# projects

application_id: 7916026
project_number: 1R13ES019025-01
project_title: 12th Annual Midwest DNA Repair Symposium
administering_ic: NIEHS
award_notice_date: 2010-03-26
opportunity_number: PA-08-149
application_type: 1
activity_code: R13
ic: ES
serial_number: 019025
program_official: QUINN, ASHLINN KO
project_start_date: 2010-04-01
project_end_date: 2011-03-31
study_section: Special Emphasis Panel[ZES1 TN-V (02)]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The 12th Annual Midwest DNA Repair Symposium (AMDRS) will take place in Louisville KY on May 15 - 16 2010 at the Shelby Campus of the University of Louisville. The AMDRS started in 1999 at the University of Michigan - Ann Arbor and has met at various universities in the Midwest every year since then. The Midwest DNA Repair Symposium was originally conceived as a forum to bring together DNA repair researchers from the Midwestern region on an annual basis to discuss ongoing research and to stimulate collaborations. Additional goals of the AMDRS include making the cost of attending the symposium as inexpensive as possible and to provide young investigators postdoctoral fellows and graduate students priority in presenting their work in oral and poster sessions. DNA repair is a fundamental cellular process critical to maintenance of genome integrity and human health. DNA repair dysfunction has been linked with many inherited diseases as well as chronic diseases such as neurodegeneration cardiovascular disease aging and cancer. The investigators are pleased that this symposia series has been very successful and has seen significant increase in attendance the past several years. One key to the success has been to keep the costs of attendance low. This low cost has been possible because the organizers for each year held the symposium at their home institutions and have secured both intramural and extramural funding to cover some of the major expenses. Especially in times of restricted funding the AMDRS is one meeting to which PI's have been able to bring their students and post-doctoral fellows to interact with leading scientists in the field and to present their work among peers. The AMDRS is now in its second decade and has started to recycle. In 2010 the AMDRS is returning to Louisville. The three principle goals of the AMDRS: 1) to provide a venue for scientists mainly from the Midwestern states to present and discuss current research in the field of DNA damage repair and mutagenesis and to provide opportunities to foster scientific collaborations. (2) To provide students postdoctoral fellows and beginning independent investigators the opportunity to p resent their work to peers and to interact with leaders in the field. (3) To provide an exceptional value of these symposia by keeping them affordable.  
  
PUBLIC HEALTH RELEVANCE:  Environmental agents that cause DNA damage contribute to the development and progression of chronic human disease including cancer and cardiovascular and neurodegenerative diseases. DNA repair is an essential cellular processes that removes the DNA damage and efficient DNA repair is essential to prevention of these chronic diseases. This symposium will bring together DNA repair researchers to discuss their newest research to exchange ideas and to develop new collaborations.

project_terms:
Age;Cardiovascular Diseases;Cardiovascular system;Cell physiology;Chronic;Chronic Disease;Collaborations;DNA Damage;DNA Repair;Development;Disease;Extramural Activities;Fostering;Functional disorder;Funding;Genome;Goals;Health;Home environment;Human;Inherited;Institution;Link;Maintenance;Malignant Neoplasms;Michigan;Mutagenesis;Nerve Degeneration;Neurodegenerative Disorders;Oral;Postdoctoral Fellow;Prevention;Recycling;Research;Research Personnel;Scientist;Secure;Series;Students;Time;Universities;Work;base;cost;environmental agent;graduate student;human disease;meetings;peer;posters;public health relevance;success;symposium

public_health_relevance:
NarrativeEnvironmental agents that cause DNA damage contribute to the development andprogression of chronic human disease including cancer and cardiovascular andneurodegenerative diseases. DNA repair is an essential cellular processes that removesthe DNA damage and efficient DNA repair is essential to prevention of these chronicdiseases. This symposium will bring together DNA repair researchers to discuss theirnewest research to exchange ideas and to develop new collaborations.


application_id: 7915845
project_number: 3R01LM008323-04S2
project_title: Histological Reasoning: Visual Cognition in Microanatomy
administering_ic: NLM
award_notice_date: 2009-09-21
application_type: 3
activity_code: R01
ic: LM
serial_number: 008323
suffix: S2
program_official: SIM, HUA-CHUAN
project_start_date: 2009-09-30
project_end_date: 2010-09-29
study_section: Biomedical Informatics, Library and Data Sciences Review Committee[BLR]
contact_pi_person_id: 1911606
contact_pi: PANI, JOHN R
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
This project is a multidisciplinary study of cognition in the practice of histology the microanatomy of tissues. Histology is a core course in the biological premedical and medical school curricula and pathologists use its methods to diagnose a variety of medical disorders. Instruction in histology centers on the recognition of tissues in microscopes. This is a very challenging task that takes years to master. Much of the basis for this difficulty is that the tissue in microscope slides differs substantially in appearance from the whole tissue. As a result ability in histology requires the development of high level skills of visual recognition and reasoning. This project will investigate the current and optimum methods for gaining expertise in basic histology through a variety of experimental studies. The specific aims of the proposed research are the following: 1) Determine the information for human perceivers in microscope slides.Two studies will generate models of the use of diagnostic information in microscope slides for individuals who have completed the first year course in histology. 2) Assess the importance of visuospatial understanding of microanatomy for identification of tissues in microscope slides. An experiment will be conducted to test the hypothesis that the ability to identify structures and tissues in microscope slides will vary directly with the degree to which people have a clear visuospatial understanding of the microanatomy of the whole tissue. 3) Assess the importance of visuospatial understanding of the slice transformation for identification of tissues in microscope slides. An experiment will be conducted to test the hypothesis that the ability to identify structures and tissues in microscope slides will vary directly with the degree towhich people have a clear visuospatial understanding of the transformation that relates 3D anatomy to 2D anatomical sections. The results of this research will lead to a detailed understanding of cognition in histology and to advances in theories of visual symbol systems used in the interpretation of images generated by human technology (e.g. x-ray mri aerial photographs). This project has the potential to generate substantial change in the methods for developing skill in histology at both the undergraduate and the medical school levels. The study of virtual reality methods of learning in conjunction with a rigorous study of histological reasoning will lead directly to the development of software that may significantly accelerate the development of skill in this challenging and important field.

project_terms:
Accounting;Anatomy;Appearance;Area;Biological;Cognition;Complex;Computer Simulation;Computer Systems;Cues;Data;Development;Diagnosis;Diagnostic;Disease;Educational Curriculum;Evaluation;Generations;Histology;Human;Image;Individual;Information Retrieval;Instruction;Knowledge;Label;Lead;Learning;MRI Scans;Maps;Medical;Medical Informatics;Memory;Methods;Microanatomy;Microscope;Modeling;Nature;Participant;Pathologist;Perception;Performance;Problem Solving;Psychology;Radar;Research;Research Project Grants;Slice;Slide;Structure;System;Technology;Testing;Tissues;Training;Visual;Visuospatial;Work;X-Ray Computed Tomography;base;extrastriate visual cortex;medical schools;mental imagery;multidisciplinary;neglect;research study;skills;software development;theories;two-dimensional;virtual reality;visual cognition


application_id: 7914363
project_number: 5R21AI083528-02
project_title: Host defense against influenza virus in the lungs of neonatal mice
administering_ic: NIAID
award_notice_date: 2010-07-26
opportunity_number: RFA-AI-08-020
application_type: 5
activity_code: R21
ic: AI
serial_number: 083528
program_official: ROTHERMEL, ANNETTE L
project_start_date: 2009-08-15
project_end_date: 2011-07-31
study_section: ZAI1-PTM-I(M2)
contact_pi_person_id: 1945284
contact_pi: GARVY, BETH A
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: Y
project_abstract:
DESCRIPTION (provided by applicant):   
  
Infants are particularly susceptible to respiratory infections which have been attributed to an immature and naive immune system that is characterized by suboptimal antigen presentation and a T helper cell bias toward Th2-type cytokines. However little is known about how the post-natally developing lungs contribute to susceptibility to pulmonary infection. Immune homeostasis in the lungs is controlled by a number of factors including epithelial cell production of IL-10 and TGFB and expression of CD200/CD200R on epithelial cells and alveolar macrophages respectively. Our data shows elevated levels of TGFB in the lungs of infant mice over the first 3 weeks of life. Moreover we have previously reported that IL-10 mRNA is constitutively expressed in neonatal lungs. We speculate that these anti-inflammatory cytokines increase the threshold of activation of immune cells in the lungs resulting dampening of inflammation in neonatal lungs. We found that unlike adults neonatal mice develop interstitial pneumonia in response to influenza virus infection which corresponds to differential expression of chemokines compared to adult mice. The goal of this project is to determine mechanisms that contribute to the differences in T cell migration that may result in the greater susceptibility to virus in neonatal mice. We will address the following hypothesis: The neonatal lung environment alters T cell responses to infection leading to interstitial pneumonia and a worse outcome than in adults. Two aims are proposed: 1) To determine whether neonatal T cells and/or the neonatal lung environment are responsible for development of interstitial pneumonia in response to influenza virus; and 2) To determine the mechanisms responsible for the migration of T cells into the neonatal interstitial spaces but not alveolar spaces. We have chosen to use influenza virus as a models system since influenza virus infection causes more morbidity and mortality than any other infection preventable by vaccination and hospitalization rates among infants with influenza virus rival those of the elderly. Understanding the underlying mucosal immune response to influenza virus in infants is an important step in formulating new treatment strategies for infants. Infants that die from influenza virus have been shown to develop interstitial pneumonia with little infiltration of T cells into the alveolar space. The goal of this project is to understand the processes in post-natally developing lungs that leads to development of interstitial pneumonia in response to infection. Understanding the nature of the failure of the neonatal immune system to control influenza virus is important for generation of new vaccine and treatment strategies.

project_terms:
4 year old;Address;Adoptive Transfer;Adult;Age-Years;Alveolar;Alveolar Macrophages;Anti-Inflammatory Agents;Anti-inflammatory;Antigen Presentation;Antigen-Presenting Cells;Antigens;Biological Models;CD4 Positive T Lymphocytes;Cell Adhesion Molecules;Cell physiology;Cessation of life;Child;Data;Development;Elderly;Environment;Epigenetic Process;Epithelial Cells;Equilibrium;Failure (biologic function);Generations;Goals;Health;Helper-Inducer T-Lymphocyte;Homeostasis;Hospitalization;Host Defense;Human;Immune;Immune Cell Activation;Immune response;Immune system;Immunohistochemistry;Infant;Infection;Infectious Agent;Infiltration;Inflammation;Inflammation Mediators;Inflammatory;Influenza;Influenza virus vaccine;Interleukin-10;Interstitial Pneumonia;Kinetics;Knock-out;Life;Lung;Measures;Messenger RNA;Modification;Morbidity - disease rate;Mortality Vital Statistics;Mucosal Immune Responses;Mus;Nature;Neonatal;Outcome;Predisposition;Process;Production;Protein Array Analysis;Recommendation;Regulation;Reporting;Respiratory Tract Infections;Risk;Signal Transduction;Site;Sterility;T cell response;T-Lymphocyte;TGFB1 gene;Th1 Cells;Time;Transgenic Mice;Vaccinated;Vaccination;Virus;Virus Diseases;base;cell motility;chemokine;cytokine;influenzavirus;interstitial;lung development;mature animal;migration;neonate;neutralizing antibody;novel vaccines;response;treatment strategy

public_health_relevance:
Infants that die from influenza virus have been shown to develop interstitial pneumonia with littleinfiltration of T cells into the alveolar space. The goal of this project is to understand theprocesses in post-natally developing lungs that leads to development of interstitial pneumonia inresponse to infection. Understanding the nature of the failure of the neonatal immune system tocontrol influenza virus is important for generation of new vaccine and treatment strategies.


application_id: 7914340
project_number: 5R01DA027031-02
project_title: New Neural Targets for Opioid Use Disorders: Human Studies
administering_ic: NIDA
award_notice_date: 2010-07-19
opportunity_number: RFA-DA-09-005
application_type: 5
activity_code: R01
ic: DA
serial_number: 027031
program_official: BOUGH, KRISTOPHER J
project_start_date: 2009-08-15
project_end_date: 2012-07-31
study_section: ZDA1-EXL-T(06)
contact_pi_person_id: 1877426
contact_pi: WALSH, SHARON L.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Opioid abuse and dependence are growing public health problems in the United States. While rates of heroin use have remained fairly stable over the past several years abuse and dependence on prescription opioids have shown sharp increases over the past decade. In 2006 (SAMHSA 2007b) it was estimated that approximately one million people were prescription opioid-dependent (based upon DSM-IV criteria) adding to the current one million people estimated by the Office of National Drug Control Policy to be addicted to heroin. While there are existing pharmacotherapies approved for the treatment of opioid dependence in the United States the most efficacious (buprenorphine and methadone) are restricted in use to specified practice conditions thus limiting their availability to patients. Substance P a neurokinin peptide is widely distributed throughout human brain and its receptors are highly expressed in brain regions involved in affect and reward. Recent evidence suggests that inactivation of substance P receptors (NK1) either through genetic deletion or pharmacological blockade significantly attenuates the rewarding effects of opioids in an array of non-human laboratory models. We hypothesize that pretreatment with a substance P receptor antagonist may reduce the direct pharmacodynamic actions of mu opioid agonists related to their abuse liability and rewarding effects in humans. Aprepitant is a NK1 receptor antagonist used clinically for its anti-emetic action. The proposed studies will enroll healthy adult male and female volunteers with histories of illicit opioid use. Two inpatient experiments will be conducted that incorporate double-blind placebo-controlled randomized within-subject designs and include careful evaluation of full dose-effect and time action curves on multi-dimensional outcomes. Experiment 1 will examine the effects of acute doses of aprepitant alone and in combination with acute doses of oral oxycodone and intranasal oxycodone in non-dependent opioid abusers (n=10). Pharmacodynamic outcomes will include subject- and observer-rated measures related to abuse potential psychomotor performance and physiological indices. Experiment 2 will examine the effects of chronic dosing with aprepitant and test its ability at steady state to alter the reinforcing effects of intranasal oxycodone (n=10). A progressive ratio self-administration procedure will be employed in this study to examine directly opioid reinforcement. Additionally the pharmacodynamic interactions after repeated dosing of aprepitant with oxycodone on an array of measures will be examined during the sample sessions. Thus these studies will provide new information on the safety of NK1 antagonist treatment under both acute and chronic dosing conditions and on its potential efficacy to alter the abuse liability and reinforcing properties of oxycodone. These studies are responsive to the RFA (DA-06-002) as they will provide proof-of-concept data and assess the utility of a novel CNS target the substance P receptor by evaluating the potential efficacy of an NK1 receptor antagonist aprepitant to reduce the abuse liability and reinforcing effects of opioids in humans.  
  
PUBLIC HEALTH RELEVANCE: This project will test the hypothesis that blockade of substance P receptors in human brain may reduce the effects of opioids related to their abuse. The substance P system has not been examined as a potential target for the development of treatments for opioid abuse and dependence. Thus these studies conducted in healthy humans will provide fundamental information regarding the potential for this system as a target for development of new treatment agents for opioid use disorders.

project_terms:
Acute;Adult;Affect;Agonist;American;Amygdaloid structure;Antiemetics;Anxiety;Attenuated;Behavior;Brain;Brain region;Buprenorphine;Chronic;Clinical Research;Compliance behavior;DSM-IV;Data;Dependence;Development;Disease;Dose;Double-Blind Method;Drug Controls;Drug Interactions;Drug usage;Effectiveness;Enrollment;Evaluation;Female;Genetic;Health;Heroin;Hippocampus (Brain);Human;Inpatients;Laboratories;Laboratory Study;Marketing;Measures;Mediation;Methadone;Modeling;Naltrexone;Narcotic Antagonists;Nausea and Vomiting;Neuraxis;Nociception;Nucleus Accumbens;Opiate Addiction;Opioid;Oral;Outcome;Oxycodone;Patients;Peptides;Pharmaceutical Preparations;Pharmacodynamics;Pharmacotherapy;Physiological;Placebo Control;Policies;Population;Procedures;Property;Psychological reinforcement;Psychomotor Performance;Randomized;Receptors Opioid mu;Recording of previous events;Rewards;Route;Safety;Sampling;Self Administration;Stress;Substance P;Substance P Receptor;Substance-Related Disorders;Surveys;System;Testing;Time;To specify;United States;United States Substance Abuse and Mental Health Services Administration;aprepitant;base;chemotherapy;design;indexing;male;novel;opioid abuse;prescription opioid;public health medicine (field);public health relevance;receptor;relating to nervous system;research study;therapy development;volunteer

public_health_relevance:
PROJECT NARRATIVE This project will test the hypothesis that blockade of substance P receptors in human brain may reducethe effects of opioids related to their abuse. The substance P system has not been examined as a potentialtarget for the development of treatments for opioid abuse and dependence. Thus these studies conducted inhealthy humans will provide fundamental information regarding the potential for this system as a target fordevelopment of new treatment agents for opioid use disorders.


application_id: 7914282
project_number: 5R01ES015375-06
project_title: Apple Peel Extract Protects UV-Induced Carcinogenesis
administering_ic: NIEHS
award_notice_date: 2010-07-29
application_type: 5
activity_code: R01
ic: ES
serial_number: 015375
program_official: HUMBLE, MICHAEL C
project_start_date: 2006-09-28
project_end_date: 2011-07-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-08-01
project_abstract:
DESCRIPTION (provided by applicant): Environmental exposure to UV light is a major etiologic factor in the development of human skin cancers. Experimentally UV acts both as tumor initiator and a tumor promoter in animal models. It is recognized that certain nutritional factors and phytochemicals play an important role in an individual's susceptibility to environmental carcinogens. Understanding of the underlying mechanisms will enhance the effectiveness of prevention and therapeutic efforts. Our preliminary studies indicate that apple peel extract has antioxidant activities. It inhibits ultraviolet (UVB 280-320 nm) radiation-induced AP-1 activation both in vitro and in vivo possibly by interfering with signal transduction events involving MAP kinase ERKs and JNK. Cell transformation studies show that apple peel extract inhibited TPA-induced cell transformation. We hypothesize that apple peel extract may function as an antioxidant and as a chemopreventive agent against oxidative stress-induced carcinogenesis. We will use UVB-induced skin carcinoma as a model to test this hypothesis. Four specific aims are proposed. Specific Aim 1 will identify the active antioxidant components of apple peel extract. We will study the antioxidant properties of various chromatographic fractions derived from apple peel extract and examine the phenolic compounds identified previously for their reaction rates toward oxygen free radicals. Specific Aim 2 will investigate antioxidant properties of apple peel extract individual fraction and previously identified phenolic compounds in JB6 cells and in living animals. Specific Aim 3 will investigate the effects of apple peel extract on UVB-induced activation of AP-1 NF-DB and NAFT in vitro and in vivo. Specific Aim 4 will evaluate the effects of apple peel extract individual fraction and previously identified phenolic compounds on UVB-induced lipid peroxidation protein oxidation oxidative DMA damage and carcinogenesis in SKH-1 hairless mice exposed to UVB. This Aim will also investigate the effects of apple peel preparations on proliferative and/or cell deletion activities by measuring proliferation and apoptosis. This application can be used as a preclinical study for nutritional intervention against cancer resulting from environmental exposure to UV light. This study is related to the priority areas of the Public Health Service program "Healthy People 2010" which is committed to achieving the promotion of health and prevention of disease. Thus the results may have an important impact on public health.

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


application_id: 7914279
project_number: 5R01HL091202-03
project_title: The SDF1-CXCR4 Axis in Cardiac Homeostasis and Regeneration
administering_ic: NHLBI
award_notice_date: 2010-08-17
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 091202
program_official: LIANG, ISABELLA Y
project_start_date: 2008-09-01
project_end_date: 2012-05-31
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF-S]
contact_pi_person_id: 7033203
contact_pi: ROKOSH, GREGG
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The prospect of a cell based therapy for cellular regeneration and functional recovery of the heart was realized with the discovery that stem cells can contribute to myocyte formation in the adult and that these stem cells may also participate in the repair of the heart after injury. It is now clear the heart has inherent regenerative capacity however it is also clear that this capacity is limited. Transplantation of mesenchymal stem cells into patients evokes a reproducible increase in function and provides insight into the potential of this therapeutic approach. To date little is known of the systems that create and maintain the inherent cardiac stem cells (CSC) and how they participate in day to day function and homeostasis or during and after injury. Stromal cell derived factor 11 (SDF1) and its receptor CXCR4 are key components of the biological system that regulates hematopoiesis and hematopoietic stem cells. We have found this SDF1-CXCR4 axis in the heart and both are expressed on myocytes and fibroblasts and are functionally coupled to MAPK and AKT signaling that serves a survival function in vitro and in vivo against ischemia reperfusion injury. Both SDF1 and CXCR4 knockouts are embryonic lethal with cardiac defects. These novel findings serve to provide the basis for our hypothesis that the cardiac SDF1-CXCR4 axis plays a role in cardiac homeostasis through the action on cardiac stem cells myocytes and fibroblasts. Myocyte and fibroblast expression of SDF1 and CXCR4 are proposed to serve a similar function for cardiac stem cell maintenance and protection (niche formation) as stromal and osteoblasts do in the bone marrow. The effectiveness of this system in protecting and maintaining the myocardium with stress or injury is limited due to attenuated SDF1-CXCR4 signaling by desensitization of SDF1-CXCR4 signaling. We propose this effectiveness may be increased by increasing the number of receptors and/or limiting desensitization of SDF1- CXCR4 signaling. The following Aims seek to further define the role of the SDF1-CXCR4 axis in cardiac homeostasis and regeneration and to determine how CSC function in cardiac regeneration can be enhanced through optimization of CXCR4 signaling as a cell based therapy in cardiac injury. Aim 1: To determine the role that cardiac SDF1-CXCR4 plays in maintaining cardiac homeostasis in myocyte myofibroblast and cardiac stem cells. Aim 2: To determine how desensitization/downregulation of SDF1-CXCR4 signaling limits the functionality of cardiac stem cells. Aim 3: To determine whether increasing signaling and signaling efficacy through the SDF1-CXCR4 axis in cardiac stem cells facilitates increased regenerative capacity by administration early and late after MI and IR injury. Aim 4: To determine whether SDF1-CXCR4 synergizes with HGF-cMET and IGF1-IGFR signaling systems to increase functions critical to stem cell engraftment and repair of functional myocardium. The seminal finding that the heart contains a population of stem cells that can contribute to repair of the injured heart has provided new hope for a cell based therapy for cardiac repair. The research described in this proposal will advance our understanding of and provide mechanistic insight into inherent cardiac systems that regulate the function of cardiac stem cells and their relationship with cardiac muscle and supporting cells. Results from these mechanistic studies will provide the impetus to design novels strategies to overcome inherent limitations of cardiac stem cell participation in cardiac regeneration after cardiac injury or with disease.

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


application_id: 7914207
project_number: 5R21NS066250-02
project_title: Targeted DNA Nanoparticles in Brain
administering_ic: NINDS
award_notice_date: 2010-08-11
opportunity_number: PA-08-053
application_type: 5
activity_code: R21
ic: NS
serial_number: 066250
program_official: TAGLE, DANILO A
project_start_date: 2009-08-15
project_end_date: 2011-07-31
study_section: Nanotechnology Study Section[NANO]
contact_pi_person_id: 7875446
contact_pi: YUREK, DAVID M.
other_pis: Not Applicable
congressional_district: 06
department: NEUROSURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The proposed studies will determine the feasibility of compacting plasmid DNA into "nanoparticles" and using these nanoparticles to deliver their payload into cells of the central nervous system (CNS) as a non-viral gene therapy technique. DNA compacting techniques will be used to form nanoparticles containing condensed DNA plasmids with diameters in the range of 8-12 nanometers. Preliminary data shows that non-targeted DNA nanoparticles (DNPs) can be injected directly into brain and produce long-term transgene expression brain cells primarily in astrocytes. The principle studies will focus on synthesizing DNPs that can be administered intracerebrally or systemically and increase the transfection efficiency in neurons. Recent studies have demonstrated that bioconjugated quantum rods can be targeted to the transferrin receptor (TfR) and traverse the blood-brain barrier (BBB). These particles have an average size and shape that are similar to our DNPs. As these are key determinants in particle transport it is reasonable to postulate that DNPs modified to target the TfR may cross the BBB. In preliminary studies we have succeeded in targeting the DNPs to neurons of the hippocampus in brain slices utilizing a ligand to the serpin enzyme complex receptor (sec-R) C105Y which has been shown to be a novel cell-penetrating peptide; and its receptor sec-R has been identified on neurons. Taken together we hypothesize that unimodal targeting of DNPs to the TfR will enable them to cross the BBB and non-specifically transfect neural cells (neurons and/or glia) while bimodal targeting of DNPs to the TfR and sec-R will enable them to cross the BBB and predominantly transfect neuronal cells. To achieve dopamine neuron specificity we will use plasmid constructs that contain the tyrosine hydroxylase (TH) promoter; TH is the rate limiting enzyme in the biosynthetic pathway for dopamine. The study design in this two year project will focus on 1) the synthesis of targeted DNPs 2) transfection efficiency of targeted DNPs in primary neuronal cultures or cell lines 3) in vivo tracking and transfection efficiency of targeted DNPs using MRI microPET and bioluminescent imaging techniques as well as immunohistochemical and protein analyses 4) toxicity of targeted DNPs in brain and 5) feasibility of repeated administration of DNPs while maintaining safe and stable transgene expression in brain. Successful results in these studies could then be applied to animal models of neurodegenerative disorders and possibly lead to translational studies for the treatment of neurological disorders such as Parkinson's disease.  
  
PUBLIC HEALTH RELEVANCE: The proposed studies will use a novel nanoparticle technology that allows nucleic acids (DNA) to be compacted near their theoretical limit; this technology almost duplicates the compaction efficiency of viruses. We present preliminary data showing proof-of-concept that these nanoparticles can be used as a non-viral gene therapy for transfecting cells in the brain. In the proposed studies we will conjugate moieties to the nanoparticles that will target receptors at the blood-brain barrier (BBB) allowing them to cross from the brain vasculature into the brain tissue. Another conjugated moiety will specifically target a novel rapid uptake mechanism that has been identified on neurons in order to increase the neuronal transfection efficient of the nanoparticles. Successful results from our animal studies could then be translated to human studies using these targeted nanoparticles as a form of non-viral gene therapy to treat various neurological disorders.

project_terms:
Animal Model;Animals;Antibodies;Antibody Formation;Astrocytes;Binding (Molecular Function);Blood - brain barrier anatomy;Brain;Caliber;Cell Culture Techniques;Cell Line;Cells;Complex;DNA;Data;Dopamine;Dose;Drug Formulations;Elements;Enzymes;Gene Expression;Gene Transfer;Hippocampus (Brain);Human;Imaging Techniques;Immune response;Injection of therapeutic agent;Intracarotid;Intravenous;Lead;Ligands;Luciferases;Magnetic Resonance Imaging;Multienzyme Complexes;Neuraxis;Neurodegenerative Disorders;Neuroglia;Neurons;Non-Viral Vector;Nucleic Acids;Parkinson Disease;Pathway interactions;Pattern;Peptides;Plasmids;Process;Production;Promotor (Genetics);Proteins;Protocols documentation;Rattus;Reporter Genes;Research Design;Rods (Retina);Serpins;Shapes;Slice;Specificity;Techniques;Technology;Testing;Tissues;Toxic effect;Transfection;Transferrin Receptor;Translating;Tyrosine 3-Monooxygenase;Virus;base;brain cell;brain tissue;cell type;dopaminergic neuron;experience;immunogenic;immunogenicity;in vivo;nanometer;nanoparticle;nervous system disorder;non-viral gene therapy;novel;particle;plasmid DNA;protein expression;public health relevance;quantum;receptor;therapeutic gene;therapeutic transgene;transgene expression;translational study;uptake

public_health_relevance:
Project NarrativeThe proposed studies will use a novel nanoparticle technology that allows nucleic acids (DNA) to be compactednear their theoretical limit; this technology almost duplicates the compaction efficiency of viruses. We presentpreliminary data showing proof-of-concept that these nanoparticles can be used as a non-viral gene therapy fortransfecting cells in the brain. In the proposed studies we will conjugate moieties to the nanoparticles that willtarget receptors at the blood-brain barrier (BBB) allowing them to cross from the brain vasculature into thebrain tissue. Another conjugated moiety will specifically target a novel rapid uptake mechanism that has beenidentified on neurons in order to increase the neuronal transfection efficient of the nanoparticles. Successfulresults from our animal studies could then be translated to human studies using these targeted nanoparticles as aform of non-viral gene therapy to treat various neurological disorders.


application_id: 7912168
project_number: 3R01NS053905-03S1
project_title: PLP alternative splicing and oligodendrocyte differentiation
administering_ic: NINDS
award_notice_date: 2009-09-30
application_type: 3
activity_code: R01
ic: NS
serial_number: 053905
suffix: S1
program_official: UTZ, URSULA
project_start_date: 2007-01-03
project_end_date: 2012-09-29
study_section: Neurogenesis and Cell Fate Study Section[NCF]
contact_pi_person_id: 1868189
contact_pi: CAMBI, FRANCA
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Functionally diverse proteins are generated by alternative splicing of primary transcripts in differentiating oligodendrocytes. PLP and DM20 are generated through the alternative selection of competing 5' splice sites in exon 3. As PLP becomes the predominant isoform the PLP/DM20 ratio increases in differentiated oligodendrocytes (OL) versus progenitors (OPC). Mutations that alter the ratio of PLP to DM20 cause neurological disorders in humans [Hobson et al. 2006; Hobson et al. 2002]. One of these mutations is a deletion of a G-rich intronic enhancer (ISE) of the PLP 5' site. In the preliminary studies we show that exon 3B contains sequences that regulate the PLP/DM20 ratio. A G-rich sequence (M2) is an enhancer of DM20 5' site while the other exonic sequences enhance the PLP 5' site. Although both are G-rich the ISE and M2 are functionally distinct. A number of hnRNP's bind to the ISE and M2 and some of them are down regulated in OL versus OPC. We hypothesize that M2 enhances the DM20 5' site in OPC while the ISE favors the PLP 5' site in OL as a result of decrease in hnRNP's and changes in the balance of general and cell-specific factors. Other exon 3B sequences favor the PLP 5' site and are both general and cell-specific. In Aim 1 we will characterize the ISE's function within the full context of the PLP gene in the developing nervous system of a novel knockin mouse that carries a deletion of the ISE. The cell-specific and differentiation-dependent function of the ISE will be elucidated in the brain nerves and non-glial tissues. In Aim 2 we will characterize the role of M2 in controlling the PLP/DM20 ratio in oligodendrocytes and non-glial cells by mapping the contribution of the G-sequences and flanking sequences to controlling the PLP/DM20 ratio. The proteins that bind to M2 and to ISE will be identified in biochemical studies and their expression will be examined in OPC and OL. In Aim 3 we will examine enhancers of the PLP 5' site and define their role in general cell-specific and differentiation-dependent regulation of PLP/DM20 ratio. In Aim 4 we will examine the function of hnRNP's in controlling the PLP/DM20 ratio with knock down studies by RNAi. These studies have broad relevance to oligodendrocyte differentiation generation of transcript diversity and alterations of splicing that causes inherited disorders of myelin.

project_terms:
5' Splice Site;Alternative Splicing;Binding (Molecular Function);Biochemical;Brain;Cells;Coupled;Data;Demyelinating Diseases;Disease;Elements;Enhancers;Equilibrium;Exons;Fibroblasts;Future;Generations;Genes;Genetic;Grant;Human;In Vitro;Inborn Genetic Diseases;Inherited;L Cells (Cell Line);Maps;Mus;Mutation;Myelin;Myelin Proteolipid Protein;Nerve;Nervous system structure;Neurodegenerative Disorders;Neuroglia;Nuclear;Oligodendroglia;Patients;Protein Binding;Protein Isoforms;Proteins;RNA Interference;RNA Splicing;Regulation;Regulatory Element;Rest;Role;Scanning;Site;Testing;Tissues;Transcript;Transcriptional Activation;cell injury;in vivo;innovation;knock-down;nervous system disorder;novel;progenitor


application_id: 7912098
project_number: 2R44RR025738-02
project_title: Creation of hyperactive transposons for mutagenesis in rodents
administering_ic: NCRR
award_notice_date: 2010-08-20
opportunity_number: PA-09-080
application_type: 2
activity_code: R44
ic: RR
serial_number: 025738
program_official: O'NEILL, RAYMOND R
project_start_date: 2010-09-01
project_end_date: 2012-09-15
study_section: Special Emphasis Panel[ZRG1 IMST-B (16)]
contact_pi_person_id: 3075176
contact_pi: OSTERTAG, ERIC M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 145182338
duns_number: 145182338
fips: US
organization_id: 10004431
organization_name: TRANSPOSAGEN BIOPHARMACEUTICALS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405071112
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-09-01
budget_end_date: 2011-09-15
project_abstract:
DESCRIPTION (provided by applicant): The rat is a favored model for many types of human disease for which mice are not suitable. As opposed to the mouse rats and humans also share more similarity in their cytochrome P450 genes making the rat a more useful model for toxicology and pharmacology studies. The rat is also a favored model for diabetes arthritis behavioral disorders (including drug addiction) and brain imaging. However until recently generating engineered mutations has been problematic due to the lack of rat stem cell lines capable of contributing to the germ line and the lack of efficient technologies to modify genomic sequences. Transposagen Biopharmaceuticals has pioneered the use of mobile DNA elements (e.g. transposons) to generate insertional mutations in the rat germ line. To date we have over made over 100 insertional mutant lines (referred to as TKOTM Knockout Rat Models). This approach utilizes gene-trap strategies to select for randomly integrated transposons which enable the rapid identification of sequence-tagged mutation sites. In Phase I studies we focused on synthesizing hyperactive transposases from three different families of transposons Sleeping Beauty (SB) piggyBac (PB) and TcBuster (TcB) to increase the efficiency of transposition in the germ line. We report the successful generation of a number of hyperactive transposases in the PB family. In Phase II studies we will generate a rat embryonic stem (rES) cell bank containing over 200000 dual reporter gene-trap insertional mutations; a EGFP reporter system will be used as a polyA trap to maximize the probability of generating insertional mutations in each of the approximately 30000 rat genes and a promoterless tdTomato reporter to screen for lineage-specific gene disruptions. In the long term we intend to use the rES cell bank to generate rat knockout lines in each locus. In Phase II studies we will focus on developing transposon-mediated knockout lines in neural cardiac and endothelial cell lineages using the hyperactive PB transposases created in Phase I studies with the aim of generating a bank of knockout lines that that will be valuable for a wide variety of applications such as toxicology behavioral and cardiovascular research. We will develop high-throughput in vitro differentiation protocols to screen pools of rES cells cultured in 96-well formats. Potential mutations in neural cardiac and endothelial cell lineages will be identified by screening for wells that contain tdTomato positive cells after lineage-specific differentiation protocols. rES cell pools in positive wells will be subcloned and re-screened to identify the individual clone that carries the potential lineage specific mutation. Genomic DNA will be isolated and used as template for splinkerette PCR which is used routinely to amplify sequences that flank DNA insertions. We will determine the genomic sites for each insertion and screen each gene for lineage-specific expression to rule out insertions that affect ubiquitously expressed loci. We will develop two products for academic and pharmaceutical end users. First we will generate chimeric animals from selected rES cell clones by injecting these cells into host blastocysts and segregate away the "irrelevant" mutations by several rounds of backcrosses to generate additional TKOTM Knockout Rat Models for human diseases. Second we will market rES cell clones containing mutations in genes that are beyond our core interests to academic and pharmaceutical end users. Mutant animals sperm isolated from mutant males and mutant rES cells will be distributed by the National Rat Resource and Research Center and shared with the academic community according to NIH policies for sharing model organisms for biomedical research.  
  
PUBLIC HEALTH RELEVANCE: In the application "Creation of hyperactive transposases for mutagenesis in rodents" we are seeking Phase II funding to use the novel transposases we created to generate new models of human disease. We have demonstrated the value of creating transposon-mediated mutations to model human diseases for basic and therapeutic research application. All of our previous models were obtained by random mutagenesis. In this proposal we outline studies that will enable us to identify transposon mediated mutations that will likely affect neural heart or blood vessel function. Such rat models will provide new and valuable tools to develop new therapies in classes of diseases that are particularly prevalent in humans. Thus if successful this project would benefit many goals of public health by making the production of mutations in the rat that model human diseases readily accessible to the research community.

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

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


application_id: 7911662
project_number: 5P20RR020171-07
project_title: Center for Biomedical Research Excellence in the Molecular Basis of Human Disease
administering_ic: NCRR
award_notice_date: 2010-08-16
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
program_official: CANTO, MARIA TERESA
project_start_date: 2004-09-01
project_end_date: 2014-06-30
study_section: ZRR1-RI-B(01)
contact_pi_person_id: 7875201
contact_pi: LOUIS HERSH, LOUIS HERSH LOUIS HERSH
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal builds upon the accomplishments made during the previous funding period and requests continuing support of COBRE the Center of Biomedical Research Excellence in the Molecular Basis of Human Disease. During the four year period this COBRE grant has been active 22 junior faculty from 9 different departments were mentored of which 8 received NIH R01 funding and an additional 4 received Other forms of extramural funding. Participating in the activities of the Center has been an additional 11 faculty 11 postdoctoral/research associates and 9 graduate students. The members of the Center published more than 175 research papers and made 38 presentations at scientific meetings. The Department of Molecular and Cellular Biochemistry in which the COBRE is housed rose from 28th to 12th in NIH rankings in terms of Public Medical Schools and 26th in terms of all Medical Schools during the tenure of the COBRE. This was accomplished by an increase in $5148302 of NIH grant dollars excluding the COBRE funds. The Center for Molecular Medicine was formed in 2007 as a direct consequence of the accomplishments made during the first phase of the COBRE (Aug 2004- July 2009).  
  
In the second phase of this COBRE we propose to establish a nationally and internationally recognized  
research center that will continue to compete effectively for extramural research funding. To accomplish this we propose i) to expand our critical mass of investigators including the mentoring of an additional 5  
promising junior investigators who are studying the molecular basis of human disease. This will include a targeted new recruit to the University. We will enhance the opportunity to translate their research to patients by facilitating interactions with clinical faculty. We will continue with the major focus in cancer diabetes and neurological diseases ii) We will expand and continue to develop our core facilities in Proteomics Chemistry Microscopy Protein characterization and Mouse Genotyping. iii) We will continue to support pilot research projects. This has been a highly effective way to enhance the research of a rather significant number of junior faculty; iv) facilitate the development of a sustainable center through the submission of program project grants and multi-PI grants. We will provide staff resource and pilot funding to enhance these activities.  
  
PUBLIC HEALTH RELEVANCE (provided by applicant): To enhance the competitiveness of junior faculty at the University of Kentucky through the funding of promising junior faculty and providing state-of-the-art research cores.

project_terms:
5'-AMP-activated protein kinase;Appointment;Area;Arts;Award;Binding (Molecular Function);Biochemistry;Biophysics;CSNK2A1 gene;Cells;Centers of Research Excellence;Chemistry;Collaborations;Complement;Core Facility;Data;Development;Diabetes Mellitus;Disease;Electrophoresis Gel Two-Dimensional;Ensure;Equipment;Extramural Activities;Faculty;Family;Fatty Acids;Fee-for-Service Plans;Fluorescence;Funding;Genotype;Goals;Grant;Housing;Image;Individual;Investments;Kentucky;Life;Longevity;Malignant Neoplasms;Mass Spectrum Analysis;Medicine;Mentors;Microscopy;Molecular;Molecular Medicine;Mus;Natural Product Drug;Neurodegenerative Disorders;Neuropilins;Nursing Faculty;Organic Synthesis;Paper;Patients;Peptides;Phase;Phosphopeptides;Polymers;Positioning Attribute;Postdoctoral Fellow;Probability;Program Development;Program Research Project Grants;Proteins;Proteomics;Publications;Publishing;Recruitment Activity;Regulation;Research;Research Personnel;Research Project Grants;Research Training;Resources;Roentgen Rays;Role;Rosa;Sampling;Science;Scientist;Security;Services;Signal Transduction;Source;Spottings;Staining method;Stains;Surveys;T-Lymphocyte;Techniques;Technology;Translating;Ultracentrifugation;United States National Institutes of Health;Universities;Wages;Work;analog;base;career;college;design;graduate student;human disease;improved;instrumentation;interest;large scale production;medical schools;meetings;member;mouse model;nervous system disorder;novel;programs;public health relevance;success

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


application_id: 7911520
project_number: 1F32AG037280-01
project_title: Harnessing microglia towards repair vs. damage: Does p38 MAPK hold the reins?
administering_ic: NIA
award_notice_date: 2010-04-15
opportunity_number: PA-09-210
application_type: 1
activity_code: F32
ic: AG
serial_number: 037280
program_official: REFOLO, LORENZO
project_start_date: 2010-04-15
project_end_date: 2012-09-14
study_section: Special Emphasis Panel[ZRG1 F01-L (20)]
contact_pi_person_id: 10095513
contact_pi: BACHSTETTER, ADAM D
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
A primary pathological component of Alzheimer's disease (AD) is brain inflammation. Activation of microglia the "macrophages of the brain" is known to occur in AD and believed to contribute to the neuronal damage. Studies of peripheral macrophages have determined that multiple distinct activation states of macrophages exist and recent studies have confirmed these findings in microglia. Macrophages/microglia can be broadly defined as being classically activated or alternatively activated. Classically activated macrophages are typified by the release of proinflammatory cytokines (e.g. IL-12 TNF-1) and reactive oxygen and nitrogen species which are components of the inflammatory response that is known to cause neuronal damage. However not all forms of microglia activation are detrimental. Some forms of microglia activation are beneficial such as alternative activation responses that lead to removal or clearance of amyloid beta (A2). This proposal will test the hypothesis that the p381 MAP kinase signaling cascade leads to the detrimental forms of microglia activation and that blocking the p381 pathway will decrease the detrimental responses of activated microglia without affecting the beneficial responses. Aim 1 will test the hypothesis that activation of the p381 MAP kinase signaling cascade occurs in microglia during the early phase of pathogenesis in an AD-relevant transgenic mouse model (the Tg6799 mouse). Aim 2 will use a novel brain-penetrant small molecule inhibitor of p381 to test the hypothesis that suppression of p381 activity will slow the pathology in the Tg6799 mouse. This aim will provide training in the use of pharmacological tools transgenic models of neurodegenerative disease and therapeutic target validation. Aim 3 will evaluate the relative contribution of p381 in microglia vs. other neural cell types in the damage produced by A2. To test this aim we will use an A2 infusion AD-relevant model in a mouse with a genetic deletion of p381 only in the microglia. This aim will provide training in the use of conditional knockout mouse models using the cre/lox system and stereotaxic surgery in mice. Successful completion of this project will provide mechanistic insight into how the key regulatory protein p381 is involved in CNS pathophysiology mechanisms and intervention responses and will form the foundation for follow-on CNS therapeutic development campaigns targeting this important protein kinase. A Career Development Plan has been formalized and includes a combination of formal classroom and specialty workshop participation regular presentations of proposed research plans and results at the laboratory and research group level presentation of independent research results in seminar format participation in national and international scientific meetings preparation of research proposals and publications and development of additional career- enhancing skills. An experienced mentor a rich scientific environment and an organized educational and training plan will assure that the applicant has optimal opportunities for scientific growth career enhancement and development into an independent academic investigator.  
  
PUBLIC HEALTH RELEVANCE:   
Neuroinflammation is increasingly being recognized as a contributor to pathology in many neurodegenerative diseases such as Alzheimer's disease a devastating disease of aging with no effective treatment or cure. Successful completion of this project will provide mechanistic insight into how the key regulatory protein p381 MAPK is involved in brain pro-inflammatory responses and CNS dysfunction caused by disease-relevant stressors. In addition the results will delineate the relative importance of microglial p381 MAPK to the disease-relevant pathological responses. Longer term the insights and knowledge generated by the proposed studies will provide a firmer foundation for future development of new classes of disease- modifying therapeutics and fuller interpretation of disease progression investigations.

project_terms:
Affect;Aging;Alzheimer's Disease;Amyloid beta-Protein;Brain;Development;Development Plans;Disease;Disease Progression;Educational workshop;Encephalitis;Environment;Excision;Foundations;Functional disorder;Future;Genetic;Growth;Inflammatory Response;Infusion procedures;Interleukin-12;International;Intervention;Investigation;Knockout Mice;Knowledge;Laboratory Research;Lead;MAP Kinase Gene;MAP Kinase Modules;MAPK14 gene;Mentors;Microglia;Modeling;Mus;Neurodegenerative Disorders;Neurons;Nitrogen;Operative Surgical Procedures;Oxygen;Pathogenesis;Pathology;Pathway interactions;Peripheral;Phase;Preparation;Protein Kinase;Publications;Relative (related person);Research;Research Personnel;Research Proposals;System;Testing;Therapeutic;Training;Transgenic Mice;Transgenic Model;Validation;career;career development;cell type;cytokine;effective therapy;experience;genetic regulatory protein;inhibitor/antagonist;insight;macrophage;medical specialties;meetings;mouse model;neuroinflammation;novel;public health relevance;repaired;response;skills;small molecule;stressor;therapeutic development;therapeutic target;tool

public_health_relevance:
7. Project Narrative Neuroinflammation is increasingly being recognized as a contributor to pathology in manyneurodegenerative diseases such as Alzheimer's disease a devastating disease of aging with no effectivetreatment or cure. Successful completion of this project will provide mechanistic insight into how the keyregulatory protein p38 MAPK is involved in brain pro-inflammatory responses and CNS dysfunction causedby disease-relevant stressors. In addition the results will delineate the relative importance of microglial p38MAPK to the disease-relevant pathological responses. Longer term the insights and knowledge generated bythe proposed studies will provide a firmer foundation for future development of new classes of disease-modifying therapeutics and fuller interpretation of disease progression investigations.


application_id: 7911506
project_number: 1R43HG005799-01
project_title: Generation of Site-Specific Recombinase-Expressing Transgenic Rats using an Enhan
administering_ic: NHGRI
award_notice_date: 2010-09-08
opportunity_number: PA-09-080
application_type: 1
activity_code: R43
ic: HG
serial_number: 005799
program_official: FLETCHER, COLIN F
project_start_date: 2010-09-09
project_end_date: 2011-12-31
study_section: Special Emphasis Panel[ZRG1 IMST-E (15)]
contact_pi_person_id: 3075176
contact_pi: OSTERTAG, ERIC M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 145182338
duns_number: 145182338
fips: US
organization_id: 10004431
organization_name: TRANSPOSAGEN BIOPHARMACEUTICALS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405071112
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-09-09
budget_end_date: 2011-05-31
project_abstract:
DESCRIPTION (provided by applicant):   
The goal is to create site-specific recombinase (SSR)-expressing transgenic rats in an efficient and unbiased manner through a transposon-mediated in vivo gene trap. Rats are very relevant for modeling human biology and disease because rats unlike mice possess key biological similarities to humans. While in vitro gene trap mutagenesis is useful for gene discovery a rapid and efficient in vivo method is preferable for two key reasons: 1) an in vivo gene trap will reveal an authentic spatio-temporal expression pattern and 2) these genetic resources of can then be immediately employed for genome manipulations in the rat. Piecemeal promoter analysis in transgenic animals is clearly not sufficient for rapidly and economically generating effective tools for SSR-mediated tissue-specific genome manipulation. The generation of transgenic rats is simply too expensive and is performed at only a few institutions. Mouse promoter elements could be used to generate SSR-expressing transgenic rats but most promoter elements lack key regulatory sequences are sensitive to position effects at genomic insertion sites or will not necessarily produce identical expression patterns across species. Considering that tens of thousands of transcribed elements likely exist in the mammalian genome an efficient in vivo method is needed to authentically and rapidly recapitulate endogenous expression patterns to generate a diverse and effective set of transgenic tools. Furthermore a method to identify new transcribed elements would accelerate a comprehensive understanding of mammalian genomics.  Gene trap mutagenesis is a standard approach for identifying and exploiting new transcription units but traditional strategies such as those targeting embryonic stem cells are simply untenable for a rapid and efficient in vivo screen. By using a PiggyBac (PB) transposon system that we have enhanced at Transposagen we will pursue an in vivo promoter trap in rats. Promoter traps will be visualized in live embryos and animals using bright fluorescent proteins (FPs). The primary reporter in this promoter trap is a Cre-EGFP fusion protein in which both Cre recombinase activity and EGFP fluorescence marks the expression domain of each trapped element. The Cre-EGFP cassette trap is delivered by a PB transposon that originates as a transgene concatemer in one transgenic line called the "donor." Another transgenic line the "driver" provides expression of the PB transposase in the germ line. Transposon mobilization is simply initiated by interbreeding driver and donor lines such that the PB transposase mobilizes the Cre-EGFP gene trap transposon within germ cells in double transgenic animals designated as "seed" rats. PB is the most efficient transposon yet described for gene mutagenesis in mammalian cells and by using an enhanced PB transposase we expect an insertion rate that should yield at least one gene trap event per gamete. As a result each G1 offspring bred from seed rats will display a unique expression pattern of the Cre-EGFP reporter. Because it is an insertional mutagen the integration site of the PB transposon is easily determined by simple PCR cloning techniques. EGFP fluorescence will be documented in E13.5 and E16.5 embryos and the identification of insertion sites will enable one to link a specific expression pattern with specific genomic locations.  As noted above tools are needed for expanding the genetic resources of the rat. A strategy to accelerate the tools for genetic manipulations in the rat is integral to our approach here. By using a Cre-EGFP reporter we will be creating recombinase-mediated tools for conditional mutagenesis. To monitor Cre activity we will create transgenic rats that express a tdTomato fluorescent protein in cells following a Cre recombination event. The tdTomato protein exhibits very bright fluorescence and has proven useful for in vivo expression analysis. Using the rat ROSA26 promoter that drives ubiquitous expression tdTomato expression will be activated only following Cre-mediated removal of an intervening sequence. These transgenic rats will be mated to the G1 offspring described above that are obtained from seed rats. We will analyze live G2 embryos for EGFP and tdTomato fluorescence. By using these FPs each gene trap can be monitored in real-time; this will create the opportunity for a further in depth analyses in future investigations. We will identify at least 25 unique Cre- expressing elements in this screen in live embryos as a proof of concept.  In addition to tdTomato Cre recombinase activity will also trigger FlpERT2 expression which is linked to the tdTomato open reading frame via an internal ribosomal expression sequence. FlpERT2 activity is dependent on 4-hydroxytamoxifen (4-OHT) and thus provides inducible Flp recombinase activity. Our design enables two key Flp-mediated manipulations: 1) Flp recombinase induction (via 4-OHT) removes the Cre-EGFP gene trap through flanking Flp recombinase target sites and 2) FlpERT2 expression will enable Flp-dependent conditional modification of FRT-containing alleles (generated through other efforts).  The tools and resources generated here will provide great advances for rat genetics. This screen will identify at least 25 transcribed elements exhibiting a unique in vivo expression pattern of Cre-EGFP. Our strategy will provide the opportunity to easily generate hundreds of additional gene trap lines. Our investigation will generate valuable rat transgenic lines for recombinase-mediated conditional mutagenesis in future studies.  
  
PUBLIC HEALTH RELEVANCE:   
This proposal describes a rapid method to discover and harness the power of tissue-specific expression patterns (where genes are turned "on") of a wide variety of genes in the rat genome in live animals. Using a mobile DNA element or "jumping gene" called piggyBac we will tag hundreds of genes in live rat embryos. The unique expression patterns that are revealed will then be exploited as tools for tissue-specific mutagenesis in future studies. The rat is highly suitable for seeking a better understanding of human genetics and biology because the rat in many ways better resembles human pathology physiology neurology and cancer biology than other popular animal models such as the mouse. The results from this study will generate valuable genetic tools for refined and subtle investigations of gene function in specific tissues.

project_terms:
4-Hydroxy-Tamoxifen;Adult;Alkaline Phosphatase;Alleles;Animal Model;Animals;Biological;Biology;Breeding;Cancer Biology;Cells;Chimeric Proteins;Cloning;Communities;DNA Transposons;Development;Disease;Drug Industry;Elements;Embryo;Event;Excision;Exhibits;Fluorescence;Future;Gene Delivery;Generations;Genes;Genetic;Genetic Recombination;Genetic Transcription;Genome;Genomics;Germ Cells;Germ Lines;Germ-Line Mutation;Goals;Human;Human Biology;Human Genetics;Human Pathology;Humulus;In Vitro;Indium;Individual;Inherited;Institution;Introns;Investigation;Jumping Genes;Knock-out;Lead;Life;Link;Location;Mammalian Cell;Mediating;Methods;Modeling;Modification;Monitor;Mus;Mutagenesis;Mutagens;Mutation;Neurology;Open Reading Frames;Organism;Partner in relationship;Pattern;Phase;Physiology;Positioning Attribute;Production;Promotor (Genetics);Proteins;Rattus;Reporter;Resources;Seeds;Site;Sleeping Beauty;Stem cells;System;Techniques;Technology;Time;Tissues;Toxicology;Transgenes;Transgenic Animals;Transgenic Organisms;Transposase;Validation;design;embryonic stem cell;falls;fusion gene;gene discovery;gene function;genetic manipulation;genetic resource;homologous recombination;human disease;in vivo;mammalian genome;mouse model;mutant;offspring;public health relevance;rapid technique;rat genome;recombinase;red fluorescent protein;retroviral transduction;sperm cell;success;tool;transposon/insertion element;vertebrate genome

public_health_relevance:
Project Narrative This proposal describes a rapid method to discover and harness the power of tissue-specific expressionpatterns (where genes are turned "on") of a wide variety of genes in the rat genome in live animals. Using amobile DNA element or "jumping gene" called piggyBac we will tag hundreds of genes in live rat embryos.The unique expression patterns that are revealed will then be exploited as tools for tissue-specific mutagenesisin future studies. The rat is highly suitable for seeking a better understanding of human genetics and biologybecause the rat in many ways better resembles human pathology physiology neurology and cancer biologythan other popular animal models such as the mouse. The results from this study will generate valuablegenetic tools for refined and subtle investigations of gene function in specific tissues.


application_id: 7911355
project_number: 1F31MH089867-01A1
project_title: GABAergic Modulation of Pulvinar Projection Cells
administering_ic: NIMH
award_notice_date: 2010-03-19
opportunity_number: PA-09-208
application_type: 1
activity_code: F31
ic: MH
serial_number: 089867
suffix: A1
program_official: PINARD, COURTNEY ROSE
project_start_date: 2010-04-01
project_end_date: 2012-03-31
study_section: Special Emphasis Panel[ZRG1 F02B-Y (20)]
contact_pi_person_id: 9419270
contact_pi: DAY-BROWN, JONATHAN DAVID
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): The function of the pulvinar nucleus is largely unexplored although it is thought to play a key role in visual attention and visual motion perception. Recently the pulvinar nucleus has gained attention because it has been found to be significantly smaller in schizophrenic brains when compared to controls and studies of patients with restricted lesions of the pulvinar nucleus exhibit some of the same visual deficits experienced by schizophrenic patients. Therefore further study of the pulvinar nucleus could shed light on brain circuits affected by schizophrenia. The proposed experiments focus on the physiological response properties and synaptic organization of the pulvinar nucleus and its projections to the striatum and amygdala with the goal of elucidating how these circuits are modulated by the neurotransmitter gamma amino butyric acid (GABA). Anatomical experiments will determine whether separate cell types project to the striatum and amygdala using tract tracing and confocal microscopy. Immunocytochemistry and electron microscopy will be used to compare the GABAergic innervation of pulvinar neurons that project to the striatum or amygdala and physiological experiments will compare the responses of these two cell types to moving visual stimuli in the presence or absence of the GABA receptor antagonist bicuculline. The proposed studies will use the tree shrew (Tupaia belangeri) which is considered to represent a prototype of early prosimian primates. Therefore our results should be easily related to primate brain organization and could shed light on human disorders such as schizophrenia.  
  
PUBLIC HEALTH RELEVANCE:  Studies of patients with restricted pulvinar lesions have revealed a wide array of visual deficits including the diminished ability to filter distracting signals difficulty in binding image features or difficulty in recognizing facial expressions. Because schizophrenic patients exhibit similar deficits and the pulvinar nucleus of schizophrenic patients has been shown to be smaller than that of control subjects our proposed studies could shed light on potential pulvinar pathways involved in symptoms of this disease.

project_terms:
Affect;Amygdaloid structure;Attention;Bicuculline;Binding (Molecular Function);Brain;Butyric Acids;Cell Nucleus;Cells;Confocal Microscopy;Controlled Study;Corpus striatum structure;Disease;Electron Microscopy;Exhibits;Facial Expression;Goals;Human;Image;Lesion;Light;Motion Perception;Neurons;Neurotransmitters;Pathway interactions;Patients;Physiological;Play;Primates;Property;Prosimii;Pulvinar structure;Role;Schizophrenia;Signal Transduction;Symptoms;Synapses;Tupaia;Tupaiidae;Visual;Visual Motion;Visual attention;cell type;experience;immunocytochemistry;nerve supply;prototype;public health relevance;receptor;research study;response;visual stimulus

public_health_relevance:
Studies of patients with restricted pulvinar lesions have revealed a wide array of visualdeficits including the diminished ability to filter distracting signals difficulty in bindingimage features or difficulty in recognizing facial expressions. Because schizophrenic patientsexhibit similar deficits and the pulvinar nucleus of schizophrenic patients has been shown tobe smaller than that of control subjects our proposed studies could shed light on potentialpulvinar pathways involved in symptoms of this disease.


application_id: 7911294
project_number: 3R01CA034627-23S1
project_title: Pharmacogenetics of drug and carcinogen metabolism
administering_ic: NCI
award_notice_date: 2009-09-25
application_type: 3
activity_code: R01
ic: CA
serial_number: 034627
suffix: S1
program_official: POLAND, ALAN P
project_start_date: 1989-09-01
project_end_date: 2010-12-01
study_section: Chemical Pathology Study Section[CPA]
contact_pi_person_id: 1924912
contact_pi: HEIN, DAVID W
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Genetic susceptibility to breast cancer is determined by an interaction of genes and environment but remains poorly understood. In this revised competing renewal of our investigation into the role of pharmacogenetic polymorphisms in carcinogen metabolism on genetic predisposition to cancer we hypothesize that aromatic amine carcinogens such as 4-aminobiphenyl (ABP) present in tobacco smoke and heterocyclic amine carcinogens such as 2-amino-3-methylimidazo [45-f]pyridine (IQ) present in deep-fried well-done meats are more likely to initiate breast cancer in those individuals with rapid and/or slow acetylator N-acetyltransferase- 1 (NAT1) and - 2 (NAT2) acetylator genotypes. We hypothesize that breast cancer frequency will be higher in tobacco smokers with very slow NAT2 acetylator / rapid NAT1 acetylator genotypes and in individuals who eat deep-fried well-done meats and are rapid for both NAT1 and NAT2 acetylator genotypes. To test this hypothesis we propose to determine the effect of single nucleotide polymorphisms (SNPs) in human NAT1 and NAT2 on ABP and IQ genotoxicity through stable transfection of human NAT1 or NAT2 variant alleles into Chinese hamster ovary cells transfected with human CYP1A1 or CYP1B1; determine the relative level of NAT1 and NAT2 expression in normal human mammary tissue as a function of genotype; construct and characterize rapid and slow acetylator rat strains congenic at the NAT2 locus to determine the frequency of breast tumors in female rapid and slow acetylator congenic rats administered ABP or IQ; determine quantity stability and regulatory effects of ABP or IQ on NAT1- and NAT2-specific mRNA protein and catalytic activity; and determine the metabolism and genotoxicity of ABP and IQ in primary mammary cell cultures derived from rapid and slow acetylator congenic rats. We also will assess the effect of NAT1 and NAT2 genotypes in breast cancer risk through participation in ongoing molecular epidemiology investigations of breast cancer in Shanghai China and in Nashville Tennessee.

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


application_id: 7910954
project_number: 3R01AA015970-05S1
project_title: S-adenosylhomocysteine and S-adenosylmethionine in Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2009-08-31
application_type: 3
activity_code: R01
ic: AA
serial_number: 015970
suffix: S1
program_official: RADAEVA, SVETLANA
project_start_date: 2005-09-30
project_end_date: 2011-06-30
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal will evaluate critical-interactions of cytokines and nutritional/ metabolic abnormalities of the hepatic transmethylation/transsulfuration pathways in the development of ALD using novel human animal and in vitro models with the ultimate goal of developing specific therapy for ALD. Abnormal metabolism of tumor necrosis factor-alpha (TNF) is well documented in both experimental models of ALD and human ALD and TNF plays a critical role in the development of experimental ALD. Abnormal methionine metabolism also is well documented in ALD with patients frequently having elevated plasma methionine concentrations which correlate with prognosis. MAT1 A the enzyme responsible for the initial conversion of methionine to S- adenosylmethionine (SAMe) is decreased in ALD. Depressed SAMe levels are observed in most forms of experimental liver injury including ALD and SAMe therapy is an effective hepatoprotective agent in experimental liver injury. Data from our group show that one potential beneficial effect of SAMe is its ability to inhibit endotoxin stimulated TNF production in monocytes/Kupffer cells. Moreover MAT1A "knockout" mice have recently been generated and these SAMe deficient mice develop spontaneous steatohepatitis and are much more sensitive to a second insult. While SAMe levels are depleted in ALD both S-adenosylhomocysteine (SAH) and homocysteine levels are elevated. The SAMe:SAH ratio and the cellular concentration of SAH critically control most methyltransferase reactions in the body and we recently reported that increased SAH sensitized to TNF induced hepatotoxicity. It is our working hypothesis that increased TNF in conjunction with altered SAMe/SAH metabolism play an etiologic role in the development/progression of liver injury in ALD. The specific objectives of this proposal are to: 1. Document that SAH sensitizes to TNF hepatotoxicity in vitro and in vivo. 2. Evaluate the effects of alcohol/SAH on induction of mitochondrial dysfunction and hepatocyte death. 3. Determine mechanisms whereby SAMe and SAH modulate LPS-stimulated cytokine production. 4. Evaluate beneficial effects of SAMe therapy on critical metabolic functions in patients with alcoholic cirrhosis. These studies utilize state-of-the-art models/techniques in a translational approach to develop an enhanced understanding of mechanisms involved in ALD and potential new therapy for ALD.

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


application_id: 7910405
project_number: 5F31CA142317-02
project_title: Functional conversion of tumor associated macrophages via cytokine therapy
administering_ic: NCI
award_notice_date: 2010-06-30
opportunity_number: PA-07-106
application_type: 5
activity_code: F31
ic: CA
serial_number: 142317
program_official: BINI, ALESSANDRA M
project_start_date: 2009-07-10
project_end_date: 2014-07-09
study_section: Special Emphasis Panel[ZRG1-SBIB-V(29)L]
contact_pi_person_id: 9679618
contact_pi: MITCHELL, COURTNEY JETUN
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Breast cancer is the leading cancer diagnosis in women and second most common cause of women cancer deaths. Although mortality has decreased and incidence has remained steady persons diagnosed with late Stage disease have dismal survival rates. Hence the need for therapies with the ability to prevent cancer altogether. The objective of this project is to determine if IL-12 induced functional conversion of tumor associated macrophages from anti-inflammatory and tumor supportive to pro-immunogenic and anti- tumorigenic can be extended for therapeutic exploitation. The mice 4T1 mammary carcinoma with lung metastases model will be employed to accomplish the objective and achieve the specific aims of this project. Specific aim 1 will examine the immune cells and cytokines that contribute to the maintenance of the IL-12 induced pro-immunogenic functional conversion of the macrophages. Two approaches will be used in this aim. First the IL-12 response of scid mice which are T and B cell deficient will be compared with NK depleted scid mice. Secondly the role of IL-18 and IFN-y in the maintenance of the IL-12 induced conversion will be assessed by neutralizing these cytokines with anti-IFN-y or anti-IL-18. In specific aim 2 the ability of IL-15 and IL-18 to extend the pro-immunogenic status of tumor associated macrophages will be examined by injecting mice bearing 4T1 tumors with the encapsulated IL-12 alone and then injecting the mice subcutaneously with encapsulated IL-15 or IL-18 one to four days later. Specific aim 3 will determine if the extension of the IL-12 induced pro-immunogenic window enhances the efficacy of a tumor-dendritic cell vaccine via immunization of 4T1 bearing mice with a 4T1-dendritic cell fusion vaccine in combination with encapsulated buffer or encapsulated IL-12 alone or in combination with other cytokines as determined by specific aim 2. Analysis for each of our aims will include q-rt-PCR for various anti-inflammatory and tumor supportive as well as pro-immunogenic and anti-tumorigenc factors ELISA for serum IFN-gamma measurement of cytoplasmic levels of IFN-gamma perforin and granzyme B perfusion assisted weight and volume measurements for the primary tumor perfusion assisted quantification of lung metastases and anti- IFN-gamma and CD71 labeling for measurement of number of infiltrating leukocytes. By exploring the effects of IL-12 on tumor associated macrophages we may gain a better understanding of how cytokines and macrophages interact for tumor maintenance and progression.   
PUBLIC HEALTH RELEVANCE: This project will benefit public health by providing new information regarding potential cancer immunotherapy including including preventative vaccines for breast cancer.

project_terms:
Anti-Inflammatory Agents;Anti-inflammatory;B-Lymphocytes;Breast Carcinoma;Buffers;Cell fusion;Cells;Cessation of life;Dendritic Cell Vaccine;Dendritic Cells;Diagnosis;Disease;Encapsulated;Enzyme-Linked Immunosorbent Assay;Immune;Immunization;Incidence;Interferon Type II;Interleukin-12;Interleukin-15;Interleukin-18;Label;Leukocytes;Lung;Maintenance;Malignant Neoplasms;Measurement;Modeling;Mortality Vital Statistics;Mus;Neoplasm Metastasis;Perfusion;Persons;Primary Neoplasm;Role;Serum;Staging;Survival Rate;TFRC gene;Therapeutic;Vaccines;Weight;Woman;breast cancer vaccine;cancer diagnosis;cancer immunotherapy;cytokine;cytokine therapy;granzyme B;immunogenic;macrophage;malignant breast neoplasm;perforin;prevent;public health medicine (field);public health relevance;response;tumor;tumorigenic


application_id: 7910149
project_number: 1R43HD065383-01
project_title: Concurrent Upper/Lower Extremity SCI Exercise with Stimulation
administering_ic: NICHD
award_notice_date: 2010-04-20
opportunity_number: PA-09-080
application_type: 1
activity_code: R43
ic: HD
serial_number: 065383
program_official: SHINOWARA, NANCY
project_start_date: 2010-05-01
project_end_date: 2011-11-30
study_section: Special Emphasis Panel[ZRG1 MOSS-F (15)]
contact_pi_person_id: 9714880
contact_pi: BARNETT, LEE
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 129360637
duns_number: 129360637
fips: US
organization_id: 4168101
organization_name: CUSTOMKYNETICS, INC.
organization_city: NICHOLASVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403401290
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-05-01
budget_end_date: 2011-11-30
project_abstract:
DESCRIPTION (provided by applicant): This proposal will develop a FES-augmented recumbent stepper that elicits lower extremity involvement through electrical stimulation while upper extremity involvement is volitionally controlled by the client. Exercise for people with spinal cord injury not only enhances physical fitness but has the potential to slow or reverse many of the secondary complications of SCI such as diabetes cardiovascular disease respiratory complications pressure sores and osteoporosis. Currently available SCI exercises however are generally targeted at the lower extremities and provide no opportunity for a concurrent lower and upper extremity exercise. In order to address this SCI exercise limitation we propose to augment a NuStep TRS4000 a recumbent cross trainer that provides a coupled reciprocal leg/arm extension exercise movement with functional electrical stimulation (FES). The FES component will exercise the lower extremity musculature at a comparable intensity to the client's volitional upper extremity input such that an enhanced cardiorespiratory exercise opportunity is provided to the patient compared to other SCI exercise opportunities. We hypothesize that the FES component may improve both efficacy and availability of TRS4000 exercise for a significant percentage of potential users. We anticipate that successful implementation would lead to a viable commercial product which would meet a clinically relevant need and build upon existing clinical acceptance of the NuStep device. The goals of this Phase I project are: 1) to modify and instrument a NuStep TRS4000 for FES-exercise following complete paraplegia due to SCI; 2) to develop KaiSTIM autonomous stimulation control algorithms for recumbent stepping via FES; 3) to demonstrate feasibility of FES-augmented TRS4000 exercise following SCI through a pilot study that will be performed in the Neuromotor Rehabilitation Research Laboratory at the Miami Project to Cure Paralysis (Miami FL) under the direction of Edelle Field-Fote PhD PT. The feasibility study will include recruitment of five (5) subjects with complete paraplegia due to spinal cord injury who will each participate in three (3) sessions of FES-augmented NuStep exercise. Feasibility will be defined as the ability for the stimulation control algorithms to develop client-specific stimulation patterns to generate lower extremity contributions in synchronization with volitional upper extremity involvement across subjects and visits without the intervention of therapists or research engineers. The target market for the device will be rehabilitation clinics that provide care to individuals with complete paraplegia due to spinal cord injury and direct sales to clients for continuing exercise at home. customKYnetics Inc. will seek a Strategic Alliance partnership with NuStep Inc. for manufacturing marketing sales and distribution of the FES-augmented TRS4000 with the goal of achieving a price point of $5000.  
  
PUBLIC HEALTH RELEVANCE: The proposed work may benefit health through development of an electrical stimulation augmented recumbent stepping device (TRS4000; NuStep Inc.) indicated for exercise following spinal cord injury (11000 cases per year). Compared to the stand-alone NuStep device the electrical stimulation component may improve efficacy of the exercise for users with limited or no volitional control and may improve availability of the exercise for individuals with insufficient volitional control to otherwise participate.

project_terms:
Address;Algorithms;Bilateral;Cardiovascular Diseases;Cardiovascular system;Caring;Client;Clinic;Clinical;Coupled;Custom;Decubitus ulcer;Development;Devices;Diabetes Mellitus;Doctor of Philosophy;Electric Stimulation;Engineering;Ergometry;Exercise;Feasibility Studies;Goals;Health Benefit;Home environment;Hormonal;Individual;Institution;Intervention;Laboratories;Lead;Leg;Life Style;Limb structure;Lower Extremity;Marketing;Movement;Muscle;Orthopedics;Osteoporosis;Paralysed;Paraplegia;Patients;Pattern;Phase;Physical Fitness;Pilot Projects;Preparation;Price;Quadriceps Muscle of the Thigh;Recruitment Activity;Rehabilitation Research;Rehabilitation therapy;Research;Role;Safety;Sales;Small Business Innovation Research Grant;Spinal cord injury;Upper Extremity;Visit;Work;arm;clinically relevant;hamstring;improved;instrument;meetings;muscle strength;programs;prototype;public health relevance;respiratory;sedentary;tool

public_health_relevance:
Project Narrative / RelevanceConcurrent Upper/Lower Extremity SCI Exercise with Stimulation Applicant Institution: customKYnetics Inc. (PI: Barnett Lee G.)The proposed work may benefit health through development of an electrical stimulation augmentedrecumbent stepping device (TRS4000; NuStep Inc.) indicated for exercise following spinal cord injury(11000 cases per year). Compared to the stand-alone NuStep device the electrical stimulationcomponent may improve efficacy of the exercise for users with limited or no volitional control and mayimprove availability of the exercise for individuals with insufficient volitional control to otherwiseparticipate.


application_id: 7909568
project_number: 3R01CA118434-02S1
project_title: Biochemical Mechanisms of Se Anticancer Activity in Lung
administering_ic: NCI
award_notice_date: 2009-08-28
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: CA
serial_number: 118434
suffix: S1
program_official: PERLOFF, MARJORIE
project_start_date: 2008-09-01
project_end_date: 2011-07-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 7213583
contact_pi: FAN, TERESA WHEI-MEI
other_pis: Not Applicable
congressional_district: 03
department: CHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):     The nutritionally essential element Se is also chemopreventive against prostate lung and several other leading human cancers when administered at supranutritional levels. The complex biochemical mechanism(s) underlying the anticancer action of Se compounds are not understood but they depend on Se metabolism in conjunction with multiple steps of redox regulation and antioxidation. Previously impractical such complexity can now be explored by combining the power of new molecular profiling tools. With metabolomics-edited transcriptomic analysis (META) to guide targeted proteomics we have recently discovered key changes in metabolic and regulatory pathways in Se-exposed lung cancer cells that control cell growth and migration. These preliminary results led to our current hypothesis: (a) the primary site(s) of Se action involve covalent modification(s) of key redox-sensitive proteins including thioredoxin reductase (TrxR) and NF:B; (b) their resultant dysfunctions lead to cell death and anti-metastasis. Here we propose to expand the approach to human Small Cell Lung Cancer cells with different metastatic potential for in vivo validation in a RAG1 null mice model. Our specific aims are: Aim 1: To define and correlate the biochemical pathway profiles with phenotypic changes of selected human lung cancer cell lines in response to treatments of different Se forms. The metabolomics data will be used to discern metabolic pathways related to growth apoptosis and metastatic potential (motility chemotaxis and adhesion); Aim 2: To acquire global and focused gene expression profiles of the treated cells for correlation to the metabolic profiles obtained from Aim 1. Using META gene expression profiles will be prioritized based on actual metabolic changes from Aim 1 to reveal Se action on regulatory pathways and key target proteins; Aim 3: To verify key working hypotheses in cell systems using a combination of immunochemical and proteomics analyses. [Potential key protein targets TrxR NF:B and IKK2] will be verified by relating their function to the modification state; Aim 4: To validate in vivo Se action on lung cancer cell metastasis in a RAG null mouse model. Emphasis will be on metastasis involving the chemokine SDF-1 and its receptor CXCR4 which is regulated by the NF:B-TrxR pathway. Altered metastasis and molecular signature of target mice tissues and blood in response to Se treatments will be related to the cell-based molecular signatures from Aims 1-3 for in vivo validation and for connection to ongoing human patient studies. This work is expected to accelerate the development of mechanistic biomarkers for lung cancer chemoprevention tumor diagnostics and anticancer efficacy. PUBLIC HEALTH RELEVANCE The nutritionally essential element Selenium (Se) has been shown to have anti-cancer properties against prostate lung and other cancers at supranutritional levels. The exact nature of this activity is presently unknown but is related to the metabolism of selenium and how it reduces the ability of cancer cells to survive oxidative damages generated by their overactive metabolism. Here we propose to use state-of-the-science "metabolomic" plus other "'omics" tools to determine the biochemical basis of Se action in lung cancers using cell cultures and mouse models. This work is expected to accelerate the development of more sensitive diagnostics for lung cancer chemoprevention tumor detection and anticancer treatment.

project_terms:
Adhesions;Anabolism;Antineoplastic Agents;Apoptosis;Biochemical;Biochemical Pathway;Biochemistry;Biological Availability;Blood;Bone Marrow;CXCR4 Receptors;CXCR4 gene;Cancer cell line;Cell Culture Techniques;Cell Cycle Arrest;Cell Death;Cell Proliferation;Cells;Chemicals;Chemopreventive Agent;Chemotaxis;Citric Acid Cycle;Clinical Trials;Complex;Data;Dependence;Detection;Development;Diagnostic;Dietary Supplements;Drug Formulations;Elements;Figs - dietary;Functional disorder;G-Protein-Coupled Receptors;Gene Expression;Gene Expression Profiling;Glycolysis;Growth;Histocompatibility Testing;Human;Knockout Mice;Laboratories;Lead;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Metabolic;Metabolic Pathway;Metabolism;Modification;Molecular;Molecular Profiling;Mus;Nature;Neoplasm Metastasis;Organ;Oxidation-Reduction;Pathway interactions;Patients;Pattern;Pentosephosphate Pathway;Plasma;Play;Polyamines;Post-Translational Protein Processing;Process;Property;Prostate;Proteins;Proteomics;Regulation;Regulatory Pathway;Research;Role;Science;Selenium;Selenium Compounds;Selenomethionine;Site;System;Testing;Tissues;Trace Elements;Validation;Work;anticancer activity;anticancer treatment;base;biomarker;cancer cell;cancer chemoprevention;cancer prevention;cell growth;cell motility;chemokine;immunodeficient mouse model;in vivo;lipid metabolism;lung small cell carcinoma;lymph nodes;metabolomics;methylselenic acid;migration;mouse model;neoplastic cell;nucleotide metabolism;oxidative damage;protein expression;public health relevance;response;thioredoxin reductase;tool;transcriptomics;tumor;urea cycle


application_id: 7909460
project_number: 1R43GM093411-01
project_title: Enhancing mammalian glycoprotein production in the baculovirus expression vector
administering_ic: NIGMS
award_notice_date: 2010-04-26
opportunity_number: PA-09-080
application_type: 1
activity_code: R43
ic: GM
serial_number: 093411
program_official: MARINO, PAMELA
project_start_date: 2010-05-01
project_end_date: 2011-10-31
study_section: Special Emphasis Panel[ZRG1 IMST-B (16)]
contact_pi_person_id: 9710810
contact_pi: FATH-GOODIN, ANGELIKA
other_pis: JARVIS, DONALD L.
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The baculovirus expression vector system (BEVS) is a proven powerful and versatile method of eukaryotic protein expression. It is used to produce vaccines diagnostics and biologically active proteins for a multitude of research projects. Like all expression systems however BEVS has its disadvantages. One is the fact that expression is short-lived due to virus-induced cell death and lysis. ParaTechs has already commercialized a product that addresses this shortcoming. Cell lines that express a viral ankyrin gene show delayed death and lysis of baculovirus-infected cells thereby significantly enhancing recombinant protein production. This activity referred to as vankyrin-enhanced BEVS (VE-BEVSTM) boosts target protein expression up to 20-fold depending on the protein and method of vankyrin delivery. A second limitation of baculovirus expression is that insect cells lack the ability to produce terminally sialylated complex N-glycans which limits the usefulness of BEVS for the expression of human therapeutic proteins. This proposal addresses that issue and aims to develop new cell lines that produce authentic "humanized" N-glycans in the context of vankyrin-enhanced baculovirus technology. To obtain this goal three different insect cell lines that have been previously engineered to produce mammalian glycosylation enzymes will be co-infected with baculoviruses that encode a vankyrin gene and different test glycoproteins. The transgenic cell line with the highest vankyrin response will be transformed with two different vankyrin genes under the control of several promoters. Polyclonal cells will be screened for enhanced glycoprotein expression and the most promising cell population will be cloned. Different monoclonal lines will be tested for production of complex terminally sialylated glycoproteins as compared to the non-transformed parental line. These cells will provide the highest yields of accurately processed secreted and transmembrane proteins and will be marketed to individual researchers and pharmaceutical companies engaged in structure-function studies of the human secretome and development of protein therapeutics. These Phase I studies will significantly expand the applications of ParaTechs' vankyrin- enhanced BEVS technology. ParaTechs personnel and the Jarvis group have experience with all of the techniques to be used in these studies and do not anticipate difficulty achieving the objectives. The data derived from funding of this Phase I proposal will position ParaTechs to initiate Phase II studies to demonstrate the utility of these cell lines for production of transmembrane and secreted proteins in collaboration with potential end users.  
  
PUBLIC HEALTH RELEVANCE: The inability of insect cells to produce terminally sialylated complex N-glycans limits the usefulness of baculovirus expression system for the production of human therapeutic proteins. This proposal addresses that deficiency and aims to develop new cell lines that produce authentic "humanized" N-glycans in the context of ParaTechs vankyrin-enhanced baculovirus technology. Successful completion of these objectives will produce cells that provide the highest levels of accurately processed secreted and transmembrane proteins and will be marketed to individual researchers and pharmaceutical companies engaged in structure-function studies of the human secretome and development of protein therapeutics.

project_terms:
Address;Ankyrins;Baculovirus Expression System;Baculoviruses;Cell Death;Cell Line;Cells;Cessation of life;Collaborations;Complex;Cytolysis;Data;Development;Diagnostic;Disadvantaged;Engineering;Enzymes;Funding;Gene Expression;Genes;Glycoproteins;Goals;Human;Human Resources;Individual;Infection;Insecta;Insecticides;Integral Membrane Protein;Life;Marketing;Methods;Pharmacologic Substance;Phase;Polysaccharides;Population;Positioning Attribute;Process;Production;Promotor (Genetics);Proteins;Recombinant Proteins;Research Personnel;Research Project Grants;Staging;Structure;System;Techniques;Technology;Testing;Therapeutic Human Experimentation;Transgenic Organisms;Vaccines;Viral;Virus;Virus Diseases;cost;experience;expression vector;glycosylation;glycosyltransferase;phase 1 study;phase 2 study;protein expression;public health relevance;response;therapeutic protein

public_health_relevance:
Project NarrativeThe inability of insect cells to produce terminally sialylated complex N-glycans limits theusefulness of baculovirus expression system for the production of human therapeutic proteins.This proposal addresses that deficiency and aims to develop new cell lines that produceauthentic "humanized" N-glycans in the context of ParaTechs vankyrin-enhanced baculovirustechnology. Successful completion of these objectives will produce cells that provide the highestlevels of accurately processed secreted and transmembrane proteins and will be marketed toindividual researchers and pharmaceutical companies engaged in structure-function studies ofthe human secretome and development of protein therapeutics.


application_id: 7909318
project_number: 2R56CA116428-05
project_title: Targeting of 6-Phosphofructo-2 kinase in Cancer
administering_ic: NCI
award_notice_date: 2009-09-02
opportunity_number: PA-07-070
application_type: 2
activity_code: R56
ic: CA
serial_number: 116428
program_official: FORRY, SUZANNE L
project_start_date: 2005-08-19
project_end_date: 2011-01-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 1923745
contact_pi: CHESNEY, JASON A.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Positron emission tomography with 2-[18F]-fluoro-2-deoxy-glucose studies have demonstrated that
tumors take up 10-fold more glucose than adjacent normal tissues in humans. Over-expression of HIF-1&#945;
activation of Ras and loss of p53 tumor suppressor function are associated with the development of human
cancers and each of these genetic alterations converge on glycolysis by activating the 6-phosphofructo-2-
kinase/fructose-26-bisphosphatases (PFKFB). The PFKFB enzymes interconvert fructose-6-phosphate (F6P)
and fructose-26-bisphosphate (F26BP)  F26BP is an allosteric activator of 6-phosphofructo-1-kinase
(PFK1) a rate-limiting enzyme and essential control point in the glycolytic pathway. There are four PFKFB
isozymes which are encoded by separate genes (PFKFB1-4) and characterized by distinct kinase:phosphatase
activity ratios. PFKFB3 and PFKFB4 are of particular interest since these isozymes have been found to be
activated in human cancer cell lines and tumors and to be increased by hypoxic exposure via HIF-1&#945;. We
recently discovered a small molecular inhibitor of PFKFB3 and PFKFB4 3-(3-pyridinyl)-1-(4-pyridinyl)-2-
propen-1-one (termed 3PO) that inhibits the growth of xenograft and oncogene transgenic tumors in mice. In
preliminary studies we examined the cellular localization of the PFKFB3 and PFKFB4 enzymes in several
transformed cells and were surprised to find that whereas PFKFB4 localized to the cytoplasm (the site of
glycolysis) PFKFB3 localized to the nucleus. We over-expressed PFKFB3 in HeLa cells and observed no
change in glucose uptake but rather an increase in cell proliferation as well as the expression of several cell
cycle regulators including cyclin dependent kinase (Cdk) 1 Cdc25C and Cyclin D3. Cdk1 and Cdk2 are
essential mammalian cell cycle regulators that promote cell cycle progression in part by phosphorylating cell
cycle suppressor proteins including p27 and Rb. We found that the purified F26BP allosterically activated
recombinant Cdk1 and Cdk2 activity using p27 or Rb as phosphorylation targets in vitro. We also found that
compound 3PO caused a decrease in glycolysis Cdk substrate phosphorylation and a G2/M arrest in HeLa
cells. We thus postulate that 3PO and its derivatives may have a dual mechanism of action that enables their
selective growth inhibitory properties: (i) inhibition of nuclear PFKFB3 which suppresses Cdk activity and G2/M
cell cycle progression; and (ii) inhibition of cytoplasmic PFKFB4 which suppresses glycolytic flux at PFK1. We
propose to test this hypothesis by conducting the following three specific aims: 1. To determine the effects of
over-expression of PFKFB3 PFKFB4 combined PFKFB3/4 or Cdk1 on the inhibitory effects of compound 3PO
on glycolysis Cdk activity and growth; 2. To determine the effect of increased Cdk activity on the anti-tumor
effects of compound 3PO in vivo; 3. To determine the effects of cre-mediated single or dual PFKFB3/PFKFB4
genomic deletion on the glucose uptake Cdk activity and growth of tumors in vivo.

project_terms:
6-Phosphofructokinase;Actins;Agar;Anchorage-Independent Growth;Antigens;Apoptosis;Binding (Molecular Function);Breast;CDC2 Protein Kinase;CDC25A gene;Cancer Cell Growth;Cancer cell line;Cell Cycle;Cell Cycle Progression;Cell Cycle Regulation;Cell Nucleus;Cell Proliferation;Cell Survival;Critical Pathways;Cyclin-Dependent Kinases;Cytoplasm;Cytostatics;Drug Delivery Systems;Drug or chemical Tissue Distribution;Ectopic Expression;Enzymes;Epithelial;Epithelial Cells;Exons;Family;Freezing;Fructose;G2/M Arrest;Genes;Genomics;Glucose;Glycolysis;Glycolysis Pathway;Goals;Growth;Hela Cells;Human;Human Development;Hypoxia;In Situ;In Situ Nick-End Labeling;In Vitro;Individual;Injection of therapeutic agent;Isoenzymes;Knockout Mice;Lung;M cell;Malignant Neoplasms;Mammalian Cell;Mammary Neoplasms;Mammary gland;Mediating;Metabolic;Metabolism;Modeling;Molecular;Molecular Target;Mus;Mutation;Neoplasms;Normal Cell;Normal tissue morphology;Nuclear;Nude Mice;Oncogenes;Open Reading Frames;Pathway interactions;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Positron-Emission Tomography;Promotor (Genetics);Property;Protein Array Analysis;Protein p53;Proteins;Recombinants;Regulation;Relative (related person);Research;Resistance;Roentgen Rays;Role;Site;Small Interfering RNA;Structure;Subfamily lentivirinae;Tamoxifen;Telomerase;Testing;Tissues;Toxic effect;Transfection;Transgenic Mice;Transgenic Organisms;Xenograft procedure;cell growth;cell transformation;cellular transduction;cyclin D3;cyclin-dependent kinase inhibitor 1B;fructose-6-phosphate;glucose uptake;in vivo;inhibitor/antagonist;interest;mouse model;mutant;neoplastic;recombinase;small molecule;sugar;tumor;tumor growth;tumorigenesis;vector;viral cyclin

public_health_relevance:
We have identified a compound called 3PO that selectively inhibits the enzyme 6-phoshofructo-2-
kinase and reduces the growth of tumors in mice. In recent studies we found that 3PO inhibits sugar
metabolism as well as the activity of a family of enzymes that regulate cell growth called cyclin dependent
kinases. We now propose to confirm the precise mechanism(s) of action of 3PO in order to better understand
how this compound inhibits tumor growth.


application_id: 7909261
project_number: 3R01CA060872-12S1
project_title: Mechanism of Apoptosis and Inhibition of Tumor Progression and Metastasis by Par-
administering_ic: NCI
award_notice_date: 2009-08-27
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: CA
serial_number: 060872
suffix: S1
program_official: SPALHOLZ, BARBARA A
project_start_date: 2009-08-01
project_end_date: 2011-07-31
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 1883986
contact_pi: RANGNEKAR, VIVEK M
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Prostate apoptosis response-4 protein (Par-4; also known as PAWR) is a leucine zipper domain protein that is conserved in vertebrates. During the previous funding period we showed the core effector domain of Par-4 (amino acids 137-195 designated the SAC domain) is necessary and sufficient to induce apoptosis. Interestingly both Par-4 and its SAC domain induce apoptosis selectively in cancer cells but not in normal cells. Although ectopic Par-4 and the SAC domain have long been thought to effect apoptosis by acting within the cell nucleus to inhibit NF-kappaB our recent transient transfection studies unexpectedly displayed apoptosis in neighboring cells that did not express the Par-4 or SAC plasmid. Moreover conditioned medium (CM) from Par-4 transfected cells induced apoptosis when applied to cancer cells but not to normal cells; this implies over-expression of Par-4 leads to the secretion of a pro-apoptotic activity. Both Par-4 and the SAC protein were detected in the CM by Western blot analysis and the apoptotic activity in this CM was neutralized by antibodies against Par-4. The apoptotic activity was diminished in the CM from Par-4 transfectants treated with brefeldin A indicating Par-4 and SAC secretion (or sPar-4 and sSAC respectively) occurs by the classical pathway (i.e. from the endoplasmic reticulum to the Golgi and then to the cell membrane). Importantly CM from normal and cancer cells contains endogenous Par-4 of which the levels increase upon treatment with TRAIL (a short term exposure that is insufficient to produce apoptosis) thereby indicating secretion is physiologically relevant and not an artifact associated with over-expression of the Par-4 and SAC constructs. Based on these data we hypothesize endogenous and exogenous sPar-4 and sSAC exert cancer-specific apoptotic effects via both intracellular and extracellular mechanisms. We will address this hypothesis from a mechanistic perspective characterizing secreted Par-4 and SAC in prostate cancer cells and clarifying the means by which they selectively initiate apoptosis in cancer cells. Specifically we will 1) Delineate the mechanism of Par-4/SAC secretion and apoptosis by sPar-4/sSac in prostate cancer cells; 2) Test the growth suppressive effects of sPar-4 and sSAC domain in prostate cancer models; and 3) Study the inter-dependence of extracellular and intracellular Par-4 in inducing apoptosis in cancer cells. As our recent studies indicate Par- 4 and its SAC domain are secreted and that recombinant (r) Par-4 or rSAC can induce apoptosis when applied exogenously to cells these data may hold significant clinical relevance. Our results introduce the novel prospect of using sPar-4 or sSAC to induce apoptosis not only in local or superficially confined tumors into which Par-4 or SAC can be readily delivered intratumorally but also to distant metastases by intravenous injection or bone-marrow transplantation which we will explore in this proposal. PUBLIC HEALTH RELEVANCE: Our research focuses on the secreted forms of Par-4 and it core effector domain SAC both of which selectively induce apoptosis in cancer cells. We will study these two proteins from a mechanistic perspective both in vitro and in vivo characterizing secreted Par-4 and SAC in prostate cancer cells and clarifying the means by which they selectively initiate apoptosis in cancer cells. The proposed science will explore the novel prospect of using sPar-4 or sSAC to induce apoptosis not only in local or superficially confined tumors into which Par-4 or SAC can be readily delivered intratumorally but also to distant metastases by intravenous injection or bone-marrow transplantation.

project_terms:
Address;Adenocarcinoma;Amino Acids;Animals;Apoptosis;Apoptotic;Binding (Molecular Function);Bone Marrow Transplantation;Brefeldin A;Cancer Model;Cell Nucleus;Cell Surface Receptors;Cell Survival;Cell membrane;Cells;Cessation of life;Conditioned Culture Media;Control Animal;Cyclic AMP-Dependent Protein Kinases;Data;Dependence;Distant Metastasis;Endoplasmic Reticulum;Exposure to;Frequencies (time pattern);Funding;Golgi Apparatus;Growth;In Vitro;Induction of Apoptosis;Inhibition of Apoptosis;Lesion;Leucine Zippers;Liver;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Morphologic artifacts;Mus;NF-kappa B;Neoplasm Metastasis;Normal Cell;PAWR gene;PAWR protein;Pathway interactions;Phosphorylation;Plasmids;Prostate;Prostatic;Prostatic Intraepithelial Neoplasias;Prostatic Neoplasms;Proteins;RNA Interference;Receptor Signaling;Recombinants;Research;Science;Signal Pathway;Spleen;Stromal Cells;TNFSF10 gene;Tertiary Protein Structure;Testing;Therapeutic;Transfection;Transgenes;Transgenic Animals;Transgenic Mice;Transgenic Organisms;Vertebrates;Western Blotting;base;cancer cell;clinically relevant;extracellular;glucose-regulated proteins;in vivo;inhibitor/antagonist;insight;intravenous injection;neutralizing antibody;novel;offspring;prevent;public health relevance;tumor;tumor growth;tumor progression


application_id: 7909147
project_number: 3R01CA102285-05S1
project_title: Role of MIF in Rb inactivation and Tumorigenesis
administering_ic: NCI
award_notice_date: 2009-08-27
application_type: 3
activity_code: R01
ic: CA
serial_number: 102285
suffix: S1
program_official: AULT, GRACE S
project_start_date: 2009-08-01
project_end_date: 2010-07-31
study_section: Cancer Molecular Pathobiology Study Section[CAMP]
contact_pi_person_id: 7360475
contact_pi: MITCHELL, ROBERT 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: Y
project_abstract:
DESCRIPTION (provided by applicant): Many human cancers require the production of soluble growth factors for tumor initiation promotion and survival. These extracellular factors contribute to and promote most stages of tumor development. For example tumors of the mammary gland are strongly influenced by the activity of epidermal growth factor (EGF) receptor family members. EGF binding to its cognate receptor is thought to contribute to breast cancer cell cycle regulation by activating signaling pathways that facilitate cyclin D1 expression cyclin dependent kinase 4 or 6 (Cdk4t6) activation and ultimately retinoblastoma (Rb) inactivation. While Rb inactivation is critically important for oncogene-induced malignancies the nature of the signals induced by oncogenes to facilitate this are incompletely understood. We recently discovered that the pro-inflammatory cytokine migration inhibitory factor (MIF) is both necessary and sufficient for mitogen and oncogene-induced cyclin D1 transcription Cdk4 activity and Rb inactivation. Moreover our results reveal that MIF is strongly induced by tumor promoting oncogenes and cells from MIF-deficient mice are resistant to oncogene-induced  malignant transformation. Despite these findings more work is needed to investigate in detail the influence mechanism and effectors of MIFs contribution to Rb inactivation malignant growth properties and de novo tumorigenesis. We hypothesize that MIF promotes both normal and neoplastic cell growth by stimulating RhoA GTPase activity that leads to the activation of the canonical MAP kinase pathway and resulting in cyclin D1 transcription and Rb inactivation. To test the fundamentals of our hypothesis and fulfill the stated objectives of this application the following specific aims are proposed: 1) Examine the regulatory and effector requirements for MIF in cyclin D1 transcription focusing on Rho GTPase activated pathways; 2) Test the requirements for MIF in human breast carcinoma Rho activation cyclin D1 expression and Rb inactivation and; 3) Investigate the contribution and functional requirements for MIF in de novo mammary tumorigenesis. This work should contribute to a greater understanding of the physiologic and pathologic importance of soluble growth factors to cell cycle regulation and neoplastic processes and may reveal a novel target for future cancer therapies.

project_terms:
Accounting;Agar;Binding (Molecular Function);Breast Cancer Cell;Breast Carcinoma;Cell Cycle Regulation;Cell Line;Cells;Cyclin D1;Cyclin-Dependent Kinase 4;Cyclins;Data;Development;Diagnostic Neoplasm Staging;Disease;Epidermal Growth Factor;Epidermal Growth Factor Receptor;Epithelial Cells;Family;Family member;Fibroblasts;Future;Genetic Transcription;Growth;Growth Factor;Growth Factor Receptors;Guanosine Triphosphate Phosphohydrolases;Human;Human Mammary Carcinoma;In-Migration;Inflammation Mediators;Inflammatory;Knowledge;Laboratories;Lead;Link;MCF7 cell;Malignant - descriptor;Malignant Epithelial Cell;Malignant Neoplasms;Mammary Neoplasms;Mammary Tumorigenesis;Mammary gland;Mediating;Mesenchymal;Migration Inhibitory Factor;Mitogen-Activated Protein Kinases;Mitogens;Mouse Mammary Tumor Virus;Mus;Mutation;Nature;Neoplasms;Neoplastic Processes;Normal Cell;Oncogenes;Oncogenic;Pathologic;Pathway interactions;Phosphorylation;Physiological;Production;Property;Proto-Oncogenes;Publishing;RNA Interference;Relative (related person);Resistance;Retinoblastoma;Role;Signal Pathway;Signal Transduction;TP53 gene;Testing;Tumor Suppressor Proteins;Tumor stage;Viral Oncogene;Work;Xenograft procedure;autocrine;base;breast tumorigenesis;cancer cell;cancer therapy;cell growth;cell motility;cell transformation;cytokine;extracellular;in vivo;insight;malignant breast neoplasm;mouse model;neoplastic;neoplastic cell;novel;overexpression;paracrine;prognostic indicator;receptor;research study;rho;rho GTP-Binding Proteins;therapeutic target;tumor;tumor growth;tumor initiation;tumorigenesis


application_id: 7908461
project_number: 1R43HL102981-01
project_title: Counterpulsation Device with Integrated ECG Sensing
administering_ic: NHLBI
award_notice_date: 2010-05-28
opportunity_number: PA-09-080
application_type: 1
activity_code: R43
ic: HL
serial_number: 102981
program_official: ADHIKARI, BISHOW B
project_start_date: 2010-06-01
project_end_date: 2010-11-30
study_section: Special Emphasis Panel[ZRG1 CVRS-B (10)]
contact_pi_person_id: 10138960
contact_pi: DOWLING, ROBERT D.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 610420817
duns_number: 610420817
fips: US
organization_id: 10006385
organization_name: SCR, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402022445
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-06-01
budget_end_date: 2010-11-30
project_abstract:
DESCRIPTION (provided by applicant):  Counterpulsation with an intra-aortic balloon pump has been widely and successfully used as a short term treatment for both acute and chronic cardiac dysfunction. SCR (Louisville KY) is developing a novel chronic implantable counterpulsation device (CPD) to treat late stage HF patients. The CPD is a 32-ml stroke volume polyurethane-lined blood chamber designed to fit comfortably in a subcutaneous pocket on the right anterior chest. The blood pumping chamber is connected to the systemic circulation by a short graft anastomosed to the subclavian artery. The CPD is connected to a small wearable pneumatic driver via a percutaneous drive line. The CPD fills with blood during native heart systole lowering ventricular workload and ejects during diastole augmenting myocardial and end-organ perfusion. Previous NIH funding has been received for development of both the blood pumping chamber and the portable driver. The timing of ejection from the pumping chamber was synchronized with EKG signals from epicardial leads which complicated the surgical procedure. To simplify the implant operation SCR has developed prototype CPD with integrated subcutaneous leads that are ready for in vivo testing. The objective of this proposal is to determine if the CPD with integrated EKG leads placed in the subcutaneous position will result in a robust durable signal and allow for ideal timing of device filling and ejection. In Specific Aim 1 standard laparoscopic instruments will be used to place subcutaneous EKG leads. The main goals of this aim are twofold: 1) to demonstrate that we are able to deliver subcutaneous EKG leads and show that they do not migrate 2) to determine which EKG lead configuration results in the best R wave detection. In Specific Aim 2 we will perform full system implants to evaluate the subcutaneous leads in a chronic bovine model. Lead position will be determined in Specific Aim 1. The data from the subcutaneous EKG leads will be used to time device ejection and compared to simultaneous data obtained from epicardial leads. Treadmill exercise testing will be performed to ensure that motion and muscular activity do not interfere with EKG signaling. Strict criteria for determining if the subcutaneous lead configurations are acceptable are outlined. If successful in Phase 2 we will perform long-term GLP animal implants with the integrated system in preparation for a clinical investigational device exemption (IDE) study.    
  
PUBLIC HEALTH RELEVANCE:  SCR Inc. (Louisville KY) is developing a long-term counterpulsation device (CPD) to treat early stage heart failure patients. The CPD has been developed for superficial implantation without the need to enter the chest and a portable pneumatic driver that the patient can carry restores mobility.

project_terms:
Acute;Anastomosis - action;Animals;Anterior;Blood;Blood Circulation;Bypass;Cardiac;Catheters;Cattle;Chest;Chronic;Clinical;Clinical Trials;Computer Simulation;Computer software;Congestive Heart Failure;Counterpulsation;Data;Detection;Development;Devices;Diastole;Electrocardiogram;Ensure;Exercise stress test;Functional disorder;Funding;Goals;Grant;Healthcare;Heart;Heart Transplantation;Heart failure;Implant;Infection;Infraclavicular region structure;Intra-Aortic Balloon Pumping;Ischemia;Lead;Left;Limb structure;Lung;Methods;Modeling;Motion;Muscle;Myocardial;Myocardial perfusion;Operative Surgical Procedures;Organ;Organ Donor;Pacemakers;Patients;Performance;Perfusion;Peripheral;Pharmacotherapy;Phase;Polyurethanes;Positioning Attribute;Preparation;Pump;Quality of life;Resources;Right-On;Safety;Signal Transduction;Small Business Innovation Research Grant;Staging;Sternotomy;Stroke Volume;Structure of subclavian artery;Surgical incisions;System;Systole;Testing;Time;Time Study;United States National Institutes of Health;Vascular Graft;Ventricular;Workload;base;blood pump;cost;design;effective therapy;implantation;in vivo;instrument;interest;novel;operation;outcome forecast;preclinical study;prototype;public health relevance;subcutaneous;ventricular assist device

public_health_relevance:
SCR Inc. (Louisville KY) is developing a long-term counterpulsation device (CPD) to treat early stage heartfailure patients. The CPD has been developed for superficial implantation without the need to enter the chestand a portable pneumatic driver that the patient can carry restores mobility.


application_id: 7908187
project_number: 1R43AG030246-01A2
project_title: Vitamin D Production by Sperti Lamp in Fat Malabsorption Patients
administering_ic: NIA
award_notice_date: 2010-08-24
opportunity_number: PA-09-080
application_type: 1
activity_code: R43
ic: AG
serial_number: 030246
suffix: A2
program_official: JOSEPH, LYNDON
project_start_date: 2010-09-01
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZRG1 ETTN-A (14)]
contact_pi_person_id: 8626436
contact_pi: SHEPHERD, JAMES GAMBLE
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 623909371
duns_number: 623909371
fips: US
organization_id: 10008490
organization_name: KBD, INC.
organization_city: CRESCENT SPRINGS
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 410171548
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-09-01
project_abstract:
DESCRIPTION (provided by applicant): Vitamin D plays a critical role in calcium metabolism and bone health in children and adults. It is now recognized that every tissue and cell in the body have a vitamin D receptor and thus every tissue and cell in the body is a target for vitamin D action. Studies suggest that increased exposure to sunlight and increased vitamin D intake reduces risk of many chronic diseases including autoimmune diseases heart disease infectious diseases type II diabetes and cancer. Vitamin D deficiency and insufficiency is the most common nutritional deficiency and medical condition in children and adults throughout the United States. The major source of vitamin D for children and adults is exposure to sunlight. There is little vitamin D in the diet and thus to maintain a normal healthy vitamin D status requires taking a vitamin D supplement. Patients with malabsorption and children and adults who are infirm and unable to be exposed to any sunlight are at particularly high risk for vitamin D deficiency and its health consequences. Artificial ultraviolet irradiation is also a good source of vitamin D. KBD Inc. is a small business that makes the Sperti vitamin D producing lamp that has been in existence for more than 50 years and marketed for producing vitamin D. The lamp has been modified so that most of the spectral output is in the UVB region thus maximally producing vitamin D. The goal of this grant is to take this newly designed lamp and test its effectiveness in producing vitamin D in patients with inflammatory bowel disease who have been demonstrated to malabsorb vitamin D. Adult IBD patients with skin types 234 and 5 will be exposed to suberythemal dose of UVB radiation from the Sperti fluorescent lamp three times a week for three months. Blood levels of 25-hydroxyvitamin D a measure of vitamin D status will be the primary outcome for the study. Results from this study should provide efficacy data to support the commercial development of this novel vitamin D producing fluorescent lamp not only for patients with malabsorption syndromes but also elderly in nursing homes and for children and adults who cannot be exposed to sunlight and have a difficult time taking a vitamin D supplement.  
  
PUBLIC HEALTH RELEVANCE: The goal of this grant is to obtain data that exposure to a novel Sperti fluorescent vitamin D producing lamp is effective in improving the vitamin D status of patients with inflammatory bowel disease who have documented vitamin D malabsorption. It is anticipated that results from this grant will provide the impetus for the small business KBD Inc. to market and sell its product to patients who suffer from the intestinal malabsorption syndromes and who are vitamin D deficient.

project_terms:
25-hydroxyvitamin D;7-dehydrocholesterol;Adult;American;Autoimmune Diseases;Blood;Bread;Businesses;Calcifediol;Calibration;Cells;Cereals;Child;Cholecalciferol;Chronic Disease;Clinical Trials;Communicable Diseases;Crohn's disease;Dairy Products;Data;Development;Devices;Diet;Dose;Effectiveness;Elderly;Epidemiology;Exposure to;Fatty acid glycerol esters;Food;Fracture;Gastroenterologist;Goals;Grant;Health;Heart Diseases;Hip Fractures;Housing;Human;In Vitro;Inflammatory Bowel Diseases;Intake;Laboratories;Laboratory Study;Lactose Intolerance;Malabsorption Syndromes;Malignant Neoplasms;Malnutrition;Marketing;Measures;Medical;Milk;Modeling;Non-Insulin-Dependent Diabetes Mellitus;Nursing Homes;Outcome Study;Output;Parathyroid Hormones;Patients;Play;Production;Risk;Role;Skin;Source;Standardization;Study Subject;Sun Exposure;Sunlight;Syndrome;Testing;The Sun;Time;Tissues;Ulcerative Colitis;Ultraviolet B Radiation;United States;Vitamin D;Vitamin D Deficiency;Vitamin D3 Receptor;Whipple Disease;Work;bone health;calcium metabolism;cost effective;design;high risk;human PTH protein;improved;middle age;novel;prevent;primary outcome;public health relevance;skeletal;sun protection;ultraviolet irradiation

public_health_relevance:
Project narrativeThe goal of this grant is to obtain data that exposure to a novel Sperti fluorescent vitamin Dproducing lamp is effective in improving the vitamin D status of patients with inflammatory boweldisease who have documented vitamin D malabsorption. It is anticipated that results from thisgrant will provide the impetus for the small business KBD Inc. to market and sell its product topatients who suffer from the intestinal malabsorption syndromes and who are vitamin Ddeficient.


application_id: 7908147
project_number: 3R01CA118114-03S1
project_title: Breast Cancer Chemoprevention Strategies
administering_ic: NCI
award_notice_date: 2009-09-09
application_type: 3
activity_code: R01
ic: CA
serial_number: 118114
suffix: S1
program_official: PERLOFF, MARJORIE
project_start_date: 2009-08-01
project_end_date: 2010-07-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 8240457
contact_pi: GUPTA, RAMESH C
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant):  Epidemiological studies have identified an association of elevated levels of estrogens with breast cancer development. In particular the natural hormone 17(3-estradiol and its catechol metabolites have been implicated in breast cancer development and it is believed that estrogen catechols cause free radical mediated direct and/or indirect DNA damage which may lead to gene mutations and ultimately breast cancer. We have detected several oxidative and other polar DMA adducts in the mammary tissue of rats and in human breast tissues by newly devised 32P-postlabeling/TLC systems. Chromatographic similarity with reference oxidative adducts suggests that tissue DNA adducts originated from free radical-mediation. These results suggest that the adducts may have resulted from redox cycling of 17-3-estradiol metabolites. We hypothesize that combination of chemopreventive agents will provide more effective prevention of breast cancer than individual agents. This will be accomplished by 1) utilizing combination of agents with different modes of action; and 2) by using a novel systemic slow-release device to circumvent toxicity. Our preliminary results by interventions with ellagic acid delivered by systemic slow-release system and diet elicited similar degree of inhibition of 17-3-estradiol-mediated mammary tumorigenesis in the ACI rat model supporting our working hypothesis. A team of experienced investigators will pursue the following specific studies to meet our goals: 1) Determine the efficacy of selected agents to modulate estrogen-metabolism and DNA repair in vivo. 2) Determine the efficacy of candidate agents to diminish 17-3-estradiol-induced cell proliferation in vivo. 3) Determine the efficacy of candidate agents to inhibit 17-3-estradiol-induced mammary tumorigenesis and correlate modulation of estrogen metabolism with tumor indices. 4) Determine if combination of agents delivered by the slow-release device will provide more effective inhibition of mammary tumorigenesis compared with the individual agents. The resulting data will reveal that combination of agents working via different arenas can provide more complete prevention of mammary tumors than individual agents and that the systemic slow-release delivery can circumvent toxicity by significantly reducing the effective dose. The data will also identify pathway(s) that can be targeted for effective prevention of breast cancer and perhaps other hormonal cancers.

project_terms:
17p;Bexarotene;Binding (Molecular Function);Biochemical;Breast Cancer Model;Breast Cancer Prevention;Carcinogens;Catechol Estrogens;Catechols;Cell Proliferation;Cell-Free System;Chemopreventive Agent;Clinical Research;Cytochromes;DNA Adducts;DNA Damage;DNA Repair;Data;Detox;Development;Devices;Diet;Disease;Dose;Ellagic Acid;Enzymes;Epidemiologic Studies;Estradiol;Estrogen Metabolism;Estrogen Receptors;Estrogen Replacement Therapy;Estrogens;Etiology;Exposure to;Female;Free Radicals;Future;Gene Mutation;Genes;Goals;Hormonal;Hormones;Human;Immunohistochemistry;Inbred ACI Rats;Incidence;Individual;Intervention;Lead;Lesion;Malignant Neoplasms;Mammary Gland Parenchyma;Mammary Tumorigenesis;Mammary gland;Measures;Mediating;Mediation;Metabolic;Methods;Modeling;Molecular Profiling;Oxidation-Reduction;Pathway interactions;Performance;Plasma;Proliferation Marker;Property;Proteins;Proteome;Rattus;Relative (related person);Research Personnel;Risk;Risk Factors;Subgroup;System;Testing;Time;Tissues;Toxic effect;Western Blotting;Woman;Work;adduct;base;biomarker;cancer chemoprevention;carcinogenicity;experience;foodborne;high risk;in vivo;indexing;lycopene;malignant breast neoplasm;meetings;novel;oltipraz;prevent;tumor


application_id: 7908142
project_number: 3R21CA127052-02S1
project_title: Coleus forskohlii extract: melanization and UV protection by a natural product
administering_ic: NCI
award_notice_date: 2009-08-31
opportunity_number: PA-06-400
application_type: 3
activity_code: R21
ic: CA
serial_number: 127052
suffix: S1
program_official: UMAR, ASAD
project_start_date: 2009-08-01
project_end_date: 2010-07-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 8508402
contact_pi: D'ORAZIO, JOHN 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
project_abstract:
DESCRIPTION (provided by applicant):     Fairness of skin correlates with diminished epidermal expression of eumelanin the brown/black pigment responsible for dark complexion. Instead there is preferential expression of pheomelanin a sulfated blonde/red melanin species that is soluble and has poor UV-blocking abilities. Persons with high levels of pheomelanin and low levels of eumelanin in the skin have little basal protection from UV radiation and therefore suffer the highest incidence of UV-mediated skin damage and skin cancer. To delineate the relationship between UV exposure and pigmentation and develop novel pigment-based UV protective strategies we have developed a mouse model of "humanized skin" with inducible pigmentation. Like in humans the fair-skinned phenotype in our animal model is caused by defective signaling in melanocytes by the melanocortin-1 receptor (MC1R) a protein that mediates adenylate cyclase activation and cAMP generation when bound by its natural ligand melanocyte stimulating hormone (MSH). Similar to fair- skinned humans who tend to burn rather than tan after sunlight exposure our fair-skinned animals demonstrate heightened UV sensitivity and failure to tan adaptively. Using this novel mouse model we study melanin induction by forskolin a labdane diterpenoid that directly activates adenylate cyclase and promotes intracellular accumulation of cAMP. By topically applying root extract from the C. forskohlii plant (the natural source of forskolin) to the skin we can induce the production of UV-protective eumelanin by chemically circumventing the defective cAMP signaling associated with the mutant MC1R. Using our animal model we will directly modulate cAMP signaling and melanin levels to clarify the protective effects of C. forskohlii extract against UV-mediated skin damage. We hypothesize that pharmacologic up- regulation of cAMP in the skin will protect against UV-mediated damage by promoting eumelanin synthesis and by enhancing the repair of UV-induced DNA photolesions. To address our hypothesis we propose three specific aims: i) Characterize the role of MC1R function in UV-mediated oxidative damage and determine whether pharmacologic replacement of MC1R function protects against oxidative UV injury; ii) Delineate the impact of MC1R function in the repair of UV-induced DNA lesions; and iii) Determine whether molecular bypass of MC1R function by cAMP up-regulation enhances repair following UV exposure. Our goal is to develop the novel approach of UV protection by sunless tanning based on topical administration of this root extract or small molecule derivatives. Our research strategy will provide a substantial foundation on which we can develop UV-protective strategies to prevent rather than treat skin cancer. PUBLIC HEALTH RELEVANCE: Our goals are to (1) understand how UV irradiation damages skin of different pigment types; (2) devise natural pigment-based strategies that protect against UV-mediated skin damage; and (3) effectively prevent skin cancer. Using unique transgenic mice that mimic human skin we will measure DNA damage and repair in UV- exposed skin and explore mitigation of this damage and enhancement of repair. Our proposed research includes both in vivo and in vitro analyses of UV effects in whole skin and in melanocytes derived from our animal model respectively.

project_terms:
Address;Adenylate Cyclase;Affect;Anatomy;Animal Model;Animals;Base Excision Repairs;Binding (Molecular Function);Biological Factors;Biological Models;Biology;Breeding;Burn injury;Bypass;Coleus forskohli;Congenic Animals;Cyclic AMP;DNA;DNA Repair;DNA lesion;Data;Diterpenes;Failure (biologic function);Forskolin;Foundations;Free Radical Formation;Functional disorder;Generations;Genetic Polymorphism;Goals;Human;In Vitro;Incidence;Individual;Injury;Inorganic Sulfates;Investigation;Labdanes;Ligands;Location;Measures;Mediating;Melanins;Melanocyte stimulating hormone;Modeling;Molecular;Mus;Nucleotides;Pathway interactions;Persons;Phenotype;Pigmentation physiologic function;Pigments;Plant Roots;Plants;Production;Proteins;Receptor Signaling;Receptor Melanocortin Type 1;Relative (related person);Reporting;Research;Role;Signal Transduction;Skin;Skin Cancer;Skin tanning;Source;Sun Exposure;System;Testing;The Sun;Thymine Dimers;Topical application;Transgenic Mice;UV Radiation Exposure;UV induced;UV induced DNA damage;UV injury;UV protection;UV sensitive;Ultraviolet Rays;Unspecified or Sulfate Ion Sulfates;Up-Regulation (Physiology);Variant;Wild Type Mouse;alpha-Melanocyte stimulating hormone;base;eumelanin;in vivo;loss of function;melanocyte;melanoma;mimicry;mouse model;mutant;novel;novel strategies;oxidative damage;pheomelanin;photolesion;prevent;protective effect;public health relevance;receptor function;repaired;response;skin cancer prevention;small molecule;ultraviolet damage;ultraviolet irradiation;ultraviolet lesions


application_id: 7907774
project_number: 5R21AG034453-02
project_title: Defining the role of satellite cells in muscle maintenance throughout the lifespa
administering_ic: NIA
award_notice_date: 2010-07-23
opportunity_number: RFA-AG-09-004
application_type: 5
activity_code: R21
ic: AG
serial_number: 034453
program_official: CARRINGTON-LAWRENCE, STACY
project_start_date: 2009-08-15
project_end_date: 2012-07-31
study_section: ZAG1-ZIJ-2(M1)
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE 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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The goal of this proposal is to develop and characterize a novel mouse line which will allow for the conditional genetic labeling of satellite cells in adult skeletal muscle. Satellite cells are the myogenic stem cell of adult skeletal muscle and have been most studied during post-natal growth and during muscle regeneration following injury. Beyond speculation the role of satellite cells in the maintenance of skeletal muscle throughout life has yet to be directly studied due to the difficulty of accurately identifying satellite cells and the inability to stably track their frequency and behavior over time. To overcome this obstacle in Aim 1 we will generate the Pax7-GNZ mouse by crossing the conditional satellite cell-specific driver/inducer mouse line (Pax7-CreER) with a nuclear-localized GFP-lacZ reporter mouse line (Rosa26-GNZ). A major strength of the proposal is that the parental strains required to generate the Pax7-GNZ line already exist. Characterization of the Pax7-GNZ mouse line will entail quantifying the specificity and magnitude to which the reporter gene effectively marks satellite cells. The role of satellite cells in maintaining muscle mass will then be determined by inducing reporter gene expression in 3 month old mice which will be analyzed at later time points throughout the lifespan of the mice. Aim 2 will begin to determine the contribution of satellite cells to the compromised ability of aging muscle to adapt to changes in demand. The Pax7-GNZ mice will be used to quantify satellite cell dynamics with muscle hypertrophy induced by synergist ablation and re-growth following muscle atrophy induced by hindlimb unloading. The Pax7-GNZ mouse line represents a powerful unique genetic tool that will allow for the first time a comprehensive and accurate quantification of satellite cell dynamics in the maintenance of muscle during normal muscle aging as well as during periods of altered demand such as hypertrophy and restoration of mass following atrophy. Furthermore results obtained will serve as the foundation for future studies using a genetic mouse model to examine the impact on muscle plasticity of specifically ablating satellite cells in adult skeletal muscle. These studies will define the function of satellite cells in skeletal muscle plasticity and homeostasis and how it may change with age.  
  
PUBLIC HEALTH RELEVANCE: Almost one-third of the elderly suffer from the debilitating condition of frailty. The cause of geriatric frailty is not known but a contributing factor is sarcopenia the progressive loss of muscle mass with age. Defects in satellite cells the primary stem cell of adult skeletal muscle are thought to play a central role. The goal of this proposal is to develop and characterize a novel mouse model to track satellite cells in aging skeletal muscle with the aim to better understand their role in sarcopenia. The long-term goal of the research project is to develop a therapeutic intervention to prevent sarcopenia and reduce the incidence of frailty in the elderly.

project_terms:
Ablation;Adult;Age;Aging;Apoptosis;Atrophic;Behavior;Cell Count;Data;Defect;Elderly;Foundations;Frequencies (time pattern);Future;Gene Expression;Genetic;Goals;Growth;Hindlimb Suspension;Homeostasis;Hypertrophy;Incidence;Injury;Label;LacZ Genes;Life;Longevity;Maintenance;Modeling;Mus;Muscle;Muscular Atrophy;Nuclear;Phenotype;Play;Reporter;Reporter Genes;Research Project Grants;Role;Skeletal Muscle Satellite Cells;Skeletal muscle structure;Specificity;Therapeutic Intervention;Time;Validation;adult stem cell;frailty;migration;mouse model;muscle aging;muscle form;muscle hypertrophy;muscle regeneration;novel;prevent;public health relevance;restoration;sarcopenia;satellite cell;skeletal muscle plasticity;tool

public_health_relevance:
Project NarrativeAlmost one-third of the elderly suffer from the debilitating condition of frailty. The cause of geriatric frailty is notknown but a contributing factor is sarcopenia the progressive loss of muscle mass with age. Defects insatellite cells the primary stem cell of adult skeletal muscle are thought to play a central role. The goal of thisproposal is to develop and characterize a novel mouse model to track satellite cells in aging skeletal musclewith the aim to better understand their role in sarcopenia. The long-term goal of the research project is todevelop a therapeutic intervention to prevent sarcopenia and reduce the incidence of frailty in the elderly.


application_id: 7907479
project_number: 2R44HL090055-04
project_title: Development of a Personalized Medicine Interface for the Safe and Effective Treat
administering_ic: NHLBI
award_notice_date: 2010-08-19
opportunity_number: PA-09-080
application_type: 2
activity_code: R44
ic: HL
serial_number: 090055
program_official: PUCIE, SUSAN
project_start_date: 2007-08-16
project_end_date: 2013-07-31
study_section: Special Emphasis Panel[ZRG1 IMST-E (15)]
contact_pi_person_id: 8776872
contact_pi: REYNOLDS, KRISTEN KEELING
other_pis: LINDER, MARK W;VALDES, ROLAND
congressional_district: 03
department: Unavailable
primary_duns: 135412190
duns_number: 135412190
fips: US
organization_id: 10011008
organization_name: PHARMACOGENETICS DIAGNOSTIC LABORATORIES
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-09-01
budget_end_date: 2011-07-31
project_abstract:
DESCRIPTION (provided by applicant):   
Improvements in the safety and efficacy of warfarin therapy will result from intelligent application of knowledge derived from inherited characteristics (CYP2C9 and VKORC1) of individual patients only when this knowledge is applied through a standardized interventional approach. The fundamental pharmacologic influences of CYP2C9 and VKORC1 have been unequivocally established and validated by numerous academic reports including those conducted by PGXL and its affiliated thought leaders. There is a clear cause and effect relationship between inherited variation in these enzymes and complications in warfarin management. Delayed metabolic clearance of S-warfarin (CYP2C9) and a lower concentration threshold for response (VKORC1) have a profound effect on the clinical pharmacology of warfarin and defeat the utility of standard dosing and monitoring practices. Current warfarin dosing practices which rely on standardized initiation dosing and INR-based dose adjustments are fundamentally flawed when applied to patients without regard to their unique metabolic and response characteristics. PGXL has developed a personalized medicine interface (PerMIT) which provides interpretive genotype-based guidance to facilitate appropriate clinical practice modifications accommodating patient individuality. PerMIT:Warfarin is the first HIPAA-compliant and secure pharmacogenetics-based interventional methodology for warfarin anticoagulation management. PerMIT:Warfarin applies fundamental pharmacologic influences of inherited patient characteristics to individually tailor warfarin therapy. The mathematical operations that form the basis of PerMIT have been validated for accuracy and PGXL is now prepared for prospective interventional trials. PGXL Laboratories has engaged all of the key external resources necessary to construct a comprehensive strategic framework to gather compelling clinical evidence of improved outcomes and to move PerMIT:Warfarin through the regulatory and commercialization processes. This SBIR Phase II Competitive Renewal application is designed to achieve the regulatory compliance and medical evidentiary standards set forth by federal regulatory bodies and the demands of the marketplace.  
  
PUBLIC HEALTH RELEVANCE:   
Individualised therapeutic management based on pharmacogenetic information requires a standardized interventional approach. PerMIT:Warfarin is the first pharmacogenetics-based interventional methodology for warfarin anticoagulation management. PerMIT:Warfarin is a Class II device under FDA classification regulation 21 CFR 864.7750. The Center for Medicare and Medicaid Services (CMS) has established a standard for warfarin pharmacogenetics reimbursement calling for multi-site randomized controlled trials to assess the benefit of pharmacogenetics to warfarin therapeutic management. This SBIR Phase II Competitive Renewal application is designed to achieve the regulatory compliance and medical evidentiary standards set forth by these regulatory bodies.

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

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


application_id: 7906006
project_number: 5R01CA122383-05
project_title: Tumor-Targeting Oligonucleotides
administering_ic: NCI
award_notice_date: 2010-07-09
application_type: 5
activity_code: R01
ic: CA
serial_number: 122383
program_official: LEES, ROBERT G
project_start_date: 2006-08-01
project_end_date: 2012-07-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 6663799
contact_pi: BATES, PAULA J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-08-01
project_abstract:
DESCRIPTION (provided by applicant): A major goal of translational cancer research is to develop targeted therapies that can specifically inhibit the expression or function of proteins that play an essential role in oncogenesis. There is considerable interest in using synthetic DNA or RNA oligonucleotides to achieve this goal because of their ability to recognize specified nucleic acid sequences or protein structures with high affinity. Several oligonucleotide-based strategies including antisense small interfering RNAs (siRNAs) protein-binding aptamers and immunostimulatory oligonucleotides have produced potent anti-cancer effects in pre-clinical studies. However clinical trials of therapeutic (antisense) oligonucleotides have been generally disappointing and this has been attributed in part to their inefficient uptake by cancer cells. The Principal Investigator and her collaborators have developed a novel antiproliferative oligonucleotide named AGRO100. This molecule has recently been tested in a clinical trial involving patients with advanced cancer and has demonstrated a remarkable lack of toxicity combined with promising clinical activity. Unlike most other oligonucleotides AGRO100 is taken up efficiently and selectively by cancer cells in culture and in vivo. We hypothesize that these extraordinary properties are related to the unusual G-quadruplex structure of AGR0100 and its ability to bind specifically to a protein that is expressed at high levels on the surface of cancer cells. The long-term goal of this project is to develop oligonucleotides that are avidly and selectively taken up by cancers in vivo. Such tumor-targeting sequences could be incorporated into oligonucleotide-based therapeutics or conjugated to chemotherapy drugs in order to enhance their efficacy and reduce unpleasant side effects. In this application we propose to elucidate the mechanism involved in the preferential uptake of AGRO100 by tumors and to identify sequence or structural motifs that lead to efficient oligonucleotide internalization by cancer cells. The first specific aim is to characterize the cellular internalization of AGRO100 and confirm the role of nucleolin in this process. The second aim is to use a SELEX approach to identify oligonucleotides (from combinatorial libraries) that have efficient and selective uptake by cancer cells. The third aim is to incorporate the optimal tumor-targeting sequences into antisense siRNA and immunomodulatory oligonucleotides in order to determine if this leads to superior uptake and activity.

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


application_id: 7904809
project_number: 5P50NS039787-10
project_title: Data Analysis and Management Core
administering_ic: NINDS
opportunity_number: PAR-03-004
application_type: 5
activity_code: P50
ic: NS
serial_number: 039787
study_section: ZNS1
subproject_number: 9002
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-08-01
budget_end_date: 2010-07-31
funding_mechanism: Research Centers
project_abstract:
Core C- Data Analysis Data management and Data Entry CoreDr. Richard J. Kryscio Professor of Statistics and Director of the Biostatistics Consulting Unit will direct theData Analysis and Data Management Core. Dr. Kryscio has over 20 years of experience consulting onprojects in biomedicine. He is familiar with the analysis of behavioral neurochemical morphological andelectrochemical endpoints taken on rhesus monkeys that have parkinsonian symptoms that have beentreated with vehicle or GDNF. Dr. Anders H. Andersen will be in charge of the analysis of the fMRI data. Dr.Andersen has over 15 years of experience in biomedical signal and image data analysis especially in thearea of MRI and fMRI data. Mike Dunlap is responsible for data entry and for the daily maintenance of thedatabase shared by all projects and cores.The specific aims of the Data Analysis and Data Management Core are to:1. advise all investigators in the Udall Center on issues related to experimental design and data analysis.2. perform the statistical analysis of the main endpoints in each of the projects and cores.3. provide quantitative assessments of each fMRI session recorded in Project 2.4. correlate the findings among the projects.5. establish and maintain a centralized database for the studies on monkeys.

project_terms:
Area;Behavioral;Biometry;Charge;Consult;Data;Data Analyses;Databases;Experimental Designs;Functional Magnetic Resonance Imaging;GDNF gene;Image;Macaca mulatta;Magnetic Resonance Imaging;Maintenance;Monkeys;Parkinson Disease;Parkinsonian Disorders;Research Personnel;Signal Transduction;Symptoms;data management;experience;neurochemistry;professor;restoration;statistics


application_id: 7904808
project_number: 5P50NS039787-10
project_title: Animal Core
administering_ic: NINDS
opportunity_number: PAR-03-004
application_type: 5
activity_code: P50
ic: NS
serial_number: 039787
study_section: ZNS1
subproject_number: 9001
contact_pi_person_id: 2154561
contact_pi: ZHANG, ZHIMING
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-08-01
budget_end_date: 2010-07-31
funding_mechanism: Research Centers
project_abstract:
Core B- Animal CoreThis Core will be in charge of taking care of the cohorts of monkeys that are to be used for the studies. Thebehavioral tests pump and cannula implant surgeries MPTP-lesions general care of the monkeys and thesurgeries for microdialysis recordings will be performed by this Core. Dr. Zhiming Zhang will coordinate theactivities of the animal Core.

project_terms:
Animals;Cannulas;Caring;Charge;Implant;MPTP Poisoning;Microdialysis;Monkeys;Operative Surgical Procedures;Parkinson Disease;Pump;behavior test;cohort;restoration


application_id: 7904807
project_number: 5P50NS039787-10
project_title: Neuropharmacological Studies
administering_ic: NINDS
opportunity_number: PAR-03-004
application_type: 5
activity_code: P50
ic: NS
serial_number: 039787
study_section: ZNS1
subproject_number: 0004
contact_pi_person_id: 8383539
contact_pi: GERHARDT, GREG A.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-08-01
budget_end_date: 2010-07-31
funding_mechanism: Research Centers
project_abstract:
Quantitative Neuropharmacoloqical.Studies of the Effects of Chronic Delivery of GDNF in Rhesus MonkeysThe neurorestorative and neuroprotective trophic actions of GDNF on midbrain DA neurons provide apromising but controversial therapeutic approach for the treatment of Parkinson's disease (PD).Based on past work we hypothesize that GDNF is affecting DA neurons through at least 3 major mechanisms:1) Upregulation of existing DA neurons - direct effects on tyrosine hydroxylase and related proteins; 2) Repairof DA neurons - improved dendritic and neuronal fiber connections; and 3) Neurogenesis and/or gliogenesis.Project 1 will investigate DA function and repair of DA neurons in conjunction with Projects 2 and 3. It is ourcentral hypothesis that dual-site chronic intraputamenal/intranigral delivery of GDNF will improve function andrestoration of damaged DA neurons with greater efficacy potency and reduced side effects. In addition wepredict based on preliminary data that GDNF treatment in milder parkinsonian animals a model of earlystage PD patients will lead to optimal restoration of the nigrostriatal DA neuronal system. We propose to usean indwelling pump that can deliver GDNF chronically in the freely-moving unilateral 1-methyl-4-phenyl-1236-tetrahydropyridine (MPTP)-lesioned middle-aged female monkeys. Project 1 of this revised programproject grant will perform quantitative neurochemical assessments using in vivo microdialysisWestern immunoblot assays immunohistochemical studies and high performance liquidchromatography coupled with electrochemical detection (HPLC-EC) to study DA neuronal systems inthe striatum (putamen and caudate nucleus) and substantia nigra of Rhesus monkeys that havereceived chronic GDNF infusions. These neurochemical changes to the monkey striatum during chronicdelivery of GDNF will be performed in conjunction with behavioral immunohistochemical histological andfunctional MRI (fMRI) studies of the same monkeys in conjunction with Projects 2 and 3. In addition Project 1will begin studies of glutamate regulation in the striatum substantia nigra and globus pallidus of 6-OHDA-lesioned rats and the effects of GDNF infusion on glutamate regulation in the basal ganglia. This is as a newarea of scientific growth of the Center. The investigation of the role of glutamate in relation of.DA function willimprove our understanding of the essential role of this neurotransmitter to basal ganglia function in PD.

project_terms:
Adverse effects;Affect;Animals;Area;Basal Ganglia;Behavioral;Biochemical Markers;Biological Assay;Cannulas;Chronic;Collaborations;Corpus striatum structure;Coupled;Data;Detection;Female;Fiber;Functional Magnetic Resonance Imaging;GDNF gene;Globus Pallidus;Glutamates;Growth;High Pressure Liquid Chromatography;Infusion procedures;Injection of therapeutic agent;Investigation;Lead;Lesion;Macaca mulatta;Measures;Microdialysis;Microelectrodes;Midbrain structure;Modeling;Monkeys;Neurons;Neurotransmitters;Oxidopamine;Parkinson Disease;Parkinsonian Disorders;Patients;Potassium;Program Research Project Grants;Proteins;Pump;Rattus;Recovery;Regulation;Role;Site;Staging;Substantia nigra structure;System;Therapeutic;Tyrosine 3-Monooxygenase;Up-Regulation (Physiology);Western Blotting;Work;base;caudate nucleus;dopaminergic neuron;gliogenesis;improved;improved functioning;in vivo;middle age;neurochemistry;neurogenesis;neurorestoration;putamen;repaired;restoration;uptake


application_id: 7904806
project_number: 5P50NS039787-10
project_title: Quantitative Morphological Studies
administering_ic: NINDS
opportunity_number: PAR-03-004
application_type: 5
activity_code: P50
ic: NS
serial_number: 039787
study_section: ZNS1
subproject_number: 0003
contact_pi_person_id: 8535427
contact_pi: GASH, DON MARSHALL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-08-01
budget_end_date: 2010-07-31
funding_mechanism: Research Centers
project_abstract:
Intrastriatal infusion of the potent dopaminergic trophic factor GDNF promotes significant behavioralimprovements in animal models of Parkinson's disease. The mechanisms of action are not fullyunderstood but include the upregulation of nigrostriatal dopaminergic functions neuroprotectionagainst some neurotoxins and over a period of weeks to months structural restoration on thenigrostriatal dopaminergic system. Another possible mechanism with extraordinary implications ifsubstantiated is the neurogenesis of nigral dopamine neurons. The studies in Project 3 focuse onanswering three major questions. 1) What is the role of neurogenesis and/or gliogenesis in GDNF-induced functional recovery of the nigrostriatal system? Experiments are designed to critically test thehypothesis that neurogenesis is a principal component of functional recovery in the substantia nigra andputamen. 2) To what extent does GDNF therapy restore normal nigrostriatal dopaminergic circuitry?Structural restoration will be correlated with the measures of functional restoration quantified in Projects 1and 2 to critically test the hypothesis that the extent of motor behavior recovery in parkinsonian rhesusmonkeys receiving GDNF therapy is directly correlated to the structural restoration of the nigrostriataldopaminergic system. 3) To identify and analyze possible neuropatholoqical sequellae arising fromintracerebral GDNF treatment. Antibodies to GDNF have been detected in some advancedParkinson's disease patients receiving intracerebral administration of the trophic factor. The effectsof circulating GDNF antibodies on the adult primate nervous system are not known. Thehypothesisbeing tested in this specific aim is that there is not anautoimmune loss of GDNF-responsive neuronsin adult primates with circulating GDNF antibodies. Five populations of GDNF-responsive neuronswill be evaluated in rhesus monkeys receiving intracerebral infusions of GDNF or vehicle. Three ofthe neuronal populations are in the CNS: midbrain dopamine neurons Purkinje cells in thecerebellum and motor neurons in the cervical spinal cord. The other two neuronal types are in thePNS: dorsal root ganglion neurons and enteric neurons in the gastrointestinal system.

project_terms:
Address;Adult;Adverse effects;Animal Model;Antibodies;Autoimmune Process;Basal Ganglia;Behavior;Behavioral;Brain;Bromodeoxyuridine;Cell Count;Cell Surface Receptors;Cells;Cerebellum;Cervical spinal cord structure;Clinical;Corpus striatum structure;Development;Dopamine;Electrons;Enteral;Enteric Nervous System;Exposure to;GDNF gene;Infusion procedures;Kidney;Label;Lesion;Lewy Bodies;Light;Macaca mulatta;Measures;Microscopic;Midbrain structure;Modeling;Monitor;Motor;Motor Neurons;NCAM1 gene;Nervous system structure;Neurites;Neuroglia;Neurons;Neurotoxins;Output;Oxidopamine;Parkinson Disease;Parkinsonian Disorders;Patients;Perikaryon;Population;Primates;Procedures;Process;Purkinje Cells;Rattus;Recovery;Recovery of Function;Risk Factors;Rodent Model;Role;Site;Source;Spinal Ganglia;Staging;Stem cells;Substantia nigra structure;System;Testing;Thalamic structure;Thymidine;Tyrosine 3-Monooxygenase;Up-Regulation (Physiology);alpha synuclein;design;dopamine transporter;dopaminergic neuron;functional improvement;functional restoration;gastrointestinal system;gene therapy;gliogenesis;injured;nerve supply;neurogenesis;neuron loss;neuroprotection;nigrostriatal system;nonhuman primate;pars compacta;putamen;receptor;relating to nervous system;research study;response;restoration;uptake


application_id: 7904805
project_number: 5P50NS039787-10
project_title: Behavioral and fMRI Studies
administering_ic: NINDS
opportunity_number: PAR-03-004
application_type: 5
activity_code: P50
ic: NS
serial_number: 039787
study_section: ZNS1
subproject_number: 0002
contact_pi_person_id: 2154561
contact_pi: ZHANG, ZHIMING
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-08-01
budget_end_date: 2010-07-31
funding_mechanism: Research Centers
project_abstract:
PROJECT 2During the last funding period we demonstrated that programmable pump delivery of GDNF promotesimprovements in motor and nigrostriatal dopamine (DA)functions in nonhuman primate models ofParkinson's disease (PD). In the proposed studies Project 2 will use behavioral and functional magneticresonance imaging (fMRI) methods to determine conditions to further enhance GDNF actions on motor aridDA functions in MPTP-lesioned rhesus monkeys which best simulate the human parkinsonian state. Inconjunction with Projects 1 & 3 Project 2 will determine if combined putamenal and nigral delivery of GDNFvia programmable pumps and intraparenchymal catheters will produce better behavioral recovery of thenigrostriatal pathway than single-site putamenal delivery alone. Project 2 will also investigate if chronicintraparenchymal delivery of GDNF will more completely restore motor and DA functions in MPTP-lesionedanimals expressing milder but stable parkinsonism versus severely impaired animals. In Project 2 theanimals will be quantitatively characterized with apomorphine and levodopa/carbidopa pre- and post-GDNFadministration. To this end we will use a variety of behavioral measurements including: 1) an automatedvideo-tracking system for analyzing whole body movements 2) an automated hand-retrieval task forevaluating fine hand/coarse arm movements and 3) a nonhuman primate rating scale for evaluatingbehavioral features characteristic of PD: bradykinesia rigidity posture balance and tremor. In addition tobehavioral testing Project 2 will use fMRI techniques to noninvasively and simultaneously measureapomorphine-evoked blood oxygen level-dependent (BOLD) changes in basal ganglia functions of alertrhesus monkeys pre- and post-GDNF administration. Collectively these studies should contribute to animproved mechanistic understanding of the effects of chronic GDNF treatment on the nigrostriatal DA systemin nonhuman primates and improved approaches for the treatment of PD.

project_terms:
Adverse effects;Affect;Age;Agonist;Animals;Apomorphine;Area;Basal Ganglia;Behavioral;Biochemical;Bradykinesia;Brain;Carbidopa;Catheters;Cell Count;Characteristics;Chronic;Computer software;Corpus striatum structure;Coupled;Critiques;Data;Dopamine;Dopamine D2 Receptor;Dopamine Receptor;Early treatment;Equilibrium;Fiber;Functional Magnetic Resonance Imaging;Funding;Globus Pallidus;Grant;Hand;Human;Imaging Techniques;Implant;Infusion procedures;Lead;Levodopa;MPTP Poisoning;Macaca mulatta;Measurement;Measures;Methods;Modeling;Monkeys;Motor;Movement;Muscle Rigidity;Parkinson Disease;Parkinsonian Disorders;Patients;Pattern Recognition;Performance;Posture;Principal Investigator;Procedures;Proteins;Pump;Recovery;Recovery of Function;Residual state;Resolution;Retrieval;Simulate;Site;Sterility;Structure;Substantia nigra structure;System;Systems Analysis;Testing;Toxic effect;Tremor;Tyrosine 3-Monooxygenase;Up-Regulation (Physiology);Upper arm;base;behavior measurement;behavior test;blood oxygen level dependent;density;digital imaging;dopamine system;dopaminergic neuron;functional restoration;glial cell-line derived neurotrophic factor;image processing;imaging modality;improved;neurochemistry;neurogenesis;nigrostriatal pathway;nigrostriatal system;nonhuman primate;normal aging;programs;putamen;relating to nervous system;repaired;restoration;synaptic function;tool


application_id: 7904492
project_number: 7R01CA133429-02
project_title: The Role of PHLPP in Colon Cancer
administering_ic: NCI
award_notice_date: 2009-08-26
opportunity_number: PA-07-070
application_type: 7
activity_code: R01
ic: CA
serial_number: 133429
program_official: YASSIN, RIHAB R
project_start_date: 2009-04-01
project_end_date: 2014-02-28
study_section: Molecular Oncogenesis Study Section[MONC]
contact_pi_person_id: 7353657
contact_pi: GAO, TIANYAN
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Colorectal cancer is the second leading cause of cancer-related deaths in the United States with 112000 new cases diagnosed per year and approximately 52000 deaths estimated in 2007. Dysregulation of Akt and protein kinase C (PKC) contributes to tumorigenesis by promoting cell proliferation and inhibiting apoptosis. The signaling activation process of Akt and PKC has been studied in great detail. However little is known about how the signals are turned off once activated. Recently we have identified a family of novel protein phosphatases PHLPP (PH domain Leucine-rich-repeats Protein Phosphatase) that directly dephosphorylates Akt and PKC. However the role of PHLPP in cancer has not been defined. In the preliminary studies we found that loss of PHLPP expression occurs with high frequency in human colorectal cancer specimens. Furthermore our studies have suggested that PHLPP plays a role in regulating cell polarity. In light of our findings the central hypothesis driving this proposal is that PHLPP serves as a tumor suppressor by regulating cell polarity in addition to its ability of turning off the growth signaling activated by Akt and PKC. The long-term goal of our studies is to better understand the physiological role of PHLPP and its contribution to colon cancer development and progression in vivo. The Specific Aims are: Aim 1: To define the molecular mechanism of PHLPP downregulation. The goal of this aim is to investigate the potential mechanism leading to PHLPP downregulation in cancer. We will test the hypothesis that the expression level of PHLPP is controlled by the ubiquitin proteasome pathway in cells and preventing PHLPP degradation leads to upregulation of the protein. Aim 2: To determine the role PHLPP in maintaining cell polarity. We hypothesize that PHLPP exerts its function as a tumor suppressor by regulating cell polarity and cell growth. The functional effect of PHLPP on establishing epithelial cell polarity will be determined. To elucidate the underlying mechanism we will test the hypothesis that PHLPP is required for epithelial junction formation by modulating PKC activity via binding to the polarity protein Scribble. Aim 3: To delineate the role of PHLPP in tumorigenesis in vivo. The hypothesis driving this aim is that loss of PHLPP expression contributes to the initiation and progression of colorectal tumors. We will address the question whether there is an increase of tumor incidence when PHLPP is knocked out both basally and in combination with other carcinogenic factors. Furthermore we will assess the contribution of altered cell polarity in normal development of gut epithelium and tumor initiation using the knockout mice. PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer-related deaths in the United States with 148000 new cases diagnosed per year and approximately 50000 deaths estimated in 2007 and among many contributing factors aberrant protein phosphorylation resulting from hyperactivation of oncogenic signaling mediated by protein kinases such as Akt and PKC is a key cause of colorectal cancer. We recently identified a novel protein phosphatase PHLPP that directly dephosphorylates Akt and PKC and terminates the growth signals activated by these kinases. We propose to determine the functional importance of PHLPP as a tumor suppressor in colorectal cancer and the results from this study will provide significant insights into the development of potential cancer therapy using PHLPP as a novel target.

project_terms:
Address;Apoptosis;Automobile Driving;Binding (Molecular Function);Biological Models;Cancer Etiology;Cell Polarity;Cell Proliferation;Cells;Cellular biology;Cessation of life;Colon Carcinoma;Colorectal Cancer;Colorectal Neoplasms;Critical Pathways;Development;Diagnosis;Down-Regulation;Epithelial;Epithelial Cells;Failure (biologic function);Family;Frequencies (time pattern);Glioblastoma;Goals;Growth;Howard Temin Award;Human;Incidence;Knock-out;Knockout Mice;Light;Malignant Neoplasms;Mammalian Cell;Mediating;Mentored Research Scientist Development Award;Molecular;Non-Small-Cell Lung Carcinoma;Oncogenic;PH Domain;Pathway interactions;Pharmacology and Toxicology;Phosphatidylinositols;Phosphorylation;Phosphotransferases;Physiological;Play;Process;Protein Kinase;Protein Kinase C;Protein phosphatase;Proteins;Proto-Oncogene Proteins c-akt;Publishing;Research;Research Personnel;Role;Signal Pathway;Signal Transduction;Specimen;Staging;Testing;Tumor Suppression;Tumor Suppressor Proteins;Ubiquitin;United States;Up-Regulation (Physiology);Xenograft procedure;base;cancer cell;cancer therapy;cell growth;design;falls;gastrointestinal epithelium;in vivo;insight;leucine-rich repeat protein;mouse model;multicatalytic endopeptidase complex;new therapeutic target;novel;overexpression;prevent;professor;public health relevance;research study;tumor;tumor growth;tumor initiation;tumor progression;tumorigenesis


application_id: 7904469
project_number: 1R43RR030684-01
project_title: A non-surgical embryo transfer device for producing gene modified rats
administering_ic: NCRR
award_notice_date: 2010-07-13
opportunity_number: PA-09-080
application_type: 1
activity_code: R43
ic: RR
serial_number: 030684
program_official: MIROCHNITCHENKO, OLEG
project_start_date: 2010-07-15
project_end_date: 2011-07-14
study_section: Special Emphasis Panel[ZRG1 EMNR-E (10)]
contact_pi_person_id: 10138071
contact_pi: STONE, BARBARA JEAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Rats represent the most commonly used physiologically and pharmacological experimental model for studying human disease. The ability to genetically modify rats through methods of gene transfer in fertilized rat embryos or by gene targeting in embryonic stem (ES) cells has significantly increased the capabilities of rats in biomedical and pharmaceutical research. Until now the production of targeted gene- modifications in rats requires the surgical transfer of embryos. This surgery is cost and labor intensive since it requires anesthesia (with potential complications) post-operative care of female rats (which may include the use of analgesics) as well as technical expertise on the part of the person carrying out the surgery. At the same time there is a strong desire in the animal research community to reduce the morbidity stress and pain of animals used for research purposes. To overcome these problems we propose to develop a Non-Surgical Embryo Transfer (NSET) device that can be used for the non-surgical transfer of embryos into female rats. We have previously developed a device for use in mice that is rapid does not require surgery (including the associated anesthesia and post-operative care) requires little expertise and preliminarily is as efficacious as standard surgical embryo transfer in the production of transgenic mice. Although the rat reproductive tract anatomy is significantly different than that of mice we believe we can successfully develop a rat NSET device prototype. The aims of this proposal are to design a rat NSET prototype manufacture the prototype device and demonstrate device efficacy for non-surgical transfer of embryos. Success in these aims will provide the foundation to seek a Phase II award and for the commercialization of the NSET device for academic and bio/pharma rat research facilities.  
  
PUBLIC HEALTH RELEVANCE: The development of a device for the non-surgical transfer of embryos into recipient female rats represents a substantial advance over existing methods for generating gene-modified rats by eliminating surgery anesthesia and post-operative care. The goal of this proposal is to develop manufacture and determine the efficacy of a non- surgical embryo transfer prototype device for the transfer of rat embryos.

project_terms:
Analgesics;Anatomy;Anesthesia procedures;Animal Experimentation;Award;Caliber;Caring;Catheters;Communities;Derivation procedure;Development;Device or Instrument Development;Devices;Distress;Embryo;Embryo Transfer;Experimental Models;Female;Foundations;Gene Targeting;Gene Transfer;Gene-Modified;Goals;Grant;Imagery;Implant;Length;Medical;Methods;Modification;Morbidity - disease rate;Morphology;Mus;Operative Surgical Procedures;Pain;Performance;Persons;Pharmacologic Substance;Phase;Postoperative Period;Production;Rat Strains;Rattus;Research;Small Business Innovation Research Grant;Source;Stress;Technical Expertise;Techniques;Testing;Time;Transgenic Mice;Ultrasonography;United States National Institutes of Health;Work;animal pain;base;commercialization;cost;design;embryo culture;embryonic stem cell;flexibility;human disease;improved;innovation;prototype;public health relevance;reproductive;research facility;skills;stem;success;tool

public_health_relevance:
Project NarrativeThe development of a device for the non-surgical transfer of embryos into recipientfemale rats represents a substantial advance over existing methods for generatinggene-modified rats by eliminating surgery anesthesia and post-operative care. Thegoal of this proposal is to develop manufacture and determine the efficacy of a non-surgical embryo transfer prototype device for the transfer of rat embryos.


application_id: 7904247
project_number: 5R21AA017937-02
project_title: Re-entry Alcohol Services for Rural Offenders
administering_ic: NIAAA
award_notice_date: 2010-07-30
opportunity_number: PA-08-008
application_type: 5
activity_code: R21
ic: AA
serial_number: 017937
program_official: ROACH, DEIDRA
project_start_date: 2009-08-01
project_end_date: 2012-07-31
study_section: Clinical, Treatment and Health Services Research Study Section[AA-3]
contact_pi_person_id: 14909213
contact_pi: STATON, MICHELE
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF SOCIAL WELFARE/WORK
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall aim of the proposed project is to examine the feasibility of using innovative telemedicine technology to deliver an evidence-based alcohol intervention (MET) to rural offenders re-entering the community from prison. Hazardous use of alcohol is a considerable problem in rural areas. A primary correlate of the problem of hazardous alcohol use in rural areas is the limited access to and availability of health and behavioral services. In the absence of available and accessible re-entry alcohol interventions rural offenders with a history of hazardous drinking are at heightened risk for alcohol relapse and recidivism when they return to the community. The study will include screening and recruiting rural offenders with a pre- incarceration history of hazardous drinking using the AUDIT. Participants (N=142) who meet criteria for hazardous drinking (AUDIT score of 8+) will be interviewed within one week of their release from prison and randomized to one of two study conditions: 1) Motivational Enhancement Telemedicine (METelemedicine) combined with usual re-entry services (n=71) and 2) Re-entry services as usual (n=71). In both study conditions participants will have a referral to a community case manager (Social Service Clinician - SSC) by their parole officer indicating that they are in need of alcohol services and will meet criteria for outpatient level of care. In the METelemedicine condition participants will also be provided with four sessions of MET with a therapist in an urban-based university treatment clinic using telemedicine videoconferencing. Outcome data will be collected at 3-months post release to examine number of days of alcohol abstinence at re-entry. The specific aims of the study include: (1) Implement innovative telemedicine technology to deliver Motivational Enhancement Therapy (METelemedicine) to re-entering rural offenders with a pre-incarceration history of hazardous drinking and (2) Examine the feasibility of using METelemedicine by re-entering rural offenders with a pre-incarceration history of hazardous drinking. If findings from this study establish feasibility of telemedicine as an approach for delivering an evidence-based practice an R01 application will be developed to test the approach in a larger scale trial. The long-term objective of this research agenda is to increase access to effective treatment approaches for rural re-entering offenders in order to promote alcohol abstinence and reduce recidivism.  
  
PUBLIC HEALTH RELEVANCE: The overall aim of the proposed project is to examine the feasibility of using innovative telemedicine technology to deliver an evidence-based alcohol intervention (MET) to rural offenders re-entering the community from prison. The significance of this study for public health includes the opportunity to build on advances made by other uses of telemedicine that have included providing health and mental health services to individuals in rural areas and to incarcerated individuals. This study is innovative with the focus on offenders at community re-entry as well as the use of telemedicine as a new technology to increase access to evidence- based alcohol services in real-world settings.

project_terms:
Address;Adherence (attribute);Affect;Alcohol abuse;Alcohol consumption;Alcohol dependence;Alcohols;Caring;Case Manager;Clinic;Communities;Consumption;Data;Emerging Technologies;Equipment;Evaluation;Evidence based intervention;Evidence based practice;Health;Health Services Accessibility;Imprisonment;Individual;Interview;Mental Health Services;National Institute on Alcohol Abuse and Alcoholism;Outcome;Outpatients;Participant;Perception;Prevalence;Prisoner;Prisons;Procedures;Process;Randomized;Recording of previous events;Recruitment Activity;Reporting;Research;Research Personnel;Research Priority;Risk;Rural;Rural Population;Screening procedure;Services;Social work (field);System;Technology;Telemedicine;Testing;Training;Transportation;Travel;United States National Institutes of Health;Universities;Videoconferences;Videoconferencing;adverse outcome;alcohol abstinence;alcohol abuse therapy;alcohol intervention;alcohol relapse;alcohol services;alcohol use disorder;base;behavioral health;community reentry;cost;cost effectiveness;drinking;effective therapy;eligible participant;evidence base;follow-up;hazardous drinking;innovation;innovative technologies;medical specialties;meetings;motivational enhancement therapy;new technology;offender;parole;public health medicine (field);public health relevance;recidivism;response;rural area;service utilization;treatment program

public_health_relevance:
The overall aim of the proposed project is to examine the feasibility of using innovative telemedicinetechnology to deliver an evidence-based alcohol intervention (MET) to rural offenders re-entering thecommunity from prison. The significance of this study for public health includes the opportunity to build onadvances made by other uses of telemedicine that have included providing health and mental health servicesto individuals in rural areas and to incarcerated individuals. This study is innovative with the focus on offendersat community re-entry as well as the use of telemedicine as a new technology to increase access to evidence-based alcohol services in real-world settings.


application_id: 7904136
project_number: 5R01AG033649-02
project_title: Metabolic syndrome and hippocampal Ca2+ dysregulation in aging-related memory dec
administering_ic: NIA
award_notice_date: 2010-07-15
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AG
serial_number: 033649
program_official: PETANCESKA, SUZANA
project_start_date: 2009-08-01
project_end_date: 2014-07-31
study_section: Neurobiology of Learning and Memory Study Section[LAM]
contact_pi_person_id: 8361727
contact_pi: THIBAULT, OLIVIER
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Increasing epidemiological and experimental evidence shows that factors associated with metabolic syndrome including glucose dysregulation insulin insensitivity and/or obesity are linked to cognitive decline in aging. Moreover the incidence of obesity and metabolic syndrome are approaching epidemic proportions. The thiazolidinediones (TZD) selective peroxisome proliferator-activated receptor-gamma (PPAR3) agonists improve several aspects of metabolic syndrome including lowering insulin resistance glucose and cholesterol levels in Type 2 diabetics and have also been linked to decreased inflammation and 2-amyloid load in models of Alzheimer's disease (AD). However the mechanisms that link peripheral metabolic syndrome to brain dysfunction are still poorly understood and few studies have analyzed these periphery-brain relationships in aged animals. Over the past years we and others have found considerable electrophysiological and imaging evidence that hippocampal Ca2+ dysregulation with aging correlates with cognitive decline. Recently our gene microarray studies also revealed downregulation of hippocampal insulin and glucose signaling that correlated with aging-related memory impairment. Here we will test the working hypothesis that peripheral components of metabolic syndrome induce alterations in Ca2+ homeostasis in the hippocampus by acting on L-type voltage-gated Ca2+ channels (L-VGCCs) NMDARs Ca2+-induced Ca2+ release (CICR) and the Ca2+-dependent afterhyperpolarization (AHP) thereby negatively affecting synaptic plasticity (LTP) and cognitive function. We will also test the hypothesis that these actions are mediated in part by changes in brain insulin/glucose signaling pathways and can be counteracted by TZDs. Specific Aim # 1 will study F344 male rats fed a normal diet and determine at 7-8 and 18-20 months of age which component of metabolic dysregulation most closely associates with measures of cognitive function and hippocampal electrophysiological/imaging function (L-VGCCs NMDARs CICR AHPs and LTP). Specific Aim #2 will test whether diet-induced obesity (DIO) exacerbates neurobiological cognitive gene expression and neuropathological indices of brain aging and whether interventions with TZDs can slow or reverse this process. Specific Aim #3 will analyze the effects of insulin on hippocampal slices testing for direct effects on electrophysiological markers of aging and will test the sub-hypothesis that neurons from aged animals exhibit insulin resistance. Together these multidisciplinary studies will provide one of the first systematic analyses of links between variables contributing to peripheral metabolic syndrome and cellular mechanisms of brain aging. Therefore even if the central hypothesis is rejected the studies proposed will provide more definitive evidence for the impact o metabolic syndrome as well as the actions of TZDs on the brain. PUBLIC HEALTH RELEVANCE Metabolic syndrome and diabetes are age- and obesity-related diseases that are rapidly approaching epidemic proportions in our society. Recent studies indicate that there may be a link between metabolic syndrome and cognitive decline. The underlying mechanisms through which individual components of peripheral metabolic dysregulation can negatively impact brain function are not known. Our research will identify new links between brain aging diabetes and obesity. If successful our project could impact public health by providing strong clues to help identify novel therapeutic targets and prevent cognitive decline in aging.

project_terms:
24-thiazolidinedione;Address;Adipose tissue;Affect;Age;Age-Months;Age-associated memory impairment;Aging;Agonist;Alzheimer's Disease;Alzheimer's disease model;Amyloid;Animals;Attenuated;Behavioral;Brain;Cells;Cholesterol;Clinical;Cognition;Cognitive;Complement;Development;Diabetes Mellitus;Diet;Down-Regulation;Drug usage;Dyslipidemias;Ensure;Epidemic;Epidemiology;Exhibits;Fatty acid glycerol esters;Functional disorder;Gene Expression;Genes;Glucose;Goals;Grant;Hippocampus (Brain);Homeostasis;Hyperglycemia;Hyperinsulinism;Hypertension;Image;Impaired cognition;Inbred F344 Rats;Incidence;Individual;Inflammation;Insulin;Insulin Resistance;Insulin Signaling Pathway;Intervention;Learning;Link;Longitudinal Studies;Measures;Mediating;Memory;Memory impairment;Metabolic;Metabolic Brain Diseases;Metabolic Marker;Metabolic Pathway;Metabolic syndrome;Monitor;Mouse Strains;N-Methyl-D-Aspartate Receptors;Neurobiology;Neurons;Obesity;Obesity associated disease;Outcome Measure;PPAR gamma;Pathway interactions;Patients;Peripheral;Pharmaceutical Preparations;Pioglitazone;Process;Rattus;Regulation;Reporting;Research;Resistance;Rodent;Rodent Model;Series;Short-Term Memory;Signal Pathway;Signal Transduction;Slice;Societies;Synaptic plasticity;Techniques;Testing;Thiazolidinediones;Time;Tissue Sample;Tissues;Vascular Diseases;Work;age effect;age related;aged;aging brain;aging gene;biomarker;brain cell;cognitive function;cytokine;diabetic;direct application;feeding;glycemic control;improved;indexing;insulin sensitivity;insulin signaling;male;multidisciplinary;new therapeutic target;normal aging;prevent;public health medicine (field);public health relevance;research study;response;voltage

public_health_relevance:
PROJECT NARRATIVEMetabolic syndrome and diabetes are age- and obesity-related diseases that are rapidly approaching epidemicproportions in our society. Recent studies indicate that there may be a link between metabolic syndrome andcognitive decline. The underlying mechanisms through which individual components of peripheral metabolicdysregulation can negatively impact brain function are not known. Our research will identify new links betweenbrain aging diabetes and obesity. If successful our project could impact public health by providing strongclues to help identify novel therapeutic targets and prevent cognitive decline in aging.


application_id: 7903491
project_number: 5R01GM079684-03
project_title: The Regulation of Smoothened in Hedgehog Signaling
administering_ic: NIGMS
award_notice_date: 2010-06-14
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 079684
program_official: HAYNES, SUSAN R
project_start_date: 2008-07-01
project_end_date: 2013-06-30
study_section: Development - 1 Study Section[DEV1]
contact_pi_person_id: 8575677
contact_pi: JIA, JIANHANG
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
  
The hedgehog (hh) family members control many aspects of development in both vertebrates and invertebrates. Hh signaling is associated with important biological phenomena such as patterning cell growth and morphogenesis. Abnormal activation of this pathway has been observed in several types of human cancers. The seven-pass transmembrane protein Smoothened (Smo) is required in both insects and mammals for transduction of the Hh signal. Our strategy is to use Drosophila as a simple and genetically tractable model system to explore the mechanisms of Hh signal transduction. The long-term goal of our research is to elucidate how Hh signals are sensed and transmitted to control downstream biological events that ultimately govern cell growth and patterning. We showed that Smo transduces the Hh signals by directly recruiting a Costal2-Fused (Cos2-Fu) complex. We also showed that Smo activation requires phosphorylation by protein kinase A (PKA) and casein kinase I (CKI) and that phosphorylation leads to increased Smo cell-surface levels and signaling activity. We recently uncovered a feedback mechanism by which Fu promotes Smo hyperphosphorylation and cell-surface accumulation by antagonizing Cos2. These findings provide new tools and hypotheses to investigate the mechanisms of Hh signaling at the cell membrane. In this project our central hypothesis is that Smo cell-surface accumulation and signaling activity are regulated by multiple kinases while phosphatase(s) act as inhibitory components to attenuate Smo activation. To test our hypothesis we will use a combination of genetic and biochemical approaches in three Specific Aims: 1) To further determine if differential Smo phosphorylation transduces gradient Hh activity; 2) to investigate the molecular mechanisms by which G protein-coupled receptor kinase 2 (GRK2) is involved in Hh signaling; and 3) to determine the role of phosphatase in Smo dephosphorylation and inactivation. HEALTH RELEVANCE Abnormal Smoothened (Smo) activation results cancers such as basal cell carcinoma (BCC) and medulloblastoma. Investigation of the Smo signaling mechanisms will provide both insights into fundamental developmental problems and new avenues for developing diagnostic tools and therapeutical treatments of cancers. PHS 398/2590 (Rev. 09/04 Reissued 4/2006) Page Project Narrative

project_terms:
Affect;Antibodies;Attenuated;Basal cell carcinoma;Beta-Adrenergic Receptor Kinase 1;Biochemical;Biological;Biological Assay;Biological Models;Biological Phenomena;Cell membrane;Cell surface;Cells;Cellular biology;Complex;Cyclic AMP-Dependent Protein Kinases;Cytoplasm;Data;Development;Diagnostic;Drosophila genus;Environment;Erinaceidae;Event;Family member;Feedback;Gene Transfer Techniques;Genes;Genetic;Goals;Human;In Vitro;Individual;Insecta;Integral Membrane Protein;Integrase;Invertebrates;Investigation;Ligands;Malignant Neoplasms;Mammals;Mediating;Molecular;Morphogenesis;Mutation;Pathway interactions;Pattern;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphorylation Site;Phosphotransferases;Promotor (Genetics);Protein Dephosphorylation;Protein phosphatase;RNA Interference;Recruitment Activity;Regulation;Research;Residual state;Role;Signal Transduction;Site;System;Testing;Therapeutic;Variant;Vertebrates;Wing;Work;base;cancer cell;cancer therapy;casein kinase I;casein kinase II;cell growth;experience;hedgehog signal transduction;human SMO protein;in vivo;innovation;insight;loss of function;medulloblastoma;mutant;novel;overexpression;research study;response;smoothened signaling pathway;tool


application_id: 7903251
project_number: 5P20NR010679-03
project_title: Data Analysis Research Program Development and Dissemination Core
administering_ic: NINR
opportunity_number: RFA-NR-07-004
application_type: 5
activity_code: P20
ic: NR
serial_number: 010679
study_section: ZNR1
subproject_number: 9002
contact_pi_person_id: 1903848
contact_pi: HALL, LYNNE ANDERSON
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
budget_end_date: 2010-06-30
funding_mechanism: Research Centers
project_abstract:
Chronic cardiovascular and pulmonary diseases adversely affect the quality of life of millions ofAmericans. Self-management is essential for disease management in those with these chronic conditions.In order to move into a new area of research focused on improving self-management of cardiovascular andpulmonary diseases and to support investigators in the development of extramural research proposalsjunior as well as established investigators need training and mentoring with research program development(e.g. establishing a research trajectory developing researchable problems conceptualizing theoreticalfoundations for hypothesis formation proposal development) data analysis (e.g. selection of appropriatestatistical methods interpretation of statistical output presentation of statistical findings) and disseminationof results via scientific presentations and publications in appropriate venues. The Research ProgramDevelopment Data Analysis and Dissemination Core will build on existing support services available inthe College of Nursing and extend services to support Center investigators in other ways.The purposes of the Research Program Development Data Analysis and Dissemination Coreare to: (1) provide support services to assist faculty in developing a focused ongoing funded program ofresearch related to evidence-based interventions to promote self-management in patients withcardiovascular and pulmonary diseases; (2) offer faculty development opportunities and mentoring inresearch proposal development psychosocial instrumentation and surveys research design and samplingdata management and analysis and data-based presentation and manuscript preparation; and (3) throughcollaboration with the Administrative Core the Self-management Pilot/Feasibility and BiobehavioralOutcomes Core the Executive Committee and the Advisory Committee provide the infrastructure andresources necessary for development of ongoing programs of research focused on improving selfmanagementof patients with cardiovascular and pulmonary diseases.

project_terms:
Address;Advisory Committees;Affect;Age;American;Annual Reports;Applications Grants;Area;Award;Cardiovascular system;Chronic;Chronic Disease;Clinical Research;Collaborations;Consultations;Data;Data Analyses;Databases;Development;Discipline;Discipline of Nursing;Disease;Disease Management;Ensure;Equipment;Evaluation;Evidence based intervention;Extramural Activities;Faculty;Foundations;Funding;Goals;Grant;Health;Health Sciences;Housing;Institution;Link;Lung;Lung diseases;Manuscripts;Mentors;Monitor;Nature;Newsletter;Nurses;Outcome;Output;Paper;Patients;Persons;Pilot Projects;Preparation;Process;Program Development;Psychometrics;Publications;Quality of life;Questionnaires;Records;Research;Research Activity;Research Design;Research Infrastructure;Research Personnel;Research Proposals;Research Support;Resources;Sampling;Scholarship;Schools;Scientist;Self Management;Senior Scientist;Services;Statistical Methods;Surveys;Training;United States Office of Research Integrity;Universities;Work;Writing;base;biobehavior;college;data management;editorial;health disparity;improved;instrumentation;meetings;member;posters;programs;psychosocial;research and development;satisfaction;service utilization;statistics;web site


application_id: 7903250
project_number: 5P20NR010679-03
project_title: Self-Management Pilot/Feasibility and Biobehavioral Outcomes Core
administering_ic: NINR
opportunity_number: RFA-NR-07-004
application_type: 5
activity_code: P20
ic: NR
serial_number: 010679
study_section: ZNR1
subproject_number: 9001
contact_pi_person_id: 1906096
contact_pi: LENNIE, TERRY A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
budget_end_date: 2010-06-30
funding_mechanism: Research Centers
project_abstract:
Development of evidence-based strategies to improve self-management of cardiovascular and pulmonarydiseases requires that investigators develop scientifically sound rigorous research studies. Measuringbiobehavioral outcomes of self-management of cardiovascular and pulmonary diseases presents challenges toinvestigators entering this field of study. The University of Kentucky College of Nursing is doubling the size ofthe undergraduate program. Funding to hire eight additional faculty members who will have 50% release timefor research has been approved by the Board of Regents. These new members who will be investigators earlyin their research careers will be hired over three years. Three of these members will start in the Fall of 2007. Inaddition we have junior faculty (Darlene Welsh and Misook Chung) and established investigators (Ann Pedenand Lynne Hall) on our faculty who are planning to join our cardiovascular and pulmonary research team(RICH Heart Program). The proposed Center will be ideally suited to assist these faculty members to developprograms of research in self-management of cardiovascular and pulmonary diseases.To meet the needs of current and future faculty members the proposed Core will assist projectinvestigators in the development and conduct of pilot/feasibility studies aimed at improving self-management ofcardiovascular and pulmonary diseases that include measurement of biobehavioral outcomes. Advice trainingand mentorship will be provided in research design as well as measurement and interpretation of three types ofoutcomes: 1) biobehavioral variables that demonstrate effectiveness of interventions (e.g. knowledgepsychological status physiological status) 2) biobehavioral variables that demonstrate improvement in selfmanagementbehaviors (e.g. adherence nutritional status physiological status) and 3) biobehavioralvariables that demonstrate improvement in clinical outcomes (e.g. physiological status mortality morbidityand quality of life).

project_terms:
Adherence (attribute);Advisory Committees;Area;Behavior;Cardiovascular system;Clinical;Collaborations;Data Analyses;Development;Discipline of Nursing;Disease;Effectiveness of Interventions;Faculty;Feasibility Studies;Funding;Future;Heart;Interdisciplinary Study;Kentucky;Knowledge;Lung;Lung diseases;Measurement;Measures;Mentorship;Morbidity - disease rate;Mortality Vital Statistics;Nutritional status;Outcome;Patients;Physiological;Program Development;Quality of life;Research;Research Design;Research Infrastructure;Research Personnel;Resources;Self Management;Time;Training;Universities;biobehavior;biobehavioral measurement;career;college;evidence base;falls;field study;improved;meetings;member;programs;psychologic;research study;sound


application_id: 7901642
project_number: 5R42AA016739-04
project_title: Hypericum extracts as potential anti-relapse medications in alcoholism
administering_ic: NIAAA
award_notice_date: 2010-06-16
opportunity_number: RFA-AA-06-007
application_type: 5
activity_code: R42
ic: AA
serial_number: 016739
program_official: FERTIG, JOANNE
project_start_date: 2007-07-20
project_end_date: 2012-06-30
study_section: ZAA1-DD(74)
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alcoholism is a complex disease and anti-relapse treatments should recognize this. For example depression is a frequent precipitant of relapse (1) and is the most common co-morbid psychiatric disorder in alcoholism. An anti-relapse agent with antidepressant properties might therefore be valuable specifically for this large subpopulation. In this regard the extracts of "St John's Wort" (Hypericum perforatum) that are effective treatments for clinical depression (see 2) also inhibit alcohol consumption in several animal models (e.g. (3). Like antidepressants H perforatum extracts contain serotonin re-uptake inhibitors (SRIs) but (less wellknown) constituents also bind to NMDA receptors (NMDARs) opioid receptors (ORs) GABAA receptors and corticotrophin releasing factor receptors (CRFRs). This is a unique pharmacological spectrum and is potentially valuable because all of these are molecular targets for anti-relapse agents with NMDARs and ORs being the targets for acamprosate and naltrexone respectively. Native Hypericum species and geneticallymodified H perforatum lines share these actions in greater or lesser degree (Preliminary studies) and their relative importance could therefore be assessed using these species or lines. However in this "fast-track" STTR the aim is simply to identify those novel Hypericum extracts that are of most potential value in alcoholism. In phase 1 the focus will be on pharmacological standardization of extracts using molecular and cellular screens developed for evaluation of synthetic anti-relapse medications. In phase 2 evaluation will continue in simple animal screens of alcohol dependence and/or depression and different models of alcohol consumption. The prediction is that some extracts will be more effective than others and that this can be related to the pharmacological activity they contain. The resulting stronger Intellectual Property (compared to known active H perforatum extracts) will make these more commercially attractive as medications for this specific use. In phase 3 the objective (with a major pharmaceutical partner) will be to commercialize extracts or active components as treatments for prevention of relapse in alcoholic patients with co-morbid depression.

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


application_id: 7901606
project_number: 5R01HL094419-02
project_title: O-GlcNAc Signaling in Heart Failure
administering_ic: NHLBI
award_notice_date: 2010-06-29
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 094419
program_official: LIANG, ISABELLA Y
project_start_date: 2009-08-01
project_end_date: 2013-06-30
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
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
project_abstract:
DESCRIPTION (provided by applicant): Cardiac hypertrophy arises from multiple often idiopathic origins. Pressure overload induces cardiomyocyte hypertrophy and eventually can lead to heart failure. The induction of pathologic hypertrophy involves the transcriptional reprogramming of metabolic machinery. Thus hypertrophy involves a metabolic disturbance leading to cardiac dysfunction. Glucose represents the quintessential substrate for metabolism albeit to a limited extent in the heart. Less than 5% of intracellular glucose is shunted to accessory pathways such as Hexosamine Biosynthetic Pathway which forms the monosaccharide donor for the post-translational modification known as O-linked-2-N- acetylglucosamine (O-GlcNAc). Many of the signaling pathways involved with the development of cardiac hypertrophy particularly during the transition to failure have been elegantly elucidated by other laboratories. The present proposal will unravel the contribution of O-GlcNAc signaling to the development of hypertrophy in addition to understanding a potential role in pressure overload-induced heart failure. PGC-11 is recognized as a regulator of metabolism and its loss can aggravate pressure overload- induced heart failure. Nothing is currently known about the relationship between O-GlcNAc signaling and PGC-11 during the development of hypertrophy and heart failure. One goal of the present study is to investigate the mechanisms through which O-GlcNAc signaling participates in myocyte response to hypertrophy by focusing on the transcriptional activity of PGC-11. This proposal will identify the role O-GlcNAc signaling in the development of cardiomyocyte hypertrophy and heart failure by: 1) Determining what changes occur in O-GlcNAc signaling in the myocardium during hypertrophy. 2) Ascertaining whether O-GlcNAc signaling is essential during hypertrophy. 3) Identifying the influence of O-GlcNAc signaling on PGC-11 during hypertrophy. 4) Elucidating the impact of altered O-GlcNAc signaling at the mitochondrial level during hypertrophy. The PI's hypothesis is that O-GlcNAc signaling is augmented during the development of hypertrophy and such augmentation of is maladaptive. Furthermore the PI posits that O-GlcNAc signaling suppresses PGC-11 and such changes are instrumental in the development of the hypertrophied and failing phenotypes. Findings from such mechanistic studies will provide novel insights into the pathophysiologic mechanisms operative during the development of hypertrophy and in the failing myocardium. PUBLIC HEALTH RELEVANCE: One limiting factor in identifying more efficacious treatments for heart failure is our lack of understanding of the initiation and progression of the disease particularly as it relates to metabolic signaling. The present series of studies will provide keen insights into mechanisms of cardiac growth metabolism and the development of pressure overload induced hypertrophy which will lay the groundwork for the creation of new therapeutics.

project_terms:
Acetylglucosamine;Address;Affect;Biological;Biology;Cardiac;Cardiac Myocytes;Development;Disease Progression;Enzymes;Failure (biologic function);Fostering;Functional disorder;Glucose;Goals;Growth;Heart;Heart Diseases;Heart Hypertrophy;Heart failure;Hexosamines;Hypertrophy;Knockout Mice;Laboratories;Lead;Light;Link;Metabolic;Metabolism;Mitochondria;Mitochondrial Proteins;Modification;Monosaccharides;Muscle Cells;Myocardium;Nuclear Protein;Nuclear Proteins;O-GlcNAc transferase;Pathologic;Pathway interactions;Patients;Phenotype;Post-Translational Protein Processing;Proteins;Role;Series;Signal Pathway;Signal Transduction;Testing;Ventricular;design;in vivo;innovation;insight;novel;novel therapeutics;pressure;public health relevance;response

public_health_relevance:
Project SynopsisOne limiting factor in identifying more efficacious treatments for heart failure is our lack ofunderstanding of the initiation and progression of the disease particularly as it relates tometabolic signaling. The present series of studies will provide keen insights into mechanismsof cardiac growth metabolism and the development of pressure overload inducedhypertrophy which will lay the groundwork for the creation of new therapeutics.


application_id: 7901596
project_number: 5R01AI067434-05
project_title: Eradication of a Primary Filariasis Vector Population at an Endemic Field Site
administering_ic: NIAID
award_notice_date: 2010-09-16
application_type: 5
activity_code: R01
ic: AI
serial_number: 067434
program_official: COSTERO-SAINT DENIS, ADRIANA
project_start_date: 2006-08-15
project_end_date: 2011-07-31
study_section: Special Emphasis Panel[ZRG1-VB-P(01)Q]
contact_pi_person_id: 7876895
contact_pi: DOBSON, STEPHEN LEONARD
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-08-01
project_abstract:
DESCRIPTION (provided by applicant): Lymphatic filariasis (Elephantiasis) affects over 120 million people in 80 countries with 1.2 billion people at risk worldwide. Over 90% of infections are caused by Wuchereria bancrofti for which humans are the exclusive host. The absence of a nonhuman reservoir suggests that transmission can be interrupted by elimination of the microfilariae reservoir via community-wide treatment (Mass Drug Administration MDA) which is the current focus of the Global Programme for the Elimination of Lymphatic Filariasis. While MDA strategies can be effective history suggests that elimination of lymphatic filariasis in Polynesia is unachievable without vector control. An example is provided by Maupiti in French Polynesia where filariasis persists despite five decades of constant MDA. The biology of the primary mosquito vector Aedes polynesiensis has been blamed for MDA failure. Since mosquitoes are obligate vectors of W. bancrofti this suggests an additional approach for filariasis elimination: eradication of the mosquito vectors will break the disease transmission cycle. Unfortunately Ae. polynesiensis currently cannot be controlled much less eradicated. Here we propose a novel strategy in which releases of male Ae. polynesiensis mosquitoes infected with Wolbachia bacteria result in the sterilization of female mosquitoes at a field site endemic for filariasis transmission. Repeated male releases will permit the eradication of the targeted Ae. polynesiensis population. We emphasize that male mosquitoes do not blood feed and therefore are not disease vectors. Furthermore the proposed strategy employs a naturally occurring bacteria infection and does NOT include genetically modified organisms. The preliminary studies section describes how a l/Vo/bac/7/a-infected Ae. polynesiensis strain has been generated and shown to sterilize female mosquitoes from Maupiti. The research plan describes laboratory and field cage tests of the eradication strategy followed by field trials in which the Ae. polynesiensis population is eradicated from an endemic focus of filariasis. Additional experiments describe the characterization of the targeted field site (an uninhabited islet in Maupiti) prior to during and following the field trial. Prior to the field trial experiments will compare the release strain and field population in their fitness population dynamics and genetic structure mating competitiveness and vector competency. Recently developed techniques for generating new Wolbachia infection types in mosquitoes via microinjection will be used to generate additional mosquito strains for use in vector eradication strategies. We discuss the development of a model for the transitioning from field trials to a vector eradication campaign. We emphasize that a vector eradication strategy is more feasible economically relative to ongoing vector control in Polynesia. Furthermore the geography of Polynesia will simplify an eradication approach by reducing problems of vector reinfestation via immigration. Relevance: History demonstrates that the current global effort to eliminate lymphatic filariasis can fail in the Pacific if it continues to rely solely upon a mass drug administration (MDA) strategy. The proposed research will demonstrate a strategy for eradicating the primary mosquito vector of filariasis at an endemic field site. Integration of the vector eradication strategy and the MDA approach will facilitate filariasis elimination in areas where MDA alone has failed.

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


application_id: 7901455
project_number: 5P20RR024489-03
project_title: Center of Excellence in Diabetes and Obesity Research
administering_ic: NCRR
award_notice_date: 2010-07-16
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 024489
program_official: CANTO, MARIA TERESA
project_start_date: 2008-09-26
project_end_date: 2013-06-30
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
project_abstract:
Description (provided by applicant): This proposal is to promote the initiation and the development of a multi-disciplinary thematic Center of Excellence in Diabetes and Obesity Research at the University of Louisville. The primary objective and the central focus of the Center are to enable promote and support scientific research related to the cardiovascular causes and consequences of diabetes and obesity. The second major aim of program is to provide mentoring and guidance to junior investigators in the Center with the overall goal of discovering new tierapies for the treatment and prevention of diabetes and obesity. Specific objectives of the program are to: [1) Build and develop a thematic multi-disciplinary research center focused on diabetes and obesity research; (2) Develop basic and clinical understanding of the molecular mechanisms of diabetes and obesity and how they contribute to the burden of cardiovascular disease (3) Expand and bridge on-going research programs to integrate current expertise into a thematically coherent program (4) Promote collaborative interactions to build complementary individual and multi-investigator research projects; (6) Foster research careers of junior investigators leading to their development as independent principal investigators; (7) Build upon our existing research capabilities and core facilities to provide the state-of-the-art infrastructure support; (8) Develop a nationally-competitive program that will attract the best clinical cardiology fellows graduate students postdoctoral fellows and new faculty; and most importantly to discover new and effective means for preventing and treating diabetes and obesity. The five related projects of junior investigators for the first phase of the Center are to: (1) delineate the contribution of oxidative stress to hyperglycemic injury and test whether antioxidant interventions prevent vascular injury in diabetes; (2) to investigate whether hyperglycemia impairs the cardiac reparative potential of mesenchymal stem cells and whether transplantation of stem cells with greater potential for cardiac repair will result in greater improvement of function in diabetic hearts following infarction; (3) delineate the mechanisms contributing to premature senescence and death of cardiac progenitor cells leading to non-ischemic diabetic cardiomyopathy; (4) examine whether hyperglycemic stimulation of foam cell formation is mediated by ER stress and the unfolded protein response and if drug that act as chemical chaperone ameliorate accelerated atherogenesis in diabetic animals; and (5) identify the regulation of high glucose-triggered inflammatory signaling (NF-KB activation) by specific micro RNAs. These investigations will be supported by establishing state-of-the-art core facilities in confocal microscopy flow cytometry cardiovascular pathology animal models and imaging and function. We believe that a Center focused on diabetes and obesity will add to the academic success of the University and will have a positive impact on the field of diabetes and obesity research in the nation.

project_terms:
Animal Model;Animals;Antioxidants;Arts;Blood Vessels;Cardiac;Cardiac Death;Cardiology;Cardiovascular Diseases;Cardiovascular Pathology;Cardiovascular system;Centers of Research Excellence;Chemicals;Clinical;Clinical Trials;Confocal Microscopy;Core Facility;Development;Diabetes Mellitus;Diabetes prevention;Epidemiology;Faculty;Flow Cytometry;Foam Cells;Fostering;Future;Glucose;Goals;Heart;Hyperglycemia;Image;Individual;Infarction;Inflammatory;Injury;Intervention;Investigation;Mediating;Mentors;Mesenchymal Stem Cells;MicroRNAs;Modality;Molecular;Molecular Chaperones;Obesity;Oxidative Stress;Pharmaceutical Preparations;Phase;Postdoctoral Fellow;Principal Investigator;Proteins;Regulation;Research;Research Infrastructure;Research Personnel;Research Project Grants;Signal Transduction;Stem cell transplant;Stem cells;Stress;Sum;Testing;Universities;Work;atherogenesis;career;diabetic;diabetic cardiomyopathy;functional improvement;graduate student;novel therapeutics;premature;prevent;programs;repaired;response;senescence;success


application_id: 7901385
project_number: 5R00NS061803-05
project_title: Novel Model Systems Link Floridean Starch Metabolism to Lafora Disease
administering_ic: NINDS
award_notice_date: 2010-07-21
application_type: 5
activity_code: R00
ic: NS
serial_number: 061803
program_official: STEWART, RANDALL R
project_start_date: 2007-09-15
project_end_date: 2013-02-28
study_section: NSS
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-09-01
project_abstract:
The focus of this grant is to determine how laforin the only phosphatase in Kingdom Animalia with acarbohydrate binding domain regulates changes in glycogen metabolism in vertebrates and invertebrates.Humans develop insoluble aberrant glycogen particles called Lafora bodies as a result of an autosomalrecessive neurodegenerative disorder known as Lafora disease (LD). LD is the result of loss of functionmutations to either of the genes that encode the dual specific phosphatase laforin or the E3 ubiquitin ligasemalin. LD is one of five major progressive myoclonus epilepsies (PMEs) and presents as a single seizure inthe second decade of the patient's life; this single event is followed by progressive central nervous systemdegeneration intellectual decline severe motor deterioration and finally death within ten years. Laforin isreported as only being conserved among vertebrates; however I recently identified laforin orthologs in fiveunicellular eukaryotes including Cyanidioschyzon merolae and Toxoplasma gondii. Additionally thebiochemical composition of LBs closely resembles that of floridean starch; an insoluble carbohydratemolecule synthesized by the same unicellular eukaryotes that have laforin. Thus there is a direct correlationbetween the presence of laforin and synthesis of floridean starch amongst invertebrates. I propose thatlaforin is involved in degrading insoluble carbohydrates either to utilize it as an energy source forinvertebrates or to protect cellular integrity in mammals and that laforin's role in these two processes isconserved from invertebrates to humans. To determine laforin's function in glycogen metabolism I will: 1)Perform rigorous phylogenomic and functional analyses of laforin's invertebrate orthologs. I will identifyevery invertebrate laforin ortholog via bioinformatics and will determine the mRNA expression proteinexpression and subcellular localization of laforin in C. merolae and T. gondii. 2) Define laforin's target infloridean starch metabolism in Toxoplasma gondii. I will generate multiple transgenic T. gondii organismsidentify any phenotypes that these organisms manifest and employ these organisms in biochemicalexperiments to identify laforin's substrate or a signal transduction pathway that it modulates. Additionally Iwill utilize a T. gondii laforin knockout line to test if other laforin orthologs complement any observedphenotype. 3) Characterize the role of floridean starch in the human myoclonic epilepsy Lafora disease. Iwill extend my findings from the invertebrate systems to the vertebrate system and LD. I will test any laforinsubstrate identified in the previous sections to see if it is also a substrate of laforin in the mammalian system.Additionally I will fully characterize the interaction I previously identified between malin and laforin todetermine both the cause and effect of this interaction. The findings from all three of my specific aims canbe applied to identify new therapeutic targets to treat LD and possibly other polyglucosan diseases.

project_terms:
Animalia;Binding (Molecular Function);Biochemical;Biochemistry;Bioinformatics;Biological Models;CNS degeneration;Carbohydrates;Cellular biology;Cessation of life;Complement;Complex;Deterioration;Disease;Eimeria tenella;Energy-Generating Resources;Eukaryota;Event;Genes;Genetic;Glycogen;Grant;Human;Invertebrates;Knock-out;Lafora Disease;Life;Link;Mammalian Cell;Mammals;Metabolism;Modeling;Motor;Myoclonic Epilepsies;Neurodegenerative Disorders;Neurologic;Organism;Orthologous Gene;Paramecium tetraurelia;Patients;Phenotype;Phosphoric Monoester Hydrolases;Process;Progressive Myoclonic Epilepsies;Protista;Reporting;Role;Seizures;Signal Transduction Pathway;Single Seizures;Starch;System;Testing;Tetrahymena thermophila;Tonic - clonic seizures;Tonic Seizures;Toxoplasma gondii;Transgenic Organisms;Vertebrates;carbohydrate metabolism;genome sequencing;glycogen metabolism;loss of function mutation;mRNA Expression;new therapeutic target;novel;particle;polyglucosan;protein expression;research study;ubiquitin-protein ligase


application_id: 7901234
project_number: 3P30AG028383-04S1
project_title: ALZHEIMER'S DISEASE CORE CENTER
administering_ic: NIA
award_notice_date: 2009-08-18
opportunity_number: RFA-AG-05-010
application_type: 3
activity_code: P30
ic: AG
serial_number: 028383
suffix: S1
program_official: SILVERBERG, NINA B
project_start_date: 2009-09-01
project_end_date: 2012-08-31
study_section: ZAG1-ZIJ-4(M1)
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This is an application for a 5-year Alzheimer's Disease Core Center (ADCC) at the University of Kentucky's Sanders-Brown Center on Aging. The application consists of the Clinical Biostatistics and Data Management Neuropathology Education and Information Transfer Cores. The UK ADC has developed a strong program in the clinical neuropathological educational and research aspects of AD that serves as a resource for the university community state and region for the past twenty years. The major goals of the UK ADC are to: a) provide clinical data serum plasma buffy coats and CSF from thoroughly evaluated longitudinally followed normal control subjects AD and non-AD dementing disorders and postmortem material from these subjects to investigators of AD and aging at UK and to national and international investigators b) continue longitudinal investigation of presymptomatic AD mild cognitive impairment early AD mixed dementias and other dementias and normal brain aging with autopsy as an end point; c) develop new research initiatives and attract new investigators to research in neurodegeneration and aging; d) place emphasis on serving minorities and involving them in research; and e) participate in multicenter efforts including NACC ADCS ADNI and others. The Clinical Core will evaluate and longitudinally follow 500 subjects in the Normal Control (BRAINS) Clinic and 200 patients with AD and other dementias in the Dementia Research Clinic - all with prearranged autopsies. This core will maintain a satellite clinic for African Americans in north Lexington in conjunction with an Administration on Aging grant for education of minorities about dementing disorders. The Neuropathology Core provides short postmortem interval brain specimens CSF and synaptosomes from longitudinally followed normal MCI early and late AD patients and non-AD dementias to investigators and maintains a tissue bank. The Biostatistics and Data Management Core manages data sets from the other Cores prepares the Uniform Data Set and the Minimum Data Set for submission to the NACC and provides statistical design and analysis. The Education and Information Transfer Core assists with recruiting control and dementia subjects provides research and clinical training for investigators and healthcare professionals and disseminates information to the lay public.


application_id: 7900479
project_number: 5R01NS045734-07
project_title: Vascular responses as therapeutic targets after SCI
administering_ic: NINDS
award_notice_date: 2010-07-13
opportunity_number: PA-08-015
application_type: 5
activity_code: R01
ic: NS
serial_number: 045734
program_official: KLEITMAN, NAOMI
project_start_date: 2004-05-03
project_end_date: 2011-07-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 6902570
contact_pi: HAGG, THEO
other_pis: WHITTEMORE, SCOTT R
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
Endothelial cells (ECs) are among the first cells to die acutely after contusive spinal cord injury (SCI) triggeringsecondary degeneration including axon and myelin loss. Remaining and newly angiogenic blood vessels areleaky and dysfunctional enabling detrimental leukocyte infiltration. We made substantial progress inunderstanding these vascular responses and targeting them with pharmacological treatments forneuroprotection. For example i.v. treatments with the Tie2 ligand angiopoietin-1 (Ang1) plus the v3/51integrin agonist C16 provide high levels of functional recovery vascular and tissue protection and reducedinflammation. Key to the success is the i.v. route which is rapid and clinically highly relevant. However it isessential that we find additional therapeutic methods or targets as we rescue less than half of the bloodvessels and white matter and no long-projecting descending pathways. This is critically important whenconsidering translation of these EC-targeted treatments to humans which do not recover neurological functioneven remotely as well as mice do. We suggest that this is possible by adding the neuroprotective effects ofprotein tyrosine phosphatase (PTP) inhibition which rescues axons projecting through the injury site. Toidentify additional opportunities for neuroprotective treatments Aim 1 will determine whether PTP inhibition canfurther enhance the effect of C16+Ang1 on EC survival and tissue sparing and whether EC sparing mediatesrescue of long-projecting axons and whether this involves VE-PTP which normally inactivates Tie2. We havealso found new avenues to study and modulate angiogenesis which we now recognize as one of the criticaland beneficial EC response to SCI. We developed a novel microvascular purification method and using EC-specific microarrays identified thrombospondin-1 (TSP-1) a potent anti-angiogenic factor which also inducesEC apoptosis as the most highly upregulated gene (60-fold) in these vessels 24 hours post-SCI. Aim 2 willdelineate the role of CD36 and CD47 two domain-specific TSP-1 EC receptors in mediating vascularresponses after SCI. We will take both gain and loss of function pharmacological approaches in vivo.Subsequent in vitro experiments will address mechanism(s) of successful treatments. These 2 revised aimswill identify additional molecular targets and much better EC-targeted intravenous treatments for improvedtissue locomotor function following traumatic SCI.

project_terms:
Acute;Address;Agonist;Angiogenic Factor;Angiopoietin-1;Apoptosis;Axon;Blood Vessels;CD36 gene;CD47 gene;Cell Death;Cell Survival;Cell physiology;Cells;Chronic;Data;Endothelial Cells;Figs - dietary;Functional disorder;Funding;Genes;Homeostasis;Hour;Human;In Vitro;Infiltration;Inflammation;Injury;Integrins;Intravenous;Knockout Mice;Lead;Leukocytes;Ligands;Mediating;Methods;Modeling;Molecular;Molecular Target;Mus;Myelin;Nervous System Physiology;Outcome;Pathway interactions;Pharmaceutical Preparations;Pharmacological Treatment;Protein Tyrosine Phosphatase;Recovery of Function;Role;Route;Signal Transduction;Site;Spinal cord injury;Therapeutic;Therapeutic Intervention;Thrombospondin 1;Tissues;Translating;Translations;Traumatic CNS injury;Wallerian Degeneration;angiogenesis;design;functional loss;functional outcomes;improved;in vivo;loss of function;minimally invasive;nervous system disorder;neuroprotection;neurovascular unit;novel;receptor;research study;response;stroke;success;therapeutic angiogenesis;therapeutic target;white matter

public_health_relevance:
Project relevanceWe use complementary classes of neuroprotective pharmacological agents that target endothelial cell deathand dysfunction as well as therapeutic angiogenesis using intravenous delivery which is rapid and clinicallyhighly relevant to acute neurotrauma in humans. If successful our studies would pave the way for translatinga minimally-invasive pharmacological strategy relevant to acute human neurological disorders includingtraumatic CNS injury and stroke. Our treatments also lead to much reduced inflammation which is relevant toa large number of more chronic conditions.


application_id: 7899934
project_number: 5R01HL090749-03
project_title: Myocardial Stiffness in Diastolic Heart Failure
administering_ic: NHLBI
award_notice_date: 2010-08-17
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 090749
program_official: LIANG, ISABELLA Y
project_start_date: 2008-09-01
project_end_date: 2013-05-31
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 8356696
contact_pi: CAMPBELL, KENNETH S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Diastolic heart failure is a major cause of illness and death. The condition is nearly always associated with increased ventricular stiffness and is more common in elderly and/or obese populations. There are no effective clinical treatments. The central hypothesis underlying this research is that diastolic myocardial stiffness is the sum of an 'active' stiffness component (due to myosin heads that continue to cycle during diastole) and a 'passive' stiffness component (attributed to titin collagen elastin and intermediate filaments). The proposed research determines the relative contributions from these components in preparations ranging from single myocytes to whole hearts and uses these results to create a predictive computational model of diastolic stiffness. Specific Aim 1 will identify the molecular components responsible for the increased stiffness of myocardium from aged rats. The working hypothesis is that the increased stiffness reflects slowed acto-myosin kinetics. Experiments will measure the mechanical properties of myocardium from 6 18 22 and 26-month-old Fischer 344 rats by subjecting chemically permeabilized single myocytes and multicellular preparations to repeated stretches at different levels of calcium activation. Additional experiments will measure ventricular stiffness in the different aged animals by rapidly inflating balloons placed inside the left ventricles of Langendorff-perfused hearts. Titin and myosin isoform content will be measured by gel electrophoresis. Collagen and elastin content and collagen cross-linking will be determined using histological and biochemical techniques. Specific Aim 2 will use identical methods to identify the molecular components responsible for the increased myocardial stiffness evident in a rat model of diet-induced obesity. The working hypothesis for this aim is that the elevated myocardial stiffness observed in obese Sprague-Dawley rats reflects increased collagen content and/or collagen cross-linking. Specific Aim 3 uses the experimental results from Aims 1 and 2 to create a predictive computational model of diastolic stiffness. The model framework will consist of elastic and visco-elastic elements (representing titin collagen elastin and intermediate filaments) arranged in parallel with a spatially-explicit simulation of acto-myosin interactions. Model parameters will be determined by multi-dimensional optimization. The final model will be used to test predictions about the cross-bridge component of myocardial stiffness and should prove useful for assessing the likely effects of potential new treatments for diastolic heart failure. NARRATIVE This research is relevant to public health because it seeks to identify why hearts become excessively stiff in a common cardiovascular disease called Diastolic Heart Failure. The experimental results should help scientists to develop better treatments for the disease in overweight and elderly patients.

project_terms:
Actins;Affect;Age;Aging;American;Animal Model;Animals;Biochemical;Calcium;Cardiac;Cardiovascular Diseases;Categories;Catheters;Cessation of life;Characteristics;Clinical;Clinical Treatment;Collagen;Computer Simulation;Control Animal;Control Groups;Data;Diagnosis;Diastole;Diastolic heart failure;Diet;Disease;EFRAC;Elastin;Elderly;Elements;Etiology;Extracellular Matrix;Failure (biologic function);Fat-Restricted Diet;Fatty acid glycerol esters;Figs - dietary;Filament;Functional disorder;Future;Gene Expression;Head;Health Care Costs;Heart;Heart failure;Histological Techniques;Inbred F344 Rats;Individual;Intermediate Filaments;Kinetics;Left ventricular structure;Measurement;Measures;Mechanics;Methods;Modeling;Molecular;Molecular Profiling;Muscle Cells;Myocardial;Myocardium;Myosin ATPase;Myosin Heavy Chains;Obesity;Overweight;Patients;Physiological;Preparation;Principal Investigator;Property;Protein Isoforms;Proteins;Rat-1;Rattus;Relative (related person);Research;Research Project Grants;Resistance;Sampling;Scientist;Simulate;Sprague-Dawley Rats;Stretching;Sum;Symptoms;Takeda brand of pioglitazone hydrochloride;Techniques;Testing;Therapeutic;Tissues;Ventricular;Ventricular Function;Weight;Work;age related;aged;connectin;crosslink;feeding;gel electrophoresis;in vivo;mathematical model;older patient;particle;pressure;public health medicine (field);research study;sensor;simulation


application_id: 7899909
project_number: 5R21OH008934-02
project_title: Evaluation of Safety Training Supervision and Injury Among Working Teenagers.
administering_ic: NIOSH
award_notice_date: 2010-06-11
opportunity_number: PAR-06-552
application_type: 5
activity_code: R21
ic: OH
serial_number: 008934
program_official: FREDERICK, LINDA J
project_start_date: 2009-08-01
project_end_date: 2012-07-31
study_section: Safety and Occupational Health Study Section[SOH]
contact_pi_person_id: 8476117
contact_pi: ZIEROLD, KRISTINA MARIE
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  A teenager is hurt on the job every 40 seconds and one dies every five days. According to the National Pediatric Trauma Registry and the National Center for Health Statistics occupational injuries are the fourth leading cause of death among youth ages 10 to 19 years; led only by motor vehicle crashes violence and recreational injuries. Teenagers are about twice as likely as adults to suffer injuries resulting in workers' compensation claims and emergency room visits. Safety training and workplace supervision are important elements in preventing occupational injury in young workers. Limited information about the safety training experiences and workplace supervision exists for teen workers. Most of the data is limited to prevalence estimates captured by surveys of teens. The proposed pilot study by a new investigator will evaluate work-place safety training workplace supervision work habits and occupational injury among a diverse group of working high school teenagers. Questionnaires will be administered to over 3500 teens in three large diverse public high schools in Jefferson Country Kentucky. The questionnaires which will be developed by the investigators using focus groups and cognitive interviews with working teens will be administered two times during the grant period; once in May to capture teen's experiences during school-year employment and once in September to capture teen's experiences during the summer. The data from the questionnaires will be used to accomplish three specific aims: (1) delineate the nature and amount of safety training that the teenagers have received during their current employment and determine if differences exist between races genders ages and occupations (2) delineate the nature of workplace supervision and determine if differences exist between races genders ages and occupations and (3) determine if teenagers with structured safety training and workplace supervision are less likely to report being injured at work. This project has several strengths including: (1) it is the first and only study to address safety training and workplace supervision among a large sample of teenagers (2) it will be the first study to evaluate teen's understanding and experiences of safety training (3) it will enroll a racially and ethnically diverse population of teens so that the investigators will be able to compare experiences across race and ethnicity as well as gender and age (3) it will be the first to address the role of safety training and supervision in workplace injury. No studies to date have evaluated teenager's experiences with safety training and supervision including what teens define as training. Safety training and supervision are important elements in preventing work-related injury. Information from this study can be used to begin developing an effective program based on teen's needs and experiences.  
  
Public Health Relevance:  Injury among working youth is a major public health problem. The National Pediatric Trauma Registry and National Center for Health Statistics report that injuries due to occupation rank fourth in injuries among youth aged 10 to 19 years led only by motor vehicle wrecks violence and recreational injuries. Safety training and workplace supervision are two methods useful in preventing occupational injury. Currently there is limited information regarding safety training and supervision for teen workers. The information that does exist on safety training is limited to prevalence estimates and there is no information about workplace supervision. This study will be the first to conduct an in-depth assessment of safety training and supervision among teenage workers. In addition it will be the first to evaluate the role safety training and supervision play in work-related injury.

public_health_relevance:
PROJECT NARRATIVEInjury among working youth is a major public health problem. The National Pediatric Trauma Registry andNational Center for Health Statistics report that injuries due to occupation rank fourth in injuries among youthaged 10 to 19 years led only by motor vehicle wrecks violence and recreational injuries. Safety training andworkplace supervision are two methods useful in preventing occupational injury. Currently there is limitedinformation regarding safety training and supervision for teen workers. The information that does exist onsafety training is limited to prevalence estimates and there is no information about workplace supervision.This study will be the first to conduct an in-depth assessment of safety training and supervision among teenageworkers. In addition it will be the first to evaluate the role safety training and supervision play in work-relatedinjury.


application_id: 7899770
project_number: 5R01CA073599-11
project_title: Redox Regulation of Tumor Suppression by MnSOD
administering_ic: NCI
award_notice_date: 2010-06-24
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 073599
program_official: JOHNSON, RONALD L
project_start_date: 1998-09-01
project_end_date: 2013-07-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this research is to elucidate the mechanisms by which the mitochondrial antioxidant enzyme manganese containing superoxide dismutase (MnSOD) modulates the carcinogenesis action of tumor promoters and UV radiation. Our studies in the previous funding period indicate that overexpression of MnSOD suppresses the incidence and multiplicity of papillomas in the 7-12-dimethylbenz (a) anthracene (DMBA)/ 12-O tetradecanoylphorbol-13-acetate (TPA) multistage skin carcinogenesis model. MnSOD- mediated tumor suppression is in part mediated by reduction of AP-1 activation and expression of proliferation related genes. Unexpectedly reduction of MnSOD by heterozygous knockout of the MnSOD gene does not result in increased tumor incidence or multiplicity using the DMBA/TPA model. The lack of increased susceptibility to DMBA/TPA-induced tumors in the MnSOD knockout mice is due in part to an increase in both apoptosis and proliferation after TPA treatment. Administration of MnSOD mimetic without interfering with TPA-induced apoptosis is very effective in reducing DMBA/TPA-induced skin papillomas in MnSOD-deficient mice. We also found that the increased apoptosis in MnSOD-deficient mice is associated with increased p53 accumulation in the mitochondria and reduced MnSOD expression. Based upon these novel findings we propose that activation of p53 enhances apoptosis in part via modulation of mitochondrial antioxidant defense capacity and that the tumor suppression effect of MnSOD is mediated in part by p53. Two specific aims are designed to test these hypotheses using TPA and UV radiation as the prototype oxidative stress generating carcinogens. The results of the proposed studies will provide insights into the common mechanisms by which MnSOD levels modulate apoptosis induced by chemical or UV radiation during an early stage of skin carcinogenesis. They will also enhance our understanding of the p53-dependent and -independent tumor suppression role of MnSOD. Identification of a common mechanism by which tumor promoter and UV radiation cause apoptosis would provide a means for developing a mechanistic based intervention that would prevent the development of skin cancers caused by a wide range of carcinogens. Thus this timely and important study will likely have a large scale impact on human health. PUBLIC HEALTH RELEVANCE:  Skin cancer is the most common human malignancy in the United States. Many chemicals and Ultraviolet radiation (UV) are well-established agents that cause skin cancer. We have recently found that by modulating the interaction between an essential antioxidant enzyme MnSOD and a key tumor suppressor protein p53 the incidence of skin tumors can be drastically reduced. In this application we will extend from this novel finding to determine how this interaction acts to prevent skin cancer and will perform proof-of-concept experiments to verify the feasibility of using the knowledge to be learned to prevent the development of skin cancer resulting from exposure to UV and other oxidative stress generating chemical carcinogens.

project_terms:
910-Dimethyl-12-benzanthracene;Acetates;Affect;Anthracenes;Antioxidants;Apoptosis;Biochemical;Cancer Etiology;Carcinogens;Cell Fractionation;Chemicals;Confocal Microscopy;Coupled;Development;Enzymes;Exposure to;Funding;Gene Targeting;Genes;Genetic Transcription;Goals;Health;Human;Immunoprecipitation;Incidence;Injury;Intervention;Knock-out;Knockout Mice;Knowledge;Learning;Malignant Neoplasms;Manganese;Manganese Superoxide Dismutase;Mediating;Mitochondria;Modeling;Molecular Biology;Mus;Nuclear;Oxidation-Reduction;Oxidative Stress;Papilloma;Phase;Predisposition;Process;Protein p53;Radiation;Regulation;Research;Role;Skin;Skin Cancer;Skin Carcinogenesis;Skin Neoplasms;Skin Papilloma;Skin Tissue;Staging;Superoxide Dismutase;TP53 gene;Testing;Tetradecanoylphorbol Acetate;Time;Transcription Factor AP-1;Tumor Promoters;Tumor Suppression;Tumor Suppressor Proteins;UV Radiation Exposure;Ultraviolet Rays;United States;Wild Type Mouse;base;carcinogenesis;cell growth;chemical carcinogen;design;insight;irradiation;mimetics;novel;nucleophosmin;overexpression;prevent;prototype;public health relevance;research study;skin cancer prevention;tumor


application_id: 7899765
project_number: 5R01CA083237-10
project_title: Molecular Mechanisms of Metastasis Suppression by NM23
administering_ic: NCI
award_notice_date: 2010-06-23
application_type: 5
activity_code: R01
ic: CA
serial_number: 083237
program_official: WOODHOUSE, ELIZABETH
project_start_date: 1999-08-01
project_end_date: 2011-07-31
study_section: Cancer Genetics Study Section[CG]
contact_pi_person_id: 7875382
contact_pi: KAETZEL, DAVID M
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-08-01
project_abstract:
DESCRIPTION (provided by applicant): While mechanisms regulating oncogenesis have been elucidated substantially in recent years comparatively little is yet known about the mechanisms that underlie metastasis of tumor cells the ultimate cause of death in cancer. Metastasis suppressor genes play pivotal roles in controlling this process but only a handful have been identified. NM23 ("negative in metastasis") genes represent the first described metastasis suppressors and are recognized for their antimetastatic activity in melanoma breast and gastric carcinoma. The overall goal of this project to systematically dissect the molecular mechanisms and genomic pathways underlying the metastasis suppressor activity of NM23. We recently found that the NM23-H1 isoform is a 3'-5' exonuclease (3'5' EXO) an activity often associated with genome integrity apoptosis and chromatin remodeling. Although there is clear potential relevance of these processes to malignant progression we will also measure the extent to which the nucleoside diphosphate kinase (NDPK) and histidine kinase (hisK) activities of NM23-H1 contribute to its metastasis suppressor properties. In Specific Aim 1 we will complete a detailed structure-function analysis to delineate the active site of the 3'5 EXO and characterize a panel of mutants harboring lesions that selectively disrupt the 3'5' EXO NDPK and hisK functions of the NM23-H1 molecule. The mutants will be used as molecular tools to determine the relative contributions of each to suppression of the metastatic phenotype (Specific Aim 2) in human melanoma cells using cell culture and in vivo models to measure tumorigenic and metastatic potential. Gene expression changes elicited by expression of NM23-H1 variants will be determined by microarray analysis and real-time PCR (Specific Aim 3). Correlational analysis will identify NM23-regulated genes whose expression tracks with metastatic phenotype and metastatic progression. Functional relevance of identified genes will be validated by viral-mediated overexpression and knockdown approaches. In Specific Aim 4 we will directly test the DMA repair activity of NM23-H1 in mammalian and yeast cell models and identify the relevant enzymatic function. These studies should provide the first systematic analysis of pathways through which NM23 proteins oppose metastasis in multiple cancer types and therefore could suggest novel strategies to combat this final and intractable stage of the disease.

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


application_id: 7899583
project_number: 1R01GM089684-01A1
project_title: DNA repair mechanisms in trinucleotide repeat instability
administering_ic: NIGMS
award_notice_date: 2010-05-06
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: GM
serial_number: 089684
suffix: A1
program_official: KRASNEWICH, DONNA M
project_start_date: 2010-06-01
project_end_date: 2014-05-31
study_section: Molecular Genetics A Study Section[MGA]
contact_pi_person_id: 7875365
contact_pi: LI, GUO-MIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of the project is to understand the mechanisms by which cells maintain trinucleotide repeat (TNR) stability. Expansions of TNR sequences e.g. (CAG)n and (CTG)n are tightly associated with progression of certain human neurological and neurodegenerative diseases including Huntington's disease (HD) and myotonic dystrophy. However the mechanisms and factors that promote/prevent TNR expansions are unknown. Because CAG and CTG repeats form thermo- stable hairpins with multiple A-A and T-T mispairs in the hairpin stem respectively DNA mismatch repair (MMR) and TNR hairpin repair have been proposed to play major roles in TNR maintenance. Surprisingly previous studies in transgenic mice suggest that mismatch recognition protein MSH2- MSH3 heterodimer (also called MutS2) promotes (CAG)n expansions by binding to (CAG)n-formed hairpins and inhibiting their repair. Our recent studies have shown that human cells catalyze error-free repair of (CAG)25 and (CTG)25 hairpins in a nick-directed PCNA-dependent manner. The repair targets the nicked strand for incisions at the repeat sequences followed by repair DNA synthesis using the continuous strand as a template thereby ensuring TNR stability. However MutS2 does not inhibit stimulates (CAG)25 or (CTG)25 hairpin repair. Interestingly our preliminary studies have shown that cell lines derived from HD patients are defective in (CAG)n hairpin repair hinting possible pathogenesis for HD. In this application Specific Aim 1 is to evaluate the model that the MMR system promotes (CAG)n expansion. Human and animal cell lines with or without MutS2 overexpression will be examined for their ability to repair (CAG)n hairpins in vitro and to replicate CAG repeats in vivo. Determination of TNR hairpin repair activity and (CAG)n stability in these cells will clarify if the MMR system is responsible for (CAG)n expansions in human cells. Specific Aim 2 is to further test the hypothesis that hairpin repair defects are associated with TNR diseases by screening hairpin repair proficiency in cell lines derived from HD patients. Specific Aim 3 is to purify and characterize a protein required for (CAG)n hairpin repair but defective in an HD cell line. A successful completion of the proposed work will provide significant insight into the mechanisms of TNR expansions and the etiology of TNR expansion-associated diseases.  
  
PUBLIC HEALTH RELEVANCE: Expansion of simple nucleotide repeats in DNA is the genetic basis for more than 40 human familial neurological neurodegenerative and neuromuscular disorders including Huntington's disease myotonic dystrophy Friedreich ataxia and fragile X syndrome. The repeat expansion can occur in any part of a gene and leads to a defective gene product. However how the repeat units expand and what cellular mechanism(s) prevent such an expansion in normal population are not fully understood. This application is to identify protein components that promote or prevent repeat expansions. A successful completion of the proposed work will provide significant insight into the pathogenesis underlying diseases associated with repeat expansions and approaches to develop effective treatments for the diseases.

project_terms:
Animals;Binding (Molecular Function);Biochemical;Biological Assay;CAG repeat;Cell Line;Cells;DNA;DNA Repair;DNA biosynthesis;Defect;Disease;Ensure;Etiology;Fragile X Syndrome;Friedreich Ataxia;Generations;Genes;Genetic;Genome;Goals;Hela Cells;Human;Huntington Disease;In Vitro;Lead;Length;Link;MSH2 gene;MSH3 gene;Maintenance;Mismatch Repair;Modeling;Myotonic Dystrophy;Nerve Degeneration;Neurodegenerative Disorders;Neurologic;Neuromuscular Diseases;Nuclear Extract;Nucleotides;Pathogenesis;Pathway interactions;Patients;Play;Population;Protein Binding;Proteins;RNA Interference;Role;Screening procedure;Site;Surgical incisions;System;Testing;Transgenic Mice;Trinucleotide Repeat Expansion;Trinucleotide Repeats;Work;base;effective therapy;in vivo;insight;overexpression;prevent;public health relevance;repaired;research study;stem

public_health_relevance:
Expansion of simple nucleotide repeats in DNA is the genetic basis for more than40 human familial neurological neurodegenerative and neuromuscular disordersincluding Huntington's disease myotonic dystrophy Friedreich ataxia and fragileX syndrome. The repeat expansion can occur in any part of a gene and leads toa defective gene product. However how the repeat units expand and whatcellular mechanism(s) prevent such an expansion in normal population are notfully understood. This application is to identify protein components that promoteor prevent repeat expansions. A successful completion of the proposed work willprovide significant insight into the pathogenesis underlying diseases associatedwith repeat expansions and approaches to develop effective treatments for thediseases.


application_id: 7898787
project_number: 5P30AG028383-04
project_title: BIOSTATISTICS AND DATA MANAGEMENT CORE
administering_ic: NIA
opportunity_number: RFA-AG-05-010
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1
subproject_number: 9002
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
budget_end_date: 2010-06-30
funding_mechanism: Research Centers
project_abstract:
The Biostatistics and Data Management Core (BDMC) has become a major part of the infrastructure of
the University of Kentucky Alzheimer's Disease Center (ADC). It plays an increasingly important role in data
management especially in reporting multiple data sets to NACC. This Core also provides an important
service in experimental design and statistical analysis to the ADC and affiliated AD research. The BDMC
has two specific aims one related to quality data management and the other related to effective statistical
consultation.
The first specific aim is to maintain a centralized database of the information collected by all ADC cores
pilot projects and affiliated AD and aging studies in an integrated manner. Relevant activities that support
this specific aim include: ensuring confidentiality at the subject level and security at the database level with
appropriate backup; assisting in the development of data collection forms and entering all data into the
centralized relational database in an accurate manner; training ADC personnel to practice quality data
collection procedures and to meet BDMC standards; providing expertise on data management procedures to
all ADC personnel and affiliated investigators; monitoring the flow of data in the longitudinal normal control
and AD cohorts and the minority satellite clinic; providing monthly summaries to the ADC Executive
Committee on subject recruitment retention and follow up; creating appropriate subsets of the database for
approved investigators and collaborative projects and archiving all such requests; and reporting accurate
and complete datasets to NACC.
The second specific aim is to provide expertise on experimental design and statistical analysis to ADC
cores pilot projects and affiliated AD projects. Relevant activities that support this specific aim include:
consultation for investigators in the early stages of all projects grant submissions presentations and
manuscripts; reviewing all ADC pilot projects for statistical content; collaborating with other Alzheimer's
Disease Centers on special projects of mutual interest such as periodic conferences on quantitative
methodologies in AD research; and incorporating advances in statistical methodology for interpreting and/or
analyzing data collected.
In addition this Core continues to contribute to the literature with innovative studies on statistical
methodology in AD research. It also participates in the training of graduate students postdoctoral
researchers and young investigators.

project_terms:
Aging;Alzheimer's Disease;Archives;Biometry;Biostatistics Core;Clinic;Clinical;Confidentiality;Consultations;Data;Data Analyses;Data Collection;Data Set;Databases;Dementia;Development;Ensure;Experimental Designs;Funding;Grant;Human Resources;Kentucky;Literature;Manuscripts;Methodology;Minority;Monitor;Participant;Pilot Projects;Play;Procedures;Program Research Project Grants;Reporting;Research;Research Infrastructure;Research Personnel;Research Project Grants;Role;Security;Services;Staging;Training;Universities;cohort;data management;follow-up;graduate student;innovation;interest;meetings;neuropathology;symposium


application_id: 7898025
project_number: 1C06RR030625-01
project_title: BSL-3/ABSL-3 Expansion for Select Agent Translational Research
administering_ic: NCRR
award_notice_date: 2010-02-17
opportunity_number: RFA-RR-09-008
application_type: 1
activity_code: C06
ic: RR
serial_number: 030625
program_official: MCCULLOUGH, WILLIE
project_start_date: 2010-02-17
project_end_date: 2015-02-16
study_section: Special Emphasis Panel[ZRR1 STRB-1 (04)]
contact_pi_person_id: 1957095
contact_pi: PIERCE, WILLIAM 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: Y
project_abstract:
DESCRIPTION (provided by applicant): The University of Louisville proposes to expand the existing Center for Predictive Medicine (CPM) Regional Biocontainment Laboratory (RBL) to support work with select agents utilizing rodents rabbits and ferrets as animal models in long term efficacy/product evaluation studies. The expansion will facilitate translational studies with the addition of hematology clinical and whole-animal imaging services and related services for efficacy/product evaluation. Further the expansion will provide receiving quarantine and vaccination space in ABSL2 prior to animal studies transfer to ABSL3. ABSL2/3 animal holding areas and BSL3 support labs will be developed as suites with shared procedure and exam spaces. These suites will take advantage of existing trimodal live animal imaging capacities within the CPM and other existing support services. Importantly the expansion will provide infrastructure for GLP studies with the Provantis(tm) system or other similar types of validated monitoring systems. The existing RBL was designed and built with infrastructure that will easily accommodate this future growth. Existing utilities (electrical sanitary sewer storm sewer water service fire service emergency power) are sized and installed to accommodate expansion. Existing animal cage and rack wash and sterilization equipment within the existing CPM can accommodate this additional capacity. Security infrastructure (internal to facility and site fencing setbacks and intrusion barriers) loading dock and service areas will be installed. All are adequate for expanded capacity. Site capacity for expansion is also accommodated and the existing facility is designed to attain LEED certification. This will permit the expansion to also achieve LEED certification and be in step with other sustainability initiatives set forth by the University of Louisville.

project_terms:
Animal Model;Animals;Area;Certification;Clinical;Docking;Emergency medical service;Equipment;Evaluation;Evaluation Studies;Ferrets;Fire - disasters;Future;Growth;Hematology;Image;Laboratories;Life;Medicine;Monitor;Oryctolagus cuniculus;Procedures;Quarantine;Research Infrastructure;Rodent;Security;Services;Site;Sterilization;System;Translational Research;Universities;Vaccination;Water;Work;design;translational study


application_id: 7897922
project_number: 5R01DE015254-08
project_title: Pattern Recognition of P. gingivalis Virulence Factors
administering_ic: NIDCR
award_notice_date: 2010-07-13
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DE
serial_number: 015254
program_official: LUNSFORD, DWAYNE
project_start_date: 2004-07-01
project_end_date: 2013-07-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6712964
contact_pi: HAJISHENGALLIS, GEORGIOS
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Innate immunity plays a central role in infection-driven inflammatory conditions including periodontitis which is one of the most common chronic disorders of infectious origin in humans. However successful microbial pathogens such as the periodontopathogen Porphyromonas gingivalis have evolved mechanisms which proactively manipulate the innate immune response. Subversion of innate immunity may additionally undermine the overall host defense since the innate immune response plays an instructive role in adaptive immunity. This research proposal has been designed to investigate and elucidate molecular mechanisms whereby P. gingivalis modifies innate immune signaling pathways leading to increased virulence and persistence within the host. Although innate recognition and signaling in response to P. gingivalis is primarily mediated by the Toll-like receptor 2 (TLR2)-centered pattern recognition apparatus preliminary studies indicate that this periodontal pathogen instigates the association of the chemokine receptor CXCR4 with TLR2 resulting in cross-talk and altered signaling downstream of TLR2. On the basis of additional preliminary evidence the overall hypothesis is that P. gingivalis through its cell surface fimbriae exploits CXCR4 and manipulates TLR2 intracellular signaling in ways that suppress the proinflammatory/antimicrobial pathway but enhance a distinct proadhesive pathway; both of these activities have the potential to increase the survival capacity of the pathogen thereby prolonging P. gingivalis infection and potentiating its impact on periodontal disease. In vitro immunological approaches using transfected cell lines or primary macrophages will elucidate the mechanistic basis of TLR2/CXCR4 cross-talk which is hypothesized to involve the cAMP-dependent protein kinase A. Moreover the biological significance of the putative exploitation of CXCR4 by P. gingivalis will be investigated using a mouse periodontitis model in which a CXCR4 antagonist (AMD3100) is expected to suppress P. gingivalis virulence. The long-term objective of investigating CXCR4-dependent mechanisms whereby P. gingivalis manipulates TLR2 signaling is to identify effective antagonists for redirecting the innate response to benefit the host. The fight against HIV and AIDS has produced a number of drugs including CXCR4 antagonists which are available for investigation in other formidable diseases where CXCR4 may play a pathophysiological role. Such CXCR4 antagonists may find therapeutic application in human periodontitis.   
  
PUBLIC HEALTH RELEVANCE: Periodontitis is one of the most common chronic disorders of infectious origin in humans and is also associated with systemic diseases such as atherosclerosis. This research proposal presents evidence that the periodontal pathogen P. gingivalis exploits a host receptor namely CXCR4 for undermining host defense and promoting its virulence. We believe that CXCR4 antagonists may find therapeutic application in human periodontitis and in this context; we will test a CXCR4 antagonist (AMD3100) for its ability to inhibit P. gingivalis-induced periodontitis in a mouse model.

project_terms:
1-Phosphatidylinositol 3-Kinase;AMD3100;Acquired Immunodeficiency Syndrome;Adhesives;Alveolar Bone Loss;Atherosclerosis;Biological;Biological Response Modifiers;CD14 gene;CXCR4 Signaling Pathway;CXCR4 gene;Cell Line;Cell surface;Chronic Disease;Complex;Cyclic AMP-Dependent Protein Kinases;Data;Development;Disease;Exhibits;Fluorescence Resonance Energy Transfer;Funding;HIV;Host Defense;Human;Immune;Immune response;In Vitro;Infection;Inflammation;Inflammatory;Integrins;Investigation;Mediating;Microbe;Modeling;Molecular;Mus;Natural Immunity;Oral cavity;Pathway interactions;Pattern Recognition;Pattern recognition receptor;Periodontal Diseases;Periodontitis;Peritonitis;Pharmaceutical Preparations;Play;Porphyromonas gingivalis;Proteins;Publishing;Research;Research Proposals;Role;Signal Pathway;Signal Transduction;Structure;Systemic disease;Testing;Therapeutic;Toll-Like Receptor 2;Toll-like receptors;Virulence;Virulence Factors;Virulent;Work;adaptive immunity;antimicrobial;base;bone loss;chemokine receptor;cytohesin-1;design;fight against;fimbria;fimbrillin;in vivo;macrophage;microbial;microbicide;mouse model;mutant;novel;pathogen;periodontopathogen;prevent;public health relevance;receptor;response


application_id: 7897920
project_number: 5R01DE014605-09
project_title: Intra- and interspecies communication in oral bacteria
administering_ic: NIDCR
award_notice_date: 2010-07-13
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DE
serial_number: 014605
program_official: LUNSFORD, DWAYNE
project_start_date: 2003-02-01
project_end_date: 2013-07-31
study_section: Special Emphasis Panel[ZRG1-MOSS-E(02)S]
contact_pi_person_id: 1859425
contact_pi: DEMUTH, DONALD R
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Periodontal disease is caused by bacterial pathogens that thrive in a complex multi-species community that forms in the gingival pocket. The initiation and growth of this biofilm requires sophisticated molecular communication among the species in this community. We have shown that the periodontal pathogens A. actinomycetemcomitans and P.gingivalis produce the quorum sensing signal autoinducer2 (AI-2) which may be involved in intra- and interspecies communication among these organisms. AI-2 regulates genes involved in virulence iron acquisition and biofilm formation and is likely an important mechanism that allows these organisms to sense and respond to their local environment. Our general hypothesis that A. actinomycetemcomitans and P. gingivalis respond differentially to AI-2 and the outcomes of these signaling systems are tailored to the specific survival strategies that are employed by these organisms in the oral biofilm. The long term goal of this proposal is to determine if AI-2 quorum sensing can be exploited to control oral biofilm development. The specific aims are to characterize the AI-2 receptors and early events that initiate the cellular response to AI-2 of A. actinomycetemcomitans and P. gingivalis since these are ideal targets for therapeutic intervention. We will determine if importation and intracellular processing of AI-2 is required to initiate the cellular response. The QseBC and GppX two component signaling systems of A. actinomycetemcomitans and P. gingivalis respectively will be studied to determine if they couple the detection of AI-2 to downstream gene regulatory events. Finally we will determine if the function of high and low affinity AI-2 receptors in A. actinomycetemcomitans facilitate colonization of both early and mature biofilms by this organism. These studies will define at the molecular level how oral pathogens detect and interact with AI-2 and how these processes lead to alteration in gene expression that facilitates their growth in microbial communities. This information may facilitate the rational design of new therapeutics that may control the growth and development of oral microbial biofilms by interfering with their communication pathways. PUBLIC HEALTH RELEVANCE: Periodontitis is a common oral disease that is present in up to 40% of the adult population in the United States and annual expenditures for treatment and prevention of periodontitis are over $14 billion. Periodontitis caused by a community of bacteria that live in the gingival pocket but it is also associated with systemic illnesses such as heart disease. Preventing periodontal disease requires eliminating or controlling the microbial community. Our studies examine a unique microbial communication pathway that facilitates the development of the bacterial community. We seek to develop new potential drugs that prevent the formation of microbial communities by interfering with this communication system in order to control or prevent periodontitis.

project_terms:
Actinobacillus actinomycetemcomitans;Address;Adult;Affinity;Aldehyde-Lyases;Bacteria;Cell Communication;Cell Density;Cell physiology;Cells;Communication;Communities;Complex;DNA Binding;Data;Dental Plaque;Dependency (Psychology);Detection;Development;Dose;Environment;Enzymes;Escherichia coli;Event;Expenditure;Feedback;Funding;Gene Expression;Gene Mutation;Genes;Gingival Pocket;Goals;Growth;Growth and Development function;Heart Diseases;Helix-Turn-Helix Motifs;Hemin;Hybrids;Individual;Iron;Kinetics;Lead;Life;Link;Mediating;Microbial Biofilms;Modeling;Molecular;Monitor;Mouth Diseases;Nutrient;Operon;Oral;Oral cavity;Organism;Outcome;Pathway interactions;Periodontal Diseases;Periodontitis;Pharmaceutical Preparations;Phosphotransferases;Population;Porphyromonas gingivalis;Prevention;Process;Promoter Regions (Genetics);Promotor (Genetics);Proteins;Regulator Genes;Reporting;Salmonella;Sampling;Series;Signal Transduction;Site;Solutions;System;Testing;Therapeutic Intervention;Transport Process;United States;VAI-2;Vibrio;Virulence;Virulence Factors;design;microbial;microbial community;mutant;novel therapeutics;oral bacteria;oral biofilm;oral pathogen;pathogen;prevent;public health relevance;quorum sensing;receptor;response;sensor;uptake

public_health_relevance:
Periodontitis is a common oral disease that is present in up to 40% of the adult population in the UnitedStates and annual expenditures for treatment and prevention of periodontitis are over $14 billion.Periodontitis caused by a community of bacteria that live in the gingival pocket but it is also associated withsystemic illnesses such as heart disease. Preventing periodontal disease requires eliminating or controllingthe microbial community. Our studies examine a unique microbial communication pathway that facilitatesthe development of the bacterial community. We seek to develop new potential drugs that prevent theformation of microbial communities by interfering with this communication system in order to control orprevent periodontitis.


application_id: 7897907
project_number: 5R01DE018215-03
project_title: NUTRITIONAL EPIGENETICS AND OROFACIAL DEVELOPMENT
administering_ic: NIDCR
award_notice_date: 2010-07-14
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DE
serial_number: 018215
program_official: SCHOLNICK, STEVEN
project_start_date: 2008-08-01
project_end_date: 2012-07-31
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 1861667
contact_pi: GREENE, ROBERT M
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Two Two major health care issues are inexorably intertwined: a woman's health and prenatal development of her unborn child. The nutritional value of a woman's diet is critical to both. Folate a water- soluble B vitamin is required for the growth of fetal tissues and normal development of the CNS and orofacial complex. In addition folate supplies the necessary methyl donors for DNA methylation one of the most common epigenetic modifications regulating gene expression in mammalian cells. Incorrect methylation patterns can result in developmental malformations including craniofacial defects. With a frequency of 1-2 in 1000 live births orofacial clefts represent nearly one-half of all craniofacial anomalies While methylation of DNA is a common epigenetic modification that contributes to the control of gene expression in mammalian cells the notion of tissue/cell-specific methylation of discrete CpG islands as a means of regulating morphogenesis of the orofacial region and as a molecular target of nutritional (folate) deficiency as outlined in the present proposal is novel. Thus the global hypothesis we plan to address in the current proposal is that folate deficiency can disrupt the normal methylation state of specific candidate genes and contribute to development of orofacial clefts.   
  
Specific aims/hypotheses addressed in the current application include:   
1 - CpG islands with tissue-dependent and differentially methylated regions (t-dmrs) exhibit distinct spatio- temporal methylation patterns during ontogeny of the 1st branchial arch.   
  
2 - Conditions of gestational folate deficiency that result in facial clefts elicit alterations in CpG island methylation patterns in the 1st branchial arch. These patterns can be reversed with folate supplementation regimens that rescue the phenotype.   
  
3 - Altered promoter CpG methylation patterns regulate expression of genes of the TGF( Signal Transduction Family in the embryonic 1st branchial arch from folate deficient (Folbp1-/-) mice.   
  
4 - Folate deficiency (Folbp1-/-) contributes to the genesis of orofacial clefts by inducing excess apoptosis within the developing 1st branchial arch.

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


application_id: 7897846
project_number: 5R21AI083861-02
project_title: A novel ternary virulence system in plague
administering_ic: NIAID
award_notice_date: 2010-05-28
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: AI
serial_number: 083861
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2009-07-22
project_end_date: 2011-12-30
study_section: Special Emphasis Panel[ZRG1-IDM-A(90)S]
contact_pi_person_id: 1864206
contact_pi: STRALEY, SUSAN C
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Yersinia pestis is the causative agent of plague in humans. We have discovered a chromosomally located bicistronic operon that encodes a novel pair of interacting surface proteins called YadB and YadC (collectively referred to as YadB-C) that belong to the trimeric autotransporter family. YadB-C promotes invasion of epithelioid cells and J774A.1 macrophage-like cells; but unlike most trimeric autotransporters appears not to promote adherence. Interestingly invasive activity requires the presence of the surface aspartyl protease Pla which also is an adhesin/invasin independent of its protease activity. In addition Pla selectively degrades YadB causing YadB-C complexes to disappear and its presence is required for release of a fragment of YadC into the culture medium. Like Pla YadB-C is crucial for virulence in bubonic plague; however it is not essential for virulence in pneumonic plague. This raises the possibility that the dominant virulence function of these proteins is directed against acute inflammation which occurs rapidly in bubonic plague but only late in pneumonic plague. The small plasmid that encodes Pla is unique to Y. pestis and its acquisition is believed to have been a key step in the evolution of Y. pestis from Y. pseudotuberculosis. Thus yadBC may be another link to the high virulence of Y. pestis. We hypothesize that YadB YadC and Pla constitute a novel ternary virulence mechanism to counteract inflammatory defenses that are mobilized early in bubonic plague. The goal of this proposed R21 project is to define the essential roles of the 3 components of this system. In Aim 1 we will exploit a set of Y. pestis strains carrying variants of these components to determine the roles of Pla YadC and YadB in YadB-C function in vitro. In Aim 2 we will characterize infections of normal mice and mice lacking key inflammatory cells to develop a hypothesis for the innate defense target of YadB-C. PUBLIC HEALTH RELEVANCE: These studies will contribute to our broad understanding of pathogenesis in the face of an acute inflammatory response. Accordingly the study of YadB-C will inform studies in many other bacterial systems in addition to improving our understanding of the pathogenesis of plague.

project_terms:
Acute;Adherence (attribute);Aspartic Endopeptidases;Bacterial Adhesins;Cells;Complex;Culture Media;Epithelioid Cells;Evolution;Face;Family;Goals;Human;In Vitro;Infection;Inflammation;Inflammatory;Inflammatory Response;Link;Membrane Proteins;Mus;Operon;Pasteurella pseudotuberculosis;Pathogenesis;Peptide Hydrolases;Phenotype;Plague;Plasmids;Pneumonic Plague;Role;Surface;System;Variant;Virulence;Yersinia pestis;improved;macrophage;novel;protein function;public health relevance

public_health_relevance:
These studies will contribute to our broad understanding of pathogenesis in the face of an acuteinflammatory response. Accordingly the study of YadB-C will inform studies in many other bacterialsystems in addition to improving our understanding of the pathogenesis of plague.


application_id: 7897809
project_number: 5R01CA116784-04
project_title: Abl Kinases in growth factor signaling motility and invasion
administering_ic: NCI
award_notice_date: 2010-08-05
application_type: 5
activity_code: R01
ic: CA
serial_number: 116784
program_official: AULT, GRACE S
project_start_date: 2007-08-01
project_end_date: 2012-07-31
study_section: Intercellular Interactions Study Section[ICI]
contact_pi_person_id: 1918859
contact_pi: PLATTNER, RINA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-08-05
project_abstract:
DESCRIPTION (provided by applicant):  Growth factors modulate cell proliferation migration and survival. Precise regulation of these processes is critical as deregulated growth factor signaling increases cellular migration and drives tumor invasion and metastasis the major cause of cancer-related deaths. Although Abl nonreceptor tyrosine kinases initiate leukemia development their role in the development or progression of solid tumors has not been studied. Previously we showed that Abl kinases are activated downstream of growth factor receptors via Src family kinases and PLC-yl and influence growth factor-mediated cytoskeletal reorganization and migration in fibroblasts. Deregulation of growth factor receptors Src kinases and PLC-yl in solid tumors such as breast cancer drives tumor invasion and metastasis. Our studies demonstrate that the Abl kinases are dramatically activated downstream of activated growth factor receptors and Src kinases in highly aggressive breast cancer cell lines and promote breast cancer invasion. Based on these findings the overall objective of this proposal is to characterize the conditions leading to Abl kinase activation in breast cancer and to define invasion-promoting signaling cascades controlled by the Abl kinases. We hypothesize that Abl family kinases translate and direct growth factor receptor and Src kinase-mediated signals to influence breast cancer invasion and metastasis. Three Specific Aims are described to evaluate this hypothesis: 1) Determine the conditions that activate the Abl kinases in breast cancer; 2) Identify biological and molecular mechanisms by which Abl kinases promote breast cancer cell invasion; and 3) Determine whether activation of the Abl kinases promotes breast cancer metastasis in vivo. To achieve our goal we will combine biochemical molecular cellular and whole animal approaches using: 1) primary breast tissue breast cancer cell lines; RNAi and inhibitors to identify mechanisms and conditions of Abl activation; 2) RNAi chemotaxis invasion and zymography assays to identify mechanisms by which Abl kinases promote invasion; and 3) in vivo metastasis studies to assess whether activation of the Abl kinases promotes metastasis in immune- compromised mice. These data are likely to provide mechanistic insight into how abnormal regulation of the Abl kinases contributes to breast cancer progression which may aid in the discovery of new drug combinations for preventing breast cancer metastasis and decreasing mortality.

project_terms:
ABL1 gene;Adhesions;Affect;Animals;Basement membrane;Biochemical;Biological;Biological Assay;Blood;Blood Vessels;Breast Cancer Cell;Cancer Etiology;Cancer cell line;Cell Line;Cell Proliferation;Cells;Cessation of life;Chemotaxis;Cultured Tumor Cells;Cytoskeletal Modeling;Data;Development;Distant;Dominant-Negative Mutation;Drug Combinations;Epidermal Growth Factor Receptor;Family;Fatty acid glycerol esters;Fibroblasts;Figs - dietary;Goals;Growth Factor;Growth Factor Receptors;Immune;In Vitro;In-Migration;Invaded;Label;Location;Malignant Neoplasms;Mammary Gland Parenchyma;Mammary Neoplasms;Mammary gland;Matrix Metalloproteinases;Mediating;Metalloproteases;Metastatic Lesion;Molecular;Mortality Vital Statistics;Mus;Neoplasm Metastasis;Normal tissue morphology;Organ;PTK2 gene;PTPN11 gene;Pathway interactions;Pharmaceutical Preparations;Phosphotransferases;Platelet-Derived Growth Factor Receptor;Play;Primary Neoplasm;Process;Proliferating;Protein Tyrosine Kinase;Proteins;RNA Interference;Regulation;Resistance development;Role;Signal Transduction;Site;Solid Neoplasm;Stream;Tail;Testing;Translating;Tumor Cell Invasion;Veins;base;c-abl Proto-Oncogenes;cell motility;fluorescence imaging;in vivo;inhibitor/antagonist;insight;kinase inhibitor;leukemia;malignant breast neoplasm;migration;prevent;research study;rho;src-Family Kinases;tumor;tumor progression


application_id: 7897637
project_number: 5R01DK082419-02
project_title: Group X sPLA2: Regulator of lipolysis and glucose homeostasis
administering_ic: NIDDK
award_notice_date: 2010-07-23
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 082419
project_start_date: 2009-08-01
project_end_date: 2014-07-31
study_section: Integrative Physiology of Obesity and Diabetes Study Section[IPOD]
contact_pi_person_id: 7875305
contact_pi: WEBB, NANCY R
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-08-01
project_terms:
Adipocytes;Adipose tissue;Adrenergic Agents;Animal Model;Biology;Blood Circulation;Bone Marrow Cells;Bone Marrow Transplantation;Cardiovascular Diseases;Catabolism;Cell physiology;Data;Defect;Deposition;Developed Countries;Development;Diabetes Mellitus;Diet;Dyslipidemias;Endocrine;Endocrine Glands;Equilibrium;Exhibits;Exposure to;Fatty acid glycerol esters;Functional disorder;Glucose;Goals;Hepatic;Hormones;Human;Hydrolysis;Hypertrophy;Impairment;Individual;Inflammation;Inflammatory Response;Insulin;Insulin Resistance;Link;Lipids;Lipolysis;Metabolic;Metabolic Diseases;Metabolic syndrome;Metabolism;Mus;Non-Insulin-Dependent Diabetes Mellitus;Nonesterified Fatty Acids;Nutrient;Obesity;Peripheral;Phospholipase A2;Play;Production;Proteins;Regulation;Risk Factors;Role;Study models;Testing;Tissues;Transplantation;Triglycerides;Wild Type Mouse;adipokines;adrenergic;base;blood glucose regulation;energy balance;glucose metabolism;glucose uptake;group X secretory phospholipase A(2);improved;insight;insulin secretion;insulin sensitivity;insulin signaling;macrophage;mouse model;novel;prevent;public health relevance;reconstitution;research study;response;sterol esterase


application_id: 7896537
project_number: 5R01HD060996-07
project_title: Effect of prior event on reward value
administering_ic: NICHD
award_notice_date: 2010-07-16
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HD
serial_number: 060996
program_official: FREUND, LISA S
project_start_date: 2009-07-20
project_end_date: 2012-12-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 7876951
contact_pi: ZENTALL, THOMAS R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
In the original 5-year proposal we had 3 specific aims. In order to compress some of the work such that it would accomplishable within a 24 month period we have deleted a part in aim 2 while retaining aims 1 and 3. We also combined parts of aim 2 with aim 3. In addition to accomplish this work in a shorter time frame we will need to hire 5 individuals (see Jobs saved or created below). We have selected aims that will contribute significantly to the base of scientific knowledge on this topic. The aims we can accomplish in are numbered and explained below.

project_terms:
Accounting;Adoption;Affect;Animals;Appearance;Behavior;Behavioral;Clinical;Cognitive Dissonance;Columbidae;Complex;Conditioned Stimulus;Development;Discrimination (Psychology);Eating;Event;Exertion;Food;Food Preferences;Food deprivation (experimental);Hand;Human;Human Characteristics;Hunger;Learning;Measures;Modeling;Monitor;Nature;Organism;Procedures;Psychological reinforcement;Psychologist;Relative (related person);Research;Rewards;Role;Schedule;Signal Transduction;Stimulus;Testing;Time;To specify;Training;Translating;Work;base;cultural values;experience;novel;preference;public health relevance;reinforcer;research study;response;social;theories

public_health_relevance:
Project NarrativeRelevanceThe proposed research will investigate the effect of prior events such as effort on the value ofreinforcers that follow. To produce healthy behavior particularly in institutional and educationalsettings it is important to have sustained effective reinforcers. If prior effort or other prior lesspreferred events affect the value of the reinforcer that follows it suggests that the value ofreinforcers may be enhanced by increasing the effort required to obtain them.


application_id: 7896467
project_number: 5U50OH007547-10
project_title: Southeast Center for Agricultural Health and Injury Prevention
administering_ic: NIOSH
award_notice_date: 2010-07-12
opportunity_number: PAR-06-057
application_type: 5
activity_code: U50
ic: OH
serial_number: 007547
program_official: ROBISON, WILLIAM
project_start_date: 2006-09-30
project_end_date: 2011-09-29
study_section: ZOH1-SBO(53)R
contact_pi_person_id: 2080884
contact_pi: MCKNIGHT, ROBERT H.
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The Southeast Center for Agricultural Health and Injury Prevention at the University of Kentucky proposes to continue functioning as a NIOSH Agricultural Center for the next five-year funding cycle. The Center is one of three centers of excellence within the College of Public Health. The Center's location on a land-grant campus permits extraordinary collaboration between the primary disciplines assembled for the projects in this renewal: Public health agriculture behavioral science communications economics education engineering epidemiology nursing and toxicology. The Center's theme is Trans-disciplinary Approaches to Improve Agricultural Safety and Health in the Southeast. The choice of a trans-disciplinary theme rather than a multidisciplinary one reflects the ability of our faculty and staff to work together in ways that comprehensively and synergistically build on each other's expertise and experience. The geographic region of the Center will be the ten southern states of AL FL GA KY MS NC SC TN VA and WV. In addition to an administrative/planning/outreach core a total of 11 projects are proposed. Of these projects two are comprehensive research and three are exploratory research; additionally two are prevention/intervention projects and four are education/translation projects. The issues in the 11 projects represent emerging ignored or persistent safety and health concerns in southeastern agriculture and they integratively coordinate topics including pesticide surveillance tractor overturns prison farm labor benzene exposure aquacultural health and safety education in both public health and nursing communications with farmers and others. An administrative core provides management leadership support and strategic planning for the Center as well as outreach activities to the ten states. Each year four feasibility project grants at $12500 each will be solicited and awarded. The Center strives to build public health infrastructure to reduce occupational injuries deaths poisonings diseases and illness in farming fishing and forestry. A substantial institutional commitment of $100000 and other resources will be provided by the University of Kentucky.


application_id: 7896455
project_number: 5R01HL062053-11
project_title: Host Response to P. carinii in Neonatal Mice
administering_ic: NHLBI
award_notice_date: 2010-06-07
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 062053
program_official: PEAVY, HANNAH H
project_start_date: 1998-09-30
project_end_date: 2014-06-30
study_section: AIDS-associated Opportunistic Infections and Cancer Study Section[AOIC]
contact_pi_person_id: 1945284
contact_pi: GARVY, BETH A
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): Pneumocystis pneumonia PCP) causes significant morbidity and mortality among HIV-infected individuals who are newly diagnosed failed retroviral therapy or do not have access to care. Infants are particularly susceptible to pulmonary infections and it has been recently appreciated that not only are individuals exposed to Pneumocystis early in life but infants appear to carry the infection as evidenced by the high incidence found in autopsy specimens from babies that died of SIDS. HIV-infected infants tend to have a more fulminant course of PCP likely because of the immature immune system along with depletion of CD4+ cells. In the previous funding period we found that in contrast to our hypothesis the delay in clearance of Pneumocystis we observed in neonatal mice was not solely due to elevated anti-inflammatory cytokines in the lungs through the first 3 weeks of life. Instead we found that alveolar macrophages from neonatal mice are intrinsically unresponsive to Pneumocystis. The goal for this funding period is to differentiate the contribution of environmental factors and intrinsic factors to neonatal alveolar macrophage function in response to Pneumocystis. Specifically we will test the hypothesis that: neonatal alveolar macrophages fail to respond to Pneumocystis due to a defect in signaling through pattern recognition receptors along with delayed second signals from proinflammatory cytokines or costimulatory molecules on T cells. To address this hypothesis we have proposed two aims. 1. We will determine whether alveolar macrophages from neonatal mice are intrinsically unresponsive to Pneumocystis. In vitro and in vivo experimental strategies will be used to determine whether neonatal alveolar macrophages can respond to stimuli through the dectin-1 ?-glucan receptor mannose receptor or TLR2. 2. We will determine whether secondary signals from T cells are required to stimulate neonatal alveolar macrophages. We will use adoptive transfer of cells and treatment with exogenous stimulatory molecules in an attempt to stimulate alveolar macrophages to respond to Pneumocystis. These studies are a logical extension of our previous funding period and will address the mechanisms responsible for neonatal unresponsiveness Pneumocystis. PUBLIC HEALTH RELEVANCE: Pneumocystis pneumonia (PCP) is an AIDs defining illness that is still prevalent in newly diagnosed HIV-infected individuals and those who fail therapy are non-compliant or do not have access to antiretroviral therapy. PCP often has a worse course in children due to the immaturity of the immune system. The goal of this project is to understand the function of alveolar macrophages and CD4 T cells and their interactions in infants with PCP.

project_terms:
Address;Adoptive Cell Transfers;Adult;Age;Agonist;Alveolar Macrophages;Anti-Inflammatory Agents;Anti-inflammatory;Antibodies;Autopsy;Binding (Molecular Function);CD 200;CD4 Positive T Lymphocytes;Cell physiology;Child;Cyst;Cytokine Activation;Data;Defect;Environment;Environmental Risk Factor;Epithelial Cells;Funding;Glucans;Goals;Health Services Accessibility;Immune response;Immune system;In Vitro;In-Migration;Incidence;Individual;Infant;Infection;Intrinsic factor;Life;Ligation;Lung;Macrophage-1 Antigen;Mannans;Morbidity - disease rate;Mortality Vital Statistics;Mus;Neonatal;Newly Diagnosed;Pattern recognition receptor;Phagocytosis Induction;Phenotype;Pneumocystis;Pneumocystis carinii;Pneumocystis carinii Pneumonia;Production;Regulatory T-Lymphocyte;Signal Pathway;Signal Transduction;Site;Specificity;Specimen;Stimulus;Sudden infant death syndrome;T-Lymphocyte;TLR2 gene;TNFSF5 gene;Testing;Transgenic Mice;Up-Regulation (Physiology);antiretroviral therapy;cytokine;dectin 1;in vivo;macrophage;mannose receptor;neonate;non-compliance;public health relevance;pup;receptor;response

public_health_relevance:
Pneumocystis pneumonia (PCP) is an AIDs defining illness that is still prevalent in newlydiagnosed HIV-infected individuals and those who fail therapy are non-compliant or do nothave access to antiretroviral therapy. PCP often has a worse course in children due to theimmaturity of the immune system. The goal of this project is to understand the function ofalveolar macrophages and CD4 T cells and their interactions in infants with PCP.


application_id: 7896189
project_number: 1R01DA027981-01A2
project_title: Victimization and Women in the Criminal Justice System
administering_ic: NIDA
award_notice_date: 2010-03-26
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: DA
serial_number: 027981
suffix: A2
program_official: DEEDS, BETHANY
project_start_date: 2010-04-01
project_end_date: 2015-02-28
study_section: Community Influences on Health Behavior Study Section[CIHB]
contact_pi_person_id: 6472821
contact_pi: GOLDER, SEANA
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF SOCIAL WELFARE/WORK
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This proposed study (R01; PA-07-070) will examine the heterogeneity of victimization its' relationship with substance use and psychological distress as well as the combined affect of these factors on the health seeking process among victimized women in the criminal justice (CJ) system. Study aims are to 1) identify and characterize latent class trajectories based on victimization substance use and psychological distress among 400 victimized women on probation and parole; 2) determine the extent to which women in the identified trajectory classes vary over a two year time period in levels of risk and protection in the health seeking process; and 3) examine the theory based components of the health seeking process among 400 victimized women on probation and parole. Findings from this research will be used to identify those groups of women that are most at risk for engagement in high risk behaviors (current drug use; psychological distress; HIV risk behavior; lawbreaking and continued CJ involvement) and to identify and characterize their associated levels of risk and protection in the health seeking process across a two year time period. Study findings will provide a theoretically guided understanding of the relationship among the component parts of the health seeking process that affect engagement in high risk behavior over time among this population. These data are necessary prerequisites to the development of tailored intervention strategies that target specific groups of women within the CJ system; these data can provide practitioners administrators and policy makers with direct information about which groups of women will be most amenable to which intervention/prevention approaches. Study findings have the potential to have broad relevance within the CJ system and other care systems (e.g. substance abuse and mental health treatment systems) that provide services to this marginalized and growing population.  
  
PUBLIC HEALTH RELEVANCE: The confluence of race and class among women in the CJ system means that increases in this population disproportionately affect the health and well-being of women of color particularly poor women of color; the increased involvement of women in the CJ system has perpetuated and fueled racial disparities and biases in the areas of child well-being and the child welfare system infectious diseases and other markers of public health and other domains of psychosocial functioning such as employment and educational attainment. Results of this study will contribute directly to the development of targeted intervention strategies to address the needs of this population; study results will allow for the identification of those groups of victimized women in the CJ system that are most at risk for engagement in high risk behaviors (current drug use; psychological distress; HIV risk behavior; lawbreaking and continued CJ involvement) and to characterize their associated levels of risk and protection in the health seeking process across time. Results will also provide a theoretically guided understanding of the health seeking process by which these women come to engage in high risk behavior.

project_terms:
Address;Administrator;Adult;Affect;Age;Alcohol or Other Drugs use;Area;Behavior;Child Welfare;Childhood;Cognitive;Color;Communicable Diseases;Communities;Crime;Criminal Justice;Data;Development;Drug usage;Emotions;Employment;Ethnicity aspects;Family;Goals;Growth;HIV;Health;Heterogeneity;Housing;Imprisonment;Individual;Information Systems;Intervention;Justice;Life;Longevity;Mental Health;Methodology;Nature;Pathway interactions;Pattern;Personal Satisfaction;Policy Maker;Population;Population Study;Prevention approach;Preventive Intervention;Process;Race;Research;Resources;Rewards;Risk;Risk Behaviors;Security;Services;Social support;Stress;Subgroup;Substance abuse problem;System;Testing;Time;Victimization;Woman;Women's Group;base;care systems;child well being;cohesion;coping;high risk behavior;men;parole;peer;person centered;physical conditioning;probation;psychological distress;psychosocial;public health medicine (field);public health relevance;response;self esteem;social;theories;therapy development;virtual


application_id: 7895909
project_number: 5R01DA025605-03
project_title: GABA Drugs for Cannabis-Use Disorders: Initial Mechanistic Studies in Humans
administering_ic: NIDA
award_notice_date: 2010-07-20
opportunity_number: PA-07-365
application_type: 5
activity_code: R01
ic: DA
serial_number: 025605
program_official: MONTOYA, IVAN
project_start_date: 2008-09-15
project_end_date: 2012-07-31
study_section: ZDA1-MXH-H(22)
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cannabis remains the most commonly used illicit drug worldwide including the United States. Not only does a relatively large percentage of the population report using cannabis but like other drugs of abuse a significant proportion of those persons use it habitually and meet diagnostic criteria for drug-use disorders. Moreover cannabis-use disorders are associated with treatment admission and relapse rates comparable to other drugs of abuse perceived as more harmful. Despite the significant public health concern posed by cannabis use there has been limited preclinical or clinical research that has focused explicitly on the identification and development of medications to treat cannabis-use disorders. Data from preclinical and clinical research suggest that agonist replacement treatment is an effective means to manage drug-use disorders and that this strategy would be viable for cannabis-use disorders as well. The experiments proposed here represent the initial step of evaluating GABAergic drugs as potential "agonist-like" pharmacotherapies for cannabis-use disorders. GABA is being targeted because there is substantial overlap in the effects produced by cannabinoids and drugs acting at central GABAergic systems and neuroanatomical neurochemical and behavioral studies support a functional link between cannabinoid and GABAergic systems. The studies proposed here will test the ability of the selective GABA reuptake inhibitor tiagabine the GABAA positive modulator diazepam and the GABAB agonist baclofen to enhance the behavioral and physiological effects of ?9-THC thus examining the "agonist-like" profile of GABAergic drugs with varying mechanisms of action. The primary outcome for these experiments is the interoceptive cue produced by ?9-THC. The interoceptive effects of ?9-THC will be measured using the drug-discrimination procedure which is a pharmacologically specific and sensitive means to characterize drugs and drug interactions. In addition subjective effects questionnaires psychomotor performance and memory tasks and cardiovascular and thermal measures of physiology will be included to more fully assess the effects of ?9-THC alone and in combination with GABAergic compounds. The experiments proposed here are novel and innovative because there are very few studies in humans to have tested the effects of GABAergic drugs on cannabinoids. In addition these studies are important for at least three reasons. First and perhaps most importantly the data generated from the proposed experiments will provide the direction and foundation for future studies aimed at the development of GABAergic treatments for cannabis-use disorders. Second these data will provide valuable information regarding the neurobiology of the effects of cannabinoids in humans by examining the interactions between cannabinoid and GABAergic systems. Finally these experiments will provide translational information regarding the extent to which the results from preclinical studies that have evaluated CB-GABA interactions generalize to humans. Public Health Relevance: Cannabis is the most commonly used illicit drug in the United States and its use is associated with rates of development of abuse and dependence treatment admission and relapse that are comparable to other illicit drugs that are misperceived as more harmful. Currently there is no effective pharmacological treatment for cannabis-use disorders. The experiments proposed here represent the initial step of evaluating GABAergic drugs as potential pharmacotherapies by characterizing interactions between ?9-THC and the selective GABA reuptake inhibitor tiagabine the GABAA positive modulator diazepam and the GABAB agonist baclofen.

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


application_id: 7895553
project_number: 5R01EY018603-02
project_title: Molecular Regulation of Epithelial-Mesenchymal Transitions
administering_ic: NEI
award_notice_date: 2010-07-15
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 018603
program_official: SHEN, GRACE L
project_start_date: 2009-08-01
project_end_date: 2012-07-31
study_section: Intercellular Interactions Study Section[ICI]
contact_pi_person_id: 1877760
contact_pi: DEAN, DOUGLAS CHASE
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
Heterozygous mutations in the ZFHX1A zinc finger homeodomain transcriptional repressor in humans cause posterior polymorphous corneal dystrophy a pathologic epithelization of the corneal endothelium. In mutant mice there are also epithelial vs. mesenchymal-like transition defects in the corneal endothelium with acquisition of E cadherin expression and loss of vimentin expression. Such epithelial/ectodermal vs. mesenchymal transition defects are also evident in the embryonic retina optic nerve cartilage mesenchyme and subventricular zones of the brain. These defects are also characterized by expansion of the epithelial marker E-cadherin and contraction of the mescenchymal/ectodermal markers vimentin and GFAP. At these affected sites there is also induction of cell proliferation inhibitor genes and accordingly diminished proliferation is seen at these sites in mutant embryonic tissues in mice injected with BrdU. Similar epithelial vs. mesenchymal transition defects are recapitulated in cells cultured from mutant embryos and the proliferative defects are also evident thereby providing a culture model to study the biochemistry of ZFHX1A action. We propose a series of experiments to assess the mechanism of transcriptional control by ZFHX1a and thus its molecular role in defining a balance between epithelia vs. mesenchymal phenotype and control of cell proliferation in vivo and in cultured cells.

project_terms:
Affect;Binding (Molecular Function);Biochemistry;Boxing;Brain;Bromodeoxyuridine;CDKN2A gene;Cartilage;Cell Aging;Cell Culture Techniques;Cell Cycle;Cell Cycle Arrest;Cell Proliferation;Cells;Complex;Corneal Endothelium;Corneal dystrophy;Cultured Cells;Defect;Dependence;E-Cadherin;EP300 gene;Ectoderm Cell;Elements;Embryo;Epigenetic Process;Epithelial;Epithelium;Equilibrium;Eye;Face;Family;Fibroblasts;Gene Targeting;Genes;Genetic Transcription;Glial Fibrillary Acidic Protein;Human;Loss of E-cadherin Expression;Lysine;Malignant Neoplasms;Mediating;Mesenchymal;Mesenchyme;Modeling;Modification;Molecular;Mus;Mutant Strains Mice;Mutation;Optic Nerve;Palate;Pathologic;Pathway interactions;Phenotype;Pigment Epithelium;Plasminogen Activator Inhibitor 1;Population;Principal Investigator;Proliferating;Promotor (Genetics);Regulation;Repression;Retina;Role;Series;Serum Response Factor;Signal Transduction;Site;Smooth Muscle Actin Staining Method;Snails;Stem cells;T-Lymphocyte;TP53 gene;Transcription Coactivator;Transcription Repressor/Corepressor;Transcriptional Regulation;Transferase;Up-Regulation (Physiology);Vimentin;Zinc Fingers;cancer cell;design;embryo tissue;epithelial to mesenchymal transition;falls;gene repression;homeodomain;in vivo;inhibitor/antagonist;mutant;outcome forecast;overexpression;premature;programs;research study;senescence;skeletal;stem;subventricular zone;transcription factor


application_id: 7895529
project_number: 5R01EY013632-06
project_title: Cannabinoid Receptors and Novel Antiglaucoma Drugs
administering_ic: NEI
award_notice_date: 2010-07-16
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 013632
program_official: AGARWAL, NEERAJ
project_start_date: 2003-08-01
project_end_date: 2012-07-31
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 2093529
contact_pi: SONG, ZHAO-HUI
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
Glaucoma is one of the leading causes of blindness worldwide. Elevated intraocular pressure (IOP) is the primary riskfactor for optic nerve damage in glaucoma. Many studies conducted on human subjects and animal models have shownthat marijuana and its active components cannabinoids lower IOP. This project is focused on understanding themechanisms by which cannabinoids potential therapeutic agents for glaucoma lower intraocular pressure (IOP). In theprevious funding period we have established that CB1 and CB2 cannabinoid receptors are expressed on the trabecularmeshwork (TM) cells and cannabinoid agonists enhance aqueous humor outflow through both CB1 and CB2 receptors.For the competitive renewal application of this project we hypothesize that non-CB1/CB2 cannabinoid derivatives maycause an enhancement of aqueous humor outflow through a novel non-CB1/CB2 cannabinoid receptor and the novelcannabinoid receptor may mediates the IOP-lowering effects of the non-CB1/CB2 cannabinoid agonists throughmetalloprotease (MMP)-mediated mechanisms. Two specific aims are designed to test the above three hypotheses.Specific Aim 1: To study the effects of non-CB1/CB2 cannabinoid agonists and the role of GPR55 a novel non-CB1/CB2 cannabinoid receptor on aqueous humor outflow. Specific Aim 2: To study the mechanisms of actions for theaqueous humor outflow-enhancing effects of non-CB1/CB2 cannabinoid agonists. Completing this project should providemechanistic insight regarding cannabinoid-induced enhancement of aqueous humor outflow facility. These studies shouldalso contribute to our understanding of the homeostasis of aqueous humor outflow and may lead to the development ofbetter therapeutic agents for lowering IOP.

project_terms:
Actins;Address;Agonist;Animal Model;Anterior;Anti-glaucoma Agent;Aqueous Humor;Binding (Molecular Function);Biological Assay;Blindness;Cannabinoids;Cells;Cytoskeleton;Development;Endocannabinoids;Funding;Glaucoma;Homeostasis;Hour;Immunohistochemistry;Knockout Mice;Lead;Ligands;Marihuana;Mass Fragmentography;Matrix Metalloproteinases;Measures;Mechanics;Mediating;Metabolism;Metalloproteases;Methods;Modeling;Optic Nerve;Organ Culture Techniques;Physiologic Intraocular Pressure;Play;Receptor Cannabinoid CB2;Risk Factors;Role;Stretching;System;Testing;Therapeutic Agents;Trabecular meshwork structure;Western Blotting;antiglaucoma drug;cannabinoid receptor;design;human subject;in vivo;inhibitor/antagonist;insight;mouse model;novel;pressure

public_health_relevance:
PROJECT NARRATIVECannabinoids are potential novel anti-glaucoma agents. This proposal aims to study themechanisms underlying the aqueous humor outflow-enhancing effects of synthetic andendogenous cannabinoids. These studies should provide mechanistic insight regarding theIOP-lowering effects of cannabinoids. These studies should also contribute to ourunderstanding of the homeostasis of aqueous humor outflow and may lead to thedevelopment of better therapeutic agents for lowering IOP.


application_id: 7895031
project_number: 5R01GM086888-03
project_title: Geometry of gene cophylogenies as relates to genome evolution and speciation
administering_ic: NIGMS
award_notice_date: 2010-07-01
opportunity_number: RFA-GM-08-607
application_type: 5
activity_code: R01
ic: GM
serial_number: 086888
program_official: ECKSTRAND, IRENE A
project_start_date: 2008-08-01
project_end_date: 2013-06-30
study_section: ZGM1-CBCB-5(BM)
contact_pi_person_id: 9408221
contact_pi: YOSHIDA, RURIKO
other_pis: Not Applicable
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
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):  A fundamental understanding of microbial genome and species evolution as well as human genome evolution is important for public health and medical science. This proposal addresses the concept of codivergence i.e. the divergence of one gene or species lineage concomitantly with the divergence of another. In this process two or more lineages stay closely associated with one another:  In this process two or more lineages stay closely associated with one another: genes with species and hosts with pathogens parasites or symbionts. Deviations from codivergence that are increasingly recognized in pathogen and human genomes include gene duplications lateral gene transfers between species retention of ancestral polymorphisms by balancing selection and accelerated evolution by neofunctionalization. This project will bring together complementary expertise and cross-train students in algebraic geometry and mathematical biology molecular biology and evolution of symbiotic systems and computer science and bioinformatics. The investigators propose to: (1) develop a new statistical model and corresponding methods and algorithms for simultaneous derivation of pairs of gene trees to allow rigorous tests of their codivergence or deviation from codivergence; (2) design and develop software that efficiently implements these new methods; and (3) apply such methods to the large number of genes available from genome sequences in order to better assess the history of speciation and genome evolution. Unlike existing methods based on independently constructed phylogenetic trees a novel statistical model is proposed based on polyhedral and algebraic geometry to determine whether sets of gene sequences exhibit codivergence. The method will develop two or more trees jointly to better reflect the properties of codivergent lineages. This approach will be implemented together with phylogenomic tools to characterize ancestral genomes or species modeling most-recent common ancestor species as "clouds" of associated gene lineages with related but nonidentical gene tree topologies. Because exact algorithms for these techniques will be computationally impractical for genome-scale data sets heuristics and approximations will also be developed and tested. The proposed methods will be applicable to a broad array of biological problems such as identifying codivergent and noncodivergent gene sets in whole genomes evaluating possible host-parasite codivergence and coevolution and testing codivergence of modules in multi-modular enzymes. In this project teams of students both graduate and undergraduate from all of the represented disciplines will conduct joint projects. They will learn how to gather sequence data design and use bioinformatic tools and analyze biological data with mathematics and statistics to infer gene and species relationships. Additionally a new phylogenetics course building on an existing interdisciplinary Informatics Certificate curriculum will be offered to graduate students.

project_terms:
Address;Algorithms;Bioinformatics;Biological;Data;Data Set;Derivation procedure;Discipline;Educational Curriculum;Enzymes;Equilibrium;Evolution;Exhibits;Gene Duplication;Genes;Genetic Polymorphism;Genome;Horizontal Gene Transfer;Human Genome;Informatics;Joints;Learning;Mathematical Biology;Mathematics;Medical;Methods;Modeling;Molecular Biology;Parasites;Phylogenetic Analysis;Process;Property;Recording of previous events;Research Personnel;Science;Statistical Models;Students;System;Techniques;Testing;Training;Trees;base;computer science;design;genome sequencing;graduate student;heuristics;microbial genome;novel;pathogen;public health medicine (field);software development;statistics;tool


application_id: 7894924
project_number: 5R01DA025649-02
project_title: Neuropharmacology of Tramadol: Clinical Efficacy and Abuse Potential
administering_ic: NIDA
award_notice_date: 2010-07-21
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DA
serial_number: 025649
program_official: BOUGH, KRISTOPHER J
project_start_date: 2009-08-01
project_end_date: 2012-07-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Prescription opioid misuse and abuse are increasing problems in the United States. In the 2006 National Survey on Drug Use and Health 5.2 million Americans had illicitly used a prescription opioid in the past month. National rates of illicit prescription opioid use are higher than those for heroin cocaine or methamphetamine and are exceeded only by marijuana. Moreover the number of individuals initiating illicit use of prescription opioids was greater than that for marijuana in 2004 and 2005. These findings indicate that illicit prescription opioid use represents a significant public health concern greater than that of cocaine heroin or methamphetamine and perhaps approaching that of marijuana. The increase in illicit prescription opioid use may be due to increased availability of opioid analgesics medications with significant abuse potential. Discovery and development of opioid analgesics with reduced abuse potential may serve to decrease prescription opioid misuse and the subsequent development of opioid use disorders. Tramadol is an unscheduled atypical analgesic with opioid activity. While rare cases of tramadol abuse and physical dependence have been reported it has reduced abuse potential relative to typical prescription opioids. The reduced abuse potential of tramadol has been attributed to its novel pharmacology. Tramadol is a mu opioid agonist but also blocks reuptake of serotonin and norepinephrine. The specific aim of the present application is to elucidate the relative contributions of mu opioid serotonin and norepinephrine receptor systems to the effects of tramadol using an array of pharmacologic measures relevant to its abuse potential and analgesic efficacy in human volunteers. The knowledge gained about tramadol from the proposed experiments in terms of its neuropharmacology will aid in the discovery and development of other opioid medications with reduced abuse potential. Specifically if the non-mu mediated effects of tramadol contribute to its analgesic efficacy and reduced abuse potential these findings would support the development of other analgesics with similar neuropharmacological mechanisms. This project will employ placebo-controlled randomized and double blind testing procedures to evaluate the behavioral effects of tramadol across three experiments. Overall this project will contribute important clinical information regarding the pharmacology of tramadol in relation to its analgesic efficacy and reduced abuse potential and provide basic science information about the behavioral effects of prescription opioids in humans. PUBLIC HEALTH RELEVANCE: The research proposed in this application seeks to understand better the human neuropharmacology of tramadol an atypical analgesic with opioid action that has reduced abuse potential relative to other opioid analgesics. We are seeking to understand how the neuropharmacology of tramadol influences both its analgesic efficacy and reduced abuse potential in an effort to aid development of other analgesic medications with reduced abuse potential. Developing analgesics with reduced abuse potential may reduce the prevalence of prescription opioid misuse and subsequent opioid use disorders.

project_terms:
Agonist;American;Analgesics;Animals;Basic Science;Behavioral;Clinical;Cocaine;Data;Development;Disease;Dose;Double-Blind Method;Drug usage;Enrollment;Future;Health;Heroin;Human;Human Volunteers;Hydrocodone;Hydromorphone;Individual;Knowledge;Marihuana;Measures;Mediating;Methamphetamine;Naltrexone;Neuropharmacology;Neurotransmitters;Norepinephrine;Norepinephrine Receptors;Opioid;Opioid Analgesics;Oxycodone;Performance;Pharmaceutical Preparations;Pharmacology;Physical Dependence;Physicians;Physiological;Placebo Control;Placebos;Prevalence;Procedures;Randomized;Receptors Opioid mu;Relative (related person);Reporting;Research;Rewards;Role;Serotonin;Stimulus;Surveys;System;Testing;Time;Tramadol;United States;aged;clinical efficacy;noradrenergic;norepinephrine system;novel;opioid abuse;opioid misuse;opioid withdrawal;prescription opioid;public health medicine (field);public health relevance;research study;reuptake;tramadol abuse;volunteer

public_health_relevance:
Project NarrativeThe research proposed in this application seeks to understand better the humanneuropharmacology of tramadol an atypical analgesic with opioid action that hasreduced abuse potential relative to other opioid analgesics. We are seeking tounderstand how the neuropharmacology of tramadol influences both its analgesicefficacy and reduced abuse potential in an effort to aid development of other analgesicmedications with reduced abuse potential. Developing analgesics with reduced abusepotential may reduce the prevalence of prescription opioid misuse and subsequentopioid use disorders.


application_id: 7894811
project_number: 5R03CA136444-02
project_title: Influence of Health Literacy and Cancer among Rural Patients in Rehabilitation
administering_ic: NCI
award_notice_date: 2010-07-20
opportunity_number: PAR-07-019
application_type: 5
activity_code: R03
ic: CA
serial_number: 136444
program_official: SHAIKH, ABDUL R
project_start_date: 2009-08-01
project_end_date: 2012-07-31
study_section: Special Emphasis Panel[ZRG1-RPHB-B(50)R]
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
other_pis: HUNTER, ELIZABETH G
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Health literacy has emerged as an important construct because it's four components: cultural and conceptual knowledge listening and speaking (oral literacy) writing and reading (print literacy) and numeracy affect the health outcomes of individuals. As individuals don't live in a vacuum it is important to understand the complex interaction of health literacy at multiple levels of interaction from the individual to the family health care system and community. Describing how these multiple points of view connect and influence each other for individuals with cancer and other chronic illnesses from rural Appalachian communities who are in a rehabilitation setting is the under explored focus of this study. The current study is the first step in developing a program of research designed to address these complex interactions and gaps in the literature. Through in-depth interviews and focus groups the goal of the present study is to explore the influence of health literacy from the individual family health care facility and the patient's rural home community point of view. We propose to achieve three specific aims: 1.) Describe the health literacy level of this population. 2.) Determine the supports and barriers found in an inpatient rehabilitation facility in terms of facilitating health communication and addressing potential health literacy issues. 3.) Address the impact of health literacy on the transition from a rehabilitation facility back to a person's rural home community. This descriptive pilot study is a critical first step toward our ultimate goal of developing and empirically assessing health literacy interventions for this population. Later inquiries will include an examination of current processes in a rehabilitation setting and how they positively or negatively support health communication particularly in terms of health literacy in rural populations. The long-term goal is to develop interventions that will decrease the barriers and enhance the supports in health communication to decrease poor health outcomes decrease health disparities in rehabilitation and positively influence transitions between settings for individuals with cancer and other chronic disease. PUBLIC HEALTH RELEVANCE: Low health literacy has the potential to negatively impact individuals with cancer and other chronic illness who are in a rehabilitation setting in terms of health and well-being. Low health literacy can negatively impact issues such as self-management of cancer and other chronic illness and medication adherence. This problem is possibly compounded if the individual is from a rural community transplanted to a metropolitan inpatient rehabilitation setting and then sent back to their rural community. It is important to understand how low health literacy interacts with the individual in their complex social setting including family health care setting and home community with the goal of reducing potential health disparities among this population.

project_terms:
Address;Adult;Affect;Age;Area;Back;Behavior;Belief;Cancer Survivor;Caring;Chronic;Chronic Disease;Client;Communities;Complex;Diagnosis;Disease;Elderly;Family;Family health status;Focus Groups;Goals;Health;Health Communication;Health Services Accessibility;Health care facility;Healthcare;Healthcare Systems;Home environment;Hospitals;Individual;Inpatients;Intervention;Interview;Kentucky;Knowledge;Life;Literature;Malignant Neoplasms;Medical;Oral;Outcome;Patients;Personal Satisfaction;Persons;Physical Function;Pilot Projects;Population;Population Intervention;Population Study;Premature Mortality;Printing;Process;Reading;Rehabilitation therapy;Research Design;Risk;Rural;Rural Community;Rural Population;Self Care;Self Management;Social Environment;Transplantation;Vacuum;Writing;burden of illness;cancer care;disability;falls;health disparity;health literacy;literacy;medication compliance;metropolitan;programs;public health relevance;rehabilitation service;social;standard care


application_id: 7894621
project_number: 5R01EY016782-04
project_title: Molecular Targets of Corneal Antiangiogenesis
administering_ic: NEI
award_notice_date: 2010-07-16
application_type: 5
activity_code: R01
ic: EY
serial_number: 016782
program_official: SHEN, GRACE L
project_start_date: 2007-08-01
project_end_date: 2010-09-30
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 1881039
contact_pi: MOHAN, ROYCE
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-08-01
project_abstract:
DESCRIPTION (provided by applicant):  The leading cause of corneal blindness world wide is from angiogenesis which is the pathogenic growth of new blood vessels from an existing vasculature. Normal wound healing in the cornea does not involve angiogenesis. Therefore identifying the molecular mechanisms that are responsible for preventing self- destructive angiogenic processes have important bearing on corneal homeostasis regeneration and transplantation. A novel biochemical feature preventing corneal stromal cells from participating in pathogenic fibrotic repair processes has recently been linked to the evolutionary conserved ubiquitin proteasome pathway (UPP). The UPP regulates protein quality control inflammatory transcription factor NF-kappa B activation cell cycle differentiation and antigen presentation. We have investigated the hypothesis that a DPP-mediated genetic program controls the angiogenic phenotype of the cornea. We show that the UPP is upregulated in vascular endothelial cells when activated by angiogenic stimulators and during injury healing in vascularized corneas in vivo. This pattern of UPP activation is attenuated by the potent small molecule angiogenesis inhibitor withaferin A. To demonstrate that a protein binding target(s) of withaferin A mediates this drug's anti-angiogenic mechanism we generated a biotinylated analog of withaferin A. We have successfully exploited this affinity reagent and isolated the withaferin binding target. In this R01 proposal we plan to exploit angiogenic and nonangiogenic models of wound healing to define the UPP-driven healing mechanism(s) of the cornea and validate newly identified molecular targets for anti-angiogenesis. For these investigations withaferin A will serve both as a pharmacological agent and a cell permeable probe of its binding-protein target's function. Specifically we will (1) characterize the drug's inhibitory mode of action on targeting the angiogenic activation of the UPP (2) investigate key components of the UPP as mediators of the drugs activity and (3) investigate withaferin-protein target-deficient mouse models to validate the requirement for drug-protein interaction in the corneal anti-angiogenic mechanism of WFA. We believe these investigations focused on the UPP and the target of withaferin A will enable us to reach our long-term objectives of discovering new therapeutic approaches to control angiogenesis and promote its homeostasis.

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


application_id: 7894252
project_number: 1R21AI088605-01
project_title: Chylomicrons promote intestinal absorption and systemic dissemination of dietary
administering_ic: NIAID
award_notice_date: 2010-03-30
opportunity_number: RFA-AI-09-011
application_type: 1
activity_code: R21
ic: AI
serial_number: 088605
program_official: DONG, GANG
project_start_date: 2010-04-01
project_end_date: 2012-03-31
study_section: Special Emphasis Panel[ZAI1 SV-I (J1)]
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
project_abstract:
DESCRIPTION (provided by applicant): The incidence of food allergies is on the rise in Western societies. Common food allergies include milk- egg- soy and peanut allergy and especially the latter can be fatal. An allergic response occurs when the dietary allergen gains access to IgE molecules on the surface of Mast cells in the intestine or in other tissues. It is therefore reasonable to assume that intestinal absorption of the allergens is detrimental. However intestinal absorption of the allergen and of dietary antigens in general is also required for the induction of broad systemic immunological tolerance ("oral tolerance") which prevents food allergies and may even be used to treat food allergies. It appears thus that the mechanism of antigen absorption plays a crucial role in the pathogenesis of food allergies. Unfortunately relatively little is currently known on the mechanism by which food antigens cross the intestinal epithelium and how they are subsequently transported through the body. Most dietary proteins including most known allergens have emulsifying properties which predicts that they show affinity for lipoprotein particles such as chylomicrons. These large emulsion particles transport dietary long-chain triglycerides (LCT "fat") through mesenteric lymph and blood. If dietary antigens are bound to chylomicrons they would then be transported to chylomicron target tissues such as mesenteric lymph nodes (MLN). Transport of dietary antigens to MLN could promote oral tolerance to the antigen since this is the common immune response in these lymph nodes. Thus chylomicron-dependent antigen absorption is hypothesized to promote oral tolerance. Most food staples including those with allergens such as milk eggs soybeans and peanuts also contain significant amounts of LCT meaning that antigen ingestion is followed by chylomicron secretion. We hypothesize that intestinal absorption and systemic transport of dietary antigens occurs through association with chylomicron secretion. More specifically we hypothesize that 1.) dietary antigens associate with newly formed chylomicron particles within intestinal epithelial cells (IEC) and are secreted into mesenteric lymph in association with nascent chylomicrons 2.) dietary antigens are transported in association with chylomicrons through mesenteric lymph via MLN into blood 3.) chylomicron-dependent antigen absorption promotes oral tolerance.These hypotheses are supported by preliminary data obtained with a prototypical food allergen ovalbumin (OVA) in mice but future experiments will also study peanut allergens. We propose to study the absorption mechanism in detail in this R21 grant application and to explore immune modulating effects of the novel chylomicron pathway. These studies are expected to significantly impact food allergy research since they define the underlying mechanism of dietary antigen absorption and provide the mechanistic framework for optimization of antigen delivery to the intestinal and peripheral immune system.

project_terms:
Address;Affect;Affinity;All-Trans-Retinol;Allergens;Allergic;Allergic Reaction;Allergy to peanuts;Antibodies;Antibody Formation;Antigen Presentation;Antigen-Presenting Cells;Antigens;Applications Grants;Binding (Molecular Function);Biological Models;Blood;Blood Circulation;Cell Line;Chylomicrons;Data;Defect;Development;Dietary Fats;Dietary Fatty Acid;Dietary Proteins;Emulsions;Epithelial Cells;Extravasation;Fatty acid glycerol esters;Food;Food Hypersensitivity;Fractionation;Future;IgE;Immune;Immune response;Immune system;In Vitro;Incidence;Individual;Ingestion;Intestinal Absorption;Intestinal Secretions;Intestines;Lamina Propria;Lipoproteins;Lymph;Maintenance;Measures;Medium chain triglycerides;Mesentery;Milk;Morbidity - disease rate;Mortality Vital Statistics;Mus;Oils;Oral;Ovalbumin;Pathogenesis;Pathway interactions;Peanuts - dietary;Peripheral;Phagocytosis;Plasma;Play;Production;Property;Regulatory T-Lymphocyte;Research;Role;Sampling;Societies;Source;Soybeans;Surface;T-Cell Proliferation;T-Lymphocyte;Testing;Tight Junctions;Tissues;Transgenic Organisms;Triglycerides;Vitamins;Water;absorption;allergic response;antigen binding;antigen challenge;egg;fast protein liquid chromatography;feeding;food allergen;in vivo;in vivo Model;inhibitor/antagonist;intestinal epithelium;lymph nodes;mast cell;monolayer;novel;oral tolerance;particle;prevent;research study;soy

public_health_relevance:
There is an increase in the incidence of food allergies such as peanut allergy. Little is known on themechanism by which dietary proteins including allergens are absorbed across the intestinal epithelium andsubsequently transported through lymph and blood. We propose an entirely novel mechanism in which dietaryantigens are taken up by intestinal epithelial cells loaded onto chylomicron particles (which transport dietaryfat) and secreted together with chylomicrons into mesenteric lymph. This is hypothesized to promote oraltolerance. Unraveling this mechanism will strongly impact food allergy research.


application_id: 7894182
project_number: 1R21AR053967-01A2
project_title: The role of endonuclease G in nuclear apoptosis of atrophying skeletal muscle
administering_ic: NIAMS
award_notice_date: 2010-03-19
opportunity_number: PA-09-164
application_type: 1
activity_code: R21
ic: AR
serial_number: 053967
suffix: A2
program_official: NUCKOLLS, GLEN H
project_start_date: 2010-04-01
project_end_date: 2012-03-31
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1884084
contact_pi: DUPONT-VERSTEEGDEN, ESTHER E
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:
DESCRIPTION (provided by applicant): Skeletal muscle atrophy is an important determinant in the loss of independence in elderly and is associated with poor prognosis in chronic disease states. Identifying mechanisms of atrophy will enable us to develop therapeutic strategies to prevent or treat the loss of muscle mass. We have shown previously that myofiber nuclear apoptosis occurs in muscles undergoing disuse-induced or age-associated muscle atrophy and that the caspase-independent mitochondrial enzyme endonuclease G (EndoG) is translocated to nuclei during atrophy possibly inducing DNA fragmentation in a subset of nuclei. Therefore we hypothesize that nuclear apoptosis which occurs in atrophying skeletal muscle is mediated by EndoG. In Specific Aim 1 we will determine whether EndoG is required for the apoptotic response in skeletal muscle during disuse atrophy using EndoG knockout (KO) mice. Mice will be hind limb suspended (HS) and nuclear loss apoptosis and atrophy will be assayed. In addition we hypothesize that increased permeability of the nuclear membrane due to elevated oxidative stress with atrophy is necessary for EndoG to enter the nucleus. Wild type (WT) mice will be treated with an iron-chelator and translocation of EndoG oxidative damage nuclear endonuclease activity and nuclear apoptosis will be measured. In Specific Aim 2 we will study the consequences of nuclear changes on skeletal muscle atrophy. First permeability changes of nuclei of WT mice after (HS) will be studied in vitro and correlated to oxidative stress to determine whether this is directly responsible for the entry of molecules into the nucleus. Additionally we will test directly whether the loss of nuclei induces atrophy by eliminating muscle nuclei by laser ablation and assaying for muscle atrophy and protein loss. Lastly we propose to develop an in vitro model of disuse atrophy by mechanical stimulus withdrawal and compare this to an in vitro atrophy model of oxidative stress. The role of EndoG in nuclear apoptosis in these models will be tested. In summary the proposed experiments will enable us to determine the role of EndoG-mediated nuclear apoptosis in skeletal muscle atrophy. These results may be not only be used to develop strategies to combat muscle atrophy but may also yield novel insight into mechanisms of apoptosis in other tissues. Relevance to public health: Muscle atrophy is associated diseases such as cancer AIDS and congestive heart failure and has been suggested as a main contributor to the loss of independence in elderly. We showed that apoptosis is an important event in the process of muscle atrophy. Identifying underlying mechanisms may lead to therapeutic interventions not just in decreasing atrophy but in preventing it. Additionally identifying pathways and molecules underlying the process of nuclear apoptosis in muscle will increase our knowledge about apoptosis in other tissues as well likely leading to interventions and treatments in fields such as cancer.  
  
PUBLIC HEALTH RELEVANCE: Skeletal muscle atrophy is associated diseases such as cancer AIDS and congestive heart failure and has been suggested as a main contributor to the loss of independence in elderly. We have shown that nuclear apoptosis is an important event in the process of muscle atrophy. Identifying underlying mechanisms may lead to new therapeutic interventions not just in decreasing atrophy but particularly in preventing it. Additionally identifying pathways and molecules underlying the process of nuclear apoptosis in muscle will increase our knowledge about apoptosis in other tissues as well possibly leading to new interventions and treatments in fields such as cancer.

project_terms:
Ablation;Acquired Immunodeficiency Syndrome;Age;Animals;Apoptosis;Apoptotic;Atrophic;Attenuated;Biological Assay;Biological Models;Cell Membrane Permeability;Cell Nucleus;Cessation of life;Chelating Agents;Chronic Disease;Congestive Heart Failure;DNA Fragmentation;Data;Deferoxamine;Development;Disease;Disuse Atrophy;Elderly;Enzymes;Event;Exhibits;Exploratory/Developmental Grant for Diagnostic Cancer Imaging;GTP-Binding Proteins;Gastrocnemius muscle structure;Goals;In Vitro;Intervention;Iron;Knock-out;Knockout Mice;Knowledge;Lasers;Lead;Limb structure;Location;Malignant Neoplasms;Measures;Mechanics;Mediating;Mitochondria;Mitochondrial Proteins;Modeling;Molecular;Mus;Muscle;Muscle Fibers;Muscle Proteins;Muscular Atrophy;NIH Program Announcements;Nuclear;Nuclear Envelope;Oxidative Stress;Pathway interactions;Permeability;Process;Protein Biosynthesis;Proteins;Regulation;Research Project Grants;Research Proposals;Role;Skeletal muscle structure;Stimulus;Structure;Study models;Suspension substance;Suspensions;System;Testing;Therapeutic;Therapeutic Intervention;Time;Tissues;United States National Institutes of Health;Wild Type Mouse;Withdrawal;Work;age related;anticancer research;base;caspase;combat;endonuclease;endonuclease G;in vitro Model;innovation;insight;interstitial cell;muscle form;novel;novel therapeutic intervention;outcome forecast;oxidative damage;prevent;public health medicine (field);public health relevance;research study;response;sarcopenia

public_health_relevance:
NarrativeSkeletal muscle atrophy is associated diseases such as cancer AIDS and congestive heart failure and hasbeen suggested as a main contributor to the loss of independence in elderly. We have shown that nuclearapoptosis is an important event in the process of muscle atrophy. Identifying underlying mechanisms may leadto new therapeutic interventions not just in decreasing atrophy but particularly in preventing it. Additionallyidentifying pathways and molecules underlying the process of nuclear apoptosis in muscle will increase ourknowledge about apoptosis in other tissues as well possibly leading to new interventions and treatments infields such as cancer.


application_id: 7894076
project_number: 1K23AA018399-01A1
project_title: Zinc supplementation in alcoholic cirrhosis
administering_ic: NIAAA
award_notice_date: 2010-03-26
opportunity_number: PA-09-043
application_type: 1
activity_code: K23
ic: AA
serial_number: 018399
suffix: A1
program_official: GENTRY, THOMAS
project_start_date: 2010-04-01
project_end_date: 2015-03-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
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): This K23 application will enable Matthew Cave M.D. to achieve his goal of becoming an independent investigator focusing on clinical and translational research in alcoholic liver disease (ALD) and nutrition. Dr. Cave will conduct a mechanistic study evaluating the effects of zinc sulfate therapy in patients with alcoholic cirrhosis (AC). Highlights of Dr. Cave's career development plan include: (i) obtaining a Master of Science degree in Interdisciplinary Studies (I-MS) focusing on toxicology clinical trial design and biostatistics and (ii) board certification in nutrition (ABPNS). These activities will occur in the setting of the recently funded University of Louisville Alcohol Research Center (P01) and will be monitored quarterly by an advisory committee. An estimated two million Americans have ALD and there are no FDA approved medications for any stage of ALD. Our preliminary data document (i) zinc deficiency in human subjects with AC and (ii) improvement in liver injury and in postulated mechanisms of liver injury with zinc supplementation in murine models. Our hypothesis is that zinc sulfate therapy will result in improvement in mechanisms postulated to play a role in the development and progression of human AC. To test this hypothesis we will perform a randomized double blind placebo-controlled "drop in" mechanistic study of zinc sulfate 220 mg daily in 30 subjects with Child-Pugh A-B AC for 24 months. The primary endpoints are reduction in (i) serum endotoxemia and (ii) ex vivo basal and endotoxin-stimulated TNF1 production. Secondary endpoints are (i) improved serum zinc status (ii) increased intestinal tight junctions with decreased permeability (iii) improved serum pro-inflammatory cytokine profile (iv) reduced oxidative stress and improved serum antioxidant status (v) reduced hepatocyte death (vi) decreased fibrosis and (vii) improved clinical status. These studies utilize state- of-the art techniques in a translational approach to develop an enhanced understanding of a potential new therapy for AC.  
  
PUBLIC HEALTH RELEVANCE: This K23 application will enable Matthew Cave M.D. to achieve his goal of becoming an independent investigator focusing on clinical and translational research in alcoholic liver disease (ALD) and nutrition. We will perform a randomized double blind placebo-controlled "drop in" mechanistic study of zinc sulfate 220 mg daily in 30 subjects with Child-Pugh A-B AC for 24 months.

project_terms:
Accounting;Advisory Committees;Alcohol consumption;Alcoholic Liver Cirrhosis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcoholism;American;Animal Model;Antioxidants;Arts;Attenuated;Biometry;Blood Circulation;Board Certification;Cell Death;Cell Wall;Cessation of life;Child;Chronic;Cirrhosis;Clinical;Clinical Trials Design;Data;Development;Development Plans;Disease;Doctor of Medicine;Double-Blind Method;Drops;Endotoxemia;Endotoxins;Epithelial;FDA approved;Fibrosis;Funding;Generations;Goals;Gram-Negative Bacteria;Health Benefit;Hepatocyte;Human;Immune system;Inflammatory;Injury;Interdisciplinary Study;Intestines;Kupffer Cells;Liver;Master of Science;Mediator of activation protein;Modeling;Monitor;Morbidity - disease rate;Mortality Vital Statistics;Mus;Oral;Oxidative Stress;Pathway interactions;Patients;Permeability;Pharmaceutical Preparations;Placebo Control;Play;Primary carcinoma of the liver cells;Principal Investigator;Production;Publishing;Randomized;Reactive Oxygen Species;Reporting;Research;Research Personnel;Research Proposals;Role;Safety;Serum;Staging;Structure;Supplementation;TNF gene;Techniques;Testing;Tight Junctions;Toxicology;Translational Research;United States;Universities;Venous;Work;Zinc;Zinc Sulfate;Zinc deficiency;alcohol research;animal data;base;career development;clinical practice;cytokine;human subject;improved;nutrition;prevent;problem drinker;programs;public health relevance;translational approach


application_id: 7893755
project_number: 5R25GM083835-03
project_title: Appalachian Kentucky Bridges to Success
administering_ic: NIGMS
award_notice_date: 2010-07-01
opportunity_number: PAR-07-039
application_type: 5
activity_code: R25
ic: GM
serial_number: 083835
program_official: GAILLARD, SHAWN R
project_start_date: 2008-07-11
project_end_date: 2013-06-30
study_section: Special Emphasis Panel[ZRG1-IMM-A(50)R]
contact_pi_person_id: 8581205
contact_pi: KNOX, TAMARA L.
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Kentucky has set a goal of increasing the educational attainment level of the Commonwealth to the national average by 2020 and to do this Kentucky needs to double the number of baccalaureate degree holders over the next 14 years from roughly 400000 in 2000 to nearly 800000 by 2020. This goal is especially daunting for educational institutions serving the eastern (Appalachian) region of Kentucky. Recent research has shown that students entering the Kentucky Community and Technical College System (KCTCS) and 4-year universities that serve the regions with the greatest need (largely comprised of eastern Kentucky) were the least prepared for college study of all students in the state. To address this problem a collaboration between the Hazard Community and Technical College University of Kentucky Center for Excellence in Rural Health and University of Kentucky has been developed to propose a program to engage promising rural Appalachian community college students in academic research psychosocial and financial support networks to enable them to successfully complete their baccalaureate degree in the biomedical or behavioral sciences. This application proposes to: (a) recruit program participants from HCTC; (b) carefully assess participants' learning- related skills and deficits; (c) provide a program that includes mentoring instruction in skills necessary to be successful in 4-year institutions of higher learning structured experiences to expose participants to career options and group support; (d) facilitate participants' efforts to transfer from community college to 4-year institutions; (e) carefully evaluate each component of the program; and (f) track participants to document and assess participant experience at 4-year institutions. Program evaluation milestones will include the successful recruitment retention transfer and graduation of promising students in the biomedical and behavioral sciences; increased communication between faculty at community colleges and baccalaureate institutions; faculty participation in transfer initiatives and program development that promotes the seamless transition of students between participating institutions; development of programs that advance and improve science teaching and mentoring; and development of program resources.  
  
This project proposes to develop a comprehensive program for community college students in southeastern Kentucky a region with very low educational levels. The program will include instruction and experiences to increase participants' awareness of career options mentoring and support in applying to transfer from community college to 4-year educational institutions. The program will be evaluated rigorously and will include documentation of all activities assessment of participant progress and follow-up after transfer from the community college.

project_terms:
Address;Appalachian Region;Awareness;Bachelor's Degree;Behavioral Sciences;Collaborations;Collection;Communication;Communities;Data;Documentation;Educational Materials;Educational Status;Educational aspects;Educational process of instructing;Ensure;Faculty;Family;Financial Support;Goals;Grant;Health Hazards;Institution;Instruction;Joints;Kentucky;Learning;Life;Mentors;Monitor;Natural Sciences;Pamphlets;Participant;Press Releases;Process;Program Development;Program Evaluation;Recruitment Activity;Research;Resources;Rural;Rural Health;Scholarship;Science;Structure;Students;System;Time;Universities;Vocational Guidance;base;career;college;data management;experience;falls;follow-up;group support;hazard;improved;programs;psychosocial;skills;success;university student;web site


application_id: 7893175
project_number: 5R01HL063760-08
project_title: Oxidative Stress and Heart Failure by Copper Restriction
administering_ic: NHLBI
award_notice_date: 2010-07-02
opportunity_number: PA-05-089
application_type: 5
activity_code: R01
ic: HL
serial_number: 063760
program_official: ERSHOW, ABBY
project_start_date: 2001-06-15
project_end_date: 2013-06-30
study_section: Integrative Nutrition and Metabolic Processes Study Section[INMP]
contact_pi_person_id: 1877629
contact_pi: KANG, Y JAMES
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Sustained pressure overload causes cardiac hypertrophy and the transition to heart failure. The aortic banding mouse model leads to hypertrophic cardiomyopathy and heart failure through the mechanism of sustained pressure overload but we have evidence that mineral imbalance may be involved. We have observed that increasing dietary copper (Cu) intake from 6 mg Cu/kg diet to 20 mg/kg diet can reverse the established hypertrophic cardiomyopathy in the aortic banding mouse model even in the presence of sustained pressure overload. Decreased cytochrome c oxidase (CCO) activity and mitochondriopathy are associated with heart failure in humans. The same CCO defect and mitochondriopathy are also found in the mouse model of pressure overload-induced cardiomyopathy and increasing dietary Cu intake recovered CCO activity and reversed mitochondriopathy. We propose this study to carry out the following aims: Aim 1 is to explore molecular mechanism by which sustained pressure overload causes Cu restriction to CCO in the heart. We will test the hypothesis that Cu mobilization and redistribution or efflux in response to oxidative stress generated by sustained pressure overload leads to Cu restriction to CCO resulting in altered CCO assembly and suppressed CCO activity. Aim 2 is to determine the essential role of recovery of suppressed CCO activity in Cu supplementation-induced regression of cardiomyopathy by sustained pressure overload. A cardiac COX10 conditional knockout mouse model in which cardiac CCO activity can be reduced by 50- 70% under the treatment with tamoxifen will be used. We hypothesize that Cu supplementation would not rescue the failing heart in the cardiac COX10-knockout or CCO-deficient mice if the recovery of CCO activity is essential even Cu supplementation can reverse alterations in other events including calcineurin/NFAT PI3K/Akt and ERK1/2 pathways or can activate other cardiomyopathy regression mechanisms. Aim 3 is to define potential application of Cu therapy to appropriate populations of heart failure patients by testing the hypothesis that Cu supplementation should be limited to pressure overload cardiomyopathy not applied to diabetic cardiomyopathy because diabetes causes liver dysfunction which in turn causes Cu retention in the system increasing the risk of Cu toxicity to the heart and other organs. Therefore Cu supplementation is not an appropriate approach to rescue diabetic cardiomyopathy.

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


application_id: 7892963
project_number: 5R21EY019778-02
project_title: Novel TLR3 inhibitors for geographic atrophy of age-related macular degeneration
administering_ic: NEI
award_notice_date: 2010-06-30
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: EY
serial_number: 019778
program_official: NEUHOLD, LISA
project_start_date: 2009-08-01
project_end_date: 2012-06-30
study_section: Special Emphasis Panel[ZRG1-CB-G(90)S]
contact_pi_person_id: 2446639
contact_pi: AMBATI, JAYAKRISHNA
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) affects some 10 million people in the United States. Blindness in AMD occurs due to either choroidal neovascularization (CNV) or geographic atrophy (GA). Whereas new treatments for CNV offer the prospect of vision improvement the nebulous understanding of GA pathogenesis has precluded the arrival of any FDA-approved therapy for the nearly 1 million Americans that have GA. In a multi-center collaboration we recently reported that a hypomorphic polymorphism in toll-like receptor-3 (TLR3) an innate immune sensor of double stranded RNA (dsRNA) conferred protection from GA making it the first candidate gene specific for GA. We showed that TLR3 activation by long dsRNA induced apoptotic cell death of primary human retinal pigmented epithelium (RPE) cells and choroidal endothelial cells (CECs) and retinal degeneration in mice resembling GA thereby establishing a functional link between TLR3 and GA. New and exciting recent work from my laboratory revealed the presence of non-physiological long dsRNA in the eyes of patients with GA but not in human eyes without AMD. Thus we hypothesize that TLR3 activation by long dsRNA triggers retinal and choroidal cell death and promotes GA. Using molecular modeling we discovered a novel class of ultrashort (us)-dsRNAs that function as TLR3 inhibitors in vivo. The objective of this proposal is to identify the optimal us-dsRNA molecules that can rescue TLR3-mediated retinal degeneration to achieve our long-term goal of advancing them as therapeutics for GA. These proof-of-concept studies will form the basis for an R01 application that will define the detailed mechanisms of action of long dsRNA and us-dsRNA. Successful completion of this project also will have the high translational impact of laying the foundation for a collaborative clinical trial for GA which is presently an unmet medical need.   
  
PUBLIC HEALTH RELEVANCE: Geographic atrophy is responsible for 10% of blindness due to age-related macular degeneration (AMD). There is no FDA-approved therapy for the 1 million Americans with GA. Our recent discovery of TLR3 as the first gene specifically associated with GA and our exciting new finding that double stranded RNA (dsRNA) which activates TLR3 is present in human eyes with GA support the pursuit of a novel class of TLR3 inhibitors that we have discovered as potential therapeutics for this unmet medical need.

project_terms:
Accounting;Affect;Age related macular degeneration;American;Americas;Apoptosis;Apoptotic;Biological Assay;Blindness;Blood Vessels;Candidate Disease Gene;Cell Culture Techniques;Cell Death;Cell Survival;Cells;Cessation of life;Chemical Structure;Choroid;Choroidal Neovascularization;Clinical Trials;Collaborations;Data;Dimerization;Double-Stranded RNA;Economics;Endothelial Cells;Epidemic;Eye;FDA approved;Fluorescein Angiography;Foundations;Fundus photography;Genes;Genetic Polymorphism;Goals;Histology;Human;Immune;Interferons;Interleukin-12;Knowledge;Laboratories;Lead;Length;Link;Measures;Mediating;Medical;Molecular;Molecular Models;Mus;Nature;Nucleotides;Ophthalmology;Panthera leo;Pathogenesis;Patients;Pharmaceutical Chemistry;Phosphorylation;Photoreceptors;Physiological;Prevalence;RNA Binding;RNA Interference;RNA Interference Pathway;Reporting;Retina;Retinal;Retinal Degeneration;Risk;Structure of retinal pigment epithelium;Therapeutic;United States;Vision;Work;Yang;aging population;base;caspase-3;cost;geographic atrophy;human TLR3 protein;improved;in vivo;inhibitor/antagonist;molecular modeling;monomer;novel;prevent;public health relevance;sensor;trafficking;transmission process

public_health_relevance:
Geographic atrophy is responsible for 10% of blindness due to age-related maculardegeneration (AMD). There is no FDA-approved therapy for the 1 million Americans with GA.Our recent discovery of TLR3 as the first gene specifically associated with GA and our excitingnew finding that double stranded RNA (dsRNA) which activates TLR3 is present in humaneyes with GA support the pursuit of a novel class of TLR3 inhibitors that we have discovered aspotential therapeutics for this unmet medical need.


application_id: 7892885
project_number: 1R21AI088585-01
project_title: Plant-produced Actinohivin as a Candidate HIV Microbicide
administering_ic: NIAID
award_notice_date: 2010-06-10
opportunity_number: RFA-AI-09-021
application_type: 1
activity_code: R21
ic: AI
serial_number: 088585
program_official: TURPIN, JIM A
project_start_date: 2010-06-10
project_end_date: 2012-05-31
study_section: Special Emphasis Panel[ZAI1 EC-A (J1)]
contact_pi_person_id: 8640855
contact_pi: MATOBA, NOBUYUKI
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Actinobacteria class;Actinomyces;Affinity;Animal Model;Antiviral Agents;Binding (Molecular Function);Biochemical;Biological;Biological Assay;Cell Line;Cells;Clinical Research;Data Set;Dendritic Cells;Development;Dose;Drug Formulations;Drug Kinetics;Epidemic;Epithelial Cells;Evaluation;Gene Expression;Giant Cells;Goals;HIV;HIV-1;Human;Immune;In Vitro;Infection;Inflammatory;Inhibitory Concentration 50;Integration Host Factors;Lactobacillus;Lectin;Local Microbicides;Macaca;Mannose;Maximum Tolerated Dose;Methods;Modeling;Molecular;Mus;Oligosaccharides;Oryctolagus cuniculus;Peripheral Blood Mononuclear Cell;Pharmacodynamics;Pharmacologic Substance;Phase;Pilot Projects;Plant Viruses;Plants;Play;Polysaccharides;Preclinical Testing;Preparation;Procedures;Production;Proteins;Rage;Recombinant Fusion Proteins;Recombinants;Reporter Genes;Role;Safety;Seminal Plasma;Solutions;Specificity;Staging;System;T-Lymphocyte;Testing;Time;Toxic effect;Vagina;Viral;Virus;base;commensal microbes;cytotoxic;cytotoxicity;dimer;immunogenicity;improved;in vitro Assay;inhibitor/antagonist;irritation;meetings;microbicide;monomer;mouse model;novel;pre-clinical;preclinical study;safety study;success;sugar;transmission process;vaginal microbicide


application_id: 7892836
project_number: 1R21CA143456-01A1
project_title: Targeting Signaling to Prevent Colon Cancer
administering_ic: NCI
award_notice_date: 2010-03-04
opportunity_number: PA-08-185
application_type: 1
activity_code: R21
ic: CA
serial_number: 143456
suffix: A1
program_official: FU, YALI
project_start_date: 2010-03-04
project_end_date: 2012-02-28
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 7649061
contact_pi: DAMODARAN, CHENDIL
other_pis: Not Applicable
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Our research focuses on complementary and alternative medicines (CAM) that possess anti- cancer properties. In the proposed study we will analyze the mechanism of action of Withaferin-A (WA) a CAM based herbal used extensively in African and Asian countries for the treatment of various ailments including cancer. Our preliminary in vitro data suggest WA targets colon cancer cells by down-regulating cleaved NOTCH1 pAkt pS6K p4E-BP1 and Bcl- 2 and simultaneously promoting caspase-3 activation and PARP cleavage. Based on these results we hypothesize WA will effectively inhibit colon cancer growth due to its ability to inactivate Notch-1/Akt/mTOR-mediated pro-survival signaling and induce apoptosis in colon cancer cells. To address our hypothesis we propose: study the mechanism(s) of WA-mediated Notch-1/Akt/mTOR inhibition in colon cancer (Aim 1) and determine the in vivo efficacy of WA and its chemosensitization effect on colon cancer xenografts that over-express either Akt or mTOR (Aim 2). For our in vitro studies we will use RT-PCR Western Blotting SiRNA strategies immunoprecipitation cell viability assays apoptotic assays kinase assays transient transfection gene transcription assays pharmacological blocking and immunocytochemistry to clarify the impact of WA on the Notch-1/Akt/mTOR signaling axis. For our in vivo studies colon cancer cells will be stably transfected with either constitutively active Akt or mTOR. Using these transfectants xenografts will be formed in nude mice and the effect of WA on the tumor bearing animal models will be studied. Additionally to determine the chemosensitization effect of WA on tumor bearing animal models we will treat mice with WA and a sub-lethal dose of 5-Fluorouracil (5-FU). Necroscopy histopathology and immunohistochemical (Notch-1 Akt mTOR cyclin D1 Par-4 and Bid) analyses will be performed on the tumor sections following the termination of the study. Additionally HPLC will be performed to determine serum concentrations of WA in the nude mice models. Our long term goal is to encourage the use of CAMs in a clinical environment where these agents can be best used for their chemopreventive and chemotherapeutic properties. Our preliminary data indicate WA is one such compound and is a viable candidate for investigating its clinical potency against colon cancer cells.  
  
PUBLIC HEALTH RELEVANCE: Colorectal cancer is the third most frequently diagnosed cancer in men and women in the United States and although its mortality rates have decreased due to early detection and adjuvant therapies the disease is incurable once metastases develop. Complementary and alternative systems of medicine (CAM) may offer novel and effective therapies not yet explored by conventional medicine. The proposed study of the dietary supplement Withaferin-A (WA) the major bioactive compound from Withania somnifera) will provide molecular level insight into the mechanism of action of Withaferin-A against colon cancer and clarify the clinical potential of WA with respect to the chemoprevention and/ or chemotherapy of colon cancer.

project_terms:
Address;Adjuvant Therapy;African;Animal Model;Animals;Apoptosis;Apoptotic;Asians;Biological Assay;Blood;Cancer Model;Cell Death;Cell Proliferation;Cell Survival;Cells;Chemoprevention;Chemopreventive Agent;Chemosensitization;Cleaved cell;Clinical;Colon;Colon Carcinoma;Colorectal Cancer;Complementary and alternative medicine;Country;Cyclin D1;Data;Diet;Dietary Supplements;Disease;Dose;Down-Regulation;Early Diagnosis;Environment;Exhibits;Fluorouracil;Foundations;Future;Genetic Transcription;Goals;Growth;Hand;Herbal Medicine;High Pressure Liquid Chromatography;Histopathology;Human;Immunoprecipitation;In Vitro;Induction of Apoptosis;Lead;Malignant Neoplasms;Mediating;Medicinal Plants;Medicine;Mitosis;Mitotic;Molecular;Molecular Target;Monitor;Mortality Vital Statistics;Mus;NOTCH1 gene;Neoplasm Metastasis;Nude Mice;PAWR gene;Pathogenesis;Pattern;Phosphotransferases;Play;Property;Reporting;Research;Resistance;Reverse Transcriptase Polymerase Chain Reaction;Role;Serum;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Signaling Molecule;Sirolimus;System;TAN-1 protein;Toxic effect;Transfection;Tumor Tissue;United States;Western Blotting;Withania somnifera;Woman;Xenograft Model;Xenograft procedure;base;biomarker;cancer cell;cancer diagnosis;caspase-3;chemotherapy;colon cancer cell line;effective therapy;feeding;immunocytochemistry;in vivo;insight;mTOR protein;men;mouse model;notch protein;novel;prevent;pro-apoptotic protein;public health relevance;tumor;tumorigenesis

public_health_relevance:
Project NarrativeColorectal cancer is the third most frequently diagnosed cancer in men and women in the United States andalthough its mortality rates have decreased due to early detection and adjuvant therapies the disease isincurable once metastases develop. Complementary and alternative systems of medicine (CAM) may offernovel and effective therapies not yet explored by conventional medicine. The proposed study of the dietarysupplement Withaferin-A (WA) the major bioactive compound from Withania somnifera) will provide molecularlevel insight into the mechanism of action of Withaferin-A against colon cancer and clarify the clinical potentialof WA with respect to the chemoprevention and/ or chemotherapy of colon cancer.


