindings.


application_id: 7940859
project_number: 5F31CA139956-02
project_title: Cigarette Smoking among Head and Neck Cancer Patients: A Prospective Study
administering_ic: NCI
award_notice_date: 2010-08-13
opportunity_number: PA-07-106
application_type: 5
activity_code: F31
ic: CA
serial_number: 139956
program_official: BINI, ALESSANDRA M
project_start_date: 2009-09-01
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZRG1-RPHB-K(29)L]
contact_pi_person_id: 9524802
contact_pi: BURRIS, JESSICA L
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Behavioral research with head and neck squamous cell carcinoma (HNSCC) patients is high priority. The etiology of HNSCC is linked to the health risk behaviors of tobacco and alcohol consumption. At diagnosis prevalence rates for cigarette smoking and alcohol use have been estimated to be above 80% and 65% respectively. Among patients who report cigarette smoking in the year preceding diagnosis about one-third continue to smoke following completion of cancer treatment. So while HNSCC diagnosis may be considered a "teachable moment" in which motivation for health behavior change is theorized to be high not all patients regard HNSCC diagnosis as a sufficient catalyst for cigarette smoking cessation. Notably this is despite the fact that continued cigarette smoking is associated with poor clinical outcomes including poorer treatment response and higher risk for recurrence. Researchers have made attempts to identify variables associated with cigarette smoking after HNSCC diagnosis but the current literature is limited. The overall objective of the proposed project is to increase understanding of factors facilitating and impeding smoking cessation among patients recently diagnosed with HNSCC. Specific aims: (1) To characterize the trajectory of cigarette smoking from the time of HNSCC diagnosis to 6 months following initiation of cancer treatment (2) To assess the utility of Ajzen's Theory of Planned Behavior (TPB) for understanding changes in HNSCC patients' cigarette smoking and (3) To assess the independent contribution of depressive symptoms and concurrent alcohol use for understanding changes in HNSCC patients' cigarette smoking. The above aims will be achieved using a prospective longitudinal design in which 120 HNSCC patients are assessed before treatment initiation and then 2 and 6 months after treatment initiation. Males and females will be included in the study and the demographic characteristics of participants are expected to reflect the population of Kentucky. At each assessment data will be collected via telephone interview. Study hypotheses will be tested using McNemar tests of paired comparisons binomial logistic regression and linear multiple regression analyses. Study results have the potential to highlight the importance of integrating discussions of behavior change into the course of cancer treatment and may inform health personnel and behavioral science researchers of significant risk factors for cigarette smoking following HNSCC diagnosis. Results of the project may also be helpful in developing more efficacious smoking cessation interventions for HNSCC patients.  PUBLIC HEALTH RELEVANCE: Overall the proposed research is important because of its emphasis on understanding factors related to the reduction health risk behaviors and associated improvement in clinical outcomes.

project_terms:
Aftercare;Alcohol consumption;Attitude;Behavior;Behavior Control;Behavioral;Behavioral Research;Behavioral Sciences;Characteristics;Clinical;Data;Diagnosis;Etiology;Event;Female;Future;Head and Neck Squamous Cell Carcinoma;Health;Health Personnel;Health behavior change;Individual;Intention;Kentucky;Link;Literature;Logistic Regressions;Mental Health;Motivation;Outcome;Paired Comparison;Participant;Patients;Planning Theory;Population;Prevalence;Prospective Studies;Recurrence;Regression Analysis;Reporting;Research;Research Personnel;Risk Behaviors;Risk Factors;Smoke;Smoking Cessation Intervention;Specific qualifier value;Telephone Interviews;Testing;Time;Tobacco;behavior change;cancer therapy;catalyst;cigarette smoking;depressive symptoms;experience;follow-up;head and neck cancer patient;high risk;longitudinal design;male;prospective;public health relevance;smoking cessation;treatment response


application_id: 7940849
project_number: 5RC1ES018636-02
project_title: Clock genes environmental challenges and cardiopulmonary disease
administering_ic: NIEHS
award_notice_date: 2010-07-23
opportunity_number: RFA-OD-09-003
application_type: 5
activity_code: RC1
ic: ES
serial_number: 018636
program_official: NADADUR, SRIKANTH
project_start_date: 2009-09-27
project_end_date: 2012-07-31
study_section: Special Emphasis Panel[ZRG1-MOSS-C(58)R]
contact_pi_person_id: 8263548
contact_pi: ESSER, KARYN A
other_pis: ANDRADE, FRANCISCO H
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): This application addresses broad Challenge Area 15: Translational Science and specific Challenge Topic 15-ES-101: Effects of environmental exposures on phenotypic outcomes using non-human models. Approximately 8.6 million Americans perform shift work which is associated with increased risk of cardiovascular and cardiopulmonary diseases. Light pollution is one of the environmental conditions that is suggested to be a contributor to the increased pathologies in shift workers. In 2007 the NIEHS released a report on light pollution noting; "that the dramatic increases in chronic diseases in modern society maybe associated with the altered patterns of light and dark". One of the key physiological targets of altered patterns of environmental lighting is the circadian timing system. There is growing recognition that the increased pathologies seen in shift workers could arise from misalignment between the molecular circadian timing system within tissues/organs and the altered environmental time cue due to disrupted light exposure. The goal of the projects described in this Challenge Topic application will use targeted tissue specific disruption of a core circadian gene Bmal1 with controlled manipulation of environmental light cues to determine the interaction between genetic and environmental factors in the progression of cardiopulmonary disease. Analyses will include use of in vivo telemetry and echocardiography to provide longitudinal data on systemic disease progression. In addition experiments will be performed that will provide mechanistic insight using molecular cellular and biochemical approaches. The overall hypothesis for this project is that targeted deletion of Bmal1 in muscle tissues (heart or smooth or skeletal) will weaken the animal's ability to handle light pollution and will be associated with a more rapid and profound progression to cardiopulmonary diseases. This is a novel area of research for this team of established investigators in muscle biology and cardiopulmonary disease. Their combined expertise and prior history of successful collaboration in the areas of circadian rhythms cardiac smooth and skeletal muscle biology will allow for rapid progression on this high priority research area. At the end of this two-year project we are confident that will have obtained significant new data regarding the interaction between the molecular clock function in cardiopulmonary tissues and environmental light challenges and their contribution to disease progression. Approximately 8.6 million Americans perform shift work which is associated with increased risk of cardiovascular and cardiopulmonary diseases. As reported in 2007 by NIEHS light pollution is one of the environmental conditions that is suggested to be a contributor to the increased pathologies in shift workers. The goal of the projects in this application will determine the interaction between altered circadian genes with environmental factors in the progression of cardiopulmonary disease.

project_terms:
Actins;Address;Adult;Age;American;Animals;Aorta;Area;Biochemical;Biology;Blood Pressure;Body Temperature;Breeding;Cardiac;Cardiopulmonary;Cell Count;Cell Size;Chronic;Chronic Disease;Circadian Rhythms;Collaborations;Collection;Cor pulmonale;Core Protein;Cues;Data;Diaphragm (Anatomy);Disease Progression;Echocardiography;Environmental Exposure;Environmental Risk Factor;Exhibits;Exposure to;Fatigue;Feedback;Freezing;Gene Proteins;Genes;Genetic;Genetic Transcription;Germ Lines;Goals;Health Personnel;Heart;Heart Rate;Heart Ventricle;Human;Industrial Health;Jet Lag Syndrome;Kentucky;Laboratories;Light;Lighting;Mechanics;Mining;Mitochondria;Modeling;Molecular;Mus;Muscle;Muscle function;Mutant Strains Mice;Myocardial tissue;National Institute of Environmental Health Sciences;Occupations;Organ;Outcome;Oxidants;Pathology;Pattern;Phase;Physiological;Pollution;Recording of previous events;Reporting;Research;Research Personnel;Research Priority;Skeletal muscle structure;Smooth muscle (tissue);Societies;Structure;System;Systemic disease;Telemetry;Testing;Time;Tissues;Translational Research;Translations;Travel;cardiovascular risk factor;cell type;cryptochrome;in vivo;insight;loss of function;mouse Cre recombinase;novel;research study;response;shift work;skeletal

public_health_relevance:
PROJECT NARRATIVE Approximately 8.6 million Americans perform shift work which is associated with increased risk ofcardiovascular and cardiopulmonary diseases. As reported in 2007 by NIEHS light pollution is one of theenvironmental conditions that is suggested to be a contributor to the increased pathologies in shift workers.The goal of the projects in this application will determine the interaction between altered circadian genes withenvironmental factors in the progression of cardiopulmonary disease.


application_id: 7939776
project_number: 5R01ES017274-02
project_title: Role of Retroelements in Environmental Atherogenesis
administering_ic: NIEHS
award_notice_date: 2010-06-28
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: ES
serial_number: 017274
program_official: NADADUR, SRIKANTH
project_start_date: 2009-09-26
project_end_date: 2012-06-30
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)S]
contact_pi_person_id: 8146758
contact_pi: LI, YONG
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: Y
project_abstract:
DESCRIPTION (provided by applicant): Atherosclerosis the leading cause of morbidity and mortality in industrialized nations is a fibro-proliferative disease associated with endothelial injury recruitment of inflammatory cells (macrophages and T cells) expansion of vascular smooth muscle cells (vSMCs) and buildup of cholesterol and extracellular matrix within the inner lining of arteries. Clinical disease results from occlusion of vessels that feed the heart brain or extremities. The early stages of atherosclerosis (atherogenesis) involve inflammatory injury to the vessel wall infiltration of macrophages and uncontrolled proliferation of vSMCs. Oxidative injury to the vessel wall is a common denominator of the atherogenic response with elevated levels of blood cholesterol high blood pressure diabetes and smoking recognized as primary risk factors. Chronic exposures to air particulates and chemicals associated with particulate matter such as polycyclic aromatic hydrocarbons have been associated with development or exacerbation of atherosclerosis in rodents and primates. Of relevance are the biological effects of benzo(a)pyrene (BaP) a carcinogen present in various forms of pollution and metabolized by cytochromes P450 to intermediates that damage DNA and cause oxidative stress. Repeated exposure of vSMCs to BaP in vivo or in vitro induces atherosclerotic changes within the vascular wall. The molecular mechanisms responsible for BaP atherogenesis involve transcriptional deregulation of gene expression and DNA damage. Of interest are responses involving activation of the c-Ha-ras gene and long interspersed nuclear elements (LINE 1 or L1) in human and murine vSMCs. L1s have emerged as interesting genomic targets in environmental atherogenesis since members of this family modify genetic programs in somatic cells through a "copy and paste" mechanism involving RNA intermediates reverse transcriptase and endonuclease. To continue previous investigations studies are proposed in this application to evaluate the expression of L1 during the course of atherosclerotic disease progression in the Apoetm1Unc mouse model to evaluate the impact of vascular specific expression of L1 on atherosclerotic lesion occurrence and severity and to elucidate molecular mechanisms of L1 activation in vSMCs and macrophages two of the principal cell types in atherosclerosis. The central hypothesis to be tested is that progression of plaque formation is associated with L1 overexpression and genomic instability in cells within the atherosclerotic plaque. Further it is hypothesized that L1 activation is mediated via epigenetic mechanisms that increase promoter activity and RNA polymerase II efficiency. These studies are the first to systematically examine the role of L1 and retrotransposition in diseases of the vascular wall. PUBLIC HEALTH RELEVANCE: Atherosclerosis continues to be responsible for most cases of cardiovascular mortality in the US. Recent studies have shown that the incidence of this disease is accelerated by environmental contaminants but the genetic mechanisms that mediate this relationship are not fully understood. Studies are proposed in this application to study the role of virus-like sequences in the onset and progression of environmentally-induced atherosclerosis in experimental systems.

project_terms:
Actins;Address;Air;Area;Aromatic Polycyclic Hydrocarbons;Arterial Fatty Streak;Arteries;Atherosclerosis;Benzo(a)pyrene;Biological;Blood;Blood Vessels;Brain;Carcinogens;Cardiovascular system;Cell Line;Cells;Chemicals;Chickens;Cholesterol;Chronic;Clinical;Code;Colon;Cytochrome P450;Cytomegalovirus;DNA Damage;Developed Countries;Development;Diabetes Mellitus;Disease;Disease Progression;Enhancers;Environmental Pollution;Epigenetic Process;Excision;Exposure to;Extracellular Matrix;Family member;Gene Expression;Genes;Genetic;Genetic Programming;Genomic Instability;Genomics;Goals;Heart;Human;Hydrocarbons;Hypertension;In Vitro;Incidence;Infiltration;Inflammatory;Injury;Investigation;Kidney;L1 Elements;Laboratories;Lesion;Limb structure;Liver;Mediating;Metabolism;Molecular;Molecular Target;Monitor;Morbidity - disease rate;Mortality Vital Statistics;Mus;Names;Nature;Nuclear;Nucleic Acid Regulatory Sequences;Onset of illness;Organ;Oxidation-Reduction;Oxidative Stress;Pancreas;Particulate;Particulate Matter;Paste substance;Pattern;Phenotype;Pollution;Primates;Promotor (Genetics);Proteins;RNA;RNA Polymerase II;RNA-Directed DNA Polymerase;Recommendation;Research;Retroelements;Retrotransposition;Risk Factors;Rodent;Role;Severities;Signal Transduction;Smoking;Smooth Muscle Myocytes;Somatic Cell;Specificity;Staging;System;T-Lymphocyte;Tail;Testing;Testis;Tissues;Tobacco smoke;Transcript;Transcriptional Activation;Transgenes;Transgenic Mice;Up-Regulation (Physiology);Vascular Diseases;Virus;atherogenesis;base;c-Ha-ras Gene;cell type;cis acting element;endonuclease;environmental chemical;feeding;in vivo;interest;macrophage;mouse model;overexpression;public health relevance;recombinase;research study;response;unpublished works;vascular smooth muscle cell proliferation

public_health_relevance:
Atherosclerosis continues to be responsible for most cases of cardiovascular mortality inthe US. Recent studies have shown that the incidence of this disease is accelerated byenvironmental contaminants but the genetic mechanisms that mediate this relationshipare not fully understood. Studies are proposed in this application to study the role ofvirus-like sequences in the onset and progression of environmentally-inducedatherosclerosis in experimental systems.


application_id: 7939773
project_number: 5P30HL101300-02
project_title: Biomedical Research Core Center (P30) on Fetal Programming
administering_ic: NHLBI
award_notice_date: 2010-08-10
opportunity_number: RFA-OD-09-005
application_type: 5
activity_code: P30
ic: HL
serial_number: 101300
program_official: CARLSON, DREW E
project_start_date: 2009-09-30
project_end_date: 2013-08-31
study_section: ZHL1-CSR-E(O1)
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): This is a NIH P30 Biomedical Research Core Center Application (RFA-OD-09-005) on Fetal Programming in the Development of Obesity-induced Cardiovascular Diseases. The request is for support of salary and start-up costs for recruit of one new investigator for appointment within the Graduate Center for Nutritional Sciences (GCNS) a multidisciplinary research and graduate program within the College of Medicine. The research area of fetal programming through dietary manipulation as a mechanism promoting obesity and cardiovascular disease in adult offspring will complement and extend an NIH funded Center of Biomedical Research Excellence (COBRE) on obesity and cardiovascular diseases. Specialized research cores extensive University Core Facilities and established mentoring mechanisms are in place to promote development of an independent research program towards R01 competitiveness within the research area. The new faculty recruit will be assigned dedicated research space within the highly collaborative environment of the GCNS with availability to common use equipment and specialized cores for analytical measurements tissue pathology radiotelemetry measurement of blood pressure and whole body metabolism in mice. The targeted research area complements and extends studies currently focused on identification of mechanisms linking diet-induced obesity in adults in the development of cardiovascular disease. In this sister P30 Center new faculty recruits will examine effects of fetal programming through dietary manipulation during pregnancy on the development of obesity and cardiovascular diseases in adult offspring. Given the increasing prevalence of obesity in the US it is important to identify the impact of maternal obesity through consumption of a western diet on disease development in offspring. Moreover these sister Centers span the breadth of current research by contrasting effects of obesity during development from adult onset obesity-induced cardiovascular disease. We will use our existing strengths in mentoring and our focused research cores within the defined area of study to assure that new investigators develop independent research programs of clinical significance to the missions of NIH HLBI.

project_terms:
Adult;Adult Children;Appointment;Area;Biomedical Research;Blood Pressure;Cardiovascular Diseases;Centers of Research Excellence;Child;Complement;Consumption;Core Facility;Development;Diet;Disease;Environment;Equipment;Faculty;Fetus;Funding;Interdisciplinary Study;Link;Measurement;Medicine;Mentors;Metabolism;Mission;Mus;Obesity;Pathology;Pregnancy;Prevalence;Recruitment Activity;Research;Research Personnel;Sister;Societies;Stimulus;Targeted Research;Tissues;United States National Institutes of Health;Universities;Wages;Woman;clinically significant;college;cost;fetal programming;member;nutrition;offspring;programs;ranpirnase;tool

public_health_relevance:
Over 29% of child-bearing women in the US are obese. This means that the fetus is frequently exposed to
dietary stimuli including the western diet consumed by our society during development. This proposal will
hire a faculty member and provide them with the tools to establish a competitive research program in
understanding the impact of dietary stimuli during pregnancy on obesity and cardiovascular diseases of
adults.


application_id: 7939704
project_number: 5R01HL096508-02
project_title: Oxidant Stress: Is it a biomarker of disease progression and response to therapy
administering_ic: NHLBI
award_notice_date: 2010-05-27
opportunity_number: RFA-HL-08-001
application_type: 5
activity_code: R01
ic: HL
serial_number: 096508
program_official: REYNOLDS, HERBERT Y
project_start_date: 2009-09-25
project_end_date: 2013-05-31
study_section: ZHL1-CSR-G(F1)
contact_pi_person_id: 1876531
contact_pi: ROMAN, JESSE
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
  
Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal disease that affects thousands of Americans for which no effective treatments are available. Several studies have demonstrated decreased levels of anti- oxidants in patients with IPF and anti-oxidant strategies seem effective in animal models of lung fibrosis. Consequently the use of anti-oxidants for the treatment of IPF has been proposed. However this approach is considered highly controversial because the role of oxidant stress in the pathogenesis of IPF is not clearly established and it is unclear whether currently available anti-oxidant strategies are capable of restoring normal redox potential in IPF patients. The IPF Clinical Research Network (IPFNET) is a multicenter network sponsored by the NIH/NHLBI and created to engage in well-controlled randomized clinical trials that test new therapeutic regimens in the setting of IPF. The PI of this proposal serves on the IPFNET Steering Committee and directs one of the IPFNET centers at Emory. The IPFNET will soon engage in a clinical trial that tests the effectiveness of what has arguably become the standard of care in the management of IPF: the combination of glucocorticoids azathioprine and the anti-oxidant N-acetylcysteine (NAC). This trial the Panther Trial will include three treatment arms: 1) placebo 2) prednisone + azathioprine + NAC and 3) NAC alone. Among other things this trial will determine if NAC (in combination or alone) is beneficial. However despite the focus on anti-oxidant therapy the Panther Trial will not identify subjects with oxidant stress due to limited resources. In other words the redox state of the recruited subjects will not be known and therefore the impact of NAC on this process will not be evaluated. This is important because it is possible that anti-oxidants might be effective in the management of fibrotic lung disorders but only in the subgroup of subjects with an oxidized redox state. If this possibility is not evaluated the IPFNET runs the risk of overlooking a potentially effective therapeutic strategy that might help a significant portion of IPF patients. We hypothesize that NAC may be effective in the treatment of IPF but only in patients with an oxidized redox state caused by deficiencies in endogenous anti-oxidant activity. Specifically we hypothesize that subjects with an oxidized redox potential as determined by oxidation of one or more of the thiol disulfide couples cysteine and cystine (Cys/CySS) and glutathione and glutathione disulfide (GSH/GSSG) will be the ones to benefit from anti-oxidant therapy. To test this we propose to: Aim 1) Measure the Cys/CySS and GSH/GSSG redox potential in plasma obtained from subjects recruited to the three arms of the IPFNET Panther Trial and determine if the redox potential relates to outcome. Aim 2) Determine if NAC can reverse oxidation of the thiol disulfide couples in those with evidence of oxidant stress. PUBLIC HEALTH RELEVANCE: Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal disease that affects thousands of Americans and has no effective medical treatment. This project will explore the role of oxidant stress as a biomarker of disease progression and response to therapy in IPF. It will be conducted in conjunction with the PANTHER TRIAL a phase 3 trial sponsored by the IPF Clinical Research Network of the NIH/NHLBI with the purpose of evaluating redox potential in the plasma of recruited patients and determine if this parameter correlates with progression of disease and response to therapy. (End of Abstract)

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

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


application_id: 7938955
project_number: 5R01MD004598-02
project_title: Does Violence Against Women result in disparities in cancer care for women with b
administering_ic: NIMHD
award_notice_date: 2010-04-21
opportunity_number: RFA-MD-09-004
application_type: 5
activity_code: R01
ic: MD
serial_number: 004598
program_official: ALVIDREZ, JENNIFER L
project_start_date: 2009-09-25
project_end_date: 2014-04-30
study_section: ZMD1-PA(R4)S
contact_pi_person_id: 1894149
contact_pi: COKER, ANN L
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by the applicant):  Violence against women (VAW) is defined by the United Nations as "any act of gender based violence that results in physical sexual or psychological harm or suffering to women." In Kentucky almost 40% of women had experienced some form of VAW in their lifetime. The frequency of VAW poses a serious public health challenge not only due to the prevalence but also the long term impact on women's health documented in an impressive body of literature. However very little research has explored the effect of lifetime VAW on cancer prevention and control. Kentucky has a high cancer burden with the highest cancer mortality rate of all US states. Incidence rates of cancer and the proportion of women diagnosed at a later stage are higher in the Appalachian region of Kentucky. VAW frequently co-occurs with social factors leading to health disparities including unemployment less education and minority race. Overall objectives of this project are to determine the extent to which VAW may explain noted disparities in cancer care based on women's race/ethnicity socioeconomic status access to health insurance or residence in high poverty and rural areas of Kentucky. Specific aims: To determine whether VAW is associated with disparities in breast cancer (aim 1) colorectal cancer (aim 2) and cervical cancer (aim 3) care outcomes to include not receiving cancer screening at recommended intervals being diagnosed with cancer at a later stage not receiving recommended cancer treatment including supportive/palliative care and poorer cancer specific survival among women diagnosed with these cancers in Kentucky and adjusting for relevant confounders including race socioeconomic status having health insurance rural residence and specific regions of high poverty (e.g. living in the Appalachian region of eastern Kentucky or the Delta region of western Kentucky). Methods: We propose a prospective cohort using the Kentucky Cancer Registry (KCR) as the source of 3150 breast cancer cases 1575 colorectal cancer cases and 525 cervical cancer cases. These 5250 women will be interviewed by phone to determine their lifetime exposure to VAW and comorbid conditions. These data will be linked with state level Medicare claims data for women completing phone surveys who are 65 or older. The Medicare claims data administered by the Center for Medicare and Medicaid Services include comprehensive coverage of medical services regardless of where the patients seek care in the nation which would allow the detailed examination of the proposed cancer care continuum: cancer screening stage at diagnosis treatment supportive or palliative care and survivorship. Both logistic regression and Cox proportional hazards modeling will be used to determine the role of VAW (by frequency duration severity and type) and socioeconomic attributes influencing disparities in cancer care. These associations will be investigated for each of the hypothesized five cancer care outcomes and by specific cancer. The mediating or moderating role of socioeconomic factors will also be explored using structural equation modeling. Relevance: This will be the first population-based cohort of the influence of VAW on the life course of cancer care in a state with high cancer burden and regions of extreme poverty. Findings will have significant public health impact in reducing disparities and improving cancer prevention and control in women.

project_terms:
Adult;Affect;Appalachian Region;Breast;Breast Cancer Treatment;Cancer Burden;Cancer Patient;Caring;Censuses;Cervical;Child;Choices and Control;Clinic;Colonoscopy;Colorectal;Colorectal Cancer;Consent;Cox Proportional Hazards Models;Data;Data Analyses;Data Set;Diagnosis;Diagnostic Neoplasm Staging;Divorce;Educational aspects;Ensure;Epidemiology;Equation;Ethnicity aspects;Event;Exposure to;Family member;Fecal occult blood;Frequencies (time pattern);Funding;Gender;Geographic state;Grant;Health;Health Insurance;Healthcare;Human Papillomavirus;Incidence;Individual;Insurance Coverage;Intervention;Interview;Kentucky;Life;Life Cycle Stages;Link;Literature;Logistic Regressions;Low income;Lung;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Mammography;Measures;Mediating;Medical;Medical Surveillance;Medicare;Medicare claim;Medicare/Medicaid;Methods;Minority;Modeling;Mortality Vital Statistics;Neighborhoods;Occult blood screen;Outcome;Outcomes Research;Palliative Care;Pap smear;Parents;Pathway interactions;Patient Self-Report;Patients;Pattern;Physicians;Positioning Attribute;Poverty;Prevalence;Psyche structure;Race;Recruitment Activity;Registries;Research;Research Personnel;Risk;Role;Rural;Schools;Screening for cancer;Screening procedure;Services;Severities;Smoke;Smoking Status;Socioeconomic Factors;Socioeconomic Status;Solutions;Source;Stage at Diagnosis;Staging;Surveys;Survivors;Telephone;Telephone Interviews;Texas;Time;Tumor stage;Unemployment;Uninsured;United Nations;United States Centers for Medicare and Medicaid Services;Violence;Woman;Women's Health;Work;base;cancer care;cancer diagnosis;cancer health disparity;cancer prevention;cancer therapy;care seeking;cohort;emotional abuse;experience;health disparity;improved;low socioeconomic status;malignant breast neoplasm;men;neoplasm registry;physical conditioning;population based;programs;prospective;psychologic;public health medicine (field);residence;rural area;social;socioeconomics;survivorship;tool;violence against women


application_id: 7937498
project_number: 7R21AI073576-03
project_title: Elimination of Toxoplasma gondii cysts by T cells
administering_ic: NIAID
award_notice_date: 2009-09-24
opportunity_number: PA-06-181
application_type: 7
activity_code: R21
ic: AI
serial_number: 073576
program_official: WALI, TONU M
project_start_date: 2007-12-01
project_end_date: 2010-11-30
study_section: Immunity and Host Defense Study Section[IHD]
contact_pi_person_id: 1882071
contact_pi: SUZUKI, YASUHIRO
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): Toxoplasma gondii establishes an important chronic infection capable of causing life-threatening disease in immunocompromised hosts. The basis of persistence of the infection is the tissue cyst which is preferentially formed in the brain and remains largely quiescent for the life of the host but can reactivate and cause disease. To understand the mechanisms of resistance against T. gondii it is essential to analyze the immune responses to the tissue cyst. However the information on in this regard is quite limited. To fill this gap we recently developed a new murine model to examine the activity of immune cells against T. gondii cysts and found that immune T cells most likely have the ability to remove the cysts from the brain of infected mice. These results suggest that it might be possible to develop a vaccine to eliminate the tissue cysts from chronically infected patients. Thus in this proposal the specific aims are designed to address three main questions to obtain fundamental information essential for beginning to understand the mechanisms of the T cell-mediated elimination of T. gondii cysts. The first specific aim is to determine whether CD4+ T cells CD8+ T cells or both subsets are required for the elimination of T. gondii cysts from the brain. We will utilize the novel technique of in vivo bioluminescence imaging: specifically we will determine which subset(s) of adoptively transferred T cells are required for removal of luciferase-expressing T. gondii cysts from the brains of T cell-deficient mice. In the second specific aim we will define the T cell mechanisms that mediate the elimination of T. gondii cysts from the brain. We will transfer immune T cells from mutant mice deficient in IFN-3 perforin or Fas- ligand into T cell-deficient mice infected with luciferase-expressing parasites and monitor changes in cyst burden in the recipients by in vivo bioluminescence imaging. The third specific aim is to determine if the genotype of T. gondii affects the T cell-mediated removal of cysts from the brain. T. gondii has three predominant genotypes (I II and III) each of which can infect humans. Thus it is important especially from clinical aspects to determine if T cells recognize and eliminate cysts in a genotype-specific manner. To address this point we will examine whether a transfer of immune T cells obtained from mice infected with a type II parasite eliminates type III cysts from the brain. The studies in these three specific aims will provide groundbreaking information on the targeting of T. gondii cysts by the immune system and dramatically improve our understanding of resistance to the parasite. This information will also be crucial for developing a novel vaccine to eliminate cysts from patients who have already been infected and to prevent establishment of chronic infection with T. gondii after a newly acquired infection.

project_terms:
Acute;Address;Adoptive Transfer;Affect;Animals;Antigens;Bioluminescence;Brain;CD4 Positive T Lymphocytes;CD8B1 gene;Cells;Chronic;Clinical;Cyst;Disease;Excision;Genes;Genotype;Goals;Histocompatibility Antigens Class I;Human;Image;Immune;Immune response;Immune system;Immunocompromised Host;Infection;Interferons;Life;Luciferases;MHC Class I Genes;Mediating;Memory;Modeling;Monitor;Mus;Mutant Strains Mice;Nude Mice;Parasite resistance;Parasites;Patients;Pharmaceutical Preparations;Phenotype;Play;Population;Research Project Grants;Resistance;Role;Staging;T-Lymphocyte;T-Lymphocyte Subsets;Techniques;Time;Tissues;Toxoplasma gondii;Tumor Necrosis Factor Ligand Superfamily Member 6;base;cytotoxicity;design;improved;in vivo;novel;novel vaccines;perforin;prevent;resistance mechanism;vaccine development


application_id: 7937027
project_number: 5RC1MH089760-02
project_title: Randomized Study of Training in Autism
administering_ic: NIMH
award_notice_date: 2010-09-08
opportunity_number: RFA-OD-09-003
application_type: 5
activity_code: RC1
ic: MH
serial_number: 089760
program_official: FREED, MICHAEL C
project_start_date: 2009-09-30
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZRG1-BBBP-L(58)R]
contact_pi_person_id: 1960113
contact_pi: RUBLE, LISA 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 EDUCATION
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant):  This application addresses broad Challenge Area (04) Clinical Research and specific Challenge Topic 04-MH-101 Autism: Addressing the challenge. Although the focus on early identification efforts in recent years has been effective in sharply increasing the number of children with autism receiving services in schools those services are of uneven quality and there is a critical need to improve access to and receipt of high quality early intervention services that are available to all children with autism regardless of family income race or geographic location. Because all special education teachers need to be adequately prepared to educate children with autism understanding effective training methods for supporting teachers' implementation of evidence-based interventions is an urgent issue for our field. The purpose of this study is to examine three types of professional development models of training and compare their effects on child and teacher outcomes. The primary aim is to generate data on the impact of consultation plus in-classroom teacher coaching vs. consultation plus web-based teacher coaching prospectively by following 25 children whose teachers receive only basic noninteractive online autism training 25 children whose teachers and parents also receive consultation followed by in-classroom teacher coaching and 25 children whose teachers and parents receive consultation followed by web- based teacher coaching. The online training acts a placebo-control for the consultation plus teacher coaching (in-classroom vs. web-based). The design of the study will allow for examination of the relative merits of different components of the intervention. The consultation model that both conditions (in-classroom and web-based teacher coaching) will receive is based on the Collaborative Model for Promoting Competence and Success (COMPASS; Ruble & Dalrymple 2002). We have received an R-34 from NIMH to collect preliminary data on the effectiveness of COMPASS (Ruble McGrew & Dalrymple 2009). Based on preliminary data we hypothesize that child outcomes will be higher for the two conditions that receive consultation and coaching compared to the placebo-control condition. The child outcome that will be measured is achievement of targeted IEP objectives. A secondary aim is to evaluate the impact of consultation type on parent stress. Based on the pilot study we expect type of condition to influence parent stress similar to that hypothesized under the primary aim. Another secondary aim is to generate data on additional factors that may account for differences in child and teacher outcomes. Variables that may contribute to variance in child and parent outcomes that will be collected include: (a) Child factors (Severity of autism; Developmental parameters - IQ language level adaptive behavior); (b) Teacher factors (Urban or rural; Quality of IEP; Years of teaching children with autism; Stress); (c) Parent/caregiver factors (Socioeconomic status; Stress). The proposed project is outcome research that addresses the Interagency Autism Coordinating Committee's aim for more "outcome studies of the effectiveness of behavioral developmental and cognitive therapies." The epidemic rise in the number of children identified with ASD represents an urgent public health issue and national priority for agencies such as the Department of Education and the Department of Health and Human Services (National Institutes of Mental Health 2003) and the critical need to improve access to and receipt of high quality early intervention services that are available to all children with autism regardless of family income race or geographic location (Liptak et al. 2008).

project_terms:
Accounting;Achievement;Adaptive Behaviors;Address;Area;Autistic Disorder;Behavioral;Caregivers;Characteristics;Child;Clinical Research;Cognitive Therapy;Communication;Competence;Complex;Consultations;Data;Development;Disputes;Early identification;Early treatment;Educational Curriculum;Educational aspects;Educational process of instructing;Effectiveness;Elements;Epidemic;Evidence based intervention;Evidence based practice;Face;Family;Fishes;Geographic Locations;Goals;Impairment;Improve Access;Income;Individual;Intervention;Language;Learning;Litigation;Longevity;Measures;Methods;Modeling;National Institute of Mental Health (U.S.);Online Systems;Outcome;Outcome Study;Outcomes Research;Parents;Persons;Pilot Projects;Placebo Control;Preparation;Provider;Race;Randomized;Relative (related person);Research;Research Design;Rice;Rural;Schools;Services;Severities;Social Interaction;Socioeconomic Status;Special Education;Stress;Students;System;Training;United States Dept. of Health and Human Services;base;combat;cost effective;evidence base;experience;high standard;interest;meetings;model development;parental influence;programs;public health medicine (field);rapid growth;safran;success;teacher

public_health_relevance:
NarrativeThe proposed project is outcome research that addresses the Interagency AutismCoordinating Committee's aim for more "outcome studies of the effectiveness ofbehavioral developmental and cognitive therapies." The epidemic rise in the number ofchildren identified with ASD represents an urgent public health issue and national priorityfor agencies such as the Department of Education and the Department of Health andHuman Services (National Institutes of Mental Health 2003) and the critical need toimprove access to and receipt of high quality early intervention services that areavailable to all children with autism regardless of family income race or geographiclocation (Liptak et al. 2008).


application_id: 7936516
project_number: 3R42AA016739-03S1
project_title: Hypericum extracts as potential anti-relapse medications in alcoholism
administering_ic: NIAAA
award_notice_date: 2009-09-25
opportunity_number: RFA-AA-06-007
application_type: 3
activity_code: R42
ic: AA
serial_number: 016739
suffix: S1
program_official: FERTIG, JOANNE
project_start_date: 2007-07-20
project_end_date: 2011-06-30
study_section: ZAA1-DD(74)
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Alcoholism is a complex disease and anti-relapse treatments should recognize this. For example depression is a frequent precipitant of relapse (1) and is the most common co-morbid psychiatric disorder in alcoholism. An anti-relapse agent with antidepressant properties might therefore be valuable specifically for this large subpopulation. In this regard the extracts of "St John's Wort" (Hypericum perforatum) that are effective treatments for clinical depression (see 2) also inhibit alcohol consumption in several animal models (e.g. (3). Like antidepressants H perforatum extracts contain serotonin re-uptake inhibitors (SRIs) but (less wellknown) constituents also bind to NMDA receptors (NMDARs) opioid receptors (ORs) GABAA receptors and corticotrophin releasing factor receptors (CRFRs). This is a unique pharmacological spectrum and is potentially valuable because all of these are molecular targets for anti-relapse agents with NMDARs and ORs being the targets for acamprosate and naltrexone respectively. Native Hypericum species and geneticallymodified H perforatum lines share these actions in greater or lesser degree (Preliminary studies) and their relative importance could therefore be assessed using these species or lines. However in this "fast-track" STTR the aim is simply to identify those novel Hypericum extracts that are of most potential value in alcoholism. In phase 1 the focus will be on pharmacological standardization of extracts using molecular and cellular screens developed for evaluation of synthetic anti-relapse medications. In phase 2 evaluation will continue in simple animal screens of alcohol dependence and/or depression and different models of alcohol consumption. The prediction is that some extracts will be more effective than others and that this can be related to the pharmacological activity they contain. The resulting stronger Intellectual Property (compared to known active H perforatum extracts) will make these more commercially attractive as medications for this specific use. In phase 3 the objective (with a major pharmaceutical partner) will be to commercialize extracts or active components as treatments for prevention of relapse in alcoholic patients with co-morbid depression.

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


application_id: 7936475
project_number: 3R01HD056002-02S1
project_title: Sensory-driven motor recovery in poorly recovered subacute stroke patients
administering_ic: NICHD
award_notice_date: 2009-09-29
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: HD
serial_number: 056002
suffix: S1
program_official: ANSEL, BETH
project_start_date: 2009-09-30
project_end_date: 2011-09-29
study_section: Musculoskeletal Rehabilitation Sciences Study Section[MRS]
contact_pi_person_id: 7375465
contact_pi: SAWAKI-ADAMS, LUMY
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Project Summary Stroke is the leading cause of long-term disability in the United States. Approximately 70-88% of persons with stroke have some degree of motor impairment. A major goal of research in stroke rehabilitation is to harness the ability of the brain to reorganize after neurologic damage has occurred and thus ultimately lead to successful recovery of function. Data from animal and human models have suggested that sensory input plays an important role in motor output possibly by influencing cortical plasticity. However in spite of the advances to date little is known about the extent to which sensory input in the form of peripheral nerve stimulation (PNS) can be successfully combined to motor training especially in poorly recovered subacute stroke patients. The proposed study will evaluate the effectiveness of sustained PNS coupled with motor training to improve hand motor function in subacute stroke patients with severe motor deficit. Our preliminary data in chronic stroke patients with severe motor deficit demonstrate that motor function can be substantially enhanced when PNS is paired with motor training. In addition a separate study in patients with mild motor deficit receiving motor training alone suggests that the optimal therapeutic time window to deliver motor training is within the first year after stroke. The improvement of behavioral motor function was associated with corticomotor reorganization. Therefore we now propose to evaluate the effectiveness of sustained PNS paired with motor training to promote functional motor recovery in subacute stroke patients with severe motor deficit. The central hypothesis is that subacute stroke patients with severe motor deficit receiving PNS and intensive task-oriented therapy will have improved motor function compared to patients receiving sham-PNS and task-oriented therapy and also when compared to patients receiving PNS-only. Further the degree of this behaviorally-measured effect will correlate with the neurophysiological effect measured by transcranial magnetic stimulation. We plan to accept or reject the central hypothesis by accomplishing two Specific Aims: 1) test the effect of PNS preceding task-oriented therapy on hand motor function and 2) test the effect of PNS preceding task-oriented therapy on motor map measured by transcranial magnetic stimulation. The long-range goals are: a) to maximize the restoration of hand motor function after stroke b) to determine the impact of this intervention in activities of daily living. PUBLIC HEALTH RELEVANCE This research project addresses a scientifically important question that cannot be answered by other means. The use of peripheral nerve stimulation has the potential to enhance recovery in subacute stroke patients with poor functional recovery. The primary objective of this proposal is to demonstrate that peripheral nerve stimulation combined with intensive motor training has the ability to further improve hand motor function when compared to intensive training alone or nerve stimulation alone. The results from this study have the potential to develop new strategies in neurorehabilitation. The risk involved to subjects in this study is very low.

project_terms:
Activities of Daily Living;Acute;Address;Adult;Affect;Animals;Area;Behavioral;Brain;Brain Injuries;Chronic;Complex;Control Groups;Coupled;Data;Disease;Effectiveness;Future;Goals;Hand;Human;Intervention;Lead;Learning;Maps;Measures;Metacarpophalangeal joint structure;Modeling;Motor;Motor Cortex;Motor Skills;Motor output;Muscle;Nerve;Neurologic;Neurorehabilitation;Patients;Peripheral Nerve Stimulation;Persons;Phase;Plastics;Play;Quality of life;Randomized Controlled Clinical Trials;Recovery;Recovery of Function;Rehabilitation therapy;Research;Research Project Grants;Risk;Role;Sensory;Solid;Testing;Therapeutic;Therapeutic Intervention;Time;Tissues;Training;Transcranial magnetic stimulation;United States;Upper Extremity;Wolves;Work;Wrist;acute stroke;animal data;chronic stroke;constraint induced therapy;disability;experience;improved;memory process;motor deficit;motor impairment;neurophysiology;post stroke;public health relevance;restoration;sensory cortex;skill acquisition;stroke;stroke rehabilitation


application_id: 7936353
project_number: 5R01CA137037-03
project_title: lung tumor exosome-mediated inflammation promotes tumor progression and growth
administering_ic: NCI
award_notice_date: 2010-07-23
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 137037
program_official: HOWCROFT, THOMAS K
project_start_date: 2009-08-01
project_end_date: 2012-07-31
study_section: Tumor Microenvironment Study Section[TME]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
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: Y
project_abstract:
The overall goal of this proposal is to elucidate the mechanisms by which lung tumor exosomes promote an inflammatory response namely the activation of macrophages and promote the progression and growth of lung tumors. Our preliminary data indicate that pretreatment of A/J mice with exosomes produced by TC-1 lung tumor cells or exosomes isolated from the lung tissue of NJ mice that have been pretreated with the carcinogen urethane results in more rapid tumor growth and earlier progression of lung carcinomas. Urethane treatment results in the recruitment of the activated form of TRAF2 to the exosomes and the exosomes with activated TRAF2 are taken up by the bone marrow-derived precursors of macrophages leading to their maturation and subsequent migration to the lung. The recruitment of the activated TRAF2 to the exosomes requires degradation of the inflammation suppressor protein CYLD in the tumor cells; moreover TRAF2 can mediate ubiquitination of CYLD thereby promoting its degradation. The results of siRNA TRAF2 knockout indicated however that TRAF2 is required but is not sufficient for ubiquitination of CYLD. We have now identified two exosomal proteins that interact with TRAF2 Itch and Jabi which have the potential to enhance the ubiquitination of CYLD in lung tumor cells. We propose to: (1) Confirm the role of lung tumor exosomal TRAF2 in the promotion of urethane-induced lung carcinomas by determining whether knockout of TRAF2 in TC-1 lung tumor cells is sufficient for (0 inhibition of macrophage differentiation and (ii) prevention of TC-1 cell exosome-mediated enhancement of urethane induced lung cancer. (2) Determine if Jabi and itch in the TC-1 exosomes are capable of promoting the differentiation of CD1 1bGr1 cells into activated macrophages. (3) Identification of cells targeted in vivo by exosomes. The data generated should permit the development a highly innovative model of the cellular and molecular basis for exosome-mediated chronic inflammation and promotion of lung tumor growth and suggest novel preventive and therapeutic strategies.

project_terms:
A/J Mouse;Acceleration;Bone Marrow;Bone Marrow Cells;Cancer Patient;Cancer cell line;Carcinogens;Cell model;Cells;Chronic;Data;Development;Dose;Epithelial;Epithelial Cells;Excision;Goals;Growth;Human;IL8 gene;ITGAM gene;Inflammation;Inflammatory Response;Interleukin-6;Knock-out;Lead;Link;Lung;Lung Neoplasms;Lysine;Macrophage Activation;Maintenance;Malignant neoplasm of lung;Mediating;Membrane;Modeling;Molecular;Mus;Myelogenous;Myeloid Cells;Play;Polyubiquitin;Prevention;Preventive;Production;Property;Proteins;Role;SCID Mice;Small Interfering RNA;Structure of parenchyma of lung;TRAF2 gene;Technology;Testing;Therapeutic;Tissues;Tumor Cell Line;Tumor Tissue;Tumor-Derived;Ubiquitination;Urethane;Vascular Endothelial Growth Factors;Vesicle;attenuation;base;cancer cell;cell growth;in vivo;innovation;lung Carcinoma;macrophage;migration;neoplastic cell;novel;peripheral blood;tumor;tumor growth;tumor progression;ubiquilin


application_id: 7936060
project_number: 5P30AA019360-02
project_title: University of Louisville Bioinformatics Faculty Recruitment for Epigenetics
administering_ic: NIAAA
award_notice_date: 2010-08-17
opportunity_number: RFA-OD-09-005
application_type: 5
activity_code: P30
ic: AA
serial_number: 019360
program_official: WANG, JOE
project_start_date: 2009-09-30
project_end_date: 2012-08-31
study_section: ZAA1-DD(02)R
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: Y
project_abstract:
DESCRIPTION (provided by applicant): This is a request to provide funding for a bioinformatics faculty member with a specialty in epigenetics. This request is put forward by the University of Louisville Alcohol Research Center (ULARCNIAAA- funded P01AA017103-01-Craig McClain PI) and the new faculty line will be in the Clinical and Translational Sciences Institute's Biomedical and Health Informatics Core and the School of Medicine. Collaborating Centers/Institutes are the University of Louisville Center for Environmental Genetics and Integrative Biology (CEGIB- NIEHS P30 ES014443 Ken Ramos PI); the University of Louisville Clinical and Translational Sciences Institute (CTSI Craig McClain Director); the Center of Excellence in Diabetes and Obesity Research (P20RR024489-01A1 Aruni Bhatnagar PI); and Cardiovascular Toxicity of Environmental Aldehydes (P01ES011860-05 Aruni Bhatnagar PI). UofL's Bioinformatics Task Force defined UofL bioinformatics capacity and needs for the next ten years. They recommended ten faculty lines. This faculty hire will fill one of the three bioinformatics faculty lines provided to the CTSI in 2007 and previously advertised. Two years of salary support has been provided after the completion of the grant. The primary objectives of this faculty position are to capture the environmental (examples; alcohol and nutrition) medical and behavioral aspects of participants; incorporate them into a usable database; integrate that information with the research information available from the investigator's epigenetic data; collaborate with the other investigators and centers; and integrate data from national registries and databases. The bioinformatics position will physically be located with the University of Louisville Alcohol Research Center and the Clinical and Translational Sciences Institute in the Clinical and Translational Sciences Building. All support services computer systems databases etc. are either available or can be accessed from this location. Tenure promotion and career development occur in the School of Medicine. Dr. McClain the PI on this grant has an exemplary tract record for mentoring new faculty with over 20 career development awards i.e. K awards. The school has a well established mentoring and new faculty assistance program with additional assistance from the Health Sciences Center Research Office. Evaluation will include the core and the faculty member. The CTSI will evaluate the Core while Dr. McClain and the department chair using the work assignment contract will evaluate the faculty member.  
  
PUBLIC HEALTH RELEVANCE: Filling this bioinformatics faculty line is essential for UL developing an epigenetics focus and the continued success of all centers included in this submission.

project_terms:
Advertising;Advisory Committees;Alcohol Nutrition;Alcohols;Aldehydes;Area;Behavioral;Bioinformatics;Biology;Cardiovascular system;Clinical;Computer Systems;Contracts;Data;Databases;Diabetes Mellitus;Environment;Epigenetic Process;Equipment;Evaluation;Faculty;Funding;Genetic;Grant;Health Sciences;Housing;Human Resources;Injury;Institutes;K-Series Research Career Programs;Location;Medical;Mentors;Molecular Profiling;National Institute of Environmental Health Sciences;Obesity;Participant;Positioning Attribute;Proteomics;Public Health Informatics;Recording of previous events;Registries;Research;Research Infrastructure;Research Personnel;Resource Sharing;Schools;Services;Specimen;Structure;Tissues;Toxic effect;Translational Research;Universities;Wages;Work;alcohol exposure;alcohol research;career development;epigenomics;medical schools;medical specialties;meetings;member;metabolomics;molecular marker;programs;public health relevance;ranpirnase;success;transcriptomics

public_health_relevance:
Filling this bioinformatics faculty line is essential for UL developing an epigenetics focus and the continued success of all centers included in this submission.


application_id: 7935559
project_number: 1G20RR031064-01
project_title: Core Rederivation and Barrier Renovation
administering_ic: NCRR
award_notice_date: 2010-03-04
opportunity_number: RFA-RR-09-007
application_type: 1
activity_code: G20
ic: RR
serial_number: 031064
program_official: JEFFERSON, MARLENE E
project_start_date: 2010-03-04
project_end_date: 2013-03-03
study_section: Special Emphasis Panel[ZRR1 STRB-2 (02)]
contact_pi_person_id: 1932320
contact_pi: TRACY, JAMES W
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: ORGANIZED RESEARCH UNITS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): The University of Kentucky (UK) requests $6432134 to renovate 5526 sq. ft. on the fourth floor of the Sanders-Brown Center for Aging. The proposed renovation will completely demolish and remove the present aged and obsolete small barrier animal facility. The new facility will provide three critically needed specific core capabilities that are presently not available at UK. A centralized core embryo cryopreservation and embryo transfer laboratory will be constructed and outfitted. This laboratory will provide embryo transfer rederivation of both in-house stock and imported transgenic strains to eliminate pathogenic or commensal organisms potentially altering research results. Additionally this laboratory will provide both sperm and embryo cryopreservation services to UK investigators permitting the long- term storage of unique transgenic strains as an alternative to continual breeding or as a research resource in the event of unanticipated colony loss. This laboratory will be adjacent to a small high- security sterile barrier for initial expansion of rederived strains prior to movement to conventional animal facilities. Finally a room for gnotobiotic rodent housing will be constructed and outfitted with three flexible film isolators to support the burgeoning need for transgenic strains with defined microbial flora. By locating these three facilities in this single location we will maximally leverage the available support sterilization equipment to provide a set of core services that have been identified by the investigators as a critical infrastructure need.

project_terms:
Aging;Animal Barrier Facility;Breeding;Cryopreservation;Embryo;Embryo Transfer;Equipment;Event;Film;Floor;Gnotobiotic;Housing;Kentucky;Laboratories;Location;Movement;Organism;Research;Research Infrastructure;Research Personnel;Resources;Rodent;Security;Services;Sterility;Sterilization;Transgenic Organisms;Universities;aged;animal facility;flexibility;microbial;sperm cell;square foot


application_id: 7935327
project_number: 5RC2NR011948-02
project_title: Biobehavioral Cardiovascular Health Promotion Intervention in a State Prison Syst
administering_ic: NINR
award_notice_date: 2010-08-11
opportunity_number: RFA-OD-09-004
application_type: 5
activity_code: RC2
ic: NR
serial_number: 011948
program_official: HUSS, KAREN
project_start_date: 2009-09-22
project_end_date: 2012-07-31
study_section: ZNR1-REV-Y(05)
contact_pi_person_id: 1906318
contact_pi: MOSER, DEBRA KAY
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): The long-term objective of our program of research is to improve the cardiovascular (CV) health of inmates by implementation of a state-wide CV risk factor reduction program in prisons. The purpose of the proposed study in male inmates is to test the effects of a behavioral CV risk reduction (BCVRR) intervention on health outcomes (i.e. Cooper Clinic Mortality Risk Index [a composite index that includes heart rate blood pressure diabetes smoking status body mass index age and cardio-respiratory fitness] lipid profile and modifiable lifestyle behaviors) in 4 Kentucky Department of Corrections (KyDOC) state-run prisons. This study will be conducted in 4 state operated prisons. A multiple baselines repeated measures design will be used in which all participants receive the intervention and all have a 3 month run-in period in which to establish their own baseline without intervention. This type of design is ideal in the prison environment where it is not possible to randomly assign inmates to a control group. We will enroll 560 inmates to reach our goal of 400 who finish the program as a drop-out rate of 30% is expected based on existing literature and our prior work. At each prison data will be gathered from inmates at four time points (run-in baseline pre-intervention baseline immediately post-intervention and 3 months post-intervention). The BCVRR intervention is a 12-week CV health education/behavior change and aerobic physical training program consisting of: 1) health education with behavior change strategies session delivered by certified health educators and other trained professionals from the community; and 2) an aerobic exercise program led by CV risk reduction trainers. Short and long-term effects will be measured immediately after the 12-week intervention and 3 months after the intervention ends. Specific Aim 1: To determine the impact of the BCVRR intervention on CV risk factor reduction (i.e. the total Cooper Clinic Mortality Risk Index [CCMRI] individual modifiable components of the CCMRI HgA1c in diabetics and lipid profile) Hypothesis 1: There will be a significant decline in total CCMRI and improvement in the individual modifiable components of the CCMRI and an improved HgA1c for diabetics and improved lipid profile over time following the intervention compared with the run-in and pre-intervention baseline for each outcome. Specific Aim 2: To determine the impact of the intervention on the self-report of modifiable lifestyle behaviors (i.e. Inmate Health Risk Assessment). Hypothesis 2: There will be a significant improvement in self-reported modifiable lifestyle behaviors compared with the run-in and pre-intervention baseline for each outcome. Specific Aim 3: To generate data from the proposed study for a proposal for state-wide testing and implementation of the intervention at all of the 13 KyDOC state-run prisons in order to sustain the program.  
  
PUBLIC HEALTH RELEVANCE: Narrative Cardiovascular disease is the main cause of death in rison and inmates have disproportionately higher rates of cardiovascular risk factors. The objective of our program of research is to improve the cardiovascular health of inmates by implementation of a cardiovascular risk factor reduction program in prisons. Effective management of cardiovascular risk factors could improve the health of inmates both while incarcerated and once released and reduce the substantial personal and societal burden of cardiovascular disease.

project_terms:
Aerobic;Aerobic Exercise;Age;Applications Grants;Behavior;Behavioral;Blood Pressure;Body mass index;Cardiovascular Diseases;Cardiovascular system;Caring;Cause of Death;Cessation of life;Clinic;Communities;Control Groups;Coronary heart disease;Cost Savings;Country;County;Data;Diabetes Mellitus;Drops;Educational aspects;Enrollment;Environment;Exercise;Goals;Health;Health Care Costs;Health Educators;Health Promotion;Health education;Heart Rate;Housing;Imprisonment;Individual;Institution;Intervention;Kentucky;Life Style;Lipids;Literature;Long-Term Effects;Measures;Medicaid;Medical;Medicare;Mortality Vital Statistics;Outcome;Participant;Patient Self-Report;Perception;Platelet Factor 4;Prisoner;Prisons;Randomized;Research;Rest;Risk;Risk Assessment;Risk Factors;Risk Reduction;Running;Security;Smoking Status;Socioeconomic Status;Specialist;Testing;Time;Training;Training Programs;Uninsured;Woman;Work;base;behavior change;biobehavior;cardiovascular risk factor;cost;design;diabetic;disorder risk;fitness;improved;indexing;low socioeconomic status;male;post intervention;programs;public health relevance;recidivism;respiratory

public_health_relevance:
Narrative Cardiovascular disease is the main cause of death in prison and inmates have disproportionately higherrates of cardiovascular risk factors. The objective of our program of research is to improve the cardiovascularhealth of inmates by implementation of a cardiovascular risk factor reduction program in prisons. Effectivemanagement of cardiovascular risk factors could improve the health of inmates both while incarcerated andonce released and reduce the substantial personal and societal burden of cardiovascular disease.


application_id: 7935227
project_number: 5RC1EY020442-02
project_title: CCR3: a molecular marker for neovascular AMD
administering_ic: NEI
award_notice_date: 2010-08-27
opportunity_number: RFA-OD-09-003
application_type: 5
activity_code: RC1
ic: EY
serial_number: 020442
program_official: SHEN, GRACE L
project_start_date: 2009-09-30
project_end_date: 2012-09-29
study_section: Special Emphasis Panel[ZRG1-CB-N(58)R]
contact_pi_person_id: 2446639
contact_pi: AMBATI, JAYAKRISHNA
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) affects as many Americans as all cancers combined and twice as many as Alzheimer's disease. The overwhelming cause of severe vision loss in AMD is choroidal neovascularization (CNV) the growth of abnormal blood vessels into the retina. Despite the use of recently approved molecular therapeutics targeting vascular endothelial growth factor (VEGF)-A the majority of patients do not recover good functional vision and a significant fraction progress to legal blindness. This is due to the present inability to detect CNV before it invades the retina and causes structural and functional tissue damage. In new and exciting findings we are reporting the discovery of the first molecular marker that is specific for human CNV (Takeda et al. Nature 2009): CCR3 a chemokine receptor best known for promoting eosinophil and mast cell trafficking is expressed in human choroidal endothelial cells in vivo only in the setting of CNV due to AMD. Targeting CCR3 or its eotaxin ligands inhibited angiogenesis in vitro and in vivo and was both superior to and safer than VEGF-A blockade. Non-invasive in vivo bioimaging using functionalized quantum dots targeting CCR3 detected CNV within the mouse choroid that had not yet invaded the retina and was invisible to fluorescein angiography. These findings define CCR3 as a novel specific molecular early diagnostic and therapeutic target in human CNV. In this proposal we will define the biological relationships between the CCR3/eotaxin axis and aging complement activation and oxidative stress to decipher how these established AMD pathogenetic factors regulate the neovascular progression of disease. We will also create and optimize new fluorescent optical bioimaging CCR3-targeting probes that can detect intrachoroidal "subclinical" CNV. These studies respond precisely to this Challenge Topic as they will illuminate how the immune system regulates this specific signature of the angiogenic switch in AMD and innovatively exploit it to enable prevention of vision loss by coupling early detection with targeted therapy. As such this proposal is perfectly aligned with the 5-year program goals of the NEI's Retinal Diseases strategic plan. It also advances the goals of the American Recovery and Reinvestment Act as it will if funded create or retain jobs for three individuals and provide economic benefits to third- party suppliers and vendors. We are committed to complete the program by the determined October 2010 deadline and are willing to complete quarterly reports pertaining to this project as outlined by NIH.   
  
PUBLIC HEALTH RELEVANCE: Choroidal neovascularization (CNV) is responsible for 90% of severe vision loss due to age- related macular degeneration (AMD) the leading cause of blindness among the elderly in the United States. Our recent discovery of CCR3 as the first molecule specifically expressed with human CNV and our exciting new finding that CCR3-targeting molecular imaging probes can detect CNV before retinal invasion support the investigation of CCR3 biology in AMD and optimization of bioimaging modalities. This proposal can transform the clinical practice paradigm by introducing an innovative bioimaging strategy that enables early detection of CNV for targeted therapy that can prevent vision loss. It also will advance the goals of the ARRA by creating or retaining multiple jobs and provide economic benefit to the University of Kentucky College of Medicine which has consistently served the Commonwealth of Kentucky as a principal force for economic development and third-party suppliers and vendors.

project_terms:
Accounting;Affect;Affinity;Age;Age related macular degeneration;Aging;Alzheimer's Disease;American;Angiogenic Switch;Animal Model;Antibodies;Automobile Driving;Biodistribution;Biological;Biology;Blindness;Blood Vessels;Bruch's basal membrane structure;Cells;Choroid;Choroidal Neovascularization;Commit;Complement Activation;Coupled;Coupling;Diagnostic;Disease;Disease Progression;Dyes;Early Diagnosis;Economic Development;Economics;Elderly;Endothelial Cells;Eotaxin;Epidemic;Exudative age-related macular degeneration;Eye;FDA approved;Fab Immunoglobulins;Fluorescein Angiography;Funding;Future;Genetic;Goals;Grant;Growth;Human;Immune;Immune system;In Vitro;Individual;Intervention;Invaded;Investigation;Kentucky;Legal Blindness;Ligands;Malignant Neoplasms;Maps;Medicine;Modality;Molecular;Molecular Profiling;Molecular Target;Mus;Natural Immunity;Nature;Nonexudative age-related macular degeneration;Occupations;Optics;Outcome;Oxidative Stress;Panthera leo;Pathogenesis;Pathology;Patients;Pharmacotherapy;Photoreceptors;Plasma Proteins;Prevalence;Prevention;Quantum Dots;Recovery;Relative (related person);Reporting;Retina;Retinal;Retinal Diseases;Source;Specificity;Specimen;Staging;Strategic Planning;Structure of retinal pigment epithelium;Techniques;Testing;Tissues;United States;United States National Institutes of Health;Universities;Vascular Endothelial Growth Factor A;Vendor;Vision;Visual;aging population;allergic response;angiogenesis;bioimaging;biomarker;chemokine receptor;clinical practice;college;cost;cytokine;eosinophil;imaging probe;improved;in vivo;innovation;legally blind;mast cell;molecular imaging;molecular marker;mouse model;nanocrystal;neovascular;novel;prevent;programs;public health relevance;therapeutic target;trafficking

public_health_relevance:
Choroidal neovascularization (CNV) is responsible for 90% of severe vision loss due to age-related macular degeneration (AMD) the leading cause of blindness among the elderly in theUnited States. Our recent discovery of CCR3 as the first molecule specifically expressed withhuman CNV and our exciting new finding that CCR3-targeting molecular imaging probes candetect CNV before retinal invasion support the investigation of CCR3 biology in AMD andoptimization of bioimaging modalities. This proposal can transform the clinical practice paradigmby introducing an innovative bioimaging strategy that enables early detection of CNV fortargeted therapy that can prevent vision loss. It also will advance the goals of the ARRA bycreating or retaining multiple jobs and provide economic benefit to the University of KentuckyCollege of Medicine which has consistently served the Commonwealth of Kentucky as aprincipal force for economic development and third-party suppliers and vendors.


application_id: 7934649
project_number: 5R01AA018274-02
project_title: Alcohol Tolerance and Behavioral Disinhibition in Humans
administering_ic: NIAAA
award_notice_date: 2010-08-26
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AA
serial_number: 018274
program_official: GRANDISON, LINDSEY
project_start_date: 2009-09-20
project_end_date: 2014-08-31
study_section: Special Emphasis Panel[ZRG1-BBBP-E(02)M]
contact_pi_person_id: 6368360
contact_pi: FILLMORE, MARK T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alcohol tolerance refers to a diminished intensity of response as doses are repeated. Tolerance has long been implicated as a factor contributing to alcohol abuse and dependence by encouraging the use of escalating doses to reinstate initial effects of the drug. Alcohol is also well-known for its acute impairing effects on neurocognitive processes involved in the regulation of behavior and attention. Yet little research has examined how such disturbances might reduce self-control over actual alcohol use leading to patterns of abusive drinking (e.g. binge drinking). Moreover despite interest in tolerance as a phenotypic marker for alcohol use disorders little research has sought to determine how differences in alcohol sensitivity and tolerance might characterize populations at-risk for alcohol abuse such as those with externalizing disorders (e.g. ADHD). The proposal is based on the working hypothesis that abuse potential of alcohol is determined by sensitivity to its reward-enhancing effects and to its disinhibiting effects. The proposed studies examine the contribution of tolerance to abuse potential as measured by changes in alcohol effects on basic mechanisms involved in the control and regulation of behavior. Studies will investigate: 1) the sensitivity of control mechanisms to the impairing effects of alcohol and their contribution to abuse potential; 2) tolerance development to the impairing effects on mechanisms that control behavior and attention; 3) the contribution of such tolerance to the abuse potential of alcohol; 4) the degree to which the inhibitory and attentional deficits associated with ADHD influence alcohol sensitivity and the development of tolerance; and 5) the degree to which the developmental course of tolerance is affected by concomitant use of stimulant drugs commonly used in the management of ADHD. PUBLIC HEALTH RELEVANCE: Excessive alcohol use contributes to many adverse health consequences (e.g. alcohol poisoning acute alcoholic hepatitis and liver cirrhosis). Tolerance has long been implicated as a factor contributing to alcohol abuse and dependence by encouraging the use of escalating doses to reinstate initial effects of the drug. Yet little research has examined how tolerance might increase the risk for alcohol abuse. The proposed studies examine the contribution of tolerance to abuse potential as measured by changes in the ability of the drug to alter basic mechanisms involved in the control and regulation of behavior. The findings of this research will provide an understanding of how drinkers' susceptibility to alcohol's acute behavioral-impairing effects can pose an early-onset risk factor for later alcohol dependence by promoting a continued pattern of abusive binge drinking. The research strategies also will provide methods for testing the role of neurocognitive mechanisms in the treatment efficacy of existing pharmacotherapies such as naltrexone and acamprosate as well as some investigational medications that might operate via neurocognitive control mechanisms.

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


application_id: 7934623
project_number: 5R01AA018869-02
project_title: Cyclic AMP Cytokine Modulation and Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2010-08-31
opportunity_number: RFA-AA-09-006
application_type: 5
activity_code: R01
ic: AA
serial_number: 018869
program_official: RADAEVA, SVETLANA
project_start_date: 2009-09-20
project_end_date: 2014-08-31
study_section: ZAA1-JJ(06)
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alcoholic Liver Disease (ALD) remains a leading cause of liver-related deaths in the U.S. and there is still no FDA-approved therapy. Abnormal cytokine metabolism is a major feature of ALD. Elevated serum concentrations of tumor necrosis factor (TNF) and TNF-inducible proinflammatory cytokines/chemokines such as IL-8 and IL-18 have been reported in patients with alcoholic hepatitis and/or cirrhosis and levels correlated with markers of the acute phase response liver function and clinical outcome. Similarly there are depressed levels of the critical anti-inflammatory cytokine IL-10. Studies in animal models support an etiologic role for cytokines in the liver injury of ALD. The major problem to be investigated in this proposal is the mechanism(s) for this dysregulated cytokine metabolism and our overall goal is the development of novel therapeutic interventions. ALD is associated with an increase in oxidative stress with a concomitant decrease in cellular antioxidants such as glutathione (GSH) and importantly S-adenosyl-L-methionine (SAM) due to subnormal synthesis. Clinical studies have suggested that SAM has beneficial effects in many hepatic disorders including ALD and numerous animal studies have clearly demonstrated the protective effects of SAM against a variety of hepatotoxins. Previous studies from our group evaluated the role of SAM in positively modulating endotoxin (LPS)-stimulated TNF and IL-10 production related to ALD. We showed that SAM decreased LPS stimulated TNF production and increased LPS stimulated IL-10 production and that SAM increased cellular levels of cyclic AMP (cAMP) which is known to positively modulate cytokine production. We therefore began an evaluation of the role of cAMP in dysregulated cytokine production in ALD which is the research focus of this current proposal. We present compelling preliminary data that cAMP is decreased in a macrophage cell line chronically cultured in alcohol and in Kupffer cells from mice chronically fed ethanol intragastrically. Our working hypothesis is that altered phosphodiesterase 4B (PDE4B) and cAMP metabolism cause abnormal TNF and IL-10 metabolism which play a critical role in the development and perpetuation of ALD. Specific Objectives for this proposal are to: 1. Document increased PDE4B expression/activity and decreased cAMP in peripheral blood monocytes from patients with alcoholic hepatitis (AH) and alcoholic cirrhosis and evaluate whether in vitro incubation of monocytes with specific phosphodiesterase inhibitors corrects dysregulated cAMP and cytokine metabolism; 2. Determine whether PDE4 (and specifically PDE4B) inhibition blocks the development of alcohol-induced liver injury in a murine intra-gastric ethanol-feeding model of chronic ALD and in a murine model of AH; 3. Evaluate potential molecular and epigenetic mechanisms whereby cAMP metabolism is altered in alcoholic liver disease; and 4. Evaluate the effects of combined consumption of a commercially- available adenyl cyclase agonist (Misoprostol - increases cAMP production) and a phosphodiesterase inhibitor (Pentoxyfilline - decreases cAMP breakdown) in normal volunteers and in patients with stable alcoholic cirrhosis.  
  
PUBLIC HEALTH RELEVANCE: Alcoholic Liver Disease (ALD) remains a leading cause of death from liver disease in the U.S. and there is still no FDA-approved therapy. Abnormal cytokine metabolism is a major feature of ALD. Elevated serum concentration levels of tumor necrosis factor (TNF) and TNF-inducible proinflammatory cytokines/chemokines such as IL-8 and IL-18 have been reported in patients with alcoholic hepatitis and/or cirrhosis and levels correlated with markers of the acute phase response liver function and clinical outcome. Similarly there are depressed levels of the critical anti-inflammatory cytokine IL-10. Studies in animal models support an etiologic role for cytokines in the liver injury of ALD. The major problem to be investigated in this proposal is the mechanism(s) for this dysregulated cytokine metabolism and our overall goal is the development of novel therapeutic interventions.

project_terms:
Acute-Phase Reaction;Adenylate Cyclase;Agonist;Alcoholic Hepatitis;Alcoholic Liver Cirrhosis;Alcoholic Liver Diseases;Alcohols;Animal Model;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Attenuated;Biological Models;Cause of Death;Cell Line;Cessation of life;Chronic;Cirrhosis;Clinical;Clinical Research;Consumption;Cyclic AMP;Data;Depressed mood;Development;Disease;Disease model;Endotoxins;Epigenetic Process;Ethanol;Evaluation;FDA approved;Glutathione;Goals;Human;IL8 gene;In Vitro;Inflammatory;Injury;Interleukin-10;Interleukin-18;Isoenzymes;Knockout Mice;Kupffer Cells;Lipopolysaccharides;Liver;Liver diseases;Mediating;Metabolism;Methionine;Misoprostol;Modeling;Modification;Molecular;Mus;Outcome;Oxidative Stress;PDE4B;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacotherapy;Phosphodiesterase Inhibitors;Play;Process;Production;Rattus;Reporting;Research;Role;Serum;Stomach;System;Therapeutic Intervention;Tumor Necrosis Factor-alpha;Tumor Necrosis Factors;Whole Blood;Work;alcohol exposure;animal data;base;bench to bedside;chemokine;cytokine;experience;feeding;hepatotoxin;inhibitor/antagonist;liver function;macrophage;monocyte;novel therapeutic intervention;peripheral blood;phosphoric diester hydrolase;protective effect;public health relevance;research study;volunteer


application_id: 7934615
project_number: 5R21AG031999-02
project_title: Role of Matrix Metalloproteinase-1 in Endothelial Cell Senescence
administering_ic: NIA
award_notice_date: 2010-08-12
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: AG
serial_number: 031999
program_official: GUO, MAX
project_start_date: 2009-09-30
project_end_date: 2011-11-30
study_section: Intercellular Interactions Study Section[ICI]
contact_pi_person_id: 7876874
contact_pi: MAO, CATHERINE D
other_pis: Not Applicable
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Premature cell senescence induced by oncogenes and oxidative stress in vitro recapitulates many facets of replicative senescence and in vivo cellular aging. With the recent findings of a tumor suppressor role for senescent cells in vivo the establishment of cell senescence emerges as a survival adaptation to stress aimed at limiting the proliferation of stressed and damaged cells. However the factors and molecular mechanisms by which cell senescence is established and maintained remain poorly understood. Lithium is commonly used to treat bipolar disorder as well as to activate the oncogenic 2-catenin signaling pathway via inhibition of glycogen synthase kinase (GSK)-32. We have previously shown that lithium induces a cell cycle arrest in primary endothelial cells associated with the activation of the tumor suppressor p53 and p21cip cascade and the development of a cell senescent phenotype characterized by the SA- 2-galactosidase marker. The lithium-induced senescent phenotype was also accompanied with the activation of the tumor suppressor FOXO1 which is involved in the control of lifespan and cell senescence and by the up-regulation of plasminogen activator inhibitor (PAI)-1 and matrix metalloproteinase (MMP)-1 two secreted markers of cell senescence and age-related diseases. MMP-1 in addition to degrade collagen can signals via cleavage and activation of the proteinase-activated-receptor (PAR)-1. Activation of PAR1 in endothelial cells triggers a pro-inflammatory state which is also a hallmark of a senescent state. Moreover MMP1 up-regulation by lithium is an early event that appears independent of inflammatory cytokines GSK32 inhibition and 2-catenin stabilization indicative of a novel lithium-dependent cascade. We propose to test the hypothesis that a novel lithium-dependent cascade induces MMP-1 expression which in turn participates in the establishment and/or maintenance of cell senescence via activation of PAR-1. In Aim 1 we will determine the role of MMP-1 in the establishment of lithium-induced cell senescent phenotype and its mechanism of action by i) monitoring the expression of senescence markers in presence of MMP-1 and in absence of MMP1 activity and expression using specific inhibitors and small RNA interference respectively and ii) by analyzing the activation of PAR-1 in response to lithium and its dependency on MMP-1 expression and activity. In Aim 2 we will identify the mechanisms of lithium-mediated up-regulation of MMP-1 in endothelial cells by i) delineating the lithium- responsive element in MMP-1 promoter ii) identifying the transcription factors regulated by lithium and iii) analyzing the signaling cascade involved using specific inhibitors and activators as well as by knock in down their expression by small RNA interference. PUBLIC HEALTH RELEVANCE: The occurrence of cancer and atherosclerosis increase with age and these age-related diseases share common features such as the appearance of senescent cells within or around the lesions. Though cell senescence is a survival response to stress these senescent cells release factors like the matrix metalloproteinase-1 that will in turn maintain and propagate cellular dysfunctional states. Thus understanding how these factors are produced and how they act on neighboring cells is crucial for developing novel and targeted therapeutic strategies to prevent or delay the propagation of cellular dysfunctions associated with aging.

project_terms:
Activation Analysis;Age;Aging;Apoptosis;Appearance;Atherosclerosis;Binding (Molecular Function);Bipolar Disorder;CDKN2A gene;Cell Aging;Cell Cycle Arrest;Cell-Cell Adhesion;Cells;Collagen;Dependency (Psychology);Development;Disease;Distal;Dose;Down-Regulation;Elements;Endothelial Cells;Event;F2R gene;Functional disorder;Galactosidase;Gene Expression;Gene Targeting;Glycogen Synthase Kinases;IL8 gene;In Vitro;Indium;Inflammatory;Inositol;Interstitial Collagenase;Knock-in Mouse;Lesion;Lithium;Longevity;Luciferases;M cell;Maintenance;Malignant Neoplasms;Mediating;Molecular;Monitor;Natural regeneration;Oncogenes;Oncogenic;Outcome;Oxidative Stress;PAR-1 Receptor;Pathway interactions;Pattern;Peptide Hydrolases;Phenotype;Plasminogen;Plasminogen Activator Inhibitor 1;Promotor (Genetics);Protein p53;Proteinase-Activated Receptors;RNA Interference;Reporter;Role;Signal Pathway;Signal Transduction;Small RNA;Stress;TP53 gene;Testing;Tumor Suppressor Proteins;Up-Regulation (Physiology);Withdrawal;activating transcription factor;age related;cell injury;cell type;cytokine;in vivo;inhibitor/antagonist;new therapeutic target;novel;premature;prevent;public health relevance;release factor;response;senescence;transcription factor

public_health_relevance:
The occurrence of cancer and atherosclerosis increase with age and these age-relateddiseases share common features such as the appearance of senescent cells within oraround the lesions. Though cell senescence is a survival response to stress thesesenescent cells release factors like the matrix metalloproteinase-1 that will in turnmaintain and propagate cellular dysfunctional states. Thus understanding how thesefactors are produced and how they act on neighboring cells is crucial for developing noveland targeted therapeutic strategies to prevent or delay the propagation of cellulardysfunctions associated with aging.


application_id: 7933998
project_number: 5R03DE019496-02
project_title: Enhanced Oral Tissue Repair via Self Assembled Polymer Multi-layer Barriers for t
administering_ic: NIDCR
award_notice_date: 2010-07-20
opportunity_number: PAR-07-418
application_type: 5
activity_code: R03
ic: DE
serial_number: 019496
program_official: DRUMMOND, JAMES
project_start_date: 2009-09-17
project_end_date: 2012-08-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 8772583
contact_pi: DZIUBLA, THOMAS DEAN
other_pis: Not Applicable
congressional_district: 06
department: ENGINEERING (ALL TYPES)
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Chronic soft tissue oral wounds (e.g. Mucositis aphthous stomatitis and periodontal disease) can be very painful and often are to develop a simple to apply polymeric barrier for the enhanced healing of these oral wounds. It is hypothesized that by rinsing the oral cavity with an aqueous polymeric solution which can self assemble at the site of injury via fibrin targeting it is possible to form a barrier that act as a platform for the sustained antioxidant therapy improving wound healing by suppressing chronic inflammation. In this project we propose to synthesize In-situ self assembled layer by layer polymers films providing a protective barrier and a platform for future delivery of antioxidants for the treatment of local oxidative stress mediated tissue damage thereby reducing healing time improving a wide variety of oral repair and regeneration therapies. Functionalized polymers of Poly(ethylene glycol)-g-poly(methacrylic acid) and poly(methacrylic acid) will be synthesized and systematically evaluated to determine identify key parameters in the layer by layer barrier assembly. These polymers will use fibrin targeting via peptide modification and biotin-streptavidin binding for layer by layer assembly. The biochemical stability of the barriers in the presence of human saliva will be tested using radiotracing. Mechanical barrier stability will be tested using a static load and cyclic contact mechanical model. Key parameters affecting barrier strength and targeting (e.g. polymer MW number of layers degree of target moiety functionalization) will be identified using a statistical design approach. Specific Aims: 1.) Design and synthesis of layer-by-layer barrier assemblies. 2.) In vitro evaluation of layer-by-layer barrier stability.  
  
PUBLIC HEALTH RELEVANCE: This project's goal is to develop a targetable polymer system which can be used to form an easy to apply self assembled barrier for the treatment of oral wounds and sores. Through a series of simple mouth rinses using complementary polymer solutions a strong persistent barrier which can be loaded with drugs to accelerate healing times can be formed. It is believed that these barriers will be useful in treating patients with extreme cases of oral sores such as Mucositis.

project_terms:
Adhesions;Affect;Affinity;Anti-Inflammatory Agents;Anti-inflammatory;Antibiotics;Antioxidants;Aphthous Stomatitis;Area;Attenuated;Binding (Molecular Function);Biochemical;Biotin;Chronic;Clinical;Development;Diet Habits;Disease;Drug Formulations;Enzymes;Epitopes;Ethylene Glycols;Evaluation;Event;Fatigue;Fibrin;Film;Friction;Future;Goals;Grant;Growth Factor;Healed;Human;Implant;In Situ;In Vitro;Infection;Inflammation;Injury;Mechanics;Mediating;Methodology;Methods;Modeling;Modification;Molecular;Mucositis;Mus;Natural regeneration;Oral;Oral cavity;Outcome;Oxidative Stress;Pain;Patients;Peptides;Periodontal Diseases;Periodontitis;Pharmaceutical Preparations;Polymers;Principal Investigator;Property;Resistance;Saliva;Series;Site;Solutions;Streptavidin;Surface;System;Testing;Therapeutic;Time;Tissue Grafts;Tissues;Wound Healing;antioxidant therapy;aqueous;catalase;copolymer;crosslink;density;design;ethylene glycol;healing;improved;maxillofacial;methacrylic acid;nanocarrier;nanocomposite;oral tissue;premature;prevent;public health relevance;reconstruction;repaired;response;soft tissue;stability testing

public_health_relevance:
____________________ Principal Investigator last first middle): Dziubla Thomas DProject NarrativeThis project's goal is to develop a targetable polymer system which can be used to form an easy to apply self-assembled barrier for the treatment of oral wounds and sores. Through a series of simple mouth rinses usingcomplementary polymer solutions a strong persistent barrier which can be loaded with drugs to acceleratehealing times can be formed. It is believed that these barriers will be useful in treating patients with extremecases of oral sores such as Mucositis._________________________________________________________________________________________________________________________PHS 398/2590 (Rev. 5/01) (Form Page 6) Page 1 FFNumber pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a 3b.


application_id: 7933489
project_number: 3R21AI069027-02S1
project_title: Novel in vivo models for cell-type specific MyD88 signaling in the intestine
administering_ic: NIAID
award_notice_date: 2009-09-28
opportunity_number: PA-04-119
application_type: 3
activity_code: R21
ic: AI
serial_number: 069027
suffix: S1
program_official: ROTHERMEL, ANNETTE L
project_start_date: 2009-09-28
project_end_date: 2010-08-31
study_section: Gastrointestinal Mucosal Pathobiology Study Section[GMPB]
contact_pi_person_id: 1898921
contact_pi: KAETZEL, CHARLOTTE S
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Innate and acquired immune responses in the intestine must promote homeostasis in the presence of large numbers of commensal microorganisms while maintaining the capacity to defend the body against invasive pathogens. The adult human intestinal tract is inhabited by 100 trillion microorganisms 10 times more than the number of human cells in the entire body. Commensal bacteria provide multiple benefits to the host including processing of essential nutrients regulation of energy balance protection against pathogens and maintenance of epithelial integrity. However inappropriate immune responses to colonic bacteria can lead to chronic inflammatory bowel disease and life-threatening colitis. Host cells recognize microorganisms through pattern recognition molecules including Toll-like receptors (TLRs) which bind microbial cell wall constituents nucleic acids and other byproducts. MyD88 is a cytoplasmic adaptor protein that transduces signals emanating from most TLRs as well as members of the IL-1R family. Recent studies have demonstrated that mice genetically deficient in MyD88 expression are more sensitive to experimental colitis than are wild-type mice suggesting a key role for TLR and/or IL-1 R signaling in regulation of intestinal inflammation. Our preliminary data demonstrate that MyD88-deficient mice have severely depressed expression of the polymeric immunoglobulin receptor (plgR) a key anti-inflammatory molecule that mediates epithelial transport of protective IgA antibodies. Recent work by others has demonstrated that plgR-deficient mice are like MyD88-deficient mice particularly sensitive to chemically-induced colitis. The goal of the proposed research is to test the hypothesis that expression of MyD88 by epithelial cells is crucial for regulation of plgR gene expression and protection against experimental colitis. As a consequence of these studies we will generate novel chimeric and transgenic mouse models for studying epithelial-specific MyD88 signaling within the intact intestine. First we will analyze the susceptibility of these mice to experimental colitis. Second we will analyze patterns of pro- and anti-inflammatory gene expression in the colon. These experiments should increase our knowledge of epithelial-specific MyD88 signaling as well as cross-talk between epithelial and immune cells which is key to the identification of normal and dysregulated responses to colonic bacteria.

project_terms:
Adult;Anti-Inflammatory Agents;Anti-inflammatory;Antibodies;Bacteria;Binding (Molecular Function);Bone Marrow;Cell Wall;Cells;Chimera organism;Chronic;Colitis;Colon;Congenic Mice;Data;Development;Epithelial;Epithelial Cells;Equilibrium;Experimental Models;Family;Gene Expression;Goals;Homeostasis;Human;Immune;Immune response;Immunoglobulin A;Inflammation;Inflammatory Bowel Diseases;Inflammatory disease of the intestine;Interleukin-1;Intestines;Knowledge;Lamina Propria;Lead;Life;Maintenance;Mediating;Microarray Analysis;Mononuclear;Mus;Nucleic Acids;Nutrient;Oral Administration;Pattern;Pattern Recognition;Polymeric Immunoglobulin Receptors;Predisposition;Process;Promotor (Genetics);Proteins;Regulation;Research;Role;Signal Transducing Adaptor Proteins;Signal Transduction;Sodium Dextran Sulfate;Testing;Time;Tissues;Toll-like receptors;Transgenes;Transgenic Mice;Wild Type Mouse;Work;cell type;commensal microbes;depressed;energy balance;in vivo Model;member;microbial;microorganism;mouse model;novel;pathogen;research study;response;selective expression


application_id: 7933287
project_number: 3R01GM059636-09S1
project_title: Pseudouridine Synthases
administering_ic: NIGMS
award_notice_date: 2009-09-30
application_type: 3
activity_code: R01
ic: GM
serial_number: 059636
suffix: S1
program_official: IKEDA, RICHARD A
project_start_date: 2009-09-30
project_end_date: 2011-02-28
study_section: Physical Biochemistry Study Section[PB]
contact_pi_person_id: 1925871
contact_pi: MUELLER, EUGENE G
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: Y
project_abstract:
DESCRIPTION (provided by applicant): Pseudouridine is the most common post-transcriptional modification of RNA and arises from the isomerization of uridine catalyzed by the pseudouridine synthases. These enzymes fall into four families that share no global sequence similarity but appear homologous on the basis of their tertiary structures. Several pseudouridine synthases are physiologically critical in prokaryotes and eukaryotes including the human enzyme dyskerin the absence of which causes the X-linked disease dyskeratosis congenita. Pseudouridine residues in small nuclear RNA are required for pre-mRNA splicing an essential function in eukaryotes. Since the families of pseudouridine synthases are so highly divergent it remains possible that they proceed by different mechanisms and such differences may eventually be exploited in new classes of antibiotics or provide a better understanding of the disease dyskeratosis congenita. The proposed experiments will elucidate the chemical mechanism followed by two E. coli pseudouridine synthases of different families RluA and TruB which are particularly tractable targets for mechanistic work because they handle small RNA substrates (stem-loop oligonucleotides). RNA containing 5-fluorouridine has been used as an inhibitor and mechanistic probe of the pseudouridine synthases favoring a mechanism involving a Michael addition. Recent results however indicate that TruB is not inhibited by 5-fluorouridine in RNA and that an assumed hydrolysis of a proposed intermediate does not occur leading to doubt concerning the mechanistic conclusions based on earlier studies with the same compound. The proposed experiments will resolve issue concerning 5-fluorouridine in RNA and allow further mechanistic insight. Such insight will also be gained using RNA containing uridine with a 2'-fluoro group similar to the series of remarkably informative experiments using fluorosugars to probe the mechanism of glycosidases. A combination of NMR mass spectrometry site-directed mutagenesis and kinetic analysis supplemented by X-ray crystallography will be employed to examine the effects of the two types of fluorinated RNA as well as site-directed mutagenesis of amino acid residues that appear to play a role in catalysis. Finally synthesized small RNA substrates will be used to examine the substrate specificity of RluA.

project_terms:
5 fluorouridine;Address;Amino Acids;Antibiotics;Anticodon;Behavior;Binding (Molecular Function);Catalysis;Chemicals;Crystallography;Disease;Dyskeratosis Congenita;Enzymes;Escherichia coli;Eukaryota;Event;Family;Fluorine;Glycoside Hydrolases;Human;Hydrolysis;Investigation;Kinetics;Link;Mass Spectrum Analysis;Methods;Oligonucleotides;Physiological;Play;Positioning Attribute;Post-Transcriptional RNA Processing;Prokaryotic Cells;Pseudouridine;Pyrimidine;Pyrimidines;RNA;RNA Splicing;RNA-Protein Interaction;Reaction;Research Personnel;Ribose;Role;Series;Side;Site-Directed Mutagenesis;Small Nuclear RNA;Small RNA;Specificity;Structure;Substrate Specificity;Testing;Transfer RNA;Uncertainty;Uridine;Work;X-Ray Crystallography;base;chemical kinetics;falls;inhibitor/antagonist;insight;mRNA Precursor;programs;research study;stem


application_id: 7932892
project_number: 5R01AI050656-07
project_title: Molecular Mechanisms Controlling NK Receptors
administering_ic: NIAID
award_notice_date: 2010-08-09
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AI
serial_number: 050656
program_official: MILLER, LARA R
project_start_date: 2003-09-01
project_end_date: 2011-09-22
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 1882143
contact_pi: LUTZ, CHARLES T.
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Natural killer (NK) cells kill infected and malignant cells and direct subsequent adaptive immunity. NK cells distinguish normal from aberrant cells largely via killer cell immunoglobulin-like receptors (KIR). Despite high homology between KIR genes individual NK cells express distinct numbers and combinations of clonally-restricted KIR (crKIR) genes. In contrast to crKIR KIR2DL4 is expressed by all NK cells preceding crKIR expression during NK development. The long-range goal is to use NK cells as effective treatments of cancer and infectious diseases. As the next logical step toward that goal the current objectives are to further characterize KIR expression control in normal physiology and during epigenetic therapy of lymphoma and myelodysplastic syndrome. The rationale for the proposed research is that once KIR gene regulation is better understood then KIR expression can be manipulated to make effective NK cells reagents in immunotherapy of cancer and infectious diseases. In this proposal 2DL4 and crKIR promoters will be investigated with special attention to mechanisms that overcome DNA methylation and repressive chromatin. Because so little is known about how lymphocyte-specific gene expression is influenced by cancer and by epigenetic therapy we will study how DNA methylation and histone deacetylase inhibitor drugs affect KIR promoter methylation KIR expression and NK cell activation in myelodysplastic syndrome and lymphoma patients. This work may explain why NK function is poor in cancer patients and might suggest strategies for boosting immunity in these patients. We will catalog NK cell microRNA expression and their target mRNAs and we will investigate the microRNA mechanisms that regulate "dangerous" cytotoxic NK cells and "unlicensed" inhibitory receptor- negative NK cells. This will provide the basic information needed for future studies on control of NK developmental decisions in health and disease. This study will 1) develop a clear understanding of the multiple layers of regulation that control the initiation and maintenance of KIR expression; 2) establish for the first time how epigenetic therapy affects nonmalignant human lymphocyte gene expression and function in vivo; and 3) reveal NK-specific microRNA patterns and elucidate how they control mRNA targets to regulate NK development and set NK cell activation thresholds. These results will be highly significant because they will be essential for understanding how NK cells distinguish normal from aberrant cells. Such an understanding will suggest new ways to manipulate NK cells in the therapy of cancer and infectious diseases. PUBLIC HEALTH RELEVANCE: Natural killer (NK) cells kill infected and malignant cells and direct subsequent adaptive immunity. The long-range goal is to use NK cells as effective treatments of cancer and infectious diseases. As the next logical step toward that goal the current objectives are to further characterize NK gene expression control in normal physiology and in cancers and pre-cancers such as lymphoma and myelodysplastic syndrome.

project_terms:
Abbreviations;Address;Affect;Aftercare;Alleles;Antibody -dependent cell cytotoxicity;Attention;Autoimmunity;Binding (Molecular Function);Bioinformatics;CREB1 gene;Cancer Patient;Cataloging;Catalogs;Cells;Chromatin;Co-Immunoprecipitations;Communicable Diseases;Complement;DNA;DNA Methylation;DNA Methyltransferase;DNA Modification Methylases;Data;Development;Disease;Distal;Double-Stranded RNA;Dysmyelopoietic Syndromes;EMSA;Electrophoretic Mobility Shift Assay;Elements;Epigenetic Process;Fluorescence;Future;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Goals;Health;Histone Deacetylase;Histone Deacetylase Inhibitor;Histone H3;Human;Human Herpesvirus 4;Immunity;Immunoglobulins;In Vitro;Individual;Interleukin-15;Interleukin-2;Investigation;Killer Cells;Knowledge;Lead;Licensing;Ligands;Lymphocyte;Lymphocyte Function;Lymphoma;Lysine;MHC Class I Genes;Maintenance;Malignant Neoplasms;Messenger RNA;Methods;Methylation;MicroRNAs;Molecular;Mus;NK Cell Activation;Natural Immunity;Natural Killer Cells;Non-Malignant;Nucleotides;Patients;Pattern;Pharmaceutical Preparations;Physiology;Production;Promotor (Genetics);Proteins;Quantitative Reverse Transcriptase PCR;RNA Polymerase II;Reagent;Receptor Gene;Regulation;Research;Research Technics;Retroviridae;Role;Serum;Site;Stem cells;T-Lymphocyte;T-Lymphocyte and Natural Killer Cell;Testing;Time;Transcription Factor TFIIB;Transcriptional Regulation;Transfection;Untranslated Regions;Virus;Work;adaptive immunity;base;cancer cell;cancer immunotherapy;cancer therapy;cell killing;chemokine;chromatin immunoprecipitation;cytokine;cytotoxic;cytotoxicity;demethylation;effective therapy;expectation;histone modification;human disease;in vivo;innovation;insight;killer immunoglobulin-like receptor;novel;public health relevance;receptor;receptor expression;response;transcription factor

public_health_relevance:
Natural killer (NK) cells kill infected and malignant cells and direct subsequent adaptiveimmunity. The long-range goal is to use NK cells as effective treatments of cancer andinfectious diseases. As the next logical step toward that goal the current objectives are to furthercharacterize NK gene expression control in normal physiology and in cancers and pre-cancerssuch as lymphoma and myelodysplastic syndrome.


application_id: 7932373
project_number: 7R01AG025908-06
project_title: Vulnerability to sepsis in old age
administering_ic: NIA
award_notice_date: 2009-09-23
application_type: 7
activity_code: R01
ic: AG
serial_number: 025908
program_official: FLORES, ROBERTO L
project_start_date: 2005-05-15
project_end_date: 2012-04-30
study_section: Special Emphasis Panel[ZRG1-ASG(01)Q]
contact_pi_person_id: 8163817
contact_pi: SAITO, HIROSHI
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-09-30
project_abstract:
DESCRIPTION (provided by applicant):   Sepsis is an infection-initiated manifestation of the systemic inflammatory response syndrome that often progresses to septic shock multiple organ failure with high risks of death. Sepsis is a particularly serious problem in the geriatric population as the elderly patients with sepsis suffer much higher morbidity and mortality than younger patients. In fact sepsis is a major cause of death in elderly patients at intensive care units in the US. Although this problem is increasingly recognized the underlying mechanism(s) responsible for this age-associated vulnerability remain largely unknown. The long-term goal of our research is to determine the mechanisms responsible for the increased septic vulnerability in the aged and to use this information to develop new treatment strategies for sepsis. The age-associated vulnerability to sepsis is also seen in animal models. We have shown that aged mice suffer significantly higher mortality than young mice in two commonly used models for sepsis; endotoxemia induced by bacterial lipopolysaccharide injection and an intra-abdominal sepsis induced by cecal ligation and puncture. We have also found that the elevated mortality in aged mice is associated with altered inflammatory and coagulation responses and increased oxidative damages. Our central hypothesis is that loss of homeostasis in old age leads to excessive inflammation oxidative damage and coagulation contributing to the age-associated vulnerability to sepsis. Our objective in this project is to define the age-associated alterations in pathophysiology and gene expression in the mouse model of sepsis and to develop strategies to improve the survival of the old mice with sepsis. To achieve these goals we pursue the following three specific aims: (1) To determine the effects of aging on the pathophysiology of sepsis (2) To identify the age-associated alterations in gene expression that affects mortality in sepsis and (3) To test likely strategies for their ability to decrease age-associated mortality in sepsis. The information obtained from this project should provide the basis for new therapeutic strategies to substantially decrease the mortality in elderly patients with sepsis.

project_terms:
Accounting;Affect;Age;Aging;Animal Model;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Cause of Death;Cessation of life;Characteristics;Clinical Trials;Coagulants;Coagulation Process;Doctor of Philosophy;Elderly;Endotoxemia;Endotoxins;Enzymes;Foundations;Functional disorder;Future;Gene Expression;Genes;Goals;Heart;Homeostasis;Incidence;Infection;Inflammation;Inflammatory;Injection of therapeutic agent;Intensive Care Units;Intra-abdominal;Kidney;Ligation;Lipopolysaccharides;Liver;Lung;Mediator of activation protein;Messenger RNA;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Multiple Organ Failure;Mus;Mutant Strains Mice;Organ;Oxidative Stress;Patients;Population;Proteins;Puncture procedure;Research;Research Personnel;Role;Saline;Sepsis;Sepsis Syndrome;Septic Shock;Spleen;Testing;Tissues;age effect;aged;base;high risk;improved;innovation;interest;juvenile animal;middle age;mouse model;novel therapeutics;older patient;oxidative damage;research study;response;septic;successful intervention;treatment strategy


application_id: 7932172
project_number: 5F30MH079531-04
project_title: Pre- and Post-operative Differences in Brain and Sleep-related Events in Children
administering_ic: NIMH
award_notice_date: 2010-08-13
opportunity_number: PA-05-151
application_type: 5
activity_code: F30
ic: MH
serial_number: 079531
program_official: CHURCHILL, JAMES D
project_start_date: 2007-08-15
project_end_date: 2011-08-14
study_section: Special Emphasis Panel[ZRG1-F12A-D(20)L]
contact_pi_person_id: 8193534
contact_pi: BARNES-DAVIS, MARIA E
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): In an estimated 1-3% of the pediatric population Obstructive Sleep Apnea (OSA) is likely responsible for many behavioral and neurocognitive dysfunctions. Recently the American Academy of Pediatrics highlighted the need to study the progression of pediatric OSA after surgical intervention. In previous studies measures of neurocognitive function were based on behavioral tasks or questionnaires completed by the caregiver. A more objective and reliable measure of the efficacy of adenotonsillectomy (AT) for OSA is needed. I hypothesize that children diagnosed with OSA by overnight polysomnography (PSG) will exhibit differences in event-related potentials (ERPs) when presented with auditory and visual tasks that tap the cognitive functions of the brain's frontal lobes. High-density ERP techniques are safe and effective in children and they provide insight into the electrical activity of the brain at the millisecond level. These time- locked waveforms can also be used to form spatial models which help localize electrical activity in the brain. ERP differences in childhood have been linked to behaviorally observed cognitive impairment and learning disorders. Differences such as decreased peak amplitudes and increased latencies of specific waveforms discussed later in the proposal might serve as markers for the cognitive deficits associated with sleep- disordered breathing. After AT these measures should normalize. I propose to contribute to the current research by accomplishing three aims: (1) measuring cognitive and electrophysiological changes in children with OSA before and after surgery using ERPs; (2) examining the postoperative changes in clinical symptoms with behavioral tasks standard neuropsychological assessments and physiological measures such as PSG; (3) obtaining the experience instruction and writing skills needed to become a functioning member of the scientific community. This proposal relates to the goals of NIH and NIMH in that it seeks to further understanding of the processes of neurobehavioral development with a focus on childhood (a period of rapid change during which the brain is particularly sensitive) and to employ several techniques to assess the severity of OSA and accompanying behavioral or psychological pathology. The proposed study will have a positive impact on public health by testing the extent to which sleep disorders like OSA affect the functioning of our children and assessing whether the commonly performed surgery actually resolves cognitive and behavioral problems. Increased awareness of the importance of sleep and treatment of sleep disorders in childhood is greatly needed. This study will further inform the scientific community and the public on the protection of sleep hygiene and the consequences and treatment of pediatric sleep disorders.

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


application_id: 7932070
project_number: 5R01AT004294-05
project_title: Curcumin reverses tumor exosomes-mediated inhibition of myeloid differentiation
administering_ic: NCCIH
award_notice_date: 2010-09-09
opportunity_number: RFA-AT-06-004
application_type: 5
activity_code: R01
ic: AT
serial_number: 004294
program_official: HOPP, CRAIG
project_start_date: 2007-09-30
project_end_date: 2014-09-29
study_section: ZAT1-SM(06)
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
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):  The naturally occurring polyphenol curcumin has been shown to be a potent chemotherapeutic agent in a variety of tumor models; however its effects on tumor-associated immunosuppression have not been investigated to any great extent. The accumulation of immature myeloid cells is a hallmark of cancer and our data indicate that exosomes produced by tumors can suppress the differentiation of immature myeloid cells (iMCs). We have now found that curcumin treatment inhibits the tumor exosome-mediated suppression of differentiation of IMCs in mice preventing their accumulation in the spleen and delaying tumor growth. Analysis of the composition of the tumor exosomes using a proteomics approach identified CSN5 as a candidate regulatory molecule and siRNA knockdown of CSN5 resulted in attenuation of the tumor exosome- mediated induction of IMCs in the spleen suggesting that exosomal CSN5 plays a key role in tumor exosome-mediated immune suppression. We have now found that curcumin treatment destabilizes exosomal CSN5. The exosomal CSN5 is stable when associated with phosphorylated STAM1. Curcumin treatment leads to the dephosphorylation of STAM1 permitting the recruitment of an E3 ligase BARD1/BRCA1 to the CSN5 complex resulting in CSN5 degradation. Our in vitro kinase assay results indicate that the curcumin- mediated disassociation of STAM1 from CSN5 complex is most likely due to the inhibition of CSN5- associated kinase activity. The clinical relevance of these studies is supported by our recent data that indicate that CSN5 is packed in exosomes isolated from the peripheral blood of breast cancer patients but not healthy subjects. We propose: (1) To use siRNA technology to determine if tumor exosomal CSN5 is a primary target of curcumin in its prevention of breast tumor exosome-mediated immunosuppression; (2) To determine whether CSN5-associated kinase activity prevents BARD1/BRCA1 E3 complex degradation of CSN5 in TS/A tumor cells; and (3) To determine whether curcumin treatment of human tumor cells results in degradation of CSN5 and prevents blocking of differentiation of CD33 (equivalent to mouse GDI lb+) Grl+ cells. We will further determine if exosomes packed with CSN5 circulate in the peripheral blood of patients with breast cancer and if overproduction of exosomes is correlated with the accumulation of iMCs in patients with breast cancer. RELEVANCE: The data generated should identify a novel mechanism for the actions of curcumin and identify its molecular targets in preventing CSN5/tumor exosome-mediated blockade of myeloid cell differentiation.

project_terms:
Address;Antineoplastic Agents;BARD1 gene;Biological Assay;Cancer Patient;Cell Differentiation process;Cells;Chemopreventive Agent;Co-Immunoprecipitations;Complex;Curcuma longa;Curcumin;Data;Doctor of Medicine;Doctor of Philosophy;Growth;Guanine Nucleotide Dissociation Inhibitors;Human;ITGAM gene;In Vitro;Knock-out;Malignant Neoplasms;Mammary Neoplasms;Mediating;Modeling;Molecular;Molecular Target;Mus;Myelogenous;Myeloid Cells;Natural immunosuppression;Nude Mice;Pathway interactions;Patients;Phosphorylation;Phosphorylation Inhibition;Phosphotransferases;Play;Prevention;Production;Protein Dephosphorylation;Proteomics;RCA1 gene;Research Personnel;Rhizome;Role;Screening procedure;Site;Small Interfering RNA;Spleen;T-Lymphocyte;Technology;Treatment Efficacy;Tumor Cell Line;Tumor Suppressor Genes;Ubiquitination;Yeasts;attenuation;chemotherapeutic agent;clinically relevant;equilibration disorder;in vitro testing;in vivo;malignant breast neoplasm;mouse model;neoplastic cell;novel;overexpression;peripheral blood;polyphenol;prevent;programs;tumor;tumor growth;ubiquitin-protein ligase;yeast two hybrid system


application_id: 7931490
project_number: 3U01DP000251-03S1
project_title: Breast and Prostate Cancer Patterns of Care in Kentucky
administering_ic: NCCDPHP
award_notice_date: 2009-09-15
opportunity_number: RFA-DP-05-071
application_type: 3
activity_code: U01
ic: DP
serial_number: 000251
suffix: S1
program_official: COLLEY GILBERT, BRENDA J
project_start_date: 2005-09-30
project_end_date: 2010-09-29
study_section: ZDP1-GXC(01)
contact_pi_person_id: 1860311
contact_pi: FLEMING, STEVEN THOMAS
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
project_abstract:
The purpose of this research is to conduct "enhanced surveillance and operations research using population-based data" from the Kentucky Cancer Registry (KCR). KCR has been a part of the Centers for DiseaseControl and Prevention (CDC) National Program of Cancer Registries (NPCR) since the inception of theinitiative and KCR is one of the recent additions to the Surveillance Epidemiology and End Results (SEER)program of the National Cancer Institute. Byfocusing on improved "completeness timeliness quality anduse of first course of treatment and stage data" we will strengthen the capacity of an already outstandingcancer registry to describe patterns of care for breast and prostate cancer. We will focus on understandinghow tumor patient provider and health system characteristics affect the degree to which patients receivethe recognized standard of care. To this end we propose the following aims: (1) Describe treatment patternsfor stages I through III of female breast cancer in terms of the proportion who receive the recognizedstandard of care; (2) Describe treatment patterns for all stages of prostate cancer; (3) Determine how tumorpatient provider and health system characteristics affect treatment strategies for breast and prostatecancer; (4) Assess the completeness and quality of stage and first course of treatment data and comparethe latter to evidence of treatment from Medicare claims data. We believe that the proposed study will makea significant contribution toward building the capacity to conduct enhanced surveillance at an alreadyoutstanding cancer registry in the state of Kentucky. We also believe that this study will help us tounderstand the degree to which breast and prostate cancer patients receive the recognized standard ofcare and the factors that move doctors and patients to deviate from that standard. Such understandingshould help us distinguish those factors that represent legitimate and reasonable causes for such deviationfrom the factors that may represent unreasonable causes such as barriers to access or discrimination.


application_id: 7931443
project_number: 3P20RR020145-05S1
project_title: Center for Biologic Basis of Oral/Systemic Diseases (CB*
administering_ic: NCRR
award_notice_date: 2009-09-24
opportunity_number: RFA-RR-03-014
application_type: 3
activity_code: P20
ic: RR
serial_number: 020145
suffix: S1
program_official: DOUTHARD, REGINE
project_start_date: 2009-09-24
project_end_date: 2012-09-23
study_section: ZRR1-RI-5(02)
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
This subproject is one of many research subprojects utilizing the
resources provided by a Center grant funded by NIH/NCRR. The subproject and
investigator (PI) may have received primary funding from another NIH source
and thus could be represented in other CRISP entries. The institution listed is
for the Center which is not necessarily the institution for the investigator.
To implement an intervention trial to effectively improve oral health in the GDM women with "at-risk" pregnancies and lower the risk of adverse pregnancy outcomes.


application_id: 7931226
project_number: 3R01GM079516-03S1
project_title: Structural and Functional Studies of the SMC5-6 Complex
administering_ic: NIGMS
award_notice_date: 2009-09-30
application_type: 3
activity_code: R01
ic: GM
serial_number: 079516
suffix: S1
program_official: PREUSCH, PETER
project_start_date: 2009-09-30
project_end_date: 2011-08-31
study_section: Macromolecular Structure and Function C Study Section[MSFC]
contact_pi_person_id: 8139941
contact_pi: YE, HONG
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: Y
project_abstract:
DESCRIPTION (provided by applicant):  The structural maintenance of chromosomes (SMC) proteins which are evolutionarily conserved from prokaryotes to eukaryotes are essential for higher order chromosome organizations and functions. Six members of SMCs have been identified in eukaryotes which form three distinct complexes: cohesin condensin and the Smc5/6 complex. Each of the SMC complexes has a unique function. Cohesin is responsible for linking sister chromatids during mitosis and meiosis whereas condensin is required for condensation of chromosomes during mitosis and meiosis. The Smc5/6 holocomplex formed by a heterodimer of Smc5 and Smc6 in association with six non-SMC components in both Saccharomyces cerevisiae and Schizosaccharomyces pombe is localized on repetitive rDNA and telomere and is important for DNA replication and double stranded DNA damage repair through homologous recombination.    SMC proteins are organized into five domains: an N-terminal head domain a long coiled-coil helix a hinge domain another long coiled-coil helix and a C-terminal head domain. The N- and C-terminal head domains associate together to form an ATPase head domain. The long coiled-coil helices associate together to form the coiled-coil arm. The hinge domain dimerizes to form the hinge of the complex. While the head appears to recognize DNA the hinge controls the spatial topology of the arms and the head and therefore the conformation of overall structure. In the Smc5/6 holocomplex the non-SMC component Mms21 a SUMO E3 ligase is important for Smc5/6-mediated DNA damage repair. The molecular mechanism of the function is unclear. In addition limited structural information is available on SMC complexes especially Smc5/6. To fill this gap we propose a series of comprehensive studies on several important aspects of this complex which will have tremendous impact on the molecular basis of Smc5/6 function as well as the functions of cohesin and condensin.

project_terms:
ATP phosphohydrolase;C-terminal;Cells;Characteristics;Chromosome Condensation;Chromosome Structures;Chromosomes;Complex;DNA;DNA Binding;DNA Repair;DNA biosynthesis;Eukaryota;Fingers;Fission Yeast;Head;Heterodimerization;In Vitro;Investigation;Length;Ligase;Link;Maintenance;Maps;Mediating;Meiosis;Mitosis;Molecular;Molecular Conformation;Mutation;N-terminal;Phenotype;Prokaryotic Cells;Proteins;Recombinant DNA;Recombinants;Research Personnel;Resolution;Saccharomyces cerevisiae;Series;Sister Chromatid;Site;Structure;Upper arm;Yeasts;base;cohesin;condensin;ds-DNA;homologous recombination;in vivo;member;programs;telomere;ubiquitin-protein ligase


application_id: 7930649
project_number: 5R01AG033036-02
project_title: The effects of bilingualism on age-related cognitive and neurobiological declines
administering_ic: NIA
award_notice_date: 2010-08-26
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AG
serial_number: 033036
program_official: WAGSTER, MOLLY V
project_start_date: 2009-09-15
project_end_date: 2014-08-31
study_section: Cognitive Neuroscience Study Section[COG]
contact_pi_person_id: 7993908
contact_pi: GOLD, BRIAN TIMOTHY
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): Executive control refers to a set of supervisory processes that enable humans to flexibly shape thoughts and behavior in order to accomplish internal goals. Normal human aging is associated with marked decline in executive control functions. However recent evidence suggests that lifelong bilingualism may attenuate age-related declines of some executive control functions. These findings suggest that bilingualism may promote neuroplasticity and/or compensatory brain reserve. However despite potentially large social and scientific implications considerable knowledge gaps exist in this field. The present work will fill several of these gaps through a series of studies aimed to understand the influences of bilingualism on cognition and neurobiology in aging. Specific Aim 1 is to obtain more detailed information about the influence of lifelong bilingualism on high-level working memory processes. Specific Aims 2-4 use cutting-edge neuroimaging methods to understand the neurobiological bases of bilingual executive control advantages. These aims are to understand potential functional neuroanatomic (Aim 2) structural grey matter (Aim 3) and white matter microstructure (Aim 4) bases of bilingual performance advantages by linking imaging patterns directly to behavioral performance. Specific Aim 5 is to determine which bilingual cognitive/neurobiological advantages correlate with degree of experience/practice with the second language. Given the projected increase in the aged population it is important to understand how specific lifestyle factors may affect age-related cognitive and neurobiological declines. Results from the present proposal will provide a detailed description of how an accessible lifestyle variable can offset age- related cognitive declines through neurobiological plasticity and/or compensatory brain reserve. Finally research relevant to understanding the consequences of bilingualism is an issue of fundamental importance in our increasingly multilingual society. PUBLIC HEALTH RELEVANCE: Normal human aging is associated with decline of executive control functions. Recent evidence suggests that bilingualism may attenuate some of these age-related declines by promoting neuroplasticity and/or compensatory brain reserve. By providing a more precise understanding of the mechanisms that are bolstered by bilingualism the present proposal will help identify cognitive/neurobiological markers that remain malleable in aging in response to an accessible lifestyle variable.

project_terms:
Address;Affect;Age-associated memory impairment;Aging;Anisotropy;Attenuated;Behavior;Behavioral;Brain;Brain region;Cognition;Cognitive;Conflict (Psychology);Educational Intervention;Functional Magnetic Resonance Imaging;Functional disorder;Goals;Human;Image;Knowledge;Language;Life Style;Link;Maintenance;Methods;Neurobiology;Neuronal Plasticity;Pattern;Performance;Population;Principal Investigator;Process;Research;Series;Shapes;Short-Term Memory;Societies;Staging;Structure;Thinking function;Update;Variant;Work;age related;aged;base;bilingualism;executive function;experience;gray matter;imaging modality;improved;interest;lifestyle factors;memory process;neurobiological mechanism;neuroimaging;neuromechanism;neuroprotection;peer;programs;public health relevance;relating to nervous system;research study;response;social;white matter


application_id: 7929884
project_number: 5R21AG034279-02
project_title: Contribution of altered muscle hemodynamics to fatigability in older persons with
administering_ic: NIA
award_notice_date: 2010-08-16
opportunity_number: PA-08-162
application_type: 5
activity_code: R21
ic: AG
serial_number: 034279
program_official: ELDADAH, BASIL A
project_start_date: 2009-09-15
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZRG1-CFS-D(01)S]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: CROFFORD, LESLIE J
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant):  Fibromyalgia (FM) is a clinical state of widespread musculoskeletal pain with multiple tender points that is most common in postmenopausal women. Fatigue particularly post-exertional is an additional hallmark of the syndrome. FM likely has no single etiology and may have neuroendocrine neurologic immune and musculoskeletal components. Fatigue and fatigability also contribute directly to functional dependence and activity limitations that impact quality of life among the aged. Although associated with co-morbidities fatigue in the elderly is often not associated with an identified medical cause. The relationship among fatigue associated with FM fatigue associated with disease and exacerbation of fatigue symptoms with age are unexplored. The goal of this pilot study is to identify defects in muscle physiology of older FM patients as well as older healthy but fatigable individuals which may contribute to this symptom. Older normal healthy women and women who are healthy but prove most fatiguable during testing as well as older women diagnosed with FM will be studied. Aim 1 will test the hypothesis that decreased blood flow and reduced muscle oxygenation contribute directly to pain and post exercise fatigue. Using novel noninvasive near-infrared diffuse optical spectroscopies muscle blood flow and oxygen saturation will be quantified before during and after an acute bout of exercise. To identify mechanisms underlying reduced tissue oxygenation muscle microvasculature will be analyzed in Aim 2. Vascular density and endothelial function will be assessed in muscle biopsies by immunofluorescent detection of endothelial cell antigens and detection of endothelial alkaline phosphatase and non-invasively with the flow-mediated dilatation (FMD) test and optical probe. Aim 3 will test the hypothesis that the long term consequence of reduced muscle oxygenation may be compromised mitochondrial function. Assays of mitochondrial oxidative phosphorylation from muscle biopsies will be performed including respiration rates and complex I-IV activities. Aberrant accumulation of mitochondrial metabolites may alter muscle vasodilatory properties further reducing oxygen availability contributing to the pain and fatigue of FM as well as fatigue in the elderly.  PUBLIC HEALTH RELEVANCE: Fibromyalgia is increasingly common in postmenopausal women. As FM is commonly associated with pain fatigue sleep disturbances depression psychological and mood disorders and cognitive deficiencies individuals with FM may suffer from temporary to permanent debilitation. This project will explore the role of altered muscle physiology as a contributor to the pain and fatigue experienced by fibromyalgic patients as well as older healthy women experiencing fatigue.

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

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


application_id: 7928721
project_number: 5R21AT004544-02
project_title: CAM Referral and Outcomes: Chronic Low Back Pain in Urban and Rural Primary Care
administering_ic: NCCIH
award_notice_date: 2010-06-11
opportunity_number: PAR-07-291
application_type: 5
activity_code: R21
ic: AT
serial_number: 004544
program_official: WEBER, WENDY J
project_start_date: 2009-09-30
project_end_date: 2012-06-30
study_section: ZAT1-LD(30)
contact_pi_person_id: 7875359
contact_pi: ELDER, WILLIAM GIBBS
other_pis: LOVE, MARGARET M
congressional_district: 06
department: FAMILY 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): Kentucky ranks 2nd in disability among states with chronic low back pain (CLBP) as a major disability especially in our rural areas. In the last few years the medical use of opiate medications has significantly increased. Their use has complicated treatment greatly with addiction rates and misuse skyrocketing. Kentucky and U.S. health care providers need alternative and effective treatments. Following NCCAM strategic research recommendations this study will investigate health services outcomes of complementary and alternative medicine (CAM) therapies in an existing primary care practice-based research network (PBRN). The Kentucky Ambulatory Network (KAN) is the partnering PBRN. Patients with CLBP are often willing to try therapeutic options outside the conventional medical spectrum. Massage and relaxation therapies have demonstrated fairly good efficacy in controlled trials but their effectiveness in the "real world" of primary care is only beginning to be evaluated. The long-term goal of the proposed project builds on the foundation of these two established therapies to improve treatment of chronic low back pain (CLBP) in primary care practices. Two alternative (CAM) therapies progressive muscle relaxation (PMR) and clinical massage therapy (CMT) will be studied. The short-term objectives of the proposed project are to: (1) examine outcomes of CAM for patients with CLBP referred from primary care practices and (2) better understand physician decision-making to recommend CAM therapy for CLBP. Specific Aim 1 will evaluate improvement in health-related outcomes for patients with CLBP when referred to PMR or CMT from primary care. Specific Aim 2 will explore selected factors in primary care physicians' decisions to recommend CAM therapy to these patients. The proposed study is unique in that it addresses "real life" clinical situations and decision-making in both urban and rural clinical practices within an existing PBRN. Should such CAM referral prove successful for ameliorating CLBP it would provide relatively low cost non-addictive treatment options for inclusion in the repertoire of primary care physicians.  
  
PUBLIC HEALTH RELEVANCE: The "CAM Referral and Outcomes: Chronic Low Back Pain in Urban and Rural Primary Care" project will investigate clinical and patient-oriented outcomes of CAM therapies in an existing practice-based research network (PBRN). For patients with chronic low back pain we will examine the outcomes of clinical massage therapy and progressive muscle relaxation when referred by primary care physicians as well as selected factors in the physicians' decisions to recommend these therapies.

project_terms:
Address;Adoption;Back Pain;Caring;Characteristics;Chronic low back pain;Client satisfaction;Clinical;Collaborations;Communication;Communities;Community Medicine;Complementary and alternative medicine;Decision Making;Educational aspects;Effectiveness;Family;Family Physicians;Foundations;Goals;Grant;Health Personnel;Health Services;Kentucky;Licensing;Life;Long-Term Effects;Massage;Medical;Methodology;Modality;Muscle relaxation phase;National Center for Complementary and Alternative Medicine;Opiates;Outcome;Pain;Patients;Pharmaceutical Preparations;Physicians;Practice based research;Preparation;Primary Care Physician;Primary Health Care;Recommendation;Relaxation Therapy;Reporting;Research;Rural;Students;Surveys;Testing;Therapeutic;Time;Training;Universities;addiction;base;clinical practice;control trial;conventional therapy;cost;disability;effective therapy;health related quality of life;improved;lectures;member;patient oriented;practice-based research network;programs;public health relevance;rural area;willingness

public_health_relevance:
Project NarrativeThe "CAM Referral and Outcomes: Chronic Low Back Pain in Urban and Rural Primary Care"project will investigate clinical and patient-oriented outcomes of CAM therapies in an existingpractice-based research network (PBRN). For patients with chronic low back pain we willexamine the outcomes of clinical massage therapy and progressive muscle relaxation whenreferred by primary care physicians as well as selected factors in the physicians' decisions torecommend these therapies.


application_id: 7928246
project_number: 5R01HD057446-02
project_title: The MMP system in human ovulation: localization regulation and function
administering_ic: NICHD
award_notice_date: 2010-08-30
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HD
serial_number: 057446
program_official: TAYMANS, SUSAN
project_start_date: 2009-09-15
project_end_date: 2014-07-31
study_section: Cellular, Molecular and Integrative Reproduction Study Section[CMIR]
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Animals;Antibodies;Apoptosis;Cell Surface Proteins;Cleaved cell;Contraceptive Agents;Data;EGF gene;Event;Extracellular Matrix;Family;Fertility;Foundations;Gonadotropins;Growth Factor;Human;Human Chorionic Gonadotropin;Interstitial Collagenase;Knock-out;Matrix Metalloproteinase Inhibitor;Matrix Metalloproteinases;Mediator of activation protein;Metalloproteases;Modeling;Oocytes;Ovarian;Ovarian Follicle;Ovarian Tissue;Ovary;Ovulation;Pattern;Peptide Hydrolases;Physiology;Play;Principal Investigator;Process;Progesterone;Prostaglandins;Proteins;Proteolysis;Proteomics;RNA Interference;Regulation;Rodent;Role;Rupture;Signal Pathway;System;Time;cell growth;cytokine;egg;inhibitor/antagonist;member;novel;programs;public health relevance;research study;theca cell


application_id: 7927942
project_number: 3K01DK080951-01A1S1
project_title: Endoplasmic Reticulum-Induced Stress and Apoptosis in the Renal Tubule
administering_ic: NIDDK
award_notice_date: 2009-09-17
opportunity_number: PA-06-001
application_type: 3
activity_code: K01
ic: DK
serial_number: 080951
suffix: A1S1
program_official: RANKIN, TRACY L
project_start_date: 2009-09-21
project_end_date: 2011-08-31
study_section: Kidney, Urologic and Hematologic Diseases D Study Section[DDK-D]
contact_pi_person_id: 9091714
contact_pi: BARATI, MICHELLE T
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 candidate's overall career goal is to establish an independent research program devoted to investigating cellular mechanisms of proteinuric nephropathies with an emphasis on diabetic nephropathy (DN). Currently DN is the leading cause of end stage renal disease in the United States. Proteinuria is an independent risk factor critical to pathogenesis and progression of renal function loss. Regardless of disease origin renal tubule function is critical to the progression of renal damage and development of renal failure. The precise molecular mechanisms and targets of proteinuria and hyperglycemia causing tubule damage in DN remain unclear. This emphasizes the health-related importance for discovery of novel regulatory events as potential therapeutic targets. The endoplasmic reticulum (ER) stress response induced by accumulation of misfolded proteins in the ER is a mechanism elicited by cells to alleviate stress through induction of specific genes. Unresolved ER stress response leads to ER stress-induced apoptosis. Initial studies from our laboratory demonstrate induction of ER stress and ER stress-induced apoptosis in tubules of proteinuric diabetic mice. This suggests the hypothesis that ER stress is pathogenic in renal tubule damage in DN. This project will define the role of proteinuria and hyperglycemia alone and in combination to tubule ER stress and apoptosis in a transgenic mouse model of type I diabetes. Next cell signaling events mediating tubule ER stress and apoptosis induction in DN will be examined. To accomplish this the candidate will be trained in development of speed congenic transgenic mice. In addition the candidate will be trained in protein purification mass spectrometry and informatic techniques to define interactions in protein complexes mediating ER stress. Finally the candidate will receive training in advanced molecular biology techniques to define the specific role of proteins involved in stress response to tubule cell function. The combination of training obtained during this award coupled to the identification of molecular events mediating tubule damage in DN will enable the candidate with resources to continue and expand research pertaining to DN.  PUBLIC HEALTH RELEVANCE: Currently DN is the leading cause of end stage renal disease in the United States. Proteinuria is an independent risk factor critical to pathogenesis and progression of renal function loss. The precise molecular mechanisms and targets of proteinuria and hyperglycemia causing tubule damage in DN remain unclear. This emphasizes the importance for discovery of novel regulatory events as potential therapeutic targets.

project_terms:
Address;Albumins;Apoptosis;Award;Calcium;Cell physiology;Cells;Coupled;Data;Defect;Development;Diabetes Mellitus;Diabetic Nephropathy;Diabetic mouse;Disease;End stage renal failure;Endoplasmic Reticulum;Event;Functional disorder;Generations;Genes;Glucose;Goals;Growth Factor;Homeostasis;Hyperglycemia;Induction of Apoptosis;Informatics;Insulin-Dependent Diabetes Mellitus;Islet Cell;Kidney;Kidney Diseases;Kidney Failure;Laboratories;Lead;Lesion;Mass Spectrum Analysis;Mediating;Molecular;Molecular Biology Techniques;Molecular Chaperones;Mus;Neurodegenerative Disorders;Oxidative Stress;Pathogenesis;Permeability;Play;Process;Protein Export Pathway;Protein Synthesis Induction;Proteins;Proteinuria;Puromycin;Quality Control;Rattus;Reactive Oxygen Species;Renal function;Renal tubule structure;Research;Resources;Risk Factors;Role;Signal Transduction;Speed (motion);Stimulus;Stress;Techniques;Testing;Training;Transgenic Mice;Tubular formation;United States;biological adaptation to stress;career;congenic;cytokine;diabetic;endoplasmic reticulum stress;mouse model;neuron loss;novel;outcome forecast;programs;protein complex;protein misfolding;protein purification;public health relevance;therapeutic target


application_id: 7927162
project_number: 5R21DA027466-02
project_title: Developmental Cigarette Smoke Exposure: Biomarkers of Neurotoxicity
administering_ic: NIDA
award_notice_date: 2010-07-29
opportunity_number: RFA-DA-09-022
application_type: 5
activity_code: R21
ic: DA
serial_number: 027466
program_official: KOUSTOVA, ELENA
project_start_date: 2009-09-15
project_end_date: 2012-08-31
study_section: ZDA1-JXR-D(06)R
contact_pi_person_id: 1866555
contact_pi: PISANO, M. MICHELE
other_pis: NEAL, RACHEL ELIZABETH
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):  Nicotine a highly addictive psychotropic drug is rapidly transported to the brain following tobacco smoke inhalation. Approximately 20% of US adults (36 million) are active smokers. Despite extensive national publicity regarding the detrimental effects of tobacco use during pregnancy 25% of women continue to smoke throughout their pregnancy. As a result approximately one million infants are exposed prenatally to cigarette smoke each year. Developmental cigarette smoke exposure is associated with decreased in utero growth and perturbations in both cellular and molecular neurodevelopment which are thought to mediate the increased rates of cognitive and behavioral problems that are observed in humans and experimental animal models. In the current application we propose to test the hypotheses that 1) exposure to tobacco smoke results in temporal dysregulation of the serum metabolome which parallels alterations in the hippocampal metabolome and proteome and 2) such dysregulation persists through the development of neurocognitive deficits. We specifically propose to examine the impact of developmental tobacco smoke exposure on the expression of molecular markers of toxicity in a readily available biofluid (serum) and hippocampal tissue in offspring from a mouse model which simulates maternal cigarette smoking during pregnancy. Metabolome profiling in both Specific Aims 1 and 2 will employ LC-LIT/FT-ICR-MS coupled to spectral preprocessing including background subtraction normalization extraction and integration of peak intensities. Spectral features of interest will be identified by accurate mass measurement of parent and daughter ions followed by database searching (metabolites-HMDB METLIN and KEGG databases; proteins-NCBInr mammalian forward and reverse databases). If the proposed hypothesis is correct we will have identified peripheral biomarkers which are directly indicative of neurodevelopmental abnormalities with corresponding alterations in the hippocampal metabolome and proteome. In addition we will have identified potential molecular markers of behavioral and neurocognitive abnormalities that persist after withdrawal of the toxic exposure. These biomarkers will provide targets for future investigations into the epigenetic effects of environmental neurotoxins on neuro/cognitive development.  
  
PUBLIC HEALTH RELEVANCE: In the United States alone approximately one million infants are exposed prenatally to cigarette smoke each year! Maternal cigarette smoking has been associated with a variety of adverse fetal infant and childhood developmental outcomes - the most striking of which affect neurodevelopment cognitive function and behavior. Since diagnosis of these outcomes are often complicated and delayed studies proposed in the current application will utilize a mouse model simulating human maternal cigarette smoking during pregnancy to identify serum biomarkers in offspring that are affected by prenatal cigarette smoke exposure-induced neurotoxicity.

project_terms:
Acrolein;Adult;Affect;Age-Months;Animal Model;Area;Behavior;Behavioral;Brain;Butadiene;C57BL/6 Mouse;Cadmium;Carbon Dioxide;Chemicals;Childhood;Chloroform;Cigarette;Cognitive;Cognitive deficits;Coupled;Data;Databases;Daughter;Defect;Development;Devices;Diagnosis;Disease;Employee Strikes;Epigenetic Process;Experimental Animal Model;Exposure to;Fourier transform ion cyclotron resonance;Future;Gene Expression Profile;Growth;Hippocampus (Brain);Human;Impairment;Infant;Intoxication;Investigation;Ions;Laboratories;Lead;Lipids;Maps;Measurement;Measures;Mediating;Methanol;Molecular;Molecular Profiling;Morphogenesis;Nature;Neurocognitive;Neurocognitive Deficit;Neurotoxins;Nicotine;Nitric Oxide;Outcome;Parents;Pattern;Peripheral;Pharmaceutical Preparations;Pregnancy;Problem behavior;Protein Databases;Proteome;Proteomics;Psychotropic Drugs;Resolution;Rodent Model;Serum;Simulate;Smoke;Smoker;Smoking;Structure;Testing;Time;Tissues;Tobacco;Tobacco Industry;Tobacco smoke;Tobacco use;Toxic effect;Toxicant exposure;United States;Withdrawal;Woman;Work;biomarker;brain behavior;cigarette smoke;cigarette smoking;cognitive function;fetal;fetal tobacco exposure;in utero;interest;maternal cigarette smoking;molecular marker;mouse model;neurochemistry;neurodevelopment;neurotoxicity;offspring;postnatal;prenatal exposure;public health relevance;smoke inhalation;socioeconomics

public_health_relevance:
PROJECT NARRATIVEIn the United States alone approximately one million infants are exposed prenatally to cigarette smoke eachyear! Maternal cigarette smoking has been associated with a variety of adverse fetal infant and childhooddevelopmental outcomes - the most striking of which affect neurodevelopment cognitive function andbehavior. Since diagnosis of these outcomes are often complicated and delayed studies proposed in thecurrent application will utilize a mouse model simulating human maternal cigarette smoking during pregancy toidentify serum biomarkers in offspring that are affected by prenatal cigarette smoke exposure-inducedneurotoxicity.


application_id: 7926898
project_number: 5R21AA017956-02
project_title: In vitro and In vivo models for ethanol withdrawal and antepartum hypoxia
administering_ic: NIAAA
award_notice_date: 2010-08-19
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: AA
serial_number: 017956
program_official: BAIZER, LAWRENCE
project_start_date: 2009-09-05
project_end_date: 2012-08-31
study_section: Neuroscience and Behavior Study Section[AA-4]
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: Y
project_abstract:
DESCRIPTION (provided by applicant):  Fetal Alcohol Spectrum Disorder describes a wide range of behaviors and deficits that can occur as a consequence of prenatal alcohol exposure. These effects can range from relatively subtle learning deficits to significant mental retardation. Various explanations for differences in sensitivity to alcohol's effects have been proposed. One theory suggests that "provocative factors" can play a role in increasing the severity and/or providing a context in which the damaging effects of ethanol are increased. We propose that prenatal alcohol exposure may increase the adverse consequences of brief periods of hypoxia during the antepartum period when brief periods of hypoxia routinely occur. Normally the fetus/newborn is fairly resilient against mild hypoxia during labor and delivery however additional challenges (such as a history of in utero alcohol exposure or alcohol withdrawal) may put these infants at increased risk for adverse outcome. In this application we propose to develop two models. The first is an in vitro organotypic hippocampal slice culture model taken from 1-day-old rats. These cultures will be exposed to chronic alcohol followed by withdrawal and challenged with oxygen glucose deprivation (as a model of hypoxia). The hypothesis is that alcohol and hypoxia will produce greater damage than exposure to either challenge alone. Sub-threshold doses will also be included in this Specific Aim to assess the sensitivity of the hippocampus to these challenges. The 2nd model we will develop involves three trimester in vivo administration of alcohol first to pregnant dams and then to Sprague Dawley rat pups on postnatal day 1-7. Following alcohol withdrawal the pups will also be exposed to a mild hypoxic challenge and subsequently tested for a variety of behavioral endpoints including activity and measures of learning and memory. Our working hypothesis is that alcohol exposure and/or withdrawal and hypoxic challenges share similar mechanisms (including overactivity of NMDAR increased GLU activity and polyamine release) that could result in increased excitotoxic damage. The studies proposed will allow us to determine the potential validity of these models. In addition once we have established these models we can begin to study the underlying mechanisms and potential pharmacotherapeutic interventions to try and reduce the damage/deficits associated with alcohol withdrawal and hypoxia. These data could have significant clinical potential since our premise (and model) focuses on a relatively narrow developmental window which conceptually overlaps a time when women would typically be seeking medical assistance (i.e. labor and delivery) and intervention would be more likely.  
  
PUBLIC HEALTH RELEVANCE:  Mild bouts of hypoxia (or reduced oxygen availability) commonly occur during normal labor and delivery and the newborn is usually not affected by these if the bouts are not severe. We propose that one of the effects of prenatal alcohol exposure is to increase the risk of these minor bouts resulting in behavioral and CNS damage. The studies in this application will develop cell culture and rodent models to begin to address this clinically-relevant question.

project_terms:
Abbreviations;Address;Affect;Alcohol withdrawal syndrome;Alcohols;Animal Model;Behavior;Behavioral;Birth;Brain;Cell Culture Techniques;Cessation of life;Chronic;Clinical;Data;Development;Dose;Environmental Risk Factor;Ethanol;Excitatory Amino Acid Antagonists;Exposure to;Fetal Alcohol Exposure;Fetal Alcohol Spectrum Disorder;Fetal Alcohol Syndrome;Fetal alcohol effects;Fetus;Future;Genetic;Glucose;Glutamates;Hippocampus (Brain);Human;Hypoxia;In Vitro;Infant;Intervention;Learning;Life;Measures;Medical Assistance;Memory;Mental Retardation;Minor;Modeling;Neonatal;Newborn Infant;Outcome;Oxygen;Perinatal;Play;Polyamines;Pregnancy;Preparation;Published Comment;Rattus;Recording of previous events;Relative (related person);Research;Risk;Rodent Model;Role;Severities;Slice;Sprague-Dawley Rats;System;Teratogens;Testing;Time;Variant;Withdrawal;Woman;Work;adverse outcome;alcohol effect;alcohol exposure;alcohol sensitivity;aspartate receptor;cell injury;clinically relevant;deprivation;excitotoxicity;expectation;in utero;in vitro Model;in vivo;in vivo Model;neurotoxicity;novel;offspring;postnatal;pregnant;prenatal;prenatal exposure;public health relevance;pup;response;theories

public_health_relevance:
Narrative: Mild bouts of hypoxia (or reduced oxygen availability) commonly occursduring normal labor and delivery and the newborn is usually not affected by these if thebouts are not severe. We propose that one of the effects of prenatal alcohol exposureis to increase the risk of these minor bouts resulting in behavioral and CNS damage.The studies in this application will develop cell culture and rodent models to begin toaddress this clinically-relevant question.


application_id: 7926295
project_number: 1R43HL103388-01
project_title: Fully Biodegradable Polymersome-encapsulated Hemoglobin as a Novel Nanoparticle-b
administering_ic: NHLBI
award_notice_date: 2010-04-07
opportunity_number: RFA-OD-09-009
application_type: 1
activity_code: R43
ic: HL
serial_number: 103388
program_official: MITCHELL, PHYLLIS
project_start_date: 2010-04-07
project_end_date: 2012-03-31
study_section: Special Emphasis Panel[ZRG1 GGG-F (53)]
contact_pi_person_id: 6721291
contact_pi: GHOROGHCHIAN, PAIMAN PETER
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 808379072
duns_number: 808379072
fips: US
organization_id: 10020780
organization_name: VINDICO NANOBIOTECHNOLOGY, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405072003
organization_country: UNITED STATES
arra_indicator: Y
budget_start_date: 2010-04-07
budget_end_date: 2012-03-31
project_abstract:
DESCRIPTION (provided by applicant):   
Vindico NanoBioTechnology Inc. (Vindico) is developing a hemoglobin-based cellular oxygen therapeutic (blood substitute) NanoHeme based on its proprietary nanoparticle-based delivery platform known as polymersome. Polymersomes are synthetic polymer vesicles that are formed in nanometric dimensions which can efficiently encapsulate oxygen-carrying proteins such as hemoglobin (Hb). The lead NanoHeme formulation comprises of a diblock copolymer comprising hydrophilic polyethylene oxide (PEO) and hydrophobic polycaprolactone (PCL). NanoHeme demonstrates all the characteristics of ideal oxygen therapeutic such as tunable oxygen binding capacity uniform and small size viscosity and oncotic pressure characteristics similar to human blood as well as ease of mass production and storage. Encapsulation of Hb inside polymersome core protects surrounding tissues and blood components from direct contact with Hb and it also allows for the use of less expensive animal Hb. It also allows for manipulation of physicochemical properties of NanoHeme to improve its intravascular persistence and colloidal state. Additionally NanoHeme exhibits several advantages over other cellular Hb-based oxygen carriers under development. PEO provides NanoHeme improved in vitro chemical stability augmented in vivo bioavailablity and prolonged blood circulation half-lives over liposome-based oxygen therapeutics. PCL a well-known implantable biomaterial forms the vesicle membrane and facilitates complete and safe in vivo degradation of resulting product by hydrolysis of its ester linkages. Polymersome membrane is significantly thicker than liposome which offers NanoHeme improved mechanical properties. Polymersomes are stable for several months in situ and for several days in blood plasma without any changes in size and morphology. Thus NanoHeme will build on the advantages while circumventing the limitations seen with synthetic oxygen therapeutics. The use of NanoHeme will meet a major unmet medical need by helping to alleviate the current US and worldwide blood shortage and by decreasing our dependence on human RBC transfusions. It will result in tremendous cost saving for transfusion centers on account of reduced reagent and labor costs and decreased costs of patient care on account of problems with RBC transfusions. It will have a market in excess of $1 billion per year in the United States alone resulting in enormous job creation and economic stimulus. Vindico's academic collaborators have demonstrated proof-of-principle encapsulation of hemoglobin in biodegradable polymersomes. In this work we will optimize the construction of polymersome encapsulated Hb dispersions by exploring range of copolymers from the PEO-b-PCL family as composite building blocks different hemoglobin sources and different production conditions to create an array of PEH dispersions. These dispersions will be rigorously characterized for particle size and morphology hemoglobin encapsulation efficiency and methamoglobin (metHb) level We will also characterize the functional properties of PEH dispersions such as their binding characteristics with oxygen and nitric oxide and their stability under physiological conditions over an extended period of time. PEH dispersions that meet our feasibility criteria will be advanced to Phase II to determine their pharmacokinetics biodistribution toxicology and tissue oxygenation in small-animal models. By the end of Phase II we anticipate having collected sufficient data to determine an appropriate regulatory path to the clinic and will have presented this plan to the FDA. By the end of the entire project Vindico will have developed world's first effective safe and reliable synthetic oxygen carrier for human and veterinary use.  
  
PUBLIC HEALTH RELEVANCE:   
Project Narrative This research will have a major impact on public health by providing a new synthetic oxygen therapeutic (blood substitute) that can be administered to patients. This product will overcome all the limitations associated with red blood cell transfusion and synthetic oxygen therapeutics under development. The use of this product will reduce the significant blood shortage in US and world. The end result will be an improved standard of patient care and less patient mortality. Significant additional advantages will be a tremendous cost savings to the health care system in reduced operating costs as well as enormous job creation and economic stimulus.

project_terms:
Accounting;Aerobic;Animal Model;Animals;Binding (Molecular Function);Biocompatible Materials;Biodistribution;Blood;Blood Circulation;Blood Substitutes;Caliber;Characteristics;Chemicals;Clinic;Clinical Trials;Cost Savings;Data;Dependence;Development;Dimensions;Drug Formulations;Drug Kinetics;Economics;Encapsulated;Equilibrium;Erythrocyte Transfusion;Esters;Exhibits;Extravasation;FDA approved;Family;Half-Life;Healthcare Systems;Hemoglobin;Human;Hydrolysis;In Situ;In Vitro;Kinetics;Lead;Lipids;Liposomes;Marketing;Measures;Mechanics;Medical;Membrane;Methods;Molecular Weight;Morphology;Mortality Vital Statistics;Nitric Oxide;Occupations;Oxygen;Particle Size;Patient Care;Patients;Permeability;Pharmacodynamics;Phase;Physiological;Plasma;Polyethylene Glycols;Polymers;Production;Property;Proteins;Radial;Reagent;Reducing Agents;Research;Solutions;Source;Stimulus;Structure;Suspension substance;Suspensions;TNFRSF5 gene;Technology;Therapeutic;Thermodynamics;Thick;Time;Tissues;Toxicology;Transfusion;United States;Vesicle;Viscosity;Weight;Work;animal data;base;chemical stability;clinical application;copolymer;cost;di-block copolymer;improved;in vivo;indexing;insight;meetings;nanobiotechnology;nanoparticle;nanoscale;novel;particle;polycaprolactone;pre-clinical;pressure;public health medicine (field);public health relevance;segregation;tissue oxygenation;uptake

public_health_relevance:
Project NarrativeThis research will have a major impact on public health by providing a new synthetic oxygen therapeutic (bloodsubstitute) that can be administered to patients. This product will overcome all the limitations associated withred blood cell transfusion and synthetic oxygen therapeutics under development. The use of this product willreduce the significant blood shortage in US and world. The end result will be an improved standard of patientcare and less patient mortality. Significant additional advantages will be a tremendous cost savings to thehealth care system in reduced operating costs as well as enormous job creation and economic stimulus.


application_id: 7926172
project_number: 3R01EY018836-02S1
project_title: Intrinsic anti-angiogenic activity of siRNA
administering_ic: NEI
award_notice_date: 2009-09-07
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: EY
serial_number: 018836
suffix: S1
program_official: SHEN, GRACE L
project_start_date: 2008-04-01
project_end_date: 2012-03-30
study_section: Special Emphasis Panel[ZRG1-CB-G(90)S]
contact_pi_person_id: 2446639
contact_pi: AMBATI, JAYAKRISHNA
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The discovery of RNA interference (RNAi) and its potential to silence any gene of interest via the RNA-induced silencing complex (RISC) has revolutionized modern genetics and launched a new class of therapeutics termed short interfering RNA (siRNA). The first clinical trials of siRNA were initiated in patients with choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) which is the leading cause of blindness among the elderly in industrialized world and afflicts more people in the United States than all cancers combined. In new and exciting recent work we made the surprising discovery that siRNAs uniformly suppress experimental CNV in mice independent of RNAi. We found that that siRNAs against non- mammalian genes genes not expressed in the eye or random sequences without homology to any known gene all suppressed CNV as did a modified siRNA incapable of RISC incorporation. This novel class effect was mediated via activation of toll like receptor-3 (TLR3) and its adaptor protein TRIF and induction of interferon-3 and interleukin-12. Interestingly siRNAs targeting vascular endothelial growth factor (VEGF)-A or its receptor VEGFR-1 which are in Phase II clinical trials also suppressed CNV via TLR3 activation and not cognate transcript knockdown. We will test the hypothesis that both targeted and non-targeted siRNAs activate TLR3 by direct interaction and trigger a cellular program of vascular growth suppression. The specific aims of this proposal are to further define the interaction between siRNA and TLR3 determine the precise anti-angiogenic mechanisms of siRNA-induced CNV suppression in mice and test the efficacy of non-targeted siRNA in a non-human primate model of CNV. These studies will provide clarifying insights into the mechanisms underlying unanticipated siRNA activities in vivo define the molecular architecture governing this intersection of vascular biology and innate immunity provide pharmacogenetic data that will enable personalized medicine in patients with TLR3 mutations and propel the development of new more affordable anti-angiogenic therapeutics for the public health epidemic that is AMD.Angiogenesis (the growth of abnormal blood vessels) is responsible for the majority of blindness in patients with age-related macular degeneration (AMD) which accounts for a lion's share of the annual $51 billion cost of blindness in the United States. The Nobel Prize winning discovery of RNA interference led to the development of short interfering RNA (siRNA) as a new class of targeted drugs which were first launched in clinical trials in AMD.     Public Health Relevance: Our surprising discovery that all siRNAs have intrinsic anti-angiogenic activity has immediate and profound implications both for ongoing clinical trials and for treating the estimated 500 million people with diseases driven by angiogenesis.

project_terms:
2-thiouridine;Accounting;Adaptor Signaling Protein;Adopted;Affect;Age related macular degeneration;Angiogenesis Modulating Agents;Apoptosis;Architecture;Ascaridil;Biology;Blindness;Blood Vessels;Breast;Cell Proliferation;Cell surface;Cells;Chemicals;Choroidal Neovascularization;Cleaved cell;Clinical Trials;Complex;Data;Development;Disease;Double Stranded RNA Virus;Double-Stranded RNA;Drug Delivery Systems;Elderly;Endothelial Cells;Epidemic;Exudative age-related macular degeneration;Eye;Fire - disasters;Gene Mutation;Genes;Genetic;Goals;Growth;Immune;Immune response;Immune system;Incidence;Individual;Infiltration;Inhibition of Cell Proliferation;Interferons;Interleukin-12;Investigation;Kinetics;Laser injury;Lasers;Lead;Length;Leukocytes;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Mediator of activation protein;Medicine;Messenger RNA;Modeling;Modification;Molecular;Molecular Profiling;Mus;Mutation;Natural Immunity;Nature;Nobel Prize;Ophthalmology;Panthera leo;Pathway interactions;Patients;Pharmacogenetics;Phase II Clinical Trials;Positioning Attribute;Prevalence;Process;Property;RNA;RNA Interference;RNA-Induced Silencing Complex;Retina;Role;Signal Pathway;Signal Transduction;Surface;System;Techniques;Testing;Therapeutic;Thrombospondin 1;Toxic effect;Transcript;United States;Vascular Endothelial Growth Factor A;Vascular Endothelial Growth Factor Receptor-1;Work;angiogenesis;chemokine;cost;design;efficacy testing;gene therapy;human DICER1 protein;human TLR3 protein;in vivo;insight;interest;mRNA Transcript Degradation;mouse model;neovascular;nonhuman primate;novel;novel strategies;pigment epithelium-derived factor;programs;public health medicine (field);public health relevance;receptor;response;thrombospondin 2;tool


application_id: 7926058
project_number: 1R43GM093748-01
project_title: Novel SCID rat models for human cell transplantation studies
administering_ic: NIGMS
award_notice_date: 2010-06-25
opportunity_number: RFA-OD-09-009
application_type: 1
activity_code: R43
ic: GM
serial_number: 093748
program_official: SOMERS, SCOTT D
project_start_date: 2010-07-01
project_end_date: 2012-06-30
study_section: Special Emphasis Panel[ZRG1 CB-D (53)]
contact_pi_person_id: 1871056
contact_pi: RUIZ, JOSEPH C.
other_pis: Not Applicable
congressional_district: 06
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: Y
budget_start_date: 2010-07-01
budget_end_date: 2012-06-30
project_abstract:
DESCRIPTION (provided by applicant): The laboratory rat is used extensively by the pharmaceutical industry for preclinical animal efficacy and toxicology studies. In addition the rat has been a valuable animal model for physiology behavior and pharmacology research programs due to ease of experimental manipulation. Their larger size facilitates procedures otherwise difficult in mice including studies using instrumentation blood sampling nerve conduction studies and surgeries. Generating inbred immunodeficient rat strains that can maintain functional human xenografts would provide unique and valuable resources for drug discovery and therapeutic research programs. This project will investigate the use of a novel rat strain carrying a transposon-mediated knockout (KO) insertional mutation within the adenosine deaminase (Ada) locus in the inbred Fischer line. This mutation is an underlying cause of severe combined immunodeficiency (SCID) in humans. In mice Ada KO mutants have no discernable thymus two-to-three-fold lower cell numbers in the spleen and livers that exhibit severe histological defects. This latter defect is the underlying cause of perinatal lethality in Ada KO mice. Each of these defects is also observed in Ada KO rats. Studies in Ada KO mice have shown that low levels of ADA activity can rescue the liver dysfunction as well as other non-immune defects associated with Ada deficiencies while maintaining the SCID phenotype. These results indicate that it may be feasible to create a conditional inbred SCID Ada KO rat line suitable for human cell transplantation studies. To achieve this goal we will assess the feasibility of using doxycycline-inducible systems to conditionally complement the non- immune defects while maintaining the SCID phenotype. In Phase I we will generate transgenic founders that co-segregate two expression modules: (a) a ubiquitously expressed Tet-repressor; and (b) an Ada mini-gene under the control of a CMV/Tet operator transcriptional element. The Tet-repressor will inhibit the expression of the Ada mini-gene; expression can be rapidly induced by providing doxycycline (dox) in the drinking water of the animals. We will identify founder animals that exhibit dox dose-dependent activation of the Ada mini-gene (referred to as conditional Ada transgenic rats; AdacTG) and determine whether Ada -/- /AdacTG rats are viable and exhibit no overt phenotypes except for immune deficiency. In Phase II we will transplant primary human cells (e.g. hepatocytes) into the transgenic animals in proof-of-principal studies to demonstrate the long-term viability and function of human cells in the new SCID rat models. In the long term we will develop Ada -/- /AdacTG rats with humanized livers for drug discovery and therapeutic applications. This project should provide for the first time an inbred rat SCID Ada model for human cell transplantation studies enabling broad applications for assessing the function of human cells in the context of the rat which is amenable to a wide variety of experimental manipulations not possible in mice.  
  
PUBLIC HEALTH RELEVANCE: The development of a rat strain that can support efficient human cell engraftment would represent a major advance for the production of humanized tissues for drug discovery and therapeutic research applications. In the application "Novel SCID rat models for human cell transplantation studies" studies are aimed at examining the feasibility of using a novel knockout immunodefective (SCID) rat line to generate animals that can serve as hosts to study the function of normal and diseased human tissues. The proposed innovations would further increase the utility of rat models for drug discovery and would aid in the development of pre-clinical animal models that represent more predicative indicators of efficacy and toxicity associated with drug candidates. Being able to generate rats that can permit the long-term propagation of human cells and tissues would provide unique and valuable resources for drug discovery and therapeutic research. In the rat such transplants would enable a wide variety of experimental manipulations that would not be possible in mice. There is a compelling need for an abundant and accessible supply of animals to screen for new therapeutic agents. Thus if successful this project would benefit many goals of public health.

project_terms:
Animal Model;Animals;B-Lymphocytes;Behavior;Biological Assay;Biological Products;Blood specimen;CD8B1 gene;Cancerous;Cell Count;Cell Transplantation;Cells;Complement;Defect;Detection;Development;Dose;Doxycycline;Drug Industry;Elements;Engraftment;Exhibits;Gene Expression;Genes;Goals;Hepatocyte;Human;Immune;Immune Sera;Immune system;Immunocompromised Host;Indirect Immunofluorescence;Kidney;Knock-out;Knockout Mice;Laboratory Rat;Letters;Liver;Liver Dysfunction;Lung;Lymphocyte;Mediating;Modeling;Monitor;Mus;Mutation;Neural Conduction;Normal tissue morphology;Nude Rats;Operative Surgical Procedures;Patients;Perinatal;Pharmacology;Phase;Phenotype;Physiology;Population;Procedures;Production;Proteins;Rat Strains;Rattus;Research;Resources;Reverse Transcriptase Polymerase Chain Reaction;Severe Combined Immunodeficiency;Spleen;System;Testing;Tetanus Helper Peptide;Therapeutic;Therapeutic Agents;Therapeutic Human Experimentation;Thymus Gland;Time;Tissues;Toxic effect;Toxicology;Transgenes;Transgenic Animals;Transgenic Organisms;Transplantation;Xenograft procedure;adenosine deaminase;animal efficacy;base;drinking water;drug candidate;drug discovery;human tissue;innovation;instrumentation;knockout animal;mouse model;mutant;novel;novel therapeutics;peripheral blood;pre-clinical;programs;public health medicine (field);public health relevance;stem cell population;success

public_health_relevance:
PROJECT NARRATIVEThe development of a rat strain that can support efficient human cell engraftment would represent a majoradvance for the production of humanized tissues for drug discovery and therapeutic research applications. Inthe application "Novel SCID rat models for human cell transplantation studies" studies are aimed at examiningthe feasibility of using a novel knockout immunodefective (SCID) rat line to generate animals that can serve ashosts to study the function of normal and diseased human tissues. The proposed innovations would furtherincrease the utility of rat models for drug discovery and would aid in the development of pre-clinical animalmodels that represent more predicative indicators of efficacy and toxicity associated with drug candidates.Being able to generate rats that can permit the long-term propagation of human cells and tissues wouldprovide unique and valuable resources for drug discovery and therapeutic research. In the rat suchtransplants would enable a wide variety of experimental manipulations that would not be possible in mice.There is a compelling need for an abundant and accessible supply of animals to screen for new therapeuticagents. Thus if successful this project would benefit many goals of public health.


application_id: 7925506
project_number: 1R43EY020787-01
project_title: Disposable Instrument for Broader Patient Access to Vision Restoration Therapy
administering_ic: NEI
award_notice_date: 2010-06-10
opportunity_number: RFA-OD-09-009
application_type: 1
activity_code: R43
ic: EY
serial_number: 020787
program_official: WUJEK, JEROME R
project_start_date: 2010-06-01
project_end_date: 2013-05-31
study_section: Special Emphasis Panel[ZRG1 IMST-W (53)]
contact_pi_person_id: 1893843
contact_pi: ARAMANT, ROBERT B
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 127181209
primary_uei: U9KYX2EZS585
duns_number: 127181209
uei: U9KYX2EZS585
fips: US
organization_id: 3904701
organization_name: OCULAR TRANSPLANTATION, LLC
organization_city: CRESTWOOD
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400148741
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Retinal diseases such as age-related macular degeneration (AMD) retinal dystrophies and retinitis pigmentosa (RP) affect millions of Americans. As the population ages this number will grow significantly. Many people will lose their sight due to degeneration of photoreceptors and/or retinal pigment epithelium (RPE). The majority of clinical studies performed to date have focused on therapies to address the early stages of these diseases in attempts to rescue the photoreceptors the light-sensitive cells of the retina. However once the photoreceptors have died they cannot be regenerated. Many patients with advanced retinal diseases not only need new photoreceptor cells and new RPE but other cells of the retina as well. Development of an FDA-approved therapy to transplant these cells to patients with retinal degenerative diseases is a compelling research opportunity. Much work has been done in rat models and human patients to prove that degenerated photoreceptor and RPE cells can be replaced with new cells and connect with the remaining inner retina to restore eye sight. In this protocol sheets of freshly harvested RPE and immature retina (containing cells that will develop into light- sensitive photoreceptors) are transplanted into the back of the rat or human eye under the retina. The transplants develop into different cell types and integrate with the damaged host retina. To make this protocol widely available the objective of this research is to prove feasibility of a disposable low-cost surgical instrument that can provide the precision needed for placement of the delicate RPE/retina tissue sheets during surgery. The instrument design must also be suitable for high-volume low-cost production in a sterile one-way package. The specific aims are to: 1) design the components (hand piece mandrel and nozzle) of a fully integrated production-ready disposable surgical instrument that will meet FDA approval requirements for medical devices; 2) fabricate three engineering prototypes and test these in eye bank (cadaver) eyes to demonstrate instrument performance; and 3) develop standardized production processes to enable low-cost manufacture and sterile packaging. Success in the proposed research will lead to development of a disposable instrument that will allow broader patient access to retinal transplantation as a vision restoration therapy.  
  
PUBLIC HEALTH RELEVANCE: Millions of Americans suffer from degenerative diseases of the retina and lose their sight. By transplanting sheets of retinal tissue vision can be saved and improved. The proposed research will develop a special surgical instrument that will help make transplant of retinal tissue broadly available as a therapy.

project_terms:
Address;Affect;Age;Age related macular degeneration;American;Back;Cadaver;Cell Transplants;Cells;Clinical Research;Degenerative Disorder;Development;Disease;Elements;Engineering;Eye;Eye Banks;FDA approved;Hand;Harvest;Human;Lead;Learning;Length;Light;Marketing;Medical Device;Modeling;Natural regeneration;Operative Surgical Procedures;Patients;Performance;Phase II Clinical Trials;Photoreceptors;Population;Positioning Attribute;Preparation;Process;Production;Protocols documentation;Rattus;Research;Retina;Retinal;Retinal Degeneration;Retinal Diseases;Retinal Dystrophy;Retinitis Pigmentosa;Staging;Sterility;Structure of retinal pigment epithelium;Suction;Surgeon;Surgical Instruments;Testing;Tissue Donors;Tissues;Transplantation;Trauma;United States;Vision;Visual;Visual Acuity;Width;Work;cell type;commercial application;cost;design;effective therapy;improved;innovation;instrument;meetings;novel;phase 2 study;photoreceptor degeneration;prototype;public health relevance;response;restoration;retina transplantation;success

public_health_relevance:
PROJECT NARRATIVEMillions of Americans suffer from degenerative diseases of the retina and lose their sight. By transplantingsheets of retinal tissue vision can be saved and improved. The proposed research will develop a specialsurgical instrument that will help make transplant of retinal tissue broadly available as a therapy.


application_id: 7924813
project_number: 5R01HL096914-02
project_title: Role of TRPV1 in Airway Hypersensitivity Induced by Inflammation
administering_ic: NHLBI
award_notice_date: 2010-08-12
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 096914
program_official: NOEL, PATRICIA
project_start_date: 2009-09-01
project_end_date: 2012-12-31
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 1857989
contact_pi: LEE, LU-YUAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Airway hypersensitivity characterized by exaggerated sensory and reflexogenic responses to inhaled irritants is a prominent pathophysiological feature of various airway inflammatory diseases (e.g. asthma bronchitis etc). Increasing and compelling evidence indicates that vagal bronchopulmonary C-fibers play a pivotal role in the manifestation of airway hypersensitivity. Recent investigations further suggest that the TRPV1 receptor a non-selective cation channel and a polymodal transducer selectively expressed in C-fiber afferents is likely involved in the airway hypersensitivity generated by airway inflammatory reaction. Indeed a recent study in our lab has demonstrated that allergen sensitization-induced airway inflammation markedly enhanced the sensitivity of pulmonary C-fiber afferents and more importantly induced TRPV1 expression in myelinated pulmonary afferents that normally do not exhibit any capsaicin sensitivity. However the physiological implication and the mechanism underlying the TRPV1 over- expression during airway inflammation are yet not fully understood. In this proposal a research plan is designed to characterize the role of TRPV1 in the development of airway hypersensitivity when chronic airway inflammation is induced by allergen sensitization. Our hypothesis is that the enhanced airway sensitivity results from a combination of increased expression and excitability of this channel in the vagal bronchopulmonary sensory terminals. We further hypothesize that tumor necrosis factor 1 a pro-inflammatory cytokine and known to be released in the lung during allergic airway inflammation is an important contributor to the over-expression of TRPV1 in these sensory neurons. Results obtained from these studies should provide important information about the mechanism that up-regulates the expression and excitability of the TRPV1 channel in the airway sensory neurons and bring a new insight into the pathogenesis and therapeutic strategy for alleviating the airway hypersensitivity caused by allergic airway inflammation.   
  
PUBLIC HEALTH RELEVANCE: In airway inflammatory diseases such as asthma and bronchitis the respiratory tract becomes overly sensitive to inhaled irritants. This research proposal is designed to test our hypothesis that a specific ion channel namely TRPV1 plays a major role in the exceedingly high excitability of airway sensory nerves caused by allergic inflammation. The results obtained from these studies should bring a new insight into the pathogenesis and therapeutic strategy for alleviating the airway hypersensitivity.

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

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


application_id: 7924665
project_number: 5R01AA018016-03
project_title: The Role of Alcohol in HIV Therapy Hepatotoxicity
administering_ic: NIAAA
award_notice_date: 2010-08-31
opportunity_number: RFA-AA-08-013
application_type: 5
activity_code: R01
ic: AA
serial_number: 018016
program_official: WANG, JOE
project_start_date: 2008-09-30
project_end_date: 2013-08-31
study_section: ZAA1-BB(02)
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: BARVE, SHIRISH S;EATON, JOHN W
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): It is clear that alcohol abuse can alter/suppress immune function including CD4 T-lymphocyte depletion which can accelerate HIV progression. Subjects who consume alcohol may be more likely to develop certain infectious diseases which can complicate HIV examples being various types of pneumonia and tuberculosis. Moreover subjects who consume alcohol are more likely to participate in high-risk behaviors that increase the likelihood of acquiring HIV. Patients who consume alcohol also may be less compliant with their HIV therapy which can affect disease progression. The research focus of this grant is the potential impact of alcohol use/abuse as a co-factor for HIV therapy-induced hepatotoxicity. Since the introduction of highly active antiretroviral therapy (HAART) in 1996 the life expectancy of patients with HIV has increased significantly. However HAART is associated with significant hepatotoxicity. The severity of liver toxicity ranges from the absence of symptoms to liver decompensation and the reported incidence of severe liver toxicity after initiating HAART ranges from 2% to 18%. The mechanisms involved in HAART-derived hepatotoxicity are not well understood which makes its management more difficult. Some likely mechanisms of hepatotoxicity include proinflammatory cytokine production mitochondrial toxicity hypersensitivity reactions steatosis and insulin resistance immune reconstitution in HCV or HBV co-infected patients and proteasome inhibition (with dysregulated cytokine metabolism and mitochondrial and proteasome dysfunction serving as the focus of this proposal). The long-term goals of this study are to: (1) define mechanisms of hepatotoxicity induced by a combination of drug therapy and alcohol abuse in HIV patients and (2) discover potential therapeutic interventions for HAART hepatotoxicity especially for patients in whom alcohol use/abuse may be a contributing factor. Specific Aims of this proposal are to: 1. Evaluate the potential hepatotoxic interactions of alcohol and HAART medications using rapid in vitro hepatocyte screening technology; 2. Determine the effects of anti- HIV drugs (selected agents based on preliminary toxicity studies from SO#1 and clinical hepatotoxicity risk) on the development and progression of hepatotoxicity in mice and the drug interactions with chronic alcohol intake; and 3. Evaluate in a human translational component: a) mitochondrial and proteasome function and ex vivo cytokine production in subsets of HIV patients b) serial non-invasive measures of mitochondrial and proteasome function and cytokine production in patients who develop HAART hepatotoxicity and c) liver histology findings including markers of proteasome and mitochondrial function using a human translational approach from a cohort of HCV+HIV coinfected subjects enrolled in a prospective NIH study based at the University of Cincinnati. We postulate that the HAART and alcohol mediated metabolic complications of dysregulated proinflammatory cytokine production and mitochondrial and proteasome dysfunction converge on the liver in an overlapping fashion to induce hepatotoxicity. In this proposal we test that hypothesis in a novel translational approach and we evaluate unique therapeutic interventions for this hepatotoxicity.  
  
PUBLIC HEALTH RELEVANCE: Alcohol abuse and HIV are important health problems. Liver disease is recognized as an increasingly important problem for the HIV population. Liver disease may be due to a variety of factors including co-infection with viral hepatitis alcohol abuse and antiretroviral hepatotoxicity. Liver disease is now a leading cause of death for patients with HIV. Hepatotoxicity due to HAART is also common and up to 30% of patients on HAART experience World Health Organization grade 3 liver enzyme elevations. Furthermore hepatotoxicity from antiretroviral drugs leads to adverse patient outcomes either from fulminant hepatic failure or more commonly AIDS following discontinuation of HAART. It is unknown why some but not all HIV patients develop drug induced liver injury from HAART. Relevant to this proposal alcohol/HAART interactions are emerging as critically important factors. Recent research has shown that alcohol abuse is associated with severe hepatotoxicity in patients on HAART. Importantly alcoholic liver disease and HAART induced liver injury share many potential mechanisms of injury. These include cytokine dysregulation mitochondrial dysfunction and proteasomal dysfunction. Through these and other mechanisms alcohol and antiretroviral medications converge on the liver in an overlapping fashion to produce hepatotoxicity. Here we will study hepatotoxicity due to alcohol/HAART interactions to further define disease mechanisms and create therapeutic interventions.

project_terms:
Acetaminophen;Acquired Immunodeficiency Syndrome;Acute Liver Failure;Affect;Alcohol abuse;Alcohol consumption;Alcoholic Liver Diseases;Alcohols;Anti-HIV Agents;Anti-HIV Therapy;Anti-Retroviral Agents;CD4 Positive T Lymphocytes;CYP2E1 gene;Caspase Inhibitor;Cause of Death;Chronic;Clinical;Combination Drug Therapy;Combivir;Communicable Diseases;Delavirdine;Depressed mood;Development;Didanosine;Disease;Disease Progression;Drops;Drug Interactions;Enrollment;Enzymes;Fatty Liver;Functional disorder;Gilead brand of tenofovir disoproxil fumarate;Goals;Grant;HIV;HIV Infections;HIV therapy;Health;Hepatic;Hepatitis;Hepatitis B Virus;Hepatitis C;Hepatitis C virus;Hepatocyte;Hepatology;Hepatotoxicity;Highly Active Antiretroviral Therapy;Histology;Human;Hypersensitivity;Immune;In Vitro;Incidence;Indinavir;Infection;Injury;Insulin Resistance;Killings;Lactic Acidosis;Lamivudine;Life Expectancy;Lipodystrophy;Liver;Liver diseases;Lopinavir/Ritonavir;Lymphocyte Count;Lymphocyte Depletion;Measures;Mediating;Metabolic;Metabolism;Mitochondria;Morbidity - disease rate;Mortality Vital Statistics;Mus;Names;Natural immunosuppression;Nelfinavir;Nevirapine;Nucleosides;Nucleotides;Outcome;Oxidative Stress;Patients;Pharmaceutical Preparations;Pneumonia;Population;Predisposition;Principal Investigator;Production;Protease Inhibitor;Proteasome Inhibition;Proteins;Reaction;Reporting;Research;Reverse Transcriptase Inhibitors;Risk;Ritonavir;Roche brand of pentafuside;Role;S-Adenosylmethionine;Saquinavir;Saquinavir Mesylate;Screening procedure;Series;Severities;Simulate;Site;Stavudine;Symptoms;T-20;TNF gene;Technology;Tenofovir;Testing;Therapeutic Intervention;Time;Toxic effect;Trizivir;Tuberculosis;Tumor Necrosis Factor-alpha;Tumor Necrosis Factors;United States National Institutes of Health;Universities;Viral hepatitis;Work;World Health Organization;Zalcitabine;Zidovudine;abacavir;alcohol effect;analog;base;caspase;cohort;crixivan;cytokine;design;efavirenz;emtricitabine;epivir;experience;feeding;fosamprenavir;high risk behavior;immune function;inhibitor/antagonist;interest;intervention program;mitochondrial dysfunction;multicatalytic endopeptidase complex;non-nucleoside reverse transcriptase inhibitors;novel;programs;prospective;public health relevance;reconstitution;sustiva;tipranavir;translational approach;truvada;viracept

public_health_relevance:
NARRATIVEAlcohol abuse and HIV are important health problems. Liver disease is recognized as anincreasingly important problem for the HIV population. Liver disease may be due to a variety offactors including co-infection with viral hepatitis alcohol abuse and antiretroviral hepatotoxicity.Liver disease is now a leading cause of death for patients with HIV. Hepatoxicity due to HAARTis also common and up to 30% of patients on HAART experience World Health Organizationgrade 3 liver enzyme elevations. Furthermore hepatoxicity from antiretroviral drugs leads toadverse patient outcomes either from fulminant hepatic failure or more commonly AIDSfollowing discontinuation of HAART. It is unknown why some but not all HIV patients developdrug induced liver injury from HAART. Relevant to this proposal alcohol/HAART interactionsare emerging as critically important factors. Recent research has shown that alcohol abuse isassociated with severe hepatotoxicity in patients on HAART. Importantly alcoholic liver diseaseand HAART induced liver injury share many potential mechanisms of injury. These includecytokine dysregulation mitochondrial dysfunction and proteasomal dysfunction. Through theseand other mechanisms alcohol and antiretroviral medications converge on the liver in anoverlapping fashion to produce hepatoxicity. Here we will study hepatotoxicity due toalcohol/HAART interactions to further define disease mechanisms and create therapeuticinterventions.


application_id: 7924472
project_number: 3R15GM085749-01S1
project_title: Analysis of Polyhydroxyalkanoate Inclusion Biogenesis
administering_ic: NIGMS
award_notice_date: 2009-09-18
opportunity_number: PA-06-042
application_type: 3
activity_code: R15
ic: GM
serial_number: 085749
suffix: S1
program_official: ANDERSON, JAMES J
project_start_date: 2009-09-30
project_end_date: 2011-08-31
study_section: Prokaryotic Cell and Molecular Biology Study Section[PCMB]
contact_pi_person_id: 9258111
contact_pi: DENNIS, DOUGLAS
other_pis: Not Applicable
congressional_district: 05
department: BIOLOGY
primary_duns: 041957010
primary_uei: MRGUP99ZAZ59
duns_number: 041957010
uei: MRGUP99ZAZ59
fips: US
organization_id: 569601
organization_name: MOREHEAD STATE UNIVERSITY
organization_city: MOREHEAD
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 403511684
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  This proposal accomplishes the AREA program objectives of: 1) supporting meritorious research; 2) exposing undergraduates to research; and 3) strengthening the research environment in non-research intensive universities. The general goal of this research is  to elucidate the mechanism of polyhydroxyalkanoate inclusion biogenesis. Polyhydroxyalkanoates (PHAs) are bacterial polymers that are synthesized in inclusions when carbon levels are high and another essential nutrient such as nitrogen is limited. There is considerable commercial interest in PHAs because they comprise a family of polyesters that can be formed into plastics that are biodegradable. Electron microscopy studies have been unable to resolve the structure of PHA inclusions and this has inhibited movement toward a cohesive model of inclusion biogenesis. Employing atomic force microscopy we have determined that there are three layers of structure an  outer envelope that is the thickness of a membrane bilayer a middle network layer and an underlying crystalline lamellar layer. Genetic studies have indicated that the middle network is comprised at least partially of PhaP and that PhaP is likely to be translocated to the periplasm. Thus it would appear that inclusion biogenesis may occur by movement of protein and/or proteins to the periplasm and budding through the cytoplasmic membrane into the cytoplasm facilitating the acquisition of the cytoplasmic  membrane as an envelope. The goal of this research is to prove or disprove this supposition. The specific aims of the research are: 1) definitively prove periplasmic localization of PhaP via fluorescence localization and Western blot analyses of subcellular fractions 2) demonstrate that the inclusion envelope is derived from the cytoplasmic membrane by proteomic analysis and 3) characterize proteins that bind transiently and permanently to PhaP in hopes of elucidating the mechanism of inclusion biogenesis. Ultimately the goal of the research is to enlarge our knowledge of inclusion  biogenesis to the point that this process can be controlled and utilized for medical applications. For instance it could be envisioned that instead of polymer being inserted into the inclusion bioactive compounds could be inserted making the inclusion into a drug delivery vehicle. Morehead State University has recently embarked upon a process whereby undergraduate research is emphasized and faculty members are encouraged to become teacher/scholars. Significant resources have been allocated to this goal. This project supports this mission and will enhance the research environment at MSU by providing undergraduate students with numerous opportunities to learn the fundamentals of biomedical research while conducting research that will enlarge our knowledge of prokaryotic processes. PUBLIC HEALTH RELEVANCE:  Using atomic force microscopy we have resolved the structural arrangement of polyhydroxyalkanoate inclusions and this has led to a preliminary model for inclusion biogenesis. The purpose of this research is to test this preliminary model in hopes of adapting the strategy of biogenesis for medical applications in which inclusions could be used as drug delivery vehicles.

project_terms:
Atomic Force Microscopy;Bacteria;Biogenesis;Biomedical Research;Carbon;Cell membrane;Cytoplasm;Data;Drug Delivery Systems;Electron Microscopy;Environment;Faculty;Family;Fluorescence;Genetic;Goals;Knowledge;Learning;Ligands;Medical;Membrane;Mission;Modeling;Molecular;Molecular Genetics;Movement;Nitrogen;Nutrient;Plastics;Polyesters;Polymers;Process;Protein Binding;Proteins;Proteomics;Research;Resources;Scaffolding Protein;Solid;Sorting - Cell Movement;Structure;Students;Subcellular Fractions;Surface;Testing;Thick;Tissues;Universities;Western Blotting;interest;member;periplasm;programs;public health relevance;receptor;teacher

public_health_relevance:
Using atomic force microscopy we have resolved the structural arrangement ofpolyhydroxyalkanoate inclusions and this has led to a preliminary model for inclusionbiogenesis. The purpose of this research is to test this preliminary model in hopes ofadapting the strategy of biogenesis for medical applications in which inclusions could beused as drug delivery vehicles.


application_id: 7924241
project_number: 3R01GM085231-02S1
project_title: Role of SR-BI in LPS detoxification
administering_ic: NIGMS
award_notice_date: 2009-09-18
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: GM
serial_number: 085231
suffix: S1
program_official: DUNSMORE, SARAH
project_start_date: 2009-09-30
project_end_date: 2012-08-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8132330
contact_pi: LI, XIANG-AN
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Americas;Animals;Antibodies;Bacteria;Bacterial Infections;Binding (Molecular Function);Biological Assay;Bone Marrow;Bone Marrow Transplantation;CD14 Antigen;Cause of Death;Cecum;Cells;Cessation of life;Chinese Hamster Ovary Cell;Co-Immunoprecipitations;Complex;Cross-Over Studies;Death Rate;Disease;Drug Metabolic Detoxication;Excision;Functional disorder;HDL cholesteryl ester;HDL receptor;Hepatic;Hepatocyte;High Density Lipoprotein Cholesterol;High Density Lipoproteins;Hypotension;Infection;Inflammatory;Intervention;Knockout Mice;Label;Ligation;Lipopolysaccharides;Liver;Living Costs;Mediating;Modeling;Molecular;Mus;Mutate;Organ;Play;Predisposition;Process;Proteins;Puncture procedure;Reaction;Relative (related person);Reporting;Role;SR-BI receptor;Sepsis;Septic Shock;Serum;TLR4 gene;Techniques;Tissues;Toxic effect;Transgenic Mice;Transplantation;Wild Type Mouse;Work;cell type;cytokine;effective therapy;in vivo;macrophage;macrophage scavenger receptors;mutant;novel;novel strategies;prevent;public health relevance;receptor;receptor binding;response;scavenger receptor;septic;uptake


application_id: 7923958
project_number: 5R01HL096589-02
project_title: Role of Serum Amyloid A in Atheroscierosis
administering_ic: NHLBI
award_notice_date: 2010-08-13
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 096589
program_official: SRINIVAS, POTHUR R
project_start_date: 2009-09-01
project_end_date: 2012-08-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 3123430
contact_pi: TANNOCK, LISA R
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
Cardiovascular disease is the leading cause of death indeveloped countries. Individuals with obesity metabolic syndrome and/or diabetes are at markedlyincreased risk of atherosclerotic cardiovascular disease although the underlying mechanisms are not fullyunderstood. The retention of atherogenic lipoproteins within the subendothelial space of the arterial wall bytheir interactions with vascular proteoglycans is thought to be a key step in the initiation of atherosclerosisas outlined in the Response to Retention Hypothesis. Obesity the metabolic syndrome and diabetes allare associated with increased levels of inflammatory markers including serum amyloid A (SAA) and SAAlevels are predictive of cardiovascular disease in humans and in animal models. The central hypothesis ofthis grant is that SAA is pro-atherogenic. This hypothesis is based on several key observations: (a) SAA ispresent within atherosclerotic lesions in close association to apolipoproteins and proteoglycans; (b) Werecently demonstrated that SAA alters vascular proteoglycan synthesis in a pro-atherogenic manner; (c)SAA is an apolipoprotein that is capable of binding to proteoglycans and thus may facilitate the retention oflipoproteins on which it is carried; (d) In preliminary studies we demonstrate accelerated atherosclerosis inmice in which SAA is over-expressed. Thus SAA may in fact be a mediator of atherosclerosis by leading toincreased retention of atherogenic lipoproteins by vascular proteoglycans. We will test this hypothesis byevaluating the effect of SAA over-expression on vascular proteoglycan synthesis lipoprotein retention andatherosclerosis development using in vivo methodology. Given the increased SAA levels observed inobesity metabolic syndrome and diabetes we propose that SAA may be a mechanism contributing to theincreased cardiovascular disease in these conditions.Program Director/Principal Investigator (Last First Middle): Tannock Lisa R.

project_terms:
Accounting;Acute;Adenoviruses;Affinity;Animal Model;Animals;Apolipoproteins;Arterial Fatty Streak;Atherosclerosis;Attenuated;Binding (Molecular Function);Blood Vessels;C-reactive protein;Cardiac;Cardiovascular Diseases;Cause of Death;Clinical;Data;Developed Countries;Development;Diabetes Mellitus;Event;Foam Cells;Goals;Grant;High Density Lipoproteins;Human;Immunodeficient Mouse;In Vitro;Individual;Injection of therapeutic agent;Intervention;Knockout Mice;Lipoprotein Binding;Lipoproteins;Low-Density Lipoproteins;Mediating;Mediator of activation protein;Medical;Metabolic syndrome;Methodology;Modeling;Mus;Obese Mice;Obesity;Phase;Plasma;Play;Principal Investigator;Property;Protein Isoforms;Proteoglycan;Recombinants;Risk;Risk Factors;Role;Serum amyloid A protein;Testing;Very low density lipoprotein;base;biglycan;cardiovascular disorder risk;in vivo;inflammatory marker;macrophage;programs;public health medicine (field);response

public_health_relevance:
Potential Impact on Public Health: Obesity metabolic syndrome and diabetes are allassociated with high rates of cardiovascular disease and are characterized by highlevels of inflammation markers including SAA. However it is not currently known if highlevels of SAA cause atherosclerosis or merely indicate the amount of atherosclerosisalready present. The goal of this proposal is to determine if SAA has a role in causingatherosclerosis and to identify new targets for medical intervention to decreaseatherosclerosis and cardiovascular disease.


application_id: 7923946
project_number: 5R01HL091924-02
project_title: Telomerase in Inflammation and Atherosclerosis
administering_ic: NHLBI
award_notice_date: 2010-08-04
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 091924
program_official: HASAN, AHMED A K
project_start_date: 2009-09-01
project_end_date: 2011-08-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8010784
contact_pi: BRUEMMER, DENNIS CHRISTOPHER
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
Telomeres the DNA TTAGGG repeat sequences at the ends of eukaryotic chromosomes are stabilized by telomerase to serve as protective capping and to prevent degradation. Stem cells constitutively overexpress the catalytic core telomerase reverse transcriptase (TERT) manifesting high levels of telomerase activity which confers an apparently indefinite lifespan and is rate limiting for tissue renewal. In contrast the majority of human adult somatic cells are thought to transcriptionally repress TERT resulting in telomere shortening and cellular senescence. Although most adult cells display low basal telomerase activity mounting evidence indicates that TERT transcription is tightly regulated and inducible in various cell types in response to changes in environmental cues. In human atherosclerosis telomerase is activated and TERT expression correlates with the extent of the disease; however the mechanisms underlying telomerase activation and the physiological role of inducible TERT expression in atherosclerosis remain to be discovered. Our preliminary studies confirm increased TERT expression in macrophages of human atherosclerotic lesions and telomerase activation during atherosclerosis development. Two specific aims are proposed to explore the significance of these findings and to test the hypothesis that telomerase is induced in macrophages and contributes to the development of atherosclerosis. In Specific Aim 1 we will utilize cellular and molecular approaches to determine the transcriptional regulation of TERT activation in macrophages and test the hypothesis that TERT constitutes a NFk _B-regulated target gene in macrophages. In Specific Aim 2 we will determine the contribution of TERT to the development of atherosclerosis. Ultimately the results of these studies will not only characterize the mechanisms underlying telomerase activation in atherosclerosis but also advance our understanding of the role of telomerase in atherosclerosis.

project_terms:
Adult;Architecture;Arterial Fatty Streak;Atherosclerosis;Biology;Blood Vessels;Catalytic Domain;Cause of Death;Cell Aging;Cells;Chromatin;Chromosomes;Cues;DNA;Development;Developmental Process;Disease;Engineering;Enzymes;Epigenetic Process;Exhibits;Figs - dietary;Gene Activation;Gene Expression;Gene Silencing;Gene Targeting;Generations;Genes;Genetic Transcription;Heterochromatin;Histones;Human;Inflammation;Inflammatory;Inflammatory Response;Longevity;Lymphoid Cell;Macrophage Activation;Molecular;Molecular Profiling;Mus;Myelogenous;Pathway interactions;Physiological;Process;Promotor (Genetics);Property;Role;Signal Pathway;Somatic Cell;Staging;Stem cells;Stimulus;Telomerase;Telomere Maintenance;Telomere Shortening;Testing;Tissues;Transcriptional Regulation;United States;atherogenesis;base;cell type;chromatin modification;improved;macrophage;novel;overexpression;prevent;programs;protein complex;research study;response;telomerase reverse transcriptase;telomere

public_health_relevance:
7. Project NarrativeAtherosclerotic cardiovascular disease is the leading cause of death in the United States and inflammatorypathways contribute to all stages of the disease. This application will investigate the mechanisms by whichtelomerase an enzyme that generates protective caps at the ends of chromosomes and controls geneexpression programs regulates inflammatory responses and influences the development of atherosclerosis.The results of these studies may ultimately characterize telomerase-dependent activation of inflammation as anovel pathway contributing to atherosclerosis and improve our understanding of the inflammatory componentsof atherosclerosis.


application_id: 7923715
project_number: 5R21MH086958-02
project_title: A Comparative Developmental Connectivity Study of Face Processing
administering_ic: NIMH
award_notice_date: 2010-06-16
opportunity_number: RFA-MH-09-080
application_type: 5
activity_code: R21
ic: MH
serial_number: 086958
program_official: BREEDEN, ANDREW LEE
project_start_date: 2009-09-01
project_end_date: 2010-07-31
study_section: ZMH1-ERB-L(04)
contact_pi_person_id: 1911365
contact_pi: JOSEPH, JANE E
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The capacity for face processing is highly developed in species like primates that have complex social structures. Disorders of face processing like Autism Williams Syndrome and developmental prosopagnosia can profoundly affect social relationships and communication. In humans some aspects of face processing develop quite early and are exhibited in very young infants. However other aspects of face processing take much longer to develop and may not reach adult levels until adolescence or later. This protracted developmental timeline for face processing may depend on a variety of factors. Some aspects of brain morphology like myelination and white matter development also have a protracted developmental time course. These features of brain maturation may not reach adult levels until late adolescence or early adulthood. The present application explores the possibility that protracted development of face processing in humans is related to the development of specific functional and anatomical connections within the brain. Such developmental changes may support a neural system for social cognition that includes face processing. Non-human primates (NHPs) exhibit many of the same face processing capacities as humans as well as some aspects of social cognition making this species an ideal candidate for animal models of typical and disordered development of social cognition. However it is not known whether large-scale brain networks for face processing are shared with humans. A comparative approach can help determine whether developmental changes in neural systems that support face processing are driven by the specific experiences of the human or whether such neural organization is present in other species despite their very different experiences. To determine species similarity and divergence for face processing in the developing brain this application will conduct functional and anatomical connectivity analyses in human children adolescents and adults and in mature NHPs (macaca mulatta). This research plan will consist of two phases an initial developmental phase (the R21 phase) that will focus on establishing and refining functional magnetic resonance imaging (fMRI; used for functional connectivity) and diffusion tensor imaging (DTI; used for anatomical connectivity) techniques in NHPs and a second R33 phase in which connectivity data from humans are collected and compared to the data in NHPs. The overall scientific goal is to characterize the large-scale anatomical and functional brain networks in humans and NHPs for the perception of faces and for the processing of emotions in the face. Both capacities are critical for highly social organisms but species-specific experiences may modulate these networks differently. One benefit of the proposed research is that the brain imaging techniques that will be used to characterize large-scale brain connectivity are non-invasive and may help guide more targeted but invasive approaches that use NHPs as an animal model for typical and atypical development. Overall the findings from this application will advance our understanding of the primate brain basis for social cognition.  
  
Public Health Relevance: A better understanding of brain connectivity patterns for face processing in humans and non-human primates can help develop animal models of typical and atypical social development. Such findings can be used to target behavioral or pharmacological interventions for conditions like Autism Spectrum Disorder or Williams Syndrome.

project_terms:
10 year old;12 year old;Adolescence;Adolescent;Adult;Affect;Age-Years;Animal Model;Autistic Disorder;Base of the Brain;Behavior;Behavioral;Brain;Brain imaging;Brain region;Child;Childhood;Communication;Complex;Data;Data Set;Development;Diffusion;Diffusion Magnetic Resonance Imaging;Discrimination (Psychology);Disease;Elderly;Emotional;Emotions;Evolution;Exhibits;Face;Face Processing;Functional Magnetic Resonance Imaging;Goals;Hand;Human;Human Development;Image;Imaging Techniques;Infant;Intervention;Laboratories;Macaca mulatta;Modeling;Organism;Participant;Pattern;Perception;Phase;Primates;Process;Research;Research Personnel;Sampling;Scientist;Social Behavior;Social Development;Structure;Support System;System;Techniques;Testing;Time;TimeLine;Visual;Williams Syndrome;autism spectrum disorder;base;brain morphology;cognitive function;comparative;developmental prosopagnosia;emerging adult;experience;face perception;frontal lobe;human data;improved;innovation;interest;myelination;neural circuit;nonhuman primate;novel;preference;public health relevance;relating to nervous system;social;social cognition;tool;visual stimulus;white matter

public_health_relevance:
PROJECT NARRATIVEA better understanding of brain connectivity patterns for face processing in humans and non-human primatescan help develop animal models of typical and atypical social development. Such findings can be used totarget behavioral or pharmacological interventions for conditions like Autism Spectrum Disorder or WilliamsSyndrome.


application_id: 7923700
project_number: 5P01AA017103-03
project_title: Alcohol Liver Disease and Alcohol-Nutrient Interactions
administering_ic: NIAAA
award_notice_date: 2010-08-10
opportunity_number: RFA-AA-07-001
application_type: 5
activity_code: P01
ic: AA
serial_number: 017103
program_official: GENTRY, THOMAS
project_start_date: 2008-09-30
project_end_date: 2012-08-31
study_section: ZAA1-BB(90)
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The University of Louisville (UofL) has had excellent success in developing an interactive research program evaluating the etiology and potential therapies for alcoholic liver disease (ALD). This U of L investigative team has chosen to submit an NIAAA P20 planning grant which will expand our research focus and support the creation of the University of Louisville Alcohol Research Center (ULARC) and the development of necessary infrastructure a critical mass of interactive investigators and appropriate education/mentoring capabilities necessary to compete for a future P50/P60 Alcohol Center. The research focus of the UofL P20 will be alcohol-nutrition interactions in the development of alcohol-induced organ injury and potential nutrition-based prevention/intervention. No existing alcohol center has a research theme relating to nutrition. Moreover the alcohol nutrient theme allows for expansion into non-liver targets of alcohol-induced injury such as cardiomyopathy. The P20 mechanism will allow us to bring new investigators into the alcohol field who have complementary research interests with our program. It will facilitate the development of unique "support cores" that will enhance our research mission and it will provide pilot funding for supporting junior investigators attracting established investigators to the field of alcohol research and generating critical new data necessary for a P50 submission. Our proposal has highly innovative pilot projects using new animal models biomarkers and clinical interventions. Education and translational research are important components of the ULARC. The aims of the University of Louisville Alcohol Research Center are to: 1. Facilitate interdisciplinary approaches to the investigation of specific alcohol-induced organ injury via the establishment of appropriate administrative pilot and core support; 2. Develop new and innovative investigations into the role of nutrition in alcohol-induced organ injury; 3. Develop unique and effective training programs for investigators performing alcohol research especially those focusing on translational research; 4. Utilize this P20 mechanism to develop the University of Louisville Alcohol Research Center as a defined translational research program that will be competitive for P50/P60 funding and be aligned with the goals of the NIAAA strategic plan and the NIH Road Map.


application_id: 7923699
project_number: 5P01AA017103-02
project_title: Administrative Core
administering_ic: NIAAA
opportunity_number: RFA-AA-07-001
application_type: 5
activity_code: P01
ic: AA
serial_number: 017103
study_section: ZAA1
subproject_number: 9001
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
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: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-09-01
budget_end_date: 2010-08-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
ADMINISTRATIVE COREThe University of Louisville Alcohol Research Center (ULARC) is a multidisciplinary program focusing onalcohol-nutrient interactions and alcohol-induced organ injury and their prevention and/or treatment. Basicscience and clinical investigators from several departments within the School of Medicine the DentalSchool the Kent School of Social Work and the School of Public Health and Information Sciences havecoalesced into a cohesive research unit to examine selected research questions regarding the specificnutrient interactions in organ and systemic sequelae of alcohol abuse. The Center will be administrativelylocated within the Department of Medicine at the U of L Health Sciences Center. The Principal Investigatorand Center Director Dr. Craig McClain reports to the Executive Vice President for Health Sciences of theUniversity of Louisville Dr. Larry Cook. Administrative support for the Center will be provided by the CenterBiostatistician Dr. Datta and a half-time administrator. The Executive Committee will be the guiding groupfor the ULARC. In addition the External Advisory Committee and the Internal Advisory Committee willprovide oversight and consultation. The theme of alcohoknutrient interactions and alcohol-induced organinjury is unique and innovative amongst alcohol centers. The administrative core has a major educationfocus including the development of a K-12 type program for translational investigators. The administrativecore focuses on collaborative interactions and mentoring (examples of both are highlighted). Innovation andtranslational research with a goal of transforming clinical practice are important directions for theAdministrative Core. The Administrative Core will be established to: 1) provide direction and prioritization ofULARC activities and assure proper accounting of grant monies; 2) coordinate the activities of the SupportCore and pilot projects; 3) ensure the quality of all ULARC functions; 4) develop a curriculum to train clinicaland translational alcohol researchers; and 5) disseminate pertinent information to ULARC investigators andthe scientific and lay community.

project_terms:
Accounting;Administrator;Advisory Committees;Alcohol Nutrition;Alcohol abuse;Alcoholic Liver Diseases;Alcohols;American;Animals;Area;Basic Science;Biology;Cardiomyopathies;Clinical;Clinical Investigator;Communities;Consultations;Country;Data;Dental Schools;Development;Disease;Drug or chemical Tissue Distribution;Educational Curriculum;Educational aspects;Ensure;Etiology;Excretory function;Fetal Alcohol Syndrome;Food Interactions;Funding;Future;Goals;Grant;Health;Health Sciences;Hepatitis C;Histologic;Human;Individual;Information Sciences;Injury;Intake;Investigation;Literature;Liver diseases;Maps;Medicine;Mentors;Metabolic;Mission;Names;National Institute on Alcohol Abuse and Alcoholism;Nutrient;Nutritional;Nutritional status;Obesity;Organ;Overweight;Patient Care;Physicians;Pilot Projects;Predisposition;Prevention;Preventive Intervention;Principal Investigator;Process;Public Health Schools;Reporting;Research;Research Infrastructure;Research Personnel;Resistance;Role;Schools;Social work (field);Steatohepatitis;Strategic Planning;TNFRSF5 gene;Time;Training;Training Programs;Translational Research;United States;United States National Institutes of Health;Universities;absorption;alcohol effect;alcohol research;base;clinical practice;cooking;drug development;drug metabolism;gene interaction;immune function;innovation;interdisciplinary approach;interest;medical schools;multidisciplinary;nonalcoholic steatohepatitis;nutrition;problem drinker;programs;success;translational study


application_id: 7923610
project_number: 3R01GM036065-22S1
project_title: Regulation of Protein N-Glycosylation in the CNS
administering_ic: NIGMS
award_notice_date: 2009-09-25
application_type: 3
activity_code: R01
ic: GM
serial_number: 036065
suffix: S1
program_official: MARINO, PAMELA
project_start_date: 2009-09-30
project_end_date: 2011-08-31
study_section: Biochemistry and Biophysics of Membranes Study Section[BBM]
contact_pi_person_id: 7875239
contact_pi: WAECHTER, CHARLES J
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant):  The co-translational N-glycosylation of many important cell surface receptors ion channels and lysosomal enzymes is essential for their correct folding intracellular routing and function in the CNS and other mammalian cells. The vital importance of protein N-glycosylation in humans is emphasized by the clinical consequences of a series of inherited genetic defects in this pathway classified as Congenital Disorders of Glycosylation (CDG). While the enzymology and topology of the biosynthesis of Glc3Man9GlcNAc2-P-P-Dol the oligosaccharyl donor in the endoplasmic reticulum (ER) have been studied extensively many gaps remain in the understanding of how the enzymes in this pathway are organized and regulated. This proposal describes further studies to learn more about the role of ER-associated proteins in the regulation of dolichyl phosphate (Dol-P) biosynthesis and recycling and the transbilayer movement of Man-P-Dol.        Three Specific Aims are planned using biochemical genetic and immunochemical approaches designed: 1) To utilize a recently cloned cDNA to learn more about the long-chain c/s-isoprenyltransferase (c/s-IPTase) catalyzing the elongation stage in Dol-P biosynthesis by investigating its regulation and the nature of its association with potential binding partners in the ER; 2) To utilize cloned cDNAs encoding dolichol kinase (DK) and Dol-P-P phosphatase an ER enzyme with a lumenally-oriented active site in in vivo and in vitro experiments aimed at elucidating their precise roles in the ote novo synthesis of Dol-P and the recycling of the glycosyl carrier lipid and 3) To purify identify and characterize the ER protein(s) mediating the transverse diffusion of Man-P-Dol in mammalian cells ("flippase"). The information gained on the structure of the Man-P-Dol flippase will be relevant to related membrane proteins mediating the transbilayer movement of other dolichyl-P-(P)-saccharide intermediates in protein O- C- and N-glycosylation glycerophospholipids glucosylceramide and glycosylphosphatidylinositol (GPI) anchor precursors and potential defects in patients with Congenital Disorders of Glycosylation (CDG).

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


application_id: 7923266
project_number: 5R01AG034605-02
project_title: Hippocampal Electrophysiology and Myelinogenesis in Healthy Cognitive Aging
administering_ic: NIA
award_notice_date: 2010-08-20
opportunity_number: RFA-AG-09-010
application_type: 5
activity_code: R01
ic: AG
serial_number: 034605
program_official: WAGSTER, MOLLY V
project_start_date: 2009-09-01
project_end_date: 2014-08-31
study_section: ZAG1-ZIJ-5(M2)
contact_pi_person_id: 2405844
contact_pi: LANDFIELD, PHILIP W.
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This application proposes to address a fundamental unresolved question in the field of cognitive aging the nature of the neurobiological factors that distinguish individuals with healthy cognitive aging (HCA) from those with unhealthy cognitive aging (UCA). The focus of the studies will be on biomarkers developing near the age of divergence of unhealthy from healthy cognitive aging as these appear particularly likely to provide important insights into causal mechanisms. A major emphasis of the project will also be testing the hypothesis that midlife activation of myelinogenic programs in the hippocampus is an important factor in converting HCA to UCA. This view derives from our recent work with both microarray and immunohistochemical techniques showing that myelinogenesis is increased around midlife in rats the same age range in which unhealthy cognitive aging begins to appear. The proposed studies will comprise a large multidisciplinary project aimed at obtaining a unique integrated perspective on neurobiological correlates of cognitive aging in an established rat model of aging. It will involve state-of-the-art intracellular electrophysiology in hippocampal slices concomitant Ca2+ imaging in recorded neurons extensive immunohistochemistry with a battery of stains diffusion tensor imaging (MRI/DTI) separate microarray analysis of each individual rat and substantial behavioral testing of each animal. Multiple techniques will be applied in each animal. These studies will pursue the aims of correlating electrophysiological and genomic markers of cognitive aging in the same animals and will relate cognitive function to myelin structure and density in cross-sectional and longitudinal analyses. Further the course of myelinogenesis will be altered in long-term studies that manipulate dietary iron and/or treat with cuprizone. Animals subjected to altered myelinogenesis will be tested on a battery of behavioral electrophysiological microarray and immunohistochemical analyses to test the proposition that conversion to UCA has been slowed and if it has to determine through which hippocampal pathways this occurred. Overall these studies should substantially elucidate neurobiological markers distinguishing UCA from HCA and should importantly determine the role of myelinogenic programs in cognitive aging. Further the proposed longitudinal studies should have direct translational relevance.  
  
PUBLIC HEALTH RELEVANCE: This proposed research will be conducted in an established rat model of aging which shows demonstrated relevance to human aging. These studies will elucidate neurobiological markers of and processes influencing the divergence of healthy and unhealthy cognitive aging. Therefore the proposed studies should have both predictive and therapeutic value in determining the course of human cognitive aging.

project_terms:
Address;Age;Age-Months;Aging;Anemia;Animal Feed;Animal Model;Animals;Arts;Astrocytes;Behavioral;Binding (Molecular Function);Bioenergetics;Bioinformatics;Brain;Cholesterol;Cognition;Cognitive;Cognitive aging;Corpus Callosum;Cuprizone;Data;Diet;Dietary Iron;Diffusion Magnetic Resonance Imaging;Elderly;Electrophysiology (science);Event;Exhibits;Figs - dietary;Fostering;Gene Expression;Genes;Genomics;Guanosine Triphosphate Phosphohydrolases;Hemochromatosis;Hippocampus (Brain);Human;Image;Immune;Immunohistochemistry;Impaired cognition;Individual;Inflammation;Inflammatory;Intake;Intervention;Investigation;Iron;Left;Link;Lipids;Liver;Longitudinal Studies;Magnetic Resonance Imaging;Measures;Mediating;Memory;Methods;Microarray Analysis;Modeling;Monkeys;Myelin;Nature;Neurites;Neurobiology;Neurons;Oligodendroglia;Oxidative Stress;Pathway interactions;Performance;Phase;Play;Process;Protocols documentation;Rattus;Regulation;Research;Resources;Role;Sampling;Serum;Signal Transduction;Slice;Staining method;Stains;Stimulus;Structure;Techniques;Testing;Therapeutic;Translating;Up-Regulation (Physiology);Validation;Work;age related;aged;aging brain;base;behavior test;biological adaptation to stress;biomarker;cognitive function;density;indexing;insight;interest;middle age;morris water maze;multidisciplinary;myelination;programs;protein degradation;public health relevance;response;trafficking;young adult

public_health_relevance:
This proposed research will be conducted in an established rat model of aging which shows demonstratedrelevance to human aging. These studies will elucidate neurobiological markers of and processes influencingthe divergence of healthy and unhealthy cognitive aging. Therefore the proposed studies should have bothpredictive and therapeutic value in determining the course of human cognitive aging.


application_id: 7923117
project_number: 5R01DA027569-02
project_title: Exercise as a novel strategy to target methamphetamine-induced cerebrovascular to
administering_ic: NIDA
award_notice_date: 2010-08-07
opportunity_number: RFA-DA-09-013
application_type: 5
activity_code: R01
ic: DA
serial_number: 027569
program_official: PUROHIT, VISHNUDUTT
project_start_date: 2009-09-01
project_end_date: 2014-08-31
study_section: ZDA1-GXM-A(05)R
contact_pi_person_id: 8260644
contact_pi: TOBOREK, MICHAL
other_pis: Not Applicable
congressional_district: 06
department: NEUROSURGERY
primary_duns: 939017877
primary_uei: 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): Current strategies aimed at combating methamphetamine (METH) abuse do not appear to be effective and it is likely that METH abuse will continue to increase in the future. This is a serious concern because METH abuse is associated with several adverse cerebrovascular pathologies of which the blood-brain barrier (BBB) breakdown is an underlying component. Interestingly METH users have decreased levels of antioxidant capacity a condition that is known to be associated with neurotoxicity and impaired vascular functions. Exercise is a modifiable behavioral factor known to have numerous health promoting effects that are mediated in part by an increase in antioxidant protection. We propose that exercise can attenuate the cerebrovascular toxicity of METH at the level of the BBB via antioxidant related mechanisms. The central hypothesis of the present application is that exercise protects against METH-induced disruption of the BBB by enhancing the antioxidant capacity of cerebral microvessels and modulating the caveolae-associated signaling. Mechanistically we will explore a link between exercise METH-induced disruption of tight junction proteins and alterations of caveolae-associated redox signaling in brain capillaries. Caveolae are the subset of lipid rafts that are characterized by the presence of caveolin proteins. The significance of METH-caveolae interaction is related to the fact that a variety of cell surface receptors and redox-regulated signaling pathways including small GTPases such as the Ras and Rho cascades are localized in caveolae. These pathways may participate in phosphorylation of tight junction proteins and thus regulate the integrity of the BBB. Importantly our data indicate that exercise can modify METH-induced caveolae-associated signaling and regulate levels of caveolin-1 protein. These observations prompted us to propose that caveolae provide the signaling platform for cerebrovascular toxicity of METH that can be effectively targeted by exercise. Data arising from this proposal will be critical not only for a better understanding of the molecular mechanisms underlying METH-related cerebrovascular injury but will also contribute to better knowledge of how exercise can protect against vascular toxicity. The strength of our approach may lead to the discovery of novel drug targets used to combat METH abuse and/or related neurotoxicity. Furthermore the results generated by the proposed research are likely to be relevant in other neurodegenerative diseases that have significant cerebrovascular components such as stroke or Alzheimer's and Parkinson's diseases. We believe that the data obtained from this proposal will provide evidence that even moderate exercise can significantly contribute to brain regeneration in chronic cerebrovascular disorders.  
  
PUBLIC HEALTH RELEVANCE: Methamphetamine (METH) abuse results in a long-term impairment of vascular functions that remain compromised in abstinent METH users. Several toxic effects of METH such as myocardial infarction stroke and cardiomyopathy are directly related to vascular or cerebrovascular dysfunction. In addition the disruption of the blood-brain barrier (BBB) has been established as one of the most prominent events of METH toxicity. We hypothesize that exercise can protect against METH-induced disruption of the BBB by enhancing the antioxidant capacity of cerebral microvessels and modulating the caveolae-associated signaling. Data arising from our proposal will be critical not only for a better understanding of the molecular mechanisms underlying METH-related cerebrovascular injury but also will contribute to better knowledge of how exercise can protect against vascular toxicity. The results generated by the proposed research are likely to be relevant to other neurodegenerative diseases that have significant cerebrovascular components such as stroke or Alzheimer's and Parkinson's diseases. We believe that the data obtained from this proposal will provide evidence that even moderate exercise can significantly contribute to brain regeneration in chronic cerebrovascular disorders.

project_terms:
Actins;Acute;Address;Alzheimer's Disease;Animals;Antioxidants;Attenuated;Behavioral;Biological Models;Blood;Blood - brain barrier anatomy;Blood Vessels;Blood capillaries;Brain;C57BL/6 Mouse;Cardiomyopathies;Caveolae;Caveolins;Cell Surface Receptors;Cells;Cerebrovascular Disorders;Cerebrum;Chronic;Cytoskeleton;Data;Development;Dose;Drug Delivery Systems;Drug abuse;Elements;Endothelial Cells;Endothelium;Enzymes;Equilibrium;Event;Exercise;Exposure to;Functional disorder;Future;GTP-Binding Proteins;Glutathione Disulfide;Goals;Health;Human;Impairment;Inflammatory;Injury;Integral Membrane Protein;Intercellular Junctions;Knowledge;Lead;Link;Manganese Superoxide Dismutase;Mediating;Membrane;Membrane Microdomains;Methamphetamine;Modeling;Moderate Exercise;Molecular;Monomeric GTP-Binding Proteins;Mus;Myocardial Infarction;Natural regeneration;Neurodegenerative Disorders;Oxidases;Oxidation-Reduction;Oxidative Stress;Parkinson Disease;Pathology;Pathway interactions;Permeability;Phosphorylation;Physical activity;Process;Promotor (Genetics);Property;Proteins;Proteomics;Regulation;Reporting;Research;Rodent;Role;Running;Signal Pathway;Signal Transduction;Solid;Substance abuse problem;Therapeutic Intervention;Tight Junctions;Tissues;Toxic effect;Very Light Exercise;Work;addiction;base;capillary;caveolin 1;cerebrovascular;combat;design;drug of abuse;in vivo Model;junctional adhesion molecule;methamphetamine abuse;methamphetamine exposure;migration;mitochondrial dysfunction;neurobiological mechanism;neuroinflammation;neurotoxicity;novel;novel strategies;nuclear factor-erythroid 2;occludin;oxidation;p66(ShcA) protein;protective effect;protein expression;public health relevance;research study;response;rho;sedentary;stroke;transcription factor

public_health_relevance:
PROJECT NARRATIVE Methamphetamine (METH) abuse results in a long-term impairment of vascularfunctions that remain compromised in abstinent METH users. Several toxic effects of METHsuch as myocardial infarction stroke and cardiomyopathy are directly related to vascular orcerebrovascular dysfunction. In addition the disruption of the blood-brain barrier (BBB) hasbeen established as one of the most prominent events of METH toxicity. We hypothesize thatexercise can protect against METH-induced disruption of the BBB by enhancing the antioxidantcapacity of cerebral microvessels and modulating the caveolae-associated signaling. Dataarising from our proposal will be critical not only for a better understanding of the molecularmechanisms underlying METH-related cerebrovascular injury but also will contribute to betterknowledge of how exercise can protect against vascular toxicity. The results generated by the proposed research are likely to be relevant to otherneurodegenerative diseases that have significant cerebrovascular components such as strokeor Alzheimer's and Parkinson's diseases. We believe that the data obtained from this proposalwill provide evidence that even moderate exercise can significantly contribute to brainregeneration in chronic cerebrovascular disorders.


application_id: 7922511
project_number: 5F31AA018588-02
project_title: Adenosine Receptors and Ethanol Withdrawal
administering_ic: NIAAA
award_notice_date: 2010-08-12
application_type: 5
activity_code: F31
ic: AA
serial_number: 018588
program_official: CUI, CHANGHAI
project_start_date: 2009-09-01
project_end_date: 2011-05-08
study_section: Neuroscience and Behavior Study Section[AA-4]
contact_pi_person_id: 9706316
contact_pi: BUTLER, TRACY RENEE
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: 2010-09-01
project_abstract:
DESCRIPTION (provided by applicant): Previous studies suggest an innate sex difference in adenosine receptor density and/or function which is mediated at least in part by NMDA receptors (Butler et al. 2008). The currently proposed studies will investigate effects of chronic ethanol (EtOH) exposure on adaptive changes in adenosine and NMDA receptor proteins which may confer sensitivity to neurotoxicity during ethanol withdrawal (EWD) in a concentration- and/or sex-dependent manner. Male and female organotypic hippocampal slice cultures will be continuously exposed to EtOH (0 25 or 50 mM) for ten days. Upon removal of EtOH immunohistochemistry will be employed for the adenosine A1 and A2A receptor subtypes and the NMDA NR1 and NR2B subunits to quantify receptor density in the primary cell layers of the dentate gyrus and the CA3 and CAI regions of the hippocampus. Western blotting will be conducted for an additional quantitative measure of changes in receptor proteins throughout the whole hippocampal formation in male and female EtOH-exposed cultures (0 25 50 mM). Additional studies will examine functional consequences of pharmacological antagonism of adenosine Al receptor antagonism during EWD. Cultures will be exposed to EtOH for ten days before twenty-four hour EWD. For the duration of EWD cultures will be exposed to an Air antagonist; an Air antagonist + Air agonist; or an Air antagonist + NMDAr antagonist; and all cultures will be exposed to propidium iodide (PI) for labeling of dead/dying cells. Cultures will then be formalin-fixed for immunohistochemical labeling of mature neurons with neuronal nuclear protein (NeuN). Additional cultures will be exposed to the same drug treatments described but will be exposed to Calcium (Ca2+) Orange at the end of twenty-four hour EWD to measure whether toxicity caused by A1r antagonism during EWD is correlated with potentiated Ca2+ influx. Slices will be visualized using fluorescent microscopy and data will be quantified using densitometry and confocal imaging. Correlational analyses will determine if the measures of cell viability (PI NeuN Ca2-*- orange) are related. These techniques allow for a comprehensive characterization of changes in the adenosinergic and NMDA receptor systems induced by EtOH exposure and the functional consequences of those hypothesized adaptations during EWD. A significant amount of evidence suggests that the female brain of both humans and rodents is more sensitive to neurotoxicity in response to EtOH exposure and/or EWD. The current studies will contribute to our knowledge of EtOH- induced neuronal adaptations and potential sex differences in brain structure and/or function and may contribute to the advent of novel pharmacotherapies to ameliorate EtOH and/or EWD-related toxicity.

project_terms:
Adenosine;Agonist;Air;Alcohol withdrawal syndrome;Brain;Calcium;Calculi;Cell Culture Techniques;Cell Death;Cell Survival;Cells;Chronic;Confocal Microscopy;Data;Densitometry;Ethanol;Excision;Excitatory Amino Acids;Female;Fluorescence;Formalin;Glutamates;Hippocampal Formation;Hippocampus (Brain);Hour;Human;Image;Imagery;Immunofluorescence Immunologic;Immunohistochemistry;In Vitro;Knowledge;Label;Laboratories;Measures;Mediating;Microscopy;Modeling;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;NMDA receptor antagonist;NR1 gene;Neurons;Nuclear Protein;Nuclear Proteins;Oranges;Pharmaceutical Preparations;Pharmacotherapy;Polyamines;Propidium Diiodide;Purinergic P1 Receptors;Rattus;Regimen;Reporting;Rodent;Sex Characteristics;Slice;Structure;System;Techniques;Toxic effect;Western Blotting;Withdrawal;Work;alcohol effect;alcohol exposure;density;dentate gyrus;design;follow-up;in vivo;male;neurotoxicity;neurotransmission;novel;polypeptide;prevent;receptor;receptor density;research study;response;sex


application_id: 7922246
project_number: 3R01EY012354-10S1
project_title: Isolation of congenital stationary night blindness genes
administering_ic: NEI
award_notice_date: 2009-08-31
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: EY
serial_number: 012354
suffix: S1
program_official: MARIANI, ANDREW P
project_start_date: 1999-02-01
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZRG1-CB-G(90)]
contact_pi_person_id: 1885008
contact_pi: GREGG, RONALD G
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
project_abstract:
Vision begins when light is converted to an electrical signal in the photoreceptors. Increases in light decreaserelease of the neurotransmitter glutamate from cone and rod photoreceptor terminals and decreases in lightincrease its release. These changes in synaptic glutamate concentration are detected by two classes of bipolarcells that then transmit the signal vertically through the retinal circuit to the ganglion cells. The neurotransmitterchanges also are detected by horizontal cells that provide lateral transmission in the form of feedback andfeedforward inhibition. There are two classes of bipolar cells hyperpolarizing (HBCs) and depolarizing (DBCs).HBCs utilize ionotropic glutamate receptors and hyperpolarize in response to a light flash. DBCs utilize ametabotropic glutamate receptor mGluR6 and depolarize in response to a light flash. Defects in transmission between photoreceptors and bipolar cells result in several forms of congenitalstationary night blindness (CSNB). The incomplete form CSNB2 results from mutations in genes critical toglutamate release in photoreceptors including the 1F subunit of voltage dependent calcium channels. Thecomplete form results from mutations in signaling in DBCs including mutations in mGluR6 and nyctalopin aprotein of unknown function. Signaling through DBCs is mediated via a metabotropic glutamate receptor mGluR6 that modulates theactivity of a non-specific cation channel of unknown identity. The details of this mGluR6 cascade are mostlyunknown. The long term goal of this project is to characterize the molecular components required for synaptictransmission between photoreceptors and DBCs. This project has four specific aims: 1) determine thestructure/function relationships of nyctalopin 2) determine the state of the non-specific cation channel inseveral night blind mice 3) determine the binding partners of nyctalopin thereby elucidating new component ofthe mGluR6 cascade and 4) create knockout mouse lines of the nyctalopin interacting proteins to determine ifthey result in nigh blindness. At the completion of this project we will have identified new members critical tosignal transmission in DBCs. Further we will have identified new candidate genes for congenital stationarynight blindness. Vision requires a light signal be converted to an electrical signal which is then transmitted to the brainvia a neuronal network. The group of diseases being studied are referred to as congenital stationarynight blindness and have defects in signal transmission between photoreceptors and the secondneuron in the pathway. The studies in this proposal will characterize the nature of the defects anddetermine new proteins critical to function.

project_terms:
Binding (Molecular Function);Biochemical;Blindness;Brain;Calcium Channel;Candidate Disease Gene;Cations;Cells;Complex;Defect;Dendrites;Disease;Electroretinography;Elements;Extracellular Matrix Proteins;Family;Family member;Feedback;Funding;Genes;Glutamate Receptor;Glutamates;Goals;Grant;Human;Hybrids;Immunoprecipitation;Individual;Knockout Mice;Lateral;Lead;Leucine-Rich Repeat;Ligands;Light;Link;Mass Spectrum Analysis;Mediating;Metabotropic Glutamate Receptors;Molecular;Mus;Mutant Strains Mice;Mutation;Nature;Neurons;Neurotransmitters;Night Blindness;Pathway interactions;Phosphatidylinositol 45-Diphosphate;Photoreceptors;Property;Proteins;Proteoglycan;Retina;Retinal;Retinal Cone;Rods (Retina);Role;Signal Transduction;Site;Structure;Structure-Activity Relationship;Synapses;Synaptic Transmission;Vision;Yeasts;blind;extracellular;ganglion cell;glycosylation;horizontal cell;in vivo;member;mouse model;mutant;neurotransmitter release;patch clamp;postsynaptic;presynaptic;protein transport;research study;response;transmission process


application_id: 7921696
project_number: 3R01HL074185-06S1
project_title: Endothelial Myocyte Matrix in Cardiac Remodeling
administering_ic: NHLBI
award_notice_date: 2009-08-25
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: HL
serial_number: 074185
suffix: S1
program_official: SCHWARTZ, LISA
project_start_date: 2003-09-05
project_end_date: 2014-08-31
study_section: Special Emphasis Panel[ZRG1-CVS-D(03)M]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this project is to understand the mechanism of endocardial endothelial-myocyte (E-M) dysfunction in chronic heart failure. Studies from the previous funding period suggested that endocardial endothelial dysfunction is associated with increased oxidized-matrix accumulation (fibrosis) activation of latent resident myocardial matrix metalloproteinases (MMPs) and inactivation of cardiac tissue inhibitor of metalloproteinase (TIMP-4) secondary to oxidative and proteolytic stresses. Administration of TIMP-4 ameliorated both the formation of reactive oxygen species (ROS oxidative stress) and MMP activation (proteolytic stress). In addition we discovered the induction of proteinase activated receptor-1 (PAR-1). However the role of PAR-1 in fibrosis and E-M uncoupling remains poorly defined. H2S gas is the most potent antioxidant in mitigating oxidative stress and recent studies have implicated a cardioprotective role of H2S. The central hypothesis of this competitive renewal proposal is that during chronic heart failure the oxidative and proteolytic stresses induce PAR-1 leading to generate mitochondrial (mt) ROS and reactive nitrogen species (RNS) and mitochondrial nitric oxide synthase (mtNOS) respectively thus activating the latent resident cardiac MMPs. These events disrupt the MMP/TIMP axis causing fibrosis between endothelium and myocyte. Treatment with H2S alleviates fibrosis and mitigates E-M uncoupling. Therefore the specific aims of this proposal are: #1: To determine whether chronic left ventricle (LV) volume overload causes mitochondrial oxidative stress (ROS and RNS) by inducing NADPH oxidase (p47 subunit) mtNOS and PAR-1 and H2S alleviates mitochondrial oxidative stress. #2: To determine whether chronic LV volume overload causes cardiac fibrosis by increasing collagen/elastin ratio MMP-2 -9 -13 TIMP-1 -3 decreasing TIMP-4 and inducing PAR-1 and H2S mitigates cardiac fibrosis. #3: To determine whether chronic LV volume overload causes E-M dysfunction and LVH by inducing PAR-1 and H2S decreases E-M uncoupling. Chronic heart failure will be created by LV volume overload by aorta-venacava fistula (AVF) in wild type (WT) PAR-1-/+ iNOS-/- MMP-9-/- TIMP-3-/- and TIMP-4++/++ mice treated with or without NaHS a H2S donor. PUBLIC HEALTH RELEVANCE: The myocyte contraction and relaxation are synchronized only when myocytes are connected by extracellular matrix (ECM). We coined the term endothelial-myocyte (E-M) coupling because endocardial endothelial (EE) cells derived cardio-active agents modulate myocyte contraction in systole and relaxation in diastole. The endothelium in the heart is the least studied system because unlike conduit arteries the endocardial endothelium is buried in the muscle and it is difficult to separate its role in myocyte function. We developed a new technique "cardiac rings" in which endothelium dependent or independent cardiac contraction and relaxation can be examined separately in LV and RV. There are two novel aspects of this proposal: 1) the proposed experiments will demonstrate the role of PAR-1 in the underlying mechanism of fibrosis and endothelial-myocyte uncoupling in heart failure; and 2) will have clinical translational ramifications of H2S in treating diastolic heart failure.

project_terms:
Abbreviations;Acetylcholine;Acids;Antigens;Antioxidants;Aorta;Apoptosis;Arteries;Arteriovenous fistula;Basement membrane;Bradykinin;CD31 Antigens;Cardiac;Cells;Chronic;Clinical;Coin;Collagen;Congestive Heart Failure;Coupling;CpG Island Methylator Phenotype;Cystathionine;Cytoskeleton;Diastole;Diastolic blood pressure;Diastolic heart failure;Dilated Cardiomyopathy;Disulfides;Echocardiography;Elastin;Endothelial Cells;Endothelium;Event;Extracellular Matrix;Fibrosis;Fistula;Functional disorder;Funding;Gases;Gelatinase A;Gelatinase B;Generations;Goals;Heart;Heart failure;Histology;Hydrogen Sulfide;Hydroxyeicosatetraenoic Acids;Hypertrophy;In Situ;Laboratories;Left;Left ventricular structure;Lyase;Matrix Metalloproteinases;Measures;Mediating;Mitochondria;Mus;Muscle;Muscle Cells;Myocardial;NADH;NADPH Oxidase;NG-Nitroarginine Methyl Ester;Nicotinamide adenine dinucleotide;Nitric Oxide;Nitric Oxide Synthase;Nitroprusside;Nuclear;Operative Surgical Procedures;Oxidation-Reduction;Oxidative Stress;PAR-1 Receptor;Poly(ADP-ribose) Polymerases;Preparation;Principal Investigator;Process;Prostaglandins;Protein Kinase C;Proteome;Radiolabeled;Reactive Nitrogen Species;Reactive Oxygen Species;Relaxation;Role;Secondary to;Sodium;Source;Stress;Sulfhydryl Compounds;System;Systole;Techniques;Testing;Time;Tissue Inhibitor of Metalloproteinase-1;Tissue Inhibitor of Metalloproteinase-3;Tissue Inhibitor of Metalloproteinases;Ventricular;Western Blotting;arginine methyl ester;drinking water;human AKAP13 protein;human NOS3 protein;in vivo;innovation;novel;prevent;progesterone 11-hemisuccinate-(2-iodohistamine);programs;public health relevance;radiotracer;relaxing factor;research study;response;sham surgery;tissue inhibitor of metalloproteinase 4


application_id: 7921271
project_number: 3K01CA106599-06S1
project_title: Regulation of apoptosis by Bcl-XL Bak and Bax
administering_ic: NCI
award_notice_date: 2009-09-14
opportunity_number: PAR-03-104
application_type: 3
activity_code: K01
ic: CA
serial_number: 106599
suffix: S1
program_official: SCHMIDT, MICHAEL K
project_start_date: 2009-09-01
project_end_date: 2010-08-31
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 6950638
contact_pi: LI, CHI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The development of cancer involves genetic changes leading to alterations in the control of tissue development and homeostatic maintenance which is tightly regulated by the cellular suicide program apoptosis. Many tumor cells are resistant to intrinsic and extrinsic apoptotic stimuli probably due to impaired apoptotic pathways in these cells. Bcl-2 family proteins are major regulators of the cellular response to apoptotic signals. Among them anti-apoptotic Bcl-XLand pro-apoptotic Bak and Bax have-been shown to play an essential role during apoptosis. Initial studies suggest that in addition to their functions at mitochondria Bcl-2 proteins also localize on the endoplasmic reticulum (ER) and function to regulate a parallel pathway of apoptosis. Experiments in this proposal are designed to elucidate the detailed molecular mechanisms of Bcl-2 proteins regulating apoptosis. The following specific aims are proposed: 1) Investigate the electrophysiological properties of Bcl-XL Bak and Bax on the ER membrane and their contribution to the induction of membrane permeabilization during apoptosis. A novel patch-clamp approach to record single ion channel activity will be used to characterize Bcl-2 proteins on the ER membrane. The electrophysiological properties of purified recombinant as well as reexpressed Bcl-XL Bak and Bax proteins on the ER membrane will be studied. The hypothesis that Bak and Bax form lipidic pores on membranes during apoptosis will also be examined; 2) Study the distinct apoptotic pathways mediated by Bcl-2 family proteins localized on different organelles. Efforts will be made to better characterize caspase pathways mediated by Bak or Bcl-XL localized on the ER or mitochondria using a RNAi approach. The importance of intracellular localizations of pro- and anti-apoptotic Bcl-2 proteins for the regulation of apoptosis will be studied by selectively targeting these proteins to specific organelles. The possible role of Ca2+ in the regulation of distinct apoptotic pathways will be investigated; and 3) Determine whether the expression of Bak and Bax affects cellular physiology and thus cellular response to death signals. Oligonucleotide-based microarray analysis will be performed to examine the changes in gene expression patterns in response to Bak or Bax expression. Genes whose expression may be involved in apoptosis regulation will be further studied.

project_terms:
Address;Affect;Agonist;Animals;Apoptosis;Apoptotic;Bax protein;Biochemical;Cell Line;Cell Lineage;Cell Membrane Permeability;Cell physiology;Cells;Cessation of life;Characteristics;Development;Embryo;Endoplasmic Reticulum;Fibroblasts;Gene Expression;Genes;Genetic;Global Change;Goals;Hematopoietic;Homeostasis;ITPR1 gene;In Vitro;Intracellular Membranes;Ion Channel;Maintenance;Malignant Neoplasms;Mediating;Membrane;Microarray Analysis;Mitochondria;Molecular;Molecular Profiling;Mus;Mutation;Nuclear;Oligonucleotides;Organelles;Pathway interactions;Pattern;Play;Property;Protein Family;Proteins;RNA Interference;Recombinants;Regulation;Research;Research Project Grants;Resistance;Role;Signal Transduction;Stimulus;Tissues;bak protein;bcl-xlong protein;caspase;cell suicide;cell type;design;neoplastic cell;novel;overexpression;patch clamp;pro-apoptotic protein;programs;reconstitution;research study;response


application_id: 7921053
project_number: 5R01AA013388-05
project_title: Hippocamppal neurotoxicity induced by ethanol withdrawal
administering_ic: NIAAA
award_notice_date: 2010-08-26
opportunity_number: PA-07-329
application_type: 5
activity_code: R01
ic: AA
serial_number: 013388
program_official: REGUNATHAN, SOUNDAR
project_start_date: 2003-06-01
project_end_date: 2014-08-31
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 8535960
contact_pi: PRENDERGAST, MARK A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Abstinence;Acute;Adrenal Cortex Hormones;Adrenal Glands;Alcohol abuse;Alcohol consumption;Alcohol dependence;Alcohol withdrawal syndrome;Alcoholism;Alcohols;Anxiety;Attenuated;Behavioral;Biochemical;Biochemical Pathway;Blood;Brain;Brain Injuries;Corticotropin-Releasing Hormone;Corticotropin-Releasing Hormone Receptors;Dependence;Ethanol;Ethanol dependence;Exposure to;Female;Funding;Glucocorticoid Receptor;Glucocorticoids;Glutamate Receptor;Glutamates;Goals;Hippocampus (Brain);Hormones;Hypothalamic structure;Image;In Vitro;Injury;Intake;Mediating;Modeling;Molecular Target;Neuronal Injury;Neurons;Ornithine Decarboxylase;Pathway interactions;Pituitary Gland;Polyamines;Rattus;Receptor Activation;Research Personnel;Rodent;Seizures;Sex Characteristics;Slice;Stress;System;Testing;Toxic effect;Tremor;Up-Regulation (Physiology);Western Blotting;Withdrawal;alcohol abuse therapy;alcohol effect;alcohol exposure;clinically relevant;craving;design;drinking;hypercortisolemia;hypothalamic-pituitary-adrenal axis;imaging modality;in vivo;in vivo Model;male;neurotoxic;neurotoxicity;new therapeutic target;novel;paraventricular nucleus;public health relevance;receptor;receptor binding;response;sex;synthetic enzyme;therapeutic target


application_id: 7921016
project_number: 5R01DE009761-18
project_title: BACTERIAL PROTEINASES IN PERIODONTAL DISEASE
administering_ic: NIDCR
award_notice_date: 2010-06-09
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DE
serial_number: 009761
program_official: LUNSFORD, DWAYNE
project_start_date: 1991-08-01
project_end_date: 2013-06-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6947603
contact_pi: POTEMPA, JAN S
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): Periodontitis is classified as a microbiota shift disease whereby a very rich and diverse commensal flora characteristic for good oral health becomes dominated by several Gram-negative anaerobic bacterial species among which Porphyromonas gingivalis Tannerella forsythia and Treponema denticola constitute the so called "red complex" of microorganisms frequently associated with the development and progression of the disease. The common consequence of these three bacteria and a secondary periodontopathogen Prevotella intermedia is their production of proteolytic enzymes. Proteases of P. gingivalis and T. denticola are known to dysregulate tissue homeostasis and/or to frustrate defensive inflammatory responses thus significantly contributing to pathological changes in the infected periodontium. In contrast virtually nothing is known about proteases of T. forsythia and P. intermedia although it has been well documented that proteases from the former organism are produced in vivo and their activity correlates with periodontal destruction. Here we postulate that novel proteases produced by T. forsythia (forsypsin) and P. intermedia (interpains) promote periodontal tissue damage by deregulation of tightly controlled host proteolytic systems. Furthermore we suggest that the combined proteolytic activity produced locally by periodontopathogens may be a primary mechanism for synergistic periodontal tissue damage and contributes to mutual survival of the red complex bacteria. Most interestingly we have found that forsypsin and interpains as well as many other acknowledged virulence factors of P. gingivalis and T. forsythia share with gingipains a conserved C-terminal domain. We have shown that this domain together with a unique periplasmic protein and a unique outer membrane translocon protein conserved in these species is essential for gingipain secretion. This implies that a novel bacterial protein export system is employed by periodontopathogens to secrete a number of confirmed and putative virulence factors. For these reasons the specific aims of this project are as follows: 1) to use an array of biochemical and molecular biological methods to investigate the mechanism of gingipain translocation through the outer membrane of P. gingivalis and confirm the presence of this unique secretion pathway in both T. forsythia and P. intermedia; 2) to characterize novel proteases from T. forsythia and P. intermedia especially with regard to their ability to complement and/or synergize with the gingipain activity and 3) to determine the complementary or synergistic role of proteases from P. gingivalis T. forsythia and P. intermedia for in vivo proliferation and dissemination of bacteria in monomicrobial and mixed microbial infections using a murine chamber model.   
  
PUBLIC HEALTH RELEVANCE: The results of these proposed studies should not only illuminate the synergistic role of bacterial proteases in mixed infections but also shed light on a novel pathway for the secretion of virulence factors unique to P. gingivalis T. forsythia and P. intermedia. This insight may enable the design of antibodies or chemical compounds to block the export of multiple virulence factors from major periodontopathogens which in the long term may revolutionize treatment and prophylaxis of periodontal disease.

project_terms:
Affect;Albumins;Anti-Bacterial Agents;Antibodies;Bacteria;Bacterial Proteins;Bacteroidetes;Biochemical;Biological;Blood Circulation;C-terminal;Cell Surface Receptors;Cell surface;Characteristics;Chemicals;Coagulation Process;Complement;Complex;Cysteine Protease;Data;Development;Disease;Disease Progression;Elements;Enzymes;Extracellular Protein;Fibrinolysis;Figs - dietary;Forsythia;Foundations;Future;Goals;Gram-Negative Bacteria;Heavy-Chain Immunoglobulins;Homeostasis;Homologous Gene;Host Defense;Host Defense Mechanism;Human;Infection;Inflammatory Response;Injury;Kinins;Light;Link;Mediating;Membrane;Membrane Proteins;Methods;Modeling;Modus;Molecular;Mono-S;Mus;Nutrient;Oral health;Organism;Outcome;Pathway interactions;Peptide Hydrolases;Periodontal Diseases;Periodontal Infection;Periodontitis;Periodontium;Periplasmic Proteins;Plasma;Play;Porphyromonas gingivalis;Prevention;Preventive Intervention;Prevotella intermedia;Production;Progress Reports;Properdin;Property;Prophylactic treatment;Protein Export Pathway;Protein Secretion;Protein translocation;Proteins;Research;Role;Secretory Component;Seminal;Serine;Signal Transduction;Site;Solid;Structure;System;Testing;Therapeutic;Tissues;Treponema denticola;Trypsin;Virulence;Virulence Factors;antibody inhibitor;arginyllysine;base;design;drug development;gingipain;human MADHIP protein;in vivo;inhibitor/antagonist;insight;microbial;microbial community;microorganism;mutant;neutrophil;novel;pathogen;periodontopathogen;proteinase In;public health relevance;streptopain;therapeutic target


application_id: 7920897
project_number: 5R01DK056132-08
project_title: Neural circuitry in the dorsal vagal complex
administering_ic: NIDDK
award_notice_date: 2010-07-21
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 056132
program_official: HYDE, JAMES F
project_start_date: 2001-06-01
project_end_date: 2014-06-30
study_section: Neuroendocrinology, Neuroimmunology, and Behavior Study Section[NNB]
contact_pi_person_id: 1911523
contact_pi: SMITH, BRET N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Neuronal communication in the dorsal vagal complex (DVC) is critical for integrating visceral afferent and other inputs and translating that integrated signal into a coordinated parasympathetic motor output via the vagus nerve. In particular GABAergic inhibition is a dominant regulator of neuronal function in the area. Despite the recognized importance of this circuitry in controlling feeding and digestion relatively little is known about local cellular interactions in the DVC. The general hypothesis of this proposal is that activity of neurons in the dorsal motor nucleus of the vagus (DMV) that control gastric function is prominently controlled by inhibitory GABAergic inputs arising from neurons in the nucleus tractus solitarius (NTS). The activity of NTS GABA neurons is regulated by both glutamatergic excitatory and GABAergic inhibitory synaptic inputs. We propose that GABAergic control of preganglionic vagal motor output is accomplished by both phasic and tonic postsynaptic GABAA receptor-mediated inhibition and that specific cellular interactions in the DVC are organized in a manner that consistent with the concept well developed in other sensory-motor systems that local inhibitory circuitry coordinates responses between functional areas of the solitary complex. Gastrointestinal and other autonomic dysfunction affects people with diabetes mellitus and hyperglycemia significantly alters central vagal motor function. We further propose that GABAA receptor-mediated currents in gastric-related DMV neurons are functionally altered in a model of type 1 diabetes mellitus. We will use a multidisciplinary approach to examine GABA-mediated synaptic transmission between neurons in the DVC focusing particularly on inhibitory synaptic control of identified GABAergic neurons in the NTS as well as on neurons in the DMV in the context of gastrointestinal control. Electrophysiological experiments will be done in vitro using brain slice preparations from mature male mice in which DMV and NTS neurons can be identified by their anatomical connection with the stomach their GABA content or both. With whole-cell patch-clamp recordings we will use photoactivation of caged glutamate to stimulate selectively the soma-dendritic regions of local neurons in order to analyze GABA-mediated connections within the solitary complex. We aim to determine: 1) the contribution of tonic GABAergic currents to neuronal activity in the DMV; 2) how identified gastric-related GABAergic neurons in the NTS are regulated by GABA input; and 3) effects of hyperglycemia on GABA currents in a model of type 1 diabetes. We will correlate electrophysiological results with pharmacological and molecular biological analyses to construct a cellular model of local GABAergic control of DMV neuron activity. PUBLIC HEALTH RELEVANCE: Inhibitory connections between neurons that regulate the gastrointestinal system are critical to feeding and digestion but how they control output to the stomach is largely unknown. We have uncovered evidence of a heretofore unstudied and powerful means of regulating how the brain controls the gut and that this mechanism is altered in a model of type 1 diabetes mellitus. The experiments here will examine the synaptic mechanisms controlling gut-related neuron activity and will point to new ways of modifying activity of the gastrointestinal system in response to specific triggers associated with feeding and under pathological conditions of metabolic dysregulation.

project_terms:
Affect;Amino Acids;Area;Autonomic Dysfunction;Binding (Molecular Function);Biological;Brain;Cell model;Cells;Characteristics;Chronic;Communication;Complex;Data;Diabetes Mellitus;Diabetic mouse;Digestion;Dorsal;Event;Glucose;Glutamates;Hyperglycemia;In Vitro;Insulin-Dependent Diabetes Mellitus;Label;Mediating;Membrane Potentials;Messenger RNA;Metabolic;Methods;Modeling;Molecular;Motor;Motor Neurons;Motor output;Mus;Neurons;Noise;Nucleus solitarius;Output;Preparation;Proteins;Regulation;Rest;Signal Transduction;Slice;Stomach;Synapses;Synaptic Transmission;Testing;Transgenic Mice;Translating;Vagus nerve structure;Viscera;Visceral Afferents;base;cell body (neuron);dorsal motor nucleus;feeding;gamma-Aminobutyric Acid;gastrointestinal;gastrointestinal system;interdisciplinary approach;male;mind control;neural circuit;patch clamp;photoactivation;photolysis;postsynaptic;public health relevance;receptor;research study;response;sensorimotor system

public_health_relevance:
Inhibitory connections between neurons that regulate the gastrointestinal system are critical to feeding anddigestion but how they control output to the stomach is largely unknown. We have uncovered evidence ofa heretofore unstudied and powerful means of regulating how the brain controls the gut and that thismechanism is altered in a model of type 1 diabetes mellitus. The experiments here will examine thesynaptic mechanisms controlling gut-related neuron activity and will point to new ways of modifying activityof the gastrointestinal system in response to specific triggers associated with feeding and underpathological conditions of metabolic dysregulation.


application_id: 7920591
project_number: 3K25DK072085-03S1
project_title: Intelligent Control Approach to Anemia Management
administering_ic: NIDDK
award_notice_date: 2009-09-17
opportunity_number: PA-06-087
application_type: 3
activity_code: K25
ic: DK
serial_number: 072085
suffix: S1
program_official: RANKIN, TRACY L
project_start_date: 2009-09-23
project_end_date: 2011-08-31
study_section: Kidney, Urologic and Hematologic Diseases D Study Section[DDK-D]
contact_pi_person_id: 8145755
contact_pi: GAWEDA, ADAM E
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Management of anemia due to end-stage renal disease is a multifactorial decision process involving administration of recombinant human erythropoietin (rHuEPO) and iron as well as assessment of other factors influencing the progress of the disease. This application aims at improving the cost-effectiveness of this process through the use of state-of-the-art numerical tools from control engineering and machine learning. The specific aims are the collection of anemia management data and development of new guidelines for period of measuring hemoglobin levels if necessary development of individualized computer-assisted approach to rHuEPO dosing based on modern control engineering and machine learning approach evaluation of the developed tools through numeric simulation and assessment of the potential improvements in therapy and projected savings in rHuEPO utilization. The final aim is to provide a physical implementation and to perform a clinical evaluation of the developed methodology. The applicant Dr. Adam E. Gaweda is an Instructor of Medicine in the Department of Medicine Division of Nephrology at the University of Louisville. His original training is in the field of electrical engineering (M.Eng.) and computer science (Ph.D.). The applicant plans to develop as an independent and well established researcher in the field of biomedical engineering with focus on translation of state-of-the-art technology to heath care. To achieve this goal the applicant will enroll into the Clinical Research Epidemiology and Statistics Training (CREST) Program at the University of Louisville School of Public Health and Information Sciences

project_terms:
Adverse event;Algorithms;Anemia;Anti-Arrhythmia Agents;Artificial Intelligence;Arts;Biological Models;Biological Neural Networks;Biomedical Engineering;Blood;Blood Vessels;Caring;Chronic;Clinical;Clinical Research;Collection;Complex;Computer Assisted;Computer Simulation;Computer software;Computing Methodologies;Controlled Clinical Trials;Data;Decision Support Systems;Development;Dialysis procedure;Disease;Doctor of Philosophy;Dose;Drug Prescriptions;Effectiveness;Electrical Engineering;End stage renal failure;Engineering;Enrollment;Epidemiology;Erythropoietin;Evaluation;Feedback;Frequencies (time pattern);Funding;Goals;Guidelines;Hemodialysis;Hemoglobin;Hemoglobin concentration result;Human;Individual;Information Sciences;Insulin;Iron;Machine Learning;Measures;Medicine;Methodology;Methods;Morbidity - disease rate;Nephrology;Outcome;Patient Monitoring;Patients;Pharmaceutical Preparations;Physiological;Population;Process;Protocols documentation;Public Health Schools;Research;Research Personnel;Safety;Sampling;Savings;Techniques;Technology;Testing;Training;Training Programs;Translations;Universities;Veterans;Waran;Work;base;clinical practice;computer science;cost effectiveness;data management;experience;improved;insight;instructor;mathematical algorithm;novel;patient population;primary outcome;programs;recombinant human erythropoietin;research clinical testing;response;simulation;statistics;theories;tool


application_id: 7920589
project_number: 3K01DK076743-03S1
project_title: Mass Spectrometry Analysis of Notch4 Networks in Diabetes-Related Tubule Injury
administering_ic: NIDDK
award_notice_date: 2009-09-17
opportunity_number: PA-06-001
application_type: 3
activity_code: K01
ic: DK
serial_number: 076743
suffix: S1
program_official: RANKIN, TRACY L
project_start_date: 2009-09-21
project_end_date: 2011-08-31
study_section: Kidney, Urologic and Hematologic Diseases D Study Section[DDK-D]
contact_pi_person_id: 8638278
contact_pi: POWELL, DAVID W.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  The Candidate's overall career goal is to establish and maintain an independent proteomic and molecular biology-based program focused on investigation of events that mediate diabetic nephropathy (DN). DN is the leading cause of end-stage renal disease (ESRD). There are no current treatments that completely prevent progression to ESRD. This emphasizes the health-related importance for discovery of novel regulatory events as potential therapeutic targets for the diagnosis prevention and treatment of DN. Tubulointerstitial fibrosis (TF) is a prominent feature of progressive DN that is mediated by transforming growth factor-beta (TGF-beta). Notch4 is a fascinating membrane-bound transcription regulator that was recently implicated in TGF signaling and renal disease. Our preliminary findings indicate that Notch4 activation inhibits TGF-beta signaling in cultured renal tubular cells and show decreased expression of Notch4 in tubular cells from diabetic mice as compared with controls. This suggests a hypothesis that down-regulation of Notch4 activity promotes the TGF-beta-mediated effects in DN. This project will develop Notch4-deficient diabetic mice. Renal pathophysiology experiments will be performed to delineate the in vivo role of Notch4 in diabetes-mediated TF and TGF signaling. It is anticipated that these animals will also provide a better model for the study of TF as none of the current diabetic animal models exactly mimic the TF observed in diabetic humans. Accumulating evidence suggests a key role of TGF-mediated epithelial to mesenchymal transition (EMT) in diabetes-associated TF. We have recently developed models for TGF-mediated EMT in human kidney (HK) tubule cell lines. We will also develop HK models for glucose and advanced glycation end product (AGE)-mediated EMT. We will use these cellular models in combination with active Notch4 transfection and RNAi-mediated Notch4 knockdown to dissect the role of Notch4 in different components of signaling and transcription activity in EMT. Lastly we will use state-of-the-art proteomic techniques with the Notch4-deficient diabetic mice to define Notch4-mediated protein expression and organelle localization in DN. In addition to molecular insight provided by these studies the animal model and pathophysiology training obtained during this Career Development Award will provide valuable resources for the Candidate to expand his diabetes-related program and obtain independent-level funding.

project_terms:
Address;Advanced Glycosylation End Products;Animal Model;Animals;Arts;Binding (Molecular Function);Cell Line;Cell model;Cells;Cellular biology;Diabetes Mellitus;Diabetic Nephropathy;Diabetic mouse;Diagnosis;Down-Regulation;End stage renal failure;Event;Fibrosis;Functional disorder;Funding;Genetic Transcription;Glucose;Goals;Human;Injury;Investigation;K-Series Research Career Programs;Kidney;Kidney Diseases;Mass Spectrum Analysis;Mediating;Membrane;Mentors;Modeling;Molecular;Molecular Biology;Molecular and Cellular Biology;Organelles;Prevention;Proteins;Proteomics;RNA Interference;Regulation;Renal tubule structure;Research;Resources;Role;Signal Transduction;Stimulus;Study models;Techniques;Training;Transfection;Transforming Growth Factor beta;Tubular formation;base;career;career development;diabetic;epithelial to mesenchymal transition;fascinate;improved;in vivo;insight;notch protein;novel;prevent;programs;protein expression;research study;therapeutic target;tool


application_id: 7920056
project_number: 5R01EY018830-03
project_title: MerTK regulation of the PTTG and RPE phagocytosis
administering_ic: NEI
award_notice_date: 2010-08-27
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 018830
program_official: MARIANI, ANDREW P
project_start_date: 2008-09-30
project_end_date: 2013-08-31
study_section: Biology and Diseases of the Posterior Eye Study Section[BDPE]
contact_pi_person_id: 8875628
contact_pi: LU, QINGXIAN
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
project_abstract:
DESCRIPTION (provided by applicant): My long-term goal is to elucidate the cellular and molecular mechanism by which MerTK exerts its effects on phagocytosis of the retina pigmental epithelium (RPE) cell. MerTK is a receptor-type protein tyrosine kinase belonging to the TAM family. MerTK knockout mice develop autoimmune disease retinitis pigmentosa (RP) in adults with characterization of defective phagocytosis of the apoptotic lymphocytes and spent retinal outer segments (OS) by macrophage and RPE cells respectively. Photoreceptor degeneration caused by a failure of the RPE phagocytosis has been observed and intensively studied in the Royal College of Surgeons (RCS) rat a model in which the RPE cells carry a MerTK null mutation. MerTK null also causes human RP. Both in vivo and in vitro studies showed that the MerTK receptor participated during OS ingestion. However the molecular mechanism on how the MerTK regulate RPE phagocytosis is still not very clear. We have analyzed gene expression profile in MerTK mutant RPE and performed functional studies on the affected genes. Of those the PTTG was dramatically upregulated by MerTK mutation and knockout one copy of PTTG in the MerTK-/- RPE partially prevented photoreceptor degeneration in vivo. We will select and focus on MerTK mediated gene regulation to study its functional role in regulation of phagocytosis. In this proposal we project to study how the MerTK regulate PTTG and whether the PTTG affect RPE phagocytosis. We will also investigate whether structural preservation of the central photoreceptor by lower PTTG is corresponding to function recovery with ERG or OKR measurements. Our investigation will aid in one step forward to understand the molecular mechanism on the MerTK regulation of RPE functions. PUBLIC HEALTH RELEVANCE: Retinitis pigmentosa (RP) is a group of inherited retinal degenerative diseases with a worldwide prevalence of 1:3000 and a leading cause of inherited blindness. RP is caused by mutation in a group of unrelated genes one of these is MerTK. Our experiments in this proposal aim to elucidate the molecular mechanism of the MerTK regulation on RPE phagocytosis through studies of one candidate gene under MerTK regulation which may in turn affect RPE function. The data from these studies is expected to provide us the new knowledge and understanding of the RPE function which will allow us to develop and implement new therapies for treatment of RP caused by RPE dysfunction.

project_terms:
Adult;Affect;Apoptotic;Autoimmune Diseases;Biological Preservation;Blindness;Candidate Disease Gene;Cell Nucleus;Cells;DNA Sequence Rearrangement;Data;Defect;Degenerative Disorder;Distal;Ectopic Expression;Epithelium;Failure (biologic function);Family;Fibroblast Growth Factor 2;Functional disorder;Gene Expression Profile;Gene Expression Profiling;Gene Expression Regulation;Gene Targeting;Genes;Goals;Homeostasis;Human;IL8 gene;In Vitro;Ingestion;Inherited;Investigation;Knock-out;Knockout Mice;Knowledge;Lymphocyte;Measurement;Mediating;Metaphase;Mitosis;Modeling;Molecular;Morphology;Mus;Mutant Strains Mice;Mutation;One-Step dentin bonding system;PTTG1 gene;Patients;Phagocytes;Phagocytosis;Phenotype;Photoreceptors;Physiological;Pigments;Prevalence;Protein Tyrosine Kinase;RNA Interference;Rattus;Recovery of Function;Regulation;Retina;Retinal;Retinal Degeneration;Retinitis Pigmentosa;Rod Outer Segments;Role;Sister Chromatid;Spatial Distribution;Structure;Surgeon;Testing;Vascular Endothelial Growth Factor Receptor;Vascular Endothelial Growth Factors;Vision Tests;Visual;college;human MERTK protein;in vivo;macrophage;mutant;neovascularization;null mutation;overexpression;photoreceptor degeneration;prevent;public health relevance;receptor;research study;transcription factor

public_health_relevance:
Retinitis pigmentosa (RP) is a group of inherited retinal degenerative diseases with aworldwide prevalence of 1:3000 and a leading cause of inherited blindness. RP iscaused by mutation in a group of unrelated genes one of these is MerTK. Ourexperiments in this proposal aim to elucidate the molecular mechanism of the MerTKregulation on RPE phagocytosis through studies of one candidate gene under MerTKregulation which may in turn affect RPE function. The data from these studies isexpected to provide us the new knowledge and understanding of the RPE functionwhich will allow us to develop and implement new therapies for treatment of RP causedby RPE dysfunction.


application_id: 7919509
project_number: 5R42AA015475-04
project_title: Potential anti-relapse drugs: a plant genomics approach
administering_ic: NIAAA
award_notice_date: 2010-08-10
opportunity_number: RFA-AA-07-010
application_type: 5
activity_code: R42
ic: AA
serial_number: 015475
program_official: EGLI, MARK
project_start_date: 2004-09-28
project_end_date: 2012-08-31
study_section: ZAA1-JJ(17)
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): In alcoholism relapse and neurodegeneration share a common molecular target glutamate NM.D.A receptor (NM.D.AR) hyperactivity which contributes to withdrawal pathological conditioning and neurotoxicity. In consequence inhibitory modulators of the NM.D.AR are both potential anti-relapse and neuroprotective agents. Agonists at the functionally similar alpha7-nicotinic acetylcholine receptors (nicAChRs) cause cross-desensitization of NM.D.ARs and should therefore have similar therapeutic value. Few synthetic drugs with these specific pharmacological actions are yet available but the presence of homologous receptors in insect CNS suggests that plants may have evolved metabolites with appropriate pharmacology as insect defenses. As part of a phase 1 STTR we applied a differential high throughput screening approach to more than 1000 native plant species to identify those containing putative novel compounds with the required pharmacology. Candidate species have now been prioritized for further investigation including 2 with inhibitory NM.D.AR activity 3 with alpha7-selective nicAChR agonist activity and 3 with both types of activity. Extract fractions from representative species inhibit NM.D.A toxicity during alcohol withdrawal in a neuroblastoma screen. None of the species have been investigated for these actions before and chemical analysis suggests that activity resides in compounds not previously known. This phase 2 STTR aims to (a) begin genomic optimization of active plant species using proprietary technology (b) separate relatively pure active compounds and tentatively identify these (c) test semi-purified active compounds rigorously in screens and models relevant to relapse and neurodegeneration. In phase 3 the aim is to commercialize genomically-optimized plant species and the best drug or lead compound candidates in partnership with a strategic partner Yaupon Pharmaceuticals. This project combines Naprogenix Incs novel plant biotechnology methods with the chemical analytical expertise and screening methods developed at the University of Kentucky. Because active compounds may be useful in many neurodegenerative conditions their potential commercial value extends far beyond alcoholism. Support for this phase 2 STTR will ensure that this use will be investigated first.

project_terms:
Agonist;Alcohol withdrawal syndrome;Alcoholism;Animal Model;Biological Factors;Biotechnology;Categories;Cell Culture Techniques;Central Nervous System Diseases;Chemicals;Commercial Sectors;Coreopsis;Drug Delivery Systems;Drug Industry;Ensure;FDA approved;Genomics;Glutamates;Helianthus;Hyperactive behavior;Ilex vomitoria;Insecta;Intellectual Property;Investigation;Kentucky;Lead;Ligands;Lobelia;Marketing;Mediating;Methods;Modeling;Modification;Molecular;Molecular Target;Mutagenesis;N-Methyl-D-Aspartate Receptors;Nerve Degeneration;Neuroprotective Agents;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Phase;Plant Extracts;Plants;Population;Prevalence;Production;Property;Receptor Inhibition;Relapse;Sales;Screening for Neuroblastoma;Screening procedure;Small Business Technology Transfer Research;Solidago;Technology;Testing;Therapeutic;Toxic effect;Traditional Medicine;Universities;Withdrawal;acamprosate;alpha-bungarotoxin receptor;base;commercialization;conditioning;desensitization;design;drug candidate;drug discovery;drug relapse;high throughput screening;model design;mutant;neurotoxicity;novel;programs;receptor;smoking cessation


application_id: 7919492
project_number: 5R37AA010762-16
project_title: TNF and Mitochondrial Dysfunction in ALD
administering_ic: NIAAA
award_notice_date: 2010-08-26
application_type: 5
activity_code: R37
ic: AA
serial_number: 010762
program_official: GENTRY, THOMAS
project_start_date: 1996-03-01
project_end_date: 2012-08-31
study_section: NSS
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-09-01
project_abstract:
Alcoholic liver disease (ALD)is an importanthealthproblem inthe United States. The major difficultyin devising specific therapies for ALD has been our limited understanding of the mechanisms of this liver injuryand its systemic complications. This proposal will evaluate the interactionsof cytokines andnutritional/metabolic abnormalities in the development of ALDusing novel animal and in vitro models. Cytokines are low molecular weight mediators of cellular communication that are produced andreleased by numerous cell types such as monocytes macrophages andof particular relevance to liverdisease Kupffer cells and hepatocytes. Pro-inflammatorycytokines such as tumor necrosisfactor-alpha (TNF) and interleukin-18 (IL-18) and chemokines such as interleukin-8 (IL-8) have been postulated to play a role in mediating manyof the systemic manifestations of ALDand the hepatotoxicity in ALD. Itis our working hypothesis that cytokines such as TNF in conjunction with certain metabolic abnormalities observed in ALDsuch as altered proteasome function and cAMP metabolism play an etiologic role inthe development and progression of liver injury in ALD. We postulate that chronic alcohol abusecauses increased gut permeability and endotoxemia(increased LPS) depletionof critical antioxidants (e.g. GSH and Vitamin E)generation of reactive oxygen intermediates altered methionine metabolism decreased cAMP activation of Kupffer cell NFtcB with increased TNFproduction mitochondrial dysfunction with mitochondrial GSH depletion proteasome dysfunction alterations in liver membrane lipid raft composition increased susceptibility to hepatic TNF cytotoxicity and liver injury.With decreased proteasome function and hepatocyte injury/death there is increased IL-8 productionwith neutrophil infiltration andincreasedIL-18 production that sustainsthis inflammatorycytokine response. The focus of our research group has been the interactions of cytokines oxidative stress and factors that sensitize to TNF mediated hepatocyte deathsuch as proteasome dysfunction in the inductionof ALD. The long-termgoals of our laboratoryare to further define the mechanism(s) involved in the development/evolution of ALDand to develop specific therapies based on this knowledge. The specific objectives of this proposal are: 1. Evaluate the role of cAMP and phosphodiesterase inhibitors on LPS-stimulated TNFproduction in ALD;2: Evaluate monocyte/Kupffer cell Toll-like receptor signaling in ALD;3: Evaluate the effects of hepatocyte lipid rafts on TNF-inducedapoptosis and NFicB activation; and 4: Determinethe effects of proteasome inhibition on "sensitization" to TNF hepatotoxicity and to hepatocyte production of proinflammatory cytokines/chemokines.

project_terms:
Alcoholic Liver Diseases;Alcohols;Animals;Antioxidants;Cessation of life;Chronic;Communication;Cyclic AMP;Development;Endotoxemia;Evolution;Functional disorder;Generations;Hepatic;Hepatocyte;Hepatotoxicity;IL8 gene;Injury;Interleukin-18;Interleukin-8;Knowledge;Kupffer Cells;Liver;Liver diseases;Mediating;Mediator of activation protein;Membrane Lipids;Membrane Microdomains;Metabolic;Metabolism;Methionine Metabolism Pathway;Mitochondria;Molecular Weight;Neutrophil Infiltration;Nutritional;Oxidative Stress;Permeability;Phosphodiesterase Inhibitors;Play;Predisposition;Production;Proteasome Inhibition;Receptor Signaling;Research;Role;Toll-like receptors;United States;Vitamin E;Work;base;cell type;chemokine;cytokine;cytotoxicity;in vitro Model;macrophage;mitochondrial dysfunction;monocyte;multicatalytic endopeptidase complex;novel;reactive oxygen intermediate;response;tumor


application_id: 7919485
project_number: 5R01AA016959-04
project_title: Ethanol alteration of the neurogenic niche
administering_ic: NIAAA
award_notice_date: 2010-09-01
opportunity_number: PA-05-074
application_type: 5
activity_code: R01
ic: AA
serial_number: 016959
program_official: REILLY, MATTHEW
project_start_date: 2007-09-30
project_end_date: 2016-12-31
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 1869834
contact_pi: NIXON, KIMBERLY
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Alcohol use disorders remain as one of the nation's major public health problems with over 17 million Americans meeting the diagnostic criteria for alcohol abuse or dependence. Chronic alcoholics demonstrate cognitive impairments that are related to a loss of brain mass or neurodegeneration effects that may recover with abstinence. Many assumed that the mechanism of this recovery was due to glial regeneration however recent discoveries from our laboratory show that alcohol-induced regulation of neural stem cells (NSCs) parallels the changes in brain mass and cognition during active alcoholism (decrease) versus abstinence (increase) in the hippocampus. The regulation of NSCs relies on the milieu of the local environment or neurogenic niche. Microglial one of three types of glia contribute to this niche. Though microglial events historically were synonymous with cytotoxicity a new role in neurogenesis is emerging. Some activated microglia secrete growth factors and anti-inflammatory cytokines an effect that is consistent with recent data that certain types of microglia promote NSC proliferation and adult neurogenesis. Thus when we observed a microglial response that precedes the neurogenic response in our model of chronic alcoholism we suspected a causal link between microglial events and the promotion of neurogenesis. Therefore this proposal will test the hypothesis that binge alcohol exposure produces a graded microglial response that drives the recruitment of quiescent NSCs into proliferation and neurogenesis in abstinence. Three specific aims address this hypothesis by asking: (1) whether binge alcohol exposure recruits additional NSCs (2) whether microglia show a graded nonphagocytic phenotype predictive of a proneurogenic microenvironment and (3) whether can we modulate this phenotype to alter neurogenesis in a model of chronic alcoholism. Multiple approaches will be used namely immunohistochemistry to assess the recruitment and proliferative dynamics of NSCs the morphology of microglia as well as in situ hybridization receptor autoradiography and Enzyme-Linked ImmunoSorbant Assays to determine microglia phenotype and cytokine expression. And finally neuroanatomical and behavioral work will confirm the role of microglia phenotype in neurodegneration and regeneration following binge alcohol exposure. Relevance to public health: This proposal will uncover a mechanism of brain regrowth in abstinence from alcohol by investigating the role of activated microglia on neural stem cells and the neurogenic environment. The results will lead to a novel approach in our long term goal of treating brain damage associated with chronic alcoholism: Identifying agents or behaviors that promote protective actions of microglia in recruiting NSCs to repair sites of damage with the hope of reversing or preventing cognitive deficits associated with alcoholic neurodegeneration.

project_terms:
Abstinence;Address;Alcohol abuse;Alcoholic Intoxication;Alcoholism;Alcohols;American;Anti-Inflammatory Agents;Anti-inflammatory;Autopsy;Autoradiography;Behavior;Behavioral;Biological Assay;Brain;Brain Injuries;Brain Mass;Cell Death;Cell Proliferation;Cells;Cellular Morphology;Chronic;Cognition;Cognitive deficits;Data;Dependence;Diagnostic;Environment;Enzymes;Ethanol;Event;Future;Goals;Grant;Growth Factor;Hippocampus (Brain);Image;Immunohistochemistry;Impaired cognition;In Situ Hybridization;Intention;Laboratories;Lead;Link;Microglia;Modeling;Morphology;Natural regeneration;Nerve Degeneration;Neuroglia;Neuroprotective Agents;Outcome;Pathway interactions;Pharmacotherapy;Phenotype;Population;Proliferating;Recovery;Recruitment (Neurology);Recruitment Activity;Regulation;Research Personnel;Role;Site;Stem cells;Structure;Testing;Work;adult neurogenesis;alcohol abstinence;alcohol abuse therapy;alcohol exposure;alcohol use disorder;binge drinking;cognitive function;cytokine;cytotoxicity;macrophage;meetings;nerve stem cell;neurogenesis;neuroprotection;new therapeutic target;novel;novel strategies;preconditioning;prevent;problem drinker;public health medicine (field);receptor;relating to nervous system;repaired;response;stem


application_id: 7918711
project_number: 2R01NS045954-07A2
project_title: Neuropeptidergic Inhibition of Spinal Pain Transmission
administering_ic: NINDS
award_notice_date: 2010-01-19
opportunity_number: PA-07-282
application_type: 2
activity_code: R01
ic: NS
serial_number: 045954
suffix: A2
program_official: PORTER, LINDA L
project_start_date: 2002-09-10
project_end_date: 2014-01-31
study_section: Special Emphasis Panel[ZRG1 IFCN-B (04)]
contact_pi_person_id: 1879170
contact_pi: TAYLOR, BRADLEY K.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Work performed during the previous funding periods indicates that intrathecal administration of NPY reduces the mechanical and thermal hypersensitivity associated with inflammation or nerve injury. The objective of the present application is to establish NPY as an endogenous pain modulator and to identify the mechanisms underlying NPY-mediated inhibition of inflammatory or neuropathic pain. The central hypothesis is that tissue or nerve injury sensitizes the dorsal horn to the pain inhibitory actions of NPY receptor signaling. Our approach involves transgenic biochemical neurophysiological anatomical and behavioral methods to determine: the anti-allodynic actions of endogenous NPY (Aim 1); the effect of injury on NPY receptor coupling to G-proteins (Aim 2); the effect of injury on the inhibition by NPY of SP release and subsequent NK1 receptor (NK1) activation in the spinal cord (Aim 3A); and the effect of NPY on the activity of spinal neurons that express the NPY Y1 receptor (Aim 3B). Our long-term goal is to understand endogenous neuropeptidergic inhibition of spinal pain transmission and to establish the therapeutic potential of NPY receptor agonists for chronic pain. AIM #1 tests the hypothesis that endogenous NPY tonically inhibits allodynia. To address the contribution of endogenous NPY to chronic pain Aim #1 will utilize transgenic mice (NPYtet) that contain a doxycycline-regulated cassette (tetracycline trans-activator tTA) at the promoter region of the npy locus. We describe data indicating that inducible NPY depletion increases behavioral signs of allodynia after tissue or nerve injury. These data led us to determine the effect of conditional NPY knockdown on the induction maintenance and reinstatement of chronic pain. We predict that NPY depletion will speed the development increase the intensity and extend the duration of inflammatory and neuropathic pain. AIM #2 tests the hypothesis that injury increases NPY receptor-G protein signaling in the dorsal horn. To determine whether and when injury increases NPY receptor-G protein coupling we will evaluate Y1- and Y2-agonist-stimulated [35S GTP3S binding at multiple time points after inflammation or nerve injury. AIM #3 tests the hypothesis that injury increases NPY inhibition of spinal pain neurotransmission. Primary afferent terminals in dorsal horn express NPY receptors. Our preliminary data indicate that NPY acts at Y1 and Y2 receptors to reduce substance P release and subsequent NK1 activation (assessed with NK1 internalization) in spinal cord slices and in vivo. We predict that injury will increase these inhibitory actions. Because dorsal horn neurons express Y1 we will test for postsynaptic actions of NPY on SP-induced nociceptive behavior NK1 internalization and spinal neuron gene action (Fos) on Y1-expressing cells. New preliminary data with the selective neurotoxin NPY-saporin suggest that Y1-expressing cells in the dorsal horn facilitate neuropathic pain transmission. We predict that the activity of this population of spinal neurons will be decreased by NPY administration and increased by NPY knockdown or Y1 / Y2 receptor antagonism.  
  
PUBLIC HEALTH RELEVANCE: Chronic pain management is a major scientific and health care challenge as current analgesic drugs rarely provide sufficient efficacy in the absence of serious side effects. Our preliminary data suggest that new drugs acting at the neuropeptide Y receptor system in the spinal cord will overcome these problems but further studies are required to determine how NPY works. Such studies are critical not only to determine whether NPY is a natural long-lasting analgesic that reduces the duration of pain but also to harness its therapeutic potential towards the development of new analgesic drugs.

project_terms:
Accounting;Address;Adverse effects;Agonist;Analgesics;Behavior;Behavioral;Binding (Molecular Function);Biochemical;Cells;Coupling;Data;Development;Doxycycline;Freund's Adjuvant;Funding;G-Protein-Coupled Receptors;GTP-Binding Proteins;Gene Activation;Gene Silencing;Genes;Goals;Healthcare;Hypersensitivity;Inflammation;Inflammatory;Injury;Interruption;Maintenance;Measures;Mechanics;Mediating;Methods;Modeling;NPY gene;Neurons;Neuropeptide Y Receptor;Neurotoxins;Nociception;Pain;Pain management;Pharmaceutical Preparations;Population;Posterior Horn Cells;Promoter Regions (Genetics);Receptor Activation;Receptor Signaling;Signal Transduction;Slice;Speed (motion);Spinal;Spinal Cord;Substance P;System;TACR1 gene;Testing;Tetracyclines;Therapeutic;Time;Tissues;Trans-Activators;Transgenic Mice;Transgenic Organisms;Work;allodynia;chronic pain;dorsal horn;in vivo;inflammatory neuropathic pain;mouse model;nerve injury;neuropeptide Y-Y1 receptor;neurophysiology;neurotransmission;painful neuropathy;postsynaptic;public health relevance;receptor;receptor coupling;receptor expression;sham surgery;transmission process


application_id: 7918591
project_number: 2R01EY014701-05
project_title: Ganglion Cell Function in Retinal Disease
administering_ic: NEI
award_notice_date: 2010-03-16
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: EY
serial_number: 014701
program_official: GREENWELL, THOMAS
project_start_date: 2004-02-01
project_end_date: 2015-03-31
study_section: Biology and Diseases of the Posterior Eye Study Section[BDPE]
contact_pi_person_id: 1905800
contact_pi: MCCALL, MAUREEN 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
project_abstract:
DESCRIPTION (provided by applicant): The goals of this research are focused on understanding signaling mechanisms that regulate the development of visual function and spatial organization of retinal ganglion cells and how they are altered in retinal disease. Normal vision begins in the retina and is initiated by photoreceptor detection of light. Parallel pathways of information flow are initiated at the first synapse between photoreceptors and depolarizing and hyperpolarizing bipolar cells which detect luminance increases and decreases and/or vision under dark- and light-adapted conditions. As a result the pathways extend the dynamic range of information processing in the intensity domain and increase specialization of information processing for salient environmental features e.g. motion direction and size. Signaling within these circuits is refined by inhibitory inputs in the outer and inner retina and these interactions culminate in and define the receptive field organization of the retinal ganglion cells. The receptive field is a basic property shared across all sensory neurons in all species. It defines the types and range of environmental stimuli that each cell encodes. Thus understanding how receptive field properties develop is key to understanding visual function in the retina and the ganglion cells are a vital part because they represent both the culmination of all retinal processing and the scaffold for the rest of visual processing. Because basic RF spatial organization is already present at the onset of visual responses in ganglion cells the processes underlying their development have been relatively intractable to investigation. That normal vision requires signaling through the depolarizing and hyperpolarizing pathways is amply indicated by the visual defects that occur in patients with and mouse models of congenital stationary night blindness (CSNB) where depolarizing bipolar cell processing is eliminated. We have three unique mouse models of CSNB1 that we will continue to use to probe the synaptic circuitry underlying CSNB in which normal photoreceptor function is retained. The nature of the changes in spontaneous and visually-evoked responses across GCs in the three mutants provides a unique opening to study the development of receptive field organization and ganglion cell signaling. The phylogenetic conservation of receptive field organization suggests that our findings in the mouse will be relevant to primate peripheral retinal processing. We suggest that the characterization of these mouse models represents a significant opportunity not afforded by other mouse or vertebrate models and represents a critical step in our understanding both the disease mechanisms in CSNB1 and normal retinal development and function.   
  
PUBLIC HEALTH RELEVANCE: This proposal seeks to understand the mechanisms that govern the development of vision in the retina and to investigate the changes in the downstream synaptic mechanisms when signaling is eliminated from one of the parallel pathways of information processing in the retina. One focus is to understand the exact changes that occur in complete congenital stationary night blindness a retinal disease that does not involve photoreceptor dysfunction or morphological defects. A second focus is to understand the fundamental processes that regulate the development of normal retinal function particularly in the ganglion cells. We believe that our results will guide diagnosis and therapeutic approaches to restore or rescue CSNB and also will be relevant to other blinding diseases in people of all ages.

project_terms:
Address;Affect;Afferent Neurons;Age;Cations;Cell physiology;Cells;Data;Defect;Detection;Development;Developmental Delay Disorders;Diagnosis;Disease;Electroretinography;Eye;Functional disorder;Funding;Genes;Glutamate Receptor;Glutamates;Goals;Human;Individual;Investigation;Lead;Light;Masks;Mediating;Modeling;Motion;Mus;Mutant Strains Mice;Mutation;Nature;Nervous system structure;Night Blindness;Pathway interactions;Patients;Pattern;Peripheral;Phenotype;Photoreceptors;Phylogenetic Analysis;Play;Primates;Principal Investigator;Process;Property;Research;Rest;Retina;Retinal;Retinal Diseases;Retinal Ganglion Cells;Role;Sensory;Signal Transduction;Stimulus;Synapses;Testing;Therapeutic;Vision;Visual;Work;disease phenotype;ganglion cell;information processing;luminance;mouse model;mutant;neural circuit;programs;public health relevance;receptive field;receptor;research study;response;scaffold;vision development;visual process;visual processing


application_id: 7917443
project_number: 5K23HD050581-05
project_title: Cervical (Neck) Auscultation Developmental Outcomes
administering_ic: NICHD
award_notice_date: 2010-08-03
opportunity_number: PA-00-004
application_type: 5
activity_code: K23
ic: HD
serial_number: 050581
program_official: RAJU, TONSE N
project_start_date: 2006-09-27
project_end_date: 2011-08-31
study_section: Pediatrics Study Section[CHHD-A]
contact_pi_person_id: 7584915
contact_pi: REYNOLDS, ERIC W
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Feeding is arguably the most complex skill a newborn infant must master in order to achieve independent survival. The integration of suck-swallow-breath rhythms is essential for development of effective feeding behavior. Patterns of suck-swallow-breath rhythms during feeding become more uniform as preterm infants grow and these rhythms are disrupted in infants with bronchopulmonary dysplasia (BPD). Inability to coordinate these rhythms may be a marker of poor neurologic outcome. Cervical auscultation (CA) with an accelerometer with digital signal processing (DSP) technology can be used to quantitatively compare the sounds of infant feeding by calculating the Variance Index (VI) of swallow-associated sounds. This method has been used to show that the swallow-associated sounds of low-risk preterm infants become more uniform with increasing post-menstrual age. As with other feeding rhythms this progression is not seen in infants with BPD. No studies have correlated CA/DSP data with developmental outcomes. The objectives of this project are: 1) to identify factors inherent in the development of stability and sources of variability of swallow-associated sounds in infant feeding 2) to correlate CA/DSP measurements of swallow-associated sounds during early rhythmic suckle feeding with long-term neurologic/developmental outcomes 3) to identify differences in rhythmic suckle feeding of infants with various pathologic conditions and 4) to measure the effects of therapeutic interventions such as speech therapy on swallow-associated sounds. Objectives 1 2 and 3 will be met with a prospective cohort study following 6 groups of infants healthy term cohort HIE term cohort drug-exposed cohort low-risk preterm cohort BPD cohort and a Grade III/IVIVH cohort (n = 25 per group). The infants will be followed from the beginning of oral feeding to two years of life. CA/DSP and biometric data will be collected during feeding. Vis will be compared between groups at various time points and within each group over time. CA/DSP data will be correlated with neurobehavioral and developmental outcome data. By correlating the VI and other DSP parameters with behavioral and developmental data CA/DSP data may be used to identify infants who are at higher risk of a poor long-term outcome thus allowing earlier developmental intervention to take place. For objective 4 we will enroll an additional 25 infants with BPD and randomize the total group so that half of the infants (25) receive speech therapy and the other half do not. CA/DSP results will be compared before and after feeding therapy. We hypothesize that if therapy is successful the VI for the intervention group will approximate the VI for the low-risk preterm infants. By successfully completing these projects we will increase our understanding of the development of successful feeding behavior and make CA/DSP technology more available as a non-invasive diagnostic technique.

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


application_id: 7917036
project_number: 7R37AG010885-19
project_title: Surgical Studies of Ontogeny Aging and the Gut
administering_ic: NIA
award_notice_date: 2009-08-31
application_type: 7
activity_code: R37
ic: AG
serial_number: 010885
program_official: MACCHIARINI, FRANCESCA
project_start_date: 1992-08-01
project_end_date: 2012-05-31
study_section: NSS
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-09-01
project_abstract:
Gastrointestinal (GI) hormones regulatea numberofimportantphysiologic functions includingintestinalsecretionmotilityand digestion ofnutrients. In additioncertain intestinal hormones havebeen shown to stimulategutmucosal proliferation.Neurotensin (NT) an importantregulatory hormone localized to specialized enterocndocrine cells (Ncells) of theadultsmall bowelfacilitatesfatty acid translocationand affects gut motility secretion and mucosal growth. Our studieshaveidentified the NT gene (designated NT/N) as an excellent molecular model to help define the complex differentiationpathways leading to gut development and maturationas wellas the process of "dedifferentiation" noted incertaincoloncancers. Expression of the NT/N gene is regulated in a strict temporal- and spatial-specific patern in the GI tract.Induction of NT/N gene expression and NT peptide secretion is regulated by signaling pathways which have yet to becompletely defined. NT acting through its cell-surface receptor (NTR) activates a cascade of signaling pathwayswhich results in the proliferationof normal gut mucosa. The central hypothesis of our proposal continues to bethatNT/N gene expression is developmentallyregulatedin the gut and isdependent upon acombinationof signaling pathwaysactivation of downstream transcription factors and in certaininstancesgene methylation; NT peptide secretion may bemediated by similar signalingpathwaysthat regulate gene expression. Identifying these regulatory mechanismsarecritical to a better understanding of normal intestinal homeostasis and the function of target tissues that are affected byNT. To examine thishypothesiswe haveplannedexperiments with the following Specific Aims: 1)to further elucidatethe mechanisms contributingto NT/N expression in vivo 2) to delineate the signaling mechanisms regulating NT/Ngene induction3) to define the mechanisms contributingto NT peptide secretion 4) to further assess proliferateveeffects of NT in the gut. Understanding the factors regulating NT/N expression and NT peptide secretion will providenovel and importantinformation regarding the function of an important intestinal hormone and its effects on target tissuessuch as normal gut mucosa. The in-depth analysisof the cellular processes leading to the expression of the "model"intest;nal gene NT/N will provide a better understanding of normal gut development and function as well aspossiblydefini ngcertain cellularevents leadingto gut neoplasia.

project_terms:
Acids;Adult;Affect;Aging;Binding (Molecular Function);Cell Proliferation;Cell Surface Receptors;Cell physiology;Cells;Complex;Development;Digestion;Enteroendocrine Cell;Fatty Acids;Gastrointestinal Hormones;Gastrointestinal tract structure;Gene Expression;Genes;Growth;Homeostasis;Hormones;Human;Intestinal Hormones;Intestines;MEKs;Malignant Neoplasms;Mediating;Methylation;Modeling;Molecular Models;Mucous Membrane;Neoplasms;Neurotensin;Operative Surgical Procedures;Pathway interactions;Pattern;Peptides;Process;Promoter Regions (Genetics);Proteins;Rattus;Regulation;Signal Pathway;Signal Transduction;Small Intestines;Tissues;base;cell motility;gene induction;in vivo;molecular modeling;neuromedin N;novel;research study;transcription factor


application_id: 7916637
project_number: 5R01AG013418-14
project_title: Neural Mechanisms Resetting the Aged Circadian Pacemaker
administering_ic: NIA
award_notice_date: 2010-08-13
application_type: 5
activity_code: R01
ic: AG
serial_number: 013418
program_official: MACKIEWICZ, MIROSLAW
project_start_date: 1996-07-17
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZRG1-IFCN-D(03)M]
contact_pi_person_id: 1891761
contact_pi: DUNCAN, MARILYN J.
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: 2010-09-01
project_abstract:
DESCRIPTION (provided by applicant):  Aging leads to deficits in many functionsincluding circadian timekeeping which has been the focus of our on-going research. Circadian rhythm disruption is associated with increased risk of cardiovascular disease and cancer as well as impaired memory. Our previous studies revealed age-related changes in serotonergic regulation of the suprachiasmatic nucleus (SON) the site of the master circadian pacemaker and the dorsal raphe nucleus (DRN) which also regulates circadian rhythms. We expanded our studies to include the hippocampus which regulates memory and observed aging changes in serotonergic regulation of this structure as well. In the SCN aging increases serotonin transporter sites and decreases VIP mRNA expression. VIP is a key peptide involved in circadian rhythm generation phase resetting and transmission of circadian output. We propose to investigate if the increase in transporter sites causes the age-related decrease in VIP mRNA since serotonin depletion attenuates VIP mRNA levels. Our previous studies also showed that aging decreases 5-HT7 receptors in the DRN and hippocampus. The age-related loss of 5-HT7 receptors in the DRN attenuates phase shifts to serotonergic drugs. We propose to investigate the neural pathways mediating DRN 5-HT7 receptor induction of phase shifts by exploring the role of the GABAergic and glutamatergic neurotransmission which are modulated by DRN 5-HT7 receptors in vitro. Finally the age-related loss of 5-HT7 receptors in the hippocampal CA1 may be related to age-related memory loss because genetic deletion of 5-HT7 receptors induces memory deficits. Exciting new studies of hippocampal neurons in vitro show that activation of 5-HT7 receptors stimulates neurite extensions critical process for synaptic connectivity. Decreased dendritic length is associated with memory impairments during aging and neurodegenerative diseases. Therefore we propose to further investigate the intriguing but relatively little explored effect of 5-HT7 receptor stimulation of neurite length. The specific aims are to investigate: 1) the role of age-related changes in serotonin transporter sites in regulating SCN VIP and GRP expression 2) the mechanisms by which 5-HT7 receptors in the dorsal raphe which are decreased with aging mediate nonphotic circadian phase shifts and 3) the effect of 5-HT7 receptors on neurite length in the hippocampus SCN and DRN and whether this effect decreases during aging.

project_terms:
Affect;Age;Aging;Agonist;Attenuated;Autoradiography;Brain region;Circadian Rhythms;Dorsal;Employee Strikes;Environment;Exhibits;Funding;Gastrin releasing peptide;Generations;Genetic;Glutamates;Hamsters;Hippocampus (Brain);Human;Impaired cognition;In Vitro;Length;Lesion;Longevity;Maintenance;Malignant Neoplasms;Mediating;Memory;Memory Loss;Memory impairment;Messenger RNA;Metabolic Diseases;Microinjections;Mus;Nerve Degeneration;Neural Pathways;Neurites;Neurodegenerative Disorders;Neurons;Neuropeptides;Organ;Output;Pedunculopontine Tegmental Nucleus;Peptides;Peripheral;Phase;Process;Prosencephalon;Rattus;Receptor Activation;Research;Research Personnel;Role;Serotonin;Serotonin Agents;Signal Transduction;Site;Sleep;Structure;Synapses;System;Time;Vasoactive Intestinal Peptide;Work;age related;aged;attenuation;base;cardiovascular disorder risk;cardiovascular risk factor;chemotherapy;circadian pacemaker;dorsal raphe nucleus;extracellular;gamma-Aminobutyric Acid;in vivo;mRNA Expression;nerve supply;neuromechanism;neuropeptide Y;neurotransmission;novel;programs;raphe nuclei;receptor;relating to nervous system;serotonergic regulation;serotonin 7 receptor;serotonin transporter;suprachiasmatic nucleus;transmission process


application_id: 7916293
project_number: 3P42ES007380-13S2
project_title: Nutrition and Superfund Chemical Toxicity
administering_ic: NIEHS
award_notice_date: 2009-09-06
opportunity_number: RFA-ES-06-003
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S2
program_official: THOMPSON, CLAUDIA L
project_start_date: 2009-09-06
project_end_date: 2012-08-31
study_section: ZES1-JAB-C(S7)
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant)  
  
The University of Kentucky is unique among land grant universities in that all colleges including Medicine and Agriculture are located on the same campus. This constellation of programs has enabled the UK-SBRP to develop uniquely productive collaborations across diverse disciplines. Such an environment will allow to study the overall theme of the SBRP research which focuses on the toxicology of Superfund chemicals and how health effects of exposure can be modulated by both intrinsic and extrinsic factors namely genetics and nutrition respectively. Given the abundance of Superfund chemicals and widespread distribution in the ecosystem it is unlikely that remediation alone will be sufficient to address their health risks. Nutritional intervention thus becomes a sensible way to address health problems associated with environmental pollutants. In the competing renewal the investigators recognize this dual need for sensing/remediation and biomedical intervention through nutrition by proposing five integrated projects. The investigators will concentrate on chlorinated organics (e.g. polychlorinated biphenyls) prevalent in most Superfund sites including those found in Kentucky. Preliminary findings by this group suggest that nutrition and dietary habits can markedly influence mechanisms of toxicity of the above-mentioned Superfund chemicals. Thus a major objective of our SBRP is to explore the paradigm that nutrition can modify Superfund chemical toxicity. All biomedical projects will focus on chronic diseases associated with vascular dysfunction such as cardiovascular disease cancer metastasis and obesity-related abdominal aortic aneurysms and will utilize a similar dietary fat regimen to study nutrient/toxicant interactions. There will be significant cross-talk with non-biomedical projects which will explore novel techniques for both remediation (detoxification) and biosensors associated with detection of PCBs and other chlorinated organics. Results from interdisciplinary research will be utilized for information/education technology transfer training policy and translational purposes as part of the objectives of the Research Translation Community Outreach and Training Cores. Nutrition may be the most sensible means to develop primary prevention strategies of diseases associated with many environmental toxic insults. Thus research proposed by the investigators may lead to novel dietary recommendations at the national level for populations at risk thus improving the health of people residing near Superfund sites.  
  
  
ADMINISTRATIVE CORE  
  
Description (provided by applicant)  
  
The Administrative Core (Core A) will oversee the entire Superfund Basic Research Program through a management mechanism that allows efficient and accountable oversight and maximum interdisciplinary and multidisciplinary interactions among all participants. The Administrative Core will be responsible for the coordination planning assessment project accounting and administrative support to the research personnel of the University of Kentucky SBRP. A major objective of the Administrative Core is to facilitate the execution of an interdisciplinary research theme through administrative support and fiscal accountability. The Administrative Core will work especially closely with the Research Translation Core (Core C) to optimize communication with NIEHS EPA and state and local constituents; communication is also facilitated by an active website that is managed by Core C with input from the Administrative Core. Research efforts will be coordinated through biweekly meetings of faculty students and research staff as well as seminars where new findings and planned activities and ideas will be discussed. It will also be critical to discuss research findings for informative/educational activities technology transfer training policy and translational purposes as part of the objectives of the Research Translation Community Outreach and Training Cores. The Administrative Core will implement feedback and cross-talk between all project and core activities to allow for maximum integration. For example optimal detection and remediation of Superfund pollutants must be linked to risk assessment and biomedical aspects of degradation products. Accountability of the University of Kentucky SBRP activities including the quality of science and administration will be achieved through regular consultations with both the External and Internal Advisory Boards. Research quality assessment and statistical consultation will be managed through the Research Support Core. General fiscal responsibilities or project accounting will be coordinated through the Administrative Office in conjunction with the University of Kentucky Research Foundation. The Program Coordinator together with the Program Director will serve as a regular contact among all SBRP activities including research projects and cores and will coordinate all reports required by the sponsoring agencies.


