# projects

application_id: 8139009
project_number: 5R01GM094155-02
project_title: Mechanism of Neuropilin Dependent Angiogenesis
administering_ic: NIGMS
award_notice_date: 2011-06-22
opportunity_number: PA-07-070
application_type: 5
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;Colon;Competitive Binding;Complex;Coupled;Coupling;Development;Dimerization;Disease;Electron Microscopy;Endothelial Cells;Extracellular Structure;Family;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;Semaphorins;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: 8138702
project_number: 3R44AG035410-01S1
project_title: Generating Blood-based Diagnosis for Alzheimer Disease
administering_ic: NIA
award_notice_date: 2010-09-14
opportunity_number: PA-09-080
application_type: 3
activity_code: R44
ic: AG
serial_number: 035410
suffix: S1
program_official: HSIAO, JOHN
project_start_date: 2010-04-15
project_end_date: 2010-11-30
study_section: Special Emphasis Panel[ZRG1-IMST-E(15)B]
contact_pi_person_id: 1860379
contact_pi: WANG, EUGENIA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 805479370
primary_uei: KPMEKJJTDUS5
duns_number: 805479370
uei: KPMEKJJTDUS5
fips: US
organization_id: 10020610
organization_name: ADVANCED GENOMIC TECHNOLOGY, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402416052
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The present lack of blood-based diagnosis requires AD patients to be subjected to either invasive spinal fluid (CSF) tapping expensive MRI or PET imaging or arduous psychological testing all unsuitable and costly for our elderly. Strategically we shall address this unmet need by generating systemic biomarkers detectable in peripheral mononuclear cells (PBMC) and serum/plasma focusing on two classes of molecules micro- RNAs and their target genes which generally exhibit an inverse relationship because the former noncoding RNA functions by partially repressing the latter"s expression as a "dimmer switch" via binding either at the co- ding region of the message thus degrading it or at the 3"-untranslated region to inhibit translation. Thus key microRNAs and their targets can serve as disease biomarkers in "see-saw" balance applicable for new diagnostics and/or therapy. Our pilot study with a small cohort of 16 AD and 16 age-matched normal elderly controls (NEC) revealed: 1. Predominant down-regulation of gene expression at the message level in AD PBMC; and 2. Correlated up-regulation of microRNA (miR) expression in PBMC of the same individuals. In this proposal we focus on a specific up-regulated microRNA miR-34a whose known targets are SIRT1 cdk4 cdk6 cyclin E2 bcl2 etc. SIRT1 is a member of the 7-member Silent Information Regulator protein family. Caloric restriction extends longevity through triggering expression of SIRT1 which can also be mimicked by resveratrol a red wine polyphenol. SIRT1 reduction is linked to accumulation of Tau and A242 production two hallmarks of AD etiopathogenesis. Thus we suggest that in AD there is a systemic effect detectable in PBMC and serum/plasma; up-regulated miR-34a may induce down-regulation of SIRT1 with attendant pathophysiologic results. In this proposal we plan to generate for this "see-saw" of changes miR-34a/SIRT1 Target Pair Ratio (TPR) indices to quantify both disease presence as well as progress; the indices should also provide an unprecedented evaluation of drug efficacy. This Fast-track proposal of two phases is planned with our existing small cohort study as the roadmap for the larger cohort investigation: Phase I of six months with our existing small 16 AD and 16 NEC sample cohorts to: Aim 1. study possible down-regulation of miR-34a"s known targets; and Aim 2. develop a feasibility study of pilot miR-34a/SIRT1 TPR-indices; and Phase II of two years with larger cohorts of 200 AD and 200 NEC participants: Aim 1.Establish a Bio-Repository of PBMC-DNA -RNA & -protein specimens and serum/plasma samples for assays in Aims 2 & 3; Aim 2. Generate PBMC-based miR34a/SIRT1 (& other targets) TPR indices; and Aim 3. Perform feasibility study to develop serum/plasma-based miR- 34a/SIRT1-TPR indices. Success of this project will allow us to generate PBMC- and serum-based miR-TPR indices as personalized diagnostics for AD victims meeting an urgent need in health care a huge gain for disease victims their caregivers and our society at large.    PUBLIC HEALTH RELEVANCE:  At present the absence of any blood-based diagnosis for Alzheimer"s disease (AD) requires patients to enduring arduous neuropsychological testing invasive cerebrospinal fluid tapping and/or expensive MRI or PET imaging with definitive diagnosis deferred until brain autopsy. Our preliminary findings based on new science concerning a novel molecular species microRNAs (miR) and their "see-saw" partial repression of the expression of their target gene(s) suggest that potential disease biomarkers for AD are detectable systemical- ly in peripheral blood mononuclear cells and/or serum/plasma and may be quantified as miR-Target Pair Ra- tios (TPR). Our plan is to define AD-specific TPR indices initially focusing on miR-34a and its target SIRT1 whose reduction is known to be associated with increased Tau and A242 two hallmarks of AD etiopathogene- sis; our ultimate goal is a "Tool-Box" of TPR indices miR-34a/SIRT1-TPR being the first such AD diagnostic indicating not only disease presence but also its progress (and even drug efficacy monitoring) a huge strate- gic gain for the victims of this costly disease and our society at large!

project_terms:
3' Untranslated Regions;Address;Age;Aging;Alzheimer's Disease;Apoptosis;Autopsy;Back;Binding (Molecular Function);Biogenesis;Biological Assay;Blood;Boxing;Brain;Brain Pathology;CDK4 gene;Caloric Restriction;Caregivers;Cell Cycle;Cells;Cerebrospinal Fluid;Code;Cohort Studies;DNA;DNA Repair;Deacetylase;Diagnosis;Diagnostic;Disease;Down-Regulation;Elderly;Equilibrium;Evaluation;Exhibits;Family;Feasibility Studies;Gene Expression;Gene Expression Profile;Gene Targeting;Genes;Genetic Transcription;Goals;Healthcare;Individual;Investigation;Investments;Knowledge;Lead;Link;Longevity;Magnetic Resonance Imaging;MicroRNAs;Modeling;Molecular;Molecular Profiling;Monitor;Mononuclear;Neurofibrillary Tangles;Neuropsychological Tests;Oxidation-Reduction;Oxidative Stress;Participant;Patients;Peripheral;Peripheral Blood Mononuclear Cell;Phase;Physiological;Pilot Projects;Plasma;Positron-Emission Tomography;Printing;Production;Protein Family;Proteins;Psychological Tests;RNA;Repression;Research;Resveratrol;Risk;Sampling;Science;Screening procedure;Senile Plaques;Serum;Signal Transduction;Societies;Specimen;Stress;Synapses;TP53 gene;Testing;Translations;Untranslated RNA;Up-Regulation (Physiology);Work;amyloid precursor protein processing;base;biomarker;cohort;cyclin E2;drug efficacy;feeding;foot;indexing;interest;meetings;member;novel;novel diagnostics;polyphenol;protein expression;public health relevance;red wine;repository;response to injury;senescence;success;tau Proteins;tau aggregation;tool;trend

public_health_relevance:
Project Title: "Generating Blood-based Diagnosis for Alzheimer's Disease" At present the absence of any blood-based diagnosis for Alzheimer"s disease (AD) requires patientsto enduring arduous neuropsychological testing invasive cerebrospinal fluid tapping and/or expensive MRI orPET imaging with definitive diagnosis deferred until brain autopsy. Our preliminary findings based on newscience concerning a novel molecular species microRNAs (miR) and their "see-saw" partial repression of theexpression of their target gene(s) suggest that potential disease biomarkers for AD are detectable systemical-ly in peripheral blood mononuclear cells and/or serum/plasma and may be quantified as miR-Target Pair Ra-tios (TPR). Our plan is to define AD-specific TPR indices initially focusing on miR-34a and its target SIRT1whose reduction is known to be associated with increased Tau and A42 two hallmarks of AD etiopathogene-sis; our ultimate goal is a "Tool-Box" of TPR indices miR-34a/SIRT1-TPR being the first such AD diagnosticindicating not only disease presence but also its progress (and even drug efficacy monitoring) a huge strate-gic gain for the victims of this costly disease and our society at large!


application_id: 8138653
project_number: 5U18IP000420-02
project_title: Anti-Influenza Therapy in Hospitalized Patients with Community-Acquired Pneumonia
administering_ic: NCIRD
award_notice_date: 2011-09-12
opportunity_number: RFA-IP-10-007
application_type: 5
activity_code: U18
ic: IP
serial_number: 000420
program_official: YEE, EILEEN
project_start_date: 2010-09-01
project_end_date: 2012-08-31
study_section: ZIP1-GCA(17)
contact_pi_person_id: 8816315
contact_pi: RAMIREZ, JULIO ALBERTO
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):  Pneumonia and influenza combined is the leading cause of infectious disease-related death in the world. The Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) have developed guidelines for the management of community-acquired pneumonia (CAP). These guidelines recommend early initiation of empiric antibiotic therapy to cover the most likely typical and atypical bacteria that may cause CAP. Several studies have indicated associations between delayed time to administration of empiric antibiotic therapy with increased clinical failure and mortality. This well documented association of a delay in appropriate antibacterial therapy and worse clinical outcomes in patients with bacterial CAP has not been evaluated in patients with influenza CAP. Since results of current diagnostic tests for influenza may be delayed and several tests have low sensitivity anti-influenza treatment for patients with influenza CAP is frequently initiated late or not at all. We hypothesize that as happens with bacterial CAP hospitalized patients with influenza CAP will benefit from early initiation of empiric antiviral therapy soon after hospitalization.  To test our hypothesis we plan a prospective randomized multicenter clinical trial of hospitalized patients with CAP. Patients will be randomized to empiric antibacterial therapy as recommended by IDSA/ATS guidelines (Group A) versus a combination approach of empiric antibacterial plus anti-influenza therapy (Group B). The primary study outcome is development of clinical failure during 30 days after enrollment. The secondary study outcome is the cost-effectiveness of the intervention. Other clinical outcomes that will be compared between study groups include: time to clinical stability duration of hospitalization development of cardiovascular events re-hospitalization short-term mortality (30 days) and long-term mortality (1 year).  The primary aim of this study is to compare in hospitalized patients with influenza CAP the rate of clinical failure between Group A and Group B. We hypothesize that patients in Group B (empiric anti-influenza therapy) will have a statistically significant decrease in the rate of clinical failure when compared with patients in Group A (guideline-recommended approach). We estimate that empiric anti-influenza therapy will decrease the rate of clinical failure in hospitalized patients with influenza CAP from approximately 30% to 14%. Considering this effect size we will need to randomize 200 patients with influenza CAP 100 in group A and 100 in group B to allow for the detection of significant differences in the proposed outcomes with 80% power with 1=0.05. Since influenza CAP is expected to occur in 20% of all hospitalized patients with CAP we will enroll a total number of 1000 patients with CAP to achieve the goal of 200 patients hospitalized with influenza CAP. Data from this clinical trial will change our current approach to empiric therapy of hospitalized patients with CAP. This study will provide evidence that to optimize patients' outcomes hospitalized patients with CAP should receive early empiric antibacterial plus anti-influenza therapy. )  
  
PUBLIC HEALTH RELEVANCE: Pneumonia may be caused by a bacterium or a virus. Our current treatment of a hospitalized patient with pneumonia includes initial treatment for bacteria (antibacterials). In this study we plan to treat hospitalized patients with pneumonia with drugs against bacteria (antibacterials) and viruses (antivirals). We plan to prove that patients that receive a combination of antibacterials plus antivirals will have better recovery from pneumonia.

public_health_relevance:
Pneumonia may be caused by a bacterium or a virus. Our current treatment of a hospitalizedpatient with pneumonia includes initial treatment for bacteria (antibacterials). In this study weplan to treat hospitalized patients with pneumonia with drugs against bacteria (antibacterials)and viruses (antivirals). We plan to prove that patients that receive a combination ofantibacterials plus antivirals will have better recovery from pneumonia.


application_id: 8138540
project_number: 5R01DK081555-03
project_title: Upstream Stimulatory Factor 2 regulation of renin in diabetic nephropathy
administering_ic: NIDDK
award_notice_date: 2011-09-08
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 081555
program_official: RYS-SIKORA, KRYSTYNA E
project_start_date: 2009-09-01
project_end_date: 2014-08-31
study_section: Pathobiology of Kidney Disease Study Section[PBKD]
contact_pi_person_id: 7837422
contact_pi: WANG, SHUXIA
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Diabetic nephropathy is the most common cause of end-stage renal failure and is highly prevalent in both type 1 and type 2 diabetics. Hyperglycemia and the activation of the intrarenal renin-angiotensin system (RAS) in diabetes have been suggested to play a critical role in the pathogenesis of diabetic nephropathy. However the mechanisms for the effectiveness of inhibitors of the RAS or for angiotensin II as a mediator of diabetic nephropathy are not well defined. Transforming growth factor- (TGF-) is a major effector leading to renal fibrosis in response to hyperglycemia. Preliminary data demonstrate that Upstream Stimulatory Factor (USF2) is an important transcription factor in high glucose-induced TGF- production in mesangial cells. Importantly USF2 expression is increased in the kidneys of diabetic mice and correlates with the glomerular mesangial matrix expansion. Furthermore over-expression of USF2 accelerates the development of diabetic nephropathy in a type 1 diabetic mouse model supporting the role of this transcription factor in the development of diabetic nephropathy. Our preliminary studies describe a novel effect of USF2 to promote renin gene expression and angiotensin II formation in mesangial cells. This effect of USF2 was linked to glucose-induced regulation of TGF- production suggesting that this pathway may contribute to the development of diabetic nephropathy. The working hypothesis of this proposal is that USF2 stimulates the renal RAS to promote production of TGF- and the development of diabetic nephropathy. The proposed studies will define the role of USF2 in the development of diabetic nephropathy focusing on regulation of mesangial cell renin as the mechanistic target. In aim 1 the mechanisms by which USF2 regulates renin gene expression and angiotensin II production in mesangial cells under normal or high glucose conditions will be determined. In aim 2 the role of USF2-mediated renin expression and angiotensin II production in high glucose induced TGF- levels and extracellular matrix protein (ECM) expression in mesangial cells will be defined. In aim 3 the role of USF2-mediated up-regulation of the renal RAS in the development of diabetic nephropathy in vivo will be determined. Our approach utilizes both in vitro and in vivo studies to provide new information on the mechanisms of activation of the intrarenal RAS system in diabetes and will lead to the development of novel therapies to ameliorate this major complication of diabetes. Public health relevance: Diabetic nephropathy is the most common cause of end-stage renal failure and is highly prevalent in both type 1 and type 2 diabetics. The proposed studies will provide new information on the mechanisms of activation of the intrarenal renin-angiotensin system in diabetes and will lead to the development of novel therapies to ameliorate this major complication of diabetes.

project_terms:
Albumins;Angiotensin II;Complications of Diabetes Mellitus;Data;Deposition;Development;Diabetes Mellitus;Diabetic Nephropathy;Diabetic mouse;Effectiveness;End stage renal failure;Excretory function;Exhibits;Extracellular Matrix;Extracellular Matrix Proteins;Fibrosis;Gene Expression;Genes;Glomerular Mesangial Cell;Glucose;Hyperglycemia;Hypertrophy;In Vitro;Injection of therapeutic agent;Insulin-Dependent Diabetes Mellitus;Kidney;Kidney Diseases;Lead;Link;Losartan;Mediating;Mediator of activation protein;Pathogenesis;Pathway interactions;Physiological;Plasma;Play;Production;Proteins;Regulation;Relative (related person);Renal function;Renin;Renin-Angiotensin System;Role;Small Interfering RNA;Streptozocin;Structure;System;Testing;Transforming Growth Factors;Transgenic Mice;Transgenic Organisms;Up-Regulation (Physiology);Wild Type Mouse;Work;aliskiren;diabetic;glomerular basement membrane;glomerular function;glomerulosclerosis;human USF2 protein;in vivo;inhibitor/antagonist;mesangial cell;mouse model;novel;protein expression;public health relevance;receptor;response;transcription factor;transcription factor USF;type I and type II diabetes;type I diabetic;urinary

public_health_relevance:
Diabetic nephropathy is the most common cause of end-stage renal failure and is highly prevalent in both type1 and type 2 diabetics. The proposed studies will provide new information on the mechanisms of activation ofthe intrarenal renin-angiotensin system in diabetes and will lead to the development of novel therapies toameliorate this major complication of diabetes.


application_id: 8138281
project_number: 3U01CA114622-05S4
project_title: Appalachia Community Cancer Network
administering_ic: NCI
award_notice_date: 2010-09-07
opportunity_number: RFA-CA-05-012
application_type: 3
activity_code: U01
ic: CA
serial_number: 114622
suffix: S4
program_official: OGUNBIYI, PETER
project_start_date: 2005-05-06
project_end_date: 2012-04-30
study_section: ZCA1-SRRB-Y(J1)
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
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
project_abstract:
DESCRIPTION (provided by applicant):  A multidisciplinary team of collaborators from academic institutions and communities in Appalachian regions of Kentucky West Virginia Ohio Pennsylvania New York Maryland and Virginia are proposing to build on a strong foundation of previous activity of the Appalachia Cancer Network (ACN) an NCI-funded Special Populations Network and develop the Appalachia Community Cancer Network (ACCN).  The proposed ACCN will expand the previous ACN and expand to address cancer health disparities in seven areas in Appalachia areas that include some of the most medically underserved distressed and economically disadvantaged areas in the US. Cancer mortality rates are elevated in each of these areas as are the incidence rates for lung cervical and colorectal cancers suggesting that factors such as late stage diagnosis and barriers to cancer care must be addressed if disparities are to be reduced.  The long-term goal of the ACCN is to contribute to the reduction of cancer health disparities in Appalachia by developing implementing and evaluating community-based participatory research and providing training.  The specific aims of the AACN are to:  1) Build on a foundation established by the ACCN and develop and maintain community partnerships to facilitate research and action to reduce cancer health disparities; 2) Conduct community based participatory research ranging from focused needs assessments to intervention research to policy assessments; 3) Develop pilot research projects that focus on primary and secondary prevention of lung cervical and colorectal cancers in Appalachia; 4) Train researchers in community-based participatory research; and 5) Conduct evaluation of the ACCN including attention to processes short term impact and achievement of outcomes.  The ACCN will build on the ACN and develop programs in cancer education; community based participatory research and training.  Proposals for two pilot projects are also included. The pilot projects address cervical and colorectal cancer two cancers targeted by the ACCN

project_terms:
Achievement;Action Research;Address;Appalachian Region;Area;Attention;Cervical;Clinical Trials;Colorectal Cancer;Communities;Comprehensive Cancer Center;Diagnosis;Distress;Economically Deprived Population;Evaluation;Foundations;Funding;Goals;Incidence;Institutes;Institution;Intervention Studies;Kentucky;Lung;Malignant Neoplasms;Maryland;Mortality Vital Statistics;Needs Assessment;New York;Ohio;Outcome;Pennsylvania;Pilot Projects;Policies;Process;Research;Research Personnel;Research Project Grants;Research Training;Secondary Prevention;Staging;Training;Universities;Virginia;West Virginia;base;cancer care;cancer education;cancer health disparity;community based participatory research;medically underserved;multidisciplinary;named group;programs


application_id: 8137944
project_number: 5R01AA016959-05
project_title: Ethanol alteration of the neurogenic niche
administering_ic: NIAAA
award_notice_date: 2011-08-10
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: 2016-08-31
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;Alcohol dependence;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;Diagnostic;Environment;Enzymes;Ethanol;Event;Future;Goals;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: 8137814
project_number: 5R25CA153954-02
project_title: The University of Kentucky Cancer Nanotechnology Training Center (UK CNTC)
administering_ic: NCI
award_notice_date: 2011-08-19
opportunity_number: RFA-CA-09-014
application_type: 5
activity_code: R25
ic: CA
serial_number: 153954
program_official: FARRELL, DOROTHY F
project_start_date: 2010-09-03
project_end_date: 2015-07-31
study_section: ZCA1-RTRB-2(M1)
contact_pi_person_id: 7875468
contact_pi: ANDERSON, BRADLEY D
other_pis: EVERS, BERNARD MARK
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): The University of Kentucky Cancer Nanotechnology Training Center (UK CNTC) will provide advanced multidisciplinary training for predoctoral students and postdoctoral fellows toward the goal of creating a new type of cancer researcher who is skilled and ready to pursue a career in cancer nanotechnology research. Nationally and internationally recognized faculty members at the University of Kentucky will collaborate to create a fertile environment for the novel exploration of nanotechnology and cancer. Expertise covers a broad multidisciplinary range of scientific areas in gastrointestinal cancer lung cancer gliomas radiation medicine surgery cancer screening imaging and pharmacokinetics and dynamics. Among these faculty are 16 nanotechnology researchers in the Departments of Chemical Engineering Materials Engineering Electrical Engineering Chemistry and Pharmaceutical Sciences and 18 biomedical scientists or clinical oncologists in the Colleges of Pharmacy or Medicine. Based on existing research collaborations we propose cancer nanotechnology projects composed of multidisciplinary focus area teams with the goal of training future leading researchers in the field of cancer nanotechnology in the following four areas: (1) early detection and diagnosis in lung colon and ovarian cancer; (2) treatment of gastrointestinal tumors and metastases; (3) lung cancer treatment; and (4) glioma therapy. Specific Aim 1 is to expand the core expertise of participants in the UK CNTC through cross-disciplinary laboratory research training projects of up to two years involving innovative applications of nanotechnology to address specific unmet needs in cancer detection and therapy. Our trainees will be at the forefront of research that will be driven toward developing novel cancer therapies and diagnostic strategies based on nanotechnology. Through these activities the trainees will obtain a detailed understanding of the molecular basis of cancer the unresolved clinical problems in treating and diagnosing the disease and acquire expertise in the field of nanotechnology. In Specific Aim 2 the CNTC will provide trainees with problem-based and experiential training through seminars workshops short courses clerkships and laboratory training modules that will build their research skills and confidence as members of multi-disciplinary research teams. Each trainee will be immersed in individualized problem-based instruction and a broad multidisciplinary training through core courses short courses participation in seminars undergraduate and early graduate student mentoring and outreach activities designed to educate the public. Trainees will be guided through these programs with effective mentorship and an evaluation program (Specific Aim 3) that will assess the effectiveness of trainee progress and development. Finally Specific Aim 4 is to highlight the accomplishments of CNTC trainees both regionally and nationally. As such our trainees will learn to envision articulate and perform nanotechnology-centered research focused on developing novel solutions to the outstanding clinical problems associated with cancer.  
  
PUBLIC HEALTH RELEVANCE: The University of Kentucky Cancer Nanotechnology Center will provide a systematic and unique multidisciplinary training environment focusing on laboratory hands-on research to create a workforce capable of using nanotechnology for solving intractable cancer research problems. Trainees of the Center will be immersed in a research environment designed to take advantage of the multiple research strengths of faculty at the University of Kentucky and will emerge with a broad yet detailed knowledge of cancer diagnostics interventions and related nanotechnology applications including drug delivery early detection and treatment.

public_health_relevance:
The University of Kentucky Cancer Nanotechnology Center will provide a systematic and uniquemultidisciplinary training environment focusing on laboratory hands-on research to create aworkforce capable of using nanotechnology for solving intractable cancer research problems.Trainees of the Center will be immersed in a research environment designed to take advantageof the multiple research strengths of faculty at the University of Kentucky and will emerge with abroad yet detailed knowledge of cancer diagnostics interventions and related nanotechnologyapplications including drug delivery early detection and treatment.


application_id: 8137427
project_number: 3R01AI051517-07S1
project_title: Paramyxovirus F protein mediated membrane fusion
administering_ic: NIAID
award_notice_date: 2010-09-13
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: AI
serial_number: 051517
suffix: S1
program_official: CASSETTI, CRISTINA
project_start_date: 2010-09-13
project_end_date: 2012-09-12
study_section: Special Emphasis Panel[ZRG1-IDM-S(02)S]
contact_pi_person_id: 8106840
contact_pi: DUTCH, REBECCA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Membrane fusion a process critical for viral entry is promoted by the paramyxovirus fusion (F) proteins. All F proteins contain a number of common features that play fundamental roles in fusion. However significant variations exist between F proteins related to protein activation and promotion of membrane fusion and many critical questions remain concerning the mechanism by which fusion is promoted by these important viral proteins. The long-term objective of our research is to understand the precise mechanism(s) of paramyxovirus F protein-promoted membrane fusion. Our overall hypothesis is that the function of domains critical for fusion promotion will be conserved in diverse F proteins but that interactions in these domains will modulate triggering mechanisms. To address this important hypothesis we will pursue the following specific aims: 1.) We will build on our exciting preliminary data which demonstrates trimer formation of isolated Hendra F transmembrane (TM) domains to define the role of TM-TM interactions in glycoprotein folding and fusion. We will therefore delineate the residues critical for TM-TM interactions and evaluate the role of this interaction in Hendra F folding trafficking and fusion; analyze the effect of HRB or cytoplasmic-tail additions on stability of TM-TM interactions; compare TM-TM interactions for the PIV5 and HMPV F proteins to those observed for the Hendra F TM; and determine if TM domains from paramyxovirus attachment proteins interact with themselves or with the F protein TM domains; 2.) We will define the role of low pH and endocytosis in HMPV viral entry and delineate the role of electrostatic repulsion in the HRB linker region in HMPV F low pH-induced conformational changes and entry of recombinant viruses and; 3.) We will analyze the role of stabilizing interactions between HRA and a conserved region of F2 which our studies of PIV5 F indicate can play a role in triggering by defining key interactions in this domain in PIV5 F assessing the stage of fusion which is affected analyzing the effect of mutations in this region on viral entry and analyzing the effect of mutations to this region in other F proteins. Accomplishing these goals will provide crucial information on the regions that control the molecular events involved in the F protein-promoted membrane fusion process and potentially identify new targets for antiviral therapy. PUBLIC HEALTH RELEVANCE The paramyxovirus family contains both established human pathogens such as measles virus and respiratory syncytial virus and newly emerged human pathogens including the highly pathogenic Hendra and Nipah viruses and the recently identified human metapneumovirus (HMPV). A detailed understanding of the fusion mechanism could lead to development of new antiviral reagents.

project_terms:
Address;Affect;Alanine;Antiviral Agents;Antiviral Therapy;Cathepsin L;Cell fusion;Cell membrane;Cells;Charge;Chimeric Proteins;Cleaved cell;Cysteine;Cytoplasmic Tail;Data;Development;Electrostatics;Endocytosis;Event;Family;Family member;Funding;Glycine;Glycoproteins;Goals;Hendra Virus;Human;Human Metapneumovirus;Human respiratory syncytial virus;Integral Membrane Protein;Kinetics;Lead;Measles virus;Mediating;Membrane Fusion;Molecular;Mutation;Nipah Virus;Paramyxovirus;Peptide Hydrolases;Peptides;Play;Positioning Attribute;Process;Proline;Proteins;Reagent;Recombinants;Recycling;Research;Respiratory syncytial virus;Role;Route;Scanning;Staging;Structure;System;Transmembrane Domain;Variant;Viral;Viral Proteins;Virus;insight;mutant;novel;parainfluenza virus;pathogen;protein activation;protein folding;public health relevance;recombinant virus;trafficking


application_id: 8137330
project_number: 5R01AA018869-03
project_title: Cyclic AMP Cytokine Modulation and Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2011-08-12
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;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: 8137327
project_number: 5R01AA018016-04
project_title: The Role of Alcohol in HIV Therapy Hepatotoxicity
administering_ic: NIAAA
award_notice_date: 2011-08-12
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;Cause of Death;Chronic;Clinical;Combination Drug Therapy;Communicable Diseases;Depressed mood;Development;Disease;Disease Progression;Drops;Drug Interactions;Enrollment;Enzymes;Fatty Liver;Functional disorder;Goals;Grant;HIV;HIV Infections;HIV therapy;Health;Hepatic;Hepatitis B;Hepatitis B Virus;Hepatitis C;Hepatitis C virus;Hepatocyte;Hepatotoxicity;Highly Active Antiretroviral Therapy;Histology;Human;Hypersensitivity;Immune;In Vitro;Incidence;Infection;Injury;Insulin Resistance;Killings;Lactic Acidosis;Life Expectancy;Lipodystrophy;Liver;Liver diseases;Lymphocyte Count;Lymphocyte Depletion;Lymphocyte Function;Measures;Mediating;Metabolic;Metabolism;Mitochondria;Morbidity - disease rate;Mortality Vital Statistics;Mus;Natural immunosuppression;Nucleosides;Opportunistic Infections;Outcome;Oxidative Stress;Patients;Pharmaceutical Preparations;Pneumonia;Population;Predisposition;Production;Protease Inhibitor;Proteasome Inhibition;Proteins;Reaction;Reporting;Research;Reverse Transcriptase Inhibitors;Risk;Role;Screening procedure;Series;Severities;Simulate;Symptoms;TNF gene;Technology;Testing;Therapeutic Intervention;Time;Toxic effect;Tuberculosis;Tumor Necrosis Factor-alpha;United States National Institutes of Health;Universities;Viral hepatitis;Work;World Health Organization;alcohol effect;base;cohort;cytokine;design;experience;feeding;high risk behavior;immune function;interest;mitochondrial dysfunction;multicatalytic endopeptidase complex;non-nucleoside reverse transcriptase inhibitors;novel;prospective;public health relevance;reconstitution;translational approach


application_id: 8136115
project_number: 5R25CA148005-02
project_title: The Development of an Interdisciplinary Oncology Palliative Care Curriculum
administering_ic: NCI
award_notice_date: 2011-08-29
opportunity_number: PAR-08-120
application_type: 5
activity_code: R25
ic: CA
serial_number: 148005
program_official: LEI, MING
project_start_date: 2010-09-01
project_end_date: 2015-08-31
study_section: Education Study Section (G)[NCI-G]
contact_pi_person_id: 8126973
contact_pi: PFEIFER, MARK P
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): In 2010 cancer is expected to surpass heart disease as the highest health-related cause of mortality in the world. Almost every family has or will face a loved one needing cancer care including curative treatment symptom control and end-of-life care. The increasing needs of our patient population and the emerging science of palliative care call for new efforts in innovative education. National organizations have called for new efforts in interdisciplinary understanding and education in approaching palliative care. Each discipline however has continued to teach palliative care principles largely in silos using existing curricular structure and constructs; there are no reports of mandatory interdisciplinary education in palliative care involving all four disciplines - medicine nursing social work and chaplaincy.   
  
The aim of this project is to design implement and evaluate an innovative integrated and interdisciplinary oncology palliative care curriculum for medical nursing social work and chaplaincy students.   
  
Specific aims are:   
1) Design an innovative interdisciplinary oncology palliative care curriculum;   
2) Implement the interdisciplinary oncology palliative care curriculum;   
3) Develop and utilize an evaluation system that measures the effectiveness of the curriculum learner outcomes and the long term impact on practitioners and patients.   
  
Project efforts will focus the design implementation and testing of an interdisciplinary oncology palliative care curriculum. Innovative as well as proven education modalities will be utilized to determine:   
1) If the educational objectives are aligned with the desired outcomes;   
2) Which modalities are most effective for each discipline?   
3) How the modalities are best integrated; and   
4) What factors contribute to the sustainability and portability of the curriculum.   
  
The new curriculum will include eight learning activities that will become a required part of the curriculum for all 3rd year medical students 3rd and 4th year nursing students masters level social work students and clinical pastoral education residents. In addition to traditional educational modalities such as clinical rotations didactic sessions and self-study modules non-traditional methods including standardized patients and families reflective writing a palliative care vignette case-solving and capstone projects will be used. The added value of interdisciplinary education will be evaluated in this field.  
  
PUBLIC HEALTH RELEVANCE: Almost every family has or will face a loved one needing cancer care including curative treatment symptom control and end-of-life care. In receiving this care patients and their families will need the services of physicians nurses chaplains and social workers. The Institute of Medicine lists working in interdisciplinary teams as one of five core competencies all health care clinicians should possess and calls for health professionals to be educated in an interdisciplinary manner to prepare them for the real world team environments they will participate in once entering the field. This project will create implement and test a novel mandatory interdisciplinary oncology palliative care curriculum for medical nursing social work and chaplaincy students.

project_terms:
Address;Adult;Awareness;Cancer Control;Cancer Patient;Caring;Clinical;Communities;Development;Discipline;Discipline of Nursing;Educational Curriculum;Educational aspects;Educational process of instructing;Environment;Evaluation;Face;Family;Health;Health Professional;Health Sciences;Healthcare;Heart Diseases;Institute of Medicine (U.S.);Knowledge;Learning;Malignant Neoplasms;Mandatory Reporting;Medical;Medical Students;Medicine;Methods;Modality;Mortality Vital Statistics;NIH Program Announcements;Nurses;Nursing Students;Outcome;Palliative Care;Patient Care;Patients;Physicians;Rotation;Science;Services;Social Workers;Social work (field);Structure;Students;Symptoms;System;Technology;Testing;Training;Translating;United States National Institutes of Health;Work;Writing;cancer care;career;clinical practice;design;effectiveness measure;end of life;evidence base;evidence based guidelines;experience;flexibility;innovation;loved ones;novel;oncology;patient population;portability;programs;public health relevance

public_health_relevance:
PROJECT NARRATIVE - RELEVANCEAlmost every family has or will face a loved one needing cancer care including curativetreatment symptom control and end-of-life care. In receiving this care patients and theirfamilies will need the services of physicians nurses chaplains and social workers. The Instituteof Medicine lists working in interdisciplinary teams as one of five core competencies all healthcare clinicians should possess and calls for health professionals to be educated in aninterdisciplinary manner to prepare them for the real world team environments they willparticipate in once entering the field. This project will create implement and test a novelmandatory interdisciplinary oncology palliative care curriculum for medical nursing social workand chaplaincy students.


application_id: 8135441
project_number: 5R01AA018274-03
project_title: Alcohol Tolerance and Behavioral Disinhibition in Humans
administering_ic: NIAAA
award_notice_date: 2011-08-11
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;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

public_health_relevance:
Project Narrative Excessive alcohol use contributes to many adverse health consequences (e.g. alcohol poisoningacute alcoholic hepatitis and liver cirrhosis). Tolerance has long been implicated as a factor contributing toalcohol abuse and dependence by encouraging the use of escalating doses to reinstate initial effects of thedrug. Yet little research has examined how tolerance might increase the risk for alcohol abuse. The proposedstudies examine the contribution of tolerance to abuse potential as measured by changes in the ability of thedrug to alter basic mechanisms involved in the control and regulation of behavior. The findings of this researchwill provide an understanding of how drinkers' susceptibility to alcohol's acute behavioral-impairing effects canpose an early-onset risk factor for later alcohol dependence by promoting a continued pattern of abusive bingedrinking. The research strategies also will provide methods for testing the role of neurocognitive mechanismsin the treatment efficacy of existing pharmacotherapies such as naltrexone and acamprosate as well as someinvestigational medications that might operate via neurocognitive control mechanisms.


application_id: 8135321
project_number: 5R01EY012354-12
project_title: Isolation of congenital stationary night blindness genes
administering_ic: NEI
award_notice_date: 2011-08-17
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 012354
program_official: GREENWELL, THOMAS
project_start_date: 1999-02-01
project_end_date: 2012-12-31
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Vision begins when light is converted to an electrical signal in the photoreceptors. Increases in light decrease release of the neurotransmitter glutamate from cone and rod photoreceptor terminals and decreases in light increase its release. These changes in synaptic glutamate concentration are detected by two classes of bipolar cells that then transmit the signal vertically through the retinal circuit to the ganglion cells. The neurotransmitter changes also are detected by horizontal cells that provide lateral transmission in the form of feedback and feedforward 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 a metabotropic glutamate receptor mGluR6 and depolarize in response to a light flash. Defects in transmission between photoreceptors and bipolar cells result in several forms of congenital stationary night blindness (CSNB). The incomplete form CSNB2 results from mutations in genes critical to glutamate release in photoreceptors including the 11F subunit of voltage dependent calcium channels. The complete form emerges from mutations in signaling in DBCs which include mutations in mGluR6 and nyctalopin (a protein of unknown function). Signaling through DBCs is mediated via a metabotropic glutamate receptor mGluR6 which modulates the activity of a non-specific cation channel of unknown identity. The details of this mGluR6 cascade are mostly unknown. The long term goal of this project is to characterize the molecular components required for synaptic transmission between photoreceptors and DBCs. This project has four specific aims: 1) determine the structure/function relationships of nyctalopin 2) determine the state of the non-specific cation channel in several night blind mice 3) determine the binding partners of nyctalopin thereby elucidating new component of the mGluR6 cascade and 4) create knockout mouse lines of the nyctalopin interacting proteins to determine if they result in nigh blindness. At the completion of this project we will have identified new members critical to signal transmission in DBCs. Further we will have identified new candidate genes for congenital stationary night blindness.   
  
PUBLIC HEALTH RELEVANCE: Vision requires a light signal to be converted to an electrical signal which is then transmitted to the brain via a neuronal network. The group of diseases being studied is referred to as congenital stationary night blindness. They have defects in signal transmission between photoreceptors and the second neuron in the pathway. The studies in this proposal will characterize the nature of the defects and determine 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;public health relevance;research study;response;transmission process


application_id: 8134817
project_number: 5R01AG033036-03
project_title: The effects of bilingualism on age-related cognitive and neurobiological declines
administering_ic: NIA
award_notice_date: 2011-08-08
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: 2014-07-31
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;Health;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;relating to nervous system;research study;response;social;white matter

public_health_relevance:
Program Director/Principal Investigator (Last First Middle):Project Narrative/RelevanceNormal human aging is associated with decline of executive control functions. Recent evidence suggeststhat bilingualism may attenuate some of these age-related declines by promoting neuroplasticity and/orcompensatory brain reserve. By providing a more precise understanding of the mechanisms that arebolstered by bilingualism the present proposal will help identify cognitive/neurobiological markers thatremain malleable in aging in response to an accessible lifestyle variable.PHS 398/2590 (Rev. 11/07) Page Continuation Format Page


application_id: 8134254
project_number: 5R42AG030239-03
project_title: Commercialization of a Diagnostic Test for Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2011-08-12
opportunity_number: PA-09-081
application_type: 5
activity_code: R42
ic: AG
serial_number: 030239
program_official: HSIAO, JOHN
project_start_date: 2007-06-15
project_end_date: 2013-08-31
study_section: Special Emphasis Panel[ZRG1-ETTN-C(11)B]
contact_pi_person_id: 2276639
contact_pi: LOVELL, MARK ANTHONY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 614763006
duns_number: 614763006
fips: US
organization_id: 10010025
organization_name: SCOUT DIAGNOSTICS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402431805
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-09-01
budget_end_date: 2013-08-31
project_abstract:
DESCRIPTION (provided by applicant): The major barriers to preventing or treating Alzheimer's disease (AD) are its unknown pathogenesis/etiology and the lack of an objective sensitive and specific biomarker of the disease particularly at the early stages when therapeutic interventions would likely have the greatest efficacy. The basic hypothesis of this project is that levels of a unique high molecular weight protein/protein complex consisting of 1 molecule of lipocalin (brain-specific) prostaglandin-d-synthase (PDS) and 1 dimer of transthyretin (TTR) quantified in cerebrospinal fluid (CSF) using an enzyme linked immunoassay (ELISA) developed and characterized by Scout Diagnostics will serve as an effective biomarker to identify Alzheimer's disease (AD) subjects early in disease progression. To convert the basic science developed during Phase I funding to a commercially viable product we propose to: a). synthesize and purify authentic PDS/TTR complex using recombinant human proteins generated in our laboratory for use as a standard for ELISA calibration and quantification; b) evaluate product storage and shipping requirements and prepare a horseradish peroxidase labeled probe antibody to decrease analysis time and; c) prepare and field test an instruction manual for use in independent diagnostic laboratories. To more fully characterize the PDS/TTR ELISA we propose to analyze CSF specimens from an additional 150 AD and 150 control subjects from three geographically distinct Alzheimer's disease centers (ADCs) and to carry out inter-laboratory validation studies by providing those ADCs with ELISA kits instructions and representative CSF specimens for analysis of duplicate aliquots of the same samples in their laboratories. In addition we will further determine the specificity of the biomarker for AD patients by analyzing CSF from 50 subjects with non-AD neurologic disorders including frontotemporal dementia corticobasal degeneration and parasupranuclear palsy. Overall our preliminary data suggest that use of the PDS/TTR complex either in CSF or in serum may provide an objective biomarker with sufficient sensitivity/specificity for the identification of AD subjects.  
  
PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the fourth leading cause of death in the United States and currently affects 4.5 million Americans. Two major barriers to treating and eventually preventing AD are: 1) the lack of understanding about the process of neuron degeneration and loss and 2) the lack of a sensitive and specific biomarker of the disease. Preliminary and future studies described in this proposal show that a novel protein-protein complex present in cerebrospinal fluid can be quantified using an enzyme linked immunoassay (ELISA). This protein-protein complex is a sensitive and specific biomarker of AD including early stages of AD (mild cognitive impairment) when therapeutic interventions are most likely to have beneficial effects.

project_terms:
Affect;Age;Aging;Aliquot;Alzheimer's Disease;American;Amyloid beta-Protein;Antibodies;Archives;Basic Science;Biological;Brain;Calibration;California;Cause of Death;Cerebrospinal Fluid;Collaborations;Collection;Complex;Data;Diagnosis;Diagnostic;Diagnostic tests;Disease;Disease Progression;Enrollment;Enzymes;Etiology;Freezing;Frontotemporal Dementia;Funding;Future;Geographic Distribution;Health Sciences;Horseradish Peroxidase;Housing;Human;Immunoassay;Institution;Institutional Review Boards;Instruction;Label;Laboratories;Laboratory Study;Letters;Link;Manuals;Modification;Molecular Weight;Nerve Degeneration;Oregon;Oryctolagus cuniculus;Paralysed;Pathogenesis;Patients;Phase;Population Heterogeneity;Prealbumin;Process;Prostaglandins;Proteins;Protocols documentation;Recombinants;Recruitment Activity;Research;Sampling;San Francisco;Sensitivity and Specificity;Serum;Shipping;Ships;Site;Small Business Technology Transfer Research;Specificity;Specimen;Staging;Statistical Data Interpretation;Testing;Therapeutic Intervention;Threonine;Time;Training;United States;Universities;Variant;Washington;Woman;base;biomarker;blind;commercialization;corticobasal degeneration;crosslink;dimer;innovation;men;mild cognitive impairment;nervous system disorder;neuron loss;novel;prevent;protein complex;public health relevance;research study;tau Proteins;tau-1;usability;validation studies

public_health_relevance:
Alzheimer's disease (AD) is the fourth leading cause of death in the United States and currently affects4.5 million Americans. Two major barriers to treating and eventually preventing AD are: 1) the lack ofunderstanding about the process of neuron degeneration and loss and 2) the lack of a sensitive andspecific biomarker of the disease. Preliminary and future studies described in this proposal show that anovel protein-protein complex present in cerebrospinal fluid can be quantified using an enzyme linkedimmunoassay (ELISA). This protein-protein complex is a sensitive and specific biomarker of ADincluding early stages of AD (mild cognitive impairment) when therapeutic interventions are most likelyto have beneficial effects.


application_id: 8134131
project_number: 4R44AG035410-02
project_title: Generating Blood-based Diagnosis for Alzheimer Disease
administering_ic: NIA
award_notice_date: 2010-11-30
opportunity_number: PA-09-080
application_type: 4
activity_code: R44
ic: AG
serial_number: 035410
program_official: HSIAO, JOHN
project_start_date: 2010-04-15
project_end_date: 2012-11-30
study_section: Special Emphasis Panel[ZRG1-IMST-E(15)B]
contact_pi_person_id: 1860379
contact_pi: WANG, EUGENIA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 805479370
primary_uei: KPMEKJJTDUS5
duns_number: 805479370
uei: KPMEKJJTDUS5
fips: US
organization_id: 10020610
organization_name: ADVANCED GENOMIC TECHNOLOGY, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402416052
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The present lack of blood-based diagnosis requires AD patients to be subjected to either invasive spinal fluid (CSF) tapping expensive MRI or PET imaging or arduous psychological testing all unsuitable and costly for our elderly. Strategically we shall address this unmet need by generating systemic biomarkers detectable in peripheral mononuclear cells (PBMC) and serum/plasma focusing on two classes of molecules micro- RNAs and their target genes which generally exhibit an inverse relationship because the former noncoding RNA functions by partially repressing the latter"s expression as a "dimmer switch" via binding either at the co- ding region of the message thus degrading it or at the 3"-untranslated region to inhibit translation. Thus key microRNAs and their targets can serve as disease biomarkers in "see-saw" balance applicable for new diagnostics and/or therapy. Our pilot study with a small cohort of 16 AD and 16 age-matched normal elderly controls (NEC) revealed: 1. Predominant down-regulation of gene expression at the message level in AD PBMC; and 2. Correlated up-regulation of microRNA (miR) expression in PBMC of the same individuals. In this proposal we focus on a specific up-regulated microRNA miR-34a whose known targets are SIRT1 cdk4 cdk6 cyclin E2 bcl2 etc. SIRT1 is a member of the 7-member Silent Information Regulator protein family. Caloric restriction extends longevity through triggering expression of SIRT1 which can also be mimicked by resveratrol a red wine polyphenol. SIRT1 reduction is linked to accumulation of Tau and A242 production two hallmarks of AD etiopathogenesis. Thus we suggest that in AD there is a systemic effect detectable in PBMC and serum/plasma; up-regulated miR-34a may induce down-regulation of SIRT1 with attendant pathophysiologic results. In this proposal we plan to generate for this "see-saw" of changes miR-34a/SIRT1 Target Pair Ratio (TPR) indices to quantify both disease presence as well as progress; the indices should also provide an unprecedented evaluation of drug efficacy. This Fast-track proposal of two phases is planned with our existing small cohort study as the roadmap for the larger cohort investigation: Phase I of six months with our existing small 16 AD and 16 NEC sample cohorts to: Aim 1. study possible down-regulation of miR-34a"s known targets; and Aim 2. develop a feasibility study of pilot miR-34a/SIRT1 TPR-indices; and Phase II of two years with larger cohorts of 200 AD and 200 NEC participants: Aim 1.Establish a Bio-Repository of PBMC-DNA -RNA & -protein specimens and serum/plasma samples for assays in Aims 2 & 3; Aim 2. Generate PBMC-based miR34a/SIRT1 (& other targets) TPR indices; and Aim 3. Perform feasibility study to develop serum/plasma-based miR- 34a/SIRT1-TPR indices. Success of this project will allow us to generate PBMC- and serum-based miR-TPR indices as personalized diagnostics for AD victims meeting an urgent need in health care a huge gain for disease victims their caregivers and our society at large.  
  
PUBLIC HEALTH RELEVANCE:  At present the absence of any blood-based diagnosis for Alzheimer"s disease (AD) requires patients to enduring arduous neuropsychological testing invasive cerebrospinal fluid tapping and/or expensive MRI or PET imaging with definitive diagnosis deferred until brain autopsy. Our preliminary findings based on new science concerning a novel molecular species microRNAs (miR) and their "see-saw" partial repression of the expression of their target gene(s) suggest that potential disease biomarkers for AD are detectable systemical- ly in peripheral blood mononuclear cells and/or serum/plasma and may be quantified as miR-Target Pair Ra- tios (TPR). Our plan is to define AD-specific TPR indices initially focusing on miR-34a and its target SIRT1 whose reduction is known to be associated with increased Tau and A242 two hallmarks of AD etiopathogene- sis; our ultimate goal is a "Tool-Box" of TPR indices miR-34a/SIRT1-TPR being the first such AD diagnostic indicating not only disease presence but also its progress (and even drug efficacy monitoring) a huge strate- gic gain for the victims of this costly disease and our society at large!

project_terms:
3' Untranslated Regions;Address;Age;Aging;Alzheimer's Disease;Apoptosis;Autopsy;Back;Binding (Molecular Function);Biogenesis;Biological Assay;Blood;Boxing;Brain;Brain Pathology;CDK4 gene;Caloric Restriction;Caregivers;Cell Cycle;Cells;Cerebrospinal Fluid;Code;Cohort Studies;DNA;DNA Repair;Deacetylase;Diagnosis;Diagnostic;Disease;Down-Regulation;Elderly;Equilibrium;Evaluation;Exhibits;Family;Feasibility Studies;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Gene Targeting;Genes;Genetic Transcription;Genotoxic Stress;Goals;Healthcare;Homeostasis;Individual;Investigation;Investments;Knowledge;Lead;Link;Longevity;Magnetic Resonance Imaging;MicroRNAs;Modeling;Molecular;Molecular Profiling;Monitor;Mononuclear;Neurofibrillary Tangles;Neuropsychological Tests;Oxidation-Reduction;Oxidative Stress;Participant;Patients;Peripheral;Peripheral Blood Mononuclear Cell;Phase;Physiological;Pilot Projects;Plasma;Positron-Emission Tomography;Printing;Production;Protein Family;Proteins;Psychological Tests;RNA;Repression;Research;Resveratrol;Risk;Sampling;Science;Screening procedure;Senile Plaques;Serum;Signal Transduction;Societies;Specimen;Stress;Synapses;Testing;Translations;Untranslated RNA;Up-Regulation (Physiology);Work;amyloid precursor protein processing;base;biomarker;cohort;cyclin E2;drug efficacy;feeding;foot;gene repression;indexing;interest;meetings;member;novel;novel diagnostics;polyphenol;protein expression;public health relevance;red wine;repository;response to injury;senescence;success;tau Proteins;tau aggregation;tool;trend

public_health_relevance:
Project Title: "Generating Blood-based Diagnosis for Alzheimer's Disease" At present the absence of any blood-based diagnosis for Alzheimer"s disease (AD) requires patientsto enduring arduous neuropsychological testing invasive cerebrospinal fluid tapping and/or expensive MRI orPET imaging with definitive diagnosis deferred until brain autopsy. Our preliminary findings based on newscience concerning a novel molecular species microRNAs (miR) and their "see-saw" partial repression of theexpression of their target gene(s) suggest that potential disease biomarkers for AD are detectable systemical-ly in peripheral blood mononuclear cells and/or serum/plasma and may be quantified as miR-Target Pair Ra-tios (TPR). Our plan is to define AD-specific TPR indices initially focusing on miR-34a and its target SIRT1whose reduction is known to be associated with increased Tau and A42 two hallmarks of AD etiopathogene-sis; our ultimate goal is a "Tool-Box" of TPR indices miR-34a/SIRT1-TPR being the first such AD diagnosticindicating not only disease presence but also its progress (and even drug efficacy monitoring) a huge strate-gic gain for the victims of this costly disease and our society at large!


application_id: 8133594
project_number: 1R01ES017244-01A1
project_title: Prevention of UV-induced carcinogenesis by cyanidin-3-glucoside
administering_ic: NIEHS
award_notice_date: 2011-03-09
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: ES
serial_number: 017244
suffix: A1
program_official: QUINN, ASHLINN KO
project_start_date: 2011-08-01
project_end_date: 2016-04-30
study_section: Special Emphasis Panel[ZRG1 OTC-N (03)]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Epidemiological clinical and laboratory studies have implicated that ultraviolet radiation (UV) is a complete environmental carcinogen and that repeated exposures can lead to the development of melanoma and nonmelanoma skin cancers. In addition to sunscreens chemoprevention of skin cancer by natural non-toxic compounds is suggested as an effective strategy to prevent the incidence of skin cancer. Our in vitro and in vivo studies on cyanidin-3-glucoside (C3G) a compound found in blackberries and other foods show that this compound is able to inhibit NF-:B AP-1 COX2 and TNF1 activation/expression neoplastic transformation cancer cell migration and invasion and induction of apoptosis in HL60 cells. C3G also functions as an antioxidant by inhibiting the generation of reactive oxygen species and inducing antioxidant-regulative transcription factors. These preliminary studies indicate that C3G may function as a potential chemopreventive and chemotherapeutic agent. The overall hypothesis of this application is that C3G functions as an antioxidant and inhibits oxidative stress activation of transcription factors and inflammatory signaling proteins leading to protection against UVB-induced carcinogenesis. Specific Aim 1. In vitro and in vivo investigation of antioxidant properties of C3G. Electron spin resonance (ESR) spin trapping will be used to determine the reaction rates of C3G toward hydroxyl (7OH) and superoxide (O27-) radicals using Fenton reaction (Fe(II) + H2O2) and xanthine/xanthine oxidase as sources of these free radicals in a non-cellular system and to investigate antioxidant activities against UVB-induced 7OH and O27- radicals in a cellular system. Low frequency (in vivo) ESR will be also used to study antioxidant activities of C3G against UVB-generated O27- and 7OH radicals in the skin of SKH-1 hairless mice. Specific Aim 2. In vivo investigation of the effects of C3G on UVB-induced oxidative stress and activation of oxidative stress sensitive transcription factors. We will investigate the effects of C3G on UVB-induced lipid peroxidation protein oxidation and oxidative DNA damage in KSH mice. We will also study the effects of C3G on UVB-induced activation of activation protein (AP)-1 nuclear factor (NF)-:B and nuclear factor of activated T cells (NAFT) in transgenic mice. Specific Aim 3. Investigate the effects of C3G on UVB-induced inflammatory mediators. These inflammatory mediators include infiltrating leukocytes and myeloperoxidase (MPO) COX-2 PGE2 and several pro-inflammatory cytokines TNF-1 IL-2 and IL-6. Specific Aim 4. Investigation of the effects of C3G on UVB-induced tumorigenesis and early biomarkers. These markers include changes in thymine-positive cells proliferative cell nuclear antigen terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and apoptotic cells together with a change in p53 and p21/cip1- positive cell population in epidermis. These studies will provide a mechanistic rationale for an early on C3G efficacy in skin cancer prevention.  
  
PUBLIC HEALTH RELEVANCE: The incidence of UV-induced skin cancer is a major public health concern. Present study attempts to identify cyanidin-3-glucoside a plant-derived compound as a mechanism-based preventive agent against UV-induced skin cancers.

project_terms:
Acetates;Animal Model;Anthocyanins;Anthracenes;Antioxidants;Apoptosis;Apoptotic;Berry;Cabbage - dietary;Cells;Chemicals;Chemoprevention;Chemopreventive Agent;Chronic;Chronic Disease;Clinical Research;Complement Factor B;Consumption;DNA Nucleotidylexotransferase;Development;Diet;Dinoprostone;EGF gene;Electron Spin Resonance Spectroscopy;Environmental Carcinogens;Enzymes;Epidemiologic Studies;Epidermis;Epigallocatechin Gallate;Exhibits;Family;Food;Free Radicals;Frequencies (time pattern);Generations;Glucosides;Grapes;Green tea (dietary);Growth Factor;HL-60 Cells;Human;Hydrogen Peroxide;Hydroxyl Radical;In Vitro;Inbred HRS Mice;Incidence;Individual;Induction of Apoptosis;Inflammation;Inflammation Mediators;Inflammatory;Interleukin-2;Interleukin-6;Investigation;Label;Laboratories;Laboratory Study;Lead;Leukocytes;Link;Lipid Peroxidation;MAP Kinase Gene;Malignant Neoplasms;Mediating;Mediator of activation protein;Methods;Micronutrients;Milk Thistle;Minerals;Mus;Neoplastic Cell Transformation;Non-Malignant;Nuclear;Nuclear Antigens;Oxidative Stress;PTGS2 gene;Peroxidases;Phytochemical;Pigments;Plants;Population;Prevention;Preventive;Property;Prostaglandins;Proteins;Reaction;Reactive Oxygen Species;Signal Pathway;Signaling Protein;Skin;Skin Cancer;Skin Carcinoma;Source;Spin Trapping;Stimulus;Sunlight;Sunscreening Agents;Superoxides;System;TNF gene;Therapeutic;Thymine;Topical application;Transgenic Mice;Tumor Necrosis Factor-alpha;UVB induced;Ultraviolet B Radiation;Ultraviolet Rays;Vitamins;Xanthine Oxidase;Xanthines;ascorbate;base;biomarker;cancer cell;carcinogenesis;cell motility;cell transformation;chemotherapeutic agent;cyclooxygenase 2;cytokine;fruits and vegetables;high risk;in vivo;melanoma;member;nuclear factor 1;nuclear factors of activated T-cells;oxidation;oxidative DNA damage;prevent;protein activation;public health medicine (field);reaction rate;silibinin;skin cancer prevention;transcription factor;tumorigenesis

public_health_relevance:
The incidence of UV-induced skin cancer is a major public health concern. Present study attempts to identify cyanidin-3-glucoside a plant-derived compound as a mechanism-based preventive agent against UV-induced skin cancers.


application_id: 8133328
project_number: 5R21OH009494-02
project_title: Strategies for Safety of Older Adult Farmers
administering_ic: NIOSH
award_notice_date: 2011-06-17
opportunity_number: PAR-09-139
application_type: 5
activity_code: R21
ic: OH
serial_number: 009494
program_official: SANDERSON, LEE M
project_start_date: 2010-08-01
project_end_date: 2013-07-31
study_section: Safety and Occupational Health Study Section[SOH]
contact_pi_person_id: 8431098
contact_pi: REED, DEBORAH BAKER
other_pis: Not Applicable
congressional_district: 06
department: 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: N
project_abstract:
DESCRIPTION (provided by applicant): Farmers over age 55 make up over one-half of the principal operators of the 2.2 million U.S. farms with over 25% of the farms being operated by farmers over age 65. Fatalities to older farmers comprised over half of all adult farm fatalities between 1992 and 2004. Currently there are no guidelines for fitness for work of aging farmers. Although farmers may be well informed about safety practices knowledge alone is not enough to change behaviors (Cole 2002). Strategies for safety that engage the farmer in decision making about  his/her farm work choices and injury risks that are founded on sound principles and that include input of  farmers and other professionals should be developed. This exploratory project is a result of the first conference on the aging farmer recent research on work and health of the aging farmer conducted by the PI  and recently completed inquiry on aging farmer work guidelines in Canada. The project combines the expertise  of leading researchers to take the first step toward injury prevention interventions that can be used by farmers  and those that interact with them. This project will replicate the consensus-development methodology used to develop The North American Guidelines for Children s Agricultural Tasks (NAGCAT).  Eight focus groups of farmers over age 55 (n = 40) and their family members (n = 40) in four states will guide the focus realism and applicability of the future interventions. Four meetings with interdisciplinary professionals (n=80) (ag health and safety professionals gerontologists cooperative extension and others) will provide formats to begin consensus development of the focus of the safety strategies and build capacity for future work to develop and test work interventions and guidelines.  The long term goal of the project is to develop strategies and products to assist older adults and their families in selecting appropriate and safe farm jobs that are acceptable to the senior farmers and their families.  The specific aims are to:  1. Identify the top ten hazardous tasks of older farmers.  2. Develop a job hazard analysis matrix that includes the task hazards minimum ability set personal risk factors and action plan for the top ten hazardous tasks.  3. Test the feasibility of developing work guidelines or other injury prevention interventions for these hazards.  4. Establish sustainable work groups to design and test strategies and interventions identified in the consensus statement.  
  
PUBLIC HEALTH RELEVANCE: The long term goal of the project is to develop strategies and products to assist older adults and their families in selecting appropriate and safe farm jobs that are acceptable to the senior farmers and their families.  This project directly impacts public health by focusing on Sections 20.1 and 20.2 of Healthy People 2010: to reduce the number of work-related deaths and injuries to workers.

public_health_relevance:
PROJECT NARRATIVE The long term goal of the project is to develop strategies and products to assist older adults and their families in selecting appropriate and safe farm jobs that are acceptable to the senior farmers and their families. This project directly impacts public health by focusing on Sections 20.1 and 20.2 of Healthy People 2010: to reduce the number of work-related deaths and injuries to workers.


application_id: 8133037
project_number: 5P20RR018733-09
project_title: Molecular Targets COBRE
administering_ic: NCRR
award_notice_date: 2011-07-08
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
program_official: CANTO, MARIA TERESA
project_start_date: 2003-09-01
project_end_date: 2013-06-30
contact_pi_person_id: 1898718
contact_pi: MILLER, DONALD M.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
DESCRIPTION (provided by applicant): The University of Louisville Molecular Targets Center of Biomedical Research Excellence (MT-COBRE) is focused on identification of novel molecular targets for cancer therapy emphasizing structural biologic approaches for development of novel therapeutics. The overall objective of the MT-COBRE is to recruit and ensure the success of junior investigators who are members of the Molecular Targets Program at the UofL's Brown Cancer Center. We have made considerable progress towards accomplishment of the goals of the original application during the first five year funding period. Four of the original five COBRE scientists have received NIH R01 funding the fifth was encouraged to pursue other directions. Five outstanding new scientists have taken their places three of whom have NIH R01 applications under review or being revised for resubmission. We have been quite fortunate during the initial funding period to have retained all of the MT-COBRE faculty. We have leveraged the MT-COBRE support to create a set of effective Core Facilities which have significantly enhanced the productivity of the MT-COBRE investigators and other Brown Cancer Center scientists. The renewal application has added a new Core the Biophysics Core Facility and deleted a Core which was underutilized the Proteomics Core Facility. The specific aims of the proposal are to: 1. develop successful independent research careers for each of the principal investigators that will lead to independent R01 grants. 2. develop core facilities that will enhance the research capability of the principal investigators and the other members of the MT program. 3. continue to develop the Molecular Targets Program as a cohesive research program which will enhance collaborative research projects and funding opportunities. 4. develop a nationally and internationally recognized program which will attract the very best graduate students postdoctoral fellows and additional faculty. 5. make discoveries leading to new and more effective treatments for patients with cancer. During the next funding period the MT-COBRE will utilize focused recruitment to enhance the scope of the program. Funding of this renewal application is critically important to allow the program to achieve its potential. Based on its current faculty and projected growth during the next funding period this program is poised to become one of the nation's premiere cancer drug development programs.


application_id: 8132938
project_number: 5R01AG034605-03
project_title: Hippocampal Electrophysiology and Myelinogenesis in Healthy Cognitive Aging
administering_ic: NIA
award_notice_date: 2011-08-11
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;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;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


application_id: 8132285
project_number: 5R44HL090055-05
project_title: Development of a Personalized Medicine Interface for the Safe and Effective Treat
administering_ic: NHLBI
award_notice_date: 2011-08-16
opportunity_number: PA-09-080
application_type: 5
activity_code: R44
ic: HL
serial_number: 090055
program_official: PUCIE, SUSAN
project_start_date: 2007-08-16
project_end_date: 2013-07-31
study_section: Special Emphasis Panel[ZRG1-IMST-E(15)B]
contact_pi_person_id: 8776872
contact_pi: REYNOLDS, KRISTEN KEELING
other_pis: LINDER, MARK W;VALDES, ROLAND
congressional_district: 03
department: Unavailable
primary_duns: 135412190
duns_number: 135412190
fips: US
organization_id: 10011008
organization_name: PHARMACOGENETICS DIAGNOSTIC LABORATORIES
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-08-01
budget_end_date: 2012-07-31
project_abstract:
DESCRIPTION (provided by applicant):   
Improvements in the safety and efficacy of warfarin therapy will result from intelligent application of knowledge derived from inherited characteristics (CYP2C9 and VKORC1) of individual patients only when this knowledge is applied through a standardized interventional approach. The fundamental pharmacologic influences of CYP2C9 and VKORC1 have been unequivocally established and validated by numerous academic reports including those conducted by PGXL and its affiliated thought leaders. There is a clear cause and effect relationship between inherited variation in these enzymes and complications in warfarin management. Delayed metabolic clearance of S-warfarin (CYP2C9) and a lower concentration threshold for response (VKORC1) have a profound effect on the clinical pharmacology of warfarin and defeat the utility of standard dosing and monitoring practices. Current warfarin dosing practices which rely on standardized initiation dosing and INR-based dose adjustments are fundamentally flawed when applied to patients without regard to their unique metabolic and response characteristics. PGXL has developed a personalized medicine interface (PerMIT) which provides interpretive genotype-based guidance to facilitate appropriate clinical practice modifications accommodating patient individuality. PerMIT:Warfarin is the first HIPAA-compliant and secure pharmacogenetics-based interventional methodology for warfarin anticoagulation management. PerMIT:Warfarin applies fundamental pharmacologic influences of inherited patient characteristics to individually tailor warfarin therapy. The mathematical operations that form the basis of PerMIT have been validated for accuracy and PGXL is now prepared for prospective interventional trials. PGXL Laboratories has engaged all of the key external resources necessary to construct a comprehensive strategic framework to gather compelling clinical evidence of improved outcomes and to move PerMIT:Warfarin through the regulatory and commercialization processes. This SBIR Phase II Competitive Renewal application is designed to achieve the regulatory compliance and medical evidentiary standards set forth by federal regulatory bodies and the demands of the marketplace.  
  
PUBLIC HEALTH RELEVANCE:   
Individualised therapeutic management based on pharmacogenetic information requires a standardized interventional approach. PerMIT:Warfarin is the first pharmacogenetics-based interventional methodology for warfarin anticoagulation management. PerMIT:Warfarin is a Class II device under FDA classification regulation 21 CFR 864.7750. The Center for Medicare and Medicaid Services (CMS) has established a standard for warfarin pharmacogenetics reimbursement calling for multi-site randomized controlled trials to assess the benefit of pharmacogenetics to warfarin therapeutic management. This SBIR Phase II Competitive Renewal application is designed to achieve the regulatory compliance and medical evidentiary standards set forth by these regulatory bodies.

project_terms:
Address;Anticoagulation;CYP2C9 gene;Characteristics;Classification;Clinical;Clinical Pharmacology;Collaborations;Computational algorithm;Computer software;Consult;Development;Devices;Dose;Enrollment;Enzymes;Feedback;Funding;Genotype;Health Care Costs;Health Insurance Portability and Accountability Act;Individual;Individuality;Inherited;Institutional Review Boards;Intellectual Property;Knowledge;Laboratories;Medical;Medicine;Metabolic;Methodology;Modification;Monitor;Online Systems;Outcome;Patients;Pharmacogenetics;Phase;Process;Randomized Controlled Trials;Records;Regulation;Reporting;Resources;Safety;Secure;Site;Small Business Innovation Research Grant;Software Design;Software Validation;System;Test Result;Testing;Therapeutic;Time;Translating;United States Centers for Medicare and Medicaid Services;United States National Institutes of Health;Universities;Variant;Warfarin;base;clinical practice;commercialization;design;improved;operation;pharmacogenetic testing;programs;prospective;public health relevance;response;standard of care;usability

public_health_relevance:
Project NarrativeIndividualised therapeutic management based on pharmacogenetic information requires astandardized interventional approach. PerMIT:Warfarin is the first pharmacogenetics-basedinterventional methodology for warfarin anticoagulation management. PerMIT:Warfarin is aClass II device under FDA classification regulation 21 CFR 864.7750. The Center for Medicareand Medicaid Services (CMS) has established a standard for warfarin pharmacogeneticsreimbursement calling for multi-site randomized controlled trials to assess the benefit ofpharmacogenetics to warfarin therapeutic management. This SBIR Phase II CompetitiveRenewal application is designed to achieve the regulatory compliance and medical evidentiarystandards set forth by these regulatory bodies.


application_id: 8131944
project_number: 2R01AG019223-07A1
project_title: Ceramide and acute phase protein elevation during aging
administering_ic: NIA
award_notice_date: 2011-07-29
opportunity_number: PA-10-067
application_type: 2
activity_code: R01
ic: AG
serial_number: 019223
suffix: A1
program_official: GUO, MAX
project_start_date: 2002-08-01
project_end_date: 2016-07-31
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 6730250
contact_pi: NIKOLOVA-KARAKASHIAN, MARIANA 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
project_abstract:
DESCRIPTION (provided by applicant): Our lab has a long standing interest in the mechanisms leading to the state of chronic low-grade inflammation which is an intrinsic component of the aging process and many aging-associated diseases. In the past we reported that the hepatic response to Interleukin 12 (IL-12) a major mediator of systemic inflammation is augmented during aging leading to excessive production of IGFBP1 a protein that is secreted by the liver binds to the Insulin-like Growth Factor 1 (IGF1) and neutralizes its bioactivity. Hepatic IL-12 hyperresponsiveness is caused by the intrinsic activation of an evolutionary conserved cellular stress response pathway involving neutral sphingomyelinase and its product ceramide.  Here we hypothesize that this IL-12 hyperresponsiveness impairs the insulin signaling pathway in liver. First we will investigate how aging-associated IL-12 hyperresponsiveness affects the insulin pathway and will study the interactions between key molecules in the two cascades PI3K Akt-1 and Foxo1 (for insulin) and ceramide IRAK-1 and JNK (for IL-12). Studies will be done in isolated hepatocytes in vitro and in animals in vivo. Young aged and aged calorie restricted rats will be used. The regulation of IGFBP1 mRNA transcription by the two pathways will be investigated. These molecular studies will be complemented by assays of insulin- and IGFBP1-dependent functions in vivo which include tests of IGF1 bioactivity muscle functions and glucose regulation. Throughout the experiments cause and effect relations will be tested by overexpression and silencing approach using adenovirus-mediated gene transfer. These studies may help to elucidate the cellular and molecular pathways responsible for muscle waste frailty and glucose dysregulation in the elderly. They may also reveal a novel mechanism for integration of inflammatory and metabolic signaling pathways and how aging affects these interactions. )  
  
PUBLIC HEALTH RELEVANCE: Understanding the mechanisms that dysregulate liver functions during aging is very important for improving the health of older Americans because liver plays critical role in many functions including glucose homeostasis innate immune response drug metabolism etc.).

project_terms:
Acute-Phase Proteins;Adenoviruses;Affect;Aging;Aging-Related Process;American;Animals;Arthritis;Attenuated;Binding (Molecular Function);Biological Assay;Caloric Restriction;Cell membrane;Cells;Cellular Stress Response;Ceramides;Chronic;Complement;Disease;Dose;EMSA;Effectiveness;Elderly;Environment;Event;Exhibits;Funding;Gene Transfer;Genetic Transcription;Glucose;Goals;Health;Hepatic;Hepatocyte;IGF1 gene;Immune response;Impairment;In Vitro;Indium;Inflammation;Inflammatory;Insulin;Insulin Signaling Pathway;Insulin-Like Growth Factor I;Insulin-Like Growth-Factor Binding Protein 1;Interleukin-12;Interleukins;Life;Link;Lipids;Liver;Longevity;Luciferases;MAPK8 gene;Mammals;Mediating;Mediator of activation protein;Messenger RNA;Metabolic;Molecular;Monitor;Muscle;Muscle function;Non-Insulin-Dependent Diabetes Mellitus;Organism;Pathway interactions;Phosphoenolpyruvate Carboxylase;Phosphorylation;Phosphotransferases;Play;Production;Promotor (Genetics);Protein Binding;Proteins;Rattus;Regulation;Reporting;Role;Serum;Signal Pathway;Signal Transduction;Sphingomyelinase;Testing;Tissues;Ubiquitination;Up-Regulation (Physiology);Work;Wound Healing;aged;blood glucose regulation;cytokine;drug metabolism;frailty;glucose tolerance;improved;in vivo;insulin sensitivity;insulin signaling;interest;juvenile animal;liver function;novel;overexpression;receptor;research study;response;sarcopenia;small hairpin RNA;success;transcription factor;wasting


application_id: 8131644
project_number: 5R44RR025738-03
project_title: Creation of hyperactive transposons for mutagenesis in rodents
administering_ic: NCRR
award_notice_date: 2011-09-17
opportunity_number: PA-09-080
application_type: 5
activity_code: R44
ic: RR
serial_number: 025738
program_official: O'NEILL, RAYMOND R
project_start_date: 2010-09-01
project_end_date: 2013-09-15
study_section: Special Emphasis Panel[ZRG1-IMST-B(16)B]
contact_pi_person_id: 3075176
contact_pi: OSTERTAG, ERIC M
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: N
budget_start_date: 2011-09-16
budget_end_date: 2013-09-15
project_abstract:
DESCRIPTION (provided by applicant): The rat is a favored model for many types of human disease for which mice are not suitable. As opposed to the mouse rats and humans also share more similarity in their cytochrome P450 genes making the rat a more useful model for toxicology and pharmacology studies. The rat is also a favored model for diabetes arthritis behavioral disorders (including drug addiction) and brain imaging. However until recently generating engineered mutations has been problematic due to the lack of rat stem cell lines capable of contributing to the germ line and the lack of efficient technologies to modify genomic sequences. Transposagen Biopharmaceuticals has pioneered the use of mobile DNA elements (e.g. transposons) to generate insertional mutations in the rat germ line. To date we have over made over 100 insertional mutant lines (referred to as TKOTM Knockout Rat Models). This approach utilizes gene-trap strategies to select for randomly integrated transposons which enable the rapid identification of sequence-tagged mutation sites. In Phase I studies we focused on synthesizing hyperactive transposases from three different families of transposons Sleeping Beauty (SB) piggyBac (PB) and TcBuster (TcB) to increase the efficiency of transposition in the germ line. We report the successful generation of a number of hyperactive transposases in the PB family. In Phase II studies we will generate a rat embryonic stem (rES) cell bank containing over 200000 dual reporter gene-trap insertional mutations; a EGFP reporter system will be used as a polyA trap to maximize the probability of generating insertional mutations in each of the approximately 30000 rat genes and a promoterless tdTomato reporter to screen for lineage-specific gene disruptions. In the long term we intend to use the rES cell bank to generate rat knockout lines in each locus. In Phase II studies we will focus on developing transposon-mediated knockout lines in neural cardiac and endothelial cell lineages using the hyperactive PB transposases created in Phase I studies with the aim of generating a bank of knockout lines that that will be valuable for a wide variety of applications such as toxicology behavioral and cardiovascular research. We will develop high-throughput in vitro differentiation protocols to screen pools of rES cells cultured in 96-well formats. Potential mutations in neural cardiac and endothelial cell lineages will be identified by screening for wells that contain tdTomato positive cells after lineage-specific differentiation protocols. rES cell pools in positive wells will be subcloned and re-screened to identify the individual clone that carries the potential lineage specific mutation. Genomic DNA will be isolated and used as template for splinkerette PCR which is used routinely to amplify sequences that flank DNA insertions. We will determine the genomic sites for each insertion and screen each gene for lineage-specific expression to rule out insertions that affect ubiquitously expressed loci. We will develop two products for academic and pharmaceutical end users. First we will generate chimeric animals from selected rES cell clones by injecting these cells into host blastocysts and segregate away the "irrelevant" mutations by several rounds of backcrosses to generate additional TKOTM Knockout Rat Models for human diseases. Second we will market rES cell clones containing mutations in genes that are beyond our core interests to academic and pharmaceutical end users. Mutant animals sperm isolated from mutant males and mutant rES cells will be distributed by the National Rat Resource and Research Center and shared with the academic community according to NIH policies for sharing model organisms for biomedical research.  
  
PUBLIC HEALTH RELEVANCE: In the application "Creation of hyperactive transposases for mutagenesis in rodents" we are seeking Phase II funding to use the novel transposases we created to generate new models of human disease. We have demonstrated the value of creating transposon-mediated mutations to model human diseases for basic and therapeutic research application. All of our previous models were obtained by random mutagenesis. In this proposal we outline studies that will enable us to identify transposon mediated mutations that will likely affect neural heart or blood vessel function. Such rat models will provide new and valuable tools to develop new therapies in classes of diseases that are particularly prevalent in humans. Thus if successful this project would benefit many goals of public health by making the production of mutations in the rat that model human diseases readily accessible to the research community.

project_terms:
Address;Affect;Animal Model;Animals;Arthritis;Backcrossings;Basic Science;Behavior Disorders;Behavioral;Biological Products;Biomedical Research;Blood Vessels;Brain imaging;Cardiac;Cardiovascular system;Cataloging;Catalogs;Cell Count;Cell Culture Techniques;Cell Differentiation process;Cell Line;Cell Lineage;Cell Separation;Cells;Characteristics;Code;Communities;Complement;Cryopreservation;Cytochrome P450;DNA;DNA Sequence;DNA Transposons;DNA analysis;Data;Defect;Derivation procedure;Diabetes Mellitus;Disease;Drug Addiction;Elements;Eligibility Determination;Embryo;Endothelial Cells;Engineering;Enhancers;Event;Exhibits;Family;Funding;Gene Expression;Generations;Genes;Genomics;Germ Lines;Goals;Heart;Hour;Housekeeping Gene;Human;In Situ;In Vitro;Individual;Knock-out;Lead;Libraries;Marketing;Mediating;Modeling;Molecular Profiling;Mus;Mutagenesis;Mutate;Mutation;Nature;Neurons;Noise;Pharmacologic Substance;Pharmacology and Toxicology;Phase;Phenotype;Plasmids;Policies;Population;Probability;Production;Protocols documentation;Publishing;Quality Control;Rattus;Reporter;Reporter Genes;Reporting;Research;Resources;Rodent;Screening procedure;Seeds;Site;Sleeping Beauty;Sorting - Cell Movement;Southern Blotting;Stem cells;System;Technology;Therapeutic Human Experimentation;Tissues;Toxicology;Transfection;Transposase;United States National Institutes of Health;blastocyst;cell bank;controlled release;drug discovery;embryonic stem cell;falls;high throughput analysis;high throughput screening;human disease;in vivo;insight;interest;male;mutant;novel;phase 1 study;phase 2 study;public health medicine (field);public health relevance;rat genome;relating to nervous system;research study;sperm cell;stem;stem cell differentiation;stem cell technology;success;tool;transposon/insertion element;vector

public_health_relevance:
PROJECT NARRATIVEIn the application "Creation of hyperactive transposases for mutagenesis in rodents" we are seeking Phase IIfunding to use the novel transposases we created to generate new models of human disease. We havedemonstrated the value of creating transposon-mediated mutations to model human diseases for basic andtherapeutic research application. All of our previous models were obtained by random mutagenesis. In thisproposal we outline studies that will enable us to identify transposon mediated mutations that will likely affectneural heart or blood vessel function. Such rat models will provide new and valuable tools to develop newtherapies in classes of diseases that are particularly prevalent in humans. Thus if successful this projectwould benefit many goals of public health by making the production of mutations in the rat that model humandiseases readily accessible to the research community.


application_id: 8131612
project_number: 5R01HL091202-04
project_title: The SDF1-CXCR4 Axis in Cardiac Homeostasis and Regeneration
administering_ic: NHLBI
award_notice_date: 2011-06-03
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 091202
program_official: SCHWARTZ, LISA
project_start_date: 2008-09-01
project_end_date: 2013-05-31
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF-S]
contact_pi_person_id: 7033203
contact_pi: ROKOSH, GREGG
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 prospect of a cell based therapy for cellular regeneration and functional recovery of the heart was realized with the discovery that stem cells can contribute to myocyte formation in the adult and that these stem cells may also participate in the repair of the heart after injury. It is now clear the heart has inherent regenerative capacity however it is also clear that this capacity is limited. Transplantation of mesenchymal stem cells into patients evokes a reproducible increase in function and provides insight into the potential of this therapeutic approach. To date little is known of the systems that create and maintain the inherent cardiac stem cells (CSC) and how they participate in day to day function and homeostasis or during and after injury. Stromal cell derived factor 11 (SDF1) and its receptor CXCR4 are key components of the biological system that regulates hematopoiesis and hematopoietic stem cells. We have found this SDF1-CXCR4 axis in the heart and both are expressed on myocytes and fibroblasts and are functionally coupled to MAPK and AKT signaling that serves a survival function in vitro and in vivo against ischemia reperfusion injury. Both SDF1 and CXCR4 knockouts are embryonic lethal with cardiac defects. These novel findings serve to provide the basis for our hypothesis that the cardiac SDF1-CXCR4 axis plays a role in cardiac homeostasis through the action on cardiac stem cells myocytes and fibroblasts. Myocyte and fibroblast expression of SDF1 and CXCR4 are proposed to serve a similar function for cardiac stem cell maintenance and protection (niche formation) as stromal and osteoblasts do in the bone marrow. The effectiveness of this system in protecting and maintaining the myocardium with stress or injury is limited due to attenuated SDF1-CXCR4 signaling by desensitization of SDF1-CXCR4 signaling. We propose this effectiveness may be increased by increasing the number of receptors and/or limiting desensitization of SDF1- CXCR4 signaling. The following Aims seek to further define the role of the SDF1-CXCR4 axis in cardiac homeostasis and regeneration and to determine how CSC function in cardiac regeneration can be enhanced through optimization of CXCR4 signaling as a cell based therapy in cardiac injury. Aim 1: To determine the role that cardiac SDF1-CXCR4 plays in maintaining cardiac homeostasis in myocyte myofibroblast and cardiac stem cells. Aim 2: To determine how desensitization/downregulation of SDF1-CXCR4 signaling limits the functionality of cardiac stem cells. Aim 3: To determine whether increasing signaling and signaling efficacy through the SDF1-CXCR4 axis in cardiac stem cells facilitates increased regenerative capacity by administration early and late after MI and IR injury. Aim 4: To determine whether SDF1-CXCR4 synergizes with HGF-cMET and IGF1-IGFR signaling systems to increase functions critical to stem cell engraftment and repair of functional myocardium. The seminal finding that the heart contains a population of stem cells that can contribute to repair of the injured heart has provided new hope for a cell based therapy for cardiac repair. The research described in this proposal will advance our understanding of and provide mechanistic insight into inherent cardiac systems that regulate the function of cardiac stem cells and their relationship with cardiac muscle and supporting cells. Results from these mechanistic studies will provide the impetus to design novels strategies to overcome inherent limitations of cardiac stem cell participation in cardiac regeneration after cardiac injury or with disease.

project_terms:
Activities of Daily Living;Acute;Address;Adult;Area;Arrestins;Attenuated;Bone Marrow;CXCR4 Receptors;CXCR4 gene;Cardiac;Cardiac Myocytes;Cell Maintenance;Cell Therapy;Cell physiology;Cells;Chemotactic Factors;Chemotaxis;Chronic;Cicatrix;Clear Cell;Congenital Heart Defects;Coupled;Cytoprotection;Disease;Down-Regulation;Effectiveness;Embryo;Engraftment;Environment;Fibroblasts;Functional disorder;G-Protein-Coupled Receptors;GRK6 gene;GTP-Binding Protein Regulators;GTP-Binding Proteins;GTPase-Activating Proteins;Growth Factor Receptors;Heart;Hematopoiesis;Hematopoietic;Hematopoietic stem cells;Homeostasis;Homing;IGF1 gene;IGF1R gene;In Vitro;Infarction;Infection;Inflammatory;Injury;Ischemia;Knock-out;Knockout Mice;Lead;MAP Kinase Gene;Maintenance;Mediating;Mesenchymal Stem Cell Transplantation;Modeling;Mus;Muscle Cells;Myocardial;Myocardial Infarction;Myocardium;Myofibroblast;Natural regeneration;Osteoblasts;Patients;Perception;Phosphotransferases;Play;Process;Proto-Oncogene Proteins c-akt;Rattus;Recovery of Function;Recruitment Activity;Reperfusion Injury;Reperfusion Therapy;Research;Role;Seminal;Signal Transduction;Site;Stem cells;Stress;Stromal Cell-Derived Factor 1;Stromal Cells;Supporting Cell;System;Testing;Therapeutic;Tissues;Transgenic Organisms;Transplantation;adult stem cell;attenuation;autocrine;base;biological adaptation to stress;biological systems;cell type;chemokine;desensitization;design;flexibility;improved;in vivo;injured;insight;novel;novel strategies;novel therapeutics;overexpression;paracrine;progenitor;protein function;receptor;regenerative;repaired;residence;response;response to injury;stem cell niche;stem cell population;therapy development;tissue regeneration;trafficking


application_id: 8131585
project_number: 5R43AA018226-02
project_title: Selection-driven plant metabolites for treatment of CNS diseases
administering_ic: NIAAA
award_notice_date: 2011-08-15
opportunity_number: PA-08-071
application_type: 5
activity_code: R43
ic: AA
serial_number: 018226
program_official: EGLI, MARK
project_start_date: 2010-08-20
project_end_date: 2012-11-30
study_section: Special Emphasis Panel[ZRG1-ETTN-C(11)B]
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): The primary aim is to transfer a biotechnology platform for plant drug discovery from the academic laboratory to industry use (i.e. this application is directly responsive to the "lab to marketplace" roadmap program). Many "defensive" metabolites in plants are targeted on key proteins in the insect CNS and homology between these and human proteins makes such metabolites potentially valuable as CNS drugs. These plant metabolites evolved in response to natural selection and so an imposed selection pressure should direct plant secondary metabolism toward more effective drugs. One way this could be achieved is by the expression of a human target protein linked to a toxic mechanism in plant cells. Now cells which are producing inhibitors of this protein are more likely to survive and repeated mutagenesis and selection should direct "evolution" toward increasingly effective inhibitors. For example the human dopamine transporter (hDAT) is a molecular target in drug dependence and neurodegenerative disease. Expression of the functional hDAT in plant cells (Preliminary studies) makes these susceptible to neurotoxins (MPTP 6hydroxydopamine) which are transported by the hDAT. Conversely the selective DAT inhibitor GBR12909 protects these cells. Therefore in a mutant population transgenic hDAT plant cells that survive these toxins should be "enriched" in clones which over-produce metabolites that inhibit the hDAT or protect against the neurotoxins in some other way. Both would be of potential therapeutic value. To identify a species for this approach extracts from ~1000 native plants were screened for relevant activity. This identified Lobelia cardinalis as the best candidate and this species is also easy to culture and transform making it ideal for proof of application. A population of transgenic hDAT L. cardinalis hairy roots mutagenized by activation tagging has now been subjected to MPTP selection. The proposal for phase 1 is to screen the resistant mutant sub-population for the presence of metabolites which inhibit the DAT in rat brain synaptosomes or protect a human dopaminergic cell line against neurotoxins. Positive clones (phase 1 deliverables) will be used in phase 2 for compound identification assessment of potential therapeutic value in complex models and for regeneration into mutant medicinal plant lines. All of these products have potential commercial value but it is the illustration of the general value of the technology and its transfer from lab to marketplace which is of most commercial value to the company.  
  
PUBLIC HEALTH RELEVANCE: Plants remain a very valuable source of complex bioactive compounds but current methods of plant drug discovery do not compete with the pharmaceutical industry techniques of combinatorial chemistry and high throughput pharmacological screening. This proposal uses a novel biotechnology approach to the directed evolution and discovery of plant metabolites with potential value in human CNS diseases. These are among the most devastating and economically important diseases in the USA and world wide. The proposal focuses on potential medications for drug dependence and alcoholism as well as for neurodegenerative conditions including psychostimulant-induced neurotoxicity and diseases associated with aging including parkinsonism and Parkinson's Disease (the second most common neurodegenerative disease in the US). The technology to be used combines plant molecular biology and molecular pharmacology and its support will accelerate the introduction of this academic research into the commercial sector. Its simplicity and rapidity suggests that it may compete with the existing synthetic chemistry approaches and might even revitalize the use of plants as a source of medicines for CNS disease.

project_terms:
1-Methyl-4-phenylpyridinium;Aging;Agonist;Agrobacterium;Alcoholism;Animal Model;Biological Factors;Biotechnology;Brain;Businesses;Carrier Proteins;Cell Death;Cell Line;Cell model;Cells;Central Nervous System Diseases;Combinatorial Chemistry Techniques;Commercial Sectors;Complex;Contracts;Disease;Dopaminergic Cell;Drug Addiction;Drug Industry;Enzymes;Exposure to;Foundations;Free Radical Scavengers;Human;Ilex vomitoria;Individual;Industry;Insecta;Intellectual Property;Investigation;Killings;Laboratories;Licensing;Link;Lobelia;Mediating;Medicinal Plants;Medicine;Metabolism;Methods;Modeling;Molecular;Molecular Biology;Molecular Target;Mutagenesis;N-Methyl-D-Aspartate Receptors;Natural Selections;Natural regeneration;Nerve Degeneration;Neuroblastoma;Neurodegenerative Disorders;Neurons;Neurotoxins;Nicotinic Receptors;Oxidopamine;Parkinson Disease;Parkinsonian Disorders;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Phase;Phenotype;Plant Roots;Plants;Population;Production;Proteins;Rattus;Research;Resistance;Screening procedure;Small Business Innovation Research Grant;Source;Synaptosomes;Synthesis Chemistry;Technology;Therapeutic;Therapeutic Agents;Toxic effect;Toxin;Transfection;Transgenic Organisms;Transgenic Plants;design;directed evolution;dopamine transporter;dopaminergic neuron;drug discovery;gain of function mutation;inhibitor/antagonist;link protein;mutant;neurotoxicity;novel;pressure;prevent;programs;protein activation;psychostimulant;public health relevance;receptor;research and development;response;stimulant abuse;success;uptake

public_health_relevance:
Project narrative (unchanged)Plants remain a very valuable source of complex bioactive compounds but current methods of plant drugdiscovery do not compete with the pharmaceutical industry techniques of combinatorial chemistry and highthroughput pharmacological screening. This proposal uses a novel biotechnology approach to the directedevolution and discovery of plant metabolites with potential value in human CNS diseases. These are amongthe most devastating and economically important diseases in the USA and world wide. The proposal focuseson potential medications for drug dependence and alcoholism as well as for neurodegenerative conditionsincluding psychostimulant-induced neurotoxicity and diseases associated with aging including parkinsonismand Parkinson's Disease (the second most common neurodegenerative disease in the US). The technology tobe used combines plant molecular biology and molecular pharmacology and its support will accelerate theintroduction of this academic research into the commercial sector. Its simplicity and rapidity suggests that itmay compete with the existing synthetic chemistry approaches and might even revitalize the use of plants as asource of medicines for CNS disease.


application_id: 8131535
project_number: 261201000031C-1-0-1
project_title: TAS::75 0849::TAS SURVEILLANCE EPIDEMIOLOGY AND END RESULTS (SEER) PROGRAM
administering_ic: NCI
project_start_date: 2010-08-01
project_end_date: 2011-09-29
contact_pi_person_id: 11064694
contact_pi: TUCKER, THOMAS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_terms:
Cancer Burden;Cancer Control;Cancer Control Research Program;Cancer Etiology;Cancer Patient;Data;Diagnosis;Disease;Incidence;Lead;Malignant Neoplasms;Medical Surveillance;Monitor;National Cancer Institute;National Cancer Program;Patients;Population;Procedures;Reporting;Resources;SEER Program;Social Characteristics;Subgroup;Time;Treatment-Related Cancer;United States;base;cancer risk;cancer therapy;cost;improved;operation;population based;programs;response;trend


application_id: 8131312
project_number: 1R01HL108621-01
project_title: Mitophagic and anti-angiogenic mechanism of heart failure
administering_ic: NHLBI
award_notice_date: 2011-04-15
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: HL
serial_number: 108621
program_official: ADHIKARI, BISHOW B
project_start_date: 2011-04-15
project_end_date: 2015-12-31
study_section: Special Emphasis Panel[ZRG1 VH-B (02)]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Although heart failure is inevitable disease its management depends on the understanding of the mechanism of ailing to failing myocardium. During heart failure the heart undergoes compensatory remodeling (i.e. left ventricle hypertrophy (LVH) and vascular angiogenesis. Unfortunately during end-stage heart failure there is dis-coordination between the LVH and angiogenesis (i.e. LVH persists but angiogenesis declines). This leads to continue increase in LV wall stress leading to failure. Remodeling by its very nature implies synthesis degradation and re-arrangement of intra and inter cellular matrix. Matrix metalloproteinases (MMPs) are designer architecture and tailor. The long-term goal of this project is to understand the differential role of MMPs in structural and functional heterogeneity in myocardial remodeling. The selective MMP-2 gene ablation reduces survival and exacerbates cardiac failure-induced by myocardial inflammation. MMP-9 gene ablation is cardioprotective. In human heart end-stage failure MMP-9 activation supersedes the MMP-2 activation. The hypothesis of this proposal is that MMP-2 is constitutive and during compensatory phase activates proteinase activated receptor-1 (PAR-1 a GPCR) and releases growth factors via the activation of anti-stress (PKB/AKT). Chronic stress leads to mitochondrial mitophagy and activation of MMP-9 and MMP-13 (an interstitial collagenase in rodent and MMP-1 in human). TIMP-3 (an apoptotic/autophagic factor) and anti-angiogenic statins are released The hypothesis will be tested by following three specific aims: Specific Aim #1: To determine whether the induction of MMP-2 PAR-1 G1s and AKT causes compensatory hypertrophy and mitochondrial mitophagy causes MMP-9 activation and decreases G1s and AKT in de-compensatory heart failure. Specific Aim #2: To determine whether the MMP-2 releases angiogenic growth factors during compensatory remodeling and MMP-9 releases anti-angiogenic statins in de-compensatory heart failure. Specific Aim #3: To determine whether the mitochondrial mitophagy attenuates angiogenesis in part by activating MMP-9 releasing TIMP-3 and generating statins during de-compensatory heart failure. These studies will delineate the causative role of PAR-1 MMP TIMP G1s and mitophagy in switch from compensatory LVH and angiogenesis to de-compensatory LVH and anti-angiogenesis and will have therapeutic ramifications for chronic heart failure.  
  
PUBLIC HEALTH RELEVANCE: These studies will delineate the differential role of mitochondrial mitophagy and anti- angiogenesis mechanisms in end-stage heart failure. The differential role of different MMPs in angiogenesis and anti-angiogenesis in transition from compensatory hypertrophy to de-compensatory heart failure will be determined. The positive outcome of this project will have therapeutic ramifications for chronic heart failure.

project_terms:
Ablation;Address;Angiography;Angiostatins;Antibodies;Apoptotic;Architecture;Attenuated;Autophagocytosis;Barium;Biological Assay;Blood Vessels;Blood flow;Cardiac;Chronic;Chronic stress;Cytoskeleton;DNA;Disease;Endostatins;Enzyme-Linked Immunosorbent Assay;Failure (biologic function);Fibroblast Growth Factor;G-Protein-Coupled Receptors;Gelatinase A;Gelatinase B;Genes;Goals;Growth Factor;Heart;Heart failure;Heterogeneity;Human;Hypertrophy;In Situ Nick-End Labeling;Inflammation;Interstitial Collagenase;Lasers;Left Ventricular Hypertrophy;Left ventricular structure;Matrix Metalloproteinases;Measures;Mitochondria;Mus;Myocardial;Myocardium;Nature;Outcome;Oxygen Consumption;PAR-1 Receptor;Pathogenesis;Pathway interactions;Phase;Protein Array;Proto-Oncogene Proteins c-akt;Rodent;Role;Small Interfering RNA;Staging;Stress;Testing;Therapeutic;Tissue Inhibitor of Metalloproteinase-1;Tissue Inhibitor of Metalloproteinase-3;Tissue Inhibitor of Metalloproteinases;Transforming Growth Factor beta;Vascular Endothelial Growth Factors;Ventricular Remodeling;angiogenesis;antiangiogenesis therapy;collagenase 3;constriction;density;in vivo;inhibitor/antagonist;matrigel;tissue inhibitor of metalloproteinase 4

public_health_relevance:
These studies will delineate the differential role of mitochondrial mitophagy and anti- angiogenesis mechanisms in end-stage heart failure. The differential role of different MMPs in angiogenesis and anti-angiogenesis in transition from compensatory hypertrophy to de-compensatory heart failure will be determined. The positive outcome of this project will have therapeutic ramifications for chronic heart failure.


application_id: 8130872
project_number: 5P20RR020171-08
project_title: Center for Biomedical Research Excellence in the Molecular Basis of Human Disease
administering_ic: NCRR
award_notice_date: 2011-07-11
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
program_official: CANTO, MARIA TERESA
project_start_date: 2004-09-01
project_end_date: 2014-06-30
study_section: ZRR1-RI-B(01)
contact_pi_person_id: 7875201
contact_pi: LOUIS HERSH, LOUIS HERSH LOUIS HERSH
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal builds upon the accomplishments made during the previous funding period and requests continuing support of COBRE the Center of Biomedical Research Excellence in the Molecular Basis of Human Disease. During the four year period this COBRE grant has been active 22 junior faculty from 9 different departments were mentored of which 8 received NIH R01 funding and an additional 4 received Other forms of extramural funding. Participating in the activities of the Center has been an additional 11 faculty 11 postdoctoral/research associates and 9 graduate students. The members of the Center published more than 175 research papers and made 38 presentations at scientific meetings. The Department of Molecular and Cellular Biochemistry in which the COBRE is housed rose from 28th to 12th in NIH rankings in terms of Public Medical Schools and 26th in terms of all Medical Schools during the tenure of the COBRE. This was accomplished by an increase in $5148302 of NIH grant dollars excluding the COBRE funds. The Center for Molecular Medicine was formed in 2007 as a direct consequence of the accomplishments made during the first phase of the COBRE (Aug 2004- July 2009).  
  
In the second phase of this COBRE we propose to establish a nationally and internationally recognized  
research center that will continue to compete effectively for extramural research funding. To accomplish this we propose i) to expand our critical mass of investigators including the mentoring of an additional 5  
promising junior investigators who are studying the molecular basis of human disease. This will include a targeted new recruit to the University. We will enhance the opportunity to translate their research to patients by facilitating interactions with clinical faculty. We will continue with the major focus in cancer diabetes and neurological diseases ii) We will expand and continue to develop our core facilities in Proteomics Chemistry Microscopy Protein characterization and Mouse Genotyping. iii) We will continue to support pilot research projects. This has been a highly effective way to enhance the research of a rather significant number of junior faculty; iv) facilitate the development of a sustainable center through the submission of program project grants and multi-PI grants. We will provide staff resource and pilot funding to enhance these activities.  
  
PUBLIC HEALTH RELEVANCE (provided by applicant): To enhance the competitiveness of junior faculty at the University of Kentucky through the funding of promising junior faculty and providing state-of-the-art research cores.

public_health_relevance:
To enhace the competitiveness of junior faculty at the University of Kentucky throught the funding of
promising junior faculty and providing state-of-the-art research cores.


application_id: 8130538
project_number: 5F31AA018584-03
project_title: Alcohol Sensitivity and Abuse Potential in ADHD
administering_ic: NIAAA
award_notice_date: 2011-08-15
application_type: 5
activity_code: F31
ic: AA
serial_number: 018584
program_official: MATOCHIK, JOHN A
project_start_date: 2009-09-27
project_end_date: 2012-07-20
study_section: Epidemiology, Prevention and Behavior Research Study Section[AA-2]
contact_pi_person_id: 9711222
contact_pi: WEAFER, JESSICA J
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-09-27
project_abstract:
DESCRIPTION (provided by applicant): There is considerable evidence that externalizing disorders such as ADHD increase risk for alcohol and other drug use. ADHD is characterized by disinhibited or undercontrolled behavior and attention and these deficits in control are suspected to contribute to the increased risk for alcohol abuse in this population. Further alcohol itself is well-known for its acute impairing effects on cognitive processes involved in the regulation of behavior and attention. Yet little research has examined how inhibitory and attentional deficits in individuals with ADHD might lead to heightened sensitivity to alcohol's acute disinhibiting effects. Because individuals with ADHD are at risk for alcohol abuse it is important to examine this potentially heightened sensitivity to the drug as well as to test how reduced control in response to alcohol might confer increased risk for abuse within this population. The proposed project will examine sensitivity to alcohol-induced increases in disinhibition and attentional bias towards alcohol-related stimuli in non-dependent adults with ADHD and a comparison group of non-dependent healthy adults as well as examine individual differences in sensitivity of these mechanisms in relation to abuse potential. The study will test the effects of controlled doses of alcohol on cognitive performance tasks that measure inhibitory control and attentional bias and examine the contribution of these measures to ad lib alcohol consumption. The findings will provide an understanding of how susceptibility to alcohol's acute behavioral-impairing effects might confer increased risk for alcohol dependence in drinkers characterized by deficits in behavioral control by promoting a continued pattern of abusive binge drinking. This will provide important information concerning mechanisms through which the acute effects of the drug contribute to its abuse potential.

project_terms:
Acute;Adult;Alcohol abuse;Alcohol consumption;Alcohol dependence;Alcohols;Attention;Attention deficit hyperactivity disorder;Attentional deficit;Behavior;Behavior Control;Behavioral;Characteristics;Cognitive;Consumption;Disease;Disinhibition;Dose;Drug usage;Goals;Heavy Drinking;Impairment;Incentives;Individual;Individual Differences;Laboratories;Lead;Link;Measures;Mentors;Modeling;Pattern;Personality;Pharmaceutical Preparations;Play;Population;Populations at Risk;Predisposition;Process;Property;Recording of previous events;Regulation;Relative (related person);Research;Risk;Role;Self Administration;Stimulus;Task Performances;Testing;alcohol and other drug;alcohol cue;alcohol effect;alcohol response;alcohol sensitivity;binge drinking;comparison group;craving;directed attention;disinhibitory psychopathology;drinking behavior;response;sobriety;social


application_id: 8130024
project_number: 1R13AI094949-01
project_title: XIIth International Nidovirus Symposium Support Proposal
administering_ic: NIAID
award_notice_date: 2011-05-27
opportunity_number: PA-10-071
application_type: 1
activity_code: R13
ic: AI
serial_number: 094949
program_official: MULACH, BARBARA L
project_start_date: 2011-06-01
project_end_date: 2012-05-31
study_section: Special Emphasis Panel[ZAI1 BDP-M (J2)]
contact_pi_person_id: 10624808
contact_pi: BALASURIYA, UDENI B. R.
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The viruses that (since 1996) constitute the taxonomic order Nidovirales (Arteriviruses Coronaviruses Toroviruses and Roniviruses) cause significant disease in humans simians a large number of livestock species poultry shrimp insects and whales. Human coronaviruses are the second leading cause of the human cold accounting for acute economic costs and the recent discovery of a previously unknown coronavirus that is now associated with Severe Acute Respiratory Syndrome (SARS) a newly emerged infectious disease in humans underpins the importance of scientific research in this field. In addition in the late 1980's porcine reproductive and respiratory syndrome virus (PRRSV) the newest member of arteriviruses family emerged in Europe and North America simultaneously and is now endemic worldwide. The emergence of these new viruses have changed the focus of nidovirus research and enticed many new investigators into this field of study. The International Nidovirus Symposium a triennial meeting is unique in bringing together scientists engaged in various aspects of nidoviruses study including molecular biology pathogenesis immunology evolution and epidemiology and vaccine development. For newcomers to this field the symposium is an excellent opportunity to obtain an overview of the most recent developments and to discuss ideas with experts in particular areas of nidovirology. Several graduate student and  th postdoctoral travel awards will be given to encourage young scientists to attend this XII International Nidovirus Symposium. In addition invited guest speakers will discuss other important research areas so that participants could update their knowledge bank and learn of new advances brought about in the larger universe of viruses.  
  
PUBLIC HEALTH RELEVANCE: The XII International Nidovirus Symposium is a high quality scientific meeting that provides a venue for virologists who are working on important group of positive stranded RNA viruses that pose a significant threat to the public health to share their research findings with other scientists from around the world. The primary objective of this symposium parallels the scientific mission of the NIH. This symposium is unique in bringing scientists together who study different aspects of nidoviruses such as molecular biology pathogenesis evolution and epidemiology immunology and vaccine development. The cost of the symposium will be covered by the registration fees and donations from private industry. However under current economic conditions obtaining donations from industry will be difficult and therefore as  th organizers of the XII International Symposium we are requesting support through this conference grant application. 1

project_terms:
Accounting;Acute;Animal Diseases;Animals;Antiviral Agents;Applications Grants;Area;Arteriviridae;Arterivirus;Asses;Award;Biology;Birds;Cells;Cellular biology;Chickens;Chiroptera;Classification;Common Cold;Communities;Coronaviridae;Coronavirus (genus);Demyelinations;Development;Diagnostic;Disease;Disease Outbreaks;Domestic Fowls;Economic Conditions;Economics;Emerging Communicable Diseases;Enteral;Epidemic;Epidemiology;Equine arteritis virus;Equus caballus;Europe;Event;Evolution;Family;Family suidae;Fees;Funding;Future;Goals;Health;Human;Immunology;Individual;Industry;Infection;Infectious bronchitis virus;Insecta;International;Knowledge;Laboratories;Lactate dehydrogenase-elevating virus;Learning;Livestock;Measures;Mediating;Messenger RNA;Michigan;Mission;Modeling;Molecular Biology;Monkey Hemorrhagic Disease Virus;Monkeys;Murine hepatitis virus;Mus;Neuraxis;Nidovirales;Nomenclature;North America;Participant;Pathogenesis;Personal Communication;Porcine respiratory and reproductive syndrome virus;Positioning Attribute;Postdoctoral Fellow;Quarantine;RNA Viruses;Research;Research Personnel;Resort;Roniviridae;Scientist;Severe Acute Respiratory Syndrome;Shrimp;Taxonomy;Therapeutic;Time;Torovirus;Transmissible gastroenteritis virus;Travel;Tropism;United States National Institutes of Health;Update;Vaccination;Veins;Viral;Viral Pathogenesis;Virus;Whales;Work;companion animal;cost;economic cost;field study;graduate student;human coronavirus;human disease;lectures;meetings;member;pathogen;posters;public health medicine (field);respiratory;structural biology;symposium;transmission process;vaccine development;virus tropism;virus virus interaction

public_health_relevance:
The XII International Nidovirus Symposium is a high quality scientific meeting that provides a venue for virologists who are working on important group of positive stranded RNA viruses that pose a significant threat to the public health to share their research findings with other scientists from around the world. The primary objective of this symposium parallels the scientific mission of the NIH. This symposium is unique in bringing scientists together who study different aspects of nidoviruses such as molecular biology pathogenesis evolution and epidemiology immunology and vaccine development. The cost of the symposium will be covered by the registration fees and donations from private industry. However under current economic conditions obtaining donations from industry will be difficult and therefore as  th organizers of the XII International Symposium we are requesting support through this conference grant application. 1


application_id: 8129995
project_number: 3R01AR045617-09S2
project_title: Intracellular signaling during skeletal muscle hypertrophy
administering_ic: NIAMS
award_notice_date: 2010-08-13
application_type: 3
activity_code: R01
ic: AR
serial_number: 045617
suffix: S2
program_official: BOYCE, AMANDA T
project_start_date: 1999-02-05
project_end_date: 2012-02-29
study_section: Special Emphasis Panel[ZRG1-MOSS-H(02)S]
contact_pi_person_id: 8263548
contact_pi: ESSER, KARYN A
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Growth and maintenance of skeletal muscle mass is critical for long-term health and quality of life. Muscle is important for mobility but it is also crucial for metabolic health because of its contribution to glucose uptake and fat metabolism. Our lab and others have demonstrated that signaling through the mammalian target of rapamycin (mTOR) is necessary for skeletal muscle growth but the molecular links between signal input and downstream function are far from understood. In our previous studies we showed that a) prolonged activation of mTOR signaling is specific to growth inducing contractions b) mechanical strain activates mTOR signaling in skeletal muscle but not in non-muscle cells c) strain-induced mTOR signaling is independent of the IGFl/insulin/PI3 kinase signaling pathways and d) cell cycle genes such as cyclin D1 and c-myc are induced during mTOR dependent growth and they likely function in the differentiated muscle cell to induce ribosomal biogenesis/protein synthesis. The overall goal of this research is to use in vitro and in vivo models of skeletal muscle growth with molecular tools to identify the necessary upstream regulators and downstream effectors of mTOR. I) mechanical strain acts synergistically with IGF1 to prolong activation of mTOR signaling and II) mTOR kinase activity is necessary for translational-regulation of critical growth mRNAs including cyclin D1 and c- myc. These hypotheses will be tested by the following specific aims: Specific Aim 1. To determine the molecular signals by which mechanical strain regulates mTOR signaling. Specific Aim 2. To demonstrate whether mechanical signaling acts synergistically with IGF1 to regulate growth-related mTOR function. Specific Aim 3. Specific Aim 3. To determine whether the kinase activity of mTOR is necessary for growth protein synthesis and increased c-myc and cyclin D1 protein levels in response to mechanical overload in vivo. The results of these studies will provide novel insight for the field of mTOR regulation and the role of mechanical strain in the growth process of skeletal muscle. The clinical implications of this work are also significant and will contribute to development of strategies to attenuate or ameliorate muscle atrophy associated with disuse aging bed rest and cachexia.

project_terms:
1-Phosphatidylinositol 3-Kinase;Ablation;Aging;Amino Acids;Area;Attenuated;Bed rest;Biogenesis;Cachexia;Clinical;Complex;Cyclin D1;Cyclins;Development;Event;Fiber;Funding;Genetic;Goals;Growth;Health;IGF1 gene;In Vitro;Incubated;Insulin;Link;Maintenance;Measures;Mechanics;Messenger RNA;Metabolic;Modeling;Molecular;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscular Atrophy;Outcome;Phosphorylation;Phosphotransferases;Process;Protein Biosynthesis;Proteins;Proto-Oncogene Proteins c-myc;Quality of life;Raptors;Regulation;Research;Research Personnel;Resistance;Ribosomal RNA;Role;Signal Pathway;Signal Transduction;Signaling Protein;Sirolimus;Skeletal muscle structure;Stretching;TSC1 gene;Testing;Transfection;Transgenic Mice;Translational Regulation;Work;c-myc Genes;cdc Genes;glucose uptake;in vivo;in vivo Model;insight;insulin receptor substrate 1 protein;knock-down;lipid metabolism;mTOR protein;muscle form;muscle hypertrophy;novel;programs;research study;response;skeletal muscle growth;tool


application_id: 8129554
project_number: 5R01DK083761-02
project_title: TGF-Beta Signaling Effectors in Prostate Growth Regulation/Tumor Progression
administering_ic: NIDDK
award_notice_date: 2011-08-18
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 083761
program_official: RANKIN, TRACY L
project_start_date: 2010-08-15
project_end_date: 2014-07-31
study_section: Special Emphasis Panel[ZRG1-DKUS-B(03)M]
contact_pi_person_id: 7875447
contact_pi: KYPRIANOU, NATASHA
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Transforming growth factor- (TGF-) is a negative regulator of normal benign and malignant prostate growth. While serving a growth-inhibitory/apoptotic role in the normal prostate overproduction of TGF-  1 in the aging prostate contributes to the development of benign prostate hyperplasia (BPH) and prostate cancer. We previously established that activation of TGF-s  signaling leads to apoptosis induction and loss of TGF  RII receptor (T2RII) contributes to prostate tumorigenic growth. Overexpression of T2RII in human prostate cancer cells enables apoptosis-mediated-growth suppression in response to TGF-  in vitro and in vivo. Using the LNCaP T2RII prostate cancer cells (androgen-sensitive and TGF-  responsive) as a model it was shown that TGF- 1 induces apoptosis and this effect was enhanced by androgens. Recent proteomic-based approaches identified two new intracellular effectors of TGF- pathway that act independent of Smads to regulate apoptotic outcomes in prostate cancer cells. In this proposal we hypothesize that TGF-  1 signaling via changes in Smad4-independent intracellular effectors and cross-talk with the androgen receptor (AR) regulates prostate growth and functional inactivation of this network accelerates the manifestation of the malignant phenotype and tumor progression. The following four Specific Aims will test this hypothesis: Specific Aim 1 will characterize the functional involvement of Smad- independent signaling effectors prohibitin and cofilin as novel mediators of TGF- action in prostate benign and malignant epithelial cells. Specific Aim 2 will identify the significance of the androgen receptor (AR) in the signaling interaction between TGF-1 and androgens towards apoptosis and epithelial to mesenchymal transition (EMT) of prostate tumor epithelial cells. Specific Aim 3 will establish the role of cofilin as a novel regulator of the ability of prostate (stroma) fibroblasts to direct TGF-  signaling in the context of the tumor microenvironment. Specific Aim 4 will characterize the in vivo physiological consequences of a functionally impaired TGF- signaling on prostate growth tumor initiation and progression using a conditional knockout mouse DNT2RII to generate double transgenics upon crossing with the TRAMP transgenic mouse model. These studies will provide new insights into the mechanistic deregulation of TGF signaling network that contributes to prostate growth and tumor progression. Understanding how cells read TGF-  will enable both the delineation of the transcriptional programs that mediate specific TGF-  effects and provide a framework for defining the mechanism via which TGF-  1 growth inhibitory/apoptotic responses in normal benign and pre-malignant prostate cells might be selectively replaced by invasive and metastatic responses in cancer cells.  
  
PUBLIC HEALTH RELEVANCE: The long term objective of the application is to characterize the functional interplay between the TGF-  1 and androgen signaling pathways that independently of Smad effectors and in the context of tissue microenvironment contribute to deregulation of TGF  1 mediated effects on prostate growth during tumor initiation and progression. The application will also pursue the mechanism converting TGF-  from a tumor suppressor in normal and benign prostate growth to a tumor promoter in advanced metastatic cancer.

project_terms:
Actins;Adhesions;Aging;Androgen Receptor;Androgens;Apoptosis;Apoptosis Promoter;Apoptotic;Benign;Benign Prostatic Hypertrophy;Bypass;Cells;Complex;Cytoskeleton;Defect;Development;Disseminated Malignant Neoplasm;Dominant-Negative Mutation;Embryonic Development;Epithelial;Epithelial Cell Proliferation;Epithelial Cells;Event;Extracellular Matrix;Family;Fibroblasts;Genetic Transcription;Goals;Growth;Growth Factor;Human;In Vitro;Induction of Apoptosis;Inhibition of Apoptosis;Knockout Mice;LNCaP;Laboratories;Ligands;Link;MAP Kinase Gene;Malignant - descriptor;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Mediator of activation protein;Modeling;Molecular;Neoplasm Metastasis;Outcome;Pathway interactions;Phosphotransferases;Physiological;Physiological Processes;Premalignant;Promotor (Genetics);Prostate;Prostatic Neoplasms;Proteins;Proteomics;Reading;Receptor Signaling;Regulation;Research;Resistance;Role;Signal Pathway;Signal Transduction;Testing;Tissues;Transforming Growth Factor beta;Transforming Growth Factors;Transgenic Mice;Transgenic Organisms;Tumor Promoters;Tumor Suppressor Proteins;Tumorigenicity;Work;Wound Healing;base;cancer cell;cell growth;cell motility;cofilin;epithelial to mesenchymal transition;evidence base;in vivo;insight;malignant phenotype;migration;mouse model;novel;overexpression;programs;prohibitin;public health relevance;receptor;response;trafficking;tumor;tumor initiation;tumor progression;tumorigenesis;tumorigenic

public_health_relevance:
NARRATIVEThe long term objective of the application is to characterize the functionalinterplay between the TGF-1 and androgen signaling pathways thatindependently of Smad effectors and in the context of tissue microenvironmentcontribute to deregulation of TGF1 mediated effects on prostate growth duringtumor initiation and progression. The application will also pursue the mechanismconverting TGF- from a tumor suppressor in normal and benign prostategrowth to a tumor promoter in advanced metastatic cancer.


application_id: 8129466
project_number: 5R01HD064993-03
project_title: Aging of Frontal Structure and Function in Down Syndrome and Dementia
administering_ic: NICHD
award_notice_date: 2011-08-09
opportunity_number: RFA-HD-09-028
application_type: 5
activity_code: R01
ic: HD
serial_number: 064993
program_official: OSTER-GRANITE, MARY LOU
project_start_date: 2009-09-30
project_end_date: 2014-08-31
study_section: ZHD1-MRG-C(28)
contact_pi_person_id: 8662513
contact_pi: HEAD, ELIZABETH
other_pis: SCHMITT, FREDERICK
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (Provided by Applicant):  Down syndrome (DS) is the major cause of intellectual disability in humans and it is estimated there are over 300000 individuals with this genetic disorder in the United States.  Virtually all DS individuals have sufficient neuropathology for a diagnosis of Alzheimer's disease (AD) in their 40th year.  However dementia may not develop until up to a decade later and some people remain cognitively intact.  Thus the investigators seek to follow a group of adults ranging in age from 20-40 years over a five year period of time to identify age and dementia-associated changes in cognition and in particular focus on frontal lobe function.  The aims are four-fold.  Aim 1 will cognitively characterize a cohort of adults with DS and follow individuals for a period of five years.  Aim 2 will use magnetic resonance imaging to measure white matter integrity on an annual basis in longitudinally followed people.  Aim 3 will assay plasma drawn annually from the cohort and measure signaling protein changes to identify biomarkers of AD development and that are also correlated with cognition.  Aim 4 will study archived and new autopsy brain samples from DS adults to identify molecular pathways that change prior and during AD development.  The outcomes of the proposed studies will contribute to the development of noninvasive biomarkers that will assist in early AD diagnosis in DS and monitor disease progression.  Further novel biomarkers that are mechanistically related to aging AD neuropathology as well as dementia will also provide outcomes for the design of future therapeutic clinical trials to treat or prevent dementia in DS.    
  
PROJECT NARRATIVE:  The proposed study will identify new ways in which to detect Alzheimer's disease (AD) in adults with Down syndrome (DS) by monitoring changes in cognitive function measuring brain changes by magnetic resonance imaging and profiling patterns of proteins in the plasma.  In parallel autopsy studies of brain samples will help us to understand how noninvasive cognitive imaging and blood measures reflect the development of AD in DS.  Treatments for AD in DS will be more effective if the disease is detected early and identifying biomarkers will greatly facilitate the development of therapeutics.

project_terms:
Accounting;Activities of Daily Living;Adult;Affect;Age;Age of Onset;Age-Years;Aging;Alzheimer's Disease;Anisotropy;Archives;Autopsy;Biological Assay;Blood;Brain;Caring;Categories;Cell Adhesion Molecules;Chromosomes Human Pair 21;Clinical;Cognition;Cognitive;Color;Data;Dementia;Development;Diagnosis;Diffusion Magnetic Resonance Imaging;Digit structure;Disease;Disease Progression;Dissociation;Down Syndrome;Elements;Event;Evolution;Fiber;Functional disorder;Future;Genes;Growth Factor;Hereditary Disease;Human;Image;Impaired cognition;Impairment;Individual;Intellectual functioning disability;International;Intervention;Intervention Studies;Lead;Link;London;Magnetic Resonance Imaging;Measures;Medial;Memory impairment;Methods;Modeling;Molecular;Monitor;Myelin;Neurobiology;Neurofibrillary Tangles;Oligodendroglia;Outcome;Parietal Lobe;Pathogenesis;Pathology;Pathway interactions;Pattern;Performance;Persons;Phase;Plasma;Plasma Proteins;Prevalence;Process;Proteins;Quality of life;Raven;Reaction Time;Receptor Signaling;Research Personnel;Risk;Sampling;Scanning;Senile Plaques;Short-Term Memory;Signaling Protein;Sorting - Cell Movement;Structure;Testing;Therapeutic;Therapeutic Clinical Trial;Time;United States;Vaccination;age related;aging brain;base;biomarker;chemokine;cognitive function;cohort;cytokine;design;disease diagnosis;early onset;executive function;frontal lobe;frontal lobe function;functional decline;high risk;improved;in vivo;indexing;inhibitor/antagonist;insight;interdisciplinary approach;middle age;nervous system disorder;neuropathology;novel;novel therapeutics;overexpression;prevent;secretase;skills;therapeutic development;tool;visual search;white matter;white matter change

public_health_relevance:
Project NarrativeThe proposed study will identify new ways in which to detect Alzheimer disease (AD) in adultswith Down syndrome (DS) by monitoring changes in cognitive function measuring brainchanges by magnetic resonance imaging and profiling patterns of proteins in the plasma. Inparallel autopsy studies of brain samples will help us to understand how noninvasive cognitiveimaging and blood measures reflect the development of AD in DS. Treatments for AD in DS willbe more effective if the disease is detected early and identifying biomarkers will greatly facilitatethe development of therapeutics.


application_id: 8127944
project_number: 5R13GM058252-13
project_title: Interactive Learning Modules for Writing Grant Proposals
administering_ic: NIGMS
award_notice_date: 2011-08-12
opportunity_number: PA-08-149
application_type: 5
activity_code: R13
ic: GM
serial_number: 058252
program_official: ZLOTNIK, HINDA
project_start_date: 1998-09-05
project_end_date: 2014-08-31
study_section: ZGM1-BRT-0(CO)
contact_pi_person_id: 8535385
contact_pi: FRAZIER, DONALD T
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall objective of this application is to continue to empower faculty at institutions with high minority enrollment to develop and submit competitive research proposals. The original goal of our training partnership with NIGMS was to translate an innovative proven grant writing workshop into an interactive hypermedia course by placing learning modules on the internet for wide dispersal. Building on our past experience with over 250 faculty and postdoctoral fellows the competing renewal has three facets which will take place concurrently: 1) up-dating and revising the 15 modules to incorporate changes in NIH guidelines and to make them more interactive; 2) plan and implement on-site pre-course workshops to instruct faulty/postdoctoral fellows and corresponding research administrators in accessing and navigating the web-based course; 3) developing and implementing a new workshop initiative focused on training programs in particular the MORE divisions RISE Bridges IMSD and MARC applications. The focal-point of our program will continue to be focused on minority faculty and the individual research grant. In response to requests from our faculty participants to improve their research environment we recently developed a workshop for research administrators at minority-serving institutions. The training program component addresses the need to enhance the pipe-line of minority students entering into biomedical research. Through on-going scientific mentoring and writing process consultation we sustain a relationship with our participants well beyond the workshops and internet course.  Thus our collaborative partnership with NIGMS should motivate and improve the skills and abilities of researchers/grant writers at minority institutions increase the number of minorities engaged in biomedical research and thereby strengthen the overall research environment at minority institutions. Success in these areas would have a substantial impact on the health and well-being of our citizens.    
  
PUBLIC HEALTH RELEVANCE: Our collaborative partnership with NIGMS should motivate and improve the skills and abilities of researchers/grant writers at minority institutions increase the number of minorities engaged in biomedical research and thereby strengthen the overall research environment at minority institutions. Success in these areas would have a substantial impact on the health and well-being of our citizens.

project_terms:
Address;Administrator;Applications Grants;Area;Biomedical Research;CCL7 gene;Consultations;Educational workshop;Enrollment;Environment;Faculty;Goals;Grant;Guidelines;Health;Hypermedia;Individual;Institution;Internet;Learning;Mentors;Minority;Minority-Serving Institution;National Institute of General Medical Sciences;Online Systems;Participant;Personal Satisfaction;Postdoctoral Fellow;Process;Research;Research Personnel;Research Project Grants;Research Proposals;Site;Students;Training;Training Programs;Translating;United States National Institutes of Health;Writing;empowered;experience;improved;innovation;programs;public health relevance;response;skills;success

public_health_relevance:
Project Narrative Our collaborative partnership with NIGMS should motivate and improve the skills andabilities of researchers/grant writers at minority institutions increase the number of minoritiesengaged in biomedical research and thereby strengthen the overall research environment atminority institutions. Success in these areas would have a substantial impact on the health andwell-being of our citizens.


application_id: 8127891
project_number: 5R03HD066012-02
project_title: The role of Core Binding Factors (CBFs) in the periovulatory process
administering_ic: NICHD
award_notice_date: 2011-08-26
opportunity_number: PA-09-163
application_type: 5
activity_code: R03
ic: HD
serial_number: 066012
program_official: TAYMANS, SUSAN
project_start_date: 2010-08-12
project_end_date: 2013-07-31
study_section: Reproduction, Andrology, and Gynecology Study Section[CHHD-R]
contact_pi_person_id: 8244639
contact_pi: JO, MISUNG
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The preovulatory gonadotropin surge initiates the final process of follicular maturation that culminates in ovulation of an expanded cumulus-oocyte complex (COC) and formation of the corpus luteum (CL). One essential step elicited by the gonadotropin surge required for successful follicular maturation is the expression of specific transcription factors. However our knowledge of the identity and regulatory actions of LH-induced key transcription factors remains very limited. Recent studies from our laboratory and others shed light on a small family of nuclear transcription factor Core binding factor (CBF) as a key transcriptional regulator involved in periovulatory processes. CBF is composed of two subunits; DNA binding alpha-subunit encoded by one of Runx1 Runx2 and Runx3 genes and non-DNA binding beta-subunit CBF2. To be functional RUNX proteins need to be dimerized with CBF2. Our preliminary data showed the rapid induction of CBF components (Runx1 Runx2 and CBF2) by the LH surge in periovulatory follicles. Using an in vitro model we further demonstrated that CBFs (RUNX1/CBF2 and RUNX2/CBF2) regulate the expression of periovulatory genes that are known to be critical for COC expansion ovulation and luteinization. Moreover our pilot study revealed that inhibition of RUNX activity blocked COC expansion in vitro. Based on these novel findings we hypothesized that CBFs are key transcriptional regulators necessary for successful COC expansion ovulation and luteinization.  Homozygous null mutation of genes for CBF components in mice results in early lethality and consequently fails to define the function of CBFs in the ovary. The additional challenge in demonstrating the physiological importance of CBFs in vivo is the overlapping expression of Runx1 and Runx2 and their functional redundancy in periovulatory follicles. To circumvent this problem we propose to establish a novel transgenic mouse model in which CBFs are inactivated specifically in ovarian cells. This will be accomplished by deleting CBF2 in ovarian cells using Cre-lox technology. Since CBF2 is a binding partner for both RUNX1 and RUNX2 targeted deletion of CBF2 abrogates the activity of all CBFs (RUNX1/CBF2 and RUNX2/CBF2). Using this transgenic mouse model we will test the hypothesis that targeted inactivation of CBFs results in defective COC expansion ovulation and luteinization by examining the ovarian phenotype of this mutant mouse (Specific Aim #1). Using this mutant mouse ovary we will identify the genes downstream of CBFs in periovulatory follicular cells and begin to delineate the transcriptional regulatory pathways necessary for the final stage of periovulatory follicle development (Specific Aim #2).  These studies will establish a genetically modified animal model not only to define the in vivo ovarian function of CBFs but also to identify the transcriptional regulatory machinery that controls the periovulatory process. Information derived from this proposal will provide new insight into the mechanism(s) involved in COC expansion ovulation and CL formation. Gaining a thorough understanding of cellular/molecular mechanisms of the periovulatory process will lead to better diagnostic evaluation of ovarian pathology and facilitate the physiological manipulation of these processes to either promote or inhibit fertility.  
  
PUBLIC HEALTH RELEVANCE: The overall goal of the proposed study is to investigate how the LH surge induces the release of a mature egg from the ovary and corpus luteum formation which are essential steps for female fertility. The current proposal focuses on determining the function of a small family of transcription factors Core binding factors (CBFs) as key LH-induced mediators in these processes. Such knowledge can be applied for promoting and inhibiting these critical facets of ovarian physiology thereby allowing us to better manage fertility infertility and ovarian-based disorders.

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

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


application_id: 8127697
project_number: 5R42AA015475-05
project_title: Potential anti-relapse drugs: a plant genomics approach
administering_ic: NIAAA
award_notice_date: 2011-08-09
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: 2013-08-31
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;Nerve Degeneration;Neuroprotective Agents;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Phase;Plant Extracts;Plants;Population;Prevalence;Production;Property;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: 8127628
project_number: 5P01AA017103-03
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: 2010-09-01
budget_end_date: 2012-08-31
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;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: 8127603
project_number: 5R01HD050571-05
project_title: ROLE OF PACAP IN THE MALE FETAL PITUITARY
administering_ic: NICHD
award_notice_date: 2011-07-11
application_type: 5
activity_code: R01
ic: HD
serial_number: 050571
program_official: LAMAR, CHARISEE A
project_start_date: 2007-08-15
project_end_date: 2014-05-31
study_section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER]
contact_pi_person_id: 2050006
contact_pi: MOORE, JOSEPH P
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-06-01
project_abstract:
DESCRIPTION (provided by applicant): Sexual maturation in the male is a complex process that involves changes in the hypothalamus pituitary testes and secondary sexual organs and in their interrelationships. Improper development of any one of these components can lead to infertility in adult life. Infertility affects approximately 15% of couples 40% of which are male factor infertility. Therefore a complete understanding of the events associated with male sexual development may allow for early detection and possible prevention of infertility during adulthood. Furthermore elucidation of the numerous factors that regulate male reproductive function could enhance the development of male contraceptive strategies. Our laboratory has been investigating the involvement of pituitary adenylate cyclase activating polypeptide (PACAP) in the regulation of the gonadotropin axis. We have previously demonstrated that PACAP is able to differentially regulate the two pituitary gonadotropins in vitro. PACAP has been shown to stimulate alpha subunit expression stabilize LH-beta mRNA and suppress FSH-beta mRNA expression. Our preliminary data in fetal male rats demonstrate a significant decline in pituitary PACAP at birth that is reciprocal to a dramatic rise in FSH-beta expression. We hypothesize that PACAP plays an important role in the development and maturation of the pituitary gonadotropin system. Specifically we propose to 1) Provide anatomical molecular and developmental evidence for dynamic changes in pituitary PACAP and its receptors during fetal and neonatal development. 2) Provide evidence that pituitary derived PACAP differentially regulates the gonadotropins during embryonic development. 3) Use gonadotroph and folliculostellate cell lines to demonstrate that pituitary products and endocrine hormones confer the high level of PACAP gene expression within the fetal anterior pituitary gland 4) Confirm the importance of PACAP on gonadotroph development by analyses of the affects of PACAP deficiency in PACAP-KO mice.

project_terms:
Activins;Adult;Affect;Anterior Pituitary Gland;Appearance;Birth;Cell Line;Cells;Complex;Couples;Data;Development;Early Diagnosis;Embryo;Embryonic Development;Endocrine;Event;Fetal development of the mammalian embryo or fetus;Follistatin;Gene Expression;Genetic Transcription;Gonadotropins;Growth;Half-Life;Hormones;Hypothalamic structure;In Vitro;Infertility;Laboratories;Lead;Life;Male Contraceptive Agents;Male Infertility;Messenger RNA;Molecular;Mus;Neonatal;Organ;Physiological;Pituitary Gland;Pituitary Gonadotropins;Play;Prevention;Process;Production;Rattus;Regulation;Role;Sexual Development;Sexual Maturation;System;Testis;Time;beta Subunit Follicle Stimulating Hormone;beta Subunit Luteinizing Hormone;falls;fetal;human male;infancy;mRNA Expression;male;pituitary adenylate cyclase activating polypeptide;receptor;reproductive function


application_id: 8126475
project_number: 5R01DA027569-03
project_title: Exercise as a novel strategy to target methamphetamine-induced cerebrovascular to
administering_ic: NIDA
award_notice_date: 2011-08-09
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: 2011-11-01
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;zonula occludens-1 protein

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: 8125915
project_number: 1F31DA030061-01A1
project_title: Longitudinal effects of custody loss on drug use and crime of African American wo
administering_ic: NIDA
award_notice_date: 2011-04-15
opportunity_number: PA-10-108
application_type: 1
activity_code: F31
ic: DA
serial_number: 030061
suffix: A1
program_official: DEEDS, BETHANY
project_start_date: 2011-06-01
project_end_date: 2013-05-31
study_section: Special Emphasis Panel[ZRG1 F16-B (20)]
contact_pi_person_id: 10223601
contact_pi: HARP, KATHI LH
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL 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: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of the present study is to understand how custody loss is related to substance use and criminal behavior among African American women who are mothers across criminal offender status. While drug use is similar across racial groups in the US African Americans disproportionately experience child welfare and criminal justice system involvement as a result of drug misuse. Very limited scientific data is available to help understand the effect of custody loss on a woman's subsequent substance use and crime. Prominent on NIDA's research agenda is the promotion of research addressing health disparities and vulnerabilities among minority populations. The proposed project addresses a facet of this mission by examining custody loss as a predictor of increased substance use and criminal behavior among African American women. Specifically the main objectives of this project are to identify risk factors for custody loss in this population and to assess the substance use and criminal behavior-related outcomes of custody loss. Because children are a significant source of social support for mothers the loss of such support is likely to increase dependence upon other sources of support such as family and friends. When this support is adequate women may be less likely to increase their substance use and criminal behavior after losing custody. This study is significant because of its potential to identify differences in the substance use and criminal behavior outcomes of custody loss among African American women and uncover disparities among drug using and non-drug using women across three levels of criminal justice involvement (n=200 per group): prison probation and community (no criminal justice involvement). Data for analyses will be derived from Waves 1-3 of the "African American Female Drug Users: HIV Health Disparities and Criminality" study (also known as "B-WISE"; NIDA R01-DA22967) an ongoing longitudinal study of 600 African American women. All women are interviewed at baseline and at 6 and 12 months after the initial interview. The specific aims of the present study are (1) To describe the characteristics of African American women who have lost custody of their children compared to women who have not; (2) To examine the mediating effect of custody loss on the relationship between individual level factors (criminal justice and drug user status) and changes in substance use and criminal behavior over the 12-month study time frame; and (3) To determine if characteristics of the child the custody loss event and perceptions of social support are significant predictors of a change in substance use and criminal behavior after losing custody. Multinomial logistic regression will be used to estimate the impact of factors such as social support criminal justice status characteristic of the child and characteristics of the custody loss event on post-custody loss changes in drug use and crime. The significance of this study includes the potential to provide data for criminal justice system and child welfare system policy for the prevention intervention and treatment of African American mothers who are substance users.  
  
PUBLIC HEALTH RELEVANCE: This study is significant to the public health field because of its potential to uncover disparities among African American women across criminal justice status and drug use status prior to and after losing custody. This knowledge can be used as a foundation for future criminal justice and child welfare systems-level interventions targeted at early detection and treatment of substance abuse that utilize women's sources of social support as allies. Such interventions would reduce the need for costly child placement services and incarceration ultimately reducing the disparities experienced by African American women.

project_terms:
Address;Affect;African American;Age;Alcohol or Other Drugs use;Ally;Characteristics;Child;Child Custody;Child Welfare;Communities;Crime;Criminal Justice;Data;Data Analyses;Dependence;Drug abuser;Drug usage;Drug user;Early Diagnosis;Early treatment;Epidemic;Event;Expenditure;Family;Federal Government;Female;Foundations;Friends;Future;Goals;HIV;Health;Health Personnel;Health behavior;Home environment;Imprisonment;Individual;Intervention;Interview;Justice;Knowledge;Literature;Logistic Regressions;Longitudinal Studies;Mediating;Minor;Minority;Mission;Mothers;National Institute of Drug Abuse;Outcome;Perception;Policies;Policy Maker;Population;Preventive Intervention;Prisoner;Prisons;Race;Recovery;Recruitment Activity;Reporting;Research;Research Personnel;Risk;Risk Factors;Sampling;Self Concept;Services;Shapes;Social support;Source;State Government;Substance abuse problem;System;Time;Time Study;Woman;addiction;criminal behavior;experience;foster care;health disparity;improved;non-drug;offender;probation;probationer;programs;public health medicine (field)

public_health_relevance:
This study is significant to the public health field because of its potential to uncover disparities among African American women across criminal justice status and drug use status prior to and after losing custody. This knowledge can be used as a foundation for future criminal justice and child welfare systems-level interventions targeted at early detection and treatment of substance abuse that utilize women's sources of social support as allies. Such interventions would reduce the need for costly child placement services and incarceration ultimately reducing the disparities experienced by African American women.


application_id: 8125909
project_number: 1F31DE021304-01A1
project_title: Counteracting microbial immune evasion for the treatment of periodontitis
administering_ic: NIDCR
award_notice_date: 2011-02-02
opportunity_number: PA-10-108
application_type: 1
activity_code: F31
ic: DE
serial_number: 021304
suffix: A1
program_official: FRIEDEN, LESLIE A
project_start_date: 2011-02-02
project_end_date: 2014-02-01
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 10310860
contact_pi: MCINTOSH, MEGAN LAVONNE
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Periodontitis is a destructive inflammatory disease instigated by a number of microbial pathogens which have evolved mechanisms to manipulate the innate immune response for their own benefit. Among those microbes Porphyromonas gingivalis stands as a primary contributor to pathology significantly via its ability to interact with and manipulate Toll-like receptors (TLRs) and other pattern-recognition receptors (PRRs) that trigger innate immune responses. P. gingivalis is predominantly recognized by TLR2 and this interaction leads to two independent downstream pathways: the TLR2 antimicrobial pathway and the TLR2 proadhesive pathway which transactivates complement receptor 3 (CR3) and allows P. gingivalis to hijack CR3 for safe entry into macrophages. This proposal hypothesizes that P. gingivalis exploits the chemokine receptor CXCR4 not only to suppress the TLR2 antimicrobial pathway (as recently shown) but also to upregulate the TLR2 proadhesive pathway the focus of Aim 1. Both of these activities have the potential to increase the survival capacity of the pathogen thereby prolonging P. gingivalis infection and potentiating its impact on periodontal disease. This notion will be tested in vivo using a mouse model of periodontitis (Aim 2). Regarding Aim 1 in vitro immunological approaches using transfected cell lines or primary cells will elucidate the mechanistic basis of P. gingivalis-induced CXCR4/TLR2 crosstalk which transactivates CR3. It is hypothesized that the CXCR4 and TLR2 signaling pathways crosstalk via cAMP-dependent protein kinase A and the small GTPase Rac1 respectively. Aim 2 is designed to show that P. gingivalis exploits CXCR4 leading to increased pathogen persistence and periodontal disease activity in vivo. Treatment with AMD3100 a mouse/human CXCR4 antagonist which has a proven safety record in HIV clinical trials will be assessed for its potential to prevent the progression of periodontal disease in an established preclinical mouse periodontitis model. Also transgenic CXCR4 conditional knockout mice will be used to substantiate our AMD3100 studies as well as provide mechanistic insight into the role CXCR4 plays in P. gingivalis-mediated periodontal disease. This investigation will involve evaluation of the host response and persistence of the infection as well as induction of periodontal bone loss. Aim 2 is expected to provide proof-of-principle evidence that by antagonizing CXCR4 with AMD3100 or ablating CXCR4 in mice therefore preventing P. gingivalis from exploiting it protection against the destructive periodontal inflammation can be provided. The long-term objective is to identify effective small- molecule antagonists like AMD3100 which can counteract microbial immune evasion mechanistically and thus redirect the immune response to benefit the host.  
  
PUBLIC HEALTH RELEVANCE: Periodontitis is perhaps the most common chronic disease of infectious origin in humans and is moreover associated with systemic inflammatory diseases such as atherosclerosis. This research proposal is based on evidence that periodontal bacteria exploit a host receptor namely CXCR4 for undermining host immunity and promoting their virulence. Using a preclinical periodontitis model this application proposes to test AMD3100 (a potent antagonist of mouse/human CXCR4 shown to be safe in clinical trials for HIV treatment) as an intervention treatment in periodontitis. This work is expected to help propel development of prophylactic and post-infection treatments which could drastically improve the quality of life of periodontal patients.

project_terms:
6H8H-34-dihydropyrimido(45-c)(12)oxazin-7-one;AMD3100;Address;Alveolar Bone Loss;Anaerobic Bacteria;Atherosclerosis;Bacteria;Binding (Molecular Function);Biological Response Modifiers;CXC Chemokines;Cell Line;Cells;Chronic Disease;Clinical Trials;Cyclic AMP-Dependent Protein Kinases;Data;Development;Disease;Evaluation;Exhibits;Figs - dietary;HIV;Host Defense;Human;Immune;Immune response;Immunity;Immunosuppressive Agents;In Vitro;Infection;Inflammation;Inflammation Mediators;Inflammatory;Intercept;Intervention;Investigation;Killings;Knockout Mice;Lead;Macrophage-1 Antigen;Mediating;Microbe;Modeling;Molecular;Monomeric GTP-Binding Proteins;Mus;Natural Immunity;Nitric Oxide;Oral cavity;Pathogenesis;Pathology;Pathway interactions;Patients;Pattern recognition receptor;Periodontal Diseases;Periodontitis;Play;Porphyromonas gingivalis;Quality of life;Research Proposals;Research Training;Role;Safety;Signal Pathway;Signal Transduction;Systemic infection;TLR2 gene;Testing;Therapeutic;Toll-like receptors;Transgenic Mice;Transgenic Organisms;Virulence;Virulent;Work;adaptive immunity;antimicrobial;base;bone loss;chemokine receptor;cytokine;design;fimbria;fitness;improved;in vivo;insight;macrophage;microbial;microbial host;mouse model;mutant;novel;pathogen;pre-clinical;prevent;prophylactic;receptor;response;small molecule

public_health_relevance:
Periodontitis is perhaps the most common chronic disease of infectious origin in humans and is moreover associated with systemic inflammatory diseases such as atherosclerosis. This research proposal is based on evidence that periodontal bacteria exploit a host receptor namely CXCR4 for undermining host immunity and promoting their virulence. Using a preclinical periodontitis model this application proposes to test AMD3100 (a potent antagonist of mouse/human CXCR4 shown to be safe in clinical trials for HIV treatment) as an intervention treatment in periodontitis. This work is expected to help propel development of prophylactic and post-infection treatments which could drastically improve the quality of life of periodontal patients.


application_id: 8125894
project_number: 1F31DC010281-01A2
project_title: Deaf infants' cognitive skills and their post-cochlear implant language outcomes
administering_ic: NIDCD
award_notice_date: 2010-12-31
opportunity_number: PA-10-108
application_type: 1
activity_code: F31
ic: DC
serial_number: 010281
suffix: A2
program_official: SCHURMAN, JACLYN REBECCA
project_start_date: 2011-01-01
project_end_date: 2013-12-31
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 9702555
contact_pi: SHAFTO, CARISSA LYNN
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The long-term research goal is to identify predictors of spoken language development in profoundly deaf children who receive a cochlear implant (CI). Decades of research have demonstrated that children with severe-to-profound deafness (including children who receive a CI) on average exhibit deficits in language and literacy as compared to their normally-hearing (NH) peers (e.g. Geers 2004; Miller 2009; Paul 1998). These literacy and spoken language deficits are thought to be responsible for the significant academic achievement gaps that are observed between deaf and NH children (e.g. Harris & Beech 1998). Further research is needed to determine the skills underlying spoken language development in deaf children so that more effective early intervention strategies can be developed.  The goal of the proposed project is to compare cognitive skills (known to be important for language acquisition) in children with profound hearing loss to those of children with NH and to examine the relationship between a nonverbal cognitive skill (VSL ability) and spoken language ability.  The first specific aim is to examine visual sequence learning (VSL) in infants aged 8 to 23 months with severe-to-profound deafness that will be undergoing cochlear implantation. Their performance on the VSL task will be compared to the performance of aged-matched infants with NH. Infants with CIs will be tested on the VSL task just prior to the initial activation of their CI (i.e. prior to auditory input). Differences in performance between the two groups will serve as an index of the effects of early auditory deprivation on VSL ability.  The second specific aim is to determine the relationship between VSL ability and later spoken language in deaf infants who use CIs. Correlational analyses will be conducted between scores on the VSL task prior to cochlear implantation and vocabulary and grammatical scores on the MacArthur-Bates Communicative Development Inventories (CDIs; Fenson et al. 2006) one year following cochlear implantation.  Because language development begins at birth infancy is an opportune time to investigate predictors of spoken language ability. A potential clinical implication of this work is the identification of early nonverbal predictors of spoken language outcome which may be used in the future to develop new early intervention strategies designed to promote spoken language development. These strategies may narrow the achievement gap between NH and deaf children. A strong positive correlation between VSL in infancy and spoken language ability one year later would suggest that early sequence learning skills are important for spoken language development. In contrast a weak correlation might suggest that VSL ability is not that important for spoken language development in deaf infants. Either pattern of results clarifies the effects of auditory deprivation on the development of cognitive skills that underlie spoken language development.  
  
PUBLIC HEALTH RELEVANCE: This research addresses the issue of why some deaf children with cochlear implants learn spoken language very well while others have poor language outcomes and consequently struggle with developing literacy skills and perform poorly in school. Discovering early predictors of language outcomes will enable clinicians to identify infants who are at risk for poor language outcomes and design appropriate early intervention strategies to reduce the chances that they will not develop adequate language to succeed in school.

project_terms:
Academic achievement;Achievement;Address;Age;Age-Months;Auditory;Beech;Birth;Child;Clinical;Cochlear Implants;Cochlear implant procedure;Cognitive;Data;Deafness;Development;Early identification;Early treatment;Equipment and supply inventories;Exhibits;Foundations;Future;Goals;Hearing;Hearing Impaired Persons;Individual;Infant;Intervention;Laboratories;Language;Language Development;Language Disorders;Learning;Linguistics;Link;Outcome;Pattern;Performance;Relative (related person);Research;Research Training;Risk;Running;School-Age Population;Schools;Short-Term Memory;Testing;Time;Training;Visual;Vocabulary;Work;aged;auditory deprivation;base;design;experience;hearing impairment;improved;indexing;infancy;literacy;meetings;peer;sequence learning;skills

public_health_relevance:
This research addresses the issue of why some deaf children with cochlear implants learn spoken language very well while others have poor language outcomes and consequently struggle with developing literacy skills and perform poorly in school. Discovering early predictors of language outcomes will enable clinicians to identify infants who are at risk for poor language outcomes and design appropriate early intervention strategies to reduce the chances that they will not develop adequate language to succeed in school.


application_id: 8125790
project_number: 1F31NS074678-01
project_title: Contribution of blast wave components to mild traumatic brain injury
administering_ic: NINDS
award_notice_date: 2011-02-04
opportunity_number: PA-10-108
application_type: 1
activity_code: F31
ic: NS
serial_number: 074678
program_official: HICKS, RAMONA R
project_start_date: 2011-07-01
project_end_date: 2013-12-31
study_section: Special Emphasis Panel[ZRG1 F01-L (20)]
contact_pi_person_id: 9821686
contact_pi: RENEER, DEXTER VINCENT
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): Blast-induced Traumatic brain injury (bTBI) has become the "signature injury" of Operations Iraqi/Enduring Freedom (OIF/OEF) and is also increasingly frequent in civilians as a result of industrial and terrorist explosions. The mechanisms by which blast shockwaves contribute to bTBI is being investigated using both large and small animal models. Small animal models of bTBI predominantly utilize compressed air-driven shock tubes to generate an injury while large animal models employ chemical explosives (i.e. RDX - the main explosive component of C-4 plastic explosives) in both open-air and a variety of enclosed spaces. The differences in model design and shockwave source make comparison of results from each model difficult. Previous bTBI studies have focused on the relationship between peak blast pressure and brain injury. However we hypothesize that other components of the shock wave may also contribute to the brain injury. In an effort to determine which components of the blast contribute to the injury we developed and characterized the McMillan Blast Device (MBD) a shock tube that can utilize compressed gas (air helium) or chemical explosives (RDX oxyhydrogen) as the shockwave source. Shockwaves produced from compressed gas sources differ substantially from those produced by chemical explosives within the MBD. This proposal seeks to determine which components of the shock wave contribute to brain pathology in rats. The overall hypothesis of this proposal is that positive phase duration in addition to peak overpressure plays a role in the injury produced by blasts. To examine this hypothesis Aim 1 will compare blasts of similar peak overpressures produced by oxhydrogen and compressed air. The oxyhydrogen-driven blasts have a shorter positive phase duration and are therefore anticipated to produce less brain injury. This will be evaluated using a range of peak overpressures. Brain injury will be assessed using markers diffuse axonal injury (DAI) blood-brain barrier (BBB) compromise oxidative stress and neuron death. Aim 2 will expand upon Aim 1 by shortening the positive phase duration of a compressed air-driven shockwave to a length comparable to oxyhydrogen-driven blasts and comparing resultant brain injury. Aim 3 will examine the hypothesis that reflection of the blast waves which extends the duration of the overpressure phase will exacerbate the extent of brain injury produced by a blast.  
  
PUBLIC HEALTH RELEVANCE: Blast-induced traumatic brain injury (bTBI) is becoming more prevalent among military and civilian populations while the mechanisms underlying the pathologic mechanisms associated with bTBI remain largely unknown. This proposal will evaluate components of the blast wave that contribute to brain injury by using both compressed gas and chemical explosive sources for the blast wave. These results will aid in the design of protective structures and personal protective gear to mitigate the effects of blast wave components which contribute to bTBI.

project_terms:
Acoustics;Air;Animal Model;Animal Testing;Animals;Automobile Driving;Blast Cell;Blast Injuries;Blood - brain barrier anatomy;Brain;Brain Injuries;Brain Pathology;Cessation of life;Chemicals;Conflict (Psychology);Devices;Diffuse Axonal Injury;Electromagnetics;Explosion;Freedom;Frequencies (time pattern);Gases;Goals;Helium;Injury;Length;Lipid Peroxidation;Medical;Methods;Military Personnel;Modeling;Neurons;Oxidative Stress;Pathologic;Phase;Plastics;Play;Population;Positioning Attribute;Proteins;Rattus;Role;Shock;Source;Structure;Testing;Thick;Time;Traumatic Brain Injury;Travel;Triage;Tube;base;design;improved;model design;neuropathology;nitration;operation;pressure;research study

public_health_relevance:
Blast-induced traumatic brain injury (bTBI) is becoming more prevalent among military and civilian populations while the mechanisms underlying the pathologic mechanisms associated with bTBI remain largely unknown. This proposal will evaluate components of the blast wave that contribute to brain injury by using both compressed gas and chemical explosive sources for the blast wave. These results will aid in the design of protective structures and personal protective gear to mitigate the effects of blast wave components which contribute to bTBI.


application_id: 8125028
project_number: 5R01ES018883-02
project_title: HIF-alphia in Cr(VI) carcinogenesis
administering_ic: NIEHS
award_notice_date: 2011-03-08
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: ES
serial_number: 018883
program_official: QUINN, ASHLINN KO
project_start_date: 2010-08-09
project_end_date: 2015-03-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 10011919
contact_pi: ZHANG, ZHUO
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): Although the carcinogenicity of Cr(VI) has been well documented by studies both in vitro and in vivo its mechanism of action remains to be investigated. Our recent studies indicate that Cr(VI) induces HIF-11 activation. MAP kinase p38 and reactive oxygen species (ROS) are involved in this process. HIF-11 is a key regulatory protein for angiogenesis which is a physiological process involving the growth of new blood vessels from pre-existing vessels. Solid tumors of smaller than 1 to 2 cubic millimeters are not vascularized. To spread they need to be supplied by blood vessels that bring oxygen and nutrients and remove metabolic wastes. Inhibition of HIF-11 decreases cell transformation capacity in hypoxia and tumor growth in vivo while overexpression of HIF-11 allows anchorage-independent growth in normoxia and development of more aggressive tumors. Since HIF-11 is important in cancer initiation and progression it is likely that HIF-11 activation and angiogenesis could be important in Cr(VI)-mediated carcinogenesis. We hypothesize that ROS and HIF-11 activation play an important role in Cr(VI)-induced carcinogenesis. Human bronchial epithelial BEAS-2B cells and athymic female nude mice (3-4 weeks old) deficient in thymus-dependent (T-cell) immunological functions will be used in the present study. Three specific aims are proposed. Aim 1 will investigate the mechanism of Cr(VI)-induced ROS generation and the role of ROS in activation of HIF-11 and angiogenesis in vitro. The regulation of HIF-1 activity could occur at multiple levels: transcription translation and post-translational modifications. The questions remain open concerning at what level Cr(VI) induces HIF-11 activation. Aim 2 will answer that question in cell system. Aim 3 will investigate the roles of ROS and HIF-1 signaling in Cr(VI)-induced cell transformation in vitro tumorigenesis tumor growth and metastasis in vivo. We anticipate that Cr(VI) induces angiogenesis via HIF-11 activation through ROS and MAP kinase p38 promoting Cr(VI)-induced cell transformation tumorigenesis tumor growth and metastasis. .  
  
PUBLIC HEALTH RELEVANCE: Hexavalent chromium [Cr(VI)] is a known human carcinogen. The carcinogenicity of Cr(VI) has been well documented by studies both in vitro and in vivo. We hypothesize that Cr(VI) induces oxidative stress and activate HIF-1 angiogenesis signalling pathway leading to cell transformation tumorigenesis tumor growth and metastasis. The goal of this proposal is to test that hypothesis.

public_health_relevance:
Hexavalent chromium [Cr(VI)] is a known human carcinogen. The carcinogenicityof Cr(VI) has been well documented by studies both in vitro and in vivo. We hypothesizethat Cr(VI) induces oxidative stress and activate HIF-1 angiogenesis signalling pathwayleading to cell transformation tumorigenesis tumor growth and metastasis. The goal ofthis proposal is to test that hypothesis.


application_id: 8124517
project_number: 1R41HL107062-01A1
project_title: Development of Percutaneous DLC for Total Cavo-pulmonary Assistance
administering_ic: NHLBI
award_notice_date: 2011-06-06
opportunity_number: PA-10-051
application_type: 1
activity_code: R41
ic: HL
serial_number: 107062
suffix: A1
program_official: BALDWIN, TIM
project_start_date: 2011-06-15
project_end_date: 2013-05-31
study_section: Special Emphasis Panel[ZRG1 SBTS-E (10)]
contact_pi_person_id: 8487070
contact_pi: WANG, DONGFANG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 832402486
primary_uei: RK1ZDCXE3LJ7
duns_number: 832402486
uei: RK1ZDCXE3LJ7
fips: US
organization_id: 10024870
organization_name: W-Z BIOTECH, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The Fontan procedure is currently standard care for patients with complex single ventricle congenital heart defects. The Fontan procedure involves the creation of a cavopulmonary (CP) shunt connecting the inferior and superior vena cava (IVC and SVC) directly to the right pulmonary artery (RPA) diverting total venous return from the IVC/SVC directly to the PA without entering the right atrium (RA) and right ventricle (RV). The Fontan procedure results in a blood flow pattern of a passively filled pulmonary circulation and a single ventricle to pump blood to the systemic circulation. Although it has improved thousands of patients' quality of life by increasing arterial O2 saturation the mortality is reported at 29.1%1. Patients with a failing Fontan follow a bimodal distribution with some failing acutely in the early post-operative period and others are failing years later2 3. Cavopulmonary assistance (CPA) is highly desired to effectively pump venous blood through the Fontan connection to the pulmonary artery and to reverse the pathophysiology of the failing Fontan circulation. However there is currently no specific device available for CPA. Our objective in this Phase I STTR is to develop and fabricate a working prototype of a percutaneous double lumen cannula (DLC) for CPA and to test this prototype in our new failing Fontan sheep model. Our ultimate goal is to develop a CPA system that avoids the need for an open surgical procedure or the use of cardiopulmonary bypass (CPB). The enabling technology will be a percutaneous DLC that will drain venous blood from both the IVC and SVC simultaneously and infuse blood directly into the pulmonary artery. Our Specific Aims are: 1) to develop and fabricate a working prototype of a percutaneous DLC to assist failing Fontan circulation and 2) to test our prototype CPA DLC in our improved failing Fontan sheep model. Our proposed cannula-based CPA will be a "game changer" in the management of failing Fontan physiology.  
  
PUBLIC HEALTH RELEVANCE: We are proposing to develop a percutaneous Cavopulmonary assistance system to bridge the patients with failing Fontan circulation for recovery reconstructive surgery and heart transplantation.

project_terms:
Acute;Anastomosis - action;Anatomy;Area;Blood;Blood Circulation;Blood Pressure;Blood flow;Businesses;Cannulas;Carbon Dioxide;Cardiac;Cardiac Output;Cardiopulmonary;Cardiopulmonary Bypass;Central venous pressure;Childhood;Chronic;Clinical;Common Ventricle;Complex;Congenital Heart Defects;Development;Devices;Drainage procedure;Engineering;Excision;Fontan Procedure;Functional disorder;Goals;Heart;Heart Transplantation;Hour;Inferior;Infusion procedures;Kentucky;Laboratory Animal Production and Facilities;Low Cardiac Output;Lung;Membrane;Modeling;Monitor;Morbidity - disease rate;Mortality Vital Statistics;Operative Surgical Procedures;Patients;Pattern;Perfusion;Phase;Physiology;Postoperative Period;Publications;Pulmonary Circulation;Pulmonary Vascular Resistance;Pulmonary artery structure;Pump;Quality of life;Reconstructive Surgical Procedures;Recovery;Reporting;Research Support;Right Heart Bypass;Right atrial structure;Right pulmonary artery;Right ventricular structure;Sheep;Side;Simulate;Small Business Technology Transfer Research;Superior vena cava structure;Surgeon;System;Technology;Testing;Transplantation;Universities;Venous;Work;artificial lung;base;blood pump;commercialization;design;experience;flexibility;improved;in vivo;multidisciplinary;patient population;pressure;prototype;research and development;respiratory;standard care

public_health_relevance:
We are proposing to develop a percutaneous Cavopulmonary assistance system to bridge the patients with failing Fontan circulation for recovery reconstructive surgery and heart transplantation.


application_id: 8123307
project_number: 5R01EY019891-02
project_title: Role of 14-3-3o in development and repair of corneal epithelium
administering_ic: NEI
award_notice_date: 2011-08-17
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 019891
program_official: MCKIE, GEORGE ANN
project_start_date: 2010-09-01
project_end_date: 2014-08-31
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 8891723
contact_pi: LI, QIUTANG
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): Exposure of the corneal epithelium to the environment leaves this important barrier susceptible to injury. Accordingly the corneal epithelium has a remarkable self-renewal capacity. This self renewal is mediated by a reservoir of limbal stem cells which migrate to sites of injury where they proliferate and differentiate to replace the damaged epithelium. This proposal is directed toward understanding the role of 14-3-3C in corneal epithelial differentiation. 14-3-3 is a family of proteins that bind phosphoproteins and regulate their subcellular localization. 14-3-3C is the epithelial-specific family member and using a mouse genetic model we demonstrate its crucial role in corneal epithelial differentiation Mutation of both copies of the gene leads to defective corneal epithelial development in the embryo. Heterozygous mutation allows for normal embryonic development; however the corneal epithelial differentiation in response to injury remains impaired. Thus 14-3-3C gene dosage distinguishes corneal epithelial development embryologically from corneal epithelial differentiation following injury. This defect in differentiation leads to outgrowth of undifferentiated cells which eventually form an opaque corneal plaque with associated inflammation and neovascularization. This plaque forms spontaneously as the heterozygous mice age and we provide evidence that this is linked to a dry eye-like effect resulting from a defective meibomian gland which fails to secrete lipid. Notch1 is essential for corneal epithelial differentiation via its activation of genes important for both differentiation (including genes in the vitamin A pathway) as well as cell cycle arrest and we have found that 14-3-3C mutant cells fail to activate Notch1. Expression of activated Notch1 restores differentiation in mutant cells and accordingly the defective differentiation phenotype and the resulting corneal plaque formation closely resemble that seem with tissue-specific knockout of the Notch1 gene. We link 14-3-3C to cell surface expression of the EGF receptor (EGFR) and thus to the Erk signaling pathway which is activated by binding of EGF to this receptor. This is important because EGF signaling represses Notch1 and this signaling must be extinguished for Notch1 expression and subsequent corneal epithelial differentiation. We propose studies to further characterize the linkage between 14-3-3C EGFR and Notch1 (and its target genes) in corneal epithelia differentiation. These studies involve both cell culture and genetic cross using 14-3-3C mutant mice.  
  
PUBLIC HEALTH RELEVANCE: The integrity of the cornea the most anterior part of the eye is indispensable for vision. Forty-five million individuals worldwide are bilaterally blind and another 135 million have severely impaired vision in both eyes because of the loss of corneal transparency. Our proposed experiments aim to elucidate the essential role of 14-3-3C in corneal epithelial homeostasis and wound healing and to understand the molecular network that controls the process. We shall study the cornea epithelium development and wound healing process barrier integrity and the molecular/genetic properties of 14-3-3C mutant mice. We hope to better understand corneal disease development and provide new strategies for prevention and treatment.

project_terms:
Affect;Age;Aging;Alleles;Anterior;Binding (Molecular Function);Calcium;Cell Culture Techniques;Cell Cycle Arrest;Cell Differentiation process;Cell Proliferation;Cell surface;Cells;Complex;Cornea;Corneal Diseases;Corneal Injury;Corneal Opacity;Defect;Development;Differentiation Antigens;EGF gene;Embryo;Embryonic Development;Environment;Epidermal Growth Factor Receptor;Epithelial;Epithelial Cells;Epithelium;Eye;Eye Part;Failure (biologic function);Family;Family member;Gene Activation;Gene Dosage;Gene Targeting;Genes;Genetic Crosses;Genetic Models;Heterozygote;Homeostasis;Individual;Inflammation;Injury;Invaded;Knock-out;Link;Lipids;MEKs;Mediating;Molecular;Molecular Genetics;Mus;Mutant Strains Mice;Mutation;Pathway interactions;Pattern;Phenotype;Phosphoproteins;Phosphoserine Motif;Phosphotransferases;Play;Prevention strategy;Process;Proliferating;Property;Protein Binding;Protein Family;Proteins;Receptor Signaling;Role;Series;Signal Pathway;Signal Transduction;Site;Stem cells;Testing;Tissues;Transgenic Mice;Tumor Suppressor Proteins;Undifferentiated;Vision;Vitamin A;Wound Healing;base;blind;corneal epithelium;design;eye dryness;in vivo;limbal;meibomian gland;mutant;neovascularization;notch protein;null mutation;prevent;progenitor;programs;public health relevance;receptor;receptor expression;repaired;research study;response to injury;self-renewal

public_health_relevance:
The integrity of the cornea the most anterior part of the eye is indispensable for vision.Forty-five million individuals worldwide are bilaterally blind and another 135 million haveseverely impaired vision in both eyes because of the loss of corneal transparency. Ourproposed experiments aim to elucidate the essential role of 14-3-3 in corneal epithelialhomeostasis and wound healing and to understand the molecular network that controlsthe process. We shall study the cornea epithelium development and wound healingprocess barrier integrity and the molecular/genetic properties of 14-3-3 mutant mice.We hope to better understand corneal disease development and provide new strategiesfor prevention and treatment.


application_id: 8123233
project_number: 5R01CA116784-05
project_title: Abl Kinases in growth factor signaling motility and invasion
administering_ic: NCI
award_notice_date: 2011-07-20
application_type: 5
activity_code: R01
ic: CA
serial_number: 116784
program_official: AULT, GRACE S
project_start_date: 2007-08-01
project_end_date: 2013-07-31
study_section: Intercellular Interactions Study Section[ICI]
contact_pi_person_id: 1918859
contact_pi: PLATTNER, RINA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-08-01
project_abstract:
DESCRIPTION (provided by applicant):  Growth factors modulate cell proliferation migration and survival. Precise regulation of these processes is critical as deregulated growth factor signaling increases cellular migration and drives tumor invasion and metastasis the major cause of cancer-related deaths. Although Abl nonreceptor tyrosine kinases initiate leukemia development their role in the development or progression of solid tumors has not been studied. Previously we showed that Abl kinases are activated downstream of growth factor receptors via Src family kinases and PLC-yl and influence growth factor-mediated cytoskeletal reorganization and migration in fibroblasts. Deregulation of growth factor receptors Src kinases and PLC-yl in solid tumors such as breast cancer drives tumor invasion and metastasis. Our studies demonstrate that the Abl kinases are dramatically activated downstream of activated growth factor receptors and Src kinases in highly aggressive breast cancer cell lines and promote breast cancer invasion. Based on these findings the overall objective of this proposal is to characterize the conditions leading to Abl kinase activation in breast cancer and to define invasion-promoting signaling cascades controlled by the Abl kinases. We hypothesize that Abl family kinases translate and direct growth factor receptor and Src kinase-mediated signals to influence breast cancer invasion and metastasis. Three Specific Aims are described to evaluate this hypothesis: 1) Determine the conditions that activate the Abl kinases in breast cancer; 2) Identify biological and molecular mechanisms by which Abl kinases promote breast cancer cell invasion; and 3) Determine whether activation of the Abl kinases promotes breast cancer metastasis in vivo. To achieve our goal we will combine biochemical molecular cellular and whole animal approaches using: 1) primary breast tissue breast cancer cell lines; RNAi and inhibitors to identify mechanisms and conditions of Abl activation; 2) RNAi chemotaxis invasion and zymography assays to identify mechanisms by which Abl kinases promote invasion; and 3) in vivo metastasis studies to assess whether activation of the Abl kinases promotes metastasis in immune- compromised mice. These data are likely to provide mechanistic insight into how abnormal regulation of the Abl kinases contributes to breast cancer progression which may aid in the discovery of new drug combinations for preventing breast cancer metastasis and decreasing mortality.

project_terms:
Adhesions;Affect;Animals;Basement membrane;Biochemical;Biological;Biological Assay;Blood;Blood Vessels;Breast Cancer Cell;Cancer Etiology;Cancer cell line;Cell Line;Cell Proliferation;Cells;Cessation of life;Chemotaxis;Cultured Tumor Cells;Cytoskeletal Modeling;Data;Development;Distant;Dominant-Negative Mutation;Drug Combinations;Epidermal Growth Factor Receptor;Family;Fatty acid glycerol esters;Fibroblasts;Goals;Growth Factor;Growth Factor Receptors;Immune;In Vitro;In-Migration;Invaded;Label;Location;MAP Kinase Gene;Malignant Neoplasms;Mammary Gland Parenchyma;Mammary Neoplasms;Mammary gland;Matrix Metalloproteinases;Mediating;Metalloproteases;Metastatic Lesion;Molecular;Mortality Vital Statistics;Mus;Neoplasm Metastasis;Normal tissue morphology;Organ;PTK2 gene;PTPN11 gene;Pathway interactions;Pharmaceutical Preparations;Phosphotransferases;Platelet-Derived Growth Factor Receptor;Play;Primary Neoplasm;Process;Proliferating;Protein Tyrosine Kinase;Proteins;RNA Interference;Regulation;Resistance development;Role;Signal Transduction;Site;Solid Neoplasm;Stream;Tail;Testing;Translating;Tumor Cell Invasion;Veins;base;cell motility;fluorescence imaging;in vivo;inhibitor/antagonist;insight;kinase inhibitor;leukemia;malignant breast neoplasm;migration;prevent;research study;rho;src-Family Kinases;tumor;tumor progression


application_id: 8122112
project_number: 5R01HL074185-08
project_title: Endothelial Myocyte Matrix in Cardiac Remodeling
administering_ic: NHLBI
award_notice_date: 2011-05-24
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 074185
program_official: SCHWARTZ, LISA
project_start_date: 2003-09-05
project_end_date: 2014-05-31
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
arra_indicator: N
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;Health;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;PECAM1 gene;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 NOS3 protein;in vivo;innovation;novel;prevent;programs;radiotracer;relaxing factor;research study;response;sham surgery;tissue inhibitor of metalloproteinase 4

public_health_relevance:
Program Director/Principal Investigator (Last First Middle): Tyagi Suresh C.The myocyte contraction and relaxation are synchronized only when myocytes are connected by extracellularmatrix (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. Theendothelium in the heart is the least studied system because unlike conduit arteries the endocardialendothelium is burried in the muscle and it is difficult to separate its role in myocyte function. We developed anew techniques "cardiac rings" in which endothelium dependent or independent cardiac contraction andrelaxation 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-1in the underlying mechanism of fibrosis and endothelial-myocyte uncoupling in heart failure; and 2) will haveclinical translational ramifications of H2S in treating diastolic heart failure.PHS 398/2590 (Rev. 11/07) Page Continuation Format Page


application_id: 8121973
project_number: 1R43GM097784-01
project_title: Use of a viral mucin-like protein to convert adherent cells to suspension culture
administering_ic: NIGMS
award_notice_date: 2011-07-25
opportunity_number: PA-10-050
application_type: 1
activity_code: R43
ic: GM
serial_number: 097784
program_official: FLICKER, PAULA F
project_start_date: 2011-08-01
project_end_date: 2012-07-31
study_section: Special Emphasis Panel[ZRG1 IMST-J (16)]
contact_pi_person_id: 9710810
contact_pi: FATH-GOODIN, ANGELIKA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Most cell culture lines are anchorage-dependent and require surface attachment for proliferation. For industrial production increased surface area can be provided by microcarrier beads but the associated increases in cost and the resulting complexity of manipulation may preclude their use. Due to these limitations anchorage-independent cells are preferred for the production of biopharmaceuticals but appropriate anchorage-independent cells are not available for all applications; e.g. production of vaccines and cell-type specific proteins. This proposal explores the use of a novel insect virus protein to transform adherent cells to cells that can thrive in suspension culture.  ParaTechs has identified a cell line from Agrotis ipsilon (black cutworm) which provides levels of recombinant protein expression that are 3-to-10 times higher than the standard Sf9 cell line. Unfortunately the cells are strongly adherent which makes them unsuitable for large-scale protein production. We intend to stably transform the A. ipsilon cells with an insect virus gene that causes a loss of adhesion in hemocytes. We predict that expression of this protein in transformed cells will enable them to grow in suspension culture. In combination with our Vankyrin-Enhanced Baculovirus Expression Vector System (VE-BEVS) which has the ability to increase protein production per cell by a factor of 4 to 22 we anticipate achieving a level of protein expression per cell that is at least 12-to-220 times higher than currently possible. This dramatic increase in yield will be significant for all BEVS users from individual researchers to large biopharmaceutical companies. We also will apply this technology to adherent mammalian tissue cultures. A simple method for converting mammalian cells from anchorage-independent to suspension culture would make a significant contribution to the production of vaccines and bio-therapeutics and would result in improved human health.  ParaTechs personnel are experienced baculovirologists and cell biologists. The protocols use standard technologies that are routinely adopted in our company. We do not anticipate difficulty with the experimentation. Current literature strongly supports our hypothesis and we are confident of our success.  
  
PUBLIC HEALTH RELEVANCE: The future of human medicine will involve a dramatic increase in development of protein-based drugs and subunit vaccines whose production will require large-scale propagation of tissue culture cells in suspension culture. Most continuous cell lines however are anchorage-dependent and no method exists to routinely and easily transform adherent cells to suspension culture. ParaTechs will test an insect virus gene that causes hemocytes to lose adhesion for the ability to adapt anchorage- dependent insect and mammalian cells to suspension culture. Achievement of this goal would make a significant contribution to biopharmacology and human health.

project_terms:
Achievement;Adherent Culture;Adhesions;Adopted;Area;Baculoviruses;Biological Products;Cell Adhesion;Cell Line;Cells;Characteristics;Data;Development;Future;Genes;Goals;Growth;Health;Hemocytes;Human;Human Resources;Individual;Insect Viruses;Insecta;Kinetics;Literature;Mammalian Cell;Marketing;Mediating;Medicine;Mesenchymal Stem Cells;Methods;Monitor;Mucins;Pharmaceutical Preparations;Phase;Platelet Factor 4;Production;Property;Proteins;Protocols documentation;Recombinant Proteins;Relative (related person);Research Personnel;Sf9 cell line;Stem cells;Subunit Vaccines;Surface;Suspension Culture;Suspension substance;Suspensions;System;Technology;Testing;Therapeutic;Time;Tissue Engineering;Transgenic Organisms;Undifferentiated;Vaccine Production;Vaccines;Viral;Viral Proteins;base;cell growth;cell transformation;cell type;continuous cell line;cost;embryonic stem cell;experience;expression vector;gene delivery system;high risk;high standard;improved;novel;protein expression;scale up;success;tissue culture;tissue/cell culture;vector

public_health_relevance:
The future of human medicine will involve a dramatic increase in development of protein-based drugs and subunit vaccines whose production will require large-scale propagation of tissue culture cells in suspension culture. Most continuous cell lines however are anchorage-dependent and no method exists to routinely and easily transform adherent cells to suspension culture. ParaTechs will test an insect virus gene that causes hemocytes to lose adhesion for the ability to adapt anchorage- dependent insect and mammalian cells to suspension culture. Achievement of this goal would make a significant contribution to biopharmacology and human health.


application_id: 8121554
project_number: 5R01CA153132-02
project_title: Oncopigs as a better model for human cancer
administering_ic: NCI
award_notice_date: 2011-05-23
opportunity_number: RFA-GM-10-009
application_type: 5
activity_code: R01
ic: CA
serial_number: 153132
program_official: MIETZ, JUDY
project_start_date: 2010-08-05
project_end_date: 2014-05-31
study_section: ZCA1-SRLB-R(M1)R
contact_pi_person_id: 8801334
contact_pi: CLARK, GEOFFREY J.
other_pis: RUND, LAURETTA ;SCHOOK, LAWRENCE B.
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): This project is driven by the hypothesis that current in vivo models for evaluating cancer therapies are too non-predictive of the human condition for efficient use. This may become a major impediment to the translation of new potential drugs into effective therapies for patients. The project proposes to determine if transgenic pigs may serve as a novel and more human-like model for cancer. Although pigs have been used extensively in biomedical research to date there is no reported transgenic swine model for cancer. Like humans pigs can live for decades and have a very low rate of spontaneous cancer. This is in contrast to common rodent-based cancer models where life span is limited to a few years and the spontaneous development of cancer is quite high. We now know that 5-6 to six genetic defects are required to convert a normal pig cell into a tumor cell. This is the same as in humans. However mouse cells can be transformed into tumor cells by as little as two genetic lesions. These simple yet profound genetic observations point to pigs as a far superior model system for the human condition.  We propose to use state of the art technology to generate transgenic pigs that can be induced to lose the expression of three major tumor suppressors simultaneously in the breast. These alterations will be coupled with an up-regulation of a growth hormone receptor. These genetic defects are often found in breast cancer and particularly in Triple Negative (TN) breast cancer. TN breast cancer is an especially aggressive and difficult to treat form of breast cancer with a high morbidity rate. We will include a far red fluorescent protein in the system which will allow non-invasive imaging of the status of the induced breast cells.  The project will involve the collaboration of laboratories with extensive experience in the molecular and cellular biology of human breast cancer and laboratories with world renown in the production and husbandry of transgenic pigs.  Animals will be tested to determine if these lesions are sufficient to provoke breast cancer and whether any such cancers have the characteristics of TN breast cancer. We will also use the population to test the effectiveness of cancer chemopreventative agents and whether the pigs respond to front line therapy for TN breast cancer in a similar manner to humans.  
  
PUBLIC HEALTH RELEVANCE: This project will establish a novel model system for evaluating new therapeutic approaches to cancer. The system should be much more predictive for the human condition thus enhancing the ability to identify and characterize effective novel therapeutics. It may also establish a unique model for the study of cancer preventative strategies that cannot be realistically modeled at present. The model is targeted towards breast cancer as over 40 thousand women are expected to die in the United states each year from this disease due to lack of sufficiently effective therapies.

project_terms:
African American;Animal Model;Animals;Arteriosclerosis;BRCA1 gene;Biological Assay;Biological Factors;Biological Models;Biomedical Research;Breast;Cancer Model;Cells;Characteristics;Clinical Trials;Collaborations;Controlled Study;Coupled;Development;Diabetes Mellitus;Disease;Disease model;Effectiveness;Epidermal Growth Factor Receptor;Failure (biologic function);Family suidae;Genetic;Growth Hormone Receptor;Hand;Human;Image;Laboratories;Lesion;Life;Lipids;Lipoproteins;Longevity;Malignant Neoplasms;Metabolism;Metastatic malignant neoplasm to brain;MicroRNAs;Modeling;Molecular;Molecular and Cellular Biology;Monitor;Morbidity - disease rate;Mus;Mutation;Neoplasm Metastasis;Patients;Pharmaceutical Preparations;Pilot Projects;Population;Production;Proteins;Reporting;Rodent;Series;Staging;Study models;System;Technology;Testing;Therapeutic;Time;Tissues;Transgenic Organisms;Translations;Tumor Suppressor Proteins;United States;Up-Regulation (Physiology);Variant;Woman;Work;arterial lesion;base;cancer genetics;cancer prevention;cancer therapy;design;effective therapy;experience;expression vector;genome sequencing;human disease;in vivo;in vivo Model;inhibitor/antagonist;interest;loss of function;malignant breast neoplasm;model development;mouse model;neoplastic cell;novel;novel therapeutic intervention;novel therapeutics;predictive modeling;public health relevance;red fluorescent protein;research study;success;triple-negative invasive breast carcinoma;tumor;tumorigenesis;tumorigenic;vector

public_health_relevance:
Narrative This project will establish a novel model system for evaluating new therapeuticapproaches to cancer. The system should be much more predictive for the humancondition thus enhancing the ability to identify and characterize effective noveltherapeutics. It may also establish a unique model for the study of cancer preventativestrategies that cannot be realistically modeled at present. The model is targeted towardsbreast cancer as over 40 thousand women are expected to die in the United states eachyear from this disease due to lack of sufficiently effective therapies.


application_id: 8120654
project_number: 5P20CA150343-02
project_title: Targeted Inhibition of P13K Pathway Components as Novel Treatment of Colectoral C
administering_ic: NCI
opportunity_number: PAR-08-020
application_type: 5
activity_code: P20
ic: CA
serial_number: 150343
study_section: ZCA1
subproject_number: 5642
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-09-01
budget_end_date: 2011-08-31
funding_mechanism: Research Centers
project_abstract:
Colorectal cancer is the second leading cause of cancer deaths in the United States. When localized to the
mucosa and submucosa of the bowel wall (Stage I) the five year survival approaches 100%; however
metastasis to lymph nodes (Stage 111) results in a precipitous decrease in five year survival and systemic
metastasis to the liver (ie Stage IV) is associated with a five year survival that is less than 5%. Activation of
phosphatidylinositol 3-kinase (PI3K) a ubiquitous lipid kinase composed of an 85 kDa regulatory subunit
(p85) and a 110 kDa catalytic subunit (p110) and its downstream effector protein Akt is associated with
the growth and progression of a number of cancers including colorectal cancer. We have shown that
inhibition of PISK/Akt decreases viability and growth increases differentiation and apoptosis of human
colorectal cancer cells. Furthermore PISK/Akt inhibition decreases colon cancer xenograft growth in
athymic nude mice and sensitizes these cancers to the apoptotic effects of chemotherapeutic agents (eg 5-
FU). Moreover we have shown altered PISK/Akt expression in colorectal cancers and surrounding stroma
with increased expression of the p8Sa subunit and Akt2 in colorectal cancers of increasing stage. Targeted
inhibition of either p8Sa or p110a by RNA interference (RNAi) increased sensitivity of resistant colorectal
cancers to the effects of chemotherapy and significantly suppressed colorectal cancer metastasis to the
liver in preclinical animal models. The central hypothesis of this project is that colorectal cancer growth
and progression are augmented by increased p85a and Akt2 expression; the selective inhibition of PISK/Akt
components can suppress colorectal cancer growth and metastasis and can sensitize resistant colorectal
cancers to chemotherapeutic agents. The long-term qoai is to develop more selected therapies for
colorectal cancer progression and metastasis based on a systematic analysis of colorectal cancers tumor
stroma and surrounding mucosa for expression of piSK/Akt pathway components. To examine our hypothesis and address the long-term goal we have designed experiments with the following Specific
Aims: 1) To provide clinical validation of the pattern and significance of PISK/Akt/PTEN pathway component expression in polyps and colorectal cancers of different stages. 2) To assess novel strategies of selective PISK component inhibition on in vivo tumor growth and liver metastasis using preclinical animal models. 3) To evaluate the therapeutic efficacy of RNAi to the PISK pathway in combination with conventional chemotherapy. The cumulative information derived from ttiese studies will lead to better targeted therapeutics and treatment paradigms for colorectal cancer.

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


application_id: 8120644
project_number: 5P20CA150343-02
project_title: Hepatitis C and Tumor Suppressors in Hepatocellular
administering_ic: NCI
opportunity_number: PAR-08-020
application_type: 5
activity_code: P20
ic: CA
serial_number: 150343
study_section: ZCA1
subproject_number: 5626
contact_pi_person_id: 1884112
contact_pi: LEMON, STANLEY M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-09-01
budget_end_date: 2011-08-31
funding_mechanism: Research Centers
project_abstract:
This project seeks to determine the clinical relevance and potential role in hepatic carcinogenesis of
interactions between host cell and hepatitis C virus (HCV) proteins that have been identified in previous cell
culture-based experiments. The retinoblastoma susceptibility protein (pRb) and the cellular DEAD-box RNA
helicase DDXS play critical roles in regulating the cell cycle. Our previous work indicates that the HCV RNA
polymerase NS5B fc^nns a complex with pRb targeting it for ubiquitination and proteasome-dependent
degradation activating E2F-responsive promoters and stimulating cell proliferation. Similarly HCV cofe
protein expression alters the cellular abundance and localization of DDX3. Our hypothesis is that these and
other interactions with host proteins (p53 and DDX5) promote proliferation of hepatocytes and impair DNA
damage responses tljiereby contributing to HCV carcinogenesis. In Aim 1 we will develop and validate
fluorescent quantum dot probes capable of sensitive detection of HCV proteins expressed in virus-infected
cells. We will also determine whether HCV protein expression conrelates with altered tumor suppressor
expression in transgenic mice. Aim 2 will utilize these novel probes in laser scanning confocal and multi
photon microscopy studies of liver tissue from patients with chronic hepatitis C and ask whether the
abundance and cellular localization of pRb p53 DDXS or DDXS is altered in infected hepatocytes. In Aim 3
we will determine whether HCV infection is associated on a single-cell basis with increased expression of the
proliferation markers Ki-67 and PCNA. We will also determine whether the proportion of cells displaying
proliferation markers is reduced after standard-of-care peg-IFN/ribavirin therapy. These results will be
correlated with oligonucleotide microarray and quantitative RT-PCR assays to determine whether liver
specimens with a high proportion of HCV-infected cells display transcriptional patterns indicative of
hepatocellular proliferation and/or E2F transcription factor activation. RELEVANCE TO PUBLIC HEATH:'
Liver cancer is one qf the most rapidly increasing types of cancers in the United States reflecting an
increased prevalence ^nd risk of liver cancer in persons with chronic hepatitis C. This project seeks a better
understanding of the interaction of HCV proteins with important regulators of cell proliferation (pRb p53
DDXS and DDXS) anc( the role of such interactions in liver cancer caused by HCV infection.
PERFORMANCE SITE

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


application_id: 8120521
project_number: 5R01EY014821-08
project_title: Mechanisms of Intermediate Distance Space Perception
administering_ic: NEI
award_notice_date: 2011-08-08
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 014821
program_official: WIGGS, CHERI
project_start_date: 2003-04-01
project_end_date: 2014-07-31
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 1965646
contact_pi: HE, ZIJIANG
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Visual space perception in the intermediate distance range (2-25 meters) serves a multi-faceted function. It allows the observer to perceive the 3D shapes sizes and locations of objects orient in space and guides our actions. Yet despite its importance in enabling the observer to interact in the natural environment knowledge of the mechanisms underlying space perception in the intermediate distance is incomplete. The long-term objectives of this project are to understand the basic mechanisms of space perception and to discover how these mechanisms mediate human space perception and action. Pertaining to the ability to locate an object on the ground previous work found that the visual system achieves this by constructing a representation of the ground surface and then uses it as a reference frame to localize an object on the ground. To localize a suspended object requires determining the relative position between the suspended object and the ground reference frame. Recent empirical studies have provided critical evidence for the notion of a ground-based space perception and led to the discovery of several fundamental mechanisms for representing the ground surface. This progress has motivated the formulation of a more comprehensive theoretical framework for understanding how the visual system forms the ground-based perceptual space in the current proposal. The specific aims are to seek quantifiable empirical proofs to substantiate and advance the framework. The following three broadly defined issues will be investigated: A. The Perceptual Mechanisms Used by the SSIP to Represent the Ground and Other Surfaces B. The Role of Top-Down Processing in Space Perception C. Locating an Object that Does Not Have a Direct Surface Contact with the Ground The research will employ the psychophysical method to test human observers predominantly in the real 3D environment. In addition to complement the research performed in the real 3D environment the proposed project will investigate space perception in the virtual environment by capitalizing on the virtual reality technology. This approach is not only useful for controlling the experimental stimulation but will also yield insights into how one can improve the immersive quality of virtual scenes. Overall the findings and insights gained from the proposed project will advance the science of human space perception in the intermediate distance range. It will also improve our understanding of the visual problems confronted by people with compromised visual functions.  PUBLIC HEALTH RELEVANCE: Research of space perception in the intermediate distance is important because a significant proportion of our daily activity such as locomotion and navigating are performed over this distance range. Besides its contribution to perceptual sciences the knowledge gained from this project can provide insights into the space perception and action problems of patients with visual deficits (e.g. in strabismus and amblyopia) and the problems encountered by ordinary people in non-optimal visual environments. The approach of using the virtual reality technology in the proposed project has the potential of being adapted into a useful tool for aiding people with space perception deficits.

project_terms:
Address;Affect;Amblyopia;Attention;Binocular Vision;Characteristics;Complement;Cues;Depth Perception;Distance Perception;Drug Formulations;Effectiveness;Environment;Eye;Figs - dietary;Financial compensation;Funding;Goals;Health;Human;Investigation;Knowledge;Learning;Link;Literature;Location;Locomotion;Measures;Mediating;Methods;Motion;Patients;Positioning Attribute;Process;Psychophysiology;Relative (related person);Research;Role;Sampling;Scanning;Science;Shapes;Source;Space Perception;Specific qualifier value;Strabismus;Surface;Technology;Testing;Texture;Vision;Vision Disparity;Visual;Visual system structure;Work;arm;base;improved;insight;meter;monocular;novel;operation;tool;virtual;virtual reality


application_id: 8120395
project_number: 5R21DA027466-03
project_title: Developmental Cigarette Smoke Exposure: Biomarkers of Neurotoxicity
administering_ic: NIDA
award_notice_date: 2011-07-28
opportunity_number: RFA-DA-09-022
application_type: 5
activity_code: R21
ic: DA
serial_number: 027466
program_official: SATTERLEE, JOHN S
project_start_date: 2009-09-15
project_end_date: 2013-08-31
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;Breathing;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;Proteins;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;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: 8119923
project_number: 3R01AA014371-05S1
project_title: Mechanisms of Alcohol-Induced Immunosuppression
administering_ic: NIAAA
award_notice_date: 2010-08-20
application_type: 3
activity_code: R01
ic: AA
serial_number: 014371
suffix: S1
program_official: JUNG, KATHY
project_start_date: 2010-08-20
project_end_date: 2011-06-30
study_section: Special Emphasis Panel[ZRG1-DIG-F(02)M]
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant):  Alcohol abuse imposes a heavy burden on the U.S. health care system. Immune dysfunction associated with chronic alcohol abuse is linked to increased clinical morbidity such as infectious diseases and neoplasia.  A critical factor in the alcohol abuse associated immune impairment is the loss of CD4+ T lymphocytes.  Based on our substantial preliminary data we hypothesize that a decrease in S-adenosylmethionine (SAMe) caused by ethanol-induced inhibition of methionine adenosyl transferase (MAT2A) enhances the susceptibility of CD4+ T-cells to Fas- and activation (T cell receptor - TCR) - mediated apoptotic death.  To test this hypothesis we will examine the effect of ethanol on PBMCs/CD4+ T-cells obtained from alcoholic patients and abstinent healthy control subjects.  The overall goals of this proposal are:  (i) to elucidate the molecular mechanisms underlying ethanol mediated depletion of CD4+ T lymphocytes and ensuing immune dysfunction and (ii) to provide a basis for clinically relevant paradigms for the development of potential therapeutic intervention(s) using S-adenosylmethionine (SAMe) in alcoholic patients.  Accordingly the effects of ethanol on Fas- and TCR-induced apoptotic signaling components will be determined.  We will perform systematic analyses of the effects of ethanol on MAT2A gene expression and activity and SAMe levels in CD4+ T-cells in order to determine the relevance of MAT2A and SAMe as molecular targets of ethanol-induced CD4+ T-cell toxicity.  We will also determine the efficacy of exogenous SAMe supplementation in attenuating CD4+ T-cell death induced by ethanol.  Overall we expect our studies to elucidate critical molecular mechanisms underlying CD4+ T-cell depletion associated with chronic alcohol abuse.  Moreover the data from these studies would support our future goals by providing a basis for relevant clinical paradigms for the development of potential therapeutic intervention(s) for alcoholic patients.

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


application_id: 8119912
project_number: 3R01NS065052-01A2S1
project_title: Neural circuit disruption by diffuse brain injury: basis for morbidity & therapy
administering_ic: NINDS
award_notice_date: 2010-08-09
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: NS
serial_number: 065052
suffix: A2S1
program_official: HICKS, RAMONA R
project_start_date: 2010-02-01
project_end_date: 2015-01-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 2048186
contact_pi: LIFSHITZ, JONATHAN
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Our long term goals are to develop effective pharmacological and rehabilitative treatment strategies that promote adaptive reorganization of brain-injured circuits to mitigate neurological dysfunction (morbidity) after diffuse traumatic brain injury (TBI). To achieve these goals we will exploit a novel reproducible late-onset neurological deficit that we have observed in the diffuse brain-injured rat analogous to agitation in brain injury survivors. In contrast to the soothing and pacifying nature of facial whisker stimulation in uninjured rats brain- injured rats react to whisker stimulation by cowering freezing and guarding the mystacial pads. This aberrant behavior is concomitant with axonal damage neuronal atrophy persistent inflammation and neuroplasticity such that whisker stimulation activates brain regions outside the conventional somatosensory whisker circuit. The current proposal tests the hypothesis that diffuse brain injury-induced inflammation drives the maladaptive structural plasticity responsible for aberrant behavioral responses to whisker stimulation. The model system afforded by the brain-injured somatosensory whisker circuit provides a reductionistic approach to the complexity of diffuse TBI to address pathological and reparative mechanisms associated with post-traumatic morbidity. This circuit in diffuse brain-injured adult male rats will be evaluated for (Aim 1) aberrant behaviors elicited by whisker stimulation (Aim 2) chronic neuropathology neuronal activation and circuit reorganization and (Aim 3) neuroinflammation-driven neuroplastic responses that contribute to circuit reorganization and morbidity. An anti-inflammatory therapeutic regimen may provide a clinically relevant intervention to prevent circuit rewiring and the onset of morbidity. The innovative combination of behavioral anatomical functional and therapeutic approaches directed at the brain-injured somatosensory whisker circuit addresses the underlying mechanisms associated with unregulated structural plasticity in the injured brain. Uncovering these processes can direct treatments to mitigate the onset reduce the duration and/or promote the resolution of neurological dysfunction. Results from this circuit can ultimately be expanded to other circuits in rodents and then man to improve quality of life for millions of TBI survivors and potentially others suffering from progressive neurodegenerative diseases.    PUBLIC HEALTH RELEVANCE: The present proposal focuses on the persistent morbidity experienced by diffuse brain injury survivors for whom treatment options are limited. In diffuse brain-injured rats aberrant responses to whisker stimulation will be employed as a tool to identify pathological and reparative mechanisms associated with somatosensory whisker circuit disruption. By developing validating and implementing an animal model of one discrete post-traumatic morbidity significant advancements can be made towards reshaping first one then other brain- injured circuits in rodents and man.

project_terms:
Acute;Address;Adult;Agitation;Animal Model;Anti-Inflammatory Agents;Anti-inflammatory;Atrophic;Attenuated;Axon;Behavior;Behavioral;Biological Models;Blood Vessels;Brain;Brain Injuries;Brain region;Cellular Membrane;Chronic;Communities;Diffuse;Diffuse Brain Injury;Dose;Face;Figs - dietary;Freezing;Functional disorder;Gene Expression;Goals;Ibuprofen;Immediate-Early Genes;Inflammation;Inflammatory;Injury;Intervention;Left;Liquid substance;Measures;Mechanics;Medical;Messenger RNA;Modeling;Molecular;Morbidity - disease rate;Nature;Neurodegenerative Disorders;Neurologic;Neurologic Dysfunctions;Neuronal Plasticity;Neurons;Pathologic Processes;Percussion;Performance;Pharmaceutical Preparations;Process;Quality of life;Rattus;Regimen;Rehabilitation therapy;Research;Resolution;Rodent;Sensory;Severities;Societies;Somatosensory Cortex;Survivors;Symptoms;Testing;Therapeutic;Time;Traumatic Brain Injury;Ventral Posterior Nucleus;Vibrissae;base;clinically relevant;effective therapy;experience;improved;in vivo Model;injured;innovation;male;man;neural circuit;neuroinflammation;neuropathology;novel;organic base;prevent;protein expression;psychologic;public health relevance;response;somatosensory;tool;treatment strategy

public_health_relevance:
7. Project Narrative The present proposal focuses on the persistent morbidity experienced by diffuse brain injury survivors forwhom treatment options are limited. In diffuse brain-injured rats aberrant responses to whisker stimulation willbe employed as a tool to identify pathological and reparative mechanisms associated with somatosensorywhisker circuit disruption. By developing validating and implementing an animal model of one discrete post-traumatic morbidity significant advancements can be made towards reshaping first one then other brain-injured circuits in rodents and man.


application_id: 8119121
project_number: 5U24HL094373-02
project_title: Preclinical Consortium to Facilitate Translation of Cardioprotective Therapies
administering_ic: NHLBI
award_notice_date: 2011-08-08
application_type: 5
activity_code: U24
ic: HL
serial_number: 094373
program_official: LIANG, ISABELLA Y
project_start_date: 2010-08-01
project_end_date: 2015-07-31
study_section: ZHL1-CSR-H(O1)
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-08-01
project_abstract:
DESCRIPTION (provided by applicant):   
  
Ischemic heart disease causes -600000 deaths/year (-20% of all deaths). An estimated 1.3 million Americans have a myocardial infarction every year; because their prognosis is determined by the size of the infarct reducing infarct size is of paramount importance to alleviate morbidity and mortality. For more than 30 years the NHLBI has invested enormous resources (at least several hundred million dollars) in preclinical studies aimed at developing infarct-sparing therapies and several hundred (if not thousands) therapies have been claimed to limit infarct size in preclinical models. Unfortunately due to methodological problems this enormous investment has not produced any notable clinical application and no cardioprotective therapy is currently available for clinical use. After >30 years of futile efforts a new approach is needed to overcome the problems that have impeded the translation of cardioprotective therapies. The time has come to apply to preclinical research the same standards of scientific rigor that are applied to clinical trials. Using the clinical trials networks established by the NHLBI as a model for developing a collaborative infrastructure for research sharing we propose a preclinical consortium that will operate in a manner analogous to a clinical network. Six Institutions will work together to conduct blinded randomized and adequately powered studies using a rigorous design full dose-response analyses optimal statistical methods independent data analysis and statistical Cores histology plasma biomarkers and relevant animal models (including conscious animals and models of comorbidities) in three species (mouse rabbit pig). To ensure reproducibilitv. each study will be performed in two Centers using identical protocols. This unique infrastructure will enable rigorous preclinical evaluation of promising cardioprotective therapies and will serve the entire scientific community (both in academia and in biomedical industry) thereby constituting a public resource. Proposals for studying therapies will be solicited from the entire scientific community and reviewed by an independent Protocol Review Committee which will select those that will be implemented. At least 3 therapies/year will be tested. The consortium structure will ensure that it will be a true public resource available to all interested investigators and that all proposed studies will be evaluated in an equitable fashion. The need for this infrastructure is attested to by 30 letters (Appendix). This will be a paradigm shift in cardioprotection. By screening promising therapies and identifying those that are reproduciblv effective in relevant experimental models and thus most likely to be effective in patients the consortium will dramatically advance our ability to rationally translate basic findings into clinical use.   
  
This proposal addresses an issue that has major importance for the NHLBI mission and for public health at large namely the failure to translate experimental studies of cardioprotection into clinical therapies. Ischemic heart disease is the number one cause of death and disability in America. Since ~1.3 million Americans have a myocardial infarction each year and their prognosis is determined by the size of the infarct reducing infarct size will have a major impact on their morbidity and mortality and thus enormous implications for public health. (End of Abstract)

project_terms:
Academia;Acute myocardial infarction;Address;American;Americas;Animal Model;Basic Science;Blast Cell;Blinded;Carbon Monoxide;Cause of Death;Cessation of life;Clinical;Clinical Trials;Clinical Trials Network;Communities;Comorbidity;Conscious;Doctor of Medicine;Dose;Educational workshop;Electronic Mail;Ensure;Evaluation;Experimental Models;Failure (biologic function);Family suidae;Funding;Future;Goals;Healthcare;Histology;Individual;Industry;Infarction;Institution;Intervention;Investments;Ischemic Preconditioning;Journals;Laboratories;Letters;Logistics;Mind;Mission;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mus;Myocardial Infarction;Myocardial Ischemia;Myocardial tissue;National Heart Lung and Blood Institute;Oryctolagus cuniculus;Participant;Patients;Phase;Plasma;Pre-Clinical Model;Probability;Protocols documentation;Publishing;Randomized;Recommendation;Reperfusion Therapy;Reporting;Reproducibility;Research;Research Infrastructure;Research Personnel;Resource Sharing;Resources;Review Committee;Role;Screening procedure;Sodium Nitrite;Statistical Data Interpretation;Statistical Methods;Structure;System;Testing;Therapeutic Intervention;Time;Translating;Translational Research;Translations;United States National Institutes of Health;Work;abstracting;biomarker;clinical application;design;disability;interest;meetings;member;myocardial infarct sizing;novel strategies;operation;outcome forecast;pre-clinical;pre-clinical research;preclinical evaluation;preclinical study;programs;public health medicine (field);research study;response;sildenafil;success;web site;working group


application_id: 8118544
project_number: 5F30NS064669-03
project_title: Functional consequences of Notch-mediated angiogenesis following SCI
administering_ic: NINDS
award_notice_date: 2011-06-17
opportunity_number: PA-05-151
application_type: 5
activity_code: F30
ic: NS
serial_number: 064669
program_official: OWENS, DAVID F
project_start_date: 2009-07-01
project_end_date: 2012-06-30
study_section: NST-2 Study Section [NST-2]
contact_pi_person_id: 9401645
contact_pi: FASSBENDER, JANELLE M
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Traumatic spinal cord injury (SCI) is complicated by secondary pathology that increases tissue loss and exacerbates functional recovery beyond the initial physical impact. Destruction of the vasculature that supports spinal cord tissue compromises blood spinal cord barrier integrity and is a major impediment to tissue sparing and regeneration. While formation of new blood vessels occurs robustly 3-7 days after contusive injury the vessels are leaky contributing to inflammation and edema. Thus it is unclear at this time whether neovascularization facilitates or impairs tissue loss and functional recovery. Notch signaling which is critical to vascular development and pathological angiogenesis is known to regulate vascular sprouting through formation of tip cells and to control endothelial cell proliferation. Importantly increased Notch signaling facilitates the maturation of vessels. Although fewer in number these vessels are larger less leaky and are capable of supporting growing tissue (Noseda et al. 2004; Harrington et al. 2007; Li et al. 2007). We hypothesize that by promoting the maturation of vessels formed 3-7 days post-SCI inflammation and tissue loss will be attenuated and functional recovery improved. Controlled proliferation with enhanced vessel maturation would provide evidence to control or attenuate angiogenic treatment in the first week following SCI. Conversely increased endothelial cell proliferation leading to a greater vascular density by 7 days post-SCI may relieve the ischemia and hypoxia that contributes to tissue loss. Moreover attenuation of the inflammatory response by decreasing pro-inflammatory activation of the microvascuiature may significantly impede repair processes. This observation would support the use of pro-angiogenic treatments that increase numbers of vessels in the absence of controlled permeability and enhanced blood spinal cord barrier integrity. Importantly it is critical to determine the impact the manipulation of Notch signaling has not only on the vasculature but also inflammation and tissue loss due to secondary pathology. PUBLIC HEALTH RELEVANCE:  Taken together it is expected that the proposed experiments will provide evidence not only to support the role of Notch in new blood vessel formation after SCI but facilitate studies that seek to target acute vascular responses to enhance functional locomotor recovery.

project_terms:
4-Hydroxy-Tamoxifen;Acute;Adult;Affect;Animals;Attenuated;Blood;Blood Vessels;Blood flow;Brain Hypoxia-Ischemia;Cell Proliferation;Cells;Cessation of life;Contusions;Cytomegalovirus;Data;Development;Dominant-Negative Mutation;Edema;Endothelial Cells;Ensure;Excision;Female;Galactosidase;Health;Inflammation;Inflammatory;Inflammatory Response;Injection of therapeutic agent;Injury;Internal Ribosome Entry Site;Label;LacZ Genes;Lesion;Locomotor Recovery;Maintenance;Mediating;Mus;Natural regeneration;Outcome Measure;Pathologic Neovascularization;Pathology;Perfusion;Permeability;Process;Rattus;Recovery of Function;Regulation;Reporter;Role;Secondary to;Signal Transduction;Specificity;Spinal Cord;Spinal cord injury;Staining method;Stains;Testing;Thoracic spinal cord structure;Time;Tissues;Transgenes;Transgenic Mice;Trauma;angiogenesis;attenuation;cadherin 5;cell type;density;enhanced green fluorescent protein;improved;interest;neovascular;neovascularization;notch protein;prevent;repaired;research study;response;transgene expression;white matter


application_id: 8118155
project_number: 5R01AI075212-04
project_title: Modulation of Neutrophil Apoptosis by Akt-Hsp27 Signalosome
administering_ic: NIAID
award_notice_date: 2011-07-25
application_type: 5
activity_code: R01
ic: AI
serial_number: 075212
program_official: DONG, GANG
project_start_date: 2008-08-08
project_end_date: 2014-07-31
study_section: Erythrocyte and Leukocyte Biology Study Section[ELB]
contact_pi_person_id: 6799635
contact_pi: RANE, MADHAVI 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: 2011-08-01
project_abstract:
DESCRIPTION (provided by applicant): Activated neutrophils (PMNs) play a critical role in sepsis ischemia-reperfusion injury and immune complex-mediated diseases. The broad long-term objective of our laboratory is to elucidate the role of Akt in regulating PMN functions. This proposal will test the hypothesis: Hsp27 regulates neutrophil cell survival/ death responses by modulating critical protein-protein interactions within the Akt signalosome by acting as a scaffolding protein. The specific aims of this proposal are: Specific Aim 1 - To determine whether Akt associated/dissociated proteins regulate Akt activation and neutrophil apoptosis in the absence of Akt- Hsp27 interaction. Specific Aim 2- To determine signaling pathways that underlie Akt-Hsp27 disruption induced neutrophil apoptosis. Specific Aim 3- To determine whether induction of neutrophil apoptosis by disruption of Akt-Hsp27 interaction results from changes in phosphorylation and subcellular redistribution of Akt and its candidate proteins. In specific aim 1 we will generate TAT-fusion proteins to 4 Akt-associating and 4 Akt-dissociating proteins identified by our proteomic studies and determine effects of transducing these proteins on Akt activation and neutrophil apoptosis. cDNA subcloning site-directed mutagenesis protein transductions cDNA transfections in vitro kinase assays and apoptosis assays will be performed to accomplish this aim. Specific aim 2 experiments will be focused on determining mechanisms that underlie activation of p38 MARK and JNK pathways after disruption of Akt-Hsp27 interaction. We will also investigate the impact of Akt-Hsp27 disruption on the regulation of proteasomal activation. In vitro kinase assays proteasome activity assays transduction of relevant TAT-peptides into PMNs will be performed to accomplish this aim. In specific aim 3 we will focus our work on those Akt-associated or Akt-dissociated proteins shown to regulate Akt activation and neutrophil apoptosis in specific aim 1. We will then determine if these relevant proteins regulate Akt activation and neutrophil apoptosis by undergoing a post-translational modification such as phosphorylation and/or ubiquitination as a consequence of disruption of Akt-Hsp27 interaction. We will also determine if these protein modifications would result in change in localization of these proteins and/or alter their function. TAT-peptide transduction cell fractionation studies western blotting site-directed mutagenesis studies and confocal microscopy studies will be performed to accomplish this specific aim. These studies will lead us to new targets for disrupting neutrophil-mediated tissue damage in inflammatory diseases.

project_terms:
Address;Antigen-Antibody Complex;Apoptosis;Apoptotic;Bacteria;Binding (Molecular Function);Biological Assay;Cell Fractionation;Cell Survival;Cessation of life;Chimeric Proteins;Complementary DNA;Complex;Confocal Microscopy;Data;Disease;Excision;Goals;Granulocyte-Macrophage Colony-Stimulating Factor;Heat Shock Protein 27;IL8 gene;Immune system;In Vitro;Infection;Infection Control;Infectious Agent;Inflammatory;Injury;Killings;Laboratories;Lead;Leukotriene B4;Lipopolysaccharides;MAP Kinase Gene;MAPK14 gene;MAPK8 gene;Mediating;Neutrophil Activation;Organ failure;Pathway interactions;Peptides;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Play;Post-Translational Protein Processing;Protein Kinase;Protein-Serine-Threonine Kinases;Proteins;Proteomics;Regulation;Reperfusion Injury;Reporting;Role;Scaffolding Protein;Sepsis;Signal Pathway;Signal Transduction;Site;Site-Directed Mutagenesis;System;Testing;Time;Tissues;Transfection;Ubiquitin;Ubiquitination;Western Blotting;Work;base;chemokine;cytokine;fighting;member;multicatalytic endopeptidase complex;neutrophil;novel;novel strategies;novel therapeutics;pathogen;prevent;protein protein interaction;research study;response


application_id: 8118053
project_number: 5R01CA153227-02
project_title: Trial of mesna to prevent doxorubicin-induced plasma protein oxidation and TNFa r
administering_ic: NCI
award_notice_date: 2011-04-07
opportunity_number: RFA-GM-10-009
application_type: 5
activity_code: R01
ic: CA
serial_number: 153227
program_official: SONG, MIN-KYUNG H
project_start_date: 2010-08-01
project_end_date: 2013-05-31
study_section: ZCA1-SRLB-R(M1)R
contact_pi_person_id: 2197937
contact_pi: MOSCOW, JEFFREY A
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cognitive dysfunction after cancer chemotherapy or 'chemobrain' occurs after anthracycline- containing regimens. Since anthracyclines such as doxorubicin do not enter the central nervous system the mechanism behind this debilitating sequela of therapy has remained obscure. In contrast cardiomyopathy is a well-established toxicity of doxorubicin therapy. We propose two paradigm- shifting hypotheses to 1) explain the cognitive and cardiac toxicities of anthracycline chemotherapy and 2) to propose a remedy. In animal models doxorubicin-induced CNS and cardiac damage can be reversed with anti-TNF-1 antibody and with the antioxidant 3-GCEE. In an initial clinical study we observed a significant decrease in oxidative modification of plasma proteins after doxorubicin administration in children who were coincidentally receiving mesna a drug closely related to 3-GCEE compared to children who were not coincidentally receiving mesna. Mesna has an extracellular mechanism of action and is frequently given in combination chemotherapy regimens to prevent hemorrhagic cystitis associated with the alkylating agents ifosfamide and high-dose cyclophosphamide and is commonly coincidentally co-administered with anthracyclines without affecting cancer therapy outcomes. One of the plasma proteins oxidized by doxorubicin in these patients was APOA1. In further animal studies we found that mesna abrogates doxorubicin-induced oxidative modification of plasma proteins and prevents induction of stress markers in heart and brain tissues and in further in vitro studies we have shown that reduced APOA1 inhibits LPS-induced TNF- 1 release from the J774.4 macrophage cell line while oxidized APOPA1 activates LPS-induced TNF- 1 release from the J774.4 cells. Therefore we hypothesize mesna will prevent doxorubicin-induced oxidative modification of plasma proteins including APOA1 and thus prevent TNF-1 production. We will test this hypothesis in a blinded prospective clinical trial. Eligible participants will be cancer patients with breast cancer scheduled to receive the standard regimen A/C (doxorubicin and cyclophosphamide) and non-Hodgkin lymphoma patients scheduled to receive doxorubicin in CHOP or R-CHOP regimens. Participants will receive one cycle with mesna 360 mg/m2 and another cycle with saline prior to and 3 hours after doxorubicin. The primary endpoint will be determination of difference in oxidation of plasma proteins and TNF-1 levels at 6 hours post doxorubicin between the mesna-containing cycles and the saline-containing cycles. If our initial findings are confirmed in this pilot trial 1) plasma protein oxidation will be established as a novel mechanism of toxicity 2) a hitherto unknown drug interaction between doxorubicin and mesna will be established and 3) a larger randomized trial would be justified to study mesna to prevent the sequelae of doxorubicin therapy.   
  
PUBLIC HEALTH RELEVANCE: Cancer patients receiving chemotherapy regimens that include the anthracycline drugs such as doxorubicin are at risk for developing cognitive and cardiac impairment. We propose a novel hypothesis that these side effects are due to direct oxidative damage of plasma proteins by doxorubicin and we have demonstrated in an animal model that the drug mesna which is used to prevent other complications of other chemotherapy drugs prevents doxorubicin-induced plasma protein oxidative damage and the subsequent induction of markers of neurologic and cardiac injury. Goal: This clinical study will determine whether mesna prevents doxorubicin-induced damage of plasma proteins in cancer patients and will establish plasma protein oxidation as a potential mechanism of anthracycline-induced cognitive and cardiac dysfunction.

project_terms:
Adverse effects;Affect;Alkylating Agents;Animal Model;Animals;Anthracyclines;Antibodies;Antineoplastic Agents;Antioxidants;Back;Blinded;Blood;Blood - brain barrier anatomy;Brain Injuries;Cancer Patient;Cardiac;Cardiomyopathies;Cardiotoxicity;Cell Line;Cells;Chemotherapy-Oncologic Procedure;Child;Clinic;Clinical Research;Clinical Trials;Cognitive;Cyclophosphamide;Cystitis;Dose;Doxorubicin;Drug Interactions;Effectiveness;Functional disorder;Goals;Heart;Hematopoietic;Hour;Ifosfamide;Impaired cognition;Impairment;In Vitro;Injury;Intravenous;Mediating;Mesna;Modeling;Modification;Moscow;Mus;Myopathy;Neuraxis;Neurologic;Non-Hodgkin's Lymphoma;Participant;Patient Schedules;Patients;Pharmaceutical Preparations;Plasma Proteins;Principal Investigator;Production;Proteins;Proteomics;Reactive Oxygen Species;Regimen;Risk;Saline;Schedule;Series;Stress;Syndrome;TNF gene;Testing;Tissues;Toxic effect;Treatment Protocols;brain tissue;cancer therapy;chemobrain;chemotherapy;eligible participant;extracellular;macrophage;malignant breast neoplasm;novel;oxidation;oxidative damage;pilot trial;prevent;programs;prospective;public health relevance;randomized trial;therapy outcome

public_health_relevance:
Program Director/Principal Investigator (Last First Middle): Moscow Jeffrey A.NarrativeRelevance: Cancer patients receiving chemotherapy regimens that include the anthracycline drugssuch as doxorubicin are at risk for developing cognitive and cardiac impairment. We propose a novelhypothesis that these side effects are due to direct oxidative damage of plasma proteins bydoxorubicin and we have demonstrated in an animal model that the drug mesna which is used toprevent other complications of other chemotherapy drugs prevents doxorubicin-induced plasmaprotein oxidative damage and the subsequent induction of markers of neurologic and cardiac injury.Goal: This clinical study will determine whether mesna prevents doxorubicin-induced damage ofplasma proteins in cancer patients and will establish plasma protein oxidation as a potentialmechanism of anthracycline-induced cognitive and cardiac dysfunction.PHS 398/2590 (Rev. 11/07) Page Continuation Format Page


application_id: 8117842
project_number: 3R01AA015970-05S2
project_title: S-adenosylhomocysteine and S-adenosylmethionine in Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2010-08-09
application_type: 3
activity_code: R01
ic: AA
serial_number: 015970
suffix: S2
program_official: RADAEVA, SVETLANA
project_start_date: 2010-08-10
project_end_date: 2011-06-30
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): This proposal will evaluate critical-interactions of cytokines and nutritional/ metabolic abnormalities of the hepatic transmethylation/transsulfuration pathways in the development of ALD using novel human animal and in vitro models with the ultimate goal of developing specific therapy for ALD. Abnormal metabolism of tumor necrosis factor-alpha (TNF) is well documented in both experimental models of ALD and human ALD and TNF plays a critical role in the development of experimental ALD. Abnormal methionine metabolism also is well documented in ALD with patients frequently having elevated plasma methionine concentrations which correlate with prognosis. MAT1 A the enzyme responsible for the initial conversion of methionine to S- adenosylmethionine (SAMe) is decreased in ALD. Depressed SAMe levels are observed in most forms of experimental liver injury including ALD and SAMe therapy is an effective hepatoprotective agent in experimental liver injury. Data from our group show that one potential beneficial effect of SAMe is its ability to inhibit endotoxin stimulated TNF production in monocytes/Kupffer cells. Moreover MAT1A "knockout" mice have recently been generated and these SAMe deficient mice develop spontaneous steatohepatitis and are much more sensitive to a second insult. While SAMe levels are depleted in ALD both S-adenosylhomocysteine (SAH) and homocysteine levels are elevated. The SAMe:SAH ratio and the cellular concentration of SAH critically control most methyltransferase reactions in the body and we recently reported that increased SAH sensitized to TNF induced hepatotoxicity. It is our working hypothesis that increased TNF in conjunction with altered SAMe/SAH metabolism play an etiologic role in the development/progression of liver injury in ALD. The specific objectives of this proposal are to: 1. Document that SAH sensitizes to TNF hepatotoxicity in vitro and in vivo. 2. Evaluate the effects of alcohol/SAH on induction of mitochondrial dysfunction and hepatocyte death. 3. Determine mechanisms whereby SAMe and SAH modulate LPS-stimulated cytokine production. 4. Evaluate beneficial effects of SAMe therapy on critical metabolic functions in patients with alcoholic cirrhosis. These studies utilize state-of-the-art models/techniques in a translational approach to develop an enhanced understanding of mechanisms involved in ALD and potential new therapy for ALD.

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


application_id: 8116968
project_number: 5R01DK053220-13
project_title: DNA sequences impact estrogen and antiestrogen activity
administering_ic: NIDDK
award_notice_date: 2011-07-27
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 053220
program_official: MARGOLIS, RONALD N
project_start_date: 1998-04-01
project_end_date: 2013-07-31
study_section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Although mitochondrial gene expression depends on nuclear genome function and reciprocally "retrograde communication" from mitochondria regulates nuclear gene expression the mechanisms coordinating these events remain to be clarified. Mitochondria are targets of estrogen action. However the mechanisms for estrogenic effects on mitochondrial function are not yet defined. The overall goal of this project is to determine the mechanism(s) by which estradiol (E2) and selective estrogen receptor (ER) modulators (SERMs) regulate the transcription of Nuclear Respiratory Factor-1 (NRF-1) and the downstream impact of NRF-1 on estrogen- and SERM- regulated mitochondrial activity in normal and neoplastic cells. NRF-1 is a transcription factor that is critical for integrating nucleo-mitochondrial function by initiating transcription of nuclear-encoded mitochondrial DNA (mtDNA) -specific transcription factors including Tfam (mtDNA maintenance factor). We recently reported that E2 induces NRF-1 transcription in MCF-7 breast cancer cells via ER1-estrogen response element (ERE) activation. In Aim 1 we will test the hypothesis that the direct interaction of ER1 and ER2 with the NRF-1 promoter recruits different coregulators in a ligand- and cell- specific manner. Chromatin immunoprecipitation (ChIP) assays will address this hypothesis. The effect of siNRF-1 on E2-regulated cell cycle and apoptotic proteins and cell cycle entry will be examined. Results will reveal if E2-induced NRF-1 plays a role in E2's anti-apoptotic activity and if there are cell-specific differences in these responses. Additionally we will examine NRF-1 protein expression by IHC in normal and neoplastic human breast specimens. Experiments in Aim 2 will determine the effect of E2 and SERMs on NRF-1 and downstream target gene expression and ER-NRF-1 promoter interaction in vivo. ChIP assays will determine if E2 increases the direct interaction of ER1 coactivators and RNA pol II with the NRF-1 promoter in vivo in MCF-7 tumor xenografts and mouse tissues focusing first on uterus. Aim 3 is the `functional outcome' aim to measure the genes/proteins/mitochondrial activity including O2 consumption mt biogenesis heat generation i.e. downstream effects of E2-induced NRF-1 expression. Experiments will test the hypothesis that the E2- stimulated increase in NRF-1 will in turn increase the expression of NRF-1 regulated genes e.g. TFAM that subsequently increase expression of its mtDNA-encoded target genes e.g. Cytochrome c oxidase subunit I (MTCO1) and anti-apoptotic genes e.g. survivn. Together the results will define the molecular mechanisms of estrogen action coordinating mitochondrial function. Understanding how E2 and SERMs regulate mitochondrial function could lead to new insights in the prevention and progression of breast and lung cancer. PUBLIC HEALTH RELEVANCE: Although mitochondrial gene expression depends on nuclear genome function and reciprocally by "retrograde communication" mitochondrial activity regulates nuclear gene expression the mechanisms coordinating these events remain to be clarified. Mitochondrial dysfunction and increased reactive oxygen species mediate the pathophysiologic mechanisms of aging acute neurodegeneration caused by trauma stroke or cardiac arrest; and cancer initiation and tumor progression. The impact of steroids on mitochondrial function "is a new and novel area of investigation" and the proposed study seeks to delineate a new biological pathway of estrogen and antiestrogens/SERMs in regulating nuclear respiratory factor-1 (NRF-1) and its downstream targets in mitochondrial activity.

project_terms:
4-Hydroxy-Tamoxifen;Acetylation;Acute;Address;Aging;Aorta;Apoptosis;Apoptotic;Area;Binding Sites;Biogenesis;Biological;Biological Assay;Breast;Breast Cancer Cell;Calorimetry;Cell Cycle;Cell Cycle Proteins;Cell Nucleus;Cell Proliferation;Cells;Communication;Consumption;Cyclin D1;Cytochrome c Reductase;DNA Maintenance;DNA Polymerase II;DNA Sequence;Estradiol;Estrogen Antagonists;Estrogen Receptor 1;Estrogen Receptor Modulators;Estrogen Receptors;Estrogens;Event;Fluorescence;Gene Expression;Gene Proteins;Gene Targeting;Generations;Genes;Genetic Transcription;Genome;Goals;Health;Heart;Heart Arrest;Heating;Histones;Human;Hypothalamic structure;Investigation;Kidney;Knockout Mice;Lead;Ligands;Liver;Lung;MCF7 cell;Malignant neoplasm of lung;Mammary Gland Parenchyma;Mammary Neoplasms;Mammary gland;Measures;Mediating;Mitochondria;Mitochondrial DNA;Molecular;Mus;Nerve Degeneration;Normal Cell;Nuclear;Output;Pathway interactions;Play;Prevention;Production;Promoter Regions (Genetics);Promotor (Genetics);Proteins;RNA;Reactive Oxygen Species;Recruitment Activity;Regulation;Reporting;Research;Respiratory Chain;Response Elements;Role;Selective Estrogen Receptor Modulators;Small Interfering RNA;Specimen;Steroids;Testing;Time;Tissues;Titrations;Trauma;Tumor Tissue;Uterus;cancer cell;cancer initiation;chromatin immunoprecipitation;cytochrome c oxidase;functional outcomes;in vivo;insight;mRNA Expression;malignant breast neoplasm;mitochondrial dysfunction;neoplastic;neoplastic cell;novel;nrf1 protein;nuclear respiratory factor;ovex (pesticide);protein expression;research study;respiratory;response;stroke;survivin;transcription factor;tumor progression;tumor xenograft

public_health_relevance:
Although mitochondrial gene expression depends on nuclear genome function and reciprocally by "retrogradecommunication" mitochondrial activity regulates nuclear gene expression the mechanisms coordinating theseevents remain to be clarified. Mitochondrial dysfunction and increased reactive oxygen species mediate thepathophysiologic mechanisms of aging acute neurodegeneration caused by trauma stroke or cardiac arrest;and cancer initiation and tumor progression. The impact of steroids on mitochondrial function "is a new andnovel area of investigation" and the proposed study seeks to delineate a new biological pathway of estrogenand antiestrogens/SERMs in regulating nuclear respiratory factor-1 (NRF-1) and its downstream targets inmitochondrial activity.


application_id: 8116204
project_number: 1P30RR031159-01A1
project_title: Mechanisms of plasticity and repair after SCI
administering_ic: NCRR
award_notice_date: 2011-07-30
opportunity_number: PAR-10-196
application_type: 1
activity_code: P30
ic: RR
serial_number: 031159
suffix: A1
program_official: GOROSPE, RAFAEL
project_start_date: 2011-08-01
project_end_date: 2016-07-31
study_section: Special Emphasis Panel[ZRR1 RI-B (01)]
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
The goal of this revised PSO grant is to expand the present COBRE-funded Kentucky Spinal Cord Injury Research Center (KSCIRC) Core facilities at the University of Louisville (UofL). We propose to broaden the scope of research that these Cores support in neural development and CNS injury and 2) bring additional PIs into the Center both to enhance their research programs and to bring their new techniques and approaches to the COBRE PIs. We will increase the number of involved PIs from 8 to 22. The Cores will facilitate the research programs of both NIH funded and non-funded junior and more senior PIs in directions that would not be possible without the highly trained Core personnel. Each Core will be directed by a funded PI and housed in independent dedicated laboratory space. All PIs will have access to these Cores. We will give priority access to junior and unfunded PIs. The UofL administration will make significant space and financial commitment to the COBRE/KSCIRC Core Facilities. 

The Cores are: A) Administration and Biostatistics B) Surgery and Animal Care C) Behavioral and Electrophysiological Assessment D) Cell and Tissue Imaging and Histology and E) Human Translational Studies. The specific aims are: 1. Support and enhance the scope of the strong ongoing UofL NINDS and non-NINDS funded research in the areas of nervous system injury and repair including our continuing development of innovative technology. 2. Make our technologies available to additional UofL neuroscientists working in other areas of nervous system development and repair to facilitate their individual research programs with novel approaches. 3. Facilitate the development of the research programs of junior and more senior unfunded Investigators. 4. Enhance collaborative opportunities between PIs that utilize these Core facilities.


application_id: 8115972
project_number: 5R37HD029957-19
project_title: Early Development with Williams or Down Syndrome
administering_ic: NICHD
award_notice_date: 2011-08-05
application_type: 5
activity_code: R37
ic: HD
serial_number: 029957
program_official: OSTER-GRANITE, MARY LOU
project_start_date: 1993-03-01
project_end_date: 2014-07-31
study_section: NSS
contact_pi_person_id: 1901361
contact_pi: MERVIS, CAROLYN B.
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-08-01
project_abstract:
Program Director/Principal Investigator(Last First Middle): Men/is Carolyn BethPROJECT SUMMARY (Seeinstructions):The overall objective of the proposed research is to delineate and make sense of the process of lexicaldevelopment and its relations to socio-communicative development grammatical development and bothgeneral and specific aspects of nonlinguistic cognitive development. The research will focus on the languageand cognitive development of children with Williams syndrome and children with Down syndrome. Williamssyndrome is associated with relative strengths in language (especially concrete vocabulary and grammar)and verbal short-term memory and severe weakness in visuospatial cognition. In contrast Down syndromeis associated with severe weaknesses in expressive language (especially grammar) and in verbal short-termmemory and relative strength in nonlinguistic aspects of cognition. Because of these differences in thegeneral nature of the relations between language and nonlinguistic cognition inclusion of these two groupsof children in the same studies provides a unique opportunity to distinguish factors that are likely to beuniversal and necessary to language development from those that are specific to particular rates or paths tolanguage development. The proposed research consists of a longitudinal study of early language andcognitive development beginning in late infancy a longitudinal study of cognitive and language developmentof school-age children as measured by standardized assessments and cross-sectional studies of languagedevelopment especially socio-communicative development. Both observational and experimental methodswill be used. There are three specific aims. The first is to delineate the different types of early lexical growthcurves and examinetheir relations to later patterns of language and cognitive development. The second is toexamine socio-communicative development and its role in language and cognitive development. The third isto determine the longitudinal trajectories of language and cognitive abilities of children with Williamssyndrome and factors that influence these trajectories. The researchwill have implications both fortheoretical models of the relations between language and cognitive development and for the design ofcognitive language and reading intervention for children with developmental or intellectual disabilities.RELEVANCE (See instructions):The results of the proposed research will provide a basis for recommendations regarding speech/languageand developmental intervention for children with developmental delay in birth - 3 and preschool programs.The results also will increase the research foundation for the design of language social skills and readingintervention for school age children with developmental or intellectual disabilities.PROJECT/

project_terms:
Birth;Child;Child Development;Cognition;Cognitive;Cross-Sectional Studies;Development;Developmental Delay Disorders;Developmental Disabilities;Down Syndrome;Foundations;Growth;Instruction;Intellectual functioning disability;Intervention;Language;Language Development;Longitudinal Studies;Methods;Nature;Nursery Schools;Pattern;Principal Investigator;Reading;Recommendation;Relative (related person);Research;Role;School-Age Population;Short-Term Memory;Speech;Theoretical model;Visuospatial;Vocabulary;Williams Syndrome;base;design;infancy;lexical;lexical processing;men;programs;social skills;standardize measure


application_id: 8115227
project_number: 5R01CA125454-05
project_title: Regulation of Snail in breast cancer progression and metastasis
administering_ic: NCI
award_notice_date: 2011-07-26
application_type: 5
activity_code: R01
ic: CA
serial_number: 125454
program_official: WOODHOUSE, ELIZABETH
project_start_date: 2007-09-13
project_end_date: 2013-07-07
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-08-01
project_abstract:
DESCRIPTION (provided by applicant): Approximately 90% of breast cancer deaths are caused by metastasis and the median survival time for patients with metastatic breast cancer is approximately 2 years. Therefore an understanding of the mechanisms at work in the initiation and progression of metastasis is important for prevention and treatment of breast cancer. Our long-term goal is to reduce the incidence of breast cancer metastasis by gaining an understanding of the molecular mechanism underlying the initial step of breast cancer metastasis. As the master switch for epithelial-mesenchymal transition (EMT) and the initial step of metastasis Snail plays a critical role in the initiation and progression of metastasis. Overexpression of Snail correlates with tumor grade and nodal metastasis of breast cancer but the mechanism remains unclear. We recently demonstrated that the activity of Snail is regulated mainly by its protein stability and cellular location. Using an unbiased approach-tandem array purification (TAP) coupled with mass spectrometry analysis we identified the interaction of Snail with EPLINb (Epithelial Protein Lost in Neoplasm). We found that downregulation of EPLINP correlated with the upregulation of Snail in breast cancer cell lines and metastatic breast cancer specimens. We further demonstrated that expression of EPLINb induces degradation of Snail and relieves suppression of the E-cadherin promoter mediated by Snail. The central hypothesis of our proposal is that EPLINb functions as a negative regulator for Snail and that loss of EPLINb in breast cancer induces the stabilization and nuclear localization of Snail thus triggering breast cancer progression and metastasis. The objective of this proposal is to decipher the functional regulation of Snail by EPLINb in breast cancer and explore the prognostic value of EPLINb and Snail as markers of metastasis in breast cancer. Guided by strong preliminary data we will test this hypothesis by pursuing three specific aims: (1) to delineate the regions on Snail and EPLINb required for their association; (2) to determine whether the loss of EPLINb enhances the stabilization of Snail; and (3) to define the functional regulation of Snail and EPLINb in mouse and human breast cancer. Our proposal is innovative and significant to public health because knowledge gained from this study will expand the understanding of the initiation and progression of metastasis and holds great promise for novel interventions for preventing and treating breast cancer.

project_terms:
20q13;Biology;Body part;Breast;Breast Cancer Cell;Breast Cancer Treatment;Cancer Center;Cancer cell line;Cause of Death;Cells;Cellular Morphology;Chromosomes;Clinical;Coupled;Data;Disease;Distant;Doctor of Medicine;Doctor of Philosophy;Documentation;Down-Regulation;E-Cadherin;Embryonic Development;Environment;Epithelial;Goals;Human;Incidence;Intervention;Knowledge;Life;Light;Location;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Medical Oncologist;Mesenchymal;Methods;Molecular;Mus;Neoplasm Metastasis;Neoplasms;Nodal;Nuclear;Outcome;Pathogenesis;Pathologist;Patients;Play;Prevention;Promotor (Genetics);Proteins;Publishing;Reagent;Regulation;Research;Research Personnel;Role;Scaffolding Protein;Snails;Specimen;Staging;Surgeon;Symptoms;Testing;Time;Up-Regulation (Physiology);Woman;Work;base;cell motility;combat;in vivo;infiltrating duct carcinoma;innovation;malignant breast neoplasm;novel;overexpression;prevent;prognostic;programs;public health medicine (field);research study;success;treatment strategy;tumor;tumor progression


application_id: 8115212
project_number: 5R01DA025605-04
project_title: GABA Drugs for Cannabis-Use Disorders: Initial Mechanistic Studies in Humans
administering_ic: NIDA
award_notice_date: 2011-07-07
opportunity_number: PA-07-365
application_type: 5
activity_code: R01
ic: DA
serial_number: 025605
program_official: MONTOYA, IVAN
project_start_date: 2008-09-15
project_end_date: 2015-07-31
study_section: ZDA1-MXH-H(22)
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
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): Cannabis remains the most commonly used illicit drug worldwide including the United States. Not only does a relatively large percentage of the population report using cannabis but like other drugs of abuse a significant proportion of those persons use it habitually and meet diagnostic criteria for drug-use disorders. Moreover cannabis-use disorders are associated with treatment admission and relapse rates comparable to other drugs of abuse perceived as more harmful. Despite the significant public health concern posed by cannabis use there has been limited preclinical or clinical research that has focused explicitly on the identification and development of medications to treat cannabis-use disorders. Data from preclinical and clinical research suggest that agonist replacement treatment is an effective means to manage drug-use disorders and that this strategy would be viable for cannabis-use disorders as well. The experiments proposed here represent the initial step of evaluating GABAergic drugs as potential "agonist-like" pharmacotherapies for cannabis-use disorders. GABA is being targeted because there is substantial overlap in the effects produced by cannabinoids and drugs acting at central GABAergic systems and neuroanatomical neurochemical and behavioral studies support a functional link between cannabinoid and GABAergic systems. The studies proposed here will test the ability of the selective GABA reuptake inhibitor tiagabine the GABAA positive modulator diazepam and the GABAB agonist baclofen to enhance the behavioral and physiological effects of ?9-THC thus examining the "agonist-like" profile of GABAergic drugs with varying mechanisms of action. The primary outcome for these experiments is the interoceptive cue produced by ?9-THC. The interoceptive effects of ?9-THC will be measured using the drug-discrimination procedure which is a pharmacologically specific and sensitive means to characterize drugs and drug interactions. In addition subjective effects questionnaires psychomotor performance and memory tasks and cardiovascular and thermal measures of physiology will be included to more fully assess the effects of ?9-THC alone and in combination with GABAergic compounds. The experiments proposed here are novel and innovative because there are very few studies in humans to have tested the effects of GABAergic drugs on cannabinoids. In addition these studies are important for at least three reasons. First and perhaps most importantly the data generated from the proposed experiments will provide the direction and foundation for future studies aimed at the development of GABAergic treatments for cannabis-use disorders. Second these data will provide valuable information regarding the neurobiology of the effects of cannabinoids in humans by examining the interactions between cannabinoid and GABAergic systems. Finally these experiments will provide translational information regarding the extent to which the results from preclinical studies that have evaluated CB-GABA interactions generalize to humans. Public Health Relevance: Cannabis is the most commonly used illicit drug in the United States and its use is associated with rates of development of abuse and dependence treatment admission and relapse that are comparable to other illicit drugs that are misperceived as more harmful. Currently there is no effective pharmacological treatment for cannabis-use disorders. The experiments proposed here represent the initial step of evaluating GABAergic drugs as potential pharmacotherapies by characterizing interactions between ?9-THC and the selective GABA reuptake inhibitor tiagabine the GABAA positive modulator diazepam and the GABAB agonist baclofen.

project_terms:
Admission activity;Agonist;Attenuated;Baclofen;Barbiturates;Behavioral;Benzodiazepine Receptor;Benzodiazepines;Cannabinoids;Cannabis;Cardiovascular system;Clinical Data;Clinical Research;Controlled Clinical Trials;Cues;Data;Dependence;Development;Diagnostic;Diazepam;Disease;Dose;Drug Interactions;Drug Use Disorder;Drug usage;Foundations;Future;GABA Receptor;Human;Illicit Drugs;Link;Maintenance;Measures;Mediating;Medication Management;Memory;Neurobiology;Patients;Persons;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacotherapy;Physiological;Physiology;Population;Procedures;Psychomotor Performance;Questionnaires;Receptor Activation;Relapse;Reporting;Short-Term Memory;Stimulus;System;Testing;United States;barbituric acid salt;drug discrimination;drug of abuse;gamma-Aminobutyric Acid;inhibitor/antagonist;innovation;meetings;memory process;neurochemistry;novel;pre-clinical research;preclinical study;primary outcome;public health medicine (field);public health relevance;receptor;research study;reuptake;tiagabine


application_id: 8114450
project_number: 4R00CA126161-03
project_title: Regulation of MAPK Activity by EGFR Endocytosis
administering_ic: NCI
award_notice_date: 2010-09-03
opportunity_number: PA-06-133
application_type: 4
activity_code: R00
ic: CA
serial_number: 126161
program_official: SPALHOLZ, BARBARA A
project_start_date: 2010-09-03
project_end_date: 2013-08-31
study_section: NSS
contact_pi_person_id: 8586925
contact_pi: GALPERIN, EMILIA
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): Mitogen-activated protein kinases (MARK) are major effector proteins involved in cell proliferation differentiation and apoptosis. Alterations in MARK signaling lead to development of various patho-physiological conditions. Signaling through MAPKs is predominantly controlled by growth factors in particular EGF. EGF receptor (EGFR) activation triggers a network of signal transduction events along with accelerated endocytosis of EGF-receptor complexes. It is proposed that endocytic trafficking regulates the intensity and duration of MARK signaling but the mechanisms of this regulation are not understood. Moreover both characteristics (signaling duration and intensity) have been shown to depend on the proper function of MARK scaffold proteins yet their role in signal propagation has not been fully elucidated. The main goal of this project is to identify the role of endocytosis in activation of the MARK cascade and to define the regulatory mechanisms of endocytosis and signaling that are critical for cancer development and progression. We will analyze how EGFR activation and endocytic trafficking provides spatial and temporal control of MARK pathway signaling. We will use a quantitative method of high-resolution microscopy fluorescence resonance energy transfer (FRET) that has been developed in our lab and has been previously used to demonstrate the presence of EGFR signaling complexes in endosomes of living cells. Here we propose a novel siRNA Knock Down And Rescue (KDAR) strategy to identify involvement of endocytic machinery in MARK activation. A number of reagents and new methodologies developed in our lab will allow us to characterize the localization of several components of MAPK1/2 module in time in living cells under conditions of physiological expression levels.

project_terms:
Affect;Apoptosis;Award;Binding (Molecular Function);Biochemical;Biological Assay;Cell Proliferation;Cell physiology;Cells;Characteristics;Colorado;Complex;Data;Development;Endocytosis;Endosomes;Epidermal Growth Factor;Epidermal Growth Factor Receptor;Event;Fluorescence Microscopy;Fluorescence Resonance Energy Transfer;Goals;Growth Factor;HRAS gene;Health Sciences;Individual;Lead;Life;Location;MAP Kinase Gene;MAP2K1 gene;MEKs;Malignant Epithelial Cell;Malignant Neoplasms;Mentors;Methodology;Methods;Microscopy;Mitogen-Activated Protein Kinase Kinases;Mitogen-Activated Protein Kinases;Modeling;Molecular;Non-Small-Cell Lung Carcinoma;Normal Cell;Pathway interactions;Pattern;Physiological;Proteins;Publishing;RAF1 gene;Reagent;Receptor Activation;Receptor Signaling;Regulation;Research;Research Proposals;Resolution;Role;Scaffolding Protein;Signal Pathway;Signal Transduction;Site;Small Interfering RNA;Son of Sevenless Proteins;Staging;Techniques;Testing;Time;Universities;Work;base;cancer cell;cell type;insight;knock-down;novel;novel diagnostics;overexpression;protein expression;receptor;reconstitution;research study;sensor;spatiotemporal;trafficking;tumor progression

public_health_relevance:
The research proposed here will provide new insight into the specific mechanisms of regulation of the signal-transduction events by endocytic trafficking. The purpose of this research is to understand the regulatory mechanisms of the molecular cascade that affect tumor progression. Results from this study will define requirements of this intracellular signaling pathway for normal cell function which will lead to development of new diagnostic markers work described in the Research Proposal will be conducted at the University of Colorado Health Sciences Center Aurora Colorado


application_id: 8114008
project_number: 5R01EY018350-05
project_title: Pro-and anti-angiogenic effects of vascular endothelial growth factor-A
administering_ic: NEI
award_notice_date: 2011-08-08
application_type: 5
activity_code: R01
ic: EY
serial_number: 018350
program_official: SHEN, GRACE L
project_start_date: 2007-08-01
project_end_date: 2012-07-31
study_section: Biology and Diseases of the Posterior Eye Study Section[BDPE]
contact_pi_person_id: 2446639
contact_pi: AMBATI, JAYAKRISHNA
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-08-01
project_abstract:
DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. The overwhelming cause of severe vision loss in these patients is choroidal neovascularization (CNV) the growth of abnormal blood vessels beneath the retina. The mechanisms responsible for this process have been deduced to angiogenesis the sprouting of new blood vessels from pre-existing vasculature and vasculogenesis the recruitment proliferation and incorporation of bone marrow-derived progenitor cells into nascent vasculature. Vascular endothelial growth factor-A (VEGF-A) is a critical mediator in both these pathways and is the target for many FDA approved therapies for CNV. Using the mouse model of laser-induced CNV we recently discovered a paradoxical effect whereby both endogenous and exogenous VEGF-A suppressed CNV during the acute phase after laser-injury whereas before injury they enhanced CNV consistent with dogma. We determined that the matricellular protein SPARC/osteonectin constitutively interacts with VEGF-A and prevents it from activating VEGF receptor (VEGFR)-1. Because SPARC levels decline transiently after injury VEGF-A activates an anti-angiogenic pathway through VEGFR-1 binding and subsequent dephosphorylation of VEGFR-2 the principal signaling receptor that promotes neovascularization. VEGF-A also downregulated the expression of monocyte chemoattractant protein-1 (Ccl-2) which suppressed cell-mediated inflammation and subsequent CNV. The molecular basis of the vexing macular predilection for CNV in humans is unknown; however the spatial confinement of SPARC in the macula of monkey retina is intriguing as a potential underpinning for this phenomenon. The specific aims of this proposal are to further define the interaction of SPARC and VEGF-A in experimental CNV determine the precise anti-angiogenic and anti-vasculogenic mechanisms of VEGF-A induced CNV suppression evaluate the efficacy of modulating SPARC in a non-human primate model of CNV and define the expression and activity profiles of SPARC and VEGF-A and its receptors in human retina and choroid. Our long term goal is to fully characterize the SPARC-VEGF-A pathway in CNV and identify novel targets for the treatment of this blinding condition which constitutes nothing short of a public health epidemic.

project_terms:
Acute;Affect;Age related macular degeneration;Animal Model;Binding (Molecular Function);Biochemical;Biology;Blindness;Blood Vessels;Bone Marrow;Cells;Choroid;Choroidal Neovascularization;Clinical;Complex;Data;Development;Disease;Elderly;Endothelial Cells;Environment;Epidemic;Extracellular Matrix;Extracellular Protein;FDA approved;Genes;Goals;Growth;Human;In Situ;In Vitro;Incidence;Inflammation;Inflammatory;Injury;Laser injury;Lasers;Leukocytes;Ligands;Link;Malignant neoplasm of prostate;Mediating;Mediator of activation protein;Membrane;Methods;Modality;Modeling;Molecular;Monkeys;Monocyte Chemoattractant Protein-1;Operative Surgical Procedures;Osteonectin;PTPN6 gene;Pathologic Neovascularization;Pathway interactions;Patients;Phase;Prevalence;Process;Promotor (Genetics);Protein Dephosphorylation;Proteins;Receptor Activation;Receptor Protein-Tyrosine Kinases;Receptor Signaling;Relative (related person);Reporting;Research Personnel;Retina;Role;Signal Transduction;Specimen;Stem cells;Structure of retinal pigment epithelium;Testing;Therapeutic;Tissues;Vascular Endothelial Growth Factor A;Vascular Endothelial Growth Factor Receptor;Vascular Endothelial Growth Factor Receptor-1;angiogenesis;base;bone;cytokine;driving force;drug development;in vivo;injured;insight;macula;malignant breast neoplasm;mouse model;neovascularization;nonhuman primate;novel;prevent;programs;public health medicine (field);receptor;receptor binding;response;stem;therapy development;vasculogenesis


application_id: 8113944
project_number: 5P20RR024489-04
project_title: Center of Excellence in Diabetes and Obesity Research
administering_ic: NCRR
award_notice_date: 2011-07-14
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 024489
program_official: CANTO, MARIA TERESA
project_start_date: 2008-09-26
project_end_date: 2013-06-30
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
Description (provided by applicant): This proposal is to promote the initiation and the development of a multi-disciplinary thematic Center of Excellence in Diabetes and Obesity Research at the University of Louisville. The primary objective and the central focus of the Center are to enable promote and support scientific research related to the cardiovascular causes and consequences of diabetes and obesity. The second major aim of program is to provide mentoring and guidance to junior investigators in the Center with the overall goal of discovering new tierapies for the treatment and prevention of diabetes and obesity. Specific objectives of the program are to: [1) Build and develop a thematic multi-disciplinary research center focused on diabetes and obesity research; (2) Develop basic and clinical understanding of the molecular mechanisms of diabetes and obesity and how they contribute to the burden of cardiovascular disease (3) Expand and bridge on-going research programs to integrate current expertise into a thematically coherent program (4) Promote collaborative interactions to build complementary individual and multi-investigator research projects; (6) Foster research careers of junior investigators leading to their development as independent principal investigators; (7) Build upon our existing research capabilities and core facilities to provide the state-of-the-art infrastructure support; (8) Develop a nationally-competitive program that will attract the best clinical cardiology fellows graduate students postdoctoral fellows and new faculty; and most importantly to discover new and effective means for preventing and treating diabetes and obesity. The five related projects of junior investigators for the first phase of the Center are to: (1) delineate the contribution of oxidative stress to hyperglycemic injury and test whether antioxidant interventions prevent vascular injury in diabetes; (2) to investigate whether hyperglycemia impairs the cardiac reparative potential of mesenchymal stem cells and whether transplantation of stem cells with greater potential for cardiac repair will result in greater improvement of function in diabetic hearts following infarction; (3) delineate the mechanisms contributing to premature senescence and death of cardiac progenitor cells leading to non-ischemic diabetic cardiomyopathy; (4) examine whether hyperglycemic stimulation of foam cell formation is mediated by ER stress and the unfolded protein response and if drug that act as chemical chaperone ameliorate accelerated atherogenesis in diabetic animals; and (5) identify the regulation of high glucose-triggered inflammatory signaling (NF-KB activation) by specific micro RNAs. These investigations will be supported by establishing state-of-the-art core facilities in confocal microscopy flow cytometry cardiovascular pathology animal models and imaging and function. We believe that a Center focused on diabetes and obesity will add to the academic success of the University and will have a positive impact on the field of diabetes and obesity research in the nation.


application_id: 8113410
project_number: 5R42CA120616-04
project_title: Development of a Perfusion-induced Systemic Hyperthermia Delivery Apparatus
administering_ic: NCI
award_notice_date: 2011-09-13
opportunity_number: PA-09-081
application_type: 5
activity_code: R42
ic: CA
serial_number: 120616
program_official: ZHAO, MING
project_start_date: 2007-09-25
project_end_date: 2016-06-30
study_section: Special Emphasis Panel[ZRG1-SBTS-E(10)B]
contact_pi_person_id: 2422224
contact_pi: ZWISCHENBERGER, JOSEPH B
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 965569747
duns_number: 965569747
fips: US
organization_id: 10028623
organization_name: EXATHERM, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-09-13
budget_end_date: 2016-06-30
project_abstract:
DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer-related deaths in men and women. The prognosis for patients with advanced stage non-small cell lung cancer (NSCLC) which accounts for 75% of all new lung cancer cases is dismal with currently available chemotherapy regimens providing only a 9-12 month median survival. Thus our long term goal is to develop a more effective treatment for late stage NSCLC. One potential candidate for advanced lung cancer therapy is hyperthermia. Our group developed a venovenous perfusion-induced systemic hyperthermia (vv-PISH) system. In a previous phase I clinical trial the vv-PISH significantly improved median survival in advanced stage NSCLC patients by 363 days. Although our vv-PISH system functioned adequately in the clinical trial the vv-PISH system was too complex with a multi-site cannulation and numerous  
dialysis problems. Our Phase I STTR results showed the feasibility of a simple and inexpensive vv-PISH system in delivering a predictable therapeutic hyperthermia dose. The objective of this Phase II STTR proposal is to establish the feasibility of our finalized vv-PISH circuit to safely deliver therapeutic hyperthermia. Specific Aim 1: To finalize and produce an integrated clinical vv-PISH prototype. In this specific aim our system will be finalized to incorporate new developments and integrate "off the shelf" components into a vv-PISH prototype suitable for preclinical and clinical testing. We will assemble the: 1) peristaltic roller pump (MC3 pump) 2) adult ECMO heat exchanger (ECMOtherm-II(tm)) 3) hemofilter (Renaflow II(r)) 4) water heater (Hemotherm(r)) and 5) double lumen cannula (Avalon Elite(tm)). Once assembled we will perform bench testing to confirm that design requirements are met. Specific Aim 2: To determine the temperature control performance and in vivo safety of the clinical vv-PISH circuit. In this specific aim we will establish the safety and reproducibility of the vv-PISH circuit in achieving the target therapeutic dose (42C for 120 minutes) in adult swine. We will examine major organ function during hyperthermia and end organ damage or emboli will be examined in a detailed necropsy. Adult swine will also be monitored for five days after hyperthermia administration. Parameters used to assess the safety of the vv-PISH system will include: 1) survival 2) multiple organ function and 3) quality of life. This outcomes study is an essential part of the preclinical testing that must precede the clinical trial. Specific Aim 3: To determine the clinical feasibility of the vv-PISH circuit in a prospective randomized clinical trial. In this specific aim a phase I clinical trial will be performed to test the clinical feasibility of the vv-PISH circuit. Advanced stage (IIIb or IV) NSCLC patients will be randomized into: 1) standard of care treatment consisting of cisplatin and etoposide chemotherapy with concurrent radiation therapy (n=10) and 2) standard of care therapy followed by systemic hyperthermia treatment via our vv-PISH clinical prototype (n=10). Hyperthermia will be given 2 weeks after the last chemotherapy dose. The impact of this work is that we have developed a new treatment strategy for a relatively unresponsive cancer.  
  
PUBLIC HEALTH RELEVANCE: Advanced stage lung cancer which has a median survival of only 10 months is present in 75% of all new cases. We developed a new circuit to deliver whole body hyperthermia which significantly increased advanced lung cancer patient survival in a previous phase I clinical trial. Since our Phase I STTR results showed the feasibility of a more simple and inexpensive hyperthermia delivery system the goal of this Phase II STTR proposal is to establish the feasibility of our finalized circuit to safely deliver therapeutic hyperthermia.

project_terms:
Accounting;Adult;Animals;Autopsy;Biomedical Engineering;Blood;Blood Vessels;Cancer Etiology;Cancer Patient;Cannulas;Cannulations;Cardiopulmonary;Cessation of life;Charcoal;Chemotherapy-Oncologic Procedure;Cisplatin;Clinical;Clinical Data;Clinical Trials;Complex;Control Groups;DNA Adducts;Development;Devices;Dialysis procedure;Doctor of Philosophy;Dose;Embolism;Etoposide;Exhibits;Family suidae;Fever;Goals;Grant;Heating;Induced Hyperthermia;Industry;Kentucky;Left;Local Hyperthermia;Malignant Neoplasms;Malignant neoplasm of lung;Medical Device;Monitor;Non-Small-Cell Lung Carcinoma;Operative Surgical Procedures;Organ;Outcome Study;Patients;Performance;Perfusion;Phase;Phase I Clinical Trials;Platinum;Preclinical Testing;Pump;Quality of life;Radiation therapy;Randomized;Randomized Clinical Trials;Reporting;Reproducibility;Research;Research Personnel;Resistance;Safety;Site;Small Business Technology Transfer Research;Staging;Students;Surgeon;System;Temperature;Testing;United States;Universities;Venous;Ventricular;Water;Woman;Work;blood pump;cancer therapy;chemotherapy;clinical efficacy;design;effective therapy;engineering design;experience;heat exchanger;hyperthermia treatment;improved;in vivo;innovation;meetings;men;next generation;outcome forecast;prospective;prototype;public health relevance;repaired;research and development;research clinical testing;standard of care;synergism;therapeutic target;treatment strategy;uptake

public_health_relevance:
NarrativeAdvanced stage lung cancer which has a median survival of only 10 months is present in 75% of all newcases. We developed a new circuit to deliver whole body hyperthermia which significantly increased advancedlung cancer patient survival in a previous phase I clinical trial. Since our Phase I STTR results showed thefeasibility of a more simple and inexpensive hyperthermia delivery system the goal of this Phase II STTRproposal is to establish the feasibility of our finalized circuit to safely deliver therapeutic hyperthermia.


application_id: 8113349
project_number: 5R01NS037717-11
project_title: Transcriptional control of oligodendrocyte differentiation and myelination
administering_ic: NINDS
award_notice_date: 2011-07-25
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 037717
program_official: MORRIS, JILL A
project_start_date: 2000-03-01
project_end_date: 2014-05-31
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 1906514
contact_pi: QIU, MENGSHENG
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Oligodendrocytes are myelinating glial cells found in all regions of the central nervous system. The major function of oligodendrocytes is to form myelin sheaths around axons to ensure the rapid and faithful transmission of electrical signals. During development oligodendrocytes precursor cells (OPCs) have to go through a series of morphological and molecular changes before they become fully differentiated into mature myelinating oligodendrocytes. The differentiation and myelination processes of oligodendrocytes are tightly controlled by transcription factors. Recent studies have demonstrated that Sox10 transcription factor directly stimulates OPC differentiation and myelin gene expression. However OPC differentiation is tightly regulated by other transcription factors (TFs) including Nkx2.2 Olig1 Hes5 and Id4 all of which are expressed in undifferentiated OPC cells in the developing central nervous system. While Nkx2.2 and Olig1 function to promote OPC differentiation Hes5 and Id4 act as inhibitors of OPC maturation. The functional relationship of these four regulatory TFs in the control of OL differentiation has not been determined. In this application we hypothesize that Nkx2.2 enhances OPC maturation indirectly by suppressing the expression or function of Hes5 and Id4 but functions synergistically with Olig1 in promoting OPC differentiation. These hypotheses will be tested in the first two aims of the proposal. Recent data showed that Nkx2.2 is rapidly down-regulated in differentiated OLs and over-expression of Nkx2.2 in oligodendrocyte cell line inhibits MBP gene expression raising the possibility that Nkx2.2 switches its role to become a repressor of myelin gene expression in mature OLs to prevent excessive myelin production. This possibility will be examined in the third aim of the proposal. Finally we will test the hypothesis that persistent expression of Sox10 in mature OLs functions to maintain myelin gene expression and myelin sheath stability. The interplay of Sox10 and Nkx2.2 in myelinating OL cells may be responsible for the delicate balance of myelin production and structural maintenance. This line of study could help us understand molecular pathways that control axonal myelination process and provide insights into the development of molecular approaches to stimulate oligodendrocyte regeneration and remyelination in demyelinating diseases. PUBLIC HEALTH RELEVANCE: The proposed studies will provide important information on the function and regulations of transcription factors that control oligodendrocyte differentiation and myelin gene expression in the developing central nervous system. Knowledge obtained from this study can help us understand the molecular pathways that govern the differentiation and myelination of oligodendrocytes and provide cues for promoting oligodendrocyte regeneration and axonal remyelination in neurological patients and spinal cord injury patients.

project_terms:
Axon;Binding (Molecular Function);Cell Differentiation process;Cell Line;Cell Maturation;Cells;Chickens;Cues;Data;Demyelinating Diseases;Development;Embryo;Ensure;Equilibrium;Gene Expression;Genes;Genetic;Health;Knowledge;Maintenance;Molecular;Mutation;Myelin;Myelin Sheath;Natural regeneration;Neuraxis;Neuroglia;Neurologic;Nkx-2.2 protein;Oligodendroglia;Pathway interactions;Patients;Principal Investigator;Process;Production;Promotor (Genetics);Proteins;Regulation;Role;Series;Signal Transduction;Spinal Cord;Spinal cord injury patients;Testing;Transcriptional Regulation;Transgenic Animals;Undifferentiated;axon regeneration;inhibitor/antagonist;insight;mutant;myelination;oligodendrocyte precursor;precursor cell;premature;prevent;programs;transcription factor;transmission process

public_health_relevance:
The proposed studies will provide important information on the function and regulationsof transcription factors that control oligodendrocyte differentiation and myelin geneexpression in the developing central nervous system. Knowledge obtained from thisstudy can help us understand the molecular pathways that govern the differentiation andmyelination of oligodendrocytes and provide cues for promoting oligodendrocyteregeneration and axonal remyelination in neurological patients and spinal cord injurypatients.


application_id: 8113175
project_number: 5K08HL077533-06
project_title: Role of Smad3 in obiliterative bronchiolitis
administering_ic: NHLBI
award_notice_date: 2011-07-28
opportunity_number: PA-06-512
application_type: 5
activity_code: K08
ic: HL
serial_number: 077533
program_official: COLOMBINI-HATCH, SANDRA
project_start_date: 2007-08-15
project_end_date: 2013-07-31
study_section: ZHL1-CSR-O(M1)
contact_pi_person_id: 7852167
contact_pi: RAMIREZ, ALLAN
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):   
  
Obliterative bronchiolitis (OB) considered to be a manifestation of chronic allograft dysfunction in lung  transplant recipients is an irreversible fibroproliferative process that represents the major barrier to long term survival. Hence research directed at identifying the factors involved in the development of OB in lung transplant recipients is paramount to finding effective treatment for this otherwise untreatable disease. We have found that Transforming Growth Factor-p (TGFp) via its signal transducer SmadS is necessary for the development of OB as well as the myofibroblast transdifferentiation that accompanies OB. Hence we have focused on the mechanisms regulating TGFp/Smad signaling in OB and have made a number of key observations. First oxidation of the extracellular cysteine-cystine (Cys/CySS) redox couple induces upregulation and activation of TGFp and SrnadS. Second SmadS expression and DNA binding in lung fibroblasts and consequently myofibroblast transformation is augmented by aberrant transitional matrix components e.g. fibronectin and type I collagen which are invariably found in the setting of OB. And third activation of the nuclear transcription factor peroxisome proliferator-activated receptor-y (PPARy) inhibits TGFpl -induced myofibroblast transdifferentiation by disrupting SmadS-dependent gene transcription. These findings led us to the hypothesis that activation of TGFp1/Smad3 signaling in airway fibroblasts is a critical driver of myofibroblast transdifferentiation in OB that is intensified by the presence of chronic extracellular oxidant stress aberrant transitional matrices and defective PPARy signaling. This hypothesis will be tested in fibroblast cultures and in experimental models of OB in three specific aims designed to: 1) examine the mechanisms by which chronic extracellular oxidative stress activates TGFp1/Smad3-dependent signaling events in vitro and in vivo through the Cys/CySS redox couple 2) examine how transitional matrices promote activation of TGFpl /SmadS signaling and myofibroblast transdifferentiation through integrin-dependent signals 3) determine the mechanisms by which PPARy affects the SmadS signaling pathway and the induction of myofibroblast transdifferentiation and matrix expression in experimental OB. These complex issues will be addressed with the assistance of expert advisors and collaborators with the broader objective of unveiling novel targets for therapy.  
(End of Abstract)

project_terms:
Address;Affect;Agonist;Allografting;Animal Model;Biopsy Specimen;Bronchioles;Bronchiolitis;Cells;Chronic;Clinical;Collagen Type I;Complex;Connective Tissue;Contractile Proteins;Cysteine;Cystine;DNA Binding;Deposition;Development;Disease;Disulfides;Effector Cell;Engineering;Event;Experimental Models;Extracellular Matrix;Fibroblasts;Fibronectins;Functional disorder;Future;Genes;Genetic Transcription;In Vitro;Inflammatory;Injury;Integrins;Investigation;Lesion;Lung;Lung Transplantation;Lymphocyte;Mediating;Mononuclear;Myofibroblast;Nuclear;Oxidants;Oxidation-Reduction;Oxidative Stress;Pathogenesis;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Phenotype;Preparation;Prevention strategy;Process;Proteins;Recovery;Regulation;Relative (related person);Research;Research Personnel;Role;Salvage Therapy;Signal Pathway;Signal Transduction;Smooth Muscle Actin Staining Method;Stress;Sulfhydryl Compounds;T-Cell Activation;Testing;Transducers;Transforming Growth Factors;Transplant Recipients;Transplantation;Up-Regulation (Physiology);Work;abstracting;allograft rejection;arm;career;design;directed attention;effective therapy;extracellular;in vivo;isoimmunity;macrophage;meetings;novel;oxidant stress;oxidation;prevent;programs;receptor;success;tool;transcription factor;transdifferentiation


application_id: 8113032
project_number: 1R03AG038909-01A1
project_title: Mechanisms of Age-Related Changes in Estrogen Receptor Beta Expression in the Rat
administering_ic: NIA
award_notice_date: 2011-03-21
opportunity_number: PA-10-064
application_type: 1
activity_code: R03
ic: AG
serial_number: 038909
suffix: A1
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 2011-04-01
project_end_date: 2013-03-31
study_section: Molecular Neurogenetics Study Section[MNG]
contact_pi_person_id: 9097391
contact_pi: WESTBERRY, JENNE MITCHELL
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): Estrogen plays a crucial role in coordinating the neuroendocrine events that control sexual development sexual behavior and reproduction. Additionally estrogen modulates numerous additional facets of brain function. In humans the primary biologically active form of estrogen is 172-estradiol (E2). E2 has been implicated in several non-reproductive brain functions such as protection against brain injury involvement in learning and memory as well as promoting the formation of synapses. Additionally a growing body of literature has shown that E2 treatment may alleviate neuronal dysfunctions from Alzheimer<s disease through multifaceted molecular and cellular mechanisms. During aging cognitive and neurodegenerative conditions increase. In particular postmenopausal women are increasingly vulnerable as their E2 levels precipitously decline. As women spend a larger proportion of their lives in a hypoestrogenic state it is critical to understand the underlying mechanisms of estrogen action in the brain. Data from the Women<s Health Initiative suggest that current hormonal therapies however do not prevent cognitive decline. One potential reason for this observation is that the timing of hormone replacement is critical and thus changes in estrogen receptor expression in the brain may over-ride any potential hormonal intervention. Estrogen receptor-alpha splice variants have been shown to be associated with neurological disorders in the aging human brain however little is known about estrogen receptor-beta expression in the aging human brain. In rodents however ER2 mRNA expression is modified by age. ER2 expression decreases in a brain region specific manner although the cause of this decline is not known.  ER2 expression in the cortex and other brain regions could be regulated by a variety of mechanisms. One potential mechanism of ER2 gene regulation is through epigenetic modification of C-G rich regions of the ER1 promoter by methylation or acetylation of histones associated with the gene. Gene silencing occurs when methyl-binding proteins become associated with the methylated region of DNA which prevents transcription machinery from binding. Examples of epigenetic regulation of ER2 are seen in breast and prostate cancer where ER2 expression has been correlated with changes in methylation. Although regulation of ER2 expression has been heavily studied in cancer models very little is known about epigenetic regulation of ER2 in the brain during aging. Understanding how methylation alters gene expression in the brain may lead to the development of interventional strategies to influence gene expression related to human neurological disease. This proposal tests the hypothesis that estrogen receptor-beta gene expression is regulated by epigenetic mechanisms in the aging female brain.  
  
PUBLIC HEALTH RELEVANCE: These studies will begin to determine the novel mechanisms of changes in gene expression caused by age on a critical gene in the female brain. These insights could lead to development of therapeutics that result in improved cognition in the postmenopausal woman by potentially preventing changes in ER2 gene expression. Furthermore we will develop a new methodology that will be critical for examining epigenetic changes in gene expression in a temporal and spatial manner in neural tissue with heterogeneous cell populations.

project_terms:
Age;Aging;Alzheimer's Disease;Area;Binding (Molecular Function);Binding Proteins;Brain;Brain Injuries;Brain region;Cancer Model;Cells;Cognition;Cognitive aging;DNA;Data;Development;Epigenetic Process;Estradiol;Estrogen Receptor alpha;Estrogen Receptor beta;Estrogen Receptors;Estrogens;Event;Female;Gene Expression;Gene Expression Regulation;Gene Silencing;Genes;Genetic Transcription;Health;Histone Acetylation;Hormonal;Hormones;Human;Impaired cognition;In Situ;Intervention;Lead;Learning;Literature;Malignant neoplasm of prostate;Memory;Methodology;Methylation;Modification;Molecular;Nerve Degeneration;Neuronal Dysfunction;Neurosecretory Systems;Ovariectomy;Play;Population;Postmenopause;Promotor (Genetics);Proteins;RNA Splicing;Rattus;Regulation;Reproduction;Rodent;Role;Sex Behavior;Sexual Development;Techniques;Testing;Time;Tissues;Variant;Woman;Women's Health;age effect;age related;brain cell;cancer cell;cell type;design;hormone therapy;improved;in vivo Model;insight;mRNA Expression;malignant breast neoplasm;nervous system disorder;novel;prevent;protein expression;receptor expression;relating to nervous system;synaptogenesis;therapeutic development

public_health_relevance:
These studies will begin to determine the novel mechanisms of changes in gene expression caused by age on a critical gene in the female brain. These insights could lead to development of therapeutics that result in improved cognition in the postmenopausal woman by potentially preventing changes in ER2 gene expression. Furthermore we will develop a new methodology that will be critical for examining epigenetic changes in gene expression in a temporal and spatial manner in neural tissue with heterogeneous cell populations.


application_id: 8112739
project_number: 5R01DE018215-04
project_title: NUTRITIONAL EPIGENETICS AND OROFACIAL DEVELOPMENT
administering_ic: NIDCR
award_notice_date: 2011-07-11
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DE
serial_number: 018215
program_official: SCHOLNICK, STEVEN
project_start_date: 2008-08-01
project_end_date: 2013-07-31
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 1861667
contact_pi: GREENE, ROBERT M
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Two Two major health care issues are inexorably intertwined: a woman's health and prenatal development of her unborn child. The nutritional value of a woman's diet is critical to both. Folate a water- soluble B vitamin is required for the growth of fetal tissues and normal development of the CNS and orofacial complex. In addition folate supplies the necessary methyl donors for DNA methylation one of the most common epigenetic modifications regulating gene expression in mammalian cells. Incorrect methylation patterns can result in developmental malformations including craniofacial defects. With a frequency of 1-2 in 1000 live births orofacial clefts represent nearly one-half of all craniofacial anomalies While methylation of DNA is a common epigenetic modification that contributes to the control of gene expression in mammalian cells the notion of tissue/cell-specific methylation of discrete CpG islands as a means of regulating morphogenesis of the orofacial region and as a molecular target of nutritional (folate) deficiency as outlined in the present proposal is novel. Thus the global hypothesis we plan to address in the current proposal is that folate deficiency can disrupt the normal methylation state of specific candidate genes and contribute to development of orofacial clefts.   
  
Specific aims/hypotheses addressed in the current application include:   
1 - CpG islands with tissue-dependent and differentially methylated regions (t-dmrs) exhibit distinct spatio- temporal methylation patterns during ontogeny of the 1st branchial arch.   
  
2 - Conditions of gestational folate deficiency that result in facial clefts elicit alterations in CpG island methylation patterns in the 1st branchial arch. These patterns can be reversed with folate supplementation regimens that rescue the phenotype.   
  
3 - Altered promoter CpG methylation patterns regulate expression of genes of the TGF( Signal Transduction Family in the embryonic 1st branchial arch from folate deficient (Folbp1-/-) mice.   
  
4 - Folate deficiency (Folbp1-/-) contributes to the genesis of orofacial clefts by inducing excess apoptosis within the developing 1st branchial arch.

project_terms:
Address;Apoptosis;Branchial arch structure;Candidate Disease Gene;Cells;Cleaved cell;Complex;CpG Islands;DNA Methylation;Defect;Development;Diet;Embryo;Epigenetic Process;Exhibits;Face;Family;Fetal Tissues;Folate;Folic Acid Deficiency;Frequencies (time pattern);Gene Expression;Growth;Healthcare;Island;Live Birth;Mammalian Cell;Methylation;Modification;Molecular Target;Morphogenesis;Mus;Nutritional;Pattern;Phenotype;Promotor (Genetics);Regimen;Signal Transduction;Supplementation;Tissues;Vitamin B Complex;Water;Woman;Women's Health;craniofacial;malformation;novel;orofacial;prenatal;spatiotemporal;unborn child


application_id: 8112434
project_number: 5U01CE001675-03
project_title: Green Dot across the Bluegrass: Evaluation of a primary prevention intervention t
administering_ic: NCIPC
award_notice_date: 2011-08-05
opportunity_number: RFA-CE-09-003
application_type: 5
activity_code: U01
ic: CE
serial_number: 001675
program_official: THIERRY, JOANN
project_start_date: 2009-09-01
project_end_date: 2014-08-31
study_section: ZCE1-JXS(09)
contact_pi_person_id: 1894149
contact_pi: COKER, ANN L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
  
Problem Statement: While rates of lifetime forced sexual intercourse have increased in Kentucky over the past five years among high school students Kentucky is working to reduce this trend. Through CDC assistance Kentucky Association of Sexual Assault Programs Inc. (KASAP) is ready to implement the "Green Dot" bystander intervention program for primary prevention of sexual violence (SV). Importance: We now have the unique and time-sensitive opportunity to evaluate a statewide bystander intervention which will be implemented by KASAP Educators across Kentucky through high schools beginning in 2010. Green Dot empowers students to actively question peer support for SV and become change agents who can play a significant role in ending SV. Innovation: While several bystander intervention programs have been implemented few been empirically evaluated and none have been evaluated on a statewide basis using the same intervention protocol. Purpose: To evaluate the statewide application of Green Dot among high schools students. We hypothesize that students in high schools with Green Dot will over time report lower rates of SV compared with students in comparable high schools randomized not to have Green Dot. This reduction in SV will be mediated through a reduction in social norms supporting SV and an increase in bystander behaviors. Specific Aims: To prospectively determine whether relative to students in high schools without Green Dot those in schools with Green Dot (Aim 1) report lower rates of SV (Aim 2) a greater frequency of bystander behaviors and (Aim 3) fewer social norms supporting SV. Finally because Green Dots draws on social diffusion of innovation theory we propose (Aim 4) to determine how Green Dot influences bystander behaviors in the first and second order social networks of students who do and do not receive Green Dot training. Methods: A population-based controlled intervention trial will be used to test the efficacy of Green Dot. Both panel and web-based cohort survey methods will be used to provide baseline and prospective data on student's attitudes supporting SV bystander behaviors and SV experiences. Setting: In each of the 13 KASAP regions 2 demographically comparable high schools with at least 200 students per grade will be recruited to participate in Green Dot either as the intervention or control site. Schools will be randomly assigned to the intervention. Study Population: All students in participating high schools will be invited to complete anonymous panel surveys beginning spring 2010 through 2014; we anticipate that 6500 students in Green Dot and 6500 in control schools will complete surveys each year. We estimate that 650 students receiving Green Dot training and 650 students not so trained will complete the web-surveys (2011-2014). External sources of data to document SV will be obtained from high schools. Implications for Prevention: This state-wide population-based multi-site controlled intervention trial will provide an empirical test of a promising intervention which if proven effective could result in the primary prevention of SV and a reduction in the health and academic consequences of SV.  
  
PUBLIC HEALTH RELEVANCE:   
  
Determining whether a promising primary prevention intervention to reduce sexual violence perpetration is effective in reducing violence in a real world setting (high schools across Kentucky) can result in an important opportunity to prevent the short and longer term health consequences of sexual violence. Sexual violence defined to include physically forced sexual activity coerced sexual activity and sexual harassment is common (~25%) has health and academic consequences and is preventable; thus this form of violence can be a high impact target for primary prevention efforts.

public_health_relevance:
Determining whether a promising primary prevention intervention to reduce sexual violenceperpetration is effective in reducing violence in a real world setting (high schools acrossKentucky) can result in an important opportunity to prevent the short and longer term healthconsequences of sexual violence. Sexual violence defined to include physically forced sexualactivity coerced sexual activity and sexual harassment is common (~25%) has health andacademic consequences and is preventable; thus this form of violence can be a high impacttarget for primary prevention efforts.


