# projects

application_id: 8373657
project_number: 1R01AR061578-01A1
project_title: BISPHOSPHONATE USE AND BONE QUALITY
administering_ic: NIAMS
award_notice_date: 2012-06-28
opportunity_number: PA-10-009
application_type: 1
activity_code: R01
ic: AR
serial_number: 061578
suffix: A1
program_official: LESTER, GAYLE E
project_start_date: 2012-07-01
project_end_date: 2016-06-30
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 7875292
contact_pi: MALLUCHE, HARTMUT H
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): Bisphosphonates (BP) have been used to halt bone loss and prevent osteoporosis-related fractures but recent reports and our experience indicate that their long-term use may be related to "atypical" bone fractures. This poses a great public health concern because it could indicate a rising tide of difficult to treat costly atypical bone
fractures now in the making. An understandable consequence of these reports is the growing mistrust from the public and physicians regarding use of BPs to treat bone loss. Thus additional "typical" osteoporosis-related fractures could result due to reluctance to use BPs. This scenario emanating from two different reasons for increasing fractures creates an urgent need to clarify the relationship between long-term BP use and bone quality. Bone quality is important because it is widely regarded that alterations in this parameter are linked to bone fragility. The central hypothesis to be evaluated is that long-term BP use is associated with slow but progressive abnormalities in bone quality. The specific aims of the proposed study are to use an engineering-based approach to: 1) quantify bone quality abnormalities associated with no short medium and long-term BP treatment and to evaluate the contributions of low bone turnover and/or osteoporosis as a disease per se and 2) analyze the relationship between bone quality parameters and the continuous duration of BP use to determine the nature of these relationships (linear second-order exponential etc.) with time. The availability of an unrivaled
archive of bone biopsy specimens (8000+) and the collaborative experience of our clinical laboratory and engineering-based research team offers the unique opportunity to efficiently achieve these specific aims. The proposed study will measure the microstructural material and mechanical parameters of cortical and cancellous bone quality in bone samples from: a) patients with osteoporosis or no short medium and long-term BP therapy and b) healthy age-matched volunteers. These measurements will be made by using histomorphometry Fourier Transform Infrared Spectroscopy and nanoindentation. The proposed research offers a strong prospect to provide a substantial and sustained benefit to patients with osteoporosis. The findings will generate new information regarding the relationship between the duration of BP treatment and bone quality. If bone quality abnormalities are observed with BP treatment then a basis will exist for reformulation of BP treatment guidelines. If no bone quality abnormalities are
observed with BP treatment then the findings will provide reassurance to patients and physicians allowing confident use of BPs. Thus either outcome will provide valuable information regarding the therapeutic use of BPs. This will result in improved health for millions of patients with osteoporosis.   
   
PUBLIC HEALTH RELEVANCE: Bisphosphonates (BPs) are commonly used drugs that improve bone mass in millions of patients with osteoporosis but recent reports link long-term BP use with atypical bone fractures. This suggests that an abnormality in bone quality must accompany long-term BP use. The proposed laboratory study uses the PI's unrivaled archive of human diagnostic bone biopsy specimens to determine how long-term BP use affects bone quality. Knowledge gained from this study should provide a substantial and sustained benefit to human life by allowing the public to use bisphosphonates without fear of drug-related complications thereby reducing the morbidity mortality and healthcare costs linked to osteoporosis.

project_terms:
Activities of Daily Living;Address;Advocate;Affect;Age;Archives;Biopsy;Biopsy Specimen;Carbonates;Caucasians;Caucasoid Race;Clinical;Collagen;Competence;Control Groups;Diagnostic;Disease;Distress;Drug usage;Engineering;Fracture;Fright;Goals;Guidelines;Hardness;Health;Health Care Costs;Human;Knowledge;Laboratories;Laboratory Study;Life;Link;Measurement;Measures;Mechanics;Minerals;Morbidity - disease rate;Mortality Vital Statistics;Nature;Osteoporosis;Outcome;Patients;Pharmaceutical Preparations;Physicians;Porosity;Postmenopause;Quality of life;Reporting;Research;Research Personnel;Resolution;Sampling;Specimen;Spectroscopy Fourier Transform Infrared;Stress;Therapeutic Uses;Thick;Time;Tissues;Woman;base;bisphosphonate;bone;bone loss;bone mass;bone quality;bone turnover;crosslink;experience;improved;inorganic phosphate;meetings;nanoindentation;prevent;public health medicine (field);treatment duration;volunteer


application_id: 8372652
project_number: 1R01EY021769-01A1
project_title: The role of Insm1a in photoreceptor differentiation
administering_ic: NEI
award_notice_date: 2012-07-16
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: EY
serial_number: 021769
suffix: A1
program_official: NEUHOLD, LISA
project_start_date: 2012-08-01
project_end_date: 2017-07-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 10184513
contact_pi: MORRIS, ANN C
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Retinitis pigmentosa (RP) and allied inherited retinal dystrophies are a leading cause of blindness for which there is currently no cure. One potential treatment for retinal degenerative diseases is cell-based transplantation therapy whereby progenitor cells are transplanted into the diseased eye to replace the lost photoreceptors. While this is an exciting possibility several challenges to the implementation of transplantation therapies must be overcome including the inefficient integration of retinal progenitor cells (RPCs) into the recipient retina and the difficulty of obtaining sufficient numbers of photoreceptor precursors for clinical application. Protocols for the in vitro culture of RPCs must be developed that will produce large numbers of photoreceptor precursors and will promote their survival and differentiation once transplanted. Defining the transcriptional networks that promote specification of photoreceptor precursors is a necessary next step for the evolution of therapeutic strategies. One of the long-term goals of our laboratory is to contribute to these efforts by studying photoreceptor development and regeneration in the zebrafish. The zebrafish is especially useful for studying photoreceptor biology because its retina contains numerous cone subtypes in addition to rods. Furthermore unlike mammals the zebrafish retina is able to regenerate neurons in response to experimental damage. We have recently identified the transcriptional repressor Insm1a as a candidate regulator of photoreceptor differentiation and regeneration. The experiments described in this proposal will define the role of Insm1a during retinal neurogenesis through the application of genetic and molecular genetics approaches. Our specific aims are as follows: Specific Aim I: Determine the role of Insm1a in regulating photoreceptor differentiation during retinal development at the cellular level using both loss- and gain-of-function experiments to place Insm1 within the genetic hierarchy of known photoreceptor development genes and to determine whether it is required for retinal progenitor cell cycle exit; Specific Aim II: Identify the molecular targets of Insm1 regulation in the retina
using a combination of gene expression profiling digital gene expression analysis in vitro reporter assays and in vivo chromatin immunoprecipitation. Completion of our proposal will bridge important gaps in our understanding of the molecular mechanisms of vertebrate photoreceptor differentiation and reveal underlying principles relevant to the development of approaches for the effective treatment of human retinal disease.   
   
PUBLIC HEALTH RELEVANCE: The development of therapies to treat visual impairment resulting from photoreceptor degeneration will directly benefit from studies of animal models such as the zebrafish which develops ex utero remains optically transparent throughout development and which displays the capacity for injury-induced neural regeneration. The goal of our proposal is to define the role of a transcriptional regulator Insm1 in the development of photoreceptor cells and to identify the genes that are controlled by Insm1 in the developing retina. This information will facilitate efforts to guide photoreceptor differentiation from stem clls in vitro and in vivo for therapeutic purposes.

project_terms:
Address;Adoption;Ally;Animal Model;Animals;Biological Assay;Biology;Blindness;Cell Cycle;Cell Cycle Progression;Cell Survival;Cell Transplants;Cells;Data;Degenerative Disorder;Development;Disease;Embryo;Evolution;Eye;Gene Expression;Gene Expression Profile;Gene Expression Profiling;Gene Targeting;Genes;Genetic;Goals;Human;Immunohistochemistry;In Situ Hybridization;In Vitro;Inherited;Injury;Investigation;Laboratories;Luciferases;Mammals;Methods;Modeling;Molecular;Molecular Genetics;Molecular Target;Mus;Mutation;Natural regeneration;Nerve Regeneration;Neurons;Pathway interactions;Photoreceptors;Population;Promotor (Genetics);Protocols documentation;Regulation;Reporter;Retina;Retinal;Retinal Cone;Retinal Degeneration;Retinal Diseases;Retinal Dystrophy;Retinitis Pigmentosa;Rods (Retina);Role;Staging;Stem cells;System;Systems Analysis;Therapeutic;Transcription Repressor/Corepressor;Transplantation;Vertebrate Photoreceptors;Visual impairment;Zebrafish;Zinc Fingers;base;blastocyst;cell type;chromatin immunoprecipitation;clinical application;digital;effective therapy;gain of function;gene therapy;in vivo;neurogenesis;photoreceptor degeneration;research study;response;retinal neuron;retinal progenitor cell;retinogenesis;stem;therapy development;transcription factor


application_id: 8372021
project_number: 1R01AR060964-01A1
project_title: Modulating Inflammation and Fibrosis to Control Scarring in Muscle Wounds
administering_ic: NIAMS
award_notice_date: 2012-07-05
opportunity_number: PA-10-009
application_type: 1
activity_code: R01
ic: AR
serial_number: 060964
suffix: A1
program_official: BOYCE, AMANDA T
project_start_date: 2012-08-01
project_end_date: 2016-07-31
study_section: Musculoskeletal Tissue Engineering Study Section[MTE]
contact_pi_person_id: 1874927
contact_pi: PULEO, DAVID A.
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
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: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Muscle injuries occurring recreationally as well as in the workplace and home are among the most common musculoskeletal conditions in the U.S. Satellite cells provide muscle with the potential for regeneration but for large defects slow healing and excessive proliferation of fibroblasts frequently results in fibrosis and scarring that
can create a mechanical barrier that delays or restricts myofibers from bridging the injury gap. Recent findings have begun to elucidate differences between inflammatory processes that promote muscle repair and regeneration following injury and those that disrupt muscle homeostasis. In light of the multiple demands needed for preventing fibrotic scarring a multidisciplinary team has been assembled to apply a proactive strategy in which multiple biomolecules are delivered in a site-specific and temporally orchestrated manner to treat different aspects of the inflammatory and wound healing processes. Aim 1 will develop and characterize a mechanically flexible controlled release system for localized delivery of anti- inflammatory anti-oxidant pro-resolution and anti-fibrotic biomolecules. With respect to this Aim it is hypothesized that the devices can be tailored to deliver anti-inflammatory anti-oxidant pro-resolution and anti-fibrotic molecules with discrete profiles that roughly follow the kineticsof the wound healing process. Aim 2 will determine the efficacy of controlled localized sequential release of anti-inflammatory anti- oxidant pro-resolution and anti-fibrotic components to enhance structural/histological biochemical and functional properties in vivo in a rodent skeletal muscle defect model. The working hypothesis is that sequential treatment devices i.e. materials that resolve inflammation and then prevent fibrosis will not only enhance muscle regeneration but these films will be more effective than those releasing only one of the components or that deliver them without regard to the sequence of events during wound healing. Furthermore the methods may be applicable not only to repair of skeletal muscle defects but also for treatment of many other diseases in which control of inflammation and subsequent wound healing processes is needed.   
   
PUBLIC HEALTH RELEVANCE: Muscle injuries occurring recreationally as well as in the workplace and home are among the most common musculoskeletal conditions in the U.S. Although muscle has the potential to regenerate slow healing of large defects frequently results in scarring and incomplete recovery. This project will develop bioerodible films that control different phases of wound healing to enhance muscle regeneration.

project_terms:
Adhesions;Affect;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Biochemical;Biocompatible Materials;Biological Response Modifier Therapy;Chronic;Cicatrix;Contracture;Data;Defect;Devices;Disease;Event;Excision;Fibroblasts;Fibrosis;Film;Gel;Generations;Goals;Healed;Home environment;Homeostasis;Inflammation;Inflammation Mediators;Inflammatory;Injury;Killings;Kinetics;Laceration;Lead;Light;Location;Mechanics;Membrane;Methods;MicroRNAs;Military Personnel;Modeling;Muscle;Musculoskeletal;Natural regeneration;Operative Surgical Procedures;Outcome;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Polymers;Process;Property;Recovery;Resolution;Rodent;Sequential Treatment;Site;Skeletal muscle structure;Surface;System;Testing;Tissues;Trauma;Ursidae Family;Vent;Work;Workplace;Wound Healing;base;combat;controlled release;design;experience;flexibility;healing;in vivo;microorganism;multidisciplinary;muscle regeneration;prevent;repaired;response;satellite cell;stem cell population;tissue regeneration;tissue repair;vehicular accident;wound

public_health_relevance:
Muscle injuries occurring recreationally as well as in the workplace and home are among the most common musculoskeletal conditions in the U.S. Although muscle has the potential to regenerate slow healing of large defects frequently results in scarring and incomplete recovery. This project will develop bioerodible films that control different phases of wound healing to enhance muscle regeneration.


application_id: 8371279
project_number: 2R01AG029623-07A1
project_title: Role of TWEAK in skeletal muscle metabolism
administering_ic: NIA
award_notice_date: 2012-08-07
opportunity_number: PA-11-260
application_type: 2
activity_code: R01
ic: AG
serial_number: 029623
suffix: A1
program_official: WILLIAMS, JOHN
project_start_date: 2007-02-01
project_end_date: 2017-06-30
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 1917770
contact_pi: KUMAR, ASHOK
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
project_abstract:
DESCRIPTION (provided by applicant): During last funding period we identified and established that TWEAK cytokine is a major regulator of skeletal muscle mass during aging and disuse conditions. We have now obtained strong evidence suggesting that the TWEAK causes insulin resistance in skeletal muscle. However the mechanisms by which TWEAK induces muscle atrophy or insulin resistance remain less well understood. PGC-1 cofactor plays a major role in regulation of skeletal muscle mass fiber-type composition and mitochondrial biogenesis. Our preliminary studies have shown that TWEAK suppresses the expression of PGC-1 and mitochondrial content and inhibits insulin signaling in skeletal muscle. We have also found that disuse conditions or type II diabetes involve the inducible expression of TWEAK receptor Fn14 (but not TWEAK itself) in skeletal muscle. Our initial analysis has revealed that both human and mouse Fn14 promoter contains CpG rich regions and that demethylation of Fn14 promoter could be a crucial event for the induction of Fn14 expression in skeletal muscle. In the next phase of this project we will investigate the mechanisms by which TWEAK causes sarcopenia disuse-related muscle atrophy and insulin resistance and how the expression of Fn14 gets up regulated in skeletal muscle in different conditions. We will address the following three specific aims: AIM I. Investigate the role of PGC-1 in TWEAK-mediated skeletal muscle atrophy in vivo. Hypothesis 1: TWEAK causes muscle atrophy and fiber-type switching through down-regulation of PGC-1 expression. AIM II. Investigate the key mechanisms by which TWEAK-Fn14 system induces insulin-resistance in adult and/or aged skeletal muscle. Hypothesis 2: TWEAK induces insulin resistance by inhibiting insulin receptor substrate (IRS1) phosphorylation and diminishing oxidative phosphorylation in skeletal muscle. AIM III: Investigate the molecular events leading to increased expression of TWEAK receptor Fn14 in skeletal muscle. Hypothesis 3: Demethylation of CpG islands in Fn14 promoter followed by binding of SP1 transcription factor triggers the expression of Fn14 in skeletal muscle in catabolic
states. Successful completion of this project will provide critical insights about sarcopenia durin aging and type II diabetes and provide novel avenues for therapeutic interventions.   
   
PUBLIC HEALTH RELEVANCE: Skeletal muscle wasting is a debilitating consequence of aging and many chronic diseases such as type II diabetes common at older age. However there is still no approved therapy for treatment of this disorder/syndrome. It is essential to develop new medicines that can preserve skeletal muscle mass during aging. The proposed studies will identify the mechanisms of action of TWEAK cytokine a recently identified mediator of muscle wasting. Successful completion of this project will improve the basic understating of etiology of muscle wasting and type II diabetes and will lead to the identification of a novel drug
target to preserve muscle mass and function in aging human population.

project_terms:
Ablation;Acquired Immunodeficiency Syndrome;Address;Adult;Age;Aging;Atrophic;Binding (Molecular Function);Binding Sites;Biogenesis;Chronic Disease;Computer Simulation;Consensus;CpG Islands;Denervation;Development;Diabetes Mellitus;Disease;Down-Regulation;Drug Delivery Systems;Epigenetic Process;Etiology;Event;Fiber;Funding;GLUT4 gene;Genetic;Glucose;HDAC5 gene;Heart failure;Human;IRS1 gene;Immobilization;In Vitro;Injury;Insulin;Insulin Receptor;Insulin Resistance;Lead;MAP3K7 gene;Malignant Neoplasms;Mediating;Mediator of activation protein;Medicine;Methyltransferase;Mitochondria;Modeling;Molecular;Morbidity - disease rate;Mus;Muscle;Muscle Fibers;Muscle Proteins;Muscle function;Muscular Atrophy;NF-kappa B;Natural regeneration;Non-Insulin-Dependent Diabetes Mellitus;Oxidative Phosphorylation;PGC1a Regulation Pathway;PPAR gamma;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Phase;Phosphorylation;Physiological;Play;Population;Promotor (Genetics);Proteins;Regulation;Reporting;Role;Signal Transduction;Skeletal muscle structure;Specificity;Syndrome;System;TRAF6 gene;Testing;Therapeutic Intervention;Transcription Initiation Site;Transgenic Organisms;Ubiquitin;Up-Regulation (Physiology);aged;cofactor;cytokine;demethylation;glucose uptake;human HDAC4 protein;improved;in vivo;insight;insulin sensitivity;insulin signaling;multicatalytic endopeptidase complex;muscle aging;muscle form;muscle metabolism;neuromuscular activity;novel;older patient;overexpression;prevent;receptor;research study;sarcopenia;skeletal muscle wasting;transcription factor;wasting

public_health_relevance:
Skeletal muscle wasting is a debilitating consequence of aging and many chronic diseases such as type II diabetes common at older age. However there is still no approved therapy for treatment of this disorder/syndrome. It is essential to develop new medicines that can preserve skeletal muscle mass during aging. The proposed studies will identify the mechanisms of action of TWEAK cytokine a recently identified mediator of muscle wasting. Successful completion of this project will improve the basic understating of etiology of muscle wasting and type II diabetes and will lead to the identification of a novel drug
target to preserve muscle mass and function in aging human population.


application_id: 8370685
project_number: 1R01DK093832-01A1
project_title: Computational Approach to Personalized Anemia Management
administering_ic: NIDDK
award_notice_date: 2012-08-08
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: DK
serial_number: 093832
suffix: A1
program_official: BISHOP, TERRY ROGERS
project_start_date: 2012-09-01
project_end_date: 2016-07-31
study_section: Biomedical Computing and Health Informatics Study Section[BCHI]
contact_pi_person_id: 8145755
contact_pi: GAWEDA, ADAM E
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Effective anemia management in End-Stage Renal Disease (ESRD) is a complex task due to large variation in erythropoietic response among the ESRD patients. Evidence shows that excessive doses of Erythropoiesis Stimulating Agents (ESA) used in hypo-responsive patients coincide with increased cardiovascular complications. In addition to health risks reimbursement restrictions imposed by Medicare demand additional vigilance in ESA administration. Iron is one of the most important elements affecting the erythropoietic response. The ongoing blood losses associated with hemodialysis treatments increased risk of gastrointestinal bleeding and access complications as well as poor iron absorption lead to iron depletion in ESRD patients. Standard anemia management protocols do not fully address the synergistic nature of interactions between erythropoietin and iron. Personalized strategies for coordinated ESA and iron dosing are therefore necessary to achieve the desired clinical outcome reduce patient risk exposure and improve the cost-effectiveness of treatment. Our long-term goal is the advancement of biomedical computing to personalize medicine and pharmacologic management of chronic conditions. The objective of this project is to address the challenge of multiple drug dosing personalization with a specific application to ESA and iron management in anemia of ESRD. The central hypothesis is that a computational approach can be developed to perform coordinated personalized dosing of erythropoiesis stimulating agents and iron in order to achieve desired clinical outcomes and minimize patient exposure resulting in optimal care. The rationale behind the proposed research is that computational models quantifying the interaction between iron and erythropoietin can be applied through the principles of control theory and machine learning to derive personalized dosing strategies for both agents. The main objective will be accomplished through three specific aims: 1) quantification of the erythropoietin-iron interaction through clinically relevant computational models 2) application of such models to derive algorithms for coordinated personalized ESA and iron dosing 3) validation of these algorithms through an "in sillico" trial for a wide range o simulated subjects and clinical conditions. The expected outcome of this project is a new systematic approach to the management of ESRD anemia using multiple agents resulting in improved patient care and decreased cost which will be broadly applicable to other therapeutic areas.   
   
PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because personalized dosing of multiple therapeutic agents broadly applicable to many chronic conditions is ultimately expected to improve cost-effectiveness of treatment and minimize patient risk. The proposed research is relevant to the NIH mission because it contributes toward advancement of personalized medicine one of the top priorities of the NIH.

project_terms:
Address;Affect;Algorithms;Anemia;Area;Biomedical Computing;Blood Vessels;Cardiovascular system;Caring;Chronic;Chronic Kidney Failure;Clinical;Complex;Complication;Computer Simulation;Computing Methodologies;Data;Dialysis procedure;Dose;Elements;End stage renal failure;Erythropoiesis;Erythropoietin;Exposure to;Goals;Health;Hemodialysis;Hemorrhage;Intestines;Iron;Lead;Machine Learning;Medicare;Medication Management;Medicine;Mission;Modeling;Mortality Vital Statistics;Nature;Outcome;Patient Care;Patients;Pharmaceutical Preparations;Population;Prevention;Protocols documentation;Quality of life;Research;Risk;Risk Factors;Simulate;Therapeutic;Therapeutic Agents;United States National Institutes of Health;Validation;Variant;Work;absorption;base;clinically relevant;cost;cost effectiveness;design;efficacy testing;gastrointestinal;improved;mathematical model;public health medicine (field);response;theories;vigilance


application_id: 8370610
project_number: 1R01AI095307-01A1
project_title: Alternative macrophage activation in acute Pseudomonas pneumonia
administering_ic: NIAID
award_notice_date: 2012-05-07
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: AI
serial_number: 095307
suffix: A1
program_official: DAVIDSON, WENDY F
project_start_date: 2012-07-01
project_end_date: 2017-06-30
study_section: Immunity and Host Defense Study Section[IHD]
contact_pi_person_id: 8968639
contact_pi: FEOLA, DAVID
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
project_abstract:
DESCRIPTION (provided by applicant): Alternative macrophage activation regulates inflammatory responses to pathogenic organisms. Most work to date has characterized their role in Th2-type immune responses. Alternatively activated macrophages (AAM) have been shown to inhibit classically activated macrophage proliferation and function as well as to suppress T cell mediated immune responses through the production of the type II cytokine transforming growth factor (TGF)- and arginase-1. While primarily functioning to orchestrate remodeling and repair mechanisms arginase-1 and TGF are also important in controlling lung homeostasis and suppressing inflammation. The function of AAM in regulating the inflammatory response to extracellular Gram-negative bacterial infection in the lungs has not been characterized. Understanding the role of AAM in this setting is critical for advancing our understanding of immune mechanisms affecting patients with cystic fibrosis (CF) and other chronic pulmonary inflammatory conditions. CF causes progressive life-threatening lung damage due in large part to repeated dysregulated inflammatory responses to Pseudomonas aeruginosa infection. Therefore this work will address the hypothesis that alternatively activated
macrophages decrease pulmonary inflammation in P. aeruginosa infection and that this is dependent upon production of TGF and arginase-1. We will utilize a model of P. aeruginosa pneumonia in normal and genetically engineered mice to address 3 distinct aims. Aim 1 will determine whether regulation of inflammation caused by P. aeruginosa lung infection is dependent upon alternative macrophage activation. Aim 2 will address whether AAM regulation of T cell disposition can control inflammation and lung damage through the production of TGF. Aim 3 will determine whether arginase-1 expression by macrophages is required to prevent inflammation induced by P. aeruginosa pneumonia. Mouse models with genetically altered AAM TGF signaling and macrophage-specific arginase-1 production will be used along with adoptive transfer methodologies and complementary in vitro experiments. The impact of these alterations will be evaluated in terms of inflammation classical macrophage function and T cell subset activation and function to determine the important mechanisms employed by macrophages in regulating these responses. Highlighting the clinical relevance of this work is the use of the antimicrobial agent azithromycin as an immunomodulator in patients with CF. This drug has been shown to slow pulmonary function decline and decrease morbidity in CF patients infected with Pseudomonas but the beneficial mechanistic effect is unknown. Recently it has been shown in both in vitro and animal studies that azithromycin polarizes macrophages to an alternative-like phenotype dramatically increasing the expression of arginase-1. This data along with the successful long-term use of azithromycin in patients with CF make studying the role of alternative macrophage activation in response to Pseudomonas pneumonia attractive and likely to yield novel therapeutic targets for intervention to alter this destructive cycle of inflammation and airway damage.   
   
PUBLIC HEALTH RELEVANCE: Cystic fibrosis and other chronic lung diseases cause progressive life-threatening lung destruction due in part to excessive inflammation with frequent exacerbations caused by repeated bacterial infections. This project will investigate the regulatory role that macrophages play in the immune response to Pseudomonas aeruginosa one of the most common bacterial pathogens in these patients. This work will lead to the identification of therapeutic targets for intervention to delay the rate of pulmonary decline in these patients.

project_terms:
Acute;Address;Adoptive Transfer;Affect;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Attenuated;Azithromycin;Bacterial Infections;Bacterial Pneumonia;Cell physiology;Cells;Characteristics;Chronic;Chronic lung disease;Cystic Fibrosis;Data;Disease;Exposure to;Future;Genes;Genetically Engineered Mouse;Goals;Gram-Negative Bacterial Infections;Homeostasis;Immune;Immune response;Immunomodulators;In Vitro;Infection;Inflammation;Inflammatory;Inflammatory Response;Injury;Intervention;Knowledge;Lead;Life;Lung;Lung Inflammation;Macrophage Activation;Methodology;Methods;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mouse Strains;Mus;Organism;Pathology;Patients;Pattern;Pharmaceutical Preparations;Phenotype;Play;Pneumonia;Process;Production;Pseudomonas;Pseudomonas aeruginosa;Randomized Clinical Trials;Regulation;Role;Series;Signal Transduction;Staging;T cell differentiation;T cell regulation;T-Lymphocyte;T-Lymphocyte Subsets;Time;Transforming Growth Factors;Up-Regulation (Physiology);Work;airway inflammation;antimicrobial drug;arginase;base;cell mediated immune response;clinically relevant;cystic fibrosis mouse;cystic fibrosis patients;cytokine;evidence base;experience;extracellular;functional decline;in vivo;macrophage;mouse model;neutrophil;new therapeutic target;pathogen;prevent;pulmonary function decline;repaired;research study;response;therapeutic target


application_id: 8369799
project_number: 5F31DA030061-02
project_title: Longitudinal effects of custody loss on drug use and crime of African American wo
administering_ic: NIDA
award_notice_date: 2012-05-24
opportunity_number: PA-10-108
application_type: 5
activity_code: F31
ic: DA
serial_number: 030061
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)L]
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
arra_indicator: N
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.

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: 8369510
project_number: 1R01AA020051-01A1
project_title: RAX PKR and ethanol neurotoxicity
administering_ic: NIAAA
award_notice_date: 2012-08-20
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: AA
serial_number: 020051
suffix: A1
program_official: REGUNATHAN, SOUNDAR
project_start_date: 2012-09-01
project_end_date: 2017-05-31
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 10212779
contact_pi: CHEN, GANG
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):  Fetal Alcohol Spectrum Disorders (FASD) are a range of permanent birth defects caused by maternal alcohol consumption during pregnancy. The prevalence of FASD in populations of younger school children is recently estimated as high as 2-5% in the United State and is more common than Down syndrome and autism. FASD-related costs are more than $6 billion annually. Identification of the mechanism of ethanol toxicity in the brain and determination of the effective therapeutic target(s) are cited as importat goals in the NIAAA Strategic Plan for 2009-2014.  Central nervous system (CNS) damage is a major feature observed in FASD patients. The cerebellum is one of the most sensitive areas in the CNS to ethanol toxicity. Neuronal loss is one of the most deleterious effects of ethanol and is responsible for many of the behavioral deficits observed in FASD. In the animal model exposure of infant rodents to ethanol during a portion of the brain growth spurt period - postnatal
day (PD) 4 to 9 equivalent to the human third trimester - causes a significant loss of cerebellum Purkinje and granule neurons. However the underlying mechanism for ethanol-induced neuronal loss in the developing cerebellum is still largely unclear. The goal of this proposed study is to identify the mechanism underlying ethanol neurotoxicity and the novel target(s) for the prevention and treatment of FASD.  The double-stranded RNA (dsRNA)-activated protein kinase (PKR) organizes the cellular self-defense system in response to diverse physiochemical stresses or viral infection by regulating a variety of downstream target proteins and signal pathways. Activation of PKR by its intracellular activator RAX under physiochemical stress conditions leads to protein synthesis inhibition as well as apoptosis and has been implicated in the pathogenesis of a number of neurodegenerative diseases.  The central hypothesis of the proposed study is that RAX-mediated PKR activation regulates ethanol- induced neuronal loss in the developing cerebellum.  Specific Aim 1: To investigate whether PKR activation through RAX/PKR interaction regulates ethanol- induced neuronal apoptosis in the developing cerebellum of the mouse.  Specific Aim 2: To determine whether inhibition of PKR by targeting RAX or PKR expression or by PKR inhibitors alleviates ethanol-induced neuronal loss in the developing cerebellum of the mouse.  Specific Aim 3: To determine whether RAX+/- mice N-PKR-/- mice or PKR-inhibitor-injected mice are more resistant to ethanol-induced cerebellar behavioral dysfunction.   
   
PUBLIC HEALTH RELEVANCE: This proposed study targets Fetal Alcohol Spectrum Disorders (FASD) a range of permanent birth defects caused by alcohol consumption during pregnancy. FASD is a national public health concern as those affected suffer a lifelong disability with no current cure. The outcome may identify therapeutic target(s) for the prevention or treatment of FASD.

project_terms:
Affect;Animal Behavior;Animal Model;Animals;Apoptosis;Apoptotic;Area;Autistic Disorder;Behavioral;Binding (Molecular Function);Brain;Cells;Cerebellum;Child;Congenital Abnormality;Cytoplasmic Granules;Development;Disease;Dominant-Negative Mutation;Double-Stranded RNA;Down Syndrome;Ethanol;Ethanol toxicity;Exposure to;Fetal Alcohol Spectrum Disorder;Functional disorder;Goals;Growth;Health;Human;In Vitro;Infant;Inhibition of Apoptosis;Investigation;Learning Disabilities;Mediating;Mental Retardation;Molecular;Mus;National Institute on Alcohol Abuse and Alcoholism;Nerve Degeneration;Nervous System Trauma;Neuraxis;Neurodegenerative Disorders;Neurons;Outcome;Oxidative Stress;Pathogenesis;Patients;Play;Population;Prevalence;Prevention;Protein Synthesis Inhibition;Proteins;Psyche structure;Reporting;Resistance;Rodent;Role;Schools;Series;Severities;Signal Pathway;Social Problems;Strategic Planning;Stress;System;Testing;Third Pregnancy Trimester;Transgenic Mice;United States;Virus Diseases;Weight;alcohol consumption during pregnancy;alcohol effect;alcohol exposure;alcohol sensitivity;behavior test;behavioral impairment;cell type;cost;disability;eIF-2 Kinase;effective therapy;inhibitor/antagonist;innovation;mouse model;neuron apoptosis;neuron loss;neurotoxicity;novel;novel strategies;postnatal;public health medicine (field);response;therapeutic target


application_id: 8369173
project_number: 1R25GM102776-01
project_title: Kentucky Bridge to a Biomedical Doctorate for Appalachian Students
administering_ic: NIGMS
award_notice_date: 2012-08-21
opportunity_number: PAR-11-279
application_type: 1
activity_code: R25
ic: GM
serial_number: 102776
program_official: HAMLET, MICHELLE R
project_start_date: 2012-09-01
project_end_date: 2017-06-30
study_section: Minority Programs Review Subcommittee A[MPRC-A]
contact_pi_person_id: 1879406
contact_pi: SPEAR, BRETT
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This Bridges to Doctorate Program is an initiative by faculty at Eastern Kentucky University (EKU) and the University of Kentucky (UK) to prepare underrepresented students for careers in biomedical research. The primary target student population for this Bridges grant will be those from Appalachian counties considered to be "distressed" or "at-risk" due to their significant unemployment and poverty rates. The rationale to
focus on distressed Appalachian counties is that they comprise a large part of the EKU service region although this Bridges program will also endeavor to recruit students from other underrepresented groups. EKU and UK are ideal partners for this particular Bridges program; both are geographically situated close to the region targeted in this grant a strong relationship already exists between these two institutions and their proximity will allow Bridge students to travel easily from EKU to UK for symposia and classes. A comprehensive plan is proposed to provide strong masters level training to Bridge students while at EKU to prepare them to transition to the UK Integrated Biomedical Sciences (IBS) program where they will pursue doctoral studies in biomedical research. The aims of this proposal are to: (1) recruit talented Appalachian students to a comprehensive interdisciplinary master's program to EKU with mentoring from EKU and UK faculty (2) provide Appalachian Bridge students with the skill sets needed for continued training at the PhD level including an intensive research experience that requires a written research proposal and thesis workshops courses and seminars (3) provide opportunities to showcase the achievements of Appalachian Bridge students at local regional and national meetings and (4) develop a series of metrics to rigorously evaluate the success of the EKU-UK Bridges to Doctorate program and make adjustments/improvements when warranted. With an excellent group of faculty from EKU and UK who have agreed to serve as mentors for this program we anticipate the ability to recruit 5 students/year to this 2-year master's program.    
   
PUBLIC HEALTH RELEVANCE: The goal of this Bridges to Doctorate program is to prepare underrepresented baccalaureate students with master level training at Eastern Kentucky University in preparation for transition to the Integrated Biomedical Sciences PhD program at the University of Kentucky. This Bridges program will primarily target students from Appalachia a disadvantaged region that is already a large part of the Eastern Kentucky University service region. The aims of this grant will provide comprehensive research-intensive training and includes an evaluation plan to insure that the program is achieving its stated objectives.

project_terms:
Achievement;Address;Admission activity;Appalachian Region;Attention;Award;Biomedical Research;Books;Country;County;Data;Data Reporting;Disadvantaged;Distress;Doctor of Philosophy;Doctor's Degree;Educational Background;Educational Curriculum;Educational Status;Educational aspects;Educational workshop;Ensure;Ethics;Evaluation;Faculty;Financial Support;Goals;Grant;Institution;Joints;Kentucky;Lead;Life;Master's Degree;Measures;Mentors;Methods;Metric;Online Systems;Oral;Peer Review;Population;Poverty;Preparation;Publications;Recruitment Activity;Research;Research Proposals;Resources;Rest;Risk;Schools;Science;Scientist;Series;Services;Students;Training;Travel;Unemployment;Universities;Work;Writing;abstracting;base;career;college;experience;improved;meetings;news;programs;skills;sobriety;success;symposium;undergraduate education


application_id: 8368281
project_number: 1R01HL111040-01A1
project_title: Epigenetic Regulation of Inflammatory Gene Expression by Telomerase
administering_ic: NHLBI
award_notice_date: 2012-09-26
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: HL
serial_number: 111040
suffix: A1
program_official: HASAN, AHMED A K
project_start_date: 2012-09-27
project_end_date: 2016-06-30
study_section: Special Emphasis Panel[ZRG1 VH-D (02)]
contact_pi_person_id: 8010784
contact_pi: BRUEMMER, DENNIS CHRISTOPHER
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Innate immune responses are central to the pathogenesis of atherosclerotic cardiovascular disease and are orchestrated through transcriptional networks involving epigenetic modification of the chromatin architecture. There is now increasing evidence that the chromatin state is affected by telomerase. In addition to its well- established function to synthesize telomere repeats at the ends of chromosomes telomerase reverse transcriptase (TERT) serves a direct role in facilitating the activation of gene
expression programs. This second activity of TERT in permitting gene transcription appears to operate independently of its role in telomere homeostasis but may involve modification of the higher-order chromatin structure. Although TERT is expressed in macrophages of human atherosclerotic lesions a physiological role of this non-canonical activity of TERT in inflammation and atherosclerosis remains to be discovered. Our recent studies confirmed that TERT activates gene promoters in macrophages. Conversely TERT-deficiency alters macrophage inflammatory gene expression by inducing chromatin modifications reminiscent of gene silencing. Two specific aims are proposed to explore the significance of these findings and to test the hypothesis that TERT promotes inflammatory gene expression in macrophages through epigenetic chromatin modifications and contributes to the development of atherosclerosis. In Specific Aim 1 we will utilize a combination of cellular and molecular approaches to determine the transcriptional mechanisms by which TERT regulates macrophage inflammatory gene expression programs. In Specific Aim 2 we will determine the contribution of TERT to the development of atherosclerosis and test the hypothesis that TERT-dependent activation of inflammatory gene expression in macrophages constitutes an important mechanism for the development of the disease. Ultimately the results of these studies will not only characterize TERT as a chromatin modifier and novel regulatory protein orchestrating macrophage inflammatory gene expression but also advance our understanding of the inflammatory mechanisms contributing to the development of atherosclerosis.   
   
PUBLIC HEALTH RELEVANCE: Atherosclerotic cardiovascular disease is the leading cause of death in the United States and inflammatory pathways contribute to all stages of the disease. This application will investigate novel mechanisms that control the activation of inflammation during atherosclerosis formation. The results of these studies may ultimately characterize novel pathways contributing to vascular diseases and lead to new therapeutic opportunities.

project_terms:
Adult;Affect;American;Architecture;Arterial Fatty Streak;Atherosclerosis;Blood Vessels;Cardiovascular Diseases;Catalytic Domain;Cause of Death;Cell physiology;Cells;Chromatin;Chromosomes;DNA;Data;Development;Developmental Process;Disease;Environment;Epigenetic Process;Exhibits;Feeds;Funding;Gene Activation;Gene Expression;Gene Silencing;Generations;Genes;Genetic Transcription;Genetically Engineered Mouse;Higher Order Chromatin Structure;Histones;Homeostasis;Human;Immune response;Inflammation;Inflammatory;Inflammatory Response;Lead;Modification;Molecular;Nucleosomes;Pathogenesis;Pathway interactions;Physiological;Promotor (Genetics);Property;Recovery;Recruitment Activity;Regulation;Relative (related person);Role;Signal Transduction;Somatic Cell;Staging;Telomerase;Telomere Maintenance;Telomere Shortening;Testing;Tissues;United States;Vascular Diseases;base;chromatin modification;chromatin remodeling;genetic regulatory protein;in vivo;innate immune function;macrophage;novel;novel therapeutics;programs;protein complex;research study;response;telomerase reverse transcriptase;telomere;vascular inflammation


application_id: 8368173
project_number: 1R03CA164831-01A1
project_title: Targeting endocrine resistant breast cancer with anacardic acid
administering_ic: NCI
award_notice_date: 2012-07-10
opportunity_number: PAR-11-079
application_type: 1
activity_code: R03
ic: CA
serial_number: 164831
suffix: A1
program_official: SEIFRIED, HAROLD E
project_start_date: 2012-07-10
project_end_date: 2014-06-30
study_section: Special Emphasis Panel[ZCA1 SRLB-2 (M1)]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: SCHULTZ, DAVID
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Dietary phytochemicals are potential sources of new drug leads to prevent breast and other cancers. Nuclear Receptor Alternative Site Modulators (NRAMs) are a recently defined class of chemicals with potential application in preventing breast cancer by blocking estrogen receptor  (ER) function through mechanisms other than blocking ligand activation. NRAMs are distinct from currently used chemopreventives such as selective ER modulators (SERMs e.g. tamoxifen (TAM)) and aromatase inhibitors (AI e.g. letrozole) against which tumor cells become resistant. We recently reported that a purified anacardic acid (AnAc 24:1n-5) inhibited the proliferation of ER-positive/TAM-responsive MCF-7 and ER-positive/endocrine-resistant LCC9 and LY2 breast cancer cells but not primary normal human mammary epithelial cells (HMECs). AnAc 24:1n-5 does not compete with [3H]estradiol (E2) for ER or ER but inhibits ER-DNA interaction and transcriptional activity with greater efficacy than ER. These data indicate that AnAc 24:1n-5 functions as a NRAM. AnAc 24:1n-5 is a congener of AnAc constituents found in caju juice (commonly consumed in Brazil) and thus establishes dietary intake as a relevant route for this potential NRAM. Our breast cancer cell-based work provides strong rationale for the proposed pilot study that addresses PAR-11-079 by 1) Investigating the mechanisms of action of AnAc as an NRAM by utilizing ER overexpression and shRNA knockdown approaches to confirm the specificity of AnAc 24:1n-5 as an NRAM. 2) Pilot testing and developing AnAc as a dietary intervention to prevent or retard carcinogen (NMU)-induced mammary tumors in female Sprague- Dawley (SD) rats. 3) Developing sensitive and reliable methods for analysis of AnAc and its metabolites in serum tumors and tissues. 4) Determining the bioavailability and dose-response of AnAc as "foods nutrients and other naturally-occurring food constituents". The hypotheses tested in these Specific Aims is that 1) AnAc acts as an ER-selective NRAM and 2) that AnAc supplied orally in AIN-93M diet will function as a natural chemopreventive to NMU-induced primary mammary tumors in female SD rats. These studies will provide the first in vivo data regarding the efficacy of AnAc in primary mammary tumor prevention and will establish the serum and tissue levels of AnAc after oral consumption.   
   
PUBLIC HEALTH RELEVANCE: It is estimated that 230480 US women will be diagnosed and 39520 will die from breast cancer in 2011. The two goals of this project are 1) to determine if anacardic acid is a Nuclear Receptor Alternate Site Modulator (NRAM) that specifically inhibits estrogen receptor-DNA binding and 2) to test the ability of anacardic acid supplied dietarily to inhibit the development of NMU-induced mammary tumors in rats. This project the first to test AnAc 25:1n-5 as a NRAM to preventative carcinogen-induced breast cancer in an animal model.

project_terms:
Acids;Address;Affect;Anacardic Acids;Androgen Receptor;Animal Model;Aromatase Inhibitors;Binding (Molecular Function);Biological Assay;Biological Availability;Brazil;Breast;Breast Cancer Cell;Breast Cancer Prevention;Cancer Patient;Carcinogens;Cathepsins;Cell Proliferation;Cells;Chemicals;Chemoprevention;Chemopreventive Agent;Computer Simulation;Consumption;DNA;DNA Binding;DNA Binding Domain;Data;Development;Diagnosis;Diet;Dietary Intervention;Dietary Phytochemical;Dietary intake;Disease;Disease Resistance;Dose;Elements;Endocrine;Epithelial Cells;Estradiol;Estrogen Receptor Modulators;Estrogen Receptors;Estrogen receptor positive;Estrogens;Female;Food;Gene Targeting;General Transcription Factors;Genetic Transcription;Glucocorticoid Receptor;Goals;Growth;Histology;Human;Hydrocarbons;In Vitro;Ingestion;Juice;Letrozole;Ligands;Liver neoplasms;MCF7 cell;Malignant Neoplasms;Mammary Neoplasms;Mammary Tumorigenesis;Mammary gland;Mediating;Methods;Methylnitrosourea;Modeling;Nuclear Receptors;Nutrient;Oral;Outcome Measure;Pathologic;Patients;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Pilot Projects;Postmenopause;Progesterone Receptors;Rattus;Recurrence;Reporting;Resistance;Resources;Response Elements;Route;Selective Estrogen Receptor Modulators;Serum;Site;Small Interfering RNA;Source;Specificity;Sprague-Dawley Rats;Staining method;Stains;Tamoxifen;Testing;Tissues;Tocopherols;Translational Research;Tumor Tissue;Woman;Work;Zinc Fingers;base;cancer risk;human GATA1 protein;in vivo;indexing;malignant breast neoplasm;neoplastic cell;overexpression;physical property;prevent;receptor binding;receptor function;response;small hairpin RNA;transcription factor;tumor;tumor growth

public_health_relevance:
It is estimated that 230480 US women will be diagnosed and 39520 will die from breast cancer in 2011. The two goals of this project are 1) to determine if anacardic acid is a Nuclear Receptor Alternate Site Modulator (NRAM) that specifically inhibits estrogen receptor-DNA binding and 2) to test the ability of anacardic acid supplied dietarily to inhibit the development of NMU-induced mammary tumors in rats. This project the first to test AnAc 25:1n-5 as a NRAM to preventative carcinogen-induced breast cancer in an animal model.


application_id: 8366806
project_number: 1K12DA035150-01
project_title: Kentucky BIRCWH Program: Training the Next Generation of Women's Health Scholars
administering_ic: NIDA
award_notice_date: 2012-07-31
opportunity_number: RFA-OD-11-002
application_type: 1
activity_code: K12
ic: DA
serial_number: 035150
program_official: FRANKENHEIM, JERRY
project_start_date: 2012-08-01
project_end_date: 2017-07-31
study_section: Special Emphasis Panel[ZRG1 PSE-K (50)]
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The University of Kentucky (UK) is uniquely positioned to continue using exceptional and outstanding research infrastructure to train the next generation of women's health scholars. We choose to focus our scholarship efforts on those health challenges unique to Appalachian Kentucky. Because the Appalachian region is disproportionately affected by drug abuse violence and poor health we will actively engage women living in Appalachian Kentucky in our research agenda with research flowing bidirectionally between communities and researchers. This approach will continue to provide our BIRCWH scholars with state-of-the-art multidisciplinary training leading to their development as faculty with independent NIH funding. The focused areas targeted towards improving women's health in this application include: 1) substance abuse 2) violence against women and 3) hormonal regulation across a woman's lifespan. UK is uniquely position to address violence against women because UK has the only US Center focusing on research to prevent violence against women. Through this BIRCWH program strengthening the capacity for women's health research will be accomplished by the following Specific Aims: 1) to provide the environment mentorship and facilities to enhance the ability of BIRCWH scholars to compete for NIH research grants in diverse areas of women's health research 2) to deepen our understanding of the unique role of gender in the manifestation of health and disease 3) to stimulate new collaborations in focused interdisciplinary and interactive research areas that are essential for
improving women's health; and 4) to use a thematic multidisciplinary focus as a platform for enhancing translational research between basic clinical and public health scientists. Key aspects of training will include: (a) pairing the BIRCWH scholar with senior level scientists and former BIRCWH scholars forming a research team and thus modeling interdisciplinary collaboration (b) providing these teams with access to cutting edge technologies and (c) providing scholars with training in concepts relevant to women's health. A strength of our BIRCWH program is its multidisciplinary cross-departmental and interactive nature positioned in an area with unique health needs. As evident by the success of our former BIRCWH scholars we are well positioned to continue the tradition of excellence in mentoring our scholars to become independent researchers in women's health.   
   
PUBLIC HEALTH RELEVANCE: Emphasizing gender differences in effective health care research and treatment is critical. We must train the next generation of scientists to recognize and apply these differences. This proposal will provide a platform to mentor and train promising young scientists in focused areas of women's health research to address the unique needs in women's health especially for those who are underserved.


application_id: 8365240
project_number: 1UL1RR033173-01
project_title: CTSA INFRASTRUCTURE FOR PEDIATRIC RESEARCH
project_terms: Clinical Sciences;Kentucky;Pediatric Research;Research Infrastructure;Translational Research
administering_ic: NCRR
award_notice_date: 2011-05-30
opportunity_number: RFA-RM-10-001
application_type: 1
activity_code: UL1
ic: RR
serial_number: 033173
project_start_date: 2011-06-01
project_end_date: 2012-02-29
study_section: ZRR1-CR-1(01)
subproject_number: 8828
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
This subproject represents an estimate of the percentage of the CTSA funding that isbeing utilized for a broad area of research (AIDS research pediatric research orclinical trials).  The Total Cost listed is only an estimate of the amount of CTSAinfrastructure going towards this area of research not direct funding provided bythe NCRR grant to the subproject or subproject staff.At the University of Kentucky (UK) we have established the Center for Clinical and Translational Science (CCTS) as a home for clinical and translational research. UK is located in Lexington on the western edge of mid-Appalachia one ofthe poorest areas ofthe country where there are unprecedented disparities in disease and mortality. Many of these disparities stem from risky behaviors such as smoking drug abuse and obesity. In this proposal our overarching goal is to transform the pace effectiveness and quality of translational research at UK which will result in better health for the people of mid-Appalachia. Scientific discovery offers the potential for improved care with community-based research offering a faster impact on health through a better dissemination of optimal medical care. However scientific discoveries often do not reach the community due to the many difficulties with navigating the complex process of clinical and translational research. In this application we will capitalize on our strengths in education basic and clinical sciences as well as our outstanding programs in practice- and community- based participatory research. These efforts will result in scientific discovery that will impact the health ofthe Appalachian rural community in the near term and prime the pipeline for the future. To accomplish these goals UK will form a collaboration with Marshall University which is 2 hr away in Huntington WV. In addition we will form an Appalachian Translational Reseach Network involving not only Marshall but also the CTSAs at the Ohio State University University of Cinncinati Morehead University and Pikeville School of Osteopathic Medicine. This network will be especially important in the further development of our strong programs in community based participatory research. To help integrate our efforts we have developed an innovative group of faculty CATalysts who will build collaborative team science programs backed by generous pilot funding that will target novel ideas at all levels of science. New CCTS programs in "Drug Development" "Novel Methodologies" and "Risk-Related Behavior Research" will capitalize on our strengths engage investigators with diverse areas of expertise and will more quickly impact the health of the Appalachian community. We have recently recruited a new leader in Biomedical Informatics and have invested heavily in this program which will greatly improve our ability to transform data into knowledge throughout the CCTS. Through these initiatives UK will fulfill its mandate as Kentucky's flagship university to improve the health of Central Appalachia and thereby add unique value to improvements in the health ofthe nation.RELEVANCE (See instructions): The CCTS at UK has developed well-integrated relationships with University programs in Central Appalachia and with rural health programs. We routinely apply a foundation principal of community based participatory research where the lay community identifies ttie research issues and co-develops solutions. This proposal seeks to make research more relevant by breaking down bamers to research translation and greatly improving the pace by which science discoveries drive improvements in health in Kentucky and the nation.


application_id: 8364914
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
project_start_date: 2011-08-01
project_end_date: 2012-07-31
study_section: ZRR1-RI-B(01)
subproject_number: 8503
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:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.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.

project_terms:
Area;Behavioral;Biometry;Centers of Research Excellence;Core Facility;D Cells;Development;Funding;Goals;Grant;Histology;Housing;Human;Human Resources;Image;Individual;Kentucky;Laboratories;National Center for Research Resources;National Institute of Neurological Disorders and Stroke;Nervous System Trauma;Operative Surgical Procedures;Principal Investigator;Research;Research Infrastructure;Research Personnel;Resources;Source;Spinal cord injury;Techniques;Technology;Tissues;Training;United States National Institutes of Health;Universities;Work;animal care;central nervous system injury;cost;injury and repair;innovative technologies;nervous system development;neurodevelopment;novel strategies;programs;repaired;research and development;translational study


application_id: 8361031
project_number: 1R21NS080091-01
project_title: Novel transgenic mice for tracing and electrophysiology of stressed neurons
administering_ic: NINDS
award_notice_date: 2012-04-30
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: NS
serial_number: 080091
program_official: LUDWIG, KIP A
project_start_date: 2012-07-01
project_end_date: 2014-06-30
study_section: Molecular Neurogenetics Study Section[MNG]
contact_pi_person_id: 9011081
contact_pi: PETRUSKA, JEFFREY C
other_pis: HAI, TSONWIN
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): Numerous neurological diseases and pathologies include or are hypothesized to include cellular injury and/or stress as part of the mechanism. Experimental approaches to examine these mechanisms or even determine if they are indeed at play in certain conditions are generally limited. They include post-mortem analyses of known stress-response genes/molecules in vivo pharmacological manipulations which are often systemic or functional assessments/manipulations which often cannot separate stressed from non-stressed neurons. Ideally it would be possible to determine a priori on a cell-by-cell basis
which neurons in a mixed population were exhibiting a cell-stress response. Further since some stress responses or at least some components of the stress response are only transiently expressed even though the overall stress responses may have a cumulative effect on the cell it would be highly useful to have an a priori indication of which neurons had exhibited a stress response at some point in the past. It would also be highly useful to be able to selectively assess the cellular and inter-cellular functionality of the stressed neurons. To these ends we propose to generate new functional-reporter transgenic mouse lines which will incorporate these characteristics. The reporters will be driven by the promoter region of Activating Transcription Factor 3 (ATF3) a "hub" protein involved in a variety of cellular stress responses. Generation of the mice will be via BAC-transgenes in order to preserve function of the native ATF3 alleles which are necessary for certain cellular processes. The BAC transgene with the ATF3 locus will drive production of the light-gated ion channel channelrhodopsin-2 (ChR2) fused to a fluorescent protein. One model will have the reporters produced in an analogue fashion (i.e. to reflect native ATF3 expression). A second model will use an inducible Cre-recombinase system to permanently "switch-on" reporter production thus allowing at any later time identification of
neurons that previously expressed a stress response. These functional-reporter models will allow offline anatomical assessments FACS or laser-capture separations fate-tracing of previously-stressed neurons and in vivo or in vitro functional assessments specifically of stressed neurons (i.e. those expressing ChR2).   
   
PUBLIC HEALTH RELEVANCE: This project is intended to generate research tools specifically 2 new lines of transgenic mice that will produce functional and anatomical reporters in response to cellular stress. These lines would significantly enhance basic science approaches to understand neurological processes and conditions that have a cellular injury and/or stress component. They would provide capabilities that are currently either highly limited or entirely lacking.

project_terms:
Acute;Address;Affect;Afferent Neurons;Alleles;Basic Science;Behavior assessment;Biochemical Genetics;Brain Concussion;Breeding;Cell physiology;Cells;Cellular Stress;Cellular Stress Response;Characteristics;Chimeric Proteins;Chronic;Core Facility;Demyelinations;Disease;Electrophysiology (science);Event;Exhibits;Gated Ion Channel;Gene Expression;Generations;Genes;Genetic;Goals;Hand;Health;Image;In Vitro;Individual;Injection of therapeutic agent;Injury;Ischemia;Knockout Mice;Label;Lasers;Life;Light;Long-Term Effects;Microscopy;Modeling;Motor Neurons;Mus;Nerve Crush;Neurologic;Neurons;Nuclear;Operative Surgical Procedures;Optics;Pain;Pathology;Peripheral Nervous System;Physiological;Play;Population;Process;Production;Promoter Regions (Genetics);Proteins;Reporter;Research;Signal Transduction;Stress;Synapses;System;Tamoxifen;Time;Tissues;Transgenes;Transgenic Mice;Transgenic Organisms;Trauma;Venus (Planet);activating transcription factor 3;analog;base;biological adaptation to stress;cell injury;chemotherapeutic agent;chronic pain;in vivo;injured;innovation;light gated;mouse model;nervous system disorder;neurological pathology;novel;optogenetics;recombinase;response;response to injury;stressor;tissue fixing;tool

public_health_relevance:
This project is intended to generate research tools specifically 2 new lines of transgenic mice that will produce functional and anatomical reporters in response to cellular stress. These lines would significantly enhance basic science approaches to understand neurological processes and conditions that have a cellular injury and/or stress component. They would provide capabilities that are currently either highly limited or entirely lacking.


application_id: 8360734
project_number: 5P20RR020145-08
project_title: GENE-ENVIRONMENT INTERACTIONS REG CVD INFL/SUCCESS OF BEHAVIORAL THERAPIES
administering_ic: NCRR
award_notice_date: 2011-08-18
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2011-08-01
project_end_date: 2012-07-31
study_section: ZRR1-RI-B(01)
subproject_number: 5146
contact_pi_person_id: 9701191
contact_pi: MUDD, GIA
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The overall goal of this study is to examine the relationship between inflammatory genotype and the effects of a cardiovascular risk-reduction intervention on systemic inflammation. The general hypothesis is that a CVD risk reduction intervention will be less effective in subjects with a hyper-inflammatory phenotype and associated genotype than in subjects that express mutable risk factors alone. Three specific aims have been designed to test this hypothesis:
Specific Aim 1: Determine the relationship between salivary and serum concentrations of selected inflammatory biomarkers (IL-1 IL-6 TNF and CRP) in persons at-risk for or with CVD.
Specific Aim 2:  Determine the effect of a behavioral CVD risk reduction intervention on salivary and serum biomarkers of inflammation and risk for adverse cardiovascular events in subjects with elevated and low CRP at baseline.
Specific Aim 3: Elucidate genotypes predictive of the response to the CVD risk reduction intervention and any effect modification by high inflammatory phenotype.
This is a leveraged research project integrated with the HRSA-funded "HeartHealth in Rural Kentucky" project. For the HeartHealth study 1000 adults diagnosed with or having two or more risk factors for CVD are being recruited from four rural community-based sites. Data on CVD risk factors including blood pressure lipid profile diabetes smoking and other lifestyle factors is being collected at baseline and immediate and extended post-intervention.
For the leveraged study additional data collected at each time point includes serum and saliva samples specimens to examine systemic biomarkers of inflammation including C-reactive protein (CRP) interleukin (IL)-1 IL-6 and tumor necrosis factor alpha (TNF). Saliva is also collected for DNA analysis to determine associations between targeted gene variants and inflammatory mediators and their contribution to variations in individual response to CVD risk-reducing interventions. Periodontal status is assessed at baseline to control for confounding.
Study subjects will be allocated to one of two groups. In group one 300 participants with a baseline hs-CRP of 3mg/L will be enrolled as representative of a high inflammatory phenotype. These subjects will be matched on age gender diagnosis of diabetes and smoking status with 300 participants with a baseline hsCRP level of 1mg/L representing a low inflammatory phenotype. The study will be restricted to Caucasians as the majority of the rural Kentucky population is Caucasian and insufficient numbers will be available to study effects of race and ethnicity.

project_terms:
Adult;Age;Behavior Therapy;Behavioral;Blood Pressure;C-reactive protein;Cardiovascular system;Caucasians;Caucasoid Race;DNA analysis;Data;Diabetes Mellitus;Diagnosis;Enrollment;Ethnicity aspects;Event;Funding;Gender;Genotype;Goals;Grant;Individual;Inflammation;Inflammation Mediators;Inflammatory;Interleukin-6;Interleukins;Intervention;Kentucky;Lipids;Modification;National Center for Research Resources;Oral;Participant;Persons;Phenotype;Population;Principal Investigator;Race;Recruitment Activity;Research;Research Infrastructure;Research Project Grants;Resources;Risk;Risk Factors;Risk Reduction;Rural;Rural Community;Saliva;Salivary;Sampling;Serum;Site;Smoking;Smoking Status;Source;Specimen;Study Subject;Systemic disease;TNF gene;Testing;Time;Tumor Necrosis Factor-alpha;United States Health Resources and Services Administration;United States National Institutes of Health;Variant;Variation (Genetics);base;biomarker;cardiovascular risk factor;cost;design;gene environment interaction;lifestyle factors;post intervention;response;success


application_id: 8360733
project_number: 5P20RR020145-08
project_title: GENE THERAPY FOR OROFACIAL PAIN
administering_ic: NCRR
award_notice_date: 2011-08-18
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2011-08-01
project_end_date: 2012-07-31
study_section: ZRR1-RI-B(01)
subproject_number: 5145
contact_pi_person_id: 8535290
contact_pi: DANAHER, ROBERT
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Chronic orofacial (OFP) pain is common worldwide adversely influences quality of life and imposes substantial costs on the healthcare system.  It has been found that inflammatory and neuropathic components can contribute to the maintenance of these pain conditions mediated by sensory neurons housed within the trigeminal (V) brain stem sensory nuclear complex.  Direct gene transfer to sensory nerves at these sites offers the ability to selectively interrupt nociceptive neurotransmission or interfere with underlying processes contributing to the maintenance of persistent pain. In this proposal we describe studies that use innovative technology (i.e. viral vector-based gene transfer) for the treatment of chronic OFP pain.  Our goal is to alleviate inflammatory (Aim 1) and neuropathic (Aim 2) OFP pain in a safe (Aim 3) and effective manner using recombinant herpes simplex virus (HSV)-based vectors that are naturally suited to provide delivery of human genes to the trigeminal ganglia (TG). Our overall hypothesis is that HSV based gene therapy can be used effectively and safely to alleviate chronic orofacial pain. To address this hypothesis we will use recombinant replication-incompetent HSV vectors engineered to produce human opioid peptides or glutamic acid decarboxylase (GAD) in TG neurons for the relief of chronic pain in the orofacial region.  The overall hypothesis of this project is that HSV based gene therapy can be used effectively and safely to alleviate orofacial pain.  Our Specific Aims are: 
1. Test the hypothesis that expression of endomorphin in rat TGs results in more effective abrogation of inflammatory orofacial pain than expression of enkephalin and glutamic acid decarboxylase. 
2. Test the hypothesis that expression of glutamic acid decarboxylase in rat TGs results in more effective abrogation of neuropathic orofacial pain than expression of enkephalin and endomorphin.

project_terms:
Address;Afferent Neurons;Brain Stem;Chronic;Complex;Engineering;Enkephalins;Funding;Gene Transfer;Genes;Glutamate Decarboxylase;Goals;Grant;HSV vector;Healthcare Systems;Housing;Human;Inflammatory;Maintenance;Mediating;National Center for Research Resources;Neurons;Neuropathy;Nociception;Nuclear;Opioid Peptide;Oral;Orofacial Pain;Pain;Pain Clinics;Persistent pain;Principal Investigator;Process;Quality of life;Rattus;Recombinants;Research;Research Infrastructure;Resources;Sensory;Simplexvirus;Site;Source;Structure of trigeminal ganglion;Systemic disease;Testing;Trigeminal System;United States National Institutes of Health;Viral Vector;afferent nerve;base;chronic pain;cost;gene therapy;innovative technologies;neurotransmission;orofacial;vector


application_id: 8360732
project_number: 5P20RR020145-08
project_title: ONTOGENY OF INNATE IMMUNE RESPONSES AT MUCOSAL SURFACES
administering_ic: NCRR
award_notice_date: 2011-08-18
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2011-08-01
project_end_date: 2012-07-31
study_section: ZRR1-RI-B(01)
subproject_number: 5144
contact_pi_person_id: 9641157
contact_pi: GONZALEZ, OCTAVIO ALBERTO
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The hallmark of the vertebrate immune system is its ability to maintain an equilibrium between reactivity and quiescence of responses while geared to respond and adapt rapidly to noxious and potentially lethal challenge.  The system must recognize the challenge develop and express a response to control the challenge and terminate the reaction in regulating the response.  These reactions are the responsibility of components of innate immunity that include cellular receptors and biomolecules at mucosal surfaces and within the systemic circulation.  Due to the complexity of the microbial challenge in the oral cavity it is clear that the innate immune system must play a crucial role in regulating host responses to the commensal microbiota.  This proposal engages a collaborative relationship to enable determination of these responses in a human-like model of oral infection and inflammation:  (1) This proposal will focus on the use of a nonhuman primate (rhesus) model of periodontal infection and inflammation. It is built upon a unique resource the Caribbean Primate Research Center (CPRC); (2) This proposal is a collaborative relationship between investigators at the University of Kentucky the CPRC and the University of Puerto Rico Dental School; (3) This proposal will provide novel information on innate immunity in cross-sectional studies related to age using various cohorts from young to aged animals and related to the expression of periodontitis; and (4) Using the nonhuman primate model of periodontal infection and disease we will determine longitudinal changes in innate immune responses througout age of development of the individual specifically related to the initiation progression and resolution of the disease process.  This model provides for a controlled study of these processes that cannot be accomplished in humans but provides a human-like model of infection disease and host responses. The General Hypothesis for the project is that "Innate immune response components in gingival tissues vary with age and periodontal disease expression."  This will enable the identification of crucial innate immune molecular events that contribute to gingival homeostasis. The studies proposed in this application will use an innovative strategy in 2 Specific Aims to interface a nonhuman primate model of periodontitis with microarray gene expression technology to address these critical questions regarding the characteristics and ontogeny of innate responses in the oral cavity.

project_terms:
Address;Age;Animals;Blood Circulation;Caribbean region;Characteristics;Controlled Study;Cross-Sectional Studies;Dental Schools;Development;Disease;Equilibrium;Event;Funding;Gene Expression;Gingiva;Grant;Growth;Homeostasis;Human;Immune;Immune response;Immune system;Individual;Infection;Inflammation;Kentucky;Macaca mulatta;Modeling;Molecular;National Center for Research Resources;Natural Immunity;Oral;Oral cavity;Periodontal Diseases;Periodontal Infection;Periodontitis;Play;Primates;Principal Investigator;Process;Puerto Rico;Reaction;Research;Research Infrastructure;Research Personnel;Resolution;Resources;Role;Source;Surface;System;Systemic disease;Technology;Tissues;United States National Institutes of Health;Universities;aged;base;cohort;cost;innovation;microbial;nonhuman primate;novel;oral infection;receptor;response


application_id: 8360731
project_number: 5P20RR020145-08
project_title: CHRONIC ORAL INFLAMMATION AND INFLAMMATORY BOWEL DISEASE
administering_ic: NCRR
award_notice_date: 2011-08-18
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2011-08-01
project_end_date: 2012-07-31
study_section: ZRR1-RI-B(01)
subproject_number: 5143
contact_pi_person_id: 9645586
contact_pi: ARSENESCU, RAZVAN I.
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The oral cavity provides a biotope for many bacterial species which may be considered commensal opportunistic or pathogenic. The host defense systems are important for monitoring the composition of the bacterial microbiota and preventing disease initiation and progression. Innate and adaptive immune mechanisms serve to prevent inappropriate responses to commensal microbes regulate opportunistic species and sequester pathogens. Dysregulation of these responses can lead to chronic inflammatory conditions in the oral cavity i.e. gingivitis and periodontitis. Understanding the molecular signaling mechanisms that maintain homeostasis in the oral cavity is key to understanding the pathology of diseases in response to oral bacteria. Host cells respond to microorganisms through pattern recognition receptors (PRRs) such as Toll-like Receptors (TLRs) which recognize broad classes of pathogen associated molecular patterns (PAMPs) including lipopolysaccharide (LPS) lipopeptides and microbial nucleic acids. Inflammatory bowel diseases (Crohn's and Ulcerative colitis) are chronic conditions that reflect an altered communication between resident gut flora and both the innate and acquired immune arms. The initiating factor is unknown but lately a primary epithelial defect has been favored. A significant number of patients with inflammatory bowel diseases develop oral lesions but the incidence of periodontitis has not been adequately established. Patients with IBD (inflammatory bowel diseases) represent a heterogeneous group more so when expression of individual genes within the gut mucosa is analyzed.  We have recently identified unique subgroups of patients with Crohn's disease based on expression of biomarkers for innate immunity in the colonic mucosa. Additionally we have uncovered strong associations with a fat derived anti-inflammatory adipokine adiponectin. The current proposal investigates the association between periodontitis and Crohn's disease and the relevance of disease specific biomarkers for this oral chronic inflammatory condition using a GENERAL HYPOTHESIS that patients with IBD have a greater risk for periodontitis due to an underlying defect in innate immune responses at mucosal surfaces. 

IBD refers to idiopathic inflammatory diseases of the intestine principally ulcerative colitis and Crohn's disease.  There is no cure for IBD and the current medical management of IBD consists of anti-inflammatory and immunosuppressive agents.  Evidence supporting inflammatory dysregulation as a critical factor in the pathogenesis of IBD and periodontitis has suggested potential underlying relationships in host response characteristics to their autochthonous microbiota in triggering these chronic inflammatory diseases. Specific Aim 1. Determine the prevalence of periodontitis in patients with chronic inflammatory bowel conditions. This  includes subsets of patients with Crohn's disease Ulcerative Colitis and Celiac Sprue.  Additionally a prospective assessment of periodontitis presentation in IBD patients receiving immunosuppressive treatment or following introduction of a gluten free diet will be performed.  Finally we will examine the likely effect of environmental (smoking) and nutritional (obesity) factors on IBD and periodontitis.  Specific Aim 2.  Correlate validated Inflammatory Bowel Disease signature biomarkers in both the oral and intestinal mucosa.  These studies will validate the biomarkers of IBD in periodontitis patients with/without IBD.  We are also evaluating the relevance of adiponectin receptor expression and salivary high molecular weight (HMW) adiponectin in patients with periodontitis with/without IBD.

project_terms:
Anti-Inflammatory Agents;Anti-inflammatory;Celiac Disease;Cells;Characteristics;Chronic;Communication;Crohn's disease;Defect;Diet;Disease;Epithelial;Fatty acid glycerol esters;Funding;Genes;Gingivitis;Gluten;Grant;Homeostasis;Host Defense;Immune;Immune response;Immunosuppressive Agents;Incidence;Individual;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Inflammatory disease of the intestine;Intestinal Mucosa;Intestines;Lead;Lipopolysaccharides;Medical;Molecular;Molecular Weight;Monitor;Mucous Membrane;National Center for Research Resources;Natural Immunity;Nucleic Acids;Nutritional;Obesity;Oral;Oral cavity;Oral mucous membrane structure;Pathogenesis;Pathology;Patients;Pattern;Pattern recognition receptor;Periodontitis;Prevalence;Principal Investigator;Research;Research Infrastructure;Resources;Risk;Salivary;Signal Transduction;Smoking;Source;Subgroup;Surface;System;Systemic disease;Toll-like receptors;Ulcerative Colitis;United States National Institutes of Health;adiponectin;arm;base;biomarker;commensal microbes;cost;large bowel Crohn's disease;microbial;microorganism;oral bacteria;oral lesion;pathogen;prevent;prospective;receptor expression;response


application_id: 8360730
project_number: 5P20RR020145-08
project_title: CHRONIC INFLAMMATION AT ORAL AND CERVICO-VAGINAL MUCOSA
administering_ic: NCRR
award_notice_date: 2011-08-18
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2011-08-01
project_end_date: 2012-07-31
study_section: ZRR1-RI-B(01)
subproject_number: 5142
contact_pi_person_id: 9342359
contact_pi: ASHFORD, KRISTIN
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Preterm birth (PTB; 37 weeks gestation) and low birthweight (LBW; 2500 g) deliveries continue to increase in the U.S. resulting in substantial economic and societal costs.  Adverse pregnancy outcomes are disproportionately expressed in ethnic and racial minority populations and historically underserved populations particularly from rural regions of the nation.  However a substantial proportion of the general overall increase in incidence of PTB and LBW including severe PTB (32 weeks) and very low birthweight (1500 g) cannot be explained by classical risk factors for these negative birth outcomes.  Thus a broader view of the potential interrelationships leading to adverse pregnancy outcomes including biologic markers or processes could provide some predictive value allowing earlier intervention to reduce this burden in the population.  This investigation will test the General Hypothesis that "women who deliver preterm will have higher levels of prenatal inflammatory markers in whole saliva serum and cervico-vaginal fluid (CVF) which are displayed earlier in pregnancy compared to women who deliver term". Three specific aims will be used to guide the study in testing this hypothesis: Specific Aim 1:  To compare and contrast the expression of trimester-specific prenatal inflammatory markers in whole saliva serum and CVF. Rationale: This aim will determine our ability of detect trimester-specific inflammatory markers in saliva serum and CVF.  Specific Aim 2: To define the differences in the expression of trimester-specific prenatal inflammatory markers between women who do and do not experience preterm birth in a multi-racial/ethnic population. Rationale: This aim will establish PTB-specific risk factors based on prenatal inflammatory biomarker profiles in a racially/ethnically diverse population of Caucasian African American and Hispanic/Latino women) and preterm birth (37 completed weeks of gestation). Specific Aim 3:  To determine if trimester-specific prenatal inflammatory markers linked with psychosocial and biobehavioral variables pose a significant risk for preterm birth in a multi-racial/ethnic sample of pregnant women. Rationale: This aim will establish if trimester-specific systemic and local prenatal markers of inflammation coupled with psychosocial and biobehavioral variables impact preterm birth risk and self-reported levels of prenatal depressive symptoms; anxiety; stress urine cotinine and self-reported prenatal SHS exposure

project_terms:
African American;Anxiety;Biological Markers;Birth;Caucasians;Caucasoid Race;Chronic;Cotinine;Coupled;Early treatment;Economics;Funding;Grant;Hispanics;Incidence;Inflammation;Inflammatory;Investigation;Latino;Link;Low Birth Weight Infant;Minority Groups;Mucous Membrane;National Center for Research Resources;Oral;Outcome;Patient Self-Report;Population;Population Heterogeneity;Predictive Value;Pregnancy;Pregnancy Outcome;Pregnant Women;Premature Birth;Principal Investigator;Process;Research;Research Infrastructure;Resources;Risk;Risk Factors;Rural;Saliva;Sampling;Serum;Source;Stress;Systemic disease;Testing;Underserved Population;United States National Institutes of Health;Urine;Vagina;Woman;base;biobehavior;biomarker;cost;depressive symptoms;experience;inflammatory marker;prenatal;psychosocial;racial and ethnic;vaginal fluid


application_id: 8360729
project_number: 5P20RR020145-08
project_title: UKY DENTAL COBRE: DENTAL CLINICAL RESEARCH CENTER
administering_ic: NCRR
award_notice_date: 2011-08-18
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2011-08-01
project_end_date: 2012-07-31
study_section: ZRR1-RI-B(01)
subproject_number: 5141
contact_pi_person_id: 7875071
contact_pi: NOVAK, MICHAEL JOHN
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The clinical research environment at the University of Kentucky is excellent.  The DDKCRC occupies 4000 sq. ft. of space in the College of Dentistry.  The clinical research initiatives of the COBRE are coordinated in the DDKCRC with 4 hygienists/study coordinators and a Clinical Research Assistant Professor clinician who manages the operations of the clinic.  A primary focus of the DDKCRC is to create a research infrastructure to: 1) develop and train clinical research professionals research coordinators and research staff; 2) define and impact oral health disparities in rural communities of Kentucky; and 3) support the clinical projects of the CBBO/SD grant.  An initial emphasis will be on investigations to determine oral-systemic disease linkages in these rural populations and to define biological genetic and socio-behavioral factors contributing to these disparities.

project_terms:
Behavioral;Biological;Centers of Research Excellence;Clinic;Clinical;Clinical Research;Dental;Dentistry;Environment;Funding;Genetic;Grant;Investigation;Kentucky;National Center for Research Resources;Oral;Oral health;Principal Investigator;Research;Research Infrastructure;Resources;Rural Community;Rural Population;Source;Systemic disease;Training;United States National Institutes of Health;Universities;base;college;cost;health disparity;operation;professor


application_id: 8360728
project_number: 5P20RR020145-08
project_title: UKY DENTAL COBRE: BIOINFORMATICS & BIOSTATISTICS CORE
administering_ic: NCRR
award_notice_date: 2011-08-18
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2011-08-01
project_end_date: 2012-07-31
study_section: ZRR1-RI-B(01)
subproject_number: 5140
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The Biostatistics and Bioinformatics Core (BBC) will provide a centralized secure database statistical consultation on study design and data analysis and bioinformatics support during development and implementation of the projects and pilot studies in the CBBO/SD. The specific aims of this BBC are:
(1) Assist investigators in resolving issues related to experimental design sample size determinations and  the statistical / bioinformatics analysis of data 
(2) Create a centralized database to assure high quality data is collected 
(3) Maintain the integrity confidentiality and security of all data in compliance with all current regulatory statutes but at a minimum cost to the projects.
(4) Provide periodic summaries of the database in clinically oriented projects to the Center Executive Committee to monitor subject recruitment and follow-up.
(5) Participate in the training of graduate students Certificate Students postdoctoral researchers and young investigators.
(6) Develop new methodology in statistics and/or bioinformatics as needed in the CBBO/SD.
(7) Collaborate with CBBO/SD investigators in preparing papers for publication
(8) Work with investigators in developing competitive research proposals

project_terms:
Bioinformatics;Biometry;Biostatistics Core;Centers of Research Excellence;Confidentiality;Consultations;Data;Data Analyses;Data Quality;Databases;Dental;Development;Experimental Designs;Funding;Grant;Methodology;Monitor;National Center for Research Resources;Oral;Paper;Pilot Projects;Principal Investigator;Publications;Research;Research Design;Research Infrastructure;Research Personnel;Research Proposals;Resources;Sample Size;Secure;Security;Source;Students;Systemic disease;Training;United States National Institutes of Health;Work;base;cost;follow-up;graduate student;statistics


application_id: 8360727
project_number: 5P20RR020145-08
project_title: UKY DENTAL COBRE: ADMINISTRATIVE AND EDUCATIONAL CORE
administering_ic: NCRR
award_notice_date: 2011-08-18
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2011-08-01
project_end_date: 2012-07-31
study_section: ZRR1-RI-B(01)
subproject_number: 5139
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The Administrative/Educational Core of the CBBO/SD has facilitated the research and training goals of the COBRE by: 
(1) To schedule and organize meetings for the CBBO/SD participants; 
(2) To organize meetings of the Scientific Advisory Committee (SAC);
(3) To provide fiscal administration and accounting; 
(4) To interface with institutional administration in new faculty recruitment;
(5) To oversee the funding of new pilot projects; 
(6) To interface and provide appropriate reporting to the NIH and other regulatory agencies; 
(7) To sponsor and organize research career development and training opportunities; and 
(8) To provide outcomes assessment of the CBBO/SD.

project_terms:
Accounting;Advisory Committees;Centers of Research Excellence;Dental;Faculty;Funding;Goals;Grant;National Center for Research Resources;Oral;Outcome Assessment (Health Care);Participant;Pilot Projects;Principal Investigator;Reporting;Research;Research Infrastructure;Research Training;Resources;Schedule;Source;Systemic disease;Training;United States National Institutes of Health;base;career development;cost;meetings


application_id: 8360673
project_number: 5P20RR018733-09
project_title: PROJ 11: RB PROTEIN INACTIVATION RESULTS IN A METABOLIC SHIFT TOWARDS GLUTAMINE
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 5085
contact_pi_person_id: 8077717
contact_pi: CLEM, BRIAN F
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:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Retinoblastoma protein (Rb) the first described tumor suppressor plays a vital role in regulating cell proliferation by modulating the expression of key genes involved in cell cycle progression. Although the majority of work investigating the role of Rb function in tumorigenesis has focused on cell cycle regulation it is clear that Rb may mediate a broad spectrum of biochemical pathways particularly those involved in cellular metabolism. Dysregulated metabolism is now considered a hallmark of tumorigenic cells as evident by increased glucose utilization as well as a dependence on glutamine consumption. Specifically glutamine serves to fulfill the metabolic need for energy production nucleotide and amino acid synthesis and the production of glutathione. Even though specific enzymes have been implicated in this phenomenon of "glutamine addiction" in tumor cells the precise signaling mechanisms and the oncogenic factors that facilitate this metabolic shift have yet to be fully described. Using genetically depleted Rb knockout mouse embryonic fibroblasts we demonstrate that Rb inactivation specifically leads to a dependence on glutamine for cell growth and survival. Our data further suggest that this metabolic shift may be through a c-Myc dependent pathway as Rb depletion increases both c-Myc transcript and protein levels. At the completion of this proposal we expect to have fully characterized the regulation of glutamine metabolism by Rb and in doing so provide a greater understanding of the nature of the neoplastic phenotype especially with respect to disruption of the Rb network.

project_terms:
Amino Acids;Biochemical Pathway;Cell Cycle Progression;Cell Cycle Regulation;Cell Proliferation;Cell Survival;Cells;Centers of Research Excellence;Consumption;Data;Dependence;Embryo;Enzymes;Fibroblasts;Funding;Genes;Glucose;Glutamine;Glutathione;Grant;Knockout Mice;Mediating;Metabolic;Metabolism;Molecular Target;National Center for Research Resources;Nature;Nucleotides;Oncogenic;Pathway interactions;Phenotype;Play;Principal Investigator;Production;Proteins;Regulation;Research;Research Infrastructure;Resources;Retinoblastoma Protein;Role;Signal Transduction;Source;Transcript;Tumor Suppressor Proteins;United States National Institutes of Health;Work;addiction;c-myc Genes;cell growth;cost;neoplastic;neoplastic cell;tumorigenesis;tumorigenic

study_section:
Research Centers in Minority Institutions and Institutional Development Award Review Committee[RIRG-M]


application_id: 8360672
project_number: 5P20RR018733-09
project_title: PROJ 12: STEM CELL-BASED VACCINE FOR CANCER PROPHYLAXIS
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 5084
contact_pi_person_id: 10807180
contact_pi: YADDANAPUDI, KAVITHA
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:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Lung Cancer is a prevalent disease that takes many lives every year.  Disease relapse invasion and metastases are the main causes of death.  Recent discoveries provide compelling evidence that at least some types of cancer are initiated and maintained by a small population of malignant cells called cancer-initiating stem cells (CSCs).  Relapse invasion and metastases are explained by the fact that CSCs have a different biology than all the other tumor cells and importantly are resistant to chemotherapies and radiation.  Lung cancer stem cells have been shown to represent about 1-15% of all tumor cells and can form tumors with injections as low as 100 cells.  Evidence from published studies have demonstrated that human as well as rodent cancers contain populations of cells that express embryonic stem (ES) cell antigens.  Cells containing these proteins also express markers used to identify lung cancer stem cells therefore we hypothesized that ES cells and cancer stem cells share several common molecular traits.  To test this hypothesis we vaccinated mice with murine ES cells and investigated whether an anti-tumor immune response was elicited.  We discovered that ES cell vaccination is very effective in preventing both implantable and carcinogen-induced lung adenocarcinoma development.  Preliminary studies from our laboratory reveal that splenocytes from ES cell-immunized mice are preferentially cytotoxic to lung cancer stem cells.  Experiments proposed in this application seek to expand these findings to demonstrate that ES cells immunize against lung cancer-associated CSCs and that anti-CSC immunity is responsible for preventing lung adenocarcinoma development.  To fulfill the stated objectives the following aims are proposed: 1) Demonstrate that lung cancer stem cells are targets of ES cell vaccination-induced anti-tumor immunity; and 2) Investigate the efficacy of ES cell vaccination in a transgenic model of spontaneous lung tumorigenesis.  Lung cancer research has seen many significant advances in recent years which have contributed to better therapies with improved patient outcomes.  Despite that it remains a major killer.  Our proposed study will provide important insights towards developing a safe prophylactic vaccine for lung cancer onset and/or recurrence.

project_terms:
Antigens;Biology;Cancer Vaccines;Cancer stem cell;Carcinogens;Cause of Death;Cells;Centers of Research Excellence;Development;Disease;Funding;Grant;Human;Immune response;Immunity;Injection of therapeutic agent;Laboratories;Lung Adenocarcinoma;Malignant Neoplasms;Malignant neoplasm of lung;Molecular;Molecular Target;Mus;National Center for Research Resources;Neoplasm Metastasis;Outcome;Patients;Population;Principal Investigator;Prophylactic treatment;Proteins;Publishing;Radiation;Recurrence;Recurrent disease;Relapse;Research;Research Infrastructure;Resistance;Resources;Rodent;Source;Splenocyte;Stem cells;Testing;Transgenic Model;Tumor Immunity;United States National Institutes of Health;Vaccinated;Vaccination;Vaccines;anticancer research;base;cancer cell;cancer type;chemotherapy;cost;cytotoxic;embryonic stem cell;improved;insight;lung tumorigenesis;neoplastic cell;prevent;prophylactic;research study;trait;tumor

study_section:
Research Centers in Minority Institutions and Institutional Development Award Review Committee[RIRG-M]


application_id: 8360671
project_number: 5P20RR018733-09
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE E: BIOPHYSICAL FACILITY
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 5083
contact_pi_person_id: 1863983
contact_pi: CHAIRES, JONATHAN B.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The Biophysics Core Facility is located on the fourth floor of the Brown Cancer Center in a newly renovated 504 square-foot laboratory.  This state-of-the-art facility provides the capability to perform calorimetry electronic spectroscopy rapid kinetics and hydrodynamics determinations.   Expertise is provided by the director Dr. J. Brad Chaires and by Dr. Nichola Garbett the facility manager both of whom have considerable experience in this area.  In addition to the instrumentation this facility provides training in biophysical methods and data analysis and is integrated with the molecular modeling and structural biology cores at the Brown Cancer Center to enhance drug discovery efforts.  The Biophysics Core Facility provides a unique resource to all MT-COBRE investigators.

project_terms:
Area;Biophysics;Calorimetry;Cancer Center;Centers of Research Excellence;Core Facility;Data Analyses;Electronics;Floor;Funding;Grant;Kinetics;Laboratories;Methods;Molecular Models;Molecular Target;National Center for Research Resources;Principal Investigator;Research;Research Infrastructure;Research Personnel;Resources;Source;Spectrum Analysis;Training;United States National Institutes of Health;cost;drug discovery;experience;instrumentation;molecular modeling;square foot;structural biology

study_section:
Research Centers in Minority Institutions and Institutional Development Award Review Committee[RIRG-M]


application_id: 8360670
project_number: 5P20RR018733-09
project_title: COBRE PROJ 10: VSEL AND BRAIN REGENERATION IN A MURINE MODEL OF SLEEP APNEA
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 5082
contact_pi_person_id: 8945910
contact_pi: KUCIA, MAGDALENA J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Magdalena Kucia PI

    Stem cells provide a novel potential source to replace dead neurons and supporting tissue in a brain damaged by chronic ischemia as seen for example in sleep apnea (SA). Some investigations of animals and short-term human bone marrow (BM) transplants have demonstrated that bone marrow cells provide a source of neurons and can repair brain damage (e.g. during stroke). The mechanisms of this functional improvement are currently the focus of intense research creating a need for new study methodologies to assess the effectiveness of such strategies. Elucidation of stem cell-related mechanisms of regeneration is crucial to developing effective stem cell-based therapies that could extend the lifespan of patients with diseases that are treatable by tissue regeneration. One such disorder is chronic brain damage due to hypoxia resulting from sleep apnea. 
     Based on preliminary data a novel hypothesis is presented that the pool of CXCR4+ epiblast-derived VSELs is deposited in the BM during early development.  These cells subsequently serve as a reserve mobile pool of stem cells that may be mobilized into peripheral blood and play an important role in brain regeneration - where they are chemoattracted by an SDF-1 gradient.  Furthermore it is hypothesized that an age-related decrease in the marrow pool of these circulating VSELs may contribute to aging of the central nervous system (CNS) resulting in less effective repair.  To investigate these issues four specific aims were proposed.
     Specific Aim 1. Neural differentiation of bone marrow-derived VSELs. We have presented evidence that BM contains a population of VSELs and that these epiblast-derived cells are deposited there early in development during rapid body growth/expansion. We will first optimize their isolation from bone marrow and neural differentiation (ability to grow neurospheres). Next we will evaluate the age-related presence of VSELs in bone marrow tissue. Once it is determined whether VSELs circulate under normal steady-state conditions in the peripheral blood (PB) at very low but detectable levels we will study their mobilization in a murine model of sleep apnea.
    Specific Aim 2. Optimize mobilization of VSELs into peripheral blood. Since mobilized peripheral blood (mPB) may be a source of VSELs for potential neural regeneration we will optimize their mobilization into PB.  We will test the effect of various mobilizing agents involving selected growth factors (G-CSF Flt3-ligand VEGF HGF) and small-molecule inhibitors (CXCR4-antagonist T140 C3aR antagonist) on the efficacy of their mobilization.  We also will investigate mobilization of these cells in response to hypoxia damage and the role of the SDF-1CXCR4 axis in this process. It is hypothesized that CXCR4+ VSELs are mobilized and subsequently chemo-attracted into a damaged brain in an SDF-1-dependent manner. 
      Specific Aim 3. Develop an approach to expand VSELs.  Since the number of VSELs that can be isolated from the BM and mPB of older individuals is relatively low an efficient ex vivo expansion system may be needed to obtain a sufficient number of these cells for neural regeneration.  It also is possible that ex vivo culture-derived VSELs will better engraft and regenerate brain cells.  We will employ selected strategies to expand these cells ex vivo involving cocktails of selected growth factors BM stroma support and our new strategy based on the expansion of stem cells in the presence of membrane-derived microvesicles isolated from embryonic stem cells (ESMV). We observed that purified VSEL cells are able to form spheres in co-cultures with C2C12 myoblastic cell line feeder layers that resemble embryoid bodies.  Cells from these spheres may again (up to 5-7 passages) grow new secondary spheres or if plated into cultures promoting tissue differentiation expand into cells from all three germ-cell layers.  We will employ this system to expand neural cells from VSEL-derived spheres.
     Specific Aim 4. Determine the efficacy of VSELs in brain regeneration in vivo in a murine model of sleep apnea (SA).  The contribution of VSELs to functional regeneration of damaged tissues will be tested in an in vivo mouse model of SA. We will compare the regeneration potential of syngeneic VSELs isolated from enhanced green immunofluorescence protein (EGFP+) transgenic mice to rescue brain cells damaged by hypoxia and the role of the SDF-1CXCR4 axis in this process.  We will employ freshly isolated VSELs from BM or mPB as well as VSEL expanded in ex vivo cultures.  As a readout of brain regeneration we will use selected behavioral tests.

project_terms:
Aging;Animals;Bone Marrow;Bone Marrow Cells;Bone Marrow Transplantation;Brain;Brain Injuries;CSF3 gene;CXCR4 gene;Cell Count;Cell Line;Cell Therapy;Cells;Centers of Research Excellence;Chronic Brain Damage;Coculture Techniques;Data;Deposition;Development;Disease;Effectiveness;Epiblast;Funding;Germ Cells;Grant;Growth;Growth Factor;Human;Hypoxia;Immunofluorescence Immunologic;Individual;Investigation;Ischemia;Ligands;Longevity;Marrow;Membrane;Methodology;Modeling;Molecular Target;Mus;National Center for Research Resources;Natural regeneration;Nerve Regeneration;Neuraxis;Neurons;Patients;Play;Population;Principal Investigator;Process;Research;Research Infrastructure;Resources;Role;Sleep Apnea Syndromes;Source;Stem cells;Stromal Cell-Derived Factor 1;System;T140 peptide;Testing;Tissue Differentiation;Tissues;Transgenic Mice;United States National Institutes of Health;Vascular Endothelial Growth Factors;age related;base;behavior test;brain cell;cell injury;cost;embryonic stem cell;enhanced green fluorescent protein;functional improvement;in vivo;in vivo regeneration;inhibitor/antagonist;mouse model;novel;peripheral blood;relating to nervous system;repaired;response;small molecule;stroke;tissue regeneration


application_id: 8360669
project_number: 5P20RR018733-09
project_title: COBRE PROJ 9: STRUCTURE-ACTIVITY ANALYSIS OF TISSUE-SPECIFIC CARCINOGENS
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 5081
contact_pi_person_id: 6088353
contact_pi: CUNNINGHAM, ALBERT R
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Albert Cunningham PI
This project will use structure-activity relationship (SAR) modeling to define groups of tissue-specific carcinogens followed by comparative toxicogenomics and proteome analyses to identify the molecular targets they interact with or influence.

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

project_terms:
Biological;Biological Assay;Carcinogens;Cell Line;Centers of Research Excellence;Chemicals;Experimental Models;Funding;Genome;Grant;Libraries;Ligands;Methods;Modeling;Molecular Models;Molecular Target;National Center for Research Resources;Principal Investigator;Proteome;Proteomics;Research;Research Infrastructure;Resources;Rodent Model;Site;Source;Structure;Structure-Activity Relationship;Tissues;Toxicogenomics;United States National Institutes of Health;Update;base;carcinogenesis;carcinogenicity;chemical carcinogen;chemical carcinogenesis;comparative;cost;in vitro testing;model development;molecular modeling;novel strategies;three dimensional structure


application_id: 8360668
project_number: 5P20RR018733-09
project_title: COBRE PROJ 8: ROLES OF IKK ?LPHA IN SKIN DEVELOPMENT AND DYSPLASIA
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 5080
contact_pi_person_id: 8891723
contact_pi: LI, QIUTANG
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Qiutang Li PI (project ended at close of business 8/31/2010)

      The long-term goal of this project is to elucidate the cellular and molecular mechanism by which IKKalpha exerts its effects on epidermal homeostasis. IKKalpha is a subunit of IKK complexes in the NF-kappa B signaling pathway. IKKalpha knockout mice die at birth from the skin defects associated with increased proliferation and impaired terminal differentiation in keratinocytes.  The function of IKKalpha in keratinocytes is independent from its kinase activity and NF-kappa B signaling pathway.  The mechanism by which the IKKalpha regulates keratinocyte proliferation and differentiation remains unclear.  In the present studies we will test the hypothesis that IKKalpha regulates keratinocyte cell cycle and functions as a tumor suppressor gene in skin. 
     Specifically the following questions will be addressed:  (1) What are the roles of the IKKalpha in regulation of the keratinocyte cell cycle and cell cycle checkpoint?  (2) What are the IKKalpha-interacting proteins in keratinocyte?  (3) How do those interacting proteins participate in the IKKalpha signaling in the keratinocytes?  (4) Does IKKalpha function as a tumor suppressor in skin? 
     Cell cycle analysis and functional studies will be performed in the primary keratinocytes isolated from either wild-type or the IKKalpha deficient embryos at embryonic day 18.5 using a combination of genetics cytological and biochemical approaches.  The data that have been generated from IKKalpha immunoprecipitation and mass spectrometry will be further validated and characterized to understand the IKKalpha function at a molecular level.  We will examine skin tumor susceptibility and metastatic potential in IKKalpha+/- mice exposed to mutagenic carcinogen and check the loss of heterozygosity frequency at the IKKalpha locus in IKKalpha+/- mouse tumors.  The knowledge will be important for elucidating clinically relevant problems such as skin cancers.

project_terms:
Address;Biochemical;Birth;Businesses;Carcinogens;Cell Cycle;Cell Cycle Checkpoint;Cell physiology;Centers of Research Excellence;Complex;Data;Defect;Development;Dysplasia;Embryo;Frequencies (time pattern);Funding;Genetic;Goals;Grant;Homeostasis;Immunoprecipitation;Knockout Mice;Knowledge;Loss of Heterozygosity;Mass Spectrum Analysis;Molecular;Molecular Target;Mus;NF-kappa B;National Center for Research Resources;Phosphotransferases;Predisposition;Principal Investigator;Proteins;Regulation;Research;Research Infrastructure;Resources;Role;Signal Pathway;Signal Transduction;Skin;Skin Cancer;Skin Neoplasms;Source;Testing;Tumor Suppressor Genes;Tumor Suppressor Proteins;United States National Institutes of Health;clinically relevant;cost;keratinocyte;tumor


application_id: 8360667
project_number: 5P20RR018733-09
project_title: COBRE PROJ 6: PROGRAMMED DEATH PATHWAY INITIATED FROM THE ENDOPLASMIC RETICULUM
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 5079
contact_pi_person_id: 6950638
contact_pi: LI, CHI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Chi Li PI Project 6

      The aims of this proposal have not changed. They are designed to examine the molecular mechanisms that regulate programmed cell death initiated from the endoplasmic reticulum (ER).  Programmed cell death plays an important role in cancer development and one of the hallmarks of cancer is the inhibition of programmed cell death.  Upon a variety of death signals cells can initiate death pathways from different subcellular compartments.  Although much attention has been focused on the death pathway initiated from mitochondria relatively little is known about the involvement of the ER during programmed cell death.  It remains unclear how signals from ER stress are transduced to induce cell death.  To address this question three specific aims are envisioned:

     1. Study the mechanisms of releasing death-inducing factors from the ER lumen during ER stress-induced cell death.
     2. Investigate the signaling pathway activated by death-inducing factors from the ER.
    3. Determine how the ER-specific death pathway communicates with the death pathway initiated from mitochondria.

project_terms:
Address;Apoptosis;Attention;Cell Death;Cell Death Signaling Process;Centers of Research Excellence;Cessation of life;Development;Endoplasmic Reticulum;Funding;Grant;Malignant Neoplasms;Mitochondria;Molecular;Molecular Target;National Center for Research Resources;Pathway interactions;Play;Principal Investigator;Research;Research Infrastructure;Resources;Role;Signal Pathway;Signal Transduction;Source;United States National Institutes of Health;cost;design;endoplasmic reticulum stress;programs


application_id: 8360666
project_number: 5P20RR018733-09
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE D: NMR & PROTEIN PURIFICATION FACILITIES
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 5078
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Andrew Lane Core D Director

      The primary aims of the core are to provide infrastructure for and support to structural analysis and metabolomics of cancer cells and tissue and for producing proteins in high yield suitable for NMR analysis. This includes stable isotope labeling strategies including N-15 and C-13 precursors. Our goals continue to be to streamline both data collection and analysis as well as introduce new labeling strategies to provide more detailed information about specific metabolic pathways. 
      Established researchers and new recruits to the program are realizing the benefits of the core facility for their research. This includes both protein production for biophysical analyses by X-ray crystallography NMR and Biophysics as well as extensive use of the metabolomics capabilities of the Core (see below). Efforts are being made to ensure that new recruits are fully cognizant of the core facilities and will be actively encouraged to use the unique capabilities.
     Dr. Chi Li (Project 6) is beginning to use metabolomics approaches for understanding metabolic consequences of apoptotic proteins on isolated mitochondria. 
     Dr. Geoffrey Clark (Project 7) is using the Protein Expression core to produce human DNMT3b (DNA (cytosine-5-)-methyltransferase 3 beta) as a GST fusion that will be used for characterization and biological experiments.
     Dr. Magda Kucia (Project 10) is working on stem cells for regenerative therapy. In addition to characterizing the gene expression profile of such cells during expansion she is interested in determining the metabolic phenotype of such cells to learn about the precise requirements for growth and differentiation in terms of energy and anabolic metabolism.
     Dr. Hong Ye (COBRE graduate) makes use of the expression core facilities for protein production advice and analysis and will need the NMR capabilities for some functional analyses of the proteins whose structures she has solved by X-ray diffraction methods.
     Dr. Jason Chesney (COBRE graduate) has continued to make extensive use of the facility and has been analyzing the metabolic consequences of expression of iPFK2 and ras (and effects of RNAi knockdowns) as well as the effects of immortalization via hTERT and large T antigen expression in a number of cell types including Jurkat cells MCF-7 bronchial epithelia and fibroblasts. Metabolite profiles and isotopomer analyses using the NMR facility have been instrumental in discovering consequences of cellular perturbations on the road to transformation (with sometimes surprising results) as well as validating (or otherwise) potential anticancer target enzymes. Some of this work has now been published and other manuscripts are in preparation.
      Dr. Binks Wattenberg (COBRE graduate) is expressing sphingosine kinase using transient expression in insect cells and also in bacteria (E. coli). The enzyme in the latter case enters inclusion bodies and has to be refolded after purification. The protein expression laboratory is working on purification schemes based on hexahis affinity chromatography as well as calmodulin affinity chromatography which has been shown to separate folded SK from unfolded enzyme. This will be used for biophysical studies including crystallography ligand binding and NMR analyses. In addition he has been analyzing the solution properties of targeting peptides using the NMR facility.

project_terms:
Affinity Chromatography;Apoptotic;Bacteria;Biological;Biophysics;Calmodulin;Cells;Centers of Research Excellence;Core Facility;Crystallography;DNMT3B gene;Data Analyses;Data Collection;Differentiation and Growth;Ensure;Enzymes;Escherichia coli;Fibroblasts;Funding;Gene Expression Profile;Goals;Grant;Human;Inclusion Bodies;Insecta;Jurkat Cells;Label;Laboratories;Large T Antigen;Learning;Ligand Binding;MCF7 cell;Manuscripts;Metabolic;Metabolic Pathway;Metabolism;Methods;Mitochondria;Molecular Target;National Center for Research Resources;Peptides;Phenotype;Preparation;Principal Investigator;Production;Property;Proteins;Publishing;RNA Interference;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Resources;Scheme;Solutions;Source;Stable Isotope Labeling;Stem cells;Structure;Tissues;United States National Institutes of Health;Work;X ray diffraction analysis;X-Ray Crystallography;X-Ray Diffraction;base;bronchial epithelium;cancer cell;cell type;cost;human DNMT3B protein;interest;metabolomics;programs;protein expression;protein purification;regenerative therapy;research study;sphingosine kinase


application_id: 8360665
project_number: 5P20RR018733-09
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE C: MOLECULAR MODELING FACILITY
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 5077
contact_pi_person_id: 7821204
contact_pi: TRENT, JOHN O
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:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.       The goals of the COBRE in Molecular Targets Molecular Modeling Core Facility have not changed. The Molecular Modeling Core Facility operated by Dr. John Trent is a state-of-the-art molecular modeling facility that has the capability of providing models based on structural data obtained from either X-ray crystallographic or NMR studies.  In particular this facility has provided important molecular modeling services for Projects 1 2 3 and 4.  Using homology modeling and virtual screening of potential inhibitors Dr. Trent has made very important contributions on a collaborative basis to members of each COBRE-MT project.  This facility is located within the Brown Cancer Center.  The capabilities of the facility include techniques such as explicitly solvated molecular dynamics homology modeling docking virtual screening ESP calculations and conformational searching.
        For Dr. Geoffrey Clark's project (7) the Core C is performing virtual screens on two targets. Finding new drug templates for two projects demonstrates excellent progress and represents a relatively unique hit rate.

project_terms:
Cancer Center;Centers of Research Excellence;Core Facility;Data;Docking;Funding;Goals;Grant;Homology Modeling;Modeling;Molecular Models;Molecular Target;National Center for Research Resources;Pharmaceutical Preparations;Principal Investigator;Research;Research Infrastructure;Resources;Roentgen Rays;Screening procedure;Services;Source;Techniques;United States National Institutes of Health;base;cost;inhibitor/antagonist;member;molecular dynamics;molecular modeling;virtual


application_id: 8360664
project_number: 5P20RR018733-09
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE B: MICROARRAY FACILITY
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 5076
contact_pi_person_id: 1969307
contact_pi: ZACHARIAS, WOLFGANG
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.  The Microarray Facility is located in the Baxter II Biomedical Research Building one block from the Brown Cancer Center. This facility contains both Affymetrix and Agilent microarray instrument systems which are available to all MT-COBRE members. The Facility is under the direction of Dr. Wolfgang Zacharias and has been fully operational for the past eight years since Spring 2001. It includes a full-time Facility Manager Sabine Waigel and two research technologists Vennila Arumugam and Xiaohong Li. They provide administrative support project logistics and management technical assistance in platform-specific sample processing and hybridization as well as data collection analysis and storage. Dr. Zacharias is available for assistance with experimental design data analysis and collaborative or consultant support for grant applications.

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

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


application_id: 8360663
project_number: 5P20RR018733-09
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE A:ADMINISTRATIVE CORE
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 5075
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:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Core A the Administrative Core is responsible for the day-to-day operations of the Molecular Targets Center of Biomedical Research Excellence (MT-COBRE).  Core A manages the scientific and administrative aspects of the COBRE.  In collaboration with Diane Konzen the COBRE Administrator Drs. Miller and Eaton are responsible for oversight of all administrative aspects of the COBRE.  This funding has provided an opportunity to recruit five additional faculty to the MT-COBRE as the original faculty have received new funding and left the COBRE.  Four of the five original project directors are faculty at the UofL Brown Cancer Center and serve as members of the Executive Committee.

project_terms:
Administrator;Cancer Center;Centers of Research Excellence;Collaborations;Faculty;Funding;Grant;Left;Molecular Target;National Center for Research Resources;Principal Investigator;Recruitment Activity;Research;Research Infrastructure;Resources;Source;United States National Institutes of Health;cost;member;operation


application_id: 8360579
project_number: 5P20RR020171-08
project_title: ROLE OF SHOC2 PROTEIN IN SPATIO-TEMPORAL REGULATION OF ERK KINASE CASCADE
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8882
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:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Activation of Epidermal Growth Factor (EGF) Receptor triggers a network of signal transduction events including activating the MAPK cascade along with accelerating endocytosis of EGF-receptor complexes. MEK and ERK proteins are localized on endosomes however the precise mechanism and the role of endosomal targeting are yet to be understood. In addition members of the Ras-RAF-MEK-ERK cascade are reported to be organized into signal-transducing modules regulated by scaffold proteins. The suggested role of scaffold proteins is to enhance the specificity and the selectivity of interactions by bringing kinase-substrate partners into these modules. We seek to elucidate endocytosis involvement in regulating of the MAPK signaling pathway by the scaffold protein Shoc2. 
Shoc2 is a positive regulator of ERK1/2 activation and signaling. We demonstrated that Shoc2 relocates to a subset of endosomes upon EGFR activation. This protein is unique in its ability to control MAPK activation that is also regulated by endocytic trafficking. However the mechanism is poorly understood. Essentially our goal will be to define the functional importance of endosomal localization of Shoc2 for MAPK activity by utilizing various biochemical assays and advanced methods of fluorescence microscopy. We will analyze the mechanism of the spatial regulation of Shoc2 and reconstitute Shoc2 in cancer cells to study the contribution of Shoc2 to MAPK activation in tumor cells. A number of reagents and newly developed methodologies will allow us to pursue this goal.

project_terms:
Biochemical;Biological Assay;Centers of Research Excellence;Complex;Endocytosis;Endosomes;Epidermal Growth Factor Receptor;Event;Fluorescence Microscopy;Funding;Goals;Grant;MAP Kinase Gene;MAPK Signaling Pathway Pathway;MAPK3 gene;MEKs;Methodology;Methods;Molecular;National Center for Research Resources;Phosphotransferases;Principal Investigator;Proteins;Reagent;Regulation;Reporting;Research;Research Infrastructure;Resources;Role;Scaffolding Protein;Signal Transduction;Source;Specificity;United States National Institutes of Health;base;cancer cell;cost;human disease;member;neoplastic cell;reconstitution;trafficking


application_id: 8360578
project_number: 5P20RR020171-08
project_title: UNDERSTANDING THE MOLECULAR BASIS OF EPIGENETIC TRANSCRIPTIONAL SILENCING
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8881
contact_pi_person_id: 10313148
contact_pi: FONDUFE-MITTENDORF, YVONNE NSOKIKA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff. Epigenetic silencing the heritable repression of transcription within chromatin domains is critical in eukaryotic gene regulation. Maintaining homeostasis requires a delicate balance of gene regulatory events involving transcription factors. Deregulation of silencing patterns ushers growth of aberrant cells and development and proliferation of cancer. However the molecular mechanism of epigenetic silencing remains unknown. My previous data indicate that silencing is initiated downstream of activator binding but upstream of TFIIB recruitment and preinitiation-complex assembly suggesting silencing acts through posttranslationally modifying histones to govern TFIIB recruitment to promoters.

This project aims to identify transcription factors and molecular mechanisms responsible for transcriptional silencing. We will determine the essential regulators of silenced genes by backtracking from TFIIB binding to activator binding and quantify the relative occupancy of these crucial regulators at silenced versus active genes. Utilizing the silenced mating system in yeast to examine the mechanism of silencing in a natural context the extent of occupancy of key regulatory factors at the silenced/active mating loci in "a" and "alpha" cells will be measured by chromatin immunoprecipitation and real-time polymerase chain reaction. We will test the hypothesis that these key regulators control silencing through ongoing reversible dynamic competition rather than through frozen inert structure.

project_terms:
Alpha Cell;Binding (Molecular Function);Cells;Centers of Research Excellence;Chromatin;Complex;Data;Development;Epigenetic Process;Equilibrium;Event;Freezing;Funding;Gene Expression Regulation;Gene Silencing;Genes;Grant;Growth;Histones;Homeostasis;Malignant Neoplasms;Measures;Molecular;National Center for Research Resources;Partner in relationship;Pattern;Polymerase Chain Reaction;Principal Investigator;Promotor (Genetics);Regulator Genes;Relative (related person);Research;Research Infrastructure;Resources;Source;Structure;System;Testing;Time;Transcription Factor TFIIB;United States National Institutes of Health;Yeasts;base;chromatin immunoprecipitation;cost;gene repression;human disease;transcription factor


application_id: 8360577
project_number: 5P20RR020171-08
project_title: MOLECULAR MECHANISM OF MAMMALIAN AUTOPHAGY
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8880
contact_pi_person_id: 8688832
contact_pi: WANG, QINGJUN
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.As a ubiquitous lysosomal pathway essential for degrading and recycling proteins and organelles autophagy has been implicated in a broad spectrum of human disease including cancer infection liver disease myopathy and neurodegeneration. However the molecular machinery comprising the mammalian autophagy pathway and the molecular mechanism of how this machinery functions are largely unknown. Our long-term goal is to understand the molecular mechanism of the mammalian autophagy pathway and its relevance to human disease for discovering much needed early diagnostic biomarkers and therapeutic targets. To achieve this goal our overall objective is to first identify novel protein-protein interactions in the mammalian autophagy pathway and subsequently to determine the functions of these novel interactors. Beclin 1 the first reported mammalian autophagy protein plays an important positive role in autophagy regulation and has been implicated in a variety of human physiology and pathology including tumor suppression neurodegeneration development and aging. Therefore for this study we will investigate Beclin 1-mediated autophagy regulation so as to begin deciphering the molecular mechanism of mammalian autophagy. Guided by strong preliminary data three specific aims will be pursued using a combination of a novel integrated mouse genetic-proteomic approach as well as biochemical and cell biological studies. In Aim 1 we will establish the framework of a context-dependent mammalian autophagy interactome through identifying Beclin 1-interacting proteins from living animals; in Aim 2 we will elucidate the molecular details of autophagy regulation by two novel Beclin 1-interacting proteins Atg14L and Rubicon; and in Aim 3 we will explore the molecular details of autophagy regulation by a third novel Beclin 1-interactor and its cancer relevance. By establishing the framework of the mammalian autophagy interactome and unraveling the molecular details of autophagy regulation by Beclin 1 and its interacting proteins this proposed work will not only provide insight into the role of autophagy in mammals but also generate novel potential targets for preventive and therapeutic interventions that may ultimately aid patients suffering from autophagy-related human disease.

project_terms:
Aging;Animals;Autophagocytosis;Biochemical;Biological;Cells;Centers of Research Excellence;Data;Development;Diagnostic;Funding;Genetic;Goals;Grant;Human;Infection;Life;Liver diseases;Malignant Neoplasms;Mammals;Mediating;Molecular;Mus;Myopathy;National Center for Research Resources;Nerve Degeneration;Organelles;Pathology;Pathway interactions;Patients;Physiology;Play;Preventive Intervention;Principal Investigator;Proteins;Proteomics;Recycling;Regulation;Reporting;Research;Research Infrastructure;Resources;Role;Source;Therapeutic Intervention;Tumor Suppression;United States National Institutes of Health;Work;base;biomarker;cost;human disease;insight;novel;protein protein interaction;therapeutic target


application_id: 8360576
project_number: 5P20RR020171-08
project_title: NEGATIVE REGULATION OF THE YEAST MRP YCF1P AND THE HUMAN MRPS BY CK2
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8879
contact_pi_person_id: 6926841
contact_pi: PAUMI, CHRISTIAN M
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Treatment of high risk acute lymphoblastic leukemia patients whom are positive for the Philadelphia chromosome mutation (ALL Ph+) which results in the fusion of BCR and Abl kinase (BCR/Abl) patients over the years have been extremely difficult.  Recently the standard hyperCVAD (Cyclophosphamide Vincristine Dexamethasone and Doxorubicin) treatment for these patients was modified to include Gleevec (imatinib).  The addition of Imatinib has been extremely successful and has increased the complete remission (CR) rate from 60 to 96% and the 2 year survival rate from about 40% of 85%.  The mechanism by which Imatinib increases the efficacy of treatment is unclear.  Cyclophosphamide metabolites doxorubicin and vincristine are all substrates of multidrug resistance protein 1 (MRP1/ABCC1).  Recent studies have shown that increased expression and function of MRP1 is associated with a much poorer prognosis a reduced CR and a decreased 2 year survival (over 65% reduction) in ALL patients.  Preliminary studies carried out in our lab suggest that BCR/Abl regulates MRP1 function via casein kinase 2 (CK2).  CK2 is regulated by BCR/Abl and Src kinases.  Interestingly treatment of ALL Ph+  cells with CK2 inhibitors in combination with Imatinib has been shown to increase Gleevec efficacy (a decrease in the IC50 by 35%) (21).  Therefore we hypothesize that inhibition of BCR-Abl with Imatinib down regulates CK2 activity and CK2-mediated induction of MRP1 function this results in increased cellular accumulation of the CVAD chemotherapeutics (BCR-AblCK2MRP1).   In this proposal we will: 1) Determine the direct mechanism by which BCR/Abl induces MRP1 function 2) Determine the role of CK2 in BCR/Abl-mediated induction of MRP1 function and 3) Test our hypothesis in a Ph+ ALL tissue culture model system Sup-B15 cells and directly in patient primary cells obtained from the University of Kentucky clinic in collaboration with Dr. Dianna Howard.

project_terms:
ABCC1 gene;Biological Models;Cells;Centers of Research Excellence;Clinic;Collaborations;Cyclophosphamide;Dexamethasone;Disease remission;Doxorubicin;Funding;Gleevec;Grant;Human;Imatinib;Inhibitory Concentration 50;Kentucky;Leukemia Lymphocytic Acute;Mediating;Molecular;National Center for Research Resources;P-Glycoprotein;Patients;Philadelphia Chromosome;Phosphotransferases;Principal Investigator;Regulation;Research;Research Infrastructure;Resources;Role;Source;Survival Rate;Testing;Treatment Efficacy;United States National Institutes of Health;Universities;Vincristine;Yeasts;base;casein kinase II;chromosome mutation;cost;high risk;human disease;inhibitor/antagonist;outcome forecast;src-Family Kinases;tissue culture


application_id: 8360575
project_number: 5P20RR020171-08
project_title: STRUCTURAL STUDIES OF NEUROPILIN SIGNALING
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8878
contact_pi_person_id: 9627039
contact_pi: VANDER KOOI, CRAIG
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Neuropilin is an essential bi-functional mammalian cell surface receptor functioning in both angiogenesis and axon guidance.  Neuropilin is of particular medical importance since in addition to its normal roles it also is required for VEGF dependent tumor angiogenesis facilitating neo-vascularization and growth of solid tumors.  During both normal and tumor-angiogenesis neuropilin binds members of the VEGF family of ligands and functions as a co-receptor for the VEGF-R receptor tyrosine kinases. During neural development neuropilin binds members of the semaphorin III family of ligands and functions as a co-receptor for members of the plexin family of receptors.  We seek to understand neuropilin ligand binding specificity and receptor activation. Additionally we seek to inform ongoing studies to define novel anti-angiogenesis targets.  Fundamentally our goal will be to answer the following questions: How does neuropilin activate and regulate VEGF dependent angiogenesis and semaphorin dependent axon guidance?  These studies will define common features of ligand binding as well as unique features that determine specificity between different protein homologues and isoforms.  Further studies will characterize the mechanism(s) by which ligand binding to neuropilin couples to activation of intracellular signaling.

project_terms:
Binding (Molecular Function);Cell Surface Receptors;Centers of Research Excellence;Couples;Family;Funding;Goals;Grant;Growth;Homologous Gene;Ligand Binding;Ligands;Mammalian Cell;Medical;Molecular;National Center for Research Resources;Neuropilins;Principal Investigator;Protein Isoforms;Proteins;Receptor Activation;Receptor Protein-Tyrosine Kinases;Research;Research Infrastructure;Resources;Role;Semaphorins;Signal Transduction;Solid Neoplasm;Source;Specificity;Tumor Angiogenesis;United States National Institutes of Health;Vascular Endothelial Growth Factor Receptor;Vascular Endothelial Growth Factors;Vascularization;angiogenesis;antiangiogenesis therapy;axon guidance;base;cost;human disease;member;neurodevelopment;novel;plexin;receptor;receptor function


application_id: 8360574
project_number: 5P20RR020171-08
project_title: ORGANIC SYNTHESIS CORE
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8877
contact_pi_person_id: 9175312
contact_pi: WATT, DAVID
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The organic synthesis core is designed to provide access to novel compounds not available through commercial sources. The well-trained technical staff as well as the core director will consult with investigators to understand the particular need and will design and synthesize appropriate molecules. The staff will undertake the synthesis and characterization of a novel probe for an enzymatic reaction for a biochemical process a photoactive analog of a drug a fluorescent derivative of a small-molecule probe a modified natural product that might covalently bind a receptor an unnatural peptide that would have better stability than its wild-type counterpart a polymer-bound a compound needed for a particular purification etc. The core is equipped with appropriateequipment to prepare and characterize organic compounds with molecular weights of 2 kDa or less and has access to appropriate chromatographic and analytical techniques including NMR and mass spectrometry that will be used to confirm structural assignments.

project_terms:
Binding (Molecular Function);Biochemical Process;Biochemical Reaction;Biological Factors;Centers of Research Excellence;Consult;Funding;Grant;Mass Spectrum Analysis;Molecular;Molecular Weight;National Center for Research Resources;Organic Synthesis;Peptides;Pharmaceutical Preparations;Polymers;Principal Investigator;Research;Research Infrastructure;Research Personnel;Resources;Source;Techniques;Training;United States National Institutes of Health;analog;base;cost;design;human disease;novel;receptor;small molecule


application_id: 8360573
project_number: 5P20RR020171-08
project_title: PROTEOMICS CORE
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8876
contact_pi_person_id: 7875249
contact_pi: ZHU, HAINING
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The proteomics core is designed to provide quantitative and qualitative protein profiling and identification analysis as well as post-translational modification and sequence analysis through a combination of 2D gel mass spectrometry and Edman sequencing analysis services. The core is equipped with Bio-Rad IPG and SDS-PAGE apparatus for 2D gel analysis a Typhoon phosphorimager/scanner system for detection and quantitation of fluorescent protein dyes (Cy-dyes) and stains (SYPRO-Ruby Pro-Q Diamond) used to analyze 1D and 2D gels a Ciphergen SELDI-TOF protein profiling system an ABI QSTAR II Q-TOF Mass Spectrometer with both MALDI and LC/ESI source capabilities Waters HPLC systems and multiple PCs for data acquisition and analysis including a site license for PDQuest software and a 5 station site license for Ciphergen software. Fully trained technical staff will assist investigators with the full range of proteomics analytical services. The staff will instruct investigators and their laboratory staff (students post-doctoral fellows and technicians) in sample preparation 2D gel analysis and quantitation by fluorescent staining methods. Protein fragmentation mass peptide mapping and protein sequencing by both MS/MS mass spectrometry and chemical sequencing will be performed by Dr. Beach on samples provided by individual investigators. Preparation and analysis of samples with the Ciphergen system will be facilitated by automated robotic work stations. Data analysis will be performed by investigators and their colleagues through multiple distant work stations connected to the Ciphergen system via the web.

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


application_id: 8360572
project_number: 5P20RR020171-08
project_title: IMAGING CORE
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8875
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The imaging core facility houses three epifluorescence microscopes (Nikon Eclipse 600 Zeiss Axiovert 100 and 200M) with digital image capture capability (Spot CE and Orca ER digital cameras with Metaview and Open Lab software). The Eclipse 600 will allow the high resolution imaging of cells and sub-cellular compartments. This instrument can be used for detailed analysis of various cellular structures. The core also contains two inverted epifluorescence microscopes. The Axiovert 200M is equipped with stage controllers to allow long term analysis of live cells. The Axiovert 100 can be used for analysis of cells in tissue culture dishes or fixed samples on slides. The flexibility of the instruments in the facility will enable the core users a wide range of analytical techniques with which to pursue their individual projects. The facility contains two computers for image processing. The computers have complete internet access and network access to color printers and to data storage. The core director Dr. Whiteheart will be available to offer advice on sample preparation on data analysis and on imaging procedures. In addition Dr. Whiteheart will also advise in the preparation of figures and selection of images for publication.

project_terms:
Cells;Cellular Structures;Centers of Research Excellence;Color;Computer software;Computers;Core Facility;Data Analyses;Data Storage and Retrieval;Funding;Grant;Housing;Image;Imaging Techniques;Individual;Internet;Life;Microscope;Molecular;National Center for Research Resources;Preparation;Principal Investigator;Publications;Research;Research Infrastructure;Resolution;Resources;Sampling;Slide;Source;Spottings;Staging;Techniques;United States National Institutes of Health;base;cellular imaging;cost;digital;digital imaging;flexibility;human disease;image processing;instrument;tissue culture


application_id: 8360571
project_number: 5P20RR020171-08
project_title: PROTEIN ANALYTICAL CORE
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8874
contact_pi_person_id: 7875214
contact_pi: RODGERS, DAVID W
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The Protein Analytical Core is designed to facilitate recombinant protein production and macromolecular characterization by the COBRE investigators key components of their proposed projects. It makes available well-maintained equipment and instrumentation that would not normally be found within individual laboratories particularly those of junior investigators. The approach is to provide training and priority access to members of the investigators'' teams rather than maintaining the personnel required to accomplish the tasks on a service basis. In this way costs are kept to a minimum. The core provides instrumentation for characterizing macromolecules including dynamic light scattering spectropolarimetry fluorescence isothermal titration calorimetry high performance liquid chromatography X-ray crystallography TIRF microscopy for single molecule studies  and analytical ultracentrifugation. In addition fermenters bioreactors tissue culture facilities cell cracking equipment and chromatography instrumentation are available for production and purification of recombinant proteins. A staff member maintains the core equipment provides training to new users and oversees scheduling.

project_terms:
Bioreactors;Calorimetry;Cells;Centers of Research Excellence;Chromatography;Equipment;Fluorescence;Funding;Grant;High Pressure Liquid Chromatography;Human Resources;Individual;Laboratories;Molecular;National Center for Research Resources;Principal Investigator;Production;Proteins;Recombinant Proteins;Research;Research Infrastructure;Research Personnel;Resources;Schedule;Services;Source;Titrations;Total Internal Reflection Fluorescent;Training;United States National Institutes of Health;X-Ray Crystallography;analytical ultracentrifugation;base;cost;design;human disease;instrumentation;light scattering;macromolecule;member;single molecule;tissue culture


application_id: 8360570
project_number: 5P20RR020171-08
project_title: ADMINISTRATIVE CORE
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8873
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:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The Administrative Core is designed to facilitate and coordinate the research and training objectives of the Molecular Basis of Human Disease (MBHD)-COBRE.  This core provides the organizational and administrative structure needed to insure that the faculty members to be mentored have access to an environment that will facilitate their success in obtaining independent ROl-type research funding. This core:
1) Provides administrative leadership and coordination of the overall research effort.
2) Provides support for grants accounting preparation of progress reports and grant writing.
3) Insures that  trainees have access to state-of-the-art training
4) Provides a mentoring environment that enhances the ability of the junior faculty to obtain extramural grant funding
5) Facilitates the use of modern research core facilities and provide funds to enhance and utilize the services of these research cores.
6) Funds pilot projects to expand research efforts in studying human disease at the molecular level.
7) Facilitates the hiring of new faculty to increase the critical mass of investigators conducting research on the molecular basis of human disease.
8) Oversees a website dedicated to the program.
9) Makes planning grant available for collaborative research.

project_terms:
Accounting;Centers of Research Excellence;Core Facility;Environment;Extramural Activities;Faculty;Funding;Grant;Health Services Research;Leadership;Mentors;Molecular;National Center for Research Resources;Pilot Projects;Preparation;Principal Investigator;Progress Reports;Research;Research Infrastructure;Research Personnel;Research Training;Resources;Source;Structure;Training;United States National Institutes of Health;Writing;base;cost;design;human disease;member;programs;success;web site


application_id: 8360419
project_number: 5P20RR024489-04
project_title: BIOENERGETIC REGULATION OF CARDIAC PROGENITOR CELLS
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 8726
contact_pi_person_id: 9543696
contact_pi: HILL, BRADFORD GUY
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:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.A restructuring of glycolysis and mitochondrial energetics is thought to be required for stem cell differentiation supporting the view that phenotype specification requires the coordination of genetic circuits and developmental bioenergetics. This implies that metabolic diseases such as diabetes may be particularly destructive to cardiac progenitor cells (CPCs) thereby limiting their ability to differentiate and tolerate stress in the milieu of the diseased myocardium. We plan to examine the role of mitogens in mediating the changes in glycolysis and mitochondrial energetics required for CPC differentiation.  The general hypothesis is that the developmental cues that relate mitogen signaling with energetics are disrupted in diabetes thereby preventing differentiation of CPCs into cardiomyocytes.  
The specific aims are to:
1. Examine the effects of mitogens on CPC energetics.  Because mitogens such as insulin and IGF-1 play important roles in CPC homing and differentiation we will examine how the absence and presence of these mitogens affect glycolytic flux and mitochondrial bioenergetics. The effect of insulin resistance on energetics will be examined and cardiomyocyte differentiation will be monitored by confocal microscopy and flow cytometry.  
2. Determine how glycolysis regulates CPC growth and differentiation. Using pharmacological and molecular interventions (e.g. koningic acid and PFK-2 knockdown or overexpression) we will examine the role of glycolysis in CPC growth and differentiation under substrate conditions that mimic the normal and diabetic phenotype.   Energetics will be examined by extracellular flux analysis and differentiation into the cardiac lineage will be measured by expression of GFP-Nkx2.5.  
3. Assess whether reimplantation of energetically competent CPCs increases their therapeutic efficacy.  CPCs with high glycolytic and/or mitochondrial capacities will be reimplanted in the infarcted heart.  Myocardial function will be evaluated by echocardiography and engraftment will be analyzed by confocal microscopy in heart tissue sections.

project_terms:
Acids;Affect;Bioenergetics;Cardiac;Cardiac Myocytes;Cell Differentiation process;Cell Energetics;Confocal Microscopy;Cues;Development;Diabetes Mellitus;Echocardiography;Engraftment;Flow Cytometry;Funding;Genetic;Glycolysis;Grant;Heart;Homing;Insulin;Insulin Resistance;Insulin-Like Growth Factor I;Intervention;Measures;Mediating;Metabolic Diseases;Mitochondria;Mitogens;Molecular;Monitor;Myocardial;Myocardial Infarction;Myocardium;National Center for Research Resources;Obesity;Phenotype;Play;Principal Investigator;Regulation;Research;Research Infrastructure;Resources;Role;Signal Transduction;Source;Stem cells;Stress;Surgical Replantation;Tissues;Treatment Efficacy;United States National Institutes of Health;cell growth;cost;diabetic;extracellular;overexpression;prevent;stem cell differentiation


application_id: 8360418
project_number: 5P20RR024489-04
project_title: RESOLUTION OF DIABETIC VASCULAR INFLAMMATION: ROLE OF LIPID MEDIATORS PROJ5
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 8725
contact_pi_person_id: 8656605
contact_pi: SPITE, MATTHEW R
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Project 5: Resolution of diabetic vascular inflammation: Role of lipid mediators
The overall aim of this project is to develop a better understanding of the mechanisms that support and sustain chronic low-grade vascular inflammation in diabetes and whether the resolution phase of inflammation could be stimulated to prevent vascular dysfunction in diabetes.  Our hypothesis is that chronic vascular inflammation during diabetes could be attributed in part to a loss in endogenous counter-regulatory lipid mediator pathways that promote the resolution of inflammation.  It follows that restoration of these deficits with synthetic pro-resolving lipid mediators such as the lipoxins and resolvins could facilitate the resolution of vascular inflammation associated with long-term diabetes. The following specific aims were designed to test this novel hypothesis:

1. Examine diabetic changes in the resolution of acute inflammation.   For this we will measure the intensity and duration of leukocyte infiltration in a murine model of microbial peritonitis in which we have defined specific resolution indices. The time course of inflammation will be studied in non-diabetic mice and in murine models of both type 1 and type 2 diabetes. Type 1 diabetes will be established by streptozotocin injections and for studying type 2 diabetes db/db mice will be used.  Comparisons between these models will help in assessing the contribution of hyperglycemia and hyperinsulinemia to diabetic changes in the resolution of inflammation and in understanding the mechanism by which diabetes affects the resolution of inflammation;

2. Assess the contribution of altered pro-resolution lipid mediator biosynthesis to diabetic changes in resolution.   To understand how diabetes affects resolution we will identify changes in lipid mediator biosynthesis during peritonitis using targeted liquid chromatography/mass spectrometry.  We will determine which lipid mediator pathways (pro-inflammatory vs. pro-resolution) are affected during the time course of peritonitis in models of both type 1 and type 2 diabetes.  Moreover to elucidate the mechanisms by which diabetes affects pro-resolution lipid mediator biosynthesis we will measure their biosynthetic intermediates and determine how they are affected by diabetes; and

3. Determine whether treatment with pro-resolution lipid mediators restores diabetic changes in resolution. We will determine how treatment with exogenous lipoxins and resolvins affects the resolution of peritonitis in non-diabetic and diabetic mice. To delineate the mechanisms by which these mediators affect inflammation we will examine their effects on leukocyte:endothelial interactions by intravital microscopy. To elcuidate the cellular mechanisms by which pro-resolution lipid mediators counter-act diabetic vascular inflammation we will examine how lipoxins and resolvins affect high glucose and high fatty acid-induced signaling pathways in microvascular endothelial cells.

project_terms:
Acute;Affect;Anabolism;Blood Vessels;Chronic;Diabetes Mellitus;Diabetic mouse;Endothelial Cells;Fatty Acids;Functional disorder;Funding;Glucose;Grant;Hyperglycemia;Hyperinsulinism;Infiltration;Inflammation;Inflammatory;Injection of therapeutic agent;Insulin-Dependent Diabetes Mellitus;Leukocytes;Lipoxins;Measures;Mediator of activation protein;Modeling;Mus;National Center for Research Resources;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathway interactions;Peritonitis;Phase;Principal Investigator;Research;Research Design;Research Infrastructure;Resolution;Resources;Role;Signal Pathway;Source;Streptozocin;Testing;Time;United States National Institutes of Health;cost;db/db mouse;design;diabetic;indexing;intravital microscopy;lipid mediator;liquid chromatography mass spectrometry;microbial;non-diabetic;novel;prevent;restoration;type I and type II diabetes;vascular inflammation


application_id: 8360417
project_number: 5P20RR024489-04
project_title: RENOVATIONS
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 8724
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:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Renovations are to upgrade and improve existing space to better promote and aid research within the Center for Excellence in Diabetes and Obesity Research.

project_terms:
Diabetes Mellitus;Funding;Grant;National Center for Research Resources;Obesity;Principal Investigator;Research;Research Infrastructure;Resources;Source;United States National Institutes of Health;cost;improved


application_id: 8360416
project_number: 5P20RR024489-04
project_title: STEM CELLS AND DIABETIC CARDIOMYOPATHY PROJ 2 2009
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 8723
contact_pi_person_id: 8492518
contact_pi: HE, JIA-QIANG
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.PROJECT #2: STEM CELLS AND DIABETIC CARDIOMYOPATHY

The central hypothesis of this project is that diabetes produces negative effects on the growth reserve of cardiac stem cells (CSC) so that the enhanced cell's death cannot be counteracted by repopulating cells that preserve the architecture and function of the myocardium. To test this hypothesis the murine models of type 1 and 2 diabetes (T1D T2D) will be used in the following specific aims (SA):

1. SA1 is to examine whether CSC from normal mice will exhibit differences of stemness and pluripotency compared with CSC from diabetic mice. The whole heart of T1D and T2D mice will be used to isolate and identify CSC with c-kit positive sca1 positive MDR1 positive also Lineage negative antigens and/or frozen tissue sections from those tissues will be stained for the markers. The total number of CSC distribution in cardiac tissue stem cell proliferation and in vitro cardiac lineage differentiation will be compared between diabetic and non-diabetic groups. Flow cytometry immunocytochemistry immunohistochemistry and echocardiography techniques will be used in these experiments.  
       
2. SA2 is to investigate how diabetes and hyperglycemia impairs the stemness and cardiac lineage differentiation of CSC isolated from diabetic and non-diabetic hearts.  Gene and protein expression patterns in c-kit sca1 MDR1 AMPK P53 PI3K/Akt Nxk2.5 Glut1&4 of CSC from diabetic hearts will be compared with those from non-diabetic CSC.  Cardiac lineage markers will be checked before and after in vitro differentiation. To mimic the in vivo diabetic condition normal CSC of control hearts will also undergo in vitro hyperglycemia treatments. The underlying mechanism related with the genes and protein change under in vivo and in vitro conditions will be explored accordingly. Gene chip protein array Western blot RT-PCR technique and cell apoptosis/viability/cytotoxicity assays will be used in the analyses. 

3. SA3 is to determine whether transplantation of CSC from normal mice will result in greater improvement in cardiac structure and function in infarcted diabetic mouse heart compared with CSC isolated from diabetic mouse heart. The normal mice and diabetic mice will be used to evaluate cardiac function and structural improvements with transplanted CSC. Echocardiography histological and pathological techniques will be used in the studies.

project_terms:
ABCB1 gene;Antigens;Apoptosis;Architecture;Biological Assay;Cardiac;Cell Death;Cell Proliferation;Cells;Diabetes Mellitus;Diabetic mouse;Echocardiography;Exhibits;Flow Cytometry;Freezing;Funding;Gene Chips;Gene Expression;Gene Proteins;Grant;Growth;Heart;Heart Transplantation;Hyperglycemia;Immunohistochemistry;In Vitro;Infarction;Insulin-Dependent Diabetes Mellitus;Modeling;Mus;Myocardium;National Center for Research Resources;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pattern;Principal Investigator;Protein Array;Proto-Oncogene Protein c-kit;Research;Research Infrastructure;Resources;Reverse Transcriptase Polymerase Chain Reaction;Source;Staining method;Stains;Stem cells;Structure;TP53 gene;Techniques;Testing;Tissues;Transplantation;United States National Institutes of Health;Western Blotting;cost;cytotoxicity;diabetic;diabetic cardiomyopathy;immunocytochemistry;in vivo;non-diabetic;pluripotency;protein expression;research study;stemness


application_id: 8360415
project_number: 5P20RR024489-04
project_title: CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH: PROJECT 4
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 8722
contact_pi_person_id: 8759282
contact_pi: BARSKI, OLEG A
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The aims of this proposal have not changed. They are designed to address the hypothesis that under hyperglycemic conditions increased metabolism of glucose by aldose reductase (AR) exacerbates hypercholesterolemia-induced endoplasmic reticulum (ER) stress and unfolded protein response (UPR) and thereby promotes macrophage activation and atherogenesis. It has been established that accumulation of excessive cholesterol in macrophage-derived foam cells leads to ER stress and activates UPR. This pathway has recently emerged as a unifying theme in atherosclerosis and diabetes research and UPR has been suggested to be the major cause of insulin resistance. Despite these advances the mechanisms leading to the activation of ER stress and specific consequences of its activation for macrophage proinflammatory response and foam cell formation is not known. Specifically we proposed: 

1. Examine whether high glucose increases foam cell formation cytokine production and apoptosis in cholesterol-loaded macrophages. 

2. Determine whether high glucose modulates cholesterol-induced macrophage activation by triggering UPR.  

3. Delineate the contribution of UPR activation to cytokine production and atherosclerotic lesion formation in diabetic mice.

project_terms:
Address;Aldehyde Reductase;Apoptosis;Arterial Fatty Streak;Atherosclerosis;Cholesterol;Diabetes Mellitus;Diabetic mouse;Foam Cells;Funding;Glucose;Grant;Hyperglycemia;Insulin Resistance;Macrophage Activation;National Center for Research Resources;Obesity;Pathway interactions;Principal Investigator;Production;Proteins;Research;Research Infrastructure;Research Project Grants;Resources;Source;United States National Institutes of Health;atherogenesis;cost;cytokine;design;endoplasmic reticulum stress;glucose metabolism;hypercholesterolemia;macrophage;response


application_id: 8360414
project_number: 5P20RR024489-04
project_title: CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH: PROJECT 1
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 8721
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Project 1:  Endothelial progenitor cell (EPC) mobilization defects in diabetes

Diabetes is associated with a wide spectrum of cardiovascular diseases that are best characterized by a dysfunctional endothelium an impaired capacity for its repair. The central hypothesis of this project is that these vascular abnormalities result from a loss of circulating EPCs due to defects in their mobilization from the bone marrow. To test this hypothesis we will:      

1. Define diabetes-induced changes in EPC populations: Using murine models of Type I and/or Type II diabetes we will quantify levels of antigenically-defined EPC populations in peripheral blood spleen and bone marrow; determine if these effects are specific to early/late or non-monocytic/monocytic EPCs; and determine when these effects become prominent during disease progression. To establish specificity we will determine whether the effects of diabetes are unique to EPCs or whether mesenchymal (MSC) and hematopoietic (HSC) stem cells are also affected; and  
2. Delineate the mechanisms by which diabetes limits EPC mobilization: To assess the involvement of integrin-mediated adhesion we will examine the properties of alpha4 beta1 and EPC levels in mice expressing alpha4 variants. To determine whether MMPs are deficient we will examine their levels in the bone marrow of diabetic mice and in the media of cultured cells. To establish a role for the polyol pathway we will characterize EPCs diacylglycerols (DAGs) reactive oxygen species (ROS) and PKC activity levels in diabetic wild type and aldose reductase (AR) knockout mice; and 

3. Evaluate the reparative efficacy of EPC mobilizing strategies: Based upon Aim 2 studies  we will examine the efficacy of interventions in promoting neo-vascularization and wound
repair in diabetes.

project_terms:
12-diacylglycerol;Adhesions;Affect;Aldehyde Reductase;Blood Vessels;Bone Marrow;Cardiovascular Diseases;Cultured Cells;Defect;Diabetes Mellitus;Diabetic mouse;Diglycerides;Disease Progression;Endothelium;Funding;Grant;Hematopoietic;Integrins;Knockout Mice;Matrix Metalloproteinases;Mediating;Mesenchymal;Modeling;Mus;National Center for Research Resources;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathway interactions;Population;Principal Investigator;Property;Reactive Oxygen Species;Research;Research Infrastructure;Research Project Grants;Resources;Role;Source;Specificity;Spleen;Stem cells;Testing;Treatment Efficacy;United States National Institutes of Health;Variant;Vascularization;Wound Healing;base;cost;diabetic;impaired capacity;peripheral blood;polyol;repaired


application_id: 8360413
project_number: 5P20RR024489-04
project_title: CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH: CORE E
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 8720
contact_pi_person_id: 1914941
contact_pi: PRABHU, SUMANTH D
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:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The role of the Cardiovascular Imaging and Function Core is to support the COBRE Projects and related investigations examining the effects of diabetes and obesity on cardiovascular performance. The services provided include echocardiographic imaging tail-cuff measurement of blood pressure and heart rate and left ventricular (LV) pressure-volume measurement. High-volume echocardiography is currently performed with Philips (HP) Sonos 5500 machine coupled to a ComPACS Computer WorkStation complete with Echo Analysis Software. All measurements and computed data are automatically stored in ComPACS MSDE or SQL database in DICOM SR format linked to Crystal Reports for generating customized output documents. Non-invasive measurement of blood pressure and heart rate in conscious mice is performed with a CODA-6 tail-cuff system (Kent Scientific). Aortic and LV catheterization is performed using a Millar pressure volume conductance system (MPCU-200) for mice. Hemodynamic data are acquired using Chart (ADInstruments) and analyzed using PVAN software (Millar) to generate indexes of contraction and relaxation. The Core not only provides procedural and technological support for the COBRE Projects but also extends the capabilities of new investigators as they embark on ongoing and future research projects requiring cardiovascular imaging. Thus the Core advances the career development of COBRE-supported investigators.

project_terms:
Blood Pressure;Cardiovascular Physiology;Cardiovascular system;Catheterization;Centers of Research Excellence;Computer Workstations;Computer software;Conscious;Coupled;Data;Databases;Diabetes Mellitus;Echocardiography;Funding;Grant;Heart Rate;Image;Investigation;Left;Link;Measurement;Mus;National Center for Research Resources;Obesity;Output;Performance;Physiologic intraventricular pressure;Principal Investigator;Relaxation;Reporting;Research;Research Infrastructure;Research Personnel;Resources;Role;Services;Source;System;Tail;United States National Institutes of Health;Ventricular;cardiovascular imaging;career development;cost;hemodynamics;indexing;pressure


application_id: 8360412
project_number: 5P20RR024489-04
project_title: CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH: CORE D
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 8719
contact_pi_person_id: 10654563
contact_pi: SRIVASATAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Major functions of the Animal Core Facility (Core D) is to house breed genotype and provide mouse models of diabetes and obesity.

project_terms:
Animals;Breeding;Core Facility;Diabetes Mellitus;Diabetic mouse;Funding;Genotype;Grant;Housing;National Center for Research Resources;Obesity;Principal Investigator;Research;Research Infrastructure;Resources;Source;United States National Institutes of Health;cost


application_id: 8360411
project_number: 5P20RR024489-04
project_title: CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH: CORE C
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 8718
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN 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: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The Cardiovascular Pathology Core serves as a central resource for generating and evaluating data from in vivo mouse models of cardiovascular disease particularly those that are complicated by diabetes.  This Core performs surgical occlusion and reperfusion in the intact mouse.  Such subjects can be evaluated over time in Core D via echocardiography and tissue can be harvested and evaluated by virtually all of the other Cores and individual Projects.  This Core has more than a decade of experience in the in vivo mouse infarction model.  Such experience will prove invaluable for the new investigators in each of the COBRE's Projects.  In addition to the in vivo models of cardiovascular disease this Core serves the basic histopathology needs of the individual projects.

project_terms:
Cardiovascular Diseases;Cardiovascular Pathology;Data;Diabetes Mellitus;Echocardiography;Funding;Grant;Harvest;Histopathology;Individual;Infarction;Modeling;Mus;National Center for Research Resources;Obesity;Operative Surgical Procedures;Principal Investigator;Reperfusion Therapy;Research;Research Infrastructure;Research Personnel;Resources;Source;Time;Tissues;United States National Institutes of Health;cost;experience;in vivo;in vivo Model;mouse model


application_id: 8360410
project_number: 5P20RR024489-04
project_title: CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH: CORE B
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 8717
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
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The Imaging and Flow Cytometry Core Laboratory consists of two Units: the Confocal Microscopy Unit (responsible for all confocal image acquisition and processing) and the Flow Cytometry Unit (responsible for all flow cytometric cell sorting and analysis). The core laboratory houses a confocal microscope with all necessary accessories and a cell sorter with all necessary accessories. The Imaging and Flow Cytometry Core maintains active collaborations and provides instruction to COBRE-affiliated faculty and related personnel.

project_terms:
Cell Separation;Cells;Centers of Research Excellence;Collaborations;Confocal Microscopy;Diabetes Mellitus;Faculty;Flow Cytometry;Funding;Grant;Housing;Human Resources;Image;Image Cytometry;Instruction;Laboratories;Microscope;National Center for Research Resources;Obesity;Principal Investigator;Process;Research;Research Infrastructure;Resources;Source;United States National Institutes of Health;cost


application_id: 8360409
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
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 8716
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:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The Administrative Core (Core A) provides scientific mentoring budgetary administrative logisitic and statistical oversight to all aspects of the Diabetes and Obesity Center of Biomedical Research Excellence (DOC-COBRE)The Core Leaders - Dr. Aruni Bhatnagar and Dr. Roberto Bolli Director and Co-Directors of the Center with assistance from Ms. Samantha Clausi the COBRE Administrator are responsible for all administrative activities for the COBRE.

project_terms:
Administrator;Centers of Research Excellence;Diabetes Mellitus;Funding;Grant;Mentors;National Center for Research Resources;Obesity;Principal Investigator;Research;Research Infrastructure;Resources;Source;United States National Institutes of Health;cost


application_id: 8360251
project_number: 5P20RR021954-04
project_title: IKKBETA LINKS MACROPHAGE INFLAMMATION TO OBESITY-INDUCED ATHEROSCLEROSIS
administering_ic: NCRR
award_notice_date: 2011-08-09
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 8564
contact_pi_person_id: 8880095
contact_pi: ZHOU, CHANGCHENG
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Obesity is associated with several diseases.  Inflammation is a common link between obesity and associated diseases.  Two such diseases influencing the obese population are diabetes in the form of insulin resistance and coronary artery disease in the form of atherosclerosis.  Both of these obesity-induced complications are associated with inflammation in either the blood vessel wall (atherosclerosis) or in adipose tissue (insulin resistance).  

Many inflammatory pathways that contribute to atherosclerosis initiation and development are regulated by transcriptional factor nuclear factor-B (NF-B) a central coordinator of the innate and adaptive immune responses (8 9).  NF-B is rapidly activated in response to various stimuli including cytokines infectious agents and reactive oxygen species (10).  IB kinase  (IKK) is the predominant catalytic subunit of the IKK complex that is required for activation of NF-B by inflammatory mediators such as TNF and IL-1s in the canonical or classical activation pathway (11 12). In the past decade IKK has been established as a critical molecular link between inflammation and pathogenesis of several chronic diseases such as cancer.  However the role of IKK in atherosclerosis has not been thoroughly investigated. 
IKK activation has been detected in atherosclerosis and in vascular inflammatory reactions in animal models and humans (13-15).  Despite the strong evidence suggesting the involvement of IKK activation in atherosclerosis progression the role of IKK-mediated inflammatory functions by macrophages in atherosclerosis remain unclear.  The previous studies using various mouse models have given inconsistent results and further research is urgently needed to define the role of macrophage IKK in atherosclerosis. 

Preliminary data demonstrate that deficiency of IKKbeta in macrophages promotes inflammation.  In addition pilot studies indicate that deficiency of IKKbeta in macrophages reduces diet-induced atherosclerosis.  We hypothesize that IKKbeta plays an important role linking macrophage inflammation to obesity-induced atherosclerosis and insulin resistance.  Studies will address the role of macrophage IKKbeta in experimental models of diet-induced atherosclerosis and insulin resistance.

project_terms:
Address;Adipose tissue;Animal Model;Atherosclerosis;Blood Vessels;Cardiovascular Diseases;Catalytic Domain;Chronic Disease;Complex;Coronary Arteriosclerosis;Data;Development;Diabetes Mellitus;Diet;Disease;Experimental Models;Funding;Grant;Human;Immune response;Infectious Agent;Inflammation;Inflammation Mediators;Inflammatory;Insulin Resistance;Link;Malignant Neoplasms;Mediating;Molecular;National Center for Research Resources;Nuclear;Obesity;Obesity associated disease;Pathogenesis;Pathway interactions;Phosphotransferases;Pilot Projects;Play;Principal Investigator;Reaction;Reactive Oxygen Species;Reducing diet;Research;Research Infrastructure;Resources;Role;Source;Stimulus;TNF gene;United States National Institutes of Health;cost;cytokine;macrophage;mouse model;response


application_id: 8360250
project_number: 5P20RR021954-04
project_title: INFLAMMATION DURING OBESITY: IMMUNE RESPONSES TO GUT ANTIGENS IN MESENTERIC FAT
administering_ic: NCRR
award_notice_date: 2011-08-09
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 8563
contact_pi_person_id: 8628150
contact_pi: ECKHARDT, ERIK
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Sub-project 5 description

BACKGROUND. Obesity is a significant risk factor for many diseases including diabetes and atherosclerosis. Obese individuals often are in a state of chronic inflammation with elevated plasma levels of cytokines and acute phase proteins which hampers insulin signaling. Their adipose tissues especially near the intestine ("visceral fat") also are often inflamed and infiltrated with lymphocytes and macrophages. The reason for this is unknown. Our hypothesis is that high-fat diets a common risk factor in obesity cause (1) intestinal absorption of inflammatory microbial antigens into visceral adipose tissue and (2) a general breakdown of immunological tolerance to gut antigens and thus chronic inflammatory responses to the microflora. DESIGN. Using mouse models we measure intestinal absorption of antigens from the gut in relation to fat intake as well as subsequent antigen content of visceral adipose tissue. We also measure the effect of high fat diets on the intestinal mucosal immune system (predominantly dendritic cells) and on systemic antibody responses against the microflora to determine whether excess fat intake prevents our body to contain the microflora in a non-inflammatory manner. Lastly we are currently identifying gut bacterial species against which IgG is being formed during diet-induced obesity in the hope to identify those species that promote inflammation during diet-induced obesity.

project_terms:
Acute-Phase Proteins;Adipose tissue;Antibody Formation;Antigens;Atherosclerosis;Cardiovascular Diseases;Chronic;Dendritic Cells;Diabetes Mellitus;Diet;Disease;Fatty acid glycerol esters;Funding;Grant;Immune response;Immune system;Immunoglobulin G;Individual;Inflammation;Inflammatory;Inflammatory Response;Intake;Intestinal Absorption;Intestines;Lymphocyte;Measures;Mesentery;National Center for Research Resources;Obesity;Plasma;Principal Investigator;Research;Research Infrastructure;Resources;Risk Factors;Source;United States National Institutes of Health;Visceral;cost;cytokine;insulin signaling;macrophage;microorganism antigen;mouse model;prevent


application_id: 8360249
project_number: 5P20RR021954-04
project_title: PLATELET ACTIVATION WITH OBESITY PROMOTES ATHEROTHROMBOTIC VASCULAR EVENTS
administering_ic: NCRR
award_notice_date: 2011-08-09
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 8562
contact_pi_person_id: 8558885
contact_pi: LI, ZHENYU
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Sub-project 4 description

Obesity is associated with an increased risk of cardiovascular death. One potential contributing factor in obesity-associated cardiovascular deaths may be related to the pro-thrombotic and pro-inflammatory states induced by increases in adipose mass both of which are critical components of the pathogenesis of the clinic manifestations of atherosclerosis. Platelets play a central role in arterial thrombosis are activated in inflammatory states and are directly influenced by specific adipokines and therefore have the potential to serve as an essential mediator of the cardiovascular consequences of obesity. alpha-Granules are essential to normal platelet activity. Many inflammatory factors and cytokines are stored in -Granules. Activated but not resting platelets are able to alter the chemotactic properties of endothelial cells by inducing the secretion of monocyte chemoattractant protein (MCP-1). Similarly transforming growth factor-beta (TGF-beta) is released from activated platelet alpha-granules and has been shown to augment the release of type-1 plasminogen activator inhibitor (PAI-1) from adipose tissue. Therefore platelet secretion may play an important role in the pro-inflammatory and pro-thrombotic consequences of diet-induced obesity. The cGMP/PKG pathway plays a critical role in platelet secretion. In addition we have recently identified a role for Src family kinses especially the Lyn kinase in platelet secretion. Therefore we will manipulate these signaling pathways to identify a role of platelet secretion in obesity-associated pro-inflammatory and pro-thrombotic states.

project_terms:
Adipose tissue;Alpha Granule;Atherosclerosis;Blood Platelets;Blood Vessels;CCL2 gene;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Clinic;Cyclic GMP;Cytoplasmic Granules;Diet;Endothelial Cells;Event;Family;Funding;Grant;Inflammatory;Mediator of activation protein;Monocyte Chemoattractant Proteins;National Center for Research Resources;Obesity;Pathogenesis;Pathway interactions;Phosphotransferases;Plasminogen Activator Inhibitor 1;Platelet Activation;Play;Principal Investigator;Property;Research;Research Infrastructure;Resources;Rest;Role;Signal Pathway;Source;Thrombosis;Transforming Growth Factor beta;United States National Institutes of Health;adipokines;cardiovascular risk factor;cost;cytokine


application_id: 8360248
project_number: 5P20RR021954-04
project_title: MATERNAL CONSUMPTION OF A WESTERN DIET PROMOTES OBESITY-INDUCED CV DISEASE AND D
administering_ic: NCRR
award_notice_date: 2011-08-09
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 8561
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Sub-project 3 Description

Since approximately 30% of child-bearing women (age 20 to 39) in the U.S. are obese it is critical to define effects of obesity on long-term health in offspring. The goal of this proposal is to find a feasible intervention during pregnancy that can limit the detrimental effects of maternal obesity. One potential candidate is a compound found in red wine resveratrol.  Resveratrol is an antioxidant that has been shown to improve survival motor function insulin sensitivity and organ pathology in mice fed a high fat diet. As a result the general hypothesis of this proposal is maternal consumption of a western (high fat) diet during pregnancy and nursing will promote obesity insulin resistance and hypertension in offspring and maternal consumption of resveratrol will block the negative effects. For this purpose we will manipulate the dietary composition of female mice prior to mating and throughout pregnancy and nursing. Female mice will be fed either a normal or western diet with or without 0.1% resveratrol supplementation. Obesity insulin resistance and hypertension will be measured in mature offspring that will be fed a standard diet from weaning. These studies will provide important new information on the potential negative impact western diet consumption during gestation and nursing may have on long-term offspring health and establish whether resveratrol consumption can protect against these effects. Obesity and diabetes are at epidemic levels and interventions targeting gestation might be an efficient way to stem the tide.

project_terms:
Antioxidants;Cardiovascular Diseases;Consumption;Diabetes Mellitus;Diet;Discipline of Nursing;Disease;Epidemic;Fatty acid glycerol esters;Female;Female of child bearing age;Funding;Goals;Grant;Health;Hypertension;Insulin Resistance;Intervention;Measures;Motor;Mus;National Center for Research Resources;Obesity;Organ;Partner in relationship;Pathology;Pregnancy;Principal Investigator;Research;Research Infrastructure;Resources;Resveratrol;Source;Supplementation;United States National Institutes of Health;Weaning;cost;feeding;improved;insulin sensitivity;offspring;red wine;stem


application_id: 8360247
project_number: 5P20RR021954-04
project_title: MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 DEFICIENCY ATTENUATES DIET-INDUCED OBESITY
administering_ic: NCRR
award_notice_date: 2011-08-09
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 8560
contact_pi_person_id: 8341067
contact_pi: KING, VICTORIA L
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Project 2 Description: Microsomal prostaglandin E synthase-1 deficiency attenuates the development of development of diet-induced obesity in male mice

The focus of our project is to determine the effect of inflammatory molecules on the development and/or progression of diet-induced obesity.  Previous studies have suggested that prostaglandin E2 (PGE2) which is an inflammatory mediator that is produced at a very high concentration during inflammation can inhibit break down of fat cells to free fatty acids and glycerol which may result in a decrease in fat mass.  Preliminary data from our studies demonstrate that deficiency of the major enzyme microsomal prostaglandin E synthase-1 which produces PGE2 during an inflammatory response attenuates the development of obesity in mice fed a high fat diet.  Our data also demonstrate that the reduction in body weight and adipose tissue mass in the mice is not due to reductions in food consumption or physical activity but due to an increase in energy expenditure in the mice.

project_terms:
Adipocytes;Adipose tissue;Attenuated;Body Weight;Cardiovascular Diseases;Data;Development;Diet;Dinoprostone;Energy Metabolism;Enzymes;Fatty acid glycerol esters;Funding;Glycerol;Grant;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Mus;National Center for Research Resources;Nonesterified Fatty Acids;Obesity;Physical activity;Principal Investigator;Research;Research Infrastructure;Resources;Source;United States National Institutes of Health;cost;feeding;food consumption;male;prostaglandin E synthase-1


application_id: 8360246
project_number: 5P20RR021954-04
project_title: PATHOLOGY AND METABOLIC RESEARCH CORE
administering_ic: NCRR
award_notice_date: 2011-08-09
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 8559
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Pathology and Metabolic Research Core Description

The pathology and metabolic core provide technical services and support to participating investigators in the areas of tissue pathology measurement of whole body metabolism in mice and for metabolism studies for collection of urine/feces in mice where food and water intake are quantified.  A major purpose of the core is to operate instrumentation for measurement of whole body metabolism in mice for metabolism studies and for pathology services on several tissue types.  Supervised equipment includes a LabMaster Phenomaster TSE system (24 computer controlled cages) a LabMaster Metabolic Cage system (8 computer controlled cages) tissue processor paraffin microtome and microscope with image analysis software.

project_terms:
Area;Cardiovascular Diseases;Collection;Computer software;Computers;Eating;Equipment;Feces;Funding;Grant;Histocompatibility Testing;Image Analysis;Measurement;Metabolic;Metabolism;Microscope;Microtome - medical device;Mus;National Center for Research Resources;Obesity;Paraffin;Pathology;Principal Investigator;Research;Research Infrastructure;Research Personnel;Resources;Services;Source;System;Tissue Cage;Tissues;United States National Institutes of Health;Urine;Water consumption;cost;instrumentation;metabolic abnormality assessment


application_id: 8360245
project_number: 5P20RR021954-04
project_title: ANALYTICAL CORE
administering_ic: NCRR
award_notice_date: 2011-08-09
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 8558
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Analytical Core Laboratory

The analytical core of the COCVD provides technical services and support to participating investigators in the broad area of detection and quantitation of biological molecules of relevance to the diagnosis treatment and experimental investigation of obesity and cardiovascular diseases. A major purpose of the core is to administer and operate sophisticated advanced instrumentation that would be beyond the capabilities of individual participating investigators.  This includes a BioPlex solution array microplate reader a gas chromatograph and sophisticated and advanced instrumentation for small molecule analysis and structural characterization by tandem mass spectrometry.  This latter instrumentation which forms the primary focus of the most unique capabilities of the core includes two hybrid triple quadruple linear ion trap mass spectrometers with a range of ion sources that are interfaced to automated HPLC systems.  One of these instruments can be operated with a matrix assisted laser desorption ion source.  The other can be operated with an automated nano electrospray ionization source.  These configurations allow us to analyze and quantitate a wide variety of molecules and to also undertake unbiased metabolite profiling studies.

project_terms:
Area;Biological;Cardiovascular Diseases;Computers and Advanced Instrumentation;Detection;Diagnosis;Electrospray Ionization;Funding;Gases;Grant;High Pressure Liquid Chromatography;Individual;Investigation;Ions;Laboratories;Lasers;National Center for Research Resources;Obesity;Principal Investigator;Reader;Research;Research Infrastructure;Research Personnel;Resources;Services;Solutions;Source;System;United States National Institutes of Health;cost;instrument;instrumentation;ion source;mass spectrometer;nano-electrospray;small molecule;synthetic polymer Bioplex;tandem mass spectrometry;yeast two hybrid system


application_id: 8360244
project_number: 5P20RR021954-04
project_title: ADMINISTRATIVE CORE
administering_ic: NCRR
award_notice_date: 2011-08-09
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2011-07-01
project_end_date: 2012-06-30
subproject_number: 8557
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Administrative Core

The administrative core coordinates research and training objectives of the Center. The aims of this core are to provide administrative leadership support for fiscal grant accounting and writing meeting organization oversight of the pilot project mechanism facilitation of hiring of new faculty construction and maintenance of a website coordination and organization of data for assessment statistical consultation and assistance with compliance issues.

project_terms:
Accounting;Cardiovascular Diseases;Consultations;Data;Faculty;Funding;Grant;Leadership;Maintenance;National Center for Research Resources;Obesity;Pilot Projects;Principal Investigator;Research;Research Infrastructure;Research Training;Resources;Source;United States National Institutes of Health;Writing;cost;meetings;web site


application_id: 8360175
project_number: 5P20RR017702-09
project_title: SPHERE-INITIATED REPROGRAMMING TO GENERATE INDUCED PLURIPOTENT STEM CELLS
administering_ic: NCRR
award_notice_date: 2011-05-26
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2011-06-01
project_end_date: 2012-05-31
subproject_number: 8489
contact_pi_person_id: 10955964
contact_pi: LIU, YONGQING
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-06-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.During early embryogenesis a single totipotent zygote gives rise to multiple identical blastomeres. After this stage cells are segregated to develop the pluripotent inner cell mass (ICM) from which mouse and human embryonic stem (ES) cells are derived. Because ES cells mirror the pluripotent stem cell functions both in vitro and in vivo they can be used as model systems to understand the mechanisms underlying basic cell-cell interactions in early mammalian embryos. However availability of such embryonic stem cells is limited and there are also ethical considerations regarding their use. Recent studies have found that expression of four stem cell-specific genes in skin cells obtained from skin biopsy is sufficient to generate patient-specific iPSC for use in transplantation for tissue regeneration. However there remains a major technical concern with the use of these cells clinically as use of virus to express stemness genes in the patient's cells runs a risk for introduction of cancer. Because of this we have tried to develop a protocol for converting differentiated somatic cells to iPSC by inducing expression of endogenous stem cell genes through sphere formation in vitro. The purpose of this work is to investigate and optimize iPSC production using a novel technique to force somatic cells to form spheres which triggers dramatic reprogramming of cells back to a stem cell phenotype.

project_terms:
Back;Biological Models;Biopsy;Cell Communication;Cell physiology;Cells;Defect;Development;Embryo;Embryonic Development;Ethics;Funding;Genes;Grant;In Vitro;Inner Cell Mass;Malignant Neoplasms;Molecular;Mus;National Center for Research Resources;Patients;Phenotype;Pluripotent Stem Cells;Principal Investigator;Production;Protocols documentation;Research;Research Infrastructure;Resources;Risk;Running;Skin;Somatic Cell;Source;Staging;Stem cells;Techniques;Transplantation;United States National Institutes of Health;Virus;Work;cost;embryo stage 2;embryonic stem cell;human embryonic stem cell;in vivo;induced pluripotent stem cell;novel;stemness;tissue regeneration;zygote


application_id: 8360174
project_number: 5P20RR017702-09
project_title: INTEGRATED ANALYSIS OF RNA EXPRESSION DURING OROFACIAL DEVELOPMENT?
administering_ic: NCRR
award_notice_date: 2011-05-26
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2011-06-01
project_end_date: 2012-05-31
subproject_number: 8488
contact_pi_person_id: 7842814
contact_pi: MUKHOPADHYAY, PARTHA
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-06-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The long-term objectives of this proposal are to clarify the role of microRNAs and their target genes during mammalian orofacial development. Formation of the mammalian orofacial tissue is a complex coordinated developmental process involving cell migration proliferation differentiation apoptosis and synthesis of extracellular matrix. All these critical cellular processes are believed to be under the control of numerous microRNAs (miRNAs) and their target genes encoding growth and differentiation factors signaling mediators transcription factors and extracellular matrix proteins. Disruptions in any one of these processes can lead to orofacial clefting. Emerging evidences strongly support central roles for miRNAs in orofacial ontogenesis. Our preliminary data demonstrated that a panoply of miRNA- and protein-coding genes are differentially expressed during the crucial period of orofacial development. Bioinformatic analysis revealed identification of several target genes (of those miRNAs) many of which have documented critical roles in orofacial morphogenesis. Furthermore pathway analysis enabled identification of important biological pathways or gene interaction networks involving the miRNAs and their target genes as well as linking vital cellular processes governing growth of the embryonic orofacial region. We thus propose to test the hypothesis that interaction between differentially-expressed miRNAs and their target mRNAs are essential for proper development of the embryonic orofacial region. Three hypothesis-driven specific aims will be pursued: 1) Within the developing orofacial tissue several differentially expressed genes encoding mRNAs are targets of miRNAs differentially expressed in that tissue. 2) Interaction between differentially-expressed miRNAs and mRNAs are essential for the regulation of specific biological processes as well as phenotypic outcomes associated with orofacial development. 3) Overexpression or inhibition of expression of discrete miRNAs modulates the expression of their target genes which in turn affects the cellular processes indispensable for the morphogenesis of the orofacial region.

project_terms:
Affect;Apoptosis;Bioinformatics;Biological;Biological Process;Cell physiology;Code;Complex;Data;Defect;Development;Developmental Process;Differentiation and Growth;Embryo;Embryonic Development;Extracellular Matrix;Extracellular Matrix Proteins;Funding;Gene Targeting;Genes;Genetic Transcription;Grant;Growth;Lead;Link;Mediator of activation protein;Messenger RNA;MicroRNAs;Molecular;Morphogenesis;National Center for Research Resources;Outcome;Pathway Analysis;Pathway interactions;Principal Investigator;Process;Proteins;Regulation;Research;Research Infrastructure;Resources;Role;Signal Transduction;Source;Testing;Tissues;United States National Institutes of Health;cell motility;cost;gene interaction;orofacial;overexpression;transcription factor


application_id: 8360173
project_number: 5P20RR017702-09
project_title: PHOSPHATIDYLCHOLINE METABOLISM & GESTATIONAL ALCOHOL INDUCED FETAL ABNORMALITIES
administering_ic: NCRR
award_notice_date: 2011-05-26
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2011-06-01
project_end_date: 2012-05-31
subproject_number: 8487
contact_pi_person_id: 8531285
contact_pi: NEAL, RACHEL ELIZABETH
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-06-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Approximately 2% of US births are affected by fetal alcohol syndrome (FAS) and related disorders (FASD).  These children are characterized by intrauterine growth retardation (IUGR) craniofacial abnormalities and neurological defects such as reflex and cognitive impairment. In selected animal models gestational alcohol exposure induced IUGR is paired with maturity onset obesity. Alcohol consumption inhibits liver desaturase activity resulting in deficits in specific Omega-3 fatty acid availability (docosahexanoic and eicosapentanoic acids). In the current application we propose to test the central hypothesis: Maternal dietary supplementation with Omega-3 will partially alleviate alcohol exposure-induced IUGR through modulation of maternal liver Sirt1 activation with coordinately increased fetal lipid availability. The alleviation of alcohol induced fetal IUGR is predicted to eliminate pup metabolic reprogramming characterized by maturity onset obesity through normalization of Omega-3 containing lipid content in the offspring hypothalamus with attendant normalization of HPA-axis function. Further metabolic protein expression in the hippocampus and cerebral cortex will be compromised which may underlie the prenatal alcohol exposure induced neurocognitive and behavioral abnormalities. 
We specifically propose to 1) examine the impact of Omega-3 fatty acid supplementation during gestational alcohol exposure on Sirt1 expression and protein markers of tissue function; and 2) examine the impact of Omega-3 fatty acid supplementation during gestational alcohol exposure on fetal nutrient availability and pup metabolic status. If correct we will have identified prenatal dietary modulation of Sirt1 signaling as preventative for FAS associated molecular tissue remodeling which persists past exposure. We will have also identified potential molecular markers in maternal plasma which are indicative of aberrant fetal development and which may be broadly applicable to diseases other than alcohol intoxication.

project_terms:
Affect;Alcohol consumption;Alcoholic Intoxication;Alcohols;Animal Model;Behavioral;Birth;Cerebral cortex;Child;Craniofacial Abnormalities;Defect;Development;Dietary Supplementation;Disease;Fetal Alcohol Exposure;Fetal Alcohol Syndrome;Fetal Growth Retardation;Fetal development of the mammalian embryo or fetus;Funding;Grant;Hippocampus (Brain);Hypothalamic structure;Impaired cognition;Lecithin;Lipids;Liver;Metabolic;Metabolism;Molecular;Molecular Abnormality;National Center for Research Resources;Neurocognitive;Neurologic;Nutrient;Obesity;Omega-3 Fatty Acids;Plasma;Principal Investigator;Reflex action;Research;Research Infrastructure;Resources;Signal Transduction;Source;Supplementation;Testing;Tissues;United States National Institutes of Health;alcohol exposure;cost;desaturase;eicosapentanoic acid;fetal;molecular marker;offspring;prenatal;protein expression;pup


application_id: 8360172
project_number: 5P20RR017702-09
project_title: REGULATION OF NEURAL CREST CELL MIGRATION BY SDF1-CXCR4 SIGNALING
administering_ic: NCRR
award_notice_date: 2011-05-26
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2011-06-01
project_end_date: 2012-05-31
subproject_number: 8486
contact_pi_person_id: 8634532
contact_pi: SEELAN, RATNAM SATHIAGANA
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-06-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The overall goal of the project is to examine if the migration of trunk neural crest cells (NCCs) to the Dorsal Root Ganglion (DRG) involves SDF1/CXCR4 signaling and to identify regulatory factors that mediate this process. Defective migration of trunk NCCs can cause perinatal lethality and affect the development and formation of the peripheral nervous system. Towards this end we generated chicken SDF1 and CXCR4 riboprobes and utilized them in in situ hybridization (ISH) analyses to determine the spatiotemporal expression of the two genes during embryonic development. The hypothesis being addressed is that trunk NCCs express CXCR4 and migrate towards mesodermal regions of high SDF-1 concentration where they differentiate into the DRG. Chicken embryos (Hamilton-Hamburger (HH) stages ~7 to 22) were used for the study as their developmental stages are well defined and are more amenable to analysis and manipulation. Gene expression profiling of SDF1 and CXCR4 spanning these developmental stages in the chick embryo has largely been accomplished. Using specific antibodies (anti-HNK-1 for NCCs and anti-Islet-1 for the DRG) we are now determining if the expression patterns of CXCR4 and SDF-1 correspond to the developmental paths undertaken by migrating NCCs to become DRG. To identify factors regulating NCC migration via SDF1/ CXCR4 signaling (e.g. TGF1 and BMP4) and the effect of this signaling on putative downstream targets such as IP3 kinase PC12 cells (derived from the adrenal gland and of neural crest origin) are being used as a model system in experiments employing transwells.

project_terms:
Address;Adrenal Glands;Affect;Antibodies;BMP4;Biological Models;CXCL12 gene;CXCR4 gene;Chick Embryo;Chickens;Defect;Development;Embryo;Embryonic Development;Funding;Gene Expression Profiling;Genes;Goals;Grant;In Situ Hybridization;Mediating;Molecular;National Center for Research Resources;Neural Crest;Neural Crest Cell;PC12 Cells;Pattern;Perinatal;Peripheral Nervous System;Phosphotransferases;Principal Investigator;Process;Regulation;Research;Research Infrastructure;Resources;Signal Transduction;Source;Spinal Ganglia;Staging;Stromal Cell-Derived Factor 1;United States National Institutes of Health;cell motility;cost;islet;migration;research study;spatiotemporal


application_id: 8360171
project_number: 5P20RR017702-09
project_title: PRE- AND POSTNATAL TOBACCO SMOKE EXPOSURE:EFFECTS ON NEUROCOGNITIVE DEVELOPMENT
administering_ic: NCRR
award_notice_date: 2011-05-26
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2011-06-01
project_end_date: 2012-05-31
subproject_number: 8485
contact_pi_person_id: 1866555
contact_pi: PISANO, M. MICHELE
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-06-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Maternal cigarette smoking has been associated with a variety of adverse fetal infant and childhood developmental outcomes.  In the United States alone approximately one million infants are exposed prenatally to cigarette smoke each year! Although maternal cigarette smoking during pregnancy is a well documented risk factor for low birth weight with its attendant complications for infant/childhood development a direct linkage between prenatal cigarette smoke exposure and postnatal neurobehavioral/cognitive impairment remains poorly defined.  The global objective of the research program is to establish mouse-human experimental correlates to mechanistically investigate the neuroanatomical cellular and molecular substrates underlying maternal cigarette smoking-induced defects in neuron/cognitive development. Since the hippocampus subserves a central role  across species   in neuro/cognition especially in the information processing involved in learning and memory the original central hypothesis under investigation was that maternal tobacco use during pregnancy interferes with the cellular and molecular ontogenesis of the hippocampus resulting in altered hippocampus-dependent learning and memory in the offspring. The animal studies conducted under this research program employ a mouse model established in our laboratory in which developmental (gestational and early postnatal) inhalation exposure to cigarette smoke simulates human maternal smoking during pregnancy. The following hypotheses are being tested.  Hypothesis #1:  Tobacco smoke exposure during development in a murine model simulating human maternal cigarette smoking during pregnancy results in neurobehavioral abnormalities involving hippocampus-dependent learning and memory.  Hypothesis #2:  Alterations in the establishment of normal cytoarchitecture and neurogenesis in the murine hippocampus are elicited by exposure to tobacco smoke during development in the absence of attendant effects on murine fetal/neonatal growth.  Hypothesis #3:  Tobacco smoke exposure during development results in hippocampal neuronal subtype-specific alterations in the expression of genes during murine ontogenesis that are critical mediators of neuronal developmental plasticity learning and memory.

project_terms:
Animals;Childhood;Cognition;Cognitive;Defect;Development;Exposure to;Funding;Gene Expression;Grant;Growth;Hippocampus (Brain);Human;Impaired cognition;Infant;Inhalation Exposure;Investigation;Laboratories;Learning;Low Birth Weight Infant;Mediator of activation protein;Memory;Modeling;Molecular;Mus;National Center for Research Resources;Neonatal;Neurocognitive;Neurons;Outcome;Pregnancy;Principal Investigator;Research;Research Infrastructure;Resources;Risk Factors;Role;Simulate;Source;Testing;Tobacco smoke;United States;United States National Institutes of Health;cigarette smoke;cigarette smoke-induced;cost;developmental plasticity;fetal;fetal tobacco exposure;information processing;maternal cigarette smoking;maternal tobacco use;mouse model;neurobehavioral;neurogenesis;offspring;postnatal;prenatal;prenatal exposure;programs


application_id: 8360170
project_number: 5P20RR017702-09
project_title: INTERMITTENT HYPOXIA-MEDIATED OLIGO DEFECTS:A MODEL OF GESTATIONAL SLEEP APNEA
administering_ic: NCRR
award_notice_date: 2011-05-26
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2011-06-01
project_end_date: 2012-05-31
subproject_number: 8484
contact_pi_person_id: 9256836
contact_pi: CAI, JUN
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-06-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.        The goal of this subproject is to identify the impact of maternal sleep apnea-associated intermittent hypoxia on white matter development in offspring CNS.  The study will focus on investigating the pathophysiological changes in oligodendroglial and axonal development elicited by maternal intermittent hypoxia exposure and exploring the long-term consequences in the developing mice.  Three aims are proposed to characterize the molecular and cellular mechanisms underlying IH-mediated white matter injury due to maternal OSA-related IH exposure: aim 1: to examine OL generation proliferation and differentiation in mouse forebrain and spinal cord at different embryonic stages following IH exposure during gestation (1st-2nd year); aim 2: to determine consequences of IH exposure on myelin-forming process and myelin architecture in developing and adult mice as well as local effects on axonal development that maybe induced or deteriorated by myelin deficit (2nd-3rd year); aim 3: to explore signaling molecules invovled in IH-mediated white matter injury occurring in maternal sleep apnea during pregnancy (2nd -4th year).  
      In our previous FY 2009 report a mouse neonatal model of IH insult during the time window (P2 to P10) that is equivalent to the human 3rd trimester has been developed because 1) clinical retrospective studies indicated that most of maternal OSA occurs in the last gestational period with severe symptoms; 2) oligodendrocyte maturation myelination axon sprouting and synapse formation initiate from the late second and early third trimesters of pregnancy suggesting that maternal OSA in the 3rd trimester may result in much severe sequelae in offspring white matter.  Our preliminary data showed that differentiation of oligodendrocyte expression of myelin-related proteins and syntheses of neurofilaments were significantly inhibited in IH-exposed developing mice. 
Based on this model oligodendroglia and axon development has been intensively investigated in the past year.  We found that IH induced hypomyelination in corpus callosum striatum fornix and cerebellum but not pons or spinal cord during critical phases of central nervous system (CNS) development. IH elicited alterations in myelin-forming processes were reflected by decreased expression of myelin proteins including MBP PLP MAG and CNPase suggesting arrested maturation of oligodendrocytes.  Ultra-structural abnormalities were apparent in the myelin sheath and axon.  Immature oligodendrocytes were more vulnerable to neonatal IH exposure than developing axons suggesting that hypomyelination may contribute at least partially to axonal deficits.  Insufficient neurofilament (NF) synthesis with anomalous components of NF subunits -tubulin and MAP2 isoforms indicated immaturity of axons in IH-exposed mouse brains.  In addition down-regulation of Synapsin I Synaptophysin and Gap-43 phosphorylation suggested a potential stunt in axonogenesis and synaptogenesis.  The region-selective and complex impairment in brain white matter induced by IH was further associated with electrophysiological changes that may underlie long-term neurobehavioral sequelae.

project_terms:
2'3'-Cyclic-Nucleotide Phosphodiesterases;Adult;Architecture;Axon;Brain;Cerebellum;Clinical;Complex;Corpus Callosum;Corpus striatum structure;Data;Defect;Development;Down-Regulation;Embryo;Funding;Generations;Goals;Grant;Human;Hypoxia;Impairment;Mediating;Modeling;Molecular;Mus;Myelin;Myelin Proteins;Myelin Sheath;National Center for Research Resources;Neonatal;Neuraxis;Oligodendroglia;Oligonucleotides;Phase;Phosphorylation;Pontine structure;Pregnancy;Principal Investigator;Process;Prosencephalon;Protein Biosynthesis;Protein Isoforms;Reporting;Research;Research Infrastructure;Resources;Retrospective Studies;Signaling Molecule;Sleep Apnea Syndromes;Source;Spinal Cord;Staging;Symptoms;Synapsin I;Synaptophysin;Third Pregnancy Trimester;Time;Tubulin;United States National Institutes of Health;base;cost;myelination;nervous system development;neurobehavioral;neurofilament;offspring;synaptogenesis;white matter;white matter injury


application_id: 8360169
project_number: 5P20RR017702-09
project_title: TGF-? SIGNALING DURING MOUSE SECONDARY PALATE ELEVATION AND FUSION
administering_ic: NCRR
award_notice_date: 2011-05-26
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2011-06-01
project_end_date: 2012-05-31
subproject_number: 8483
contact_pi_person_id: 7594575
contact_pi: DING, JIXIANG
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-06-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Cleft palate is a common birth defect caused by malformation in secondary palate development. Palate formation requires signaling pathways to function interactively rather than in isolation. However our understanding of the signaling networks during palate fusion growth and elevation remains poor. The proposed research will focus on the interactions among major signaling pathways during palate development. TGF-3 is an essential signaling molecule mediating palate fusion but the mechanism of action is unknown. We found that TGF-3 is required for the down-regulation of Jag2 expression during fusion suggesting TGF- and Notch pathways function synergistically during fusion. Jag2 IRF6 and IKKa are key regulator factors in preventing pathogenic palate fusion with the tongue and other tissues and recent studies have revealed the integration of these factors in controlling palate adhesion and fusion. We will pursue two specific aims:
 
I) Interactions between TGF-3 Notch1/Jag2 during normal and pathogenic palate fusion. We will 1) take a genetic approach to test the hypothesis that TGF-3 mediates palate fusion by down-regulating Jag2 expression in the MEE; 2) investigate the functional significance of Jag2 down-regulation in MEE during wild type palate fusion.

II) Investigation of TGF- signaling and its interaction with Wnt5a during palate elevation. We will 1) investigate the downstream target genes of Zfhx1a during palate elevation focusing on the genes involving cell migration; 2) investigation of the function of TGF-12 during palate by generating TGF-12 double mutants; 3) examine the effects of TGF-s on Wnt5a mediated non-canonical signaling.

project_terms:
Adhesions;Cleft Palate;Congenital Abnormality;Defect;Development;Down-Regulation;Funding;Gene Targeting;Genes;Genetic;Grant;Growth;Investigation;Mediating;Molecular;Mus;National Center for Research Resources;Palate;Pathway interactions;Principal Investigator;Research;Research Infrastructure;Resources;Secondary Palate;Signal Pathway;Signal Transduction;Signaling Molecule;Source;Testing;Tissues;Tongue;United States National Institutes of Health;cell motility;cost;malformation;mutant;notch protein;prevent


application_id: 8360168
project_number: 5P20RR017702-09
project_title: FGF SIGNALING AND ZINC FINGER PROTEINS IN GONAD DEVELOPMENT AND REPRODUCTION
administering_ic: NCRR
award_notice_date: 2011-05-26
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2011-06-01
project_end_date: 2012-05-31
subproject_number: 8482
contact_pi_person_id: 6574851
contact_pi: LAN, ZI-JIAN
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-06-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Characterization of the in vivo function of phosphatidylinositol 3-kinase (PI3K) signaling in theca and interstitial (TI) cells was our research focus in the past year of COBRE support. Theca cells are differentiated from ovarian interstitial cells. The major function of theca cells is to produce androgen for estrogen biosythesis and genomic action in granulosa cells. The principal disorder associated with theca cells is polycystic ovary syndrome (PCOS) in which an excess of androgen and other ovarian defects are often observed. However the in vivo function of signaling pathway(s) key for androgen production in theca and interstitial (TI) cells in the ovary remains to be characterized as well as the etiology of PCOS. Phosphatase and tensin homolog (Pten) is a negative regulator of PI3K signaling. Recent studies of Pten and other PI3K signaling molecules have shown that PI3K signaling (especially in the oocyte) plays a critical role in normal ovarian development and female fertility. However the in vivo function of this signaling in TI cells remains to be characterized. To explore the function of PI3K signaling in TI cells in vivo we have generated TI-cell specific Pten mutant (tPtenMT) mice. Increased phosphorylation of PI3K signaling downstream molecules such as 3-phosphoinositide-dependent protein kinase 1 (PDK1) and protein kinase B (AKTs) were observed in tPtenMT ovaries indicating that deletion of Pten in TI cells causes an overactivation of PI3K signaling in the ovary. More importantly premature loss of female fertility with aberrant estrous cycle and natural ovulation were observed in tPtenMT mice. These physiological defects in tPtenMT mice were due to abnormal ovarian development as there existed a variety of histological defects in the ovary (e.g. ovary enlargement). Abnormalities displayed in tPtenMT ovaries should result from deletion of Pten in TI cells and the primary defect should be in TI cells. To support this androgen excess was observed in tPtenMT mice and elevated expression of Lhcgr and several steroidogenic enzyme genes key for androgen biosynthesis in tPtenMT ovaries and TI cells as well as in luteinizing hormone (LH)-treated Pten-siRNA lentiviral knockdown TI cells. LHCGR is located on a recently identified PCOS susceptibility locus. Modulation of the LH and Lhcgr action in androgen production by PI3K signaling in TI cells could be an underlying etiology of certain types of PCOS. Consistent with this hypothesis the abnormalities displayed in young adult tPtenMT mice mimic PCOS in humans. Like PCOS patients tPtenMT mice were able to ovulate in response to gonadotropins. Moreover API-2 a specific AKT inhibitor was able to attenuate the ovary enlargement and the increase of ovary weight displayed in young adult tPtenMT mice. Together our results suggest that Pten in TI cells is critical for normal ovarian development and female fertility and that overactivation of PI3K signaling in TI cells can lead to development of PCOS-like syndrome in young adulthood.

project_terms:
1-Phosphatidylinositol 3-Kinase;3-Phosphoinositide Dependent Protein Kinase-1;Anabolism;Androgens;Attenuated;Cells;Centers of Research Excellence;Defect;Development;Disease;Enzyme Gene;Estrogens;Estrous Cycle;Etiology;Female;Fertility;Fibroblast Growth Factor;Funding;Genomics;Gonadal structure;Gonadotropins;Grant;Human;Lead;Luteinizing Hormone;Molecular;Mutant Strains Mice;National Center for Research Resources;Oocytes;Ovarian;Ovary;Ovulation;PTEN gene;Patients;Phosphorylation;Physiological;Play;Polycystic Ovary Syndrome;Predisposition;Principal Investigator;Production;Proteins;Proto-Oncogene Proteins c-akt;Reproduction;Research;Research Infrastructure;Resources;Role;Signal Pathway;Signal Transduction;Signaling Molecule;Small Interfering RNA;Source;Syndrome;United States National Institutes of Health;Weight;Zinc Fingers;cost;granulosa cell;in vivo;inhibitor/antagonist;interstitial cell;microbial alkaline proteinase inhibitor;mutant;premature;response;theca cell;young adult


application_id: 8360167
project_number: 5P20RR017702-09
project_title: COBRE: UL: ADMIN CORE: MOLECULAR DETERMINANTS OF DEVELOPMENTAL DEFECTS
administering_ic: NCRR
award_notice_date: 2011-05-26
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2011-06-01
project_end_date: 2012-05-31
subproject_number: 8481
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
budget_start_date: 2011-06-01
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.DESCRIPTION (provided by applicant): The purpose of this application for a Center of Biomedical Research Excellence (COBRE) is to foster health-related research and increase the competitiveness of junior unfunded investigators at the Birth Defects Center at the UL School of Dentistry for independent funding. This COBRE augments and strengthens the biomedical research capacity at the Birth Defects Center through provision of flexible support to expand and develop biomedical faculty research capability. The program is led by an established biomedical research scientist well recognized for his extensive expertise central to the research theme of the proposal. The COBRE supports junior investigators from several complementary disciplines each of whom is mentored by an established well-funded senior biomedical research faculty member recognized for his/her scientific expertise in the area of the junior investigator's research proposal. This approach is a critical assurance of success of this initiative. This COBRE represents an integrated series of studies focusing on two common themes - molecular mechanisms of birth defects and cellular signal transduction - that encompass a number of diverse scientific disciplines.  Faculty from the Schools of Dentistry Medicine and Public Health representing a multiplicity of scientific disciplines present a multifunctional approach to questions of the molecular basis of developmental anomalies. The COBRE substantially enhances the development of eight young investigators with outstanding potential to develop into competitive independent and collaborative investigators. A detailed plan for their research career development has been formulated expectations and goals for achieving extramural support is outlined the extent of departmental and university support provided to these junior faculty is substantial clear and tangible evidence of institutional commitment has been documented and sufficient and adequate space and equipment resources for the conduct of the proposed studies exists.

project_terms:
Area;Biomedical Research;Centers of Research Excellence;Congenital Abnormality;Defect;Development;Discipline;Equipment;Extramural Activities;Faculty;Fostering;Funding;Goals;Grant;Health;Medicine;Mentors;Molecular;National Center for Research Resources;Principal Investigator;Research;Research Infrastructure;Research Personnel;Research Proposals;Resources;School Dentistry;Scientist;Series;Signal Transduction;Source;United States National Institutes of Health;Universities;base;career development;cost;expectation;flexibility;member;programs;public health medicine (field);success


application_id: 8360129
project_number: 5P20RR016481-11
project_title: CURRICULUM DEVELOPMENT FOR HEALTH ASPECTS
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8443
contact_pi_person_id: 2451207
contact_pi: BONAGURO, JOHN A
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.To develop curriculum for health aspects in the areas of Biology Dental Hygiene Nursing Public Health Psychology and related areas.

project_terms:
Area;Biology;Biomedical Research;Dental Hygiene;Development;Discipline of Nursing;Educational Curriculum;Funding;Grant;Health;Health Psychology;National Center for Research Resources;Principal Investigator;Research;Research Infrastructure;Resources;Source;United States National Institutes of Health;cost


application_id: 8360128
project_number: 5P20RR016481-11
project_title: KBRIN-COMMUNITY-BASED PARTICIPATORY RESEARCH CORE
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8442
contact_pi_person_id: 8483139
contact_pi: KALBFLEISCH, THEODORE
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The IDeA states in the SE region of the United States contain a large segment of under-insured and medically under-served people. The NIH goal to support clinical and translational awards (CTSAs) to connect the benefits of research to health care outcomes is commendable. We plan to develop a core which would not be duplicative of the CTSAs but which would complement their activities by connecting to underserved populations who are not currently partners in planned CTSAs. The goal of our core will be to make health information collected from this SE region patient community accessible to researchers for collaboration on a national level. We propose to initiate this activity by involving a rural community in western Kentucky through a collaboration with one of our comprehensive institutions that is already actively working to provide medical care and collect medical information in the region Western Kentucky University (WKU).  Health care professionals from WKU's Institute for Rural Health Development and Research (IRHDR) have engaged this medically underserved community in their region via a Mobile Health and Wellness Unit (MHWU).  The MWHU allows them to access these remote areas and perform basic health and dental screens.

project_terms:
Area;Award;Biomedical Research;Caring;Clinical;Collaborations;Communities;Complement;Funding;Goals;Grant;Health;Health Professional;Healthcare;Institutes;Institution;Kentucky;Medical;National Center for Research Resources;Oral health;Outcome;Patients;Principal Investigator;Research;Research Infrastructure;Research Personnel;Resources;Rural Community;Rural Health;Source;Underserved Population;United States;United States National Institutes of Health;Universities;Work;community based participatory research;cost;medically underserved;research and development


application_id: 8360127
project_number: 5P20RR016481-11
project_title: KBRIN PROGRAM EVALUATION
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8441
contact_pi_person_id: 11005052
contact_pi: STONE, RACHEL
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The premise for our evaluation of student outcomes includes the notion that students who have a quality research experience in the laboratory of a competitively funded investigator are more likely to develop a career in research. 

The focus of this study is on student learning outcomes and on the contexts in which these outcomes are expected to occur. INBRE funding has an immediate impact on ability of faculty to conduct research gain research independence and involve students in their research projects. There is also an impact on institutions because administrators have agreed to provide time release from teaching to aid the development of research activity. Thus the campus climate - where acceptance of research as an important activity at regional universities - is becoming the norm and will have an effect on student involvement in research and implicitly a positive impact on student learning. 

The overarching questions for this program evaluation are: How do we know if the INBRE has any influence on students' learning and ultimately on their career decisions? How do we define influence? When what and how are student-learning outcomes measured? What results are obtained? What do the results mean? 

To answer these questions the research evaluation study includes a formative and a summative component.  The formative evaluation investigates the program's development process and implementation while the summative evaluation investigates the results (outputs and outcomes).

project_terms:
Administrator;Biomedical Research;Climate;Educational process of instructing;Evaluation;Evaluation Studies;Faculty;Funding;Grant;Institution;Laboratories;Learning;National Center for Research Resources;Outcome;Outcome Measure;Output;Principal Investigator;Process;Program Development;Program Evaluation;Research;Research Activity;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Source;Students;Time;United States National Institutes of Health;Universities;career;cost;experience;research and development


application_id: 8360126
project_number: 5P20RR016481-11
project_title: DENNIS POST-DOC/TECHNICIAN SUPPORT
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8440
contact_pi_person_id: 9258111
contact_pi: DENNIS, DOUGLAS
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source and thus could be represented in other CRISP entries. The institution listed is for the Center which is not necessarily the institution for the investigator. This proposal accomplishes the AREA program objectives of: 1) supporting meritorious research; 2) exposing undergraduates to research; and 3) strengthening the research environment in non-research intensive universities. The goal of this research is to elucidate the mechanism of polyhydroxyalkanoate inclusion biogenesis. Electron microscopy studies have been unable to resolve the structure of PHA inclusions and this has inhibited movement toward a cohesive model of inclusion biogenesis. Employing atomic force microscopy we have determined that there are three layers of structure an outer envelope that is the thickness of a membrane bilayer a middle network layer and an underlying crystalline lamellar layer. Genetic studies have indicated that the middle network is comprised at least partially of PhaP and that PhaP is likely to be translocated to the periplasm. Thus it would appear that inclusion biogenesis may occur by movement of protein and/or proteins to the periplasm and budding through the cytoplasmic membrane into the cytoplasm facilitating the acquisition of the cytoplasmic membrane as an envelope. The goal of this research is to prove or disprove this supposition. The specific aims of the research are: 1) definitively prove periplasmic localization of PhaP via fluorescence localization and Western blot analyses of subcellular fractions 2) demonstrate that the inclusion envelope is derived from the cytoplasmic membrane by proteomic analysis and 3) characterize proteins that bind transiently and permanently to PhaP in hopes of elucidating the mechanism of inclusion biogenesis. Ultimately the goal of the research is to enlarge our knowledge of inclusion biogenesis to the point that this process can be controlled and utilized for medical applications. For instance it could be envisioned that instead of polymer being inserted into the inclusion bioactive compounds could be inserted making the inclusion into a drug delivery vehicle.

project_terms:
Atomic Force Microscopy;Biogenesis;Biomedical Research;Cell membrane;Computer Retrieval of Information on Scientific Projects Database;Cytoplasm;Drug Delivery Systems;Electron Microscopy;Environment;Fluorescence;Funding;Genetic;Goals;Grant;Institution;Knowledge;Medical;Membrane;Modeling;Movement;National Center for Research Resources;Polymers;Postdoctoral Fellow;Principal Investigator;Process;Protein Binding;Proteins;Proteomics;Research;Research Infrastructure;Research Personnel;Resources;Source;Structure;Subcellular Fractions;Thick;United States National Institutes of Health;Universities;Western Blotting;cost;periplasm;programs


application_id: 8360125
project_number: 5P20RR016481-11
project_title: CIRCADIAN PATTERNS OF BEHAVIOR AND GENE EXPRESSION FOLLOWING ?RECREATIONAL? OR ?
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8439
contact_pi_person_id: 1885629
contact_pi: WHITE, WESLEY O
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The goal of the research is to compare behavioral and gene expression changes produced by a "recreational" pattern of drug use and by a pattern entailing abuse. Our subjects are rats. For the behavioral work each animal will be continuously housed in a station with a 12-12 hour light-dark cycle and devices for providing food and water. Food intake will be monitored 24 hours a day. One group of animals will be exposed to a regime that mimics recreational drug use: They will receive a moderately high but non-toxic dose of amphetamine (2.0 mg/kg) at five-day intervals. A transient withdrawal state or "hangover" characterized by hypo-activity and reduced food intake occurs 18-26 hours after this dose. Another group of animals will be exposed to an escalating "binge" pattern of amphetamine administration. After food intake stabilizes five-day tests will be run. On test day 1 animals will receive a saline administration and on day 3 they will receive a "challenge" administration of 2.0 mg/kg amphetamine. Circadian patterns of food intake produced by the binge regime will be compared to those produced by a recreational drug use regime. For the gene expression work rats will be housed in individual tubs in cabinets and they will receive recreational or binge amphetamine and tests according to the schedule just described for the behavioral studies. We will assess expression for genes related to dopamine glutamate and GABA receptors in nucleus accumbens dorsal striatum and frontal cortex at times corresponding to the psychomotor stimulant state (hour 1-6 post-treatment) and the transient withdrawal state observed during the recreational drug use regime. INBRE provided funding to support an individual who will conduct this research. So far the individual has received training on some of the behavioral and pharmacological procedures that will be employed in the study.

project_terms:
Aftercare;Amphetamines;Animals;Behavior;Behavioral;Biomedical Research;Circadian Rhythms;Corpus striatum structure;Devices;Dopamine Receptor;Dorsal;Dose;Drug usage;Eating;Food;Funding;GABA Receptor;Gene Expression;Glutamate Receptor;Goals;Grant;Hour;Housing;Individual;Light;Monitor;National Center for Research Resources;Nucleus Accumbens;Pattern;Principal Investigator;Procedures;Rattus;Research;Research Infrastructure;Resources;Running;Saline;Schedule;Source;Testing;Time;Training;United States National Institutes of Health;Water;Withdrawal;Work;cost;frontal lobe;hangover;recreational drug use


application_id: 8360124
project_number: 5P20RR016481-11
project_title: REGULATION AND CELLULAR CONSEQUENCES OF SLIT2 EXPRESSION
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8438
contact_pi_person_id: 8567496
contact_pi: WATERSTRAT, AMANDA JO
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Work on this project has been ongoing since the summer of 2010.  Major accomplishments include:

1.Recruitment of 3 undergraduate and 1 graduate student in research activity.  This included the completion of an honors thesis project for one undergraduate student Jesse Orloff involving bioinformatic analysis of Slit2.
2. Submission of primary research article publishing the novel findings of Slit2-mediated regulation of hematopoietic stem cells.  The manuscript has been reviewed and is currently under revision for the journal Blood.
3. Student research activities include:
a. Jesse Orloff 
i.completion of honors thesis  "Determination of Expression Profiles and Regulatory Elements for Slit2 with Gene Expression and Genomic Databases"
ii.submission of abstract for Experimental Biology - "Determination of Expression Profiles and Regulatory Elements for Slit2 with Gene Expression and Genomic Databases"
iii.work as lab assistant
b.Sam Handshoe 
i.evaluating effects of Slit2 on NIH-3T3 cell growth 
c.Johnna Sizemore
i.Designing primers for analysis of SNPs in the regulatory regions of the Slit2 gene in mice
d.Abagail Cornette
i.Designing experiments for Masters thesis to evaluate the effects of Slit2 on cell cycle activity

project_terms:
Bioinformatics;Biology;Biomedical Research;Blood;Cell Cycle;Databases;Funding;Gene Expression;Genes;Genomics;Grant;Hematopoietic stem cells;Journals;Manuscripts;Mediating;Molecular Profiling;Mus;NIH 3T3 Cells;National Center for Research Resources;Nucleic Acid Regulatory Sequences;Principal Investigator;Publishing;Regulation;Regulatory Element;Research;Research Activity;Research Infrastructure;Resources;Source;Students;United States National Institutes of Health;Work;abstracting;cell growth;cell growth regulation;cost;design;graduate student;novel;research study


application_id: 8360123
project_number: 5P20RR016481-11
project_title: ACUTE EFFECTS OF ALCOHOL AND ENERGY DRINKS ON BEHAVIORAL CONTROL
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8437
contact_pi_person_id: 10253421
contact_pi: MARCZINSKI, CECILE A.
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The working hypothesis of this proposal is that the consumption of AmED may be riskier than alcohol consumption alone. Mixing alcohol with another beverage with strong stimulant properties may decrease selfperceptions of intoxication and may increase the reinforcing properties of alcohol. In addition the acute effects of alcohol impair impulse control and this impairment may not be counteracted by co-administration of a stimulant. The proposed research will examine the acute effects of alcohol energy drinks AmED or a placebo beverage in social drinkers. The effects of these beverages will be determined by performance on tasks that measure neurocognitive control mechanisms and the subjective effects of alcohol. The specific aims of the proposed research are: 1) to determine whether the consumption of AmED alters neurocognitive and subjective measures of intoxication compared to the consumption of alcohol alone and 2) to establish whether the consumption of AmED enhances priming of the motivation to drink alcohol compared with the consumption of alcohol alone. The results of these studies should elucidate whether the consumption of AmED increases alcohol consumption and may be escalating binge drinking in young people.

project_terms:
Acute;Alcohol consumption;Alcohols;Behavior Control;Beverages;Biomedical Research;Consumption;Funding;Grant;Impairment;Intoxication;Measures;Motivation;National Center for Research Resources;Neurocognitive;Performance;Placebos;Principal Investigator;Property;Research;Research Infrastructure;Resources;Self Perception;Source;United States National Institutes of Health;Work;alcohol effect;binge drinking;cost;drinking;social


application_id: 8360122
project_number: 5P20RR016481-11
project_title: TOWARDS UNDERSTANDING THE NON-CLASSICAL SECRETION OF HUMAN INTERLEUKIN-1 ALPHA
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8436
contact_pi_person_id: 10281309
contact_pi: DAKSHINAMURTHY, RAJALINGAM
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Interleukins (IL's) are involved in a wide spectrum of biological processes associated with infection inflammation and autoimmunity. IL-1's in particular are pro-inflammatory cytokines and they assist the host in fighting infection. Deficiency in IL-1's is known to result in lethality in bacterial infections. In addition recent studies suggest that IL-1 also plays a role in wound healing carcinogenesis tumor invasion rheumatoid arthritis and Alzheimer's disease. IL-1 lacks the N-terminal signal peptide therefore unlike most other extracellular proteins it is not secreted through the classical endoplasmic recticulum  Golgi pathway. Preliminary studies have suggested that the release of IL-1 into the extracellular compartment occurs by the formation of a multi-protein complex to the calcium- binding protein S100A13 in the presence of copper. Although useful information exists on the IL-1 signaling process the exact mechanism of IL-1 secretion into the extracellular compartment is not clear. Until now structure- function data have been limited for IL-1 because of the difficulty in its overexpression in mammalian cells. In this context the purpose of the proposed research is to fully understand IL-1's non-classical release and it's binding to copper and S100A13. Specific aims of this proposal include: 1) determing the binding affinity of IL-1 for copper and S100A13; 2) characterizing the molecular interactions necessary for the non-classical secretion of IL-1. A complete understanding of the non-classical secretion of IL-1 will provide valuable information towards understanding the general principles of export of proteins without signal peptide. Furthermore over the funding period this project will engage numerous undergraduates and master's level graduate students in independent research enhancing their learning of scientific principles giving them an opportunity to make unique contributions to the study the role played by IL-1 in this devastating family of diseases and stimulating their excitement for future careers in biomedical research. Moreover the funding of this application will expand student research in protein stability structure and function and enable more students from Kentucky a state traditionally underrepresented in biomedical sciences to successfully advance into biomedical graduate programs.

project_terms:
Affinity;Alzheimer's Disease;Autoimmunity;Bacterial Infections;Binding (Molecular Function);Biological Process;Biomedical Research;Calcium-Binding Proteins;Copper;Data;Disease;Extracellular Protein;Family;Funding;Future;Golgi Apparatus;Grant;Human;Infection;Inflammation;Inflammatory;Interleukin-1;Interleukin-1 alpha;Interleukins;Kentucky;Learning;Mammalian Cell;N-terminal;National Center for Research Resources;Pathway interactions;Peptide Signal Sequences;Play;Principal Investigator;Protein Export Pathway;Proteins;Research;Research Infrastructure;Resources;Rheumatoid Arthritis;Role;Science;Source;Structure;Students;Tumor Cell Invasion;United States National Institutes of Health;Wound Healing;carcinogenesis;career;computerized data processing;cost;cytokine;extracellular;fighting;graduate student;overexpression;programs;protein complex


application_id: 8360121
project_number: 5P20RR016481-11
project_title: PROTEOMIC ANALYSIS OF OXIDATIVE STRESS OF OXIDATIVELY MODIFIED GLYCOLYTIC PROTEI
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8435
contact_pi_person_id: 9835336
contact_pi: REED, TANEA TYLETTE
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.In this project I plan to first examine the amyloid beta hypothesis of Alzheimer's disease (AD) and apply it to a novel Down Syndrome (DS) model by developing a mechanism in which the p3 fragment of the DS preamyloid can possibly be equivalent to the earliest stage of Alzheimer Disease mild cognitive impairment (MCI). Secondly by specifically focusing on glycolytic protein oxidation in this model a basis for the reduced glucose metabolism observed in Alzheimer's disease may be determined and further support of the altered energy metabolism hypothesis of AD may be provided. Investigation of oxidatively modified glycolytic proteins in this novel DS model may also create a new focal point for potential biomarkers in AD and potential therapeutics. 
Down syndrome is a genetic disease in which persons have reduced mental capacity. Persons with DS have a trisomy at chromosome 21 the location of amyloid precursor protein. This trisomy causes A overproduction which could possibly be a correlate to the early development of AD in persons with DS. Enzymatic cleavage by -secretase and -secretase forms the toxic p3 fragment A(17-42) which is the major form of A peptide in Down syndrome. No correlation has yet been made between the p3 fragment and AD pathogenesis. 
Glycolysis is a metabolic pathway that converts glucose to pyruvate and generates 2 ATP molecules in the process. Many key glycolytic enzymes such as -enolase -enolase glyceraldehyde 3-phosphate phosphoglycerate mutase and triosephosphate isomerase are oxidized in AD brain confirming the inability to effectively metabolize glucose the brain's principal source of energy. In the three progressive stages of Alzheimer's disease MCI EAD and late-stage AD 70% of glycolytic enzymes undergo oxidative modification which can greatly affect their enzyme activity and subsequent protein function. All enzymes affected react after the production of fructose 16-bisphosphate (FBP). If oxidatively modified pre-FBP proteins are observed in DS this will provide further support for the altered energy metabolism of AD.

project_terms:
Affect;Alzheimer's Disease;Amyloid beta-Protein;Amyloid beta-Protein Precursor;Biomedical Research;Brain;Chromosomes Human Pair 21;Development;Down Syndrome;Energy Metabolism;Energy-Generating Resources;Enzymes;Funding;Glucose;Glyceraldehyde 3-Phosphate;Glycolysis;Grant;Hereditary Disease;Investigation;Location;Metabolic Pathway;Modeling;Modification;National Center for Research Resources;Oxidative Stress;Pathogenesis;Peptides;Persons;Phosphoglycerate Mutase;Principal Investigator;Process;Production;Proteins;Proteomics;Proteus;Psyche structure;Pyruvate;Research;Research Infrastructure;Resources;Source;Staging;Therapeutic;Triose-Phosphate Isomerase;Trisomy;United States National Institutes of Health;base;biomarker;cost;enolase;enzyme activity;fructose-16-diphosphate;glucose metabolism;mild cognitive impairment;novel;oxidation;protein function;secretase


application_id: 8360120
project_number: 5P20RR016481-11
project_title: PHOTOCHEMISTRY AND PHOTOPHYSICS OF ESTROGENS
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8434
contact_pi_person_id: 9857887
contact_pi: HARE, PATRICK MICHAEL
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The overarching goal of the proposed research is to determine the mechanisms of photodegradation of the natural estrogens and the effect of solvent environment on that photodegradation. Steady-state and time resolved spectroscopy and computational chemistry will be used to elucidate the photochemistry and the underlying photophysics of the estrogens. Natural estrogens are potent endocrine disruptors in surface waters and are known to photodegrade naturally but the mechanisms are poorly understood. Understanding how they are photodegraded in the environment may also lead to better removal strategies for the estrogens in the waste stream. The effects of solvent on the excited states of estrogens will first be determined by steady-state spectroscopy and computational chemistry. The time-dependent population of these excited states will then be determined by time-resolved spectroscopy with guidance from computation of the excited state properties. Finally the solvent and wavelength depedence of the photodegradation will be carried out with product assignments being guided by infrared spectroscopy and computational modeling of likely product structures. Determining how solvent and excitation wavelength affect the population of the estrogen excited states that lead to photochemistry will allow better modeling of photodegradation in surface waters and may lead to more efficient removal strategies for the estrogens in municipal waste streams.

project_terms:
Affect;Biomedical Research;Computer Simulation;Endocrine Disruptors;Environment;Estrogens;Excision;Funding;Goals;Grant;Lead;Modeling;National Center for Research Resources;Photochemistry;Population;Principal Investigator;Property;Research;Research Infrastructure;Resources;Solvents;Source;Spectrum Analysis;Stream;Structure;Surface;Time;United States National Institutes of Health;Water;computational chemistry;cost;infrared spectroscopy;wasting


application_id: 8360119
project_number: 5P20RR016481-11
project_title: REGULATION OF MIRNAS IN ESTROGEN MEDIATED INHIBITION OF CARDIOMYOCYTE HYPER
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8433
contact_pi_person_id: 9528523
contact_pi: WAIKEL, REBEKAH
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Estrogen has been shown to play a protective role in cardiac hypertrophy and heart failure in both humans and rodent models. My current working hypothesis is that male/female differences in susceptibility to systolic LV dysfunction in the setting of cardiac hypertrophy is due to regulation of miRNAs by estrogens. During the first year I have completed Specific Aim 1 by characterizing pressure overload induced cardiac remodeling in female C57BL6 and 129SvImJ mice. This work was published in collaboration with my mentor Dr. Susan Smyth in the American Journal of Physiology  Heart Circulation Physiology in Sept 2009. Our work has demonstrated that female C57BL6 are relatively protected in terms of cardiac remodeling and function in response to pressure overload. Our work further showed that there is no male susceptibility gene present on the Y chromosome thus further supporting the presence of a female "factor" provides the protection from cardiac hypertrophy and heart failure. In addition during my first year of KBRIN funding I was able to establish a rodent wing of our current animal care facility including the appropriate IACUC protocol approval. I am now able to do the rat experiments at my home institution Eastern Kentucky University. During year 2 I will work to accomplish the remaining 2 aims: I have Aim 2) to establish separate miRNA profiles for males and females cardiac remodeling following pressure overload. Aim 3) to determine which miRNAs play a functional role in estrogen mediated inhibition of cardiomyocyte hypertrophy.

project_terms:
American;Biomedical Research;Cardiac;Cardiac Myocytes;Collaborations;Estrogens;Female;Functional disorder;Funding;Grant;Heart Hypertrophy;Heart failure;Home environment;Human;Hypertrophy;IACUC;Institution;Journals;Kentucky;Mediating;Mentors;MicroRNAs;Mus;National Center for Research Resources;Physiology;Play;Predisposition;Principal Investigator;Protocols documentation;Publishing;Rattus;Regulation;Research;Research Infrastructure;Resources;Rodent;Rodent Model;Role;Source;Susceptibility Gene;United States National Institutes of Health;Universities;Wing;Work;Y Chromosome;animal care;cost;heart circulation;male;pressure;research study;response


application_id: 8360118
project_number: 5P20RR016481-11
project_title: GENETIC SUSCEPTIBILITY TO PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8432
contact_pi_person_id: 8110072
contact_pi: CURRAN, CHRISTINE PERDAN
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Polychlorinated biphenyls (PCBs) are persistent organic pollutants that bio-accumulate in the food chain and cause a number of adverse health effects including learning and memory deficits in children exposed in utero and during lactation. The principal investigator's previous research in mice uncovered two genes that increase susceptibility to developmental PCB exposure  the aryl hydrocarbon receptor (Ahr) and cytochrome P450 1A2 (Cyp1a2) a gene directly regulated by the AHR.  Coplanar PCBs bind to the AHR triggering changes in gene expression. Many of these AHR-regulated genes are involved in central nervous system development. AHR activation was also recently shown to affect the activity of DNA methylases. The glucocorticoid receptor is well known to be regulated by differential methylation and changes in receptor levels can alter learning memory and the response to stress. Interestingly many pollutants that bind to the AHR produce changes in stress hormone levels or an animal's response to stress. This project was designed to test the hypothesis that persistent activation of the AHR alters normal brain development and the response to stress via epigenetic mechanisms. The specific aims were to:

1.) Compare corticosterone levels anxiety and response to stress in PCB-treated and control animals differing at the Ahr and Cyp1a2 loci.

2.) Determine if developmental PCB exposure alters gene-specific DNA methylation patterns in the hippocampus cortex and hypothalamus.

project_terms:
Affect;Animals;Anxiety;Aryl Hydrocarbon Receptor;Binding (Molecular Function);Biomedical Research;Brain;Child;Control Animal;Corticosterone;Cytochrome P-450 CYP1A2;DNA;DNA Methylation;Development;Epigenetic Process;Food Chain;Funding;Gene Expression;Genes;Genetic Predisposition to Disease;Glucocorticoid Receptor;Grant;Health;Hippocampus (Brain);Hormones;Hypothalamic structure;Lactation;Learning;Memory;Memory impairment;Methylation;Methyltransferase;Mus;National Center for Research Resources;Neuraxis;Pattern;Polychlorinated Biphenyls;Predisposition;Principal Investigator;Research;Research Infrastructure;Resources;Source;Stress;Testing;United States National Institutes of Health;cost;design;developmental neurotoxicity;in utero;nervous system development;pollutant;receptor;response


application_id: 8360117
project_number: 5P20RR016481-11
project_title: MENTORING CORE
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8431
contact_pi_person_id: 9258139
contact_pi: MATTINGLY, BRUCE A
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Consistent with the overall aims of the KY-INBRE program the primary goal of the mentoring core is provide an array of services to further enhance the competitiveness of our biomedical researchers at primarily undergraduate institutions (PUIs) in obtaining NIH funding.  During this first year of funding for this core three new services have been provided. First an intensive all-day grant writing workshop was developed and presented in conjunction with the annual Kentucky Academy of Science meeting. Focusing exclusively on the development of the NIH-Academic Research Enhancement Award (AREA-R15) proposals this workshop included interactive presentations and discussions led by the PI (Nigel Cooper) PC (Bruce Mattingly) and several KY-INBRE network PIs who are currently funded through the R15 mechanisms ( Mark Bardgett Patrick Schultheis Doug Dennis Rodney King Eimear Mullin and Stephan Paula). The morning session was directed primarily toward PUI researchers with little or no NIH grant writing experience .The afternoon session built upon this foundation by providing more specific information and advice related to the development of successful R15 proposals. 

In an effort to help prepare faculty for successful NIH-R15 proposal submissions we utilize R15 guidelines and forms for our internal small grant program referred to as KBRIN-AREA Fellowships grants ($25000/year). To further enhance NIH grant writing skills we are now providing extensive reviews and feedback to the PIs from steering and mentoring core members utilizing NIH review criteria. These reviews are then used by the funded PIs in preparing their NIH-R15 proposals. So far the PIs seem very appreciative of the extensive review comments and suggestions. 

The third mentoring core initiative introduced this year is our individualized consultation service. Specifically PIs who are unsuccessful in their quest for R15 funding are invited to submit their proposals and critiques to the mentoring core. The director of the mentoring core then arranges an individual consultation to help the PI revise and strengthen their proposal for resubmission. We just now receiving reviews from September/October NIH submissions and are currently working with two PIs to revise their proposals. 

It should also be noted that our mentoring core is collaborating with the Puerto Rico (PR)  INBRE leadership to provide assistance in improving their success rate in receiving NIH R15 funding. Dr. Nigel Cooper (PI) and Dr. Bruce Mattingly (PC) recently met with Dr. Sandra Pena (PR PI) to plan an NIH R15 grant writing workshop for researchers at PR PUIs in early May 2010.

project_terms:
Academic Research Enhancement Awards;Academy;Biomedical Research;Consultations;Critiques;Development;Educational workshop;Faculty;Feedback;Fellowship;Foundations;Funding;Goals;Grant;Guidelines;Individual;Institution;Kentucky;Leadership;Mentors;National Center for Research Resources;Principal Investigator;Published Comment;Puerto Rico;Research;Research Infrastructure;Research Personnel;Resources;Science;Services;Source;Suggestion;United States National Institutes of Health;Work;Writing;cost;experience;improved;meetings;member;programs;skills;success


application_id: 8360116
project_number: 5P20RR016481-11
project_title: SUMMER RESEARCH PROGRAM
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8430
contact_pi_person_id: 1956866
contact_pi: ANDERSON, DAWN J
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Participating students at University of Louisville and University of Kentucky attended a research ethics training seminar prior to beginning their research experience.  They also attended weekly research seminars. During their KBRIN SUR experience students also attended presentations given by researchers and graduate school & medical/dental school faculty about biomedical research and career options. Students attended numerous field trips and social outings arranged by their KBRIN university coordinator or research mentor as well.  At the end of their research experience students were required to prepare and present either an oral presentation or poster presentation at their respective institutions.  Participating students were also expected to present their research at the Annual Meeting of the Kentucky Academy of Science.  Meeting registration and housing are provided by the KBRIN SUR Program.  Many students also presented their KBRIN SUR results at research symposia at their home institutions.

project_terms:
Academy;Biomedical Research;Dental Schools;Faculty;Funding;Grant;Home environment;Housing;Institution;Kentucky;Mentors;National Center for Research Resources;Oral;Principal Investigator;Research;Research Ethics;Research Infrastructure;Research Personnel;Resources;Science;Source;Students;Training;United States National Institutes of Health;Universities;career;cost;experience;medical schools;meetings;posters;programs;social;symposium


application_id: 8360115
project_number: 5P20RR016481-11
project_title: ANALYSIS OF POLYHYDROXYALKANOATE INCLUSION BIOGENESIS
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8429
contact_pi_person_id: 9258111
contact_pi: DENNIS, DOUGLAS
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.This proposal accomplishes the AREA program objectives of: 1) supporting meritorious research; 2) exposing undergraduates to research; and 3) strengthening the research environment in non-research intensive universities. The goal of this research is 
to elucidate the mechanism of polyhydroxyalkanoate inclusion biogenesis. Electron microscopy studies have been unable to resolve the structure of PHA inclusions and this has inhibited movement toward a cohesive model of inclusion biogenesis. Employing atomic force microscopy we have determined that there are three layers of structure an outer envelope that is the thickness of a membrane bilayer a middle network layer and 
an underlying crystalline lamellar layer. Genetic studies have indicated that the middle network is comprised at least partially of PhaP and that PhaP is likely to be translocated to the periplasm. Thus it would appear that inclusion biogenesis may occur by 
movement of protein and/or proteins to the periplasm and budding through the cytoplasmic membrane into the cytoplasm facilitating the acquisition of the cytoplasmic membrane as an envelope. The goal of this research is to prove or disprove this supposition. The specific aims of the research are: 1) definitively prove periplasmic 
localization of PhaP via fluorescence localization and Western blot analyses of subcellular fractions 2) demonstrate that the inclusion envelope is derived from the cytoplasmic membrane by proteomic analysis and 3) characterize proteins that bind transiently and permanently to PhaP in hopes of elucidating the mechanism of inclusion biogenesis. Ultimately the goal of the research is to enlarge our knowledge of inclusion biogenesis to the point that this process can be controlled and utilized for medical applications. For instance it could be envisioned that instead of polymer being inserted into the inclusion bioactive compounds could be inserted making the inclusion into a drug delivery vehicle.

project_terms:
Atomic Force Microscopy;Biogenesis;Biomedical Research;Cell membrane;Cytoplasm;Drug Delivery Systems;Electron Microscopy;Environment;Fluorescence;Funding;Genetic;Goals;Grant;Knowledge;Medical;Membrane;Modeling;Movement;National Center for Research Resources;Polymers;Principal Investigator;Process;Protein Binding;Proteins;Proteomics;Research;Research Infrastructure;Resources;Source;Structure;Subcellular Fractions;Thick;United States National Institutes of Health;Universities;Western Blotting;cost;periplasm;programs


application_id: 8360114
project_number: 5P20RR016481-11
project_title: DISSECTING DOMAINS OF UMUD ALLELE W NOVEL REGULATORY FUNCTION IN ACINETOBACTER
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8428
contact_pi_person_id: 9257147
contact_pi: HARE, JANELLE M
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The long term goal of this research is to understand the mechanisms by which cells respond to DNA damage. The link between DNA damage and human health is well-established: the inability to correctly repair damaged DNA can result in various forms of colon breast and ovarian cancers in humans. The existence of similar extensive DNA damage sensing and repair mechanisms in organisms ranging from humans to bacteria demonstrates this central role of DNA integrity. In the typical bacterial SOS response pathway after DNA damage the UmuD protein self-cleaves and then acts with its partner UmuC to function as a translesion synthesis DNA polymerase.

project_terms:
Acinetobacter;Alleles;Bacteria;Biomedical Research;Cells;Cleaved cell;Colon Carcinoma;DNA;DNA Damage;DNA Repair;DNA-Directed DNA Polymerase;Funding;Goals;Grant;Health;Human;Link;Malignant neoplasm of ovary;National Center for Research Resources;Organism;Pathway interactions;Principal Investigator;Proteins;Research;Research Infrastructure;Resources;Role;SOS Response (Genetics);Source;United States National Institutes of Health;cost;human DNA damage;malignant breast neoplasm;novel;repaired


application_id: 8360113
project_number: 5P20RR016481-11
project_title: IMMUNOMODULATION OF INFLUENZA A AND RESPIRATROY SYNCYTIAL VIRUS VIRONS
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8427
contact_pi_person_id: 9061178
contact_pi: MESTER, JOSEPH CHARLES
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Cells of the innate and adaptive immune system are capable of exerting a range of potent anti-viral effects both directly and in collaboration with other cell types. These responses are critical for protection against pathogenic respiratory viruses such as human respiratory syncytial virus (HRSV) and influenza A virus. Pathogenic viruses in turn have evolved mechanisms for escaping exacerbating or suppressing human cellular immune responses. The work completed over the previous year focused on the interaction between human immune cells of the monocyte/macrophage natural killer (NK) and T cell lineages with virion components of HRSV and influenza A virus with the goal of distinguishing between protective and pathological responses triggered by specific virion proteins. Immune cells were cultured with whole inactivated virions fractionated virion components or synthetic peptides corresponding to viral proteins to examine their effect on the immune cells. Expression of immunologically relevant inflammatory mediators cytokines and cell surface molecules by the human immune cells were characterized by real-time polymerase chain reaction (RT-PCR) following a two or four hour exposure. HRSV is known to promote an allergic-type inflammatory response by boosting interleukin (IL)-5 and IL-13 expression. The role of specific human immune cells in this inappropriate response is not well-defined. We have shown that HRSV exposure caused an upregulation of IL-5IL -6 IL-10 and IL-13 gene expression in human NK cells. These cytokines are linked to either immune suppression or an aberrant inflammatory response and the results indicate that NK cells as one of the first immune cells to reach the site of viral infection may be important mediators of a deleterious immune response. Additional results have linked regions of both the F and G virion proteins to these cytokine responses from NK cells. Exposure of NK cells to influenza A virus enhanced IL-17A expression. High expression levels of this cytokine are associated with pathological inflammation. Both HRSV and influenza A virus altered the expression of other immunologically relevant genes such as colony stimulating factor I and OX40 ligand. Altered expression of these immune response mediators in vivo would impact the course of infection and the effectiveness of innate and adaptive immune responses. Future work will continue to investigate the cause of these immune modulations with virion fractionation and testing of isolated viral glycoproteins. Signaling molecules involved in generating the NK cell response will also be investigated. Understanding the immunomodulatory potential of virion components will yield insights into viral pathogenesis and allow the design of more effective subunit vaccines.

project_terms:
Allergic;Biomedical Research;Cell Lineage;Cell surface;Cells;Collaborations;Colony-Stimulating Factors;Effectiveness;Fibrinogen;Fractionation;Funding;Future;Gene Expression;Genes;Glycoproteins;Goals;Grant;Hour;Human;Human respiratory syncytial virus;IL13 gene;Immune;Immune response;Immune system;Infection;Inflammation;Inflammation Mediators;Inflammatory Response;Influenza;Influenza A virus;Interleukin-10;Interleukin-13;Interleukin-5;Interleukin-6;Interleukins;Link;Mediator of activation protein;National Center for Research Resources;Natural Killer Cells;Natural immunosuppression;Polymerase Chain Reaction;Principal Investigator;Proteins;Research;Research Infrastructure;Resources;Role;Signaling Molecule;Site;Source;Subunit Vaccines;Testing;Time;United States National Institutes of Health;Up-Regulation (Physiology);Viral;Viral Pathogenesis;Viral Proteins;Virion;Virus;Virus Diseases;Work;cell type;cost;cytokine;design;immunoregulation;in vivo;insight;killer T cell;macrophage;monocyte;respiratory virus;response;synthetic peptide;tumor necrosis factor ligand superfamily member 4;viron


application_id: 8360112
project_number: 5P20RR016481-11
project_title: THE EFFECTS OF SOY ISOFLAVONES ON CHOLESTEROL METABOLISM IN VIVO
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8426
contact_pi_person_id: 9482332
contact_pi: MULLEN, EIMEAR M.
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Soy is known to lower cholesterol levels and this corresponds to a decrease in cardiovascular disease risk. However the mechanisms of this hypocholesterolemic effect as well as the components of soy that cause thiseffect are a source of controversy. It is also unknown whether soy protein containing endogenous isoflavones would have the same effect as soy protein containing low isoflavones with isoflavones supplemented back to the protein source. 
We have previously shown in a cell culture model that the isoflavones genistein and daidzein increase the processing of the Sterol Regulatory Element Binding Proteins (SREBPs) and the expression SREBP-regulated genes such as HMG CoA reductase HMG CoA synthase and the LDL receptor. This study will address whether isoflavones cause a similar increase in SREBP processing and SREBP-regulated gene expression in an in vivo model. We will use the C57BL/6J mouse and feed it an atherogenic diet for either 2 days 10 days or 6 weeks. The diets will contain soy protein with low endogenous amounts of isoflavones with or without 
isoflavone supplementation or soy protein with high amounts of endogenous isoflavones. The animals will be sacrificed and their plasma and liver tissue lipids will be analyzed. The processing of SREBP-2 and the protein levels of HMG CoA reductase will be measured by immunoblotting. The expression levels of SREBP regulated genes will also be investigated by quantitative real time PCR. We hypothesize that there will be a decrease in plasma cholesterol and triglyceride levels and that this will correspond to an increase in SREBP processing as well as SREBP-regulated gene expression. However we do not know if we will observe the same results for soy protein containing high amounts of endogenous isoflavones or soy protein containing low amounts of isoflavones with isoflavones supplemented back to the protein source.

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


application_id: 8360111
project_number: 5P20RR016481-11
project_title: THE CIRCADIAN TIMING SYSTEM IN THE MODEL ORGANISM CHLAMYDOMONAS
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8425
contact_pi_person_id: 8234056
contact_pi: JACOBSHAGEN, SIGRID
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.We were able to determine the optimal time of giving a light pulse. Greatest phase shifts can be observed 7 h into the dark phase of a 12 h light/12 h dark cycle. We have not optimized the duration of the light pulse yet. However since two of the photoreceptors we are investigating for their possible involvement in circadian entrainment by light in our model organism absorb in the blue region of the light spectrum we already tested blue light. We have preliminary evidence that blue light is indeed effective. This is contrary to previously reported findings that were based on a particular mutant of the organism and obtained under ambiguous conditions. Plant-like cryptochrome: We succeeded in identifying several of our transformants with the RNA interference construct for this particular photoreceptor as having indeed reduced amounts of the protein. They will now provide the basis for experiments that test whether these strains also show reduced abilities to phase shift upon blue light pulses. Animal-like cryptochrome: We did not succeed in cloning the coding sequence for this protein because we were not able to amplify it by PCR. We only succeeded in amplifying shorter fragments most likely due to the high GC content of the DNA. Because of our difficulties and because the protein is most likely a DNA photolyase rather than a photoreceptor as previously suggested we have abandoned this part of the project. Chlamyopsin: Experiments are currently underway to clone a marker into an RNA interference construct received by a collaborator so that strains with reduced amounts of this photoreceptor can be created. Phototropin: When testing RNA interference strains for this photoreceptor that we received from a colleague we did not succeed in detecting the protein in western blots. There is some evidence that the problem arises from degradation problems with the antibodies during shipment and subsequent storage. Our collaborator has kindly agreed to send us another sample in a more secure fashion.

project_terms:
Amino Acid Sequence;Animal Model;Animals;Antibodies;Biomedical Research;Chlamydomonas;Circadian Rhythms;Cloning;Code;DNA;DNA Photolyase;Funding;Grant;Guanine + Cytosine Composition;Light;National Center for Research Resources;Organism;Peptide Sequence Determination;Phase;Photoreceptors;Physiologic pulse;Plants;Principal Investigator;Proteins;RNA Interference;Reporting;Research;Research Infrastructure;Resources;Sampling;Secure;Source;System;Testing;Time;United States National Institutes of Health;Western Blotting;base;cost;cryptochrome;light entrainment;mutant;phototropin;research study


application_id: 8360110
project_number: 5P20RR016481-11
project_title: REQUEST FOR SUPPORT OF A TEACHING POSTDOCTORAL FELLOW
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8424
contact_pi_person_id: 8527958
contact_pi: PAULA, STEFAN FRANZ
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Inhibitors of the enzyme sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) are valuable research tools for the study of the enzyme's role in physiological processes and they also have the potential of being developed into new anti-cancer agents. A series of 25-disubstitued hydroquinones will be synthesized and their ability to inhibit SERCA will be assessed in bioassays. Based on the results computational techniques such as structure-activity relationship modeling and ligand docking will be used to develop models capable of predicting the activities of yet untested hydroquinone-based compounds. With the aid of these models compound libraries will be screened virtually for novel SERCA inhibitors that then will be obtained and tested in bioassays.

project_terms:
Antineoplastic Agents;Biological Assay;Biomedical Research;Ca(2+)-Transporting ATPase;Computational Technique;Docking;Educational process of instructing;Endoplasmic Reticulum;Enzyme Inhibitor Drugs;Enzyme Inhibitors;Enzymes;Funding;Grant;Hydroquinones;Libraries;Ligands;Modeling;National Center for Research Resources;Physiological Processes;Postdoctoral Fellow;Principal Investigator;Research;Research Infrastructure;Resources;Role;Series;Source;Structure-Activity Relationship;Testing;United States National Institutes of Health;base;cost;hydroquinone;inhibitor/antagonist;novel;tool


application_id: 8360109
project_number: 5P20RR016481-11
project_title: ZEBRAFISH: A POTENTIAL MODEL FOR MAMMALIAN HAIR CELL DEATH AND REGENERATION
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8423
contact_pi_person_id: 2128827
contact_pi: SMITH, MICHAEL
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Auditory hair cells are the sensory cells that transduce acoustical signals into neural ones in vertebrates thus providing the ability to hear. In mammals when these terminally-differentiated cells are damaged or lost the result is permanent loss of hearing since lost mammalian hair cells do not regenerate. In fish and birds damaged auditory sensory epithelia have the capability of regenerating new hair cells resulting in recovery of hearing. Recent studies show that goldfish exhibit both structural (hair cells) and functional (hearing) recovery following noise exposure. To fully understand what normal cellular processes lead to regeneration in fishes knowledge of how specific genes mediate hair cell growth (proliferation and transdifferentiation) is essential. The overall goal of this project is to study the process of hair cell regeneration in zebrafish since zebrafish has become a productive model for studying the gene expression of many cellular pathways. The current proposal has three aims directed at this goal: 1) to determine the time course of hair cell death and regeneration in noise-exposed zebrafish (using immunocytochemistry); 2) to determine the time course of functional recovery of hearing following noise exposure in zebrafish (using auditory brainstem response); and 3) to examine gene expression during the process of hair cell death and regeneration in the zebrafish ear using rtPCR and microarray analysis. We were initially interested in examining expression of three genes (p27Kip1 Atoh1 and Rb1). These genes have recently been shown to regulate hair cell development in mammals. We have performed a microarray experiment that examined gene expression during the process of hair cell generation and the three genes of interest above were not highly regulated but growth hormone and a number of other genes were. We recently validated our microarray experiments with real-time PCR using significantly regulated genes. These studies will provide a basis for future investigations in hair cell regeneration research and may be critical in establishing a link between hair cell proliferation and development of new therapeutics to treat deafness.

project_terms:
Auditory;Auditory Brainstem Responses;Biomedical Research;Birds;Cell Death;Cell Proliferation;Cell physiology;Deafness;Development;Ear structure;Epithelium;Exhibits;Fishes;Funding;Future;Gene Expression;Generations;Genes;Goals;Goldfish;Grant;Hair Cells;Hearing;Investigation;Knowledge;Lead;Link;Mammals;Mediating;Microarray Analysis;Modeling;National Center for Research Resources;Natural regeneration;Noise;Pathway interactions;Principal Investigator;Process;Recovery;Recovery of Function;Research;Research Infrastructure;Resources;Sensory;Signal Transduction;Somatotropin;Source;Study models;Time;United States National Institutes of Health;Vertebrates;Zebrafish;base;cell growth;cell injury;cellular transduction;cost;hair cell regeneration;hearing impairment;immunocytochemistry;interest;novel therapeutics;relating to nervous system;research study;transdifferentiation


application_id: 8360108
project_number: 5P20RR016481-11
project_title: WKU LEAD FACULTY
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8422
contact_pi_person_id: 7326029
contact_pi: DAVIS, CHERYL D
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.As Western Kentucky University's Lead Faculty Representative my role in the INBRE program is primarily administrative.  During this budget year I have overseen institutional activities related to the program I have represented WKU on the KBRIN steering committee and the KBRIN AREA subcommittee I have promoted and facilitated interactions and exchange of ideas between faculty postdocs technicians and students in our biomedical research community and I have served as a liaison between the Administrative Core of the INBRE program and the faculty investigators and administrators at WKU. Between May 1 2009 and April 30 2010 the INBRE program provided support for one junior faculty investigator (Michael Smith) and three tenured faculty investigators (Sigrid Jacobshagen Rodney King and Nancy Rice).  All four investigators directed successful and productive research programs involving numerous undergraduate and masters level graduate students as well as 3 full time technicians and 1 post doc.  Three of our INBRE investigators are also currently funded by NIH-AREA grants.  Three additional junior faculty members from WKU Di Wu from the Department of Mathematics Rajalingam Dakshinamurthy from the Department of Chemistry and Nilesh Sharma from the Department of Biology participated in the INBRE program during this budget year through our KBRIN AREA initiative.  In addition the Director of our Bioinformatics and Information Science Center Claire Rinehart received funding from the INBRE program to allow the BISC to take on increasing responsibility for arranging and facilitating the annual Kentucky/Tennessee Bioinformatics Summit.  
A record number of six faculty members from Ogden College of Science and Technology at WKU submitted NIH AREA proposals during the current budget year.  We are also pleased to report that two INBRE funded students from WKU received national level scholarships/awards during this budget year.  Patrick Stewart and undergraduate research student in Michael Smith's lab was the recipient of a Morris K. Udall Scholarship and Joseph Chavarria-Smith from Nancy Rice's lab received an NSF Graduate Fellowship to pursue doctoral studies at the University of California-Berkeley.

project_terms:
Administrator;Award;Bioinformatics;Biology;Biomedical Research;Budgets;California;Chemistry;Communities;Faculty;Fellowship;Funding;Grant;Information Sciences;Kentucky;Lead;Mathematics;National Center for Research Resources;Postdoctoral Fellow;Principal Investigator;Reporting;Research;Research Infrastructure;Research Personnel;Resources;Rice;Role;Scholarship;Science;Source;Students;Technology;Tennessee;Time;United States National Institutes of Health;Universities;college;cost;graduate student;member;programs


application_id: 8360107
project_number: 5P20RR016481-11
project_title: RNA-BASED MECHANISMS OF TRANSCRIPTION ELONGATION CONTROL
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8421
contact_pi_person_id: 8534212
contact_pi: KING, RODNEY ALLEN
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The goal of this project is to understand a unique mechanism of transcription elongation control originally discovered in the bacteriophage HK022. Most members of the lambda phage family use phage-encoded proteins to promote early gene expression by suppressing transcription termination. HK022 does not encode an antitermination protein but relies instead on the direct interaction of sites in the nascent transcript with RNA polymerase. The specific hypothesis is that the activity of RNA-based antiterminators depends upon the recognition of sequence and structural information in the nascent transcript by RNA polymerase. This hypothesis is based upon previous studies that 1) have shown that mutations that disrupt base pairing in the RNA reduce antitermination and secondary mutations that re-establish base pairing restore terminator read through 2) interchanging segments of antiterminator RNAs drastically affects activity and 3) RNA-mediated antitermination is blocked by mutations in the beta prime subunit of E. coli RNA polymerase. The goal of this proposal is to identify the required sequence and structural elements of RNA based antiterminators. The specific aims are: 1) to identify additional examples of antiterminator RNAs in lambdoid phages; 2) to use in vivo in vitro and in silico approaches to determine the structurally and functionally important features of the newly identified antiterminator RNAs; and 3) to complete the annotation of two new phage genomes that possess RNA-based antiterminators. The antiterminator sequences discovered in HK022 provide unique examples of RNAs that control gene expression by directly modifying the transcription apparatus. Unusual modes of gene regulation are potential targets for drug design. Therefore a better understanding of antiterminator RNAs and their recognition by RNA polymerase may facilitate the discovery or development of therapeutic agents capable of altering the expression of virulence genes and thus attenuating disease processes.

project_terms:
Affect;Attenuated;Bacteriophage HK022;Bacteriophage lambda;Bacteriophages;Base Pairing;Biomedical Research;Computer Simulation;DNA-Directed RNA Polymerase;Development;Disease;Drug Design;Elements;Escherichia coli;Family;Funding;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genome;Goals;Grant;In Vitro;Mediating;Mutation;National Center for Research Resources;Principal Investigator;Process;Proteins;RNA;Reading;Research;Research Infrastructure;Resources;Site;Source;Therapeutic Agents;Transcript;Transcription Elongation;United States National Institutes of Health;Virulence;antitermination;base;cost;in vivo;member;transcription termination


application_id: 8360106
project_number: 5P20RR016481-11
project_title: NKU LEAD FACULTY
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8420
contact_pi_person_id: 1893500
contact_pi: BARDGETT, MARK EDWARD
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Funds have been used to support continued coordination of research administration between INBRE faculty and administrators at NKU in addition to the timely and effective communication of information with INBRE administrators at other KY universities. Dr. Bardgett will continue to attend state and regional meetings related to INBRE. Among new faculty and students at NKU he will continue to increase awareness of the KBRIN faculty fellowship program the KBRIN Summer Student program the Bioinformatics summit and other INBRE-sponsored research and training initiatives.

project_terms:
Administrator;Awareness;Bioinformatics;Biomedical Research;Communication;Faculty;Fellowship Program;Funding;Grant;Lead;National Center for Research Resources;Principal Investigator;Research;Research Infrastructure;Research Training;Resources;Source;Students;United States National Institutes of Health;Universities;cost;meetings;programs


application_id: 8360105
project_number: 5P20RR016481-11
project_title: BEHAVIORAL NEUROANATOMICAL CHARACTERIZATION NOVEL GENETIC ANIMAL PARKINSON'S
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8419
contact_pi_person_id: 6945317
contact_pi: SCHULTHEIS, PATRICK JOHN
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.P-type ATPases which transport ions across cell membranes have been grouped into five subfamilies. The P1- P2- and P3-ATPases have been well characterized and include heavy metal ATPases NaK-ATPases HK-ATPases SERCAs and other Ca2+-ATPases and bacterial Mg2+-ATPases. The P4-ATPases are found only in eukaryotes and have been implicated in the transport of aminophospholipids. Although they are present in all eukaryotes little is known about the P5-ATPases other than the observations that loss of Cod1p one of the two yeast P5-ATPases leads to defects in glycoprotein processing endoplasmic reticulum associated protein degradation (ERAD) and constitutive activation of the unfolded protein response (UPR). Thus our objective is to obtain basic information regarding the distribution and ion specificity of the mammalian P5-ATPases. In preliminary studies we have identified 5 mammalian P5-ATPases termed Atp13a1-Atp13a5 determined their sequences and mRNA tissue distribution and begun development of isoform-specific antibodies and expression constructs. In Aim 1 we will develop isoform-specific antibodies and in situ hybridization probes and determine the membrane location and cell-type distribution of mouse Atp13a1-Atp13a5 using a combination of Western blot analysis of tissues and subcellular membrane fractions immunocytochemistry and in situ hybridization. In Aim 2 the ion specificity of the murine P5-ATPases will be determined. Membrane fractions from cell lines in which histidine-tagged versions of Atp13a1-Atp13a5 are over-expressed will be prepared and subjected to detergent solubilization. The His-tagged transporters will then be purified by nickel affinity chromatography and ion specificities will be determined by measuring cation-dependent ATP hydrolysis using sensitive assays of ATPase activity and phosphoenzyme formation. Ion uptake in whole cells or isolated membrane vesicles will also be analyzed using the appropriate radioisotope to confirm ion specificity. These studies will provide basic information that will be critical for more detailed mechanistic studies of the cell biological and physiological functions of this most poorly understood subfamily of mammalian P-type ATPases.

project_terms:
ATP Hydrolysis;ATP phosphohydrolase;Affinity Chromatography;Animal Genetics;Antibodies;Behavioral;Biological;Biological Assay;Biomedical Research;Ca(2+) Mg(2+)-ATPase;Ca(2+)-Transporting ATPase;Cations;Cell Line;Cell membrane;Cells;Defect;Detergents;Development;Drug or chemical Tissue Distribution;Endoplasmic Reticulum;Eukaryota;Funding;Glycoproteins;Grant;H(+)-K(+)-Exchanging ATPase;Heavy Metals;Histidine;In Situ Hybridization;Ion Transport;Ions;Location;Measures;Membrane;Messenger RNA;Mus;Na(+)-K(+)-Exchanging ATPase;National Center for Research Resources;Nickel;Parkinson Disease;Physiological;Principal Investigator;Process;Protein Isoforms;Proteins;Radioisotopes;Research;Research Infrastructure;Resources;Source;Specificity;Tissues;United States National Institutes of Health;Vesicle;Western Blotting;Yeasts;cell type;cost;immunocytochemistry;novel;protein degradation;response;uptake


application_id: 8360104
project_number: 5P20RR016481-11
project_title: THE ROLE OF NITRIC OXIDE SIGNALING IN MYOFIBROBLAST FUNCTION
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8418
contact_pi_person_id: 6773495
contact_pi: RICE, NANCY AYERS
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.Myofibroblasts are necessary cells for tissue remodeling and repair. The fact that under certain circumstances myofibroblasts persist and continue to secrete extracellular matrix has implicated them in interstitial fibrosis of the lung. Several studies suggest that nitric oxide (NO)-mediated signals may be important in regulating myofibroblast phenotypes. Inhibition of NO production leads to increased accumulation of myofibroblasts; NO reduces myofibroblast accumulation and collagen deposition; and transforming growth factor  (TGF) a known activator of myofibroblast differentiation blocks myofibroblast apoptosis. In vivo endothelial NOS (eNOS) knockout mice experience prolonged pulmonary fibrosis in response to the profibrotic agent bleomycin suggesting that eNOS operates in regulating myofibroblast proliferation and/or apoptosis. The fact that the eNOS gene promoter can be induced by the mechanical force of laminar flow in epithelial cells and the observation that other genes  smooth muscle actin (ASMA) in particular are mechanotranscriptionally regulated in myofibroblasts suggests a potential mechanism for regulating the expression of eNOS and thus apoptosis in myofibroblasts. Therefore we hypothesize that contraction of myofibroblasts mediates their apoptosis via eNOS signaling. In our current proposal we are investigating three specific aims to extend our knowledge of the role of mechanical stress and NO in regulating myofibroblasts. One we are evaluating the role of mechanical stress on pulmonary myofibroblast eNOS expression; two we are determining the role of NO on pulmonary myofibroblast apoptosis; and three we are assessing the deletion of sarcomeric myosin on bleomycin induced pulmonary fibrosis in vivo.

project_terms:
Apoptosis;Biomedical Research;Bleomycin;Cells;Collagen;Deposition;Epithelial Cells;Extracellular Matrix;Fibrosis;Funding;Genes;Grant;Knockout Mice;Knowledge;Lung;Mechanical Stress;Mechanics;Mediating;Myofibroblast;Myosin ATPase;National Center for Research Resources;Nitric Oxide;Phenotype;Principal Investigator;Production;Promotor (Genetics);Pulmonary Fibrosis;Research;Research Infrastructure;Resources;Role;Signal Transduction;Smooth Muscle Actin Staining Method;Source;Tissues;Transforming Growth Factors;United States National Institutes of Health;cost;experience;human NOS3 protein;in vivo;interstitial;repaired;response


application_id: 8360103
project_number: 5P20RR016481-11
project_title: MICROBIAL METABOLIC MUTUALISM UNDER EXTREME STARVATION
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8417
contact_pi_person_id: 7614787
contact_pi: BARTON, HAZEL A
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The goal of my project is to understand the metabolic activity that supports microbial growth under extreme starvation. In understanding the interactions and processes that sustain microbial communities in starved environments we hope to better understand one of the outstanding questions of microbial ecology: why are the majority of organisms identified in the environment unculturable in the laboratory? This unculturability is presumed to be due to the inability to reproduce the fastidious growth requirements of many of these species making them viable within the environment but unculturable under laboratory conditions. Through this proposal we aim to test our hypothesis that microbial communities subsist in extremely oligotrophic environments by establishing mutualistic interactions allowing species to more efficiently utilize the complex nutrient sources entering the system. While such interactions may promote diversity under extreme starvation obligate mutualism prevents cultivation of these species using traditional techniques. The experiments proposed are geared toward understanding the role that the amount and type of available energy entering these systems have on community diversity and mutualism. The specific aims are: 1) to determine whether microbial mutualistic interactions are occurring under extreme starvation conditions and what role they play in supporting community growth; 2) to determine whether such mutualism increases the usable energy sources and metabolic efficiency under extreme starvation driving community diversity; and 3) to increase the number of previously unculturable bacterial species from these extremely oligotrophic environments by separating previously interdependent species. By using a combination of techniques to monitor how nutrient flow affects community diversity we endeavor to understand some of the more complex metabolic interactions capable of supporting life under starvation while increasing the diversity and number of culturable microbial species.

project_terms:
Affect;Automobile Driving;Biomedical Research;Communities;Complex;Ecology;Energy-Generating Resources;Environment;Funding;Goals;Grant;Growth;Laboratories;Life;Metabolic;Monitor;National Center for Research Resources;Nutrient;Organism;Play;Principal Investigator;Process;Research;Research Infrastructure;Resources;Role;Source;Starvation;System;Techniques;Testing;United States National Institutes of Health;cost;microbial;microbial community;mutualism;prevent;research study


application_id: 8360102
project_number: 5P20RR016481-11
project_title: BARDGETT POST-DOC/TECHNICIAN SUPPORT
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8416
contact_pi_person_id: 1893500
contact_pi: BARDGETT, MARK EDWARD
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The goal of the proposed research is to develop and use models of modest excitotoxic hippocampal injury to assess the cognitive enhancing ability of specific candidate compounds. Our preliminary data demonstrate that excitotoxic injury to the dorsal hippocampus produces enduring deficits in spatial working memory. We have also shown in preliminary studies that antagonists at histamine H3 receptors alleviate injury-induced deficits in spatial working memory. The specific aims of our currently-funded R15 research have been to answer the following questions: 1) Can H3 antagonists alleviate spatial working memory deficits in rats with adult-onset hippocampal injury 2) Can direct infusion of H3 antagonists into the prefrontal cortex improve memory in rats with adult-onset hippocampal injury & 3) Can H3 antagonists alleviate changes in spatial working memory prepulse inhibition and locomotor activity in rats with neonatal-onset hippocampal injury? For this application we requested INBRE supplemental support for a research associate who can advance the aims of our R15 research and supervise undergraduate research. Between May 2009 and the present we have assessed the effects of H3 antagonists on spatial memory deficits and other behavioral anomalies produced by drugs that block NMDA receptors. These studies mainly performed by Molly Griffith our research associate and several undergraduates in the lab have shown that H3 antagonists exacerbate the effects of NMDA antagonists on locomotor activity but also alleviate the spatial memory deficits produced by such drugs. We submitted an R15 to continue these studies in June 2009 and it received a priority score of 37. We will revise and resubmit this application in February 2010. Having INBRE support for our research associate has greatly facilitated the pace of our R15 research and resulted in two published papers support for award-winning undergraduate research and an R15 renewal application that received a favorable (although unfundable) score.

project_terms:
Adult;Award;Behavioral;Biomedical Research;Cognitive;Data;Dorsal;Funding;Goals;Grant;Hippocampus (Brain);Histamine H3 Receptors;Infusion procedures;Injury;Memory;Memory impairment;Modeling;Mollies;Motor Activity;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;National Center for Research Resources;Neonatal;Paper;Pharmaceutical Preparations;Postdoctoral Fellow;Prefrontal Cortex;Principal Investigator;Publishing;Rattus;Request for Applications;Research;Research Infrastructure;Resources;Short-Term Memory;Source;United States National Institutes of Health;cost;improved;prepulse inhibition


application_id: 8360101
project_number: 5P20RR016481-11
project_title: UK BIOINFOMRATICS
administering_ic: NCRR
award_notice_date: 2011-05-10
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8415
contact_pi_person_id: 8383697
contact_pi: PETERSON, MARTHA L.
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing the resourcesprovided by a Center grant funded by NIH/NCRR. Primary support for the subprojectand the subproject's principal investigator may have been provided by other sourcesincluding other NIH sources.  The Total Cost listed for the subproject likelyrepresents the estimated amount of Center infrastructure utilized by the subprojectnot direct funding provided by the NCRR grant to the subproject or subproject staff.The UK Bioinformatics Core provides bioinformatics and statistical consulting on multiple genomics projects. The facility supports the BLAST server Computational Proteomics Analysis System (CPAS) proteomics suite and other custom bioinformatics applications. Facility personnel are actively engaged in statistical consulting and program development and all are members of the Center for Biomedical Informatics of the UK Center for Clinical and Translational Sciences. The INBRE bioinformatics core particularly Dr. Stromberg continues to serve as the primary statistical consultant on transcription microarray analyses at UK serving approximately 30 investigators per year and analyzing data from approximately 1000 expression arrays. Dr. Stromberg is a co-PI on numerous grants and participates in writing the statistical parts of proposals. Of particular note Dr. Stromberg is a Co-PI with Dr. Randal Voss as the PI on a recently awarded $2000000 grant from the Department of Defense. Dr. Voss and the Salamander Genome Project had been supported in part by this core for eight years but was discontinued this year due to the great success he has had in obtaining extramural support for his work. The core also provides informatics support of proteomics and protein expression analyses. Dr. Viele is developing statistical methods to handle mass spectroscopic protein quantification. Dr. Bert Lynn the director of the University of Kentucky Mass Spectrometry Facility (UKMSF) helps direct the efforts of Mr. William Nelson in the proteomics area. They recently designed and implemented Massively Parallel Peptide Discovery methods that they have submitted for publication and which form the basis of an NIH RO1 grant application. UK is a participant in the national LabKey software development consortium and offers support that can be deployed statewide. This year Mr. Nelson provided training for the Labkey Computational Proteomics Analysis System (CPAS) at the University of Louisville for ten members of the CREAM grant and installed CPAS at the CREAM facility. Their CPAS install is integrated with the SEQUEST cluster at the UKMSF. A publication from this effort should be submitted soon. Mr. Nelson also provided a prototype and training on the Labkey Server Study Module for twelve researchers from the Markey Cancer Center and the Kentucky Cancer Registry (KCR). The Study module provides data management and statistical analysis tools for Clinical Translational Studies. As a result the Study module is being adopted by the KCR to support the Markey Cancer Center's SPORE grant. The KCR is hiring a permanent administrator to support the Labkey server. Also Dr. Andre Baron's group has adopted the Labkey for their cancer biomarker research. His project has been implemented at the UKMSF's Labkey installation. Dr. Sujin Kim is developing tools to segment pathology images to facilitate computer identification and standardization of pathology data. She has submitted several grants and publications as well as supervised multiple master's-level students in projects to develop web-based information systems. Dr. Jinze Liu has established multiple bioinformatics collaborations across campus including developing robust methods for analyzing RNA-seq data for an equine gene annotation project (with Dr. James Macleod) and a plant annotation project (with Dr. Chris Schardl). She recently received an NSF ARRA grant to develop methods to discover alternative splicing patterns from RNA-seq data. Dr. Dave Fardo a biostatistician who studies genome-wide association studies has established collaborations on campus with colleagues at U of L and internationally. Dr. Bert Lynn has recently agreed to mentor and collaborate with Dr. Darrin Smith from the EKU department of chemistry. Dr. Peter Mirabito organized and supervised the KBRIN-supported students working at UK over the summer.

project_terms:
Administrator;Adopted;Alternative Splicing;Applications Grants;Area;Award;Bioinformatics;Biomedical Research;Cancer Center;Chemistry;Clinical;Clinical Sciences;Collaborations;Computers;Consult;Custom;Data;Data Analyses;Department of Defense;Equus caballus;Extramural Activities;Funding;Genes;Genetic Transcription;Genome;Genomics;Grant;Human Resources;Image;Informatics;Information Systems;Kentucky;Malignant Neoplasms;Mass Spectrum Analysis;Mentors;Methods;National Center for Research Resources;Online Systems;Participant;Pathology;Pattern;Peptides;Plants;Principal Investigator;Program Development;Proteins;Proteomics;Publications;RNA;Research;Research Infrastructure;Research Personnel;Resources;Salamander;Source;Standardization;Statistical Methods;Students;Systems Analysis;Training;Translational Research;United States National Institutes of Health;Universities;Work;Writing;base;biomarker;biomedical informatics;cost;data management;design;genome wide association study;member;neoplasm registry;protein expression;prototype;software development;success;tool;translational study


