# projects

application_id: 8024244
project_number: 1R01DK090460-01
project_title: Maternal Exercise Protects Offspring from Obesity and Insulin Resistance
administering_ic: NIDDK
award_notice_date: 2010-12-24
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: DK
serial_number: 090460
program_official: SILVA, CORINNE M
project_start_date: 2011-01-01
project_end_date: 2015-12-31
study_section: Integrative Physiology of Obesity and Diabetes Study Section[IPOD]
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The intrauterine environment affects the development of the growing embryo and an unsuitable environment can lead to termination of pregnancy. However emerging research has shown that more subtle factors can potentially influence long-term health in the offspring. For instance malnourished pregnant mothers produce smaller offspring that have a higher incidence of obesity diabetes and heart disease during adulthood. To this point most published studies have focused on negative changes in offspring caused by detrimental diets or stressful behavior. However in the Western world maternal obesity is an ever-increasing problem and epidemiology studies are now pointing to metabolic derangements in their offspring. In an attempt to be pro-active maternal voluntary exercise during pregnancy was chosen as a potential short-term intervention to improve health outcomes in offspring. Fasting circulating glucose and insulin levels were lower in offspring born to exercised dams compared to those born to non-exercised dams and glucose disposal and insulin sensitivity were significantly improved. As a result our hypothesis for this proposal is that maternal voluntary exercise during pregnancy and nursing will improve glucose regulation and decrease obesity and hypertension in offspring. The first aim is designed to determine whether maternal voluntary exercise can improve insulin sensitivity in offspring fed a normal standard diet and protect against obesity insulin resistance and hypertension progression in high calorie diet-fed offspring. The second aim hopes to elucidate the mechanism for long-lasting insulin sensitivity in offspring born to exercised dams which is likely through enhanced insulin signaling. The third aim will determine whether maternal exercise can be used as an intervention to improve pathology outcomes in offspring resulting from maternal consumption of a high calorie diet or gestational diabetes mellitus. To explore these aims female mice will be placed into sedentary or voluntary exercise groups. The exercise dams will have 24 hour access to running wheels before mating and throughout pregnancy and nursing. The maturing offspring will not have access to running wheels for any portion of the study. Obesity glucose and insulin tolerance and hypertension will be monitored in the offspring fed either standard or high calorie diet. These studies will provide important information on the potential positive impact maternal exercise can have on offspring health. Obesity diabetes and cardiovascular disease are at epidemic levels and interventions targeting gestation might be an efficient way to stem the tide.  
  
PUBLIC HEALTH RELEVANCE:  Exercise is currently used as a treatment for gestational diabetes but the long-term influence of this intervention on offspring health has been ignored. The proposed studies will provide novel information on whether maternal exercise can be used as an intervention to decrease obesity diabetes and hypertension development in offspring. Maternal exercise during pregnancy is a very realistic intervention that may provide a lifetime of benefits for the next generation.

project_terms:
Acetylation;Adult;Adult Children;Affect;Age;Behavior;Biological Assay;Blood Pressure;Body Composition;Cardiovascular Diseases;Commit;Consumption;CpG Islands;Development;Diabetes Mellitus;Diet;Discipline of Nursing;Disease;Embryo;Environment;Epidemic;Epigenetic Process;Exercise;Fasting;Female;Genes;Gestational Diabetes;Glucokinase;Glucose;Glucose Transporter;Health;Heart Diseases;Histone Acetylation;Home environment;Hour;Human;Hypertension;Incidence;Injection of therapeutic agent;Insulin;Insulin Receptor;Insulin Resistance;Insulin Signaling Pathway;Intervention;Laboratories;Lead;Liver;Longevity;Measures;Metabolic;Methylation;Modeling;Monitor;Mothers;Motor;Mus;Obese Mice;Obesity;Outcome;Parents;Partner in relationship;Pathology;Pathway interactions;Performance;Phenotype;Phosphorylation;Pilot Projects;Population;Pregnancy;Probability;Promoter Regions (Genetics);Proteins;Publishing;Research;Role;Running;Skeletal muscle structure;Termination of pregnancy;Testing;Tissues;Ursidae Family;Very Light Exercise;Western World;blood glucose regulation;design;epidemiology study;fasting glucose;feeding;glucose disposal;glucose tolerance;glucose-6-phosphatase;improved;insulin sensitivity;insulin signaling;insulin tolerance;leptin receptor;next generation;novel;offspring;pregnant;programs;protein expression;response;sedentary;stem;trend;unborn child

public_health_relevance:
Exercise is currently used as a treatment for gestational diabetes but the long-term influence of this intervention on offspring health has been ignored. The proposed studies will provide novel information on whether maternal exercise can be used as an intervention to decrease obesity diabetes and hypertension development in offspring. Maternal exercise during pregnancy is a very realistic intervention that may provide a lifetime of benefits for the next generation.


application_id: 8020447
project_number: 1R21ES020123-01
project_title: Repair of Airway Epithelium Following Chlorine Lung Injury
administering_ic: NIEHS
award_notice_date: 2010-09-23
opportunity_number: PAR-10-019
application_type: 1
activity_code: R21
ic: ES
serial_number: 020123
program_official: HEACOCK, MICHELLE
project_start_date: 2010-09-23
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZRG1 MDCN-J (50)]
contact_pi_person_id: 2736750
contact_pi: HOYLE, GARY W.
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):  Acute high-level exposures to chemicals that damage the respiratory tract can cause life-threatening lung injury. Chlorine gas is a highly toxic respiratory irritant that is considered a chemical threat agent because of the possibility that it could be released in industrial accidents or terrorist attacks. Chlorine like many pulmonary toxicants produces injury to epithelial cells lining the respiratory tract. Loss of the respiratory epithelial cell barrier contributes to other sequelae observed in acute lung injury including pulmonary edema airway obstruction inflammation and respiratory infections. Efficient repair of respiratory epithelium and restoration of barrier function are essential for resolution of chlorine-induced lung injury. The epithelium of the respiratory tract is repaired following injury through the proliferation and differentiation of stem cells. One type of cell involved in the repair of airway epithelium is the basal cell. The low-affinity nerve growth factor receptor (NGFR) has been identified as a marker for basal cells as well as for epithelial stem cells in other tissues but the role of this protein in stem cell function is unknown. NGFR binds multiple neurotrophin ligands including nerve growth factor (NGF) brain-derived neurotrophic factor and neurotrophin 3. The hypothesis to be tested in the proposed studies is that NGFR controls the proliferation survival and differentiation of lung epithelial stem cells following chlorine-induced lung injury. In Specific Aim 1 basal cells will be purified from the trachea of normal mice and from mutant mice lacking functional NGFR. The ability of the cultured cells to survive proliferate and differentiate into other types of epithelial cells (ciliated cells and Clara cells) will be measured in the presence or absence of NGFR ligands. In Specific Aim 2 wild-type NGFR knockout and NGF transgenic mice will be exposed to chlorine gas according to a protocol established in the Principal Investigator's laboratory. Effects of neurotrophins will be tested by delivering ligands intranasally or by using NGF-overexpressing transgenic mice previously developed in the Principal Investigator's laboratory. The extent of tracheal epithelial repair will be measured at various times after chlorine exposure. In Specific Aim 3 the effect of neurotrophins on epithelial repair following chlorine exposure in rabbits will be investigated. Rabbits will be used for these studies because of the wider distribution of basal cells in the airways in this species which is more similar to that in humans. The proposed experiments will not only investigate mechanisms of epithelial repair but will also foster the development of therapeutic agents that could be used to stimulate resolution of lung injury following inhalation of toxic chemicals.  
PUBLIC HEALTH RELEVANCE:  This application is submitted in response to PAR-10-019 CounterACT Exploratory/Developmental Projects in Translational Research (R21). The proposed experiments are designed to understand how the lung repairs itself after inhalation of a toxic gas with the goal of developing therapy for lung injury based on stimulating lungs cells to accelerate repair. This type of research is sought through the Funding Opportunity Announcement because of concerns that U. S. civilians could be adversely affected by highly toxic chemicals released intentionally in terrorist attacks or unintentionally in industrial accidents or natural disasters.

project_terms:
Acute;Affect;Airway Obstruction;Basal Cell;Brain-Derived Neurotrophic Factor;Breathing;Cell Differentiation process;Cell Line;Cell physiology;Cells;Characteristics;Chemicals;Chlorine;Clara cell;Clinical;Coughing;Cultured Cells;Development;Distal;Dyspnea;Epithelial;Epithelial Cells;Epithelium;Exposure to;Fostering;Funding Opportunities;Future;Gases;Goals;Human;Industrial Accidents;Inflammation;Injury;Irritants;Knock-out;Knockout Mice;Laboratories;Life;Ligands;Lung;Lung Injury Acute;Measures;Microarray Analysis;Mus;Mutant Strains Mice;NGFR Protein;Natural Disasters;Natural regeneration;Nerve Growth Factor Receptors;Nerve Growth Factors;Neurotrophin 3;Oryctolagus cuniculus;Peptides;Poisons;Population;Principal Investigator;Proliferating;Proteins;Protocols documentation;Pseudostratified Epithelium;Pulmonary Edema;Receptor Signaling;Recording of previous events;Research;Resolution;Respiratory System;Respiratory Tract Infections;Respiratory tract structure;Role;Stem cells;Structure of respiratory epithelium;Symptoms;Testing;Therapeutic Agents;Time;Tissues;Toxic effect;Trachea;Tracheal Epithelium;Transgenic Mice;Translational Research;Unconscious State;United States;Wild Type Mouse;airway epithelium;base;cell type;chemical release;chlorine gas;design;embryonic stem cell;injured;injured airway;lung injury;neurotrophic factor;novel strategies;overexpression;receptor binding;repaired;research study;respiratory;response;restoration;small molecule;stem cell differentiation;therapy development;toxicant;treatment strategy

public_health_relevance:
This application is submitted in response to PAR-10-019 CounterACT Exploratory/DevelopmentalProjects in Translational Research (R21). The proposed experiments are designed to understand howthe lung repairs itself after inhalation of a toxic gas with the goal of developing therapy for lung injurybased on stimulating lungs cells to accelerate repair. This type of research is sought through theFunding Opportunity Announcement because of concerns that U. S. civilians could be adverselyaffected by highly toxic chemicals released intentionally in terrorist attacks or unintentionally inindustrial accidents or natural disasters.


application_id: 8019700
project_number: 7R01CA116092-06
project_title: Breast tumor exosomal Jak3BP mediated immunosuppression
administering_ic: NCI
award_notice_date: 2010-03-12
application_type: 7
activity_code: R01
ic: CA
serial_number: 116092
program_official: HOWCROFT, THOMAS K
project_start_date: 2005-08-01
project_end_date: 2012-03-31
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-03-11
project_abstract:
DESCRIPTION (provided by applicant):  The goal of this proposal is to identify the mechanisms underlying tumor exosome-mediated suppression of NK cell activity. Our preliminary data indicate that pretreatment of BALB/c mice with exosomes produced by TS/A breast tumor cells results in more rapid tumor growth and earlier metastasis. We have identified a novel breast tumor exosomal protein (Jak3BP) that is capable of binding to Jak3 in the NK cells resulting in the ubiquitination of Jak3. siRNA Jak3BP knockout results indicated however that although Jak3BP is required it is not sufficient for ubiquitination of Jak3. We have now identified two exosomal proteins that interact with Jak3BP Nedd4 and ubiquilin which have the potential to enhance the ubiquitination of Jak3 or protect Jak3BP  against its degradation in IL-2-stimulated NK cells. Our aims are (1) To use siRNA technology to determine if knockout of exosomal Jak3BP in tumor cells is sufficient for reversal of the inhibition of NK-cell activation mediated by TS/A exosomes or whether other exosomal proteins such as Nedd4 and ubiquilin are required. (2) To use siRNA technology to determine if other exosomal proteins that interact with Jak3BP participate in the ubiquitination of Jak3 in NK cells and to identify the molecular determinants of these interaction. We will determine if modification of Jak3BP regulates its choice of interaction partners and in parallel use bioluminescence resonance energy transfer assay technology to identify a peptide that can block the interaction of Jak3 and Jak3BP thus reversing the tumor exosome-mediated inhibition of NK-cell activation. (3) To determine which tumor exosomal proteins contribute to the stabilization of Jak3BP in IL-2 stimulated NK cells and further determine if the elimination of these exosome proteins causes degradation of Jak3BP thus resulting in the attenuation of inhibition of NK cell activation and prevention of tumor growth. (4) To determine if human breast tumor Jak3BP also regulates the ubiquitination of Jak3 of NK cells and to determine if Jak3BP is  over expressed in patients with ductal adenocarcinoma of the breast. The data generated should elucidate the cellular and molecular basis underlying tumor immunosuppression mediated by the exosomes produced by tumor cells and indicate the feasibility of various therapeutic strategies.

project_terms:
A Mouse;Adenocarcinoma;Binding (Molecular Function);Biological Assay;Bioluminescence;Breast Adenocarcinoma;Cells;Complex;Data;Doctor of Philosophy;Ductal;Energy Transfer;Figs - dietary;Goals;Growth;Human;Immune;Immune response;Immune system;Implant;Inbred BALB C Mice;Interleukin-2;Invaded;Knock-out;Laboratories;Lymphocyte;Mammary Neoplasms;Mediating;Membrane;Modeling;Modification;Molecular;Mus;NK Cell Activation;Natural Killer Cells;Natural immunosuppression;Neoplasm Metastasis;Patients;Peptides;Play;Prevention;Protein Binding;Proteins;Research Personnel;Role;Small Interfering RNA;Technology;Testing;Therapeutic;Tumor-Derived;Ubiquitination;Vesicle;attenuation;base;cancer cell;cytotoxicity;host neoplasm interaction;in vivo;malignant breast neoplasm;neoplastic cell;novel;overexpression;perforin;programs;tumor;tumor growth;ubiquilin;ubiquitin-protein ligase


application_id: 8019092
project_number: 5R24MD002757-04
project_title: Faith Moves Mountains: A CBPR Appalachian Wellness & Cancer Prevention Program
administering_ic: NIMHD
award_notice_date: 2011-01-27
opportunity_number: RFA-MD-07-003
application_type: 5
activity_code: R24
ic: MD
serial_number: 002757
program_official: GOODWIN, PAULA
project_start_date: 2008-05-22
project_end_date: 2013-01-31
study_section: ZMD1-RN(01)R
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
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): Appalachian communities are disproportionately affected by many of the leading risk factors associated with cancer incidence and mortality factors amenable to primary and secondary prevention. Extensive involvement with our community partners has demonstrated strong community preference for a holistic approach toward cancer prevention; The proposed intervention extends our successful faith-based trained lay health advisor tailored intervention "Faith Moves Mountains" (R01CA108696) initiated three years ago to administer a culturally appropriate CBPR intervention. Working in partnership with 70 faith based institutions in rural Southeastern Kentucky we propose to administer evaluate and disseminate a tailored wellness and cancer prevention program focused on four of the most common prevention activities that have the potential of greatly preventing and reducing cancer morbidity and mortality. These prevention activities include smoking cessation (targeting all chronic diseases cervical and lung cancer); energy balance including dietary modification and physical activity promotion (targeting all chronic diseases and colorectal cancer (CRC)) and cancer screenings (targeting CRC cervical and breast cancer).  
  
Consistent with our Faith Moves Mountains and cancer control approach faith-based organizations will sponsor a "kick off event" or health fair in which participants will undergo a health risk appraisal (baseline). Participants will then select one or more wellness activities (smoking cessation energy balance cancer screening); then trained lay health advisors will offer modules on each of these wellness activities. Smoking cessation will include the culturally relevant Cooper-Clayton method (outcome: smoking abstinence). For those targeting dietary modification and physical activity a rural Appalachian modified Healthy Body/Healthy Spirit program will be administered (outcome: dietary change and physical activity participation). Tailored cancer screening promotion will be based on our current Faith Moves Mountains design (outcome: receipt of any recommended CRC screening test Pap test for cervical cancer and/or mammogram). To assess the intervention but remain consistent with community norms we will employ a staggered intervention design. Throughout the project the RE-AIM model will inform our evaluation. During phase three this CBPR wellness approach to cancer prevention will undertake qualitative process evaluation interviews and disseminate the intervention to medically underserved Appalachian Ohio in collaboration with partners at Ohio State University. This collaboration will facilitate dissemination of successful intervention to additional rural Appalachian populations with high rates of cancer health disparities.

project_terms:
Abstinence;Address;Affect;Cancer Control;Cervical;Chronic Disease;Collaborations;Colorectal Cancer;Communities;Diet;Diet Modification;Effectiveness of Interventions;Ensure;Evaluation;Event;Fostering;Goals;Health;Health Fairs;Health Risk Appraisals;Incidence;Institution;Intervention;Intervention Studies;Interview;Kentucky;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Mammography;Methods;Modeling;Monoclonal Antibody R24;Morbidity - disease rate;Mortality Vital Statistics;National Center on Minority Health and Health Disparities;Ohio;Outcome;Pap smear;Participant;Phase;Physical activity;Population;Prevention;Prevention program;Primary Prevention;Process;Randomized;Regimen;Research;Research Design;Risk Factors;Rural;Rural Health;Screening for cancer;Secondary Cancer Prevention;Secondary Prevention;Smoking;Testing;Training;Trust;Universities;Work;base;cancer health disparity;cancer prevention;cancer risk;colorectal cancer screening;community based participatory research;design;diet and exercise;energy balance;health disparity;holistic approach;malignant breast neoplasm;medically underserved;member;preference;prevent;programs;response;smoking cessation;successful intervention;therapy design


application_id: 8018743
project_number: 3P30NS051220-05S1
project_title: UK Spinal Cord & Brain Injury Research Center Core Grant
administering_ic: NINDS
award_notice_date: 2010-05-03
opportunity_number: PAR-02-059
application_type: 3
activity_code: P30
ic: NS
serial_number: 051220
suffix: S1
program_official: MILLER, THOMAS
project_start_date: 2005-05-01
project_end_date: 2010-11-30
study_section: Neurological Sciences and Disorders B Study Section[NSD-B]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
This application is in response to the NINDS Program Announcement requesting institutional center core
grants to support neuroscience research. Accordingly the current application seeks to create the UK Spinal
Cord & Brain Injury Research Center (SCoBIRC) Core Grant to accelerate the research projects of 10
NINDS-funded investigators who are currently Pis on 12 NINDS R01s and to enhance . The application
asks for support for five core facilities: an Administrative and Bioinformatics Core an Animal Surgery &
TBI/SCI Model Core a Behavioral Testing Core a Microscopy Image Analysis & Stereology Core and a
Pharmacokinetics and Biomarker Core. Although some of the proposed technologies are currently in place in
the laboratories of individual investigators none of the cores currently exists. The proposal is for these
resources to be centralized in some cases upgraded and added to with additional equipment. Dedicated
technical support is requested for each of the cores to insure that they will be run efficiently with minimal
downtime and equipment failure and serve to enhance the productivity of SCoBIRC and other NINDSsupported
investigators. It is also expected that these cores will promote communication of data and foster
overall collaboration. All of the participating investigators have documented needs for the use of most of the
core facilities: 6 of 10 will use all 5 cores 3 will use 4 of the cores and only 1 will use 3 of them. Use of the
cores will be shared with other non-qualifying neurological investigators. The PI has had considerable
administrative experience and each of the Core Directors is fully qualified to direct the use of the proposed
technologies. They will be backed up in 4 of the 5 cases with equally experienced Assistant Directors and
dedicated technical staff who will perform pilot studies train new investigators handle scheduling maintain
supplies and equipment maintenance. The performance of the cores will be reviewed quarterly by a Steering
Committee consisting of all of the qualifying investigators. It is anticipated that the existence of these cores
will greatly enhance the accomplishment of the SCoBIRC mission which is directed at the discovery and
clinical translation of therapeutic approaches for spinal cord and brain injury. In addition these facilities will
make available centralized technologies which will benefit UK neurological research in general and improve
the ability of both experienced and young investigators to compete for extramural funding.

project_terms:
Animals;Back;Bioinformatics;Center Core Grants;Clinical;Collaborations;Communication;Core Facility;Data;Drug Kinetics;Equipment;Equipment Failure;Equipment and Supplies;Extramural Activities;Fostering;Funding;Image Analysis;Individual;Laboratories;Maintenance;Microscopy;Mission;Modeling;NIH Program Announcements;National Institute of Neurological Disorders and Stroke;Neurologic;Neurosciences Research;Operative Surgical Procedures;Performance;Pilot Projects;Productivity;Qualifying;Research;Research Personnel;Research Project Grants;Resources;Running;Schedule;Technology;Therapeutic;Training;Translations;behavior test;biomarker;experience;improved;response;spinal cord and brain injury


application_id: 8018638
project_number: 5R44AR055014-03
project_title: Injectable collagen crosslink augmentation for degenerative disc disease
administering_ic: NIAMS
award_notice_date: 2011-01-07
opportunity_number: PA-09-080
application_type: 5
activity_code: R44
ic: AR
serial_number: 055014
program_official: PANAGIS, JAMES S
project_start_date: 2007-08-15
project_end_date: 2012-07-31
study_section: Special Emphasis Panel[ZRG1-MOSS-L(10)B]
contact_pi_person_id: 6575299
contact_pi: HEDMAN, THOMAS P
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 602492451
duns_number: 602492451
fips: US
organization_id: 10009769
organization_name: ORTHOPEUTICS, LP
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405111285
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-02-01
budget_end_date: 2012-07-31
project_abstract:
DESCRIPTION (provided by applicant): With regard to prevalence and cost to society low-back pain has few peers. With a patient population in excess of 15 million/year the societal cost is estimated to be in the realm of $100 billion/year. Current treatment options for this disease have shown limited success including physical therapy medication and surgery. This proposal involves a novel nonsurgical and cost-effective tissue revitalization approach which shows promise for treatment of mechanically and nutritionally challenged tissues like the spinal disc. Previous in vitro and in vivo studies have demonstrated the efficacy of Injectable collagen crosslink augmentation in stabilizing spinal joints decreasing disc bulge under load increasing the strength tear resistance and durability of the tissue while also improving nutritional flow to these largely avascular tissues. Phase I testing was successful in characterizing the crosslinking effects of seven candidate agents in disc annulus fibrosis (AF) tissue using mechanical thermal and protease digestion assays. At least one preferred agent was identified and concentration pH conditioning and buffering were optimized to maximize the efficiency of crosslinking and mechanical effect. Recently in vitro assays have been undertaken to determine agent and buffer biocompatibility. The proposed Phase II testing will provide data necessary for regulatory filings and first-in-man clinical trials. Reagent delivery penetration reaction kinetics permanency (effect duration) and storage requirements (shelf life) will be thoroughly investigated. Acute functional biocompatibility and neurotoxicity studies will be conducted to quantify expected and worst-case treatment effects in an animal model. Further characterization of crosslinking effects will be determined using different subgroups of human AF tissues (variations in age composition degeneration). By bringing this path-breaking treatment to the doorstep of clinical trials SBIR funding will play a vital role in enabling progress towards the ultimate goal of providing a novel cost-effective treatment in the struggle against low back pain and disability.  
  
PUBLIC HEALTH RELEVANCE:  Back pain and disability associated with spinal degeneration and instability remains among the most costly and prevalent health problems in the US today. With a patient population in excess of 15 million/year the societal cost is estimated to be in the realm of $100 billion/year. Due to the limited success of current treatment options it is reasonable to expect that an effective nonsurgical solution could revolutionize clinical care for this pandemic.

project_terms:
Acute;Address;Age;Animal Model;Animals;Back Pain;Biological Assay;Blood Chemical Analysis;Buffers;Cattle;Chemicals;Clinical;Clinical Trials;Collagen;Cross-Linking Reagents;Crosslinker;Data;Digestion;Disease;Drug Formulations;Effectiveness;Extracellular Matrix;Fatigue;Fibrosis;Funding;Future;Goals;Health;High Pressure Liquid Chromatography;Human;In Vitro;Injectable;Injection of therapeutic agent;Intervertebral disc structure;Investigation;Joints;Kinetics;Life;Low Back Pain;Mechanics;Modeling;Modification;Neurologic;Nutritional;Operative Surgical Procedures;Penetration;Peptide Hydrolases;Pharmaceutical Preparations;Phase;Physical therapy;Play;Preparation;Prevalence;Rattus;Reaction;Reagent;Resistance;Role;Small Business Innovation Research Grant;Societies;Solutions;Spinal;Structure;Subcutaneous Injections;Subgroup;Testing;Tissues;Variant;aged;base;biomaterial compatibility;clinical care;conditioning;cost;cost effective;crosslink;design;disability;effective therapy;efficacy testing;improved;in vitro Assay;in vivo;intervertebral disk degeneration;man;neurotoxicity;novel;pandemic disease;patient population;peer;prevent;programs;public health relevance;reaction rate;response;success;surfactant;treatment effect

public_health_relevance:
Back pain and disability associated with spinal degeneration and instability remainsamong the most costly and prevalent health problems in the US today. With a patientpopulation in excess of 15 million/year the societal cost is estimated to be in the realm of $100billion/year. Due to the limited success of current treatment options it is reasonable to expectthat an effective nonsurgical solution could revolutionize clinical care for this pandemic.


application_id: 8018633
project_number: 5R01AR049010-07
project_title: Microsomal Prostaglandin E Synthase in Rheumatoid Arthritis
administering_ic: NIAMS
award_notice_date: 2010-12-29
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AR
serial_number: 049010
program_official: MAO, SU-YAU
project_start_date: 2004-09-29
project_end_date: 2014-12-31
study_section: Arthritis, Connective Tissue and Skin Study Section[ACTS]
contact_pi_person_id: 1888793
contact_pi: CROFFORD, LESLIE J
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The effectiveness of non-specific and cyclooxygenase (COX)-2-specific non-steroidal anti-inflammatory drugs for treatment of the pain swelling and stiffness of arthritis provides clinical evidence that increased prostaglandin (PG) production is an important contributor to the disease process. PG biosynthesis requires the sequential action of COX-1 or COX-2 and terminal synthases to generate PGs that function as pleiotropic mediators by acting on a variety of cell surface receptors. After stimulation with pro-inflammatory cytokines there is a preferential increase of PGE2 in many different cell types and tissues including the synovium. We demonstrated that increased PGE2 in these tissues requires the inducible PGE synthase microsomal PGE synthase (mPGES)-1. We have also shown that absence of mPGES-1 results in a shift of the PG profile of cells and tissues with the specific profile dependent on the other synthases present. For this reason absence or inhibition of mPGES-1 is a markedly different biology than absence or inhibition of COX. The overall goal of this proposal is to characterize the role of mPGES-1 in immune inflammatory arthritis and how it differs from the role of COX-2. We hypothesize that upregulated mPGES-1 is required for the production of PGE2 and that its specific absence or inhibition results in an altered eicosanoid profile that fundamentally changes the immune inflammatory response. To evaluate this hypothesis we will make use of mice genetically deficient in mPGES-1 (Dba1/LacJ.mPGES-1 -/-) and inhibition of mPGES-1 using a specific inhibitor with activity in humans and mice (AF3485). We will determine the role for mPGES-1-derived PGE2 in comparison with other eicosanoids for initiation and progression of inflammation and immunity. We will determine the specific role of mPGES-1 deficiency for the developing immune response. Having shown profound differences in T- dependent humoral immune responses and in the Th phenotype we will determine the mechanism by which mPGES-1 deficiency leads to these changes. In order to translate these findings we will evaluate the differences between COX inhibition and mPGES-1 inhibition in human immune and inflammatory responses. We will determine effects of different compounds that inhibit PG production on T-helper phenotype and induced T-regulatory cells. These data will provide the scientific basis by which to determine if mPGES-1 is an appropriate target for therapeutic intervention in arthritis.  
  
PUBLIC HEALTH RELEVANCE: The discovery of COX-2 and subsequent development of specific COX-2 inhibitors represented an enormous conceptual advance in eicosanoid biology and opened new possibilities for pharmacologic treatment of inflammation and pain. It is clear however that COX-2-specific NSAIDs have their own toxicities. The finding of a PGE synthase isoform induced during inflammation and required for high level PGE2 production represents a conceptual advance of similar magnitude. In view of the existence of multiple PGES enzymes and other PG subclasses the specific role of mPGES-1-derived PGE2 in inflammation and autoimmunity remains uncertain. Furthermore information on the biology that will inform the development of mPGES-1 as a therapeutic target remains incomplete. It is our expectation that our work will yield new insights into the role of PGs in the functioning of eicosanoids during initiation and resolution of inflammation and the transition from the innate to the acquired immune response.

project_terms:
9-deoxy-delta-9-prostaglandin D2;Acute;Alprostadil;Anabolism;Aneurysm;Anti-Inflammatory Agents;Anti-inflammatory;Antibodies;Antigen Presentation;Arachidonic Acids;Arthritis;Autoimmune Process;Autoimmunity;Back;Biology;Blood Platelets;Blood Vessels;Bone Marrow;CD4 Positive T Lymphocytes;Cardiovascular system;Cell Surface Receptors;Cell physiology;Cell surface;Cells;Chimera organism;Clinical;Clinical Data;Clinical Trials;Collagen;Collagen Arthritis;Collagen Type II;Coxibs;Cytokine Signaling;Data;Dendritic Cells;Development;Dinoprostone;Disease;Effectiveness;Effector Cell;Eicosanoids;Embryo;Enzymes;Epoprostenol;Equilibrium;Event;Exhibits;Failure (biologic function);Fever;Fibroblasts;Generations;Genetic;Goals;Hematopoietic;Homeostasis;Human;Immune;Immune response;Immunity;Inflammation;Inflammatory;Inflammatory Response;Interleukin-12;Interleukin-17;K/BxN model;Knockout Mice;Lead;Learning;Leukotriene B4;Lipids;Literature;Lymphocyte;Matrix Metalloproteinases;Mediator of activation protein;Mesenchymal;Modeling;Mus;Pain;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Phenotype;Phospholipase A2;Phospholipids;Play;Process;Production;Property;Prostaglandin D2;Prostaglandin H2;Prostaglandin Production;Prostaglandin-Endoperoxide Synthase;Prostaglandins;Protein Isoforms;Regulatory T-Lymphocyte;Resistance;Resolution;Rheumatoid Arthritis;Risk;Role;Serum;Shunt Device;Small Interfering RNA;Stimulus;Swelling;Synovial Membrane;T-Cell Receptor;T-Lymphocyte;Therapeutic;Therapeutic Intervention;Tissues;Toxic effect;Transgenic Mice;Translating;Up-Regulation (Physiology);Work;analog;base;cell type;cyclooxygenase 1;cyclooxygenase 2;cytokine;expectation;gastrointestinal;human NOS2A protein;immunoregulation;inhibitor/antagonist;insight;mouse PGE synthase 1;peripheral blood;pre-clinical;prostaglandin E synthase;public health relevance;research study;response;therapeutic target

public_health_relevance:
PROJECT NARRATIVEThe discovery of COX-2 and subsequent development of specific COX-2 inhibitorsrepresented an enormous conceptual advance in eicosanoid biology and opened newpossibilities for pharmacologic treatment of inflammation and pain. It is clear howeverthat COX-2-specific NSAIDs have their own toxicities. The finding of a PGE synthaseisoform induced during inflammation and required for high level PGE2 productionrepresents a conceptual advance of similar magnitude. In view of the existence ofmultiple PGES enzymes and other PG subclasses the specific role of mPGES-1-derivedPGE2 in inflammation and autoimmunity remains uncertain. Furthermore information onthe biology that will inform the development of mPGES-1 as a therapeutic target remainsincomplete. It is our expectation that our work will yield new insights into the role of PGsin the functioning of eicosanoids during initiation and resolution of inflammation and thetransition from the innate to the acquired immune response.


application_id: 8018187
project_number: 5R01DK055664-09
project_title: Hepatocyte Nitric Oxide Synthase Regulation by Glucagon and Insulin
administering_ic: NIDDK
award_notice_date: 2010-12-21
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 055664
program_official: SERRANO, JOSE
project_start_date: 2001-02-15
project_end_date: 2012-11-30
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 2093531
contact_pi: HARBRECHT, BRIAN G.
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The immune response to sepsis involves a series of complex highly integrated homeostatic responses that if prolonged and excessive can lead to organ dysfunction and death. Nitric oxide (NO) synthesis is upregulated by sepsis in many tissues and is an essential component of the host immune response. Nitric oxide synthesis can be beneficial and improve immune and organ function but if synthesis is excessive and prolonged NO can promote organ injury tissue inflammation and death. NO is produced in hepatocytes by the inducible nitric oxide synthase (iNOS) that is stimulated by cytokines and proinflammatory stimuli. Excessive NO from iNOS produces cellular dysfunction and hepatic injury. Glucagon and cyclic adenosine monophosphate (cAMP) regulate hepatic iNOS expression in vitro and in vivo and by doing so decrease NO-mediated hepatic injury. Our preliminary data demonstrate that insulin also down-regulates cytokine-induced iNOS expression. Both glucagon and insulin alter specific intracellular signaling pathways in hepatocytes but the mechanisms involved in the regulation of hepatocyte function in sepsis by glucagon and insulin and specifically the regulation of hepatocyte iNOS expression have not been identified. In this proposal we will determine the mechanisms responsible for the regulation of hepatocyte iNOS expression by glucagon and insulin. In Aim I we will continue our work in determining the mechanism for the glucagon and cAMP-induced inhibition of hepatocyte iNOS expression. We will focus on protein kinase A (PKA)-independent pathways induced by cAMP and evaluate the role of the guanine nucleotide exchange factor Epac and the role of calcium. In Aim II we will determine the mechanisms responsible for the inhibition of iNOS by insulin. By defining how these hormones regulate hepatocyte iNOS expression we will provide a framework for understanding the basic pathophysiologic cellular events in shock and sepsis that may lead to novel cellular-based therapies for critically ill patients. Project Narrative: Nitric oxide is synthesized in critically ill patients during septic shock and when overproduced can increase cellular dysfunction tissue injury and death. Glucagon and insulin primarily regulate blood glucose which has become an important facet of the care of critically ill patients but we have found that they also regulate hepatic nitric oxide production. We will determine the mechanisms responsible for the regulation of hepatocyte inducible nitric oxide synthase (iNOS) expression by glucagon and insulin. By defining these mechanisms we will provide a framework for understanding the basic cellular events in shock and sepsis which may lead to novel cellular-based therapies for critically ill patients.

project_terms:
Adult;Area;Biology;Blood Glucose;Calcium;Caring;Cell physiology;Cessation of life;Complex;Critical Care;Critical Illness;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Data;Development;Endocrinology;Event;Functional disorder;Glucagon;Guanine Nucleotide Exchange Factors;Hepatic;Hepatocyte;Hormones;Immune;Immune response;In Vitro;Infection;Inflammation;Injury;Insulin;Intracellular Second Messenger;Lead;Mediating;Mediator of activation protein;Metabolism;Molecular;Mortality Vital Statistics;Multiple Organ Failure;Nitric Oxide;Nuclear;Operative Surgical Procedures;Organ;Pathway interactions;Patients;Physiological;Production;Regulation;Research;Role;Second Messenger Systems;Sepsis;Septic Shock;Series;Shock;Signal Pathway;Signal Transduction;Stimulus;Study Section;Tissues;Transplantation;Work;base;cytokine;human NOS2A protein;improved;in vivo;novel;nutrition;prevent;programs;response;septic


application_id: 8017866
project_number: 1R25CA134283-01A2
project_title: University of Louisville Cancer Education Program
administering_ic: NCI
award_notice_date: 2011-09-14
opportunity_number: PAR-08-120
application_type: 1
activity_code: R25
ic: CA
serial_number: 134283
suffix: A2
program_official: LEI, MING
project_start_date: 2011-09-14
project_end_date: 2016-08-31
study_section: Education Study Section (G)[NCI-G]
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
project_abstract:
DESCRIPTION (provided by applicant): Cancer incidence morbidity and mortality in the Commonwealth of Kentucky are among the highest in the nation. The James Graham Brown Cancer Center's mission is to reduce cancer incidence morbidity and mortality particularly within the Commonwealth and the region we serve. The clinical and research programs of the James Graham Brown Cancer Center have experienced tremendous growth in faculty recruitment and in the development of scientific and clinical programs and shared use facilities. The long-term objective of the University of Louisville Cancer Education Program is to recruit educate and motivate outstanding undergraduate and professional students to pursue further training and future careers in cancer research. The program fits exceptionally well within the strategic plans of the University of Louisville and we will implement novel recruitment evaluation and dissemination strategies to achieve the objectives of the program.  
  
PUBLIC HEALTH RELEVANCE: Cancer incidence morbidity and mortality in the Commonwealth of Kentucky are among the highest in the nation. The James Graham Brown Cancer Center's mission is to reduce cancer incidence morbidity and mortality particularly within the Commonwealth and the region we serve. The clinical and research programs of the James Graham Brown Cancer Center have experienced tremendous growth in faculty recruitment and in the development of scientific and clinical programs and shared use facilities. The long-term objective of the University of Louisville Cancer Education Program is to recruit educate and motivate outstanding undergraduate and professional students to pursue further training and future careers in cancer research.

project_terms:
American Association of Cancer Research;Benchmarking;Cancer Center;Cancer Research Project;Clinical;Clinical Research;Development;Educational Curriculum;Evaluation;Faculty;Future;Growth;Health Professional;Incidence;Kentucky;Malignant Neoplasms;Mentors;Mission;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Motivation;Outcome;Recruitment Activity;Research;Research Project Grants;Selection Criteria;Strategic Planning;Students;Time;Training;United States;Universities;anticancer research;cancer education;career;experience;medical schools;meetings;novel;programs;research and development;skills;symposium


application_id: 8017377
project_number: 5R01AI067869-05
project_title: YopM and protective innate defenses against plague
administering_ic: NIAID
award_notice_date: 2011-02-11
opportunity_number: PA-04-119
application_type: 5
activity_code: R01
ic: AI
serial_number: 067869
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2007-03-16
project_end_date: 2013-02-28
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 1864206
contact_pi: STRALEY, SUSAN C
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Yersinia pestis the causative agent of plague delivers a set of 6 Yop toxins that act within host cells to negate and modulate signaling pathways that orchestrate host innate defenses that are crucial for developing an effective immune response. This proposal focuses on the mechanism of YopM. We have found that YopM specifically causes a global loss of natural killer cells and those NK cells remaining do not contain detectable mRNA for IFNg. Concomitantly YopM causes down-regulation in macrophages of net mRNA expression for key proinflammatory cytokines. In this project we will test the hypothesis that YopM acts directly on cells such as macrophages and dendritic cells to prevent expression of cytokines such as IL- 15 and IL-12 that synergize to activate effector cells such as macrophages polymorphonuclear neutrophils natural killer cells and cytolytic T cells for controlling numbers of Y. pestis. In Aim 1 we will determine whether YopM's action is mediated by hypothesized key cells by comparing the infection dynamics for virulent and YopM- Y. pestis (viable numbers dissemination as a function of time) and host response (cell populations and cytokines) in primary pneumonic plague and bubonic plague in mice ablated for the cells genetically or by manipulation. In Aim 2 we will test our hypothesis that the Th1 cytokine and chemokine pathway mediates different host responses to YopM+ and YopM- Y. pestis between d 1 and d 3 to 4 p.i. in bubonic and pneumonic plague by infecting knockout mice or mice ablated for hypothesized key cytokines and analyzing the resulting infection dynamics and host response. In Aim 3 we will map the signaling circuitry of YopM's pathogenic effects by comparing transcriptional profiles (cDNA microarrays) and analyses of intracellular cytokines in purified macrophages from mice with pneumonic or bubonic plague due to virulent and YopM- Y. pestis. The data will reveal the pathogenic mechanism of YopM by identifying cells cytokines and signaling pathways modulated by YopM during plague. The findings will provide a completely new understanding of the biology of plague from both microbial and host perspectives as well as provide a framework for rational enhancement of resistance to plague in people threatened with exposure to plague. The data will reveal immune deviation points during plague and could identify potential therapeutic intervention targets. The findings also will provide a better understanding of mammalian innate defenses and insight into evasive mechanisms of pathogens and will facilitate the defeat of important human pathogens that are not select agents.

project_terms:
Biology;Bubonic Plague;CD8B1 gene;Cells;Cytokine Signaling;Cytotoxic T-Lymphocytes;Data;Dendritic Cells;Down-Regulation;Effector Cell;Exposure to;Foundations;Human;Immune;Immune response;Infection;Interleukin-1;Interleukin-12;Interleukin-15;Interleukin-18;Knockout Mice;Lung;Maps;Mediating;Messenger RNA;Mus;Natural Killer Cells;Parents;Pathway interactions;Plague;Pneumonic Plague;Population;Predictive Value;Reporting;Resistance;Signal Pathway;Signal Transduction;Spleen;T-Lymphocyte;Testing;Therapeutic Intervention;Time;Toxin;Virulence;Virulent;Yersinia pestis;cDNA Arrays;chemokine;cytokine;insight;mRNA Expression;macrophage;microbial host;mouse model;mutant;neutrophil;pathogen;prevent;research study


application_id: 8015491
project_number: 7R01CA137037-02
project_title: lung tumor exosome-mediated inflammation promotes tumor progression and growth
project_terms: Growth;Inflammation;Lung Neoplasms;Mediating;tumor progression
administering_ic: NCI
award_notice_date: 2010-04-12
opportunity_number: PA-07-070
application_type: 7
activity_code: R01
ic: CA
serial_number: 137037
program_official: HOWCROFT, THOMAS K
project_start_date: 2009-08-01
project_end_date: 2011-07-31
study_section: Tumor Microenvironment Study Section[TME]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
The overall goal of this proposal is to elucidate the mechanisms by which lung tumor exosomes promote an inflammatory response namely the activation of macrophages and promote the progression and growth of lung tumors. Our preliminary data indicate that pretreatment of A/J mice with exosomes produced by TC-1 lung tumor cells or exosomes isolated from the lung tissue of NJ mice that have been pretreated with the carcinogen urethane results in more rapid tumor growth and earlier progression of lung carcinomas. Urethane treatment results in the recruitment of the activated form of TRAF2 to the exosomes and the exosomes with activated TRAF2 are taken up by the bone marrow-derived precursors of macrophages leading to their maturation and subsequent migration to the lung. The recruitment of the activated TRAF2 to the exosomes requires degradation of the inflammation suppressor protein CYLD in the tumor cells; moreover TRAF2 can mediate ubiquitination of CYLD thereby promoting its degradation. The results of siRNA TRAF2 knockout indicated however that TRAF2 is required but is not sufficient for ubiquitination of CYLD. We have now identified two exosomal proteins that interact with TRAF2 Itch and Jabi which have the potential to enhance the ubiquitination of CYLD in lung tumor cells. We propose to: (1) Confirm the role of lung tumor exosomal TRAF2 in the promotion of urethane-induced lung carcinomas by determining whether knockout of TRAF2 in TC-1 lung tumor cells is sufficient for (0 inhibition of macrophage differentiation and (ii) prevention of TC-1 cell exosome-mediated enhancement of urethane induced lung cancer. (2) Determine if Jabi and itch in the TC-1 exosomes are capable of promoting the differentiation of CD1 1bGr1 cells into activated macrophages. (3) Identification of cells targeted in vivo by exosomes. The data generated should permit the development a highly innovative model of the cellular and molecular basis for exosome-mediated chronic inflammation and promotion of lung tumor growth and suggest novel preventive and therapeutic strategies.

public_health_relevance:
Lung cancer is the leading cause of cancer-related death in the United States. Chronic inflammation plays a causative role in lung cancer. Therefore the finding that exosomes isolated from lung tissues of mouse lung cancer model play a role in induction and subsequently activation of macrophages as proposed in this grant has several implications in the field of chronic inflammation related disease research including cancer obesity rheumatoid arthritis atherosclerosis and chronic obstructive pulmonary diseases. First it suggests a central mechanism that regulates an important mode of cell-cell communication which may be of importance in communication among normal cells as well as several types of chronic inflammation driven diseases. The results of the experiments proposed in this application should indicate whether this mechanism is tumor-specific or not. Second the identification of this mechanism provides a tool that can be used to clearly define the functions of carcinogen induced exosomes in the promotion of tumor growth which has proven difficult to assign unambiguously. This will be addressed in this application for the analysis of the role of carcinogen (urethane) induced lung tumor exosomes in the activation of macrophages. Finally the establishment of role of exosames CYLD cross-talked with TRAF2 in regulation of induction of activated macrophages will be of central importance as both molecules has long been recognized as a intracellular regulator of pro- and anti- inflammation proteins. But their role in intercellular communication has not been studied. This finding may also pinpoint novel molecular targets for the development of novel therapeutic strategies for the treatment of patients with chronic inflammation driven diseases like lung cancer. A finding that TRAF2 alone or with other proteins in the exosomes is associated with the promotion of tumor growth may suggest a non-invasive procedure that will assist in prognosis of human lung cancer.


application_id: 8015158
project_number: 2R01DE017138-06
project_title: Oral immunity and adjuvant receptors
administering_ic: NIDCR
award_notice_date: 2010-09-14
opportunity_number: PA-10-067
application_type: 2
activity_code: R01
ic: DE
serial_number: 017138
program_official: BURGOON, PENNY W
project_start_date: 2006-02-01
project_end_date: 2015-08-31
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):  This application addresses the compelling need to develop new and improved vaccine adjuvants for stimulating protective immunity at mucosal surfaces. The proposal involves a consortium arrangement between the University of Louisville the University at Buffalo and the Hauptman-Woodward Institute and brings together complementary and integrated expertise in vaccine adjuvant research structural and molecular biology and induction of mucosal immunity. Studies by this group have succeeded to dissociate useful adjuvant properties from the toxicity of LT-IIb an AB5-type heat-labile enterotoxin of Escherichia coli. Specifically the recombinantly expressed B pentameric subunit of LT-IIb (LT-IIb-B5) not only lacks enterotoxicity but strikingly can activate the Toll-like receptor (TLR)-2/TLR1 signaling complex and stimulate antibody responses to co-administered vaccine proteins. Proof-of-concept preliminary studies have shown that certain engineered point-substitution mutations in the active region of LT-IIb-B5 enhance its ability to interact with TLR2 and TLR1. The overall objective of this application is to better characterize the physical and functional interaction of LT-IIb-B5 with the TLR2/TLR1 heterodimer engineer improved versions of LT-IIb-B5 in terms of TLR2/TLR1-mediated adjuvanticity and develop potential adjuvants through studies in preclinical models of vaccination against oral infection. This will be accomplished through appropriate and innovative molecular biological structural and immunological studies outlined in the following four specific aims: 1) To rationally engineer enhanced TLR2-interactive versions of LT-IIb-B5. 2) To structurally characterize the LT-IIb- B5-TLR2/TLR1 interaction using small-angle X-ray scattering (SAXS). 3) To evaluate the engineered LT-IIb-B5 mutants for in vitro TLR2/TLR1-dependent immunostimulatory activities. 4) To determine the ability of LT-IIb-B5 and improved engineered versions thereof to induce protective immunity in vivo. The generated data will form the basis for the long-term goal which is to establish LT-IIb-B5 and improved engineered derivatives as effective adjuvants in vaccine formulations against pathogens which colonize or invade via oral respiratory or urogenital mucosal surfaces.  
  
PUBLIC HEALTH RELEVANCE:  The objective of this application is to rationally engineer novel Toll-like receptor-dependent mucosal adjuvants. These constructs will be evaluated for their capacity to stimulate protective immunity using appropriate preclinical mouse models. The focus of this proposal is on a novel vaccine against periodontitis an oral inflammatory disease with an impact on systemic health although the developed mucosal adjuvants can also be used in vaccine formulations against pathogens which colonize or invade via oral respiratory or urogenital mucosal surfaces. This work is timely and important given the paucity of safe and effective vaccine adjuvants and the tremendous health impact of infectious diseases.

project_terms:
Address;Adjuvant;Adjuvanticity;Antibody Formation;Area;Binding (Molecular Function);Biological;Bone Marrow;Buffaloes;CD4 Positive T Lymphocytes;Collaborations;Communicable Diseases;Complex;Crystallography;Data;Dendritic Cells;Dependence;Disease;Drug Formulations;Engineering;Enterotoxins;Escherichia coli;Exhibits;Figs - dietary;Funding;Gangliosides;Genitourinary system;Goals;Health;Heating;Immunity;Immunization;In Vitro;Infection;Inflammatory;Institutes;Invaded;Ligands;Lipid Binding;Masks;Mediating;Membrane Microdomains;Modeling;Molecular;Molecular Biology;Mucosal Immunity;Mus;Mutation;Oral;Paper;Parents;Periodontitis;Porphyromonas gingivalis;Pre-Clinical Model;Property;Proteins;Qualifying;Relative (related person);Research;Research Personnel;Roentgen Rays;Serum;Signal Transduction;Site;Solutions;Solvents;Structure;Surface;TLR1 gene;Technology;Testing;Time;Toll-Like Receptor 2;Toll-like receptors;Toxic effect;Universities;Vaccination;Vaccine Adjuvant;Vaccines;Work;base;improved;in vivo;innovation;interdisciplinary collaboration;mouse model;mutant;novel;novel vaccines;oral immunity;oral infection;pathogen;pre-clinical;receptor;respiratory;structural biology

public_health_relevance:
Project NarrativeThe objective of this application is to rationally engineer novel Toll-like receptor-dependent mucosal adjuvants.These constructs will be evaluated for their capacity to stimulate protective immunity using appropriatepreclinical mouse models. The focus of this proposal is on a novel vaccine against periodontitis an oralinflammatory disease with an impact on systemic health although the developed mucosal adjuvants can alsobe used in vaccine formulations against pathogens which colonize or invade via oral respiratory or urogenitalmucosal surfaces. This work is timely and important given the paucity of safe and effective vaccine adjuvantsand the tremendous health impact of infectious diseases.


application_id: 8014346
project_number: N01DA68866-12-0-1
project_title: Development & Manufacture of Pharmaceutical Products for Addiction Treatment
administering_ic: NIDA
project_start_date: 2006-09-17
project_end_date: 2011-09-17
contact_pi_person_id: 8538852
contact_pi: MURTY, RAM B.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 943117366
primary_uei: DNJBTJ3XBQM6
duns_number: 943117366
uei: DNJBTJ3XBQM6
fips: US
organization_id: 3514301
organization_name: MURTY PHARMACEUTICALS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405091016
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
The purpose of this contract is to carry out the development & manufacture of pharmaceutical preparations to be used in the medications development program of the National Institute on Drug Abuse (NIDA) for addiction treatment.

project_terms:
Clinical Trials;Contractor;Contracts;Data Reporting;Development;Dosage Forms;Drug Formulations;Evaluation;Generations;Maintenance;National Institute of Drug Abuse;Pharmaceutical Preparations;Pharmacologic Substance;Placebos;Preparation;Resources;Site;Validation;addiction;analytical method;method development;pre-clinical;programs


application_id: 8013901
project_number: 5R01DA024598-04
project_title: Social networks and HIV risk among rural drug users
administering_ic: NIDA
award_notice_date: 2011-02-01
opportunity_number: PA-07-103
application_type: 5
activity_code: R01
ic: DA
serial_number: 024598
program_official: HARTSOCK, PETER
project_start_date: 2008-04-05
project_end_date: 2013-01-31
study_section: Behavioral and Social Science Approaches to Preventing HIV/AIDS Study Section[BSPH]
contact_pi_person_id: 7018622
contact_pi: HAVENS, JENNIFER 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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  This application is in response to PA-06-478 "Research on Rural Mental Health and Drug Abuse Disorders". One of the research areas highlighted by this PA is the examination of rural HIV transmission using social network analysis. The overall goal of the study is to examine the prevalence incidence and risk factors for HIV and other blood borne infections (BBIs) such as hepatitis B (HBV) and C (HCV) among rural Appalachian drug users using social network analysis and multilevel modeling. HIV continues to be a major public health problem in the United States especially among drug users. However little is known about HIV in rural areas in which there are marked health disparities. Therefore given that studies among urban drug users have found that social network indicators are robust predictors of HIV risk both social network and individual characteristics will be measured for their association with HIV risk among rural drug users. The specific aims are: 1) To determine the prevalence and incidence of HIV HCV and HBV among rural injection and non- injection drug users; 2) To examine HIV and other BBI risk among rural injection and non-injection drug users; and 3) To examine longitudinal changes in rural HIV HCV and HBV risk at 6-months 12-months and 18- months post-baseline. To meet these aims a sample 500 rural injection and non-injection drug users will be recruited using respondent driven sampling (RDS). In addition to biologic testing for HIV HCV and HBV rural participants will be given an interviewer-administered questionnaire pertaining to their social networks (drug sexual and support networks) sociodemographics drug use HIV risk behaviors psychiatric diagnoses intravention and norms. Since individuals will be nested within networks data will be analyzed using multilevel random effects regression that allows for the simultaneous examination of social network and individual-level risk. Consistent with the priorities of the NIDA AIDS Research Program this proposal will explore the social network structure in a rural drug using population in order to better understand how network factors may affect HIV risk in rural areas using an innovative multilevel approach. Results from the proposed study will inform the design and implementation of HIV interventions in rural areas and help to determine the appropriate population for which to target such activities in order to reduce the morbidity and mortality associated with HIV and other BBIs.   
  
Although HIV remains a significant public health problem in the United States especially among drug users little is known about HIV risk in rural areas such as Appalachia. It has been shown in urban populations that relationships among drug users also known as social networks are important predictors of HIV risk. Therefore this study seeks to characterize rural HIV risk by measuring both social network and individual behaviors in order to inform prevention activities in health resource-deprived rural areas.

project_terms:
Acquired Immunodeficiency Syndrome;Affect;Appalachian Region;Area;Automobile Driving;Behavior;Blood;Centers for Disease Control and Prevention (U.S.);Characteristics;Communities;Data;Disease;Drug Prescriptions;Drug abuse;Drug usage;Drug user;Epidemic;Goals;Growth;HIV;HIV Infections;Health Resources;Hepatitis B;Hepatitis B Virus;Hepatitis C;Hepatitis C virus;Human immunodeficiency virus test;Incidence;Individual;Individual Adjustment;Infection;Injecting drug user;Injection of therapeutic agent;Intervention;Interview;Interviewer;Kentucky;Measures;Mental Health;Modeling;Morbidity - disease rate;Mortality Vital Statistics;National Institute of Drug Abuse;Participant;Pathway Analysis;Pharmaceutical Preparations;Population;Prevalence;Prevention;Principal Investigator;Psychiatric Diagnosis;Questionnaires;Recruitment Activity;Reporting;Research;Research Priority;Respondent;Risk;Risk Behaviors;Risk Factors;Rural;Rural Population;Sampling;Serologic tests;Seroprevalences;Social Network;Structure;Testing;Time;United States;Urban Population;design;disorder prevention;health disparity;high risk;innovation;meetings;multilevel analysis;programs;public health medicine (field);response;rural area;transmission process;urban area


application_id: 8013889
project_number: 5R01NS065052-02
project_title: Neural circuit disruption by diffuse brain injury: basis for morbidity & therapy
administering_ic: NINDS
award_notice_date: 2011-01-13
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 065052
program_official: HICKS, RAMONA R
project_start_date: 2010-02-01
project_end_date: 2015-01-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 2048186
contact_pi: LIFSHITZ, JONATHAN
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Our long term goals are to develop effective pharmacological and rehabilitative treatment strategies that promote adaptive reorganization of brain-injured circuits to mitigate neurological dysfunction (morbidity) after diffuse traumatic brain injury (TBI). To achieve these goals we will exploit a novel reproducible late-onset neurological deficit that we have observed in the diffuse brain-injured rat analogous to agitation in brain injury survivors. In contrast to the soothing and pacifying nature of facial whisker stimulation in uninjured rats brain- injured rats react to whisker stimulation by cowering freezing and guarding the mystacial pads. This aberrant behavior is concomitant with axonal damage neuronal atrophy persistent inflammation and neuroplasticity such that whisker stimulation activates brain regions outside the conventional somatosensory whisker circuit. The current proposal tests the hypothesis that diffuse brain injury-induced inflammation drives the maladaptive structural plasticity responsible for aberrant behavioral responses to whisker stimulation. The model system afforded by the brain-injured somatosensory whisker circuit provides a reductionistic approach to the complexity of diffuse TBI to address pathological and reparative mechanisms associated with post-traumatic morbidity. This circuit in diffuse brain-injured adult male rats will be evaluated for (Aim 1) aberrant behaviors elicited by whisker stimulation (Aim 2) chronic neuropathology neuronal activation and circuit reorganization and (Aim 3) neuroinflammation-driven neuroplastic responses that contribute to circuit reorganization and morbidity. An anti-inflammatory therapeutic regimen may provide a clinically relevant intervention to prevent circuit rewiring and the onset of morbidity. The innovative combination of behavioral anatomical functional and therapeutic approaches directed at the brain-injured somatosensory whisker circuit addresses the underlying mechanisms associated with unregulated structural plasticity in the injured brain. Uncovering these processes can direct treatments to mitigate the onset reduce the duration and/or promote the resolution of neurological dysfunction. Results from this circuit can ultimately be expanded to other circuits in rodents and then man to improve quality of life for millions of TBI survivors and potentially others suffering from progressive neurodegenerative diseases.  
  
PUBLIC HEALTH RELEVANCE: The present proposal focuses on the persistent morbidity experienced by diffuse brain injury survivors for whom treatment options are limited. In diffuse brain-injured rats aberrant responses to whisker stimulation will be employed as a tool to identify pathological and reparative mechanisms associated with somatosensory whisker circuit disruption. By developing validating and implementing an animal model of one discrete post-traumatic morbidity significant advancements can be made towards reshaping first one then other brain- injured circuits in rodents and man.

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

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


application_id: 8013783
project_number: 5R01NS045954-08
project_title: Neuropeptidergic Inhibition of Spinal Pain Transmission
administering_ic: NINDS
award_notice_date: 2011-01-27
opportunity_number: PA-07-282
application_type: 5
activity_code: R01
ic: NS
serial_number: 045954
program_official: PORTER, LINDA L
project_start_date: 2002-09-10
project_end_date: 2014-01-31
study_section: Special Emphasis Panel[ZRG1-IFCN-B(04)M]
contact_pi_person_id: 1879170
contact_pi: TAYLOR, BRADLEY K.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Work performed during the previous funding periods indicates that intrathecal administration of NPY reduces the mechanical and thermal hypersensitivity associated with inflammation or nerve injury. The objective of the present application is to establish NPY as an endogenous pain modulator and to identify the mechanisms underlying NPY-mediated inhibition of inflammatory or neuropathic pain. The central hypothesis is that tissue or nerve injury sensitizes the dorsal horn to the pain inhibitory actions of NPY receptor signaling. Our approach involves transgenic biochemical neurophysiological anatomical and behavioral methods to determine: the anti-allodynic actions of endogenous NPY (Aim 1); the effect of injury on NPY receptor coupling to G-proteins (Aim 2); the effect of injury on the inhibition by NPY of SP release and subsequent NK1 receptor (NK1) activation in the spinal cord (Aim 3A); and the effect of NPY on the activity of spinal neurons that express the NPY Y1 receptor (Aim 3B). Our long-term goal is to understand endogenous neuropeptidergic inhibition of spinal pain transmission and to establish the therapeutic potential of NPY receptor agonists for chronic pain. AIM #1 tests the hypothesis that endogenous NPY tonically inhibits allodynia. To address the contribution of endogenous NPY to chronic pain Aim #1 will utilize transgenic mice (NPYtet) that contain a doxycycline-regulated cassette (tetracycline trans-activator tTA) at the promoter region of the npy locus. We describe data indicating that inducible NPY depletion increases behavioral signs of allodynia after tissue or nerve injury. These data led us to determine the effect of conditional NPY knockdown on the induction maintenance and reinstatement of chronic pain. We predict that NPY depletion will speed the development increase the intensity and extend the duration of inflammatory and neuropathic pain. AIM #2 tests the hypothesis that injury increases NPY receptor-G protein signaling in the dorsal horn. To determine whether and when injury increases NPY receptor-G protein coupling we will evaluate Y1- and Y2-agonist-stimulated [35S GTP3S binding at multiple time points after inflammation or nerve injury. AIM #3 tests the hypothesis that injury increases NPY inhibition of spinal pain neurotransmission. Primary afferent terminals in dorsal horn express NPY receptors. Our preliminary data indicate that NPY acts at Y1 and Y2 receptors to reduce substance P release and subsequent NK1 activation (assessed with NK1 internalization) in spinal cord slices and in vivo. We predict that injury will increase these inhibitory actions. Because dorsal horn neurons express Y1 we will test for postsynaptic actions of NPY on SP-induced nociceptive behavior NK1 internalization and spinal neuron gene action (Fos) on Y1-expressing cells. New preliminary data with the selective neurotoxin NPY-saporin suggest that Y1-expressing cells in the dorsal horn facilitate neuropathic pain transmission. We predict that the activity of this population of spinal neurons will be decreased by NPY administration and increased by NPY knockdown or Y1 / Y2 receptor antagonism.  
  
PUBLIC HEALTH RELEVANCE: Chronic pain management is a major scientific and health care challenge as current analgesic drugs rarely provide sufficient efficacy in the absence of serious side effects. Our preliminary data suggest that new drugs acting at the neuropeptide Y receptor system in the spinal cord will overcome these problems but further studies are required to determine how NPY works. Such studies are critical not only to determine whether NPY is a natural long-lasting analgesic that reduces the duration of pain but also to harness its therapeutic potential towards the development of new analgesic drugs.

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

public_health_relevance:
PUBLIC HEALTH RELEVANCE STATEMENTChronic pain management is a major scientific and health care challenge as current analgesic drugsrarely provide sufficient efficacy in the absence of serious side effects. Our preliminary data suggestthat new drugs acting at the neuropeptide Y receptor system in the spinal cord will overcome theseproblems but further studies are required to determine how NPY works. Such studies are critical notonly to determine whether NPY is a natural long-lasting analgesic that reduces the duration of painbut also to harness its therapeutic potential towards the development of new analgesic drugs.


application_id: 8013681
project_number: 3R01DK072032-05S1
project_title: Podocytes and oxidative stress in diabetic kidney
administering_ic: NIDDK
award_notice_date: 2010-03-08
application_type: 3
activity_code: R01
ic: DK
serial_number: 072032
suffix: S1
program_official: RYS-SIKORA, KRYSTYNA E
project_start_date: 2010-03-08
project_end_date: 2011-02-28
study_section: Pathobiology of Kidney Disease Study Section[PBKD]
contact_pi_person_id: 1927079
contact_pi: EPSTEIN, PAUL N
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
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 single largest cause of end stage renal disease in the United States is diabetic nephropathy (DN). We have recently characterized the progression of DN in a transgenic mouse model of Type I diabetes called OVE26. This model is a significant improvement over previous DN models in that 9 month old OVE26 mice exhibit many characteristics of advanced DN. They show a 100 fold increase in albuminuria extensive interstitial fibrosis and a modest reduction in GFR. We will use this model to assess the role of reactive oxygen species (ROS) in the glomerular podocyte for development of DN. OVE26 mice will also allow us to assess changes in glomerular gene expression by laser capture and Affymetrix gene array analysis during the progression from early DN at two months of age to severe DN at fourteen months of age in OVE26 mice. In addition the severe DN in OVE26 animals will allow us to make the first test of the ability of oral antioxidant therapy to block advance DN.    ROS have been shown to be a critical component of DN. Systemic treatment with antioxidants or ubiquitously expressed antioxidant transgenes protect diabetic animals from early stage DN. However by systemic treatment it is not possible to identify which cells in the glomerulus are injured by ROS or protected by antioxidant treatment. Podocytes are an important candidate cell. They make up a critical component of the selective glomerular filtration membrane and many podocytes are lost during the progression of DN. In addition they have been shown to produce ROS. We developed transgenic mice that use the podocyte selective nephrin promoter to overexpress a transgene for the potent antioxidant protein metaliothionein. We demonstrated elevated podocyte expression of the metaliothionein transgene by immunohistochemistry and western blotting. Mice that overexpress metaliothionein in podocytes were bred to OVE26 Type I diabetic mice. Our initial results demonstrate that podocyte overexpression of metaliothionein dramatically reduces diabetes-induced macroalbuminuria and significantly reduces glomerular hypertrophy. These mice will be used to assess the role of ROS damage to the podocyte in the changing gene expression and deteriorating structure and function that lead to diabetic end stage renal disease.

project_terms:
2266-tetramethyl-4-piperidinol-N-oxyl;Age-Months;Albuminuria;Animals;Antioxidants;Ascorbic Acid;Breeding;Cardiac Myocytes;Cells;Characteristics;Chronic;Clinical;Data;Deterioration;Development;Diabetes Mellitus;Diabetic Nephropathy;Diabetic mouse;End stage renal failure;Event;Exhibits;Failure (biologic function);Fibrosis;Gene Expression;Genes;Glomerular Filtration Rate;Human;Hypertrophy;Immunohistochemistry;Inflammation;Injury;Insulin-Dependent Diabetes Mellitus;Kidney;Lasers;Lead;Light;Lipid Peroxidation;Malondialdehyde;Membrane;Metallothionein;Modeling;Morphology;Mus;Nephrons;Oligonucleotide Microarrays;Oral;Oxidative Stress;Pancreas;Production;Promotor (Genetics);Proteins;Publishing;RNA;Reactive Oxygen Species;Regimen;Renal function;Research Personnel;Rodent Model;Role;Source;Staging;Structural Genes;Structure;Superoxide Dismutase;Testing;Therapeutic;Thioctic Acid;Transgenes;Transgenic Mice;Transgenic Organisms;Tubular formation;United States;Urine;Weaning;Western Blotting;antioxidant therapy;biomarker;cell injury;cell type;diabetic;glomerular filtration;injured;interstitial;kidney cell;macroalbuminuria;mouse model;nephrin;overexpression;oxidative damage;podocyte;prevent;programs;type I diabetic


application_id: 8013578
project_number: 5R01HL082772-05
project_title: Angiotensin Induced Proteoglycans in Atherosclerosis
administering_ic: NHLBI
award_notice_date: 2011-01-31
application_type: 5
activity_code: R01
ic: HL
serial_number: 082772
program_official: HASAN, AHMED A K
project_start_date: 2007-02-15
project_end_date: 2013-01-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 3123430
contact_pi: TANNOCK, LISA R
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-02-01
project_abstract:
DESCRIPTION (provided by applicant): The mechanisms underlying the initiation and development of atherosclerosis are not fully understood. As outlined in the response to retention hypothesis the retention of atherogenic lipoproteins within the sub-endothelial space by their interactions with vascular proteoglycans is thought to be one of the earliest steps in the development of atherosclerosis. LDL that is bound to proteoglycans is more susceptible to oxidation and oxidized LDL is avidly taken up by macrophages or smooth muscle cells leading to the formation of foam cells. Proteoglycan content differs between atherosclerotic and non-atherosclerotic regions of the artery wall and apolipoproteins B and E demonstrate striking co-localization with biglycan. However it is not clear if altered vascular proteoglycan content precedes and contributes to the development of atherosclerosis or is a consequence of the development of atherosclerosis. The renin angiotensin system (RAS) has been shown to play a critical role in the development of atherosclerosis. Angll the major biologically active peptide is clearly pro-atherogenic. Angll increases proteoglycan synthesis especially up- regulating biglycan. Numerous clinical trials demonstrate that inhibition of the RAS has broad impacts on cardiovascular disease events and risk factors including decreased risk of death myocardial infarction stroke diabetes mellitus and renal failure. In preliminary studies we show that angll infusion induces increased aortic biglycan content increased vascular LDL retention and accelerates atherosclerosis. The overall goal of this grant is to test the hypothesis that induction of biglycan content by angll plays a critical role in the initiation of atherosclerosis. This will be tested in mouse models of atherosclerosis with increased angll levels and using biglycan deficient mice. A major focus is to identify mechanisms by which angll induces biglycan. The USA has a very high prevalence of atherosclerotic cardiovascular disease. The results of the experiments in this application will establish the role of the response to retention hypothesis in atherosclerosis development demonstrate a mechanism linking the RAS to atherosclerosis and identify novel targets for intervention to decrease vascular lipoprotein retention as a strategy to prevent atherosclerosis.

project_terms:
AGTR2 gene;Angiotensins;Animals;Apolipoproteins;Apolipoproteins B;Arteries;Atherosclerosis;Attenuated;Binding (Molecular Function);Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Clinical Trials;Data;Development;Diabetes Mellitus;Employee Strikes;Event;Foam Cells;Goals;Grant;High Prevalence;Human;In Vitro;Infusion procedures;Intervention;Kidney Failure;Link;Lipoproteins;Low-Density Lipoproteins;Mediating;Modeling;Mus;Myocardial Infarction;Peptides;Play;Promotor (Genetics);Proteoglycan;Relative (related person);Renin-Angiotensin System;Research Personnel;Risk;Risk Factors;Role;Saline;Smooth Muscle Myocytes;Testing;Transcriptional Regulation;biglycan;in vivo;macrophage;mouse model;novel;oxidation;oxidized low density lipoprotein;prevent;programs;protective effect;receptor;research study;response;stroke


application_id: 8013539
project_number: 5R01DA022967-04
project_title: African American Female Drug Users: HIV Health Disparities & Criminality
administering_ic: NIDA
award_notice_date: 2011-01-13
opportunity_number: PA-07-114
application_type: 5
activity_code: R01
ic: DA
serial_number: 022967
program_official: JONES, DIONNE
project_start_date: 2008-04-01
project_end_date: 2013-01-31
study_section: Behavioral and Social Consequences of HIV/AIDS Study Section[BSCH]
contact_pi_person_id: 6264981
contact_pi: OSER, CARRIE BETH
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this study is to understand how drug use and criminality are related to health disparities particularly HIV and service utilization among African American drug using and non-drug using women across criminal justice status. While drug use is similar across racial groups in the US African Americans are disproportionately more likely to experience severe health consequences and criminal involvement as a result of drug misuse. Adequate health care may not be received by African American female offenders because they experience the burden of their race class gender and criminal offender status. There is limited scientific data to help understand the linkages between health disparities such as HIV untreated drug abuse barriers to service utilization and status as a criminal offender among African American females. This study is significant because of its potential to identify differences in health disparities and service utilization among African American drug using and non-drug using women in selected levels of criminal justice status (intensive correctional supervision-prison (n=200) moderate correctional supervision-jail (n=200) community supervision-probation (n=200) and no criminal justice involvement (n=200)). All 800 African American females will be followed longitudinally for three 6-month intervals to examine health status and the use of health services across time. The specific aims are: (1) To describe the prevalence of health problems among African American women across criminal justice status and drug use status; (2) To determine the cultural predisposing historical health and potential enabling factors that are predictors of health problems among African American drug using and non-drug using women across criminal justice status over 18 months; (3) To describe the prevalence of untreated health problems the patterns of health services utilization and the cultural barriers to service utilization among African American women across criminal justice status and drug use status; and (4) To examine the factors that predict the likelihood of using health services among African American drug using and non-drug using women across criminal justice status over 18 months. The significance of this study includes the potential to provide criminal justice systems-level data for health planning and health policy for prevention intervention and treatment of African American female drug users.   
  
This study is significant to the public health field because of its potential to understand the severity of health disparities among African American women across criminal justice status and drug use status and to predict health status and the use of health services over time. This knowledge of African American females can be used as a foundation for future criminal justice systems-level interventions to increase the use of preventative health care and subsequently reduce the need for expensive medical services as well as to decrease HIV risk behaviors including drug use unprotected sex and recidivism.

project_terms:
Accident and Emergency department;African American;Alcohol or Other Drugs use;Alcohols;Applications Grants;Biological Assay;Chlamydia;Communities;Criminal Justice;Data;Dependence;Development;Drug abuse;Drug abuser;Drug usage;Drug user;Economics;Enabling Factors;Epidemiology;Event;Female;Foundations;Fright;Future;Gender;General Population;Goals;Gonorrhea;HIV;Health;Health Personnel;Health Planning;Health Policy;Health Services;Health Status;Healthcare;Hepatitis C;Hepatitis C virus;Hospitalization;Imprisonment;Incidence;Individual;Inpatients;Intervention;Interview;Jail;Kentucky;Knowledge;Life;Literature;Location;Mediating;Medical;Mental Health;Modeling;Multivariate Analysis;NIH Program Announcements;Participant;Patient Self-Report;Pattern;Pharmaceutical Preparations;Physicians;Population;Prevalence;Preventive Intervention;Prisoner;Prisons;Race;Recruitment Activity;Reporting;Research;Risk Behaviors;Sampling;Series;Seroprevalences;Services;Severities;Sexually Transmitted Diseases;Structure;Supervision;Surveys;System;Time;Trust;Universities;Unsafe Sex;Woman;Women's Health;Work;alcohol research;base;criminal offending;experience;follow-up;health care service utilization;health disparity;innovation;longitudinal design;non-drug;offender;physical conditioning;probation;probationer;public health medicine (field);racism;recidivism;service utilization;substance abuse treatment;time use


application_id: 8013067
project_number: 5R03MH089536-02
project_title: Discovery of Small Molecule Probes for Influenza NS1A
administering_ic: NIMH
award_notice_date: 2010-11-10
opportunity_number: PAR-09-129
application_type: 5
activity_code: R03
ic: MH
serial_number: 089536
program_official: YAO, YONG
project_start_date: 2010-01-15
project_end_date: 2012-11-30
study_section: Special Emphasis Panel[ZRG1-BST-J(50)R]
contact_pi_person_id: 1871909
contact_pi: JONSSON, COLLEEN B
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):  Influenza viruses are negative-sense single-stranded RNA viruses that infect the upper and lower respiratory tracts and cause substantial morbidity and mortality annually. In the United States approximately 36000 deaths are attributed to influenza or its complications each year. Influenza A viruses which also infect a wide number of avian and mammalian species pose a considerable public health burden with epidemic and pandemic potential. Mechanisms. The proposed research effort seeks to identify small molecule inhibitors for the RNA binding activity of NS1A. The NS1A protein of influenza is a highly conserved multifunctional viral protein which interacts with host RNA and proteins. The influenza viral protein NS1A is regarded as an important viral factor by which these viruses antagonize host cell anti-viral defense. We have developed an AlphaScreen(R) (Perkin Elmer)-based 1536-well high throughput screen (HTS) for NS1A protein to identify small molecule inhibitors of the NS1A double-stranded (ds) RNA binding activity. The Z-value for the assay ranges from 0.82-0.89. Identification of probes for this activity would provide valuable tools for probing its dsRNA binding function within the cell. Theoretically this domain could also serve as a target for antiviral drug discovery. For this effort we propose two Aims: (1) Aim 1. Assist the MLPCN in transferring the validated HTS assay for Influenza NS1A to the appropriate screening center for primary screening and provide technical support for implementation of secondary assays of hits to remove false positives and validate biological relevance of the screening hits and (2) Aim 2. Collaborate with the MLPCN Chemistry Center in analyses of the hits acquired in the NS1A HTS with tertiary assays that will be used for the purpose of hit-to-probe development and probe characterizations (e.g. selectivity specificity cell and tissue penetration and mechanisms of action).  
  
PUBLIC HEALTH RELEVANCE: Influenza viruses are negative-sense single-stranded RNA viruses that infect the upper and lower respiratory tracts and cause substantial morbidity and mortality annually. In the United States approximately 36000 deaths are attributed to influenza or its complications each year. Influenza A viruses which also infect a wide number of avian and mammalian species pose a considerable public health burden with epidemic and pandemic potential. The proposed research effort seeks to identify small molecule inhibitors for the RNA binding activity of NS1A a key viral protein in the life cycle of the virus.

project_terms:
Antiviral Agents;Binding (Molecular Function);Biological;Biological Assay;Birds;Cells;Cessation of life;Chemistry;Development;Double-Stranded RNA;Epidemic;Flu virus;Hospitalization;Influenza;Influenza A virus;Life Cycle Stages;Lower respiratory tract structure;Mexico;Morbidity - disease rate;Mortality Vital Statistics;North America;Penetration;Proteins;RNA;RNA Binding;RNA Viruses;Research;Screening procedure;Specificity;Tissues;United States;Viral;Viral Proteins;Virus;Virus Diseases;base;drug discovery;high throughput screening;influenzavirus;inhibitor/antagonist;pandemic disease;public health medicine (field);public health relevance;small molecule;swine flu;tool

public_health_relevance:
Influenza viruses are negative-sense single-stranded RNA viruses that infect the upper andlower respiratory tracts and cause substantial morbidity and mortality annually. In the UnitedStates approximately 36000 deaths are attributed to influenza or its complications each year.Influenza A viruses which also infect a wide number of avian and mammalian species pose aconsiderable public health burden with epidemic and pandemic potential. The proposedresearch effort seeks to identify small molecule inhibitors for the RNA binding activity of NS1A akey viral protein in the life cycle of the virus.


application_id: 8013061
project_number: 5R01HL099014-02
project_title: Role of Glutathione S-Transferase P in Heart Failure
administering_ic: NHLBI
award_notice_date: 2011-01-24
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 099014
program_official: LIANG, ISABELLA Y
project_start_date: 2010-02-01
project_end_date: 2011-09-30
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 1914941
contact_pi: PRABHU, SUMANTH D
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Although oxidative stress is a hallmark of heart failure (HF) clinical trials with antioxidants targeting first generation reactive oxygen species (ROS) such as O2/ and H2O2 have not yielded compelling benefits. However ROS also generate secondary intermediates derived from lipid peroxidation including peroxides and aldehydes that amplify oxidative injury. Glutathione S-transferases (GSTs) metabolize aldehydes by catalyzing their conjugation with glutathione (GSH). Select GST isoforms also have important non-catalytic functions such as physical interactions with c-Jun N-terminal kinase (JNK) that are modulated by oxidative stress. Although GSTs play a vital role in oxidative stress responses how GSTs impact HF is unknown. Our goal is to define the functional role of GSTP most abundant cardiac GST isoform in HF. Our preliminary studies indicate that GSTP is downregulated in HF and that GSTP deficiency worsens cardiac remodeling augments protein- aldehyde adducts depresses circulating endothelial progenitor cells (EPCs) and impairs neovascularization. Our central hypothesis therefore is that GSTP is a critical cardioprotective protein in post-infarction HF that ameliorates remodeling and promotes cardiac repair. To test this hypothesis we will perform three Specific Aims. In Aim 1 we will define the role of GSTP and the human GSTP variants hGSTP1*A and hGSTP1*C in HF by examining post-infarction LV remodeling in wild-type (WT) GSTP-/- and cardiac-specific hGSTP1*A and hGSTP1*C transgenic (Tg) mice. We will evaluate apoptosis fibrosis and inflammation together with glutathione levels protein-adducted aldehydes and JNK activation in the heart. In Aim 2 we will determine the metabolic contribution of GSTP to the detoxification of lipid peroxidation products in the failing heart. In isolated perfused sham-operated and failing hearts from WT GSTP-/- and hGSTP Tg mice using isotope labeling and mass spectrometry we will characterize the metabolism and detoxification of unsaturated aldehydes. In tissue homogenates we will also determine GSTP-related peroxidase activity and levels of aldehydes and lipid peroxides. In Aim 3 we will delineate the cardiac and bone marrow (BM)-related effects by which GTSP modulates neovascularization in the failing heart. We will first determine EPC and BM progenitor cell function in WT and GSTP -/- mice both with and without concomitant JNK inhibition. Next we will define how GSTP ablation and hGSTP overexpression affect neovascularization and angiogenic gene expression in the sham and failing hearts from Aim 1. Lastly we will evaluate post-infarction remodeling inflammation EPC mobilization and neovascularization in chimeric mice: WT mice with GSTP-/- BM and GSTP-/- mice with WT BM. These studies will establish the role of myocardium-localized versus BM-localized GSTP in the process of remodeling neovascularization and inflammation in the failing heart. Collectively this work will establish a novel paradigm of GSTP as an essential antioxidant anti-inflammatory and pro-angiogenic protein in HF. This model can have important diagnostic and therapeutic implications for HF patients with regard to oxidant injury.  
  
PUBLIC HEALTH RELEVANCE: These studies will establish glutathione S-transferase P (GSTP) as a critical antioxidant and tissue reparative protein in heart failure and identify new determinants of oxidative injury. Hence the results can help design new non-classical antioxidant and regenerative therapies in heart failure. We will also evaluate the cardioprotective potency of human GSTP variants in the failing heart; important differences between GSTP variants can establish a genetic basis for variability of antioxidant responses in the heart and provide a novel biomarker for the progression of heart failure.

project_terms:
4 hydroxynonenal;Ablation;Accounting;Acrolein;Affect;Aldehydes;Alleles;Angiogenic Proteins;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Apoptosis;Bone Marrow;Cardiac;Cardiomyopathies;Cell physiology;Chronic;Clinical;Clinical Trials;Coronary;Depressed mood;Diagnostic;Disease;Disease susceptibility;Drug Metabolic Detoxication;Enzymes;Failure (biologic function);Fibrosis;Functional disorder;GSTP1 gene;Gene Expression;Generations;Genetic;Genetic Polymorphism;Glutathione;Glutathione S-Transferase;Glutathione S-Transferase P;Goals;Heart;Heart failure;Hematopoietic;Human;Hydrogen Peroxide;Individual Differences;Infarction;Inflammation;Inflammatory;Injury;Isotope Labeling;Left Ventricular Remodeling;Ligation;Lipid Peroxidation;Lipid Peroxides;Malignant Neoplasms;Mass Spectrum Analysis;Measures;Membrane;Metabolic;Metabolism;Modeling;Mus;Muscle Cells;Myeloproliferation;Myocardial;Myocardium;N-terminal;Oxidants;Oxidation-Reduction;Oxidative Stress;Patients;Peroxidases;Peroxides;Phosphotransferases;Play;Predisposition;Process;Property;Protein Isoforms;Proteins;Reactive Oxygen Species;Role;Selenium;Stem cells;Stress;Systemic disease;Testing;Therapeutic;Tissues;Transgenic Mice;Transgenic Organisms;Variant;Wild Type Mouse;Work;Xenobiotics;adduct;antioxidant therapy;base;biological adaptation to stress;biomarker;chemotherapy;cytotoxic;design;gain of function;in vivo;neovascularization;novel;overexpression;peroxiredoxin;public health relevance;regenerative therapy;repaired;response;stress-activated protein kinase 1

public_health_relevance:
Relevance: These studies will establish glutathione S-transferase P (GSTP) as a critical antioxidant and tissuereparative protein in heart failure and identify new determinants of oxidative injury. Hence the results can helpdesign new non-classical antioxidant and regenerative therapies in heart failure. We will also evaluate thecardioprotective potency of human GSTP variants in the failing heart; important differences between GSTPvariants can establish a genetic basis for variability of antioxidant responses in the heart and provide a novelbiomarker for the progression of heart failure.


application_id: 8011983
project_number: 5U01NS066915-02
project_title: NIM811 FOR THE TREATMENT OF ACUTE SPINAL CORD INJURY
administering_ic: NINDS
award_notice_date: 2011-06-27
opportunity_number: PAR-08-233
application_type: 5
activity_code: U01
ic: NS
serial_number: 066915
program_official: KLEITMAN, NAOMI
project_start_date: 2010-02-01
project_end_date: 2011-07-01
study_section: Neurological Sciences and Disorders A Study Section[NSD-A]
contact_pi_person_id: 7875165
contact_pi: SPRINGER, JOE 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: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Spinal cord injury (SCI) is a devastating event that constitutes a major health issue. At the present time no effective treatments exist for the treatment of SCI and strategies that promote functional recovery are clearly warranted. The objective of this UOI proposal is to conduct IND-enabling preclinical studies for the use of NIM811 an inhibitor of mitochondrial permeability transition (mPT) in the treatment of acute SCI. This approach is based on the underlying hypothesis that maintaining mitochondrial function a critical process for limiting ongoing cell death and dysfunction will enhance recovery of function following SCI. Current experimental studies and clinical observations suggest that the cyclosporin A (CsA) which inhibits mPT and promotes mitochondrial stability can be of therapeutic benefit in the treatment of acute traumatic brain injury spinal cord injury and more recently in reperfusion injury following acute myocardial infarction. However CsA has a high toxicity profile and its immunosuppressive properties make it difficult to attribute any neuroprotective effects on inhibition of mPT. Therefore compounds that mimic the cytoprotective actions of CsA on mPT but exhibit minimal immunosuppressive properties and lower cytotoxicity have high therapeutic potential. NIM811 (Novartis) is a non-immunosuppressive cyclosporin analog that inhibits mPT at nanomolar concentrations and exhibits a significantly lower toxicity profile. Substantial "proof-of-concept" studies from this lab have demonstrated in vivo efficacy of NIM811 on a number of functional outcomes using an experimental rat model of moderate SCI. The experimental plan will expand on these previous observations by documenting NIM811 functional efficacy in models of moderate and severe SCI using a repeated dosing paradigm (Specific Aim 1). Pharmacokinetic studies and assays of mitochondrial function will be used to identify a clinically relevant therapeutic time window (Specific Aim 2). Long-term functional studies will then be performed using the most effective repeated dose and optimal therapeutic window (Specific Aim 3). A pre-IND meeting will then be held with the FDA to identify and conduct if necessary any additional IND- enabling toxicity studies (Specific Aim 4). The completion of these Aims will culminate in the filing of an IND application in order to initiate a Phase I human clinical trial.   
  
RELEVANCE: Spinal cord injury (SCI) is a devastating event that constitutes a major health issue. In the United States alone approximately 12000 new cases occur each year and some 250000 people are currently living with SCI. The lifetime health care-related costs per individual are estimated to be around $1000000. At the present time no effective treatments exist for the treatment of SCI. These experimental studies will focus on testing a highly promising drug designed to promote recovery using an early intervention approach.

project_terms:
Acute;Acute myocardial infarction;Biological Assay;Cell Death;Clinical;Clinical Trials;Cyclosporine;Cyclosporins;Dose;Drug Design;Drug Kinetics;Early treatment;Event;Exhibits;Functional disorder;Health;Healthcare;Human;Immunosuppressive Agents;Individual;Life;Measures;Mitochondria;Modeling;Permeability;Phase;Process;Property;Rattus;Recovery;Recovery of Function;Reperfusion Injury;Spinal cord injury;Testing;Therapeutic;Time;Tissues;Toxic effect;Traumatic Brain Injury;United States;analog;base;clinically relevant;cost;cytotoxicity;effective therapy;functional outcomes;improved;in vivo;inhibitor/antagonist;meetings;preclinical study;research study


application_id: 8011333
project_number: 5R01CA138410-02
project_title: Regulation of miRNA in breast cancer
administering_ic: NCI
award_notice_date: 2010-12-17
opportunity_number: PA-07-021
application_type: 5
activity_code: R01
ic: CA
serial_number: 138410
program_official: FORRY, SUZANNE L
project_start_date: 2010-01-01
project_end_date: 2013-12-31
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The selective estrogen receptor modulator (SERM) tamoxifen (TAM) is the most widely used endocrine therapy for the treatment and prevention of estrogen receptor alpha (ER1) positive breast cancer. However ~ 40% of initially TAM-sensitive tumors become endocrine/TAM-resistant. The mechanism behind such acquired TAM resistance is unknown and biomarkers of TAM-response may be useful to monitor clinical response. MicroRNAs (miRNAs) are a class of naturally-occurring small non-coding RNA molecules that are involved in regulating the translation and processing of mRNAs usually by binding to the 3' untranslated region of target mRNAs and targeting the mRNA transcript to be degraded or by blocking translation. The human genome contains > 700 miRNAs. Aberrant patterns of miRNA expression have been recently implicated in human disease with miRNAs differentially expressed in concordance with other well-established markers of breast cancer stage and patient prognosis including ER1 and progesterone receptor tumor stage number of positive lymph nodes and vascular invasion. Using the NIH-R21 mechanism we obtained preliminary data identifying miRNAs regulated by estradiol (E2) in an ER1-dependent manner in MCF-7 human breast cancer cells and identified downstream target genes that were upregulated via E2 downregulation of miR-21. However to date no one has examined TAM affects the pattern of miRNA expression in human breast cancer and only 2 reports have identified miRNA expression patterns in TAM-resistant derivatives of MCF-7 breast cancer cells. Specific Aim 1 is to identify miRNAs that are differentially regulated by E2 and 4-hydroxyTAM (4-OHT) in antiestrogen- sensitive MCF-7 and T47D breast cancer cells. Specific Aim 2 is to identify miRNAs and their target genes in antiestrogen/ TAM- sensitive versus -resistant breast cancer cell lines and tumor xenografts. This Aim tests the hypothesis that miRNA expression is dysregulated in endocrine/TAM- resistant versus -sensitive breast cancer cells. Specific Aim 3 is to determine if the E2- regulated and 4-OHT- regulated miRNAs identified in breast cancer cell lines show aberrant expression in human breast tumors and correlate with clinical diagnostic measures and patient response to tamoxifen therapy. The overall goal of the proposed research is to determine the identity and gene targets of miRNAs that may provide novel biomarkers and new insights into the mechanisms by which breast tumors gain endocrine/TAM-resistance and become invasive and metastatic.  
  
PUBLIC HEALTH RELEVANCE: Aromatase inhibitor therapy is not useful for all ER1 positive breast cancer patients and the selective estrogen receptor modulator tamoxifen (TAM) remains the most widely used endocrine therapy for the treatment and prevention of estrogen receptor alpha (ER1) positive breast cancer. However ~ 40% of initially TAM-sensitive tumors become endocrine/TAM-resistant. The mechanism behind such acquired TAM/endocrine resistance is unknown. The overall goal of the proposed research is to determine the identity and gene targets of miRNAs that may provide novel biomarkers and new insights into the mechanisms by which breast tumors gain endocrine/TAM-resistance and become invasive and metastatic.

project_terms:
3' Flanking Region;3' Untranslated Regions;4-Hydroxy-Tamoxifen;Affect;Aromatase Inhibitors;BCL2 gene;Binding (Molecular Function);Bioinformatics;Biological Assay;Blood Vessels;Breast;Breast Cancer Cell;Cancer Patient;Cancer cell line;Cells;Clinical;Clinical Markers;Cloning;Computer Simulation;Data;Development;Diagnostic;Diagnostic Neoplasm Staging;Down-Regulation;Endocrine;Estradiol;Estrogen Antagonists;Estrogen Receptor Modulators;Estrogen Receptor alpha;Estrogen Receptors;Estrogen receptor negative;Estrogen receptor positive;Estrogens;Exploratory/Developmental Grant;Functional RNA;Gene Expression;Gene Targeting;Genes;Goals;Human;Human Genome;ICI 182780;In Vitro;Individual;Lead;Luciferases;MAPK3 gene;MCF7 cell;Malignant Neoplasms;Mammary Neoplasms;Measures;Messenger RNA;MicroRNAs;Monitor;PTEN gene;Patients;Pattern;Positive Lymph Node;Prevention;Progesterone Receptors;Promotor (Genetics);Proteins;RNA;Regulation;Renilla Luciferases;Reporter;Reporting;Repression;Research;Resistance;Response Elements;Reverse Transcriptase Polymerase Chain Reaction;Role;Sampling;Seeds;Selective Estrogen Receptor Modulators;Site;Small Interfering RNA;T47D;Tamoxifen;Testing;Therapeutic;Time;Transcript;Transcription Factor AP-1;Transfection;Translation Process;Translations;Tumor stage;United States National Institutes of Health;Western Blotting;biomarker;cancer therapy;expression vector;follow-up;hormone therapy;human disease;in vivo;inhibitor/antagonist;insight;mRNA Stability;malignant breast neoplasm;migration;non-genomic;novel;outcome forecast;overexpression;public health relevance;research study;response;treatment planning;tumor;tumor xenograft

public_health_relevance:
Aromatase inhibitor therapy is not useful for all ER positive breast cancer patients and the selective estrogenreceptor modulator tamoxifen (TAM) remains the most widely used endocrine therapy for the treatment andprevention of estrogen receptor alpha (ER) positive breast cancer. However ~ 40% of initially TAM-sensitivetumors become endocrine/TAM-resistant. The mechanism behind such acquired TAM/endocrine resistance isunknown. The overall goal of the proposed research is to determine the identity and gene targets of miRNAsthat may provide novel biomarkers and new insights into the mechanisms by which breast tumors gainendocrine/TAM-resistance and become invasive and metastatic.


application_id: 8009753
project_number: 1R25CA153954-01
project_title: The University of Kentucky Cancer Nanotechnology Training Center (UK CNTC)
administering_ic: NCI
award_notice_date: 2010-09-03
opportunity_number: RFA-CA-09-014
application_type: 1
activity_code: R25
ic: CA
serial_number: 153954
program_official: GRODZINSKI, PIOTR
project_start_date: 2010-09-03
project_end_date: 2015-07-31
study_section: Special Emphasis Panel[ZCA1 RTRB-2 (M1)]
contact_pi_person_id: 7875468
contact_pi: ANDERSON, BRADLEY D
other_pis: EVERS, BERNARD MARK
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The University of Kentucky Cancer Nanotechnology Training Center (UK CNTC) will provide advanced multidisciplinary training for predoctoral students and postdoctoral fellows toward the goal of creating a new type of cancer researcher who is skilled and ready to pursue a career in cancer nanotechnology research. Nationally and internationally recognized faculty members at the University of Kentucky will collaborate to create a fertile environment for the novel exploration of nanotechnology and cancer. Expertise covers a broad multidisciplinary range of scientific areas in gastrointestinal cancer lung cancer gliomas radiation medicine surgery cancer screening imaging and pharmacokinetics and dynamics. Among these faculty are 16 nanotechnology researchers in the Departments of Chemical Engineering Materials Engineering Electrical Engineering Chemistry and Pharmaceutical Sciences and 18 biomedical scientists or clinical oncologists in the Colleges of Pharmacy or Medicine. Based on existing research collaborations we propose cancer nanotechnology projects composed of multidisciplinary focus area teams with the goal of training future leading researchers in the field of cancer nanotechnology in the following four areas: (1) early detection and diagnosis in lung colon and ovarian cancer; (2) treatment of gastrointestinal tumors and metastases; (3) lung cancer treatment; and (4) glioma therapy. Specific Aim 1 is to expand the core expertise of participants in the UK CNTC through cross-disciplinary laboratory research training projects of up to two years involving innovative applications of nanotechnology to address specific unmet needs in cancer detection and therapy. Our trainees will be at the forefront of research that will be driven toward developing novel cancer therapies and diagnostic strategies based on nanotechnology. Through these activities the trainees will obtain a detailed understanding of the molecular basis of cancer the unresolved clinical problems in treating and diagnosing the disease and acquire expertise in the field of nanotechnology. In Specific Aim 2 the CNTC will provide trainees with problem-based and experiential training through seminars workshops short courses clerkships and laboratory training modules that will build their research skills and confidence as members of multi-disciplinary research teams. Each trainee will be immersed in individualized problem-based instruction and a broad multidisciplinary training through core courses short courses participation in seminars undergraduate and early graduate student mentoring and outreach activities designed to educate the public. Trainees will be guided through these programs with effective mentorship and an evaluation program (Specific Aim 3) that will assess the effectiveness of trainee progress and development. Finally Specific Aim 4 is to highlight the accomplishments of CNTC trainees both regionally and nationally. As such our trainees will learn to envision articulate and perform nanotechnology-centered research focused on developing novel solutions to the outstanding clinical problems associated with cancer.  
  
PUBLIC HEALTH RELEVANCE: The University of Kentucky Cancer Nanotechnology Center will provide a systematic and unique multidisciplinary training environment focusing on laboratory hands-on research to create a workforce capable of using nanotechnology for solving intractable cancer research problems. Trainees of the Center will be immersed in a research environment designed to take advantage of the multiple research strengths of faculty at the University of Kentucky and will emerge with a broad yet detailed knowledge of cancer diagnostics interventions and related nanotechnology applications including drug delivery early detection and treatment.

project_terms:
Address;Applied Research;Archives;Area;Basic Science;Cancer Biology;Cancer Center;Cancer Detection;Cancer Diagnostics;Chemical Engineering;Clinical;Collaborations;Colon;Development;Diagnosis;Diagnostic;Discipline;Doctor of Pharmacy;Drug Delivery Systems;Drug Kinetics;Early Diagnosis;Educational workshop;Effectiveness;Electrical Engineering;Engineering;Ensure;Environment;Environment Design;Ethics;Evaluation;Faculty;Feedback;Fostering;Funding;Future;Gastrointestinal Neoplasms;Glioma;Goals;Grant;Hand;Hour;Image;Immersion Investigative Technique;Instruction;International;Intervention;Journals;Kentucky;Knowledge;Laboratories;Laboratory Finding;Laboratory Research;Learning;Link;Lung;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of lung;Malignant neoplasm of ovary;Medicine;Mentors;Mentorship;Mission;Molecular;Monitor;Nanotechnology;Neoplasm Metastasis;Oncologist;Participant;Performance;Pharmaceutical Chemistry;Pharmacy facility;Postdoctoral Fellow;Program Effectiveness;Program Evaluation;Published Comment;Publishing;Radiation;Research;Research Personnel;Research Project Grants;Research Training;Rotation;Science;Screening for cancer;Solutions;Students;Suggestion;System;Therapeutic Human Experimentation;Time;Training;Translating;Universities;Update;Work;Writing;anticancer research;base;biomedical scientist;cancer diagnosis;cancer surgery;cancer therapy;cancer type;career;clinical conference;college;design;disease diagnosis;graduate student;improved;in vivo;innovation;interest;meetings;member;molecular imaging;multidisciplinary;novel;outreach;outreach program;pre-doctoral;programs;public health relevance;skills;training project;web site


application_id: 8009501
project_number: 5K01ES017105-02
project_title: Ubiquitous pollutant acrolein inhibits IFN?? antiviral signaling: relevance to HC
administering_ic: NIEHS
award_notice_date: 2011-01-12
opportunity_number: PA-09-040
application_type: 5
activity_code: K01
ic: ES
serial_number: 017105
program_official: SHREFFLER, CAROL A
project_start_date: 2010-01-01
project_end_date: 2014-12-31
study_section: ZES1-LKB-J(K6)
contact_pi_person_id: 9367807
contact_pi: JOSHI-BARVE, SWATI
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):  Chronic Hepatitis C virus (HCV) infection remains a global health concern with nearly 200 million carriers worldwide. It can be a precursor to cirrhosis hepatocellular carcinoma and end-stage liver disease. In the absence of a vaccine the current FDA approved standard of care for chronic hepatitis C is a combination of pegylated interferon-alpha (IFN1) and ribavirin. Unfortunately this regimen is only effective in about 50% of patients emphasizing the need for studies defining the molecular mechanisms underlying resistance to IFN1. Clinical studies have identified several potential cofactors that may contribute to the failure of anti-HCV therapy including obesity diabetes alcohol abuse oxidative stress cigarette smoking and environmental pollutants. Acrolein is a ubiquitous highly reactive environmental and industrial pollutant and is designated by the U.S. Environmental Protection Agency (EPA) as a high priority air and water pollutant. Notably acrolein is also formed endogenously as a byproduct of lipid peroxidation (LPO) and is itself known to cause oxidative stress. Moreover acrolein is a major component of cigarette smoke and recent studies suggest that smokers with chronic hepatitis C have a lower response rate to IFN1 compared to non-smokers. We have convincing preliminary data showing that non-toxic concentrations of acrolein significantly down-regulate IFN1 signaling and antiviral gene expression in vitro (cultured human hepatic cells) and in vivo (mice).  Published literature and our own compelling data strongly support our hypothesis that acrolein adversely influences IFN1 therapy outcomes by inhibiting or disrupting IFN1 mediated signaling and antiviral gene expression in hepatocytes and that high acrolein exposure (environmental and/or endogenous) will correlate with poor IFN1 response in HCV infected individuals. Our hypotheses will be tested by examining the effects of acrolein on early IFN1-mediated signaling (including components of the Jak/STAT pathway) and antiviral gene expression using well established in vitro and in vivo experimental systems as well as an HCV replicon that directly reports on HCV viral replication. Additionally the investigators will establish a clinical/translational aspect of our hypothesis by conducting a retrospective analysis using banked serum urine and/or liver biopsy samples from healthy uninfected individuals and HCV-infected patients (responders and non-responders). This analysis will explore a possible correlation between acrolein exposure and poor IFN1 response (lack of sustained virologic response SVR).  The investigators expect their studies will elucidate critical mechanisms underlying resistance to IFN1 treatment and will identify potential targets for novel therapeutic intervention.  
  
Public Health Relevance:  Acrolein is one of the major reactive aldehydes ubiquitously present in foods water and in the environment. It is a major constituent of cigarette smoke. Recent data suggest that HCV- infected smokers have worse IFN1 therapeutic outcomes compared with non-smokers. Acrolein is also generated endogenously due to cellular metabolism and this may constitute a significant source of intracellular acrolein in situations of oxidative stress and inflammation. Elevated acrolein adducts have been detected in several disease conditions that are also known to be associated with failure of IFN therapy. Hence based on available literature and the investigators' own compelling preliminary results they have opted to use acrolein as the model compound for this study. The aim of the study is to determine the contribution of acrolein to the mechanisms of IFN1 resistance. The investigators have preliminary evidence to demonstrate that acrolein at nontoxic concentrations significantly down-regulates IFN1 signaling and antiviral/anti-HCV gene expression.

project_terms:
Acrolein;Acrylates;Air Pollutants;Alcohol abuse;Aldehydes;Alzheimer's Disease;Amino Acids;Antiviral Agents;Atherosclerosis;Automobile Exhaust;Binding (Molecular Function);Biocide;Biological Models;Biology;Biopsy Specimen;Cell Line;Cessation of life;Chemical Weapons;Chronic;Chronic Disease;Chronic Hepatitis C;Cirrhosis;Clinical;Clinical Research;Cysteine;Data;Development;Diabetes Mellitus;Disease;Dose;Double-Stranded RNA;Environment;Environmental Exposure;Environmental Pollutants;Exposure to;FDA approved;Failure (biologic function);Family;Fatty acid glycerol esters;Food;Free Radicals;Functional disorder;Future;Gene Expression;Genes;Genotype;Hepatitis C;Hepatitis C virus;Hepatocyte;Histidine;Human;Hydroxyl Radical;Imidazole;In Vitro;Individual;Industrial Waste;Inflammation;Interferons;Kidney Failure;Ligand Binding;Ligase;Lipid Peroxidation;Literature;Liver;Liver diseases;Lysine;Mediating;Medicine;Messenger RNA;Metabolism;Methionine;Modeling;Modification;Molecular;Mus;Non-Insulin-Dependent Diabetes Mellitus;Non-smoker;Nucleic Acids;Obesity;Organic Chemicals;Outcome;Oxidative Stress;PTPN11 gene;Pathway interactions;Patients;Pegylated Interferon Alfa;Phospholipids;Phosphorylation;Plastics;Play;Polyamines;Polymers;Primary carcinoma of the liver cells;Protein Phosphatase 2A Regulatory Subunit PR53;Protein Tyrosine Kinase;Protein phosphatase;Proteins;Publications;Publishing;Rattus;Regimen;Replicon;Reporting;Research;Research Personnel;Resistance;Response Elements;Ribavirin;Role;STAT protein;STAT1 gene;STAT2 gene;Serum;Side;Signal Transduction;Smoke;Smoker;Smoking;Source;Specimen;Staging;System;TYK2;Testing;Therapeutic;Tissues;Transcriptional Activation;Treatment outcome;United States;United States Environmental Protection Agency;Urine;Vaccines;Viral;Water;Water Pollutants;Wood material;adduct;amino group;anti-hepatitis C;base;biomarker;cigarette smoke;cigarette smoking;cofactor;cooking;eIF-2 Kinase;efficacy testing;global health;improved;in vivo;insight;liver biopsy;mouse model;novel therapeutic intervention;oligoadenylate;pollutant;protein activation;public health relevance;receptor;receptor internalization;response;standard of care;therapy outcome


application_id: 8009209
project_number: 3R01DK053220-11S1
project_title: DNA sequences impact estrogen and antiestrogen activity
administering_ic: NIDDK
award_notice_date: 2010-01-26
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: DK
serial_number: 053220
suffix: S1
program_official: MARGOLIS, RONALD N
project_start_date: 2010-02-01
project_end_date: 2010-04-30
study_section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Although mitochondrial gene expression depends on nuclear genome function and reciprocally "retrograde communication" from mitochondria regulates nuclear gene expression the mechanisms coordinating these events remain to be clarified. Mitochondria are targets of estrogen action. However the mechanisms for estrogenic effects on mitochondrial function are not yet defined. The overall goal of this project is to determine the mechanism(s) by which estradiol (E2) and selective estrogen receptor (ER) modulators (SERMs) regulate the transcription of Nuclear Respiratory Factor-1 (NRF-1) and the downstream impact of NRF-1 on estrogen- and SERM- regulated mitochondrial activity in normal and neoplastic cells. NRF-1 is a transcription factor that is critical for integrating nucleo-mitochondrial function by initiating transcription of nuclear-encoded mitochondrial DNA (mtDNA) -specific transcription factors including Tfam (mtDNA maintenance factor). We recently reported that E2 induces NRF-1 transcription in MCF-7 breast cancer cells via ER1-estrogen response element (ERE) activation. In Aim 1 we will test the hypothesis that the direct interaction of ER1 and ER2 with the NRF-1 promoter recruits different coregulators in a ligand- and cell- specific manner. Chromatin immunoprecipitation (ChIP) assays will address this hypothesis. The effect of siNRF-1 on E2-regulated cell cycle and apoptotic proteins and cell cycle entry will be examined. Results will reveal if E2-induced NRF-1 plays a role in E2's anti-apoptotic activity and if there are cell-specific differences in these responses. Additionally we will examine NRF-1 protein expression by IHC in normal and neoplastic human breast specimens. Experiments in Aim 2 will determine the effect of E2 and SERMs on NRF-1 and downstream target gene expression and ER-NRF-1 promoter interaction in vivo. ChIP assays will determine if E2 increases the direct interaction of ER1 coactivators and RNA pol II with the NRF-1 promoter in vivo in MCF-7 tumor xenografts and mouse tissues focusing first on uterus. Aim 3 is the `functional outcome' aim to measure the genes/proteins/mitochondrial activity including O2 consumption mt biogenesis heat generation i.e. downstream effects of E2-induced NRF-1 expression. Experiments will test the hypothesis that the E2- stimulated increase in NRF-1 will in turn increase the expression of NRF-1 regulated genes e.g. TFAM that subsequently increase expression of its mtDNA-encoded target genes e.g. Cytochrome c oxidase subunit I (MTCO1) and anti-apoptotic genes e.g. survivn. Together the results will define the molecular mechanisms of estrogen action coordinating mitochondrial function. Understanding how E2 and SERMs regulate mitochondrial function could lead to new insights in the prevention and progression of breast and lung cancer. PUBLIC HEALTH RELEVANCE: Although mitochondrial gene expression depends on nuclear genome function and reciprocally by "retrograde communication" mitochondrial activity regulates nuclear gene expression the mechanisms coordinating these events remain to be clarified. Mitochondrial dysfunction and increased reactive oxygen species mediate the pathophysiologic mechanisms of aging acute neurodegeneration caused by trauma stroke or cardiac arrest; and cancer initiation and tumor progression. The impact of steroids on mitochondrial function "is a new and novel area of investigation" and the proposed study seeks to delineate a new biological pathway of estrogen and antiestrogens/SERMs in regulating nuclear respiratory factor-1 (NRF-1) and its downstream targets in mitochondrial activity.

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

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


application_id: 8008810
project_number: 5F32AI081480-02
project_title: Role of a Borrelia burgdorferi fibronection-binding protein in Lyme Disease
administering_ic: NIAID
award_notice_date: 2010-08-24
opportunity_number: PA-07-107
application_type: 5
activity_code: F32
ic: AI
serial_number: 081480
program_official: BREEN, JOSEPH J
project_start_date: 2009-09-16
project_end_date: 2010-11-30
study_section: Special Emphasis Panel[ZRG1-F13-C(20)L]
contact_pi_person_id: 9359764
contact_pi: BRISSETTE, CATHERINE AYN
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): Lyme disease is an NIAID/NIH Group 1 Priority Emerging and Re-emerging Infectious Disease and the most frequently reported arthropod-borne disease in the United States. Borrelia burgdorferi the Lyme disease spirochete can persistently infect humans for years. B. burgdorferi is often found in the connective tissues and associates with components of the extracellular matrix (ECM) such as fibronectin. Understanding the mechanisms behind borrellal adhesion to ECM components will permit the development of strategies to disrupt these interactions. Recently we discovered that an antigenic outer surface lipoprotein RevA binds to fibronectin. We hypothesize that borrelial-ECM interactions especially those mediated by fibronectin-binding proteins are crucial for mammalian infection and persistence In the host. Studies are proposed to (1) Elucidate the mechanisms of RevA binding to fibronectin through site-directed mutagenesis of the RevA protein and analyses of specifically-bound fragments of fibronectin and (2) Characterize how RevA expression is regulated during the infection process over time and in several tissues in the mouse model. PUBLIC HEALTH RELEVANCE: The bacterium which causes Lyme disease Borrelia burgdorferi can infect humans and other animals for years. Proteins on the outer surface of Borrelia play important roles in establishing infection in animals. Appreciating how these proteins are made and how they interact with the host will be an important step towards understanding the ability of this pathogen to infect humans. Data obtained in these studies will direct development of improved tools for treatment prevention and diagnosis of Lyme disease.

project_terms:
Adhesions;Animals;Arthropods;Bacteria;Binding (Molecular Function);Binding Proteins;Borrelia;Borrelia burgdorferi;Connective Tissue;Data;Development;Diagnosis;Diagnostic;Disease;Emerging Communicable Diseases;Extracellular Matrix;Fibronectins;Foundations;Future;Goals;Human;Infection;Lyme Disease;Mediating;Play;Prevention;Process;Production;Proteins;Reporting;Research;Role;Site-Directed Mutagenesis;Surface;Techniques;Time;Tissues;United States;improved;insight;mouse model;outer surface lipoprotein;pathogen;post-doctoral training;public health relevance;therapy development;tool


application_id: 8008799
project_number: 5R01CA116697-05
project_title: Oxidative Stress in Cr(VI)-induced Carcinogenesis
administering_ic: NCI
award_notice_date: 2010-12-08
application_type: 5
activity_code: R01
ic: CA
serial_number: 116697
program_official: BLAIR, DONALD G
project_start_date: 2007-02-07
project_end_date: 2011-12-31
study_section: Special Emphasis Panel[ZRG1-ONC-T(04)M]
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: 2011-01-01
project_abstract:
DESCRIPTION (provided by applicant): Hexavalent chromium [Cr(VI)] is a known environmental carcinogen. Environmental exposure to Cr(VI)-containing compounds causes cancers of various organs. Its mechanism of carcinogenic actions remains to be investigated. Recent studies have demonstrated that reduction of Cr(VI) to its lower oxidation states is important for Cr(VI)-induced carcinogenesis. It has been shown that cellular reduction of Cr(VI) generates reactive oxygen species (ROS) which cause various cellular injuries. We hypothesize that Cr(VI) induces generation of ROS which activate nuclear transcription factors leading to cell transformation and tumorigenesis. In Specific Aim 1 we will identify ROS generated in Cr(VI) treated human lung bronchial epithelial (BEAS-2B) cells and the mechanism involved. We will emphysize the role of CDC42 signaling and the involvement of p47phox and NADPH oxidases in the molecular mechanism of Cr(VI)-induced ROS production. In Specific Aim 2 we will detect reactive Cr(V) intermediates produced in Cr(VI) reduction by living animals and identify the chemical structures of these intermediates. We will also detect and identify superoxide (O2'-) and hydroxyl ('OH) radicals produced by intact animals exposed to Cr(VI). Major methods to be used in this aim are low frequency electron spin resonance (ESR) spectroscopy and ESR spin trapping. In Specific Aim 3 we will investigate Cr(VI)-induced activation of NF-kappaB and AP-1 in BEAS-2B cells and in transgenic mice. We will use a dominant negative mutant MEK1/2 a dominant negative mutant ERK2 or a dominant negative mutant c-jun (TAM67) respectively to investigate the role of the MEK1/2-ERKs-AP-1 pathway in Cr(VI)-induced cell transformation. We will also use a dominant negative mutant IkappaBa or a dominant negative mutant IKK? respectively to determine the role of the IKK?-lkappaBa-NF-kappaB pathway in Cr(VI)-induced cell transformation. The involvement of ROS in these pathways will be investigated using expressions of specific antioxidant enzymes. Tumorigenesis will be investigated by injecting the transformed cells into athymic nude mice. We anticipate that Cr(VI) causes activation of transcription factors through ROS reactions leading to cell transformation and tumorigenesis. We attempt to link the cell transformation and tumorigenesis with specific transcription factors and specific reactive oxygen species.

project_terms:
Animals;Antioxidants;Biology;CDC42 gene;California;Cancer Etiology;Carcinogens;Cells;Chemical Structure;Chemicals;Consumption;DNA Damage;Detection;Development;Dominant-Negative Mutation;Early Diagnosis;Electron Spin Resonance Spectroscopy;Environmental Carcinogens;Environmental Exposure;Enzymes;Epithelial;Exposure to;Free Radicals;Frequencies (time pattern);Generations;Goals;Human;Hydroxyl Radical;Incidence;Inhalation Exposure;International Agency for Research on Cancer;Intervention;JUN gene;Life;Link;Lipid Peroxidation;Lung;MAP2K1 gene;MAPK1 gene;Malignant neoplasm of lung;Medicine;Methods;Molecular;NADPH Oxidase;NF-kappa B;Nose;Nuclear;Nude Mice;Occupational;Occupational Groups;Oral;Organ;Oxidative Stress;Pathway interactions;Play;Post-Translational Protein Processing;Prevention strategy;Production;Reaction;Reactive Oxygen Species;Risk Assessment;Role;Signal Transduction;Spin Trapping;Stress;Superoxides;Techniques;Testing;Transcription Factor AP-1;Transgenic Mice;Water;cancer risk;carcinogenesis;carcinogenicity;cell injury;cell transformation;chromium hexavalent ion;free radical oxygen;in vivo;oxidation;response;transcription factor;tumorigenesis


application_id: 8008715
project_number: 1R13AI091316-01
project_title: Autumn Immunology Conference
administering_ic: NIAID
award_notice_date: 2010-06-15
opportunity_number: PA-08-149
application_type: 1
activity_code: R13
ic: AI
serial_number: 091316
program_official: COULTER, NANCY A
project_start_date: 2010-07-01
project_end_date: 2013-06-30
study_section: Special Emphasis Panel[ZAI1 MMT-M (M1)]
contact_pi_person_id: 1863468
contact_pi: WOODWARD, JEROLD G
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
  
Abstract  
PI: WOODWARD JEROLD G   Project:  1R13AI091316-01 Title:  Autumn Immunology Conference  Accession Number:  3256374  
==================  
NOTICE: THIS ABSTRACT WAS EXTRACTED FROM APPLICATION AND HAS NOT BEEN PROOFED BY AN SRA.WHEN THERE ARE PROBLEMS WITH THE APPLICATION SCANNING PROCESS THE EXTRACTED TEXT MAY BE INCORRECT OR INCOMPLETE.  
==================  
This proposal requests funds to support the annual Autumn Immunology Conference (AIC). The AIC was established in 1972 to promote Immunology research in the upper Midwest region of the United States. The conference provides a forum for the exchange of scientific data and ideas fosters collaborations between scientists at different institutions and provides career development and education opportunities to a diverse group of individuals with an interest in Immunology. The scientific focus of the meeting is intentionally broad; it includes basic Immunology and related biomedical fields such as cancer biology pathogenesis vaccine development inflammation and autoimmunity. Special emphasis is given to providing pre- and post-doctoral trainees with an opportunity to share their data participate in scientific and career discussions and to meet and exchange ideas with established investigators. We also seek to attract involve and promote the careers of women and racial/ethnic minorities that are underrepresented in science. These objectives are met by inviting a group of outstanding Immunology researchers (12-13 each year) from around the world to speak at the meeting. All presenters present both an oral and poster presentation and are designed to provide the greatest opportunity for feedback to the trainees. Finally scholarship programs career development workshops and mentoring luncheons promote the inclusion of minority scientists and seek to recruit undergraduates into the discipline of Immunology. High quality scientific conferences are vital to the public health mission of the NIH. This application requests funding for an annual scientific conference called the Autumn Immunology Conference. The purpose of this meeting is to exchange and disseminate information and to explore contemporary problems in the field of Immunology. Thus it is consistent with the fiscal and programmatic priorities of the National Institutes of Allergy and Infectious Diseases (NIAID) which is to conduct and support basic and applied research to better understand treat and ultimately prevent infectious immunologic and allergic diseases.

project_terms:
Allergic Disease;Applied Research;Autoimmunity;Cancer Biology;Collaborations;Data;Discipline;Educational aspects;Educational workshop;Feedback;Fostering;Funding;Immunologics;Immunology;Individual;Inflammation;Institution;Mentors;Minority;Minority Groups;Mission;National Institute of Allergy and Infectious Disease;Oral;Pathogenesis;Postdoctoral Fellow;Process;Recruitment Activity;Request for Applications;Request for Proposals;Research;Research Personnel;Scanning;Scholarship;Science;Scientist;Text;United States;United States National Institutes of Health;Woman;abstracting;career;career development;design;interest;meetings;posters;prevent;programs;public health medicine (field);symposium;vaccine development


application_id: 8006601
project_number: 7R03NS065451-02
project_title: Towards a Behavioral Index of Seizure Susceptibility
project_terms: Behavioral;Predisposition;Seizures;indexing
administering_ic: NINDS
award_notice_date: 2009-12-21
opportunity_number: PA-06-180
application_type: 7
activity_code: R03
ic: NS
serial_number: 065451
program_official: STEWART, RANDALL R
project_start_date: 2009-05-15
project_end_date: 2011-04-30
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 9484873
contact_pi: SUNDERAM, SRIDHAR
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): There is overwhelming clinical evidence of the interactions between sleep and epilepsy but the literature on seizure prediction has largely disregarded the effects of state of vigilance (SOV) on seizure generation. Existing seizure prediction algorithms (SPAs) are not accurate enough for use in epilepsy care due to high false prediction rates. Recent SPA assessments reveal that false seizure predictions are more likely during certain stages of sleep arousal or times of day. These observations suggest that (1) SPAs confuse certain normal states of vigilance with truly preictal states (should they exist) or (2) SPA measures merely track transitions to normal states of vigilance that are more susceptible to seizure. In order to investigate the mechanism of seizure generation from different brain states methods are needed to accurately track changes in SOV from continuous physiological measurements. We have developed SOV discrimination methods that utilize acceleration measurements from head-mounted accelerometers to significantly improve on methods that rely on EEG alone (Sunderam et al. J. Neurosci. Methods 2007). We propose to develop a methodology for tracking SOV in real time by (1) Applying a combination of supervised Fisher discrimination and unsupervised Bayesian discrimination to establish ground truth labels for SOV; and (2) Constructing state-space models (hidden Markov models and switching Kalman filters) to track the noisy nonstationary SOV dynamics. In the current project we will test the ability of these methods to perform accurate real-time brain state tracking using chronic EEG and kinematic measurements from a rodent model of temporal lobe epilepsy as well as normal controls. The output will be used to quantify the relative probability of seizure onset from different states of vigilance. The long term goal of this project is to track state of vigilance in epilepsy patients and investigate behavioral states with a high probability of seizure generation. The formulation of a behavioral index of seizure susceptibility will help improve the performance of SPAs and serve as the basis for state-dependent seizure detection anticipation and preventive control using low frequency electric field modulation. It will also be useful for testing whether candidate SPA measures truly discriminate between the preseizure period and normal behavioral states. PUBLIC HEALTH RELEVANCE: Our long term goal is to develop for use in implantable seizure control devices methods for real-time tracking of state of vigilance in epilepsy patients. Certain states particularly related to sleep and arousal are more likely to lead to seizure. The availability of a behavioral index of seizure susceptibility will lead to improved performance of existing seizure prediction and control algorithms.

public_health_relevance:
Project NarrativeOur long term goal is to develop for use in implantable seizure control devices methods for real-time trackingof state of vigilance in epilepsy patients. Certain states particularly related to sleep and arousal are morelikely to lead to seizure. The availability of a behavioral index of seizure susceptibility will lead to improvedperformance of existing seizure prediction and control algorithms.


application_id: 8005849
project_number: 7R01CA109136-05
project_title: Novel Mechanisms of Carcinoma Cell Migration
administering_ic: NCI
award_notice_date: 2010-02-23
application_type: 7
activity_code: R01
ic: CA
serial_number: 109136
program_official: WOODHOUSE, ELIZABETH
project_start_date: 2006-03-09
project_end_date: 2012-03-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1947523
contact_pi: O'CONNOR, KATHLEEN L.
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: 2010-02-23
project_abstract:
The majority of breast cancer deaths are directly due to tumor dissemination through invasion and metastasis. Cell motility is a fundamental and indispensable aspect of both tumor cell invasion and metastasis. As such cell motility is an excellent target for therapeutic intervention with the potential to decrease breast cancer patient morbidity and mortality. To better understand motility we studyintegrins which are receptors for the extracellular matrix that transduce signals that are critical for cell motility. Recently integrins have been shown to regulate Protein Kinase A (PKA). Importantly this regulation of PKA is critical for cell motility due to the involvement of PKA in the control of Rac and Rho GTPases. However the mechanisms governing integrin regulation of PKA and how PKA regulates Rac and Rho are unclear. The long-term goal of this project is to understand how integrins and their control of PKA activity promote carcinoma cell invasion so that PKA activity may be properly targeted for therapeutic intervention. The objective of this proposal is to understand how pi integrin regulation of PKA activitycontrols Rac and Rho small GTPases in the chemotactic migration of carcinoma cells. Our first aim is to determine how pi integrins regulate PKA. Our next two aims are designed to elucidate the mechanisms by whichPKA activity regulates the activities of RhoA and Racl. In our fourth aim we will identify which PKA subunits are associated with breast cancer cell motility and dissemination using surgical samples in vitro motility and invasion assays and animal models. With the results from this proposal we expect to delineate the signaling molecules upstream and downstream of PKA that are required for cell migration so that we can intelligently target PKA for therapeutic intervention of late stage cancer.

project_terms:
Adenylate Cyclase;Animal Model;Biological Assay;Biological Models;Breast Cancer Cell;Breast Carcinoma;Cancer Patient;Cell Line;Cell Polarity;Cells;Cellular biology;Cessation of life;Clinical Trials;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;DOCK1 protein;Diagnostic Neoplasm Staging;Doctor of Philosophy;ECM receptor;Environment;Failure (biologic function);GTPase-Activating Proteins;Goals;Growth Factor;Guanine Nucleotide Exchange Factors;Guanosine Triphosphate Phosphohydrolases;Heterotrimeric GTP-Binding Proteins;In Vitro;Integrins;Light;Location;Malignant Epithelial Cell;Mediating;Modeling;Monomeric GTP-Binding Proteins;Morbidity - disease rate;Morphology;Mortality Vital Statistics;Neoplasm Metastasis;One-Step dentin bonding system;Operative Surgical Procedures;Protease Inhibitor;Proteolysis;Regulation;Research;Research Personnel;Sampling;Signal Transduction;Signaling Molecule;Speed (motion);Testing;Therapeutic Intervention;Traction;Translations;Tumor Cell Invasion;Work;base;bench to bedside;cancer cell;cell motility;design;innovation;malignant breast neoplasm;migration;novel;programs;receptor;rho;rho GTP-Binding Proteins;rho GTPase-activating protein;tumor


application_id: 8005803
project_number: 1RC4DK089866-01
project_title: The Kentucky Diabetes and Obesity Collaborative (KDOC)
administering_ic: NIDDK
award_notice_date: 2010-08-09
opportunity_number: RFA-OD-09-010
application_type: 1
activity_code: RC4
ic: DK
serial_number: 089866
program_official: HUNTER, CHRISTINE
project_start_date: 2010-08-15
project_end_date: 2013-08-31
study_section: Special Emphasis Panel[ZRG1 HDM-D (58)]
contact_pi_person_id: 1961672
contact_pi: PEARCE, KEVIN A
other_pis: DIGNAN, MARK B
congressional_district: 06
department: FAMILY MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Broad goals and specific aims: Kentucky ranks among the worst in the nation for its burdens of diabetes (41st ) and obesity (46th) which are major contributors to the fact that Kentucky ranks 44th for its all-cause mortality rate. The proposed Kentucky Diabetes and Obesity Collaborative (KDOC) represents a transformative initiative to develop a novel and sustainable research infrastructure designed for the long-term goals of mitigating the public health burdens of obesity and diabetes in a rural medically underserved population and generating new knowledge applicable to similar populations. KDOC partners will include a network of rural primary care providers Public Health Departments Kentucky Medicaid and key units of the University of Kentucky Academic Health Center (UK AHC). This three year infrastructure- building project will has these specific aims: Specific Aim 1: Engage the partners listed above to collaboratively develop the proposed research infrastructure and define mutual research priorities and training needs related to its use Specific Aim 2: Develop test and refine new web-based informatics tools to facilitate translational research and disease management across the KDOC network Specific Aim 3: Develop implement and evaluate training of AHC-community partners for effective research collaborations congruent with KDOC goals Methods: The project will create a partnership linking 10 rural Federally-Qualified Community Health Centers 6 Public Health Department Diabetes Centers of Excellence Kentucky Medicaid and the UK AHC to form the KDOC infrastructure. Funding project input and responsibilities will be shared across the partners. Information technologies will support KDOC operations; including a new web-based patient clinical data registry linked to Medicaid claims data and a web-based suite of tools for research communications protocol management and training. Training needs of users of the infrastructure will be assessed via focus groups and key informants then addressed using in-person and distance- learning techniques. Regular KDOC project personnel visits to partner sites tele-video meetings annual KDOC conferences a 'flat' governing structure and marketing of the research infrastructure to potential users will be used to assure its utility and productive use. The UK Center for Clinical and Translational Science and the UK Center for Public Health Services and Systems Research will provide extensive support and expertise for development and use of KDOC.  
  
PUBLIC HEALTH RELEVANCE: Obesity and diabetes cause enormous burdens of disease in Kentucky and many other rural states where they pose major threats to public health and strain the capacity of healthcare systems. This project aims to develop new University-Community partnerships for research that will lead to reductions in the burdens of obesity diabetes and their complications among rural Kentuckians and generate new knowledge applicable to other medically underserved populations.

project_terms:
Address;Bioinformatics;Caring;Case Management;Charge;Clinical;Clinical Data;Collaborations;Communication;Communication Research;Communities;Community Health Centers;Data;Development;Diabetes Mellitus;Disease Management;Distance Learning;Educational aspects;Effectiveness;Faculty;Federally Qualified Health Center;Focus Groups;Fostering;Funding;Goals;Health;Health Personnel;Health Science Library;Health Services Research;Healthcare;Healthcare Systems;Human Resources;Informatics;Information Systems;Information Technology;Kentucky;Knowledge;Lead;Life;Link;Market Research;Medicaid;Medical;Methods;Mission;Mortality Vital Statistics;Obesity;Online Systems;Patients;Persons;Population;Postdoctoral Fellow;Preparation;Primary Health Care;Professional Organizations;Protocols documentation;Provider;Qualifying;Registries;Research;Research Infrastructure;Research Personnel;Research Priority;Research Support;Research Training;Resources;Rural;Rural Community;Self Management;Services;Site;Specificity;Structure;Target Populations;Techniques;Technology;Testing;Training;Training and Infrastructure;Translational Research;United States Public Health Service;Universities;Visit;base;burden of illness;college;design;disease registry;health information technology;improved;informant;innovation;medically underserved population;meetings;multidisciplinary;novel;operation;payment;protocol development;public health medicine (field);public health relevance;rural area;symposium;systems research;tool

public_health_relevance:
Project NarrativeObesity and diabetes cause enormous burdens of disease in Kentucky and many other ruralstates where they pose major threats to public health and strain the capacity of healthcaresystems. This project aims to develop new University-Community partnerships for research thatwill lead to reductions in the burdens of obesity diabetes and their complications among ruralKentuckians and generate new knowledge applicable to other medically underservedpopulations.


application_id: 8005793
project_number: 1RC4MD005760-01
project_title: Enhancing the Capacity of the Kentucky Appalachian Rural Rehabilitation Network
administering_ic: NIMHD
award_notice_date: 2010-07-06
opportunity_number: RFA-OD-09-010
application_type: 1
activity_code: RC4
ic: MD
serial_number: 005760
program_official: ALVIDREZ, JENNIFER L
project_start_date: 2010-07-06
project_end_date: 2013-06-30
study_section: Special Emphasis Panel[ZRG1 HDM-D (58)]
contact_pi_person_id: 1904484
contact_pi: KITZMAN, PATRICK H.
other_pis: COSTICH, JULIA ;HARRISON, ANNE LEATH
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): Kentuckians living in rural Appalachia suffer a disproportionate burden of negative health disparities which is especially evident for persons with neurological conditions (spinal cord injury (SCI) traumatic brain injury (TBI) and stroke). Recently the Kentucky Appalachian Rural Rehabilitation Network (KARRN) was established as a collaboration among the academic healthcare center (AHC) community healthcare providers and community partners to identify develop and disseminate information and strategies to improve outcomes and quality of life for these individuals. However essential infrastructure is needed to capitalize on the potential of KARRN to provide education and training and to effectively conduct translational research. We propose to expand the capacity of KARRN through accomplishment of the following specific aims: Aim 1: Expand the linkage among essential community partnerships to facilitate new research translate existing knowledge and disseminate information. Community Research Associates (CRAs) and community liaisons will be identified videoconferencing capacity among partners will be expanded and the KARRN website will be expanded. Aim 2: Identify supports and barriers across the continuum of care for people with SCI stroke and TBI living in rural Appalachian regions. Focus groups and surveys and in-depth asset mapping of available resources will be conducted. Aim 3: Promote bidirectional education between the community and AHC to facilitate new research translate existing knowledge and disseminate information. CRAs and community partners will be trained in research methodology and AHC members will be educated to clearly understand community needs. Aim 4: Develop central databases for identification and tracking of clients as well as collection and analysis of research data. A centralized registry will be developed to follow clients as they transition among healthcare environments and through community integration. A research database for the KARRN will be developed. Aim 5: Develop research agenda for the KARRN. Short-term and long-term research agenda will be set with funding for pilot studies made available to community partners. The proposed work will expand the capacity of the KARRN allowing longitudinal study across the continuum of care and community integration with the goal of reducing disability and increasing participation and quality of life in rural Appalachia. AHC and community partnerships will be strengthened and will link resources based on the individuals' and families' needs. The proposed infrastructure will enhance communication throughout the entire continuum of care inform the KARRN research agenda and facilitate the dissemination of new knowledge into community practice by linking basic scientists clinical researchers and community-based researchers. Once established this infrastructure can easily be expanded as a base for similar work for other populations.  
  
PUBLIC HEALTH RELEVANCE: This project seeks to promote the expansion of the Kentucky Appalachian Rural Rehabilitation Network which is focused on research and education to improve healthcare and community integration of individuals with neurological conditions living in Appalachian rural Kentucky.

project_terms:
Academic Training;Appalachian Region;Caring;Client;Clinical;Collaborations;Collection;Communication;Communities;Community Health;Community Healthcare;Community Integration;Community Practice;Continuity of Patient Care;Data;Databases;Development;Diagnosis;Educational aspects;Environment;Family;Focus Groups;Funding;Goals;Health Personnel;Healthcare;Healthcare Systems;Individual;Kentucky;Knowledge;Language;Leadership;Life;Link;Longitudinal Studies;Maintenance;Maps;Neurologic;Outcome;Persons;Pilot Projects;Population;Postdoctoral Fellow;Procedures;Quality of life;Registries;Rehabilitation therapy;Research;Research Infrastructure;Research Methodology;Research Personnel;Resources;Rural;Rural Community;Scientist;Spinal cord injury;Staging;Surveys;Training;Training and Education;Translating;Translational Research;Traumatic Brain Injury;Videoconferences;Videoconferencing;Work;base;development policy;disability;falls;health disparity;improved;innovation;knowledge base;member;public health relevance;stroke;symposium;web site

public_health_relevance:
This project seeks to promote the expansion of the Kentucky Appalachian Rural RehabilitationNetwork which is focused on research and education to improve healthcare and communityintegration of individuals with neurological conditions living in Appalachian rural Kentucky.


application_id: 8004397
project_number: 3R01DK073586-04S1
project_title: Prolonged Diabetic Damage to Cardiac Mitochondria
administering_ic: NIDDK
award_notice_date: 2009-12-21
opportunity_number: RFA-DK-05-001
application_type: 3
activity_code: R01
ic: DK
serial_number: 073586
suffix: S1
program_official: JONES, TERESA L Z
project_start_date: 2009-12-23
project_end_date: 2010-09-30
study_section: ZDK1-GRB-N(O1)S
contact_pi_person_id: 1927079
contact_pi: EPSTEIN, PAUL N
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
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:
In diabetic patients complications such as cardiomyopathy develop over many years of hyperglycemia. Weare proposing that the prolonged time course stems from the gradual accumulation of damage tomitochondrial DNA caused by increased mitochondrial generation of reactive oxygen species (ROS) andreactive nitrogen species (RNS). For several reasons mitochondrial DNA is especially vulnerable to damageand some types of damage are poorly repaired. We hypothesize that mitochondrial DNA damage is causal forcellular and organ dysfunction in the diabetic state. Our laboratory developed the OVE26 mouse model ofType I diabetes optimal for following chronic development of complications. Cardiac mitochondria fromlong-term diabetic OVE26 mice exhibit morophological degeneration decreased glutathione content andincreased DNA damage. Transgenic mice with increased activity of the mitochondrial antioxidant MnSODtargeted to the heart when crossed onto the OVE26 background show less contractile dysfunction improvedmitochondrial morphology and a significant improvement in mitochondrial respiration. We propose thatMnSOD overexpression suppresses damage to the mitochondrial genome and that this accounts for improvedcardiomyocyte function. To test the hypothesis that progressive mitochondrial DNA damage by ROS or RNScontributes to the development of diabetic cardiomyopathy we will carry out the following Specific Aims:Aim 1: Evaluate mutations and deletions in mitochondrial DNA and correlate these changes withmitochondrial respiratory function electron transport chain complex activities cellular and mitochondrialROS generation and cardiomyocyte contractility. Aim 2: Determine if there is a cause and effect relationshipbetween mitochondrial DNA damage and diabetic cardiomyopathy. On the OVE26 diabetic backgroundmitochondrial DNA will be protected by cardiac overexpression of MnSOD and mitochondrial targetedOGG1. We will also determine whether both DNA damage and diabetic cardiomyopathy are exacerbated bycrossing existing OGG1 knockout animals to our diabetic mice. Aim 3: Assess whether systemic therapywith agents that bind free transition metals can prevent superoxide from forming more reactive species thatdamage mitochondrial DNA. Results of these investigations may be directly applicable to the development ofnew therapies which minimize or absolutely prevent certain diabetic complications.

project_terms:
8-Oxoguanine DNA Glycosylase;Accounting;Age;Aging;Animal Model;Animals;Antioxidants;Binding (Molecular Function);Cardiac;Cardiac Myocytes;Cardiomyopathies;Cell Nucleus;Chronic;Complex;Complications of Diabetes Mellitus;DNA Damage;DNA Repair;DNA Repair Enzymes;Data;Deletion Mutation;Development;Diabetes Mellitus;Diabetic mouse;Elderly;Electron Transport;Enzymes;Exhibits;Functional disorder;Generations;Glutathione;Heart;Histones;Human;Hydroxyl Radical;Hyperglycemia;Individual;Insulin-Dependent Diabetes Mellitus;Investigation;Laboratories;Life;Lyase;Mitochondria;Mitochondrial DNA;Morphology;Mus;OGG1 gene;Organ;Pathology;Peroxonitrite;Process;Production;Proteins;Publishing;Reactive Nitrogen Species;Reactive Oxygen Species;Research Personnel;Respiration;Respiratory physiology;Sampling;Source;Superoxides;Systemic Therapy;Testing;Time;Transgenic Mice;Transition Elements;Work;cell type;diabetic;diabetic cardiomyopathy;diabetic patient;improved;knockout animal;mitochondrial genome;mouse model;overexpression;prevent;programs;repaired;stem


application_id: 8004349
project_number: 3R01DK074566-03S1
project_title: INTRACELLULAR ENERGY DELIVERY AND DIABETIC WOUNDS
administering_ic: NIDDK
award_notice_date: 2009-12-21
application_type: 3
activity_code: R01
ic: DK
serial_number: 074566
suffix: S1
program_official: JONES, TERESA L Z
project_start_date: 2009-12-23
project_end_date: 2010-09-30
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 1885914
contact_pi: CHIEN, SUFAN
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant):  The long-term goal of our program is to develop a safe and effective technique to combat various tissue ischemic damages. The specific aim of this proposal is to use our newly developed proprietary intracellular energy delivery technique to promote healing of diabetic wounds. Of the 17 million Americans with diabetes approximately 2.5 to 4.5 million will develop a chronic wound in their lifetime. The overall cost of diabetic foot problems including loss of productivity could be as high as $20 billion per year. Despite thousands of dressing products developed to treat wounds none have shown consistent effect. We propose a new approach for chronic wounds. Our central hypoth- esis is that wound tissue hypoxia results in depletion of adenosine triphosphate (ATP) which is the fundamental cause of non-healing chronic wounds and a direct intracellular ATP delivery will improve microenvironment of wound tissue and facilitate healing process. Direct energy supply for wound treatment has never been attempted before and the relationship between increased energy supply and wound healing process is entirely unknown. During the tenure of the Pi's NIH grant entitled "Enhanced glycolysis for hypothermic heart preservation" a new technique for direct intracellular delivery of ATP has been developed in which a special carrier is used to encapsulate ATP. The composition of this carrier is similar to the cell membrane. When the carrier meets with the cell membrane it fuses with it and delivers the contents into the cytosol. Preliminary results indicate that this new energy delivery technique can provide significant protection to ischemic cells and tissues. The technique has shown very promising effects on normal and ischemic wounds. Three US patents and more than 12 international patents have been filed and the innovation has also been reported to the NIH. Our preliminary results also indicated that high-energy phos- phate contents were severely depleted in human chronic wounds and treatment with ATP-vesicles in animal wounds increased tissue high-energy contents. Five hypotheses will be tested: (1) high-energy phosphate contents are decreased in chronic diabetic wounds; 2) an ischemic wound model created using a minimally invasive surgical technique can be tolerable to diabetic animals; 3) intracellular ATP delivery will increase wound tissue energy levels to facilitate healing; (4) by providing energy to wound tissue improved healing is achieved through coordinated upregulation of growth factors and other healing mechanisms; and (5) direct intracellular energy delivery will enhance wound healing by improved tissue perfusion. These issues have not been explored in the past but our preliminary results have established the basis for the success of this project. The expansion of usage of the direct intracellular energy delivery is likely to have a major impact on medicine. It will not only improve chronic wound care but also help our treatment to various ischemic conditions such as severe trauma shock stroke heart attack spinal cord injury cardiopulmonary bypass organ transplant and many other acute and chronic ischemic diseases.

project_terms:
Acute;Adenosine Triphosphate;Affect;American;Amputation;Animals;Biochemical;Caliber;Cardiopulmonary Bypass;Caring;Cell membrane;Cells;Chronic;Chronic Care;Chronic lung disease;Country;Cytosol;Data;Development;Diabetes Mellitus;Diabetic Foot;Diabetic wound;Disease;Ear structure;Encapsulated;Energy Supply;Family suidae;Generations;Glycolysis;Goals;Grant;Growth Factor;Healed;Human;Hypoxia;Immune System Diseases;Infection;International;Ischemia;Legal patent;Lipids;Lower Extremity;Medicine;Modeling;Myocardial Infarction;Neuropathy;Operative Surgical Procedures;Organ Transplantation;Oryctolagus cuniculus;Penetration;Perfusion;Phase;Procedures;Process;Rattus;Reporting;Research Personnel;Shock;Skin;Spinal cord injury;Sterile coverings;Techniques;Testing;Thick;Tissues;Trauma;Ulcer;United States National Institutes of Health;Up-Regulation (Physiology);Vascular Diseases;Vesicle;Wound Healing;base;combat;cost;diabetic;diabetic patient;diabetic wound healing;healing;heart preservation;improved;innovation;inorganic phosphate;meetings;minimally invasive;novel strategies;productivity loss;programs;protective effect;research study;stroke;success;sufan;wound


application_id: 8003639
project_number: 1F31DA029374-01A1
project_title: Clinical Evaluation of Novel Methods for Extending Microneedle Pore Lifetime
administering_ic: NIDA
award_notice_date: 2010-05-24
opportunity_number: PA-09-208
application_type: 1
activity_code: F31
ic: DA
serial_number: 029374
suffix: A1
program_official: LAO, GUIFANG
project_start_date: 2010-07-01
project_end_date: 2012-06-30
study_section: Special Emphasis Panel[ZRG1 F10A-S (20)]
contact_pi_person_id: 10105185
contact_pi: BROGDEN, NICOLE 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 PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The long-term objective of the proposed research project entitled "Clinical evaluation of novel methods for extending microneedle pore lifetime" is to improve current methods of transdermal drug delivery by increasing the lifetime of pores created from inserting microneedles into the skin. Improvement of transdermal drug delivery techniques (via the use of microneedles) would have important clinical implications by providing a less invasive means to deliver drugs systemically which would lead to greater patient safety and compliance. This could also have strong implications in developing better treatments for alcoholism and opiate addiction as this proposal examines the delivery of naltrexone (an opiate antagonist used for the treatment of opioid and alcohol abuse) following microneedle insertion. Effective transdermal delivery would be an excellent alternative to the current oral and parenteral formulations of naltrexone. The specific aims of the proposal include 1) inhibition of the cyclooxygenase (COX) pathway as a means to inhibit pore closure 2) pharmacokinetic analysis of naltrexone to characterize pore lifetime following COX inhibition and 3) employing small-interfering RNA (siRNA) methods to inhibit pore closure. The research methods will involve the use of in vitro and in vivo models (cell culture qRT-PCR ELISAs) animal models (hairless guinea pigs and Yucatan miniature pigs) and human studies. Many of the methods described in the proposal involve novel applications of commercially available products or development of innovative means to improve transdermal drug delivery with the use of microneedles. Studying these compounds and delivery methods makes it feasible to do translational bioengineering and biopharmaceutical training research in human proof-of-concept studies.

project_terms:
Alcohol abuse;Alcoholism;Animal Model;Biological Products;Biomedical Engineering;Cavia;Cell Culture Techniques;Clinical;Development;Diclofenac;Drug Formulations;Drug Kinetics;Family suidae;Goals;Healed;Heroin Abuse;Human;In Vitro;Knowledge;Lead;Medical;Methods;Modeling;Naltrexone;Narcotic Antagonists;Opiate Addiction;Opioid;Oral;Pain;Pathway interactions;Pharmaceutical Preparations;Process;Prostaglandin-Endoperoxide Synthase;Research;Research Methodology;Research Project Grants;Research Training;Skin;Small Interfering RNA;Solid;Stainless Steel;Techniques;Time;Topical application;Transdermal substance administration;Vascular Endothelial Growth Factors;Work;Wound Healing;alcoholism therapy;celecoxib;clinical application;clinically relevant;healing;improved;in vivo Model;innovation;novel;patient safety;public health medicine (field);public health relevance;research clinical testing

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Project Narrative This research will lead to a better understanding of new methods for delivering drugs through the skin. This will help to improve public health by leading to less painful and potentially safer ways of treating many different medical conditions including heroin abuse and alcoholism.


application_id: 8003242
project_number: 3R01DK069766-05S1
project_title: Tolerance Induction to Islet Transplants
administering_ic: NIDDK
award_notice_date: 2010-01-08
application_type: 3
activity_code: R01
ic: DK
serial_number: 069766
suffix: S1
program_official: APPEL, MICHAEL C
project_start_date: 2010-01-11
project_end_date: 2010-09-30
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 1878929
contact_pi: ILDSTAD, SUZANNE T
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant): The focus of this proposal is to develop a novel "conditioning" approach that will replace myelotoxic agents to establish chimerism in NOD mice. We will induce immune deviation to promote host-versus-graft hyporesponsiveness thereby giving the hematopoietic stem cell (HSC) an opportunity to engraft and establish subsequent self-perpetuating deletional tolerance to islet allografts. Our recent studies in a mouse model suggest that the primary role for conditioning for HSC transplantation is to suppress host-versus-graft alloreactivity rather than to prepare vacant niches in the recipient's bone marrow compartment. This observation suggests that one could replace myelotoxic agents with antigen-specific approaches to induce host-versus-graft hyporeactivity or anergy at the time of HSC transplantation. As the mechanisms underlying T cell activation are defined highly specific approaches to suppress this alloreactivity have emerged. In AIM I. we will ESTABLISH CHIMERISM THROUGH IMMUNE DEVIATION OF THE RECIPIENT. We will immunomodulate the recipient: (a) targeting alloreactive cells in the host microenvironment; (b) inducing anergy and/or antigen-specific apoptosis of alloreactive host cells; and (c) through generation of regulatory T cells (Treg) and develop a novel nonmyeloablative conditioning regimen to induce antigen-specific hyporesponsiveness to the HSC and islet allografts. Cell-based therapies have great potential for inducing transplantation tolerance. Of greatest interest are the new subpopulations of bone marrow-derived dendritic cells (DC) that have recently been shown to be potently tolerogenic in vitro under certain circumstances. We are the first to demonstrate an in vivo engraftment-enhancing effect for precursor plasmacytoid DC (p-preDC). The exploitation of this discovery in vivo and its potential to reduce the need for myelotoxic conditioning has not yet been tested. Hematopoietic growth factors have also been used to drive the immune response to a tolerogenic T helper 2 (Th2) phenotype through production of p-preDC or other tolerance-promoting cells (graft facilitating cells {FC}) that in turn generate Treg. In AIM II we will USE PRE-TRANSPLANT IMMUNOMODULATION OF THE DONOR WITH HEMATOPOIETIC GROWTH FACTORS TO GENERATE TOLEROGENIC CELLS IN THE HSC ALLOGRAFT. We will use these factors and the cells they generate to modulate the tolerogenicity of the donor marrow inoculum in vivo to tip the immune milieu in favor of graft acceptance enhancing bone marrow chimerism without myelotoxic conditioning. We will examine the mechanism by which this occurs and identify which cell types in the graft are critical to tolerance induction. P-preDC exposed to apoptotic donor antigens are potently tolerizing in vitro through generation of Treg. The therapeutic application of this approach has not been tested in vivo. In AIM III we will USE EX VIVO IMMUNOMODULATION OF THE MARROW to expand p-preDC and FC and induce a tolerogenic inoculum for HSC transplantation.

project_terms:
Acute;Address;Adverse effects;Allogenic;Allografting;Antigens;Apoptosis;Apoptotic;Autoimmune Diseases;Autoimmune Process;Autoimmunity;Bone Marrow;Bone Marrow Transplantation;Cell Therapy;Cells;Cessation of life;Chimerism;Clinical Treatment;Clinical Trials;Data;Dendritic Cells;Diabetes Mellitus;Doctor of Medicine;Engraftment;Generations;Goals;Graft-vs-Host Disease;Hematopoietic Cell Growth Factors;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Immune;Immune response;Immunization;In Vitro;Inbred NOD Mice;Infusion procedures;Insulin;Insulin-Dependent Diabetes Mellitus;Islets of Langerhans Transplantation;Journals;Maintenance;Marrow;Medicine;Methods;Morbidity - disease rate;Phenotype;Population;Principal Investigator;Production;Productivity;Regimen;Regulatory T-Lymphocyte;Role;Staging;T-Cell Activation;Testing;Therapeutic;Time;Transplantation;Transplantation Immunology;Transplantation Tolerance;anergy;blood glucose regulation;cell type;clinical application;conditioning;disorder prevention;immunoregulation;in vivo;interest;islet;islet allograft;mouse model;novel;prevent;programs;research study;reverse tolerance;systemic autoimmune disease


application_id: 8002948
project_number: 1F31AA019853-01
project_title: Role of Anandamide in a Rodent Model of an Alcohol Use Disorder
administering_ic: NIAAA
award_notice_date: 2010-08-19
opportunity_number: PA-09-208
application_type: 1
activity_code: F31
ic: AA
serial_number: 019853
program_official: LIU, QI-YING
project_start_date: 2010-09-30
project_end_date: 2012-09-29
study_section: Neuroscience and Behavior Study Section[AA-4]
contact_pi_person_id: 10296753
contact_pi: LIPUT, DANIEL JAMES
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alcohol Use Disorders (AUDs) represent a major public health problem in the United States with over 8% of Americans meeting the DSM-IV criteria for an AUD. Excessive alcohol intake causes progressive neurodegeneration that often leads to cognitive and behavioral deficits and subsequently alcoholism. To date there are no approved therapies for alcohol-induced neurodegeneration thus warranting investigation into novel mechanisms of neuroprotection. The endocannabinoid system has been implicated as a novel neuroprotective system in a variety brain injury models. Studies suggest that the endocannabinoid anandamide (AEA) is elevated after ischemic and traumatic brain injuries which affords endogenous neuroprotection. However it is not know if AEA affords similar neuroprotection for alcohol-induced neurodegeneration. Therefore the guiding hypothesis for this present proposal is that AEA tone is amplified by alcohol-induced brain damage as a neuroprotective mechanism and therefore potentiating AEA tone by inhibiting AEA degradation affords additional neuroprotection. Specific Aim 1 will utilize HPLC/MS/MS techniques to assess levels of AEA in the entorhinal/perirhinal cortex and hippocampus two regions susceptible to alcohol-induced neurodegeneration in a binge model of an AUD. Additionally immunoblotting will be used to elucidate the mechanism of altered AEA tone. Specific Aim 2 will utilize receptor autoradiography to assess cannabinoid 1 (CB1) receptor expression during a binge-alcohol exposure paradigm in the brain regions mentioned above. This will allow us to gain insight to the relationship between CB1 receptors and elevations of AEA in context of neuroprotection as AEA may cause CB1 down-regulation. Aim 3 will consist of two experiments to evaluate the efficacy of enhancing AEA tone by inhibiting fatty acid amide hydrolase (FAAH) to attenuate alcohol- induced neurodegeneration. Experiment 1 will determine an optimum dose of URB-595 a FAAH inhibitor to attenuate alcohol-induced neurodegeneration in the entorhinal/perirhinal cortex and ventral dentate gyrus of the hippocampus using fluoro-jade b stain. The second experiment will test whether AEA neuroprotection is mediated through the CB1 receptor using the CB1 receptor antagonist SR-141716. These studies will provide important insight into the effects of binge alcohol administration on the endocannabinoid system as well as neuroprotective properties of the endocannabinoid system in alcohol-induced brain damage. These studies will lead to future investigation into the specific mechanisms linking the endocannabinoid system to alcohol- induced neurodegeneration. Additionally these results will lead to novel approaches and/or novel pharmaceutical agents for the treatment of neurodegeneration linked to AUD's.  
  
PUBLIC HEALTH RELEVANCE: Current treatments for alcohol use disorders commonly referred to as alcoholism although effective for some are less than adequate.  With over 8% percent of the population currently suffering from an alcohol use disorder it is essential that new therapies become available for these individuals. The proposed studies will give insight into novel treatment strategies for the treatment of alcohol use disorders specifically for the treatment of alcoholic brain damage.

project_terms:
Alcoholism;Alcohols;American;Attenuated;Autoradiography;Behavioral;Brain Injuries;Brain region;Cannabinoids;Cognitive;DSM-IV;Dose;Down-Regulation;Endocannabinoids;Future;Heavy Drinking;Hippocampus (Brain);Immunoblotting;Individual;Investigation;Lead;Link;Mediating;Modeling;Nerve Degeneration;Parahippocampal Gyrus;Pharmacologic Substance;Population;Property;Rodent Model;Role;Staining method;Stains;System;Techniques;Testing;Traumatic Brain Injury;United States;alcohol exposure;alcohol use disorder;anandamide;dentate gyrus;fatty acid amide hydrolase;fluoro jade;inhibitor/antagonist;insight;meetings;neuroprotection;novel;novel strategies;problem drinker;progressive neurodegeneration;public health medicine (field);public health relevance;receptor;receptor expression;research study;treatment strategy

public_health_relevance:
7. Project Narrative Current treatments for alcohol use disorders commonly referred to as alcoholism although effective for some are less than adequate.  With over 8% percent of the population currently suffering from an alcohol use disorder it is essential that new therapies become available for these individuals. The proposed studies will give insight into novel treatment strategies for the treatment of alcohol use disorders specifically for the treatment of alcoholic brain damage.


application_id: 8002565
project_number: 1F31NS067899-01A1
project_title: Alterations in Glutamate Neurotransmission after Experimental Brain Injury
administering_ic: NINDS
award_notice_date: 2010-07-01
opportunity_number: PA-09-208
application_type: 1
activity_code: F31
ic: NS
serial_number: 067899
suffix: A1
program_official: HICKS, RAMONA R
project_start_date: 2010-07-04
project_end_date: 2012-07-03
study_section: Special Emphasis Panel[ZRG1 F01-L (20)]
contact_pi_person_id: 9814689
contact_pi: HINZMAN, JASON MICHAEL
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Glutamate the predominant excitatory neurotransmitter in the central nervous system is released from multiple stores after a TBI as primary mechanical forces from the injury can breakdown the blood-brain-barrier and create pores in cell membranes leading to glutamate release into the extracellular space. In addition redistribution of ions after the injury can create a massive depolarization leading to neuronal release of glutamate [1-3]. Glutamate plays a pivotal role in the pathophysiology of secondary damage after injury by excessively activating ionotropic glutamate receptors disrupting ionic homeostasis increasing the energy demand of the cell and producing reactive oxygen species [4-7]. Increased glutamate levels could produce excessive excitation and neuronal damage that may be responsible for motor behavioral and cognitive deficits following TBI.  Central hypothesis: TBI alters glutamate regulation elevating the extracellular concentration of glutamate. Specific Aims: (1) TBI increases tonic glutamate levels and neuronal release of glutamate (2) TBI decreases the ability of glutamate transporters to clear glutamate from the extracellular space (3) Elevated extracellular levels of glutamate contribute to the post-traumatic pathophysiology (4) Pretreatment with a recently developed adeno-associated virus expressing the glutamate transporter GLT-1 (AAV1-GLT-1) will improve glutamate regulation and motor function after injury.  The proposed project examines TBI induced alterations in glutamate signaling using a novel technology enzyme-based microelectrode arrays (MEAs) coupled with in vivo amperometry. MEAs allow for selective measures of extracellular glutamate and measure the fast dynamics of glutamate release and uptake involved in glutamate neurotransmission. Examining injury-induced alterations in glutamate signaling in different regions of the central nervous system may reveal specific mechanisms responsible for increased extracellular glutamate levels. Monitoring extracellular levels of glutamate in awake animals for multiple days after injury will examine if increases in extracellular glutamate contribute to post-traumatic pathophysiology. These studies may reveal important mechanistic discoveries and the therapeutic window available to improve motor behavioral and cognitive outcomes following TBI. Finally we will examine if pretreatment with AAV1- GLT-1 can improve glutamate regulation and reduce motor deficits after injury.  
  
PUBLIC HEALTH RELEVANCE: Approximately 1.5 million Americans suffer from a traumatic brain injury (TBI) each year with mild TBI accounting for as many as 75% of all the injuries [8]. Survivors of TBI suffer from a wide spectrum of deficits including impairments in working memory attention learning cognitive function and motor function [9-13]. Future research needs to examine the pathological mechanisms responsible for producing these deficits which may provide novel therapeutic targets to improve outcomes after injury.

project_terms:
Accounting;American;Animals;Attention;Behavioral;Blood - brain barrier anatomy;Brain Injuries;Cell membrane;Cells;Cognitive;Cognitive deficits;Coupled;Dependovirus;Enzymes;Extracellular Space;Functional disorder;Future;Glutamate Receptor;Glutamate Transporter;Glutamates;Homeostasis;Impairment;Injury;Ions;Learning;Measures;Mechanics;Microelectrodes;Monitor;Motor;Neuraxis;Neurons;Neurotransmitters;Outcome;Play;Reactive Oxygen Species;Regulation;Research;Role;Short-Term Memory;Signal Transduction;Survivors;Therapeutic;Traumatic Brain Injury;awake;base;cognitive function;extracellular;improved;in vivo;motor deficit;neurotransmission;new technology;new therapeutic target;public health relevance;uptake

public_health_relevance:
7. Project Narrative Approximately 1.5 million Americans suffer from a traumatic brain injury (TBI) each year withmild TBI accounting for as many as 75% of all the injuries [8]. Survivors of TBI suffer from a widespectrum of deficits including impairments in working memory attention learning cognitive functionand motor function [9-13]. Future research needs to examine the pathological mechanisms responsiblefor producing these deficits which may provide novel therapeutic targets to improve outcomes afterinjury.


application_id: 8002412
project_number: 2R56DK067581-06
project_title: Beta-Cell Transcription Factors and Insulin Gene Expression
administering_ic: NIDDK
award_notice_date: 2010-01-19
opportunity_number: PA-07-070
application_type: 2
activity_code: R56
ic: DK
serial_number: 067581
program_official: SATO, SHERYL M
project_start_date: 2010-09-01
project_end_date: 2013-08-31
study_section: Special Emphasis Panel[ZRG1-EMNR-H(02)M]
contact_pi_person_id: 7875121
contact_pi: OZCAN, SABIRE
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
The beta cells of the pancreas produce and secrete insulin in response to increasing blood glucose levels and this process is essential for maintaining normal glucose homeostasis. Defects in insulin production and secretion result in type 1 as well as type 2 diabetes. Although three beta-cell specific transcription factors (Pdx-1 MafA and NeuroD1) have been implicated in glucose regulation of insulin production the exact molecular mechanisms by which glucose modulates the function of these transcription factors remain unknown. The long-term goal of this research is to gain a detailed understanding of the mechanisms and pathways leading to glucose induction of insulin gene expression via modulation of the transcription factors Pdx-1 MafA and NeuroD1. Our previous findings suggest that glucose regulates the function of the these transcription factors by different mechanisms and pathways to ensure a tight control of insulin gene expression in pancreatic beta cells. Based on our preliminary data we hypothesize that glucose regulates insulin gene expression by 1) influencing the interaction of Pdx-1 with other transcriptional regulators; 2) controlling MafA expression via O-linked GlcNAc modification of proteins; and 3) regulating the nucleo-cytoplasmic shuttling of NeuroD1. We propose to test this hypothesis in cultured pancreatic beta cell lines as well as isolated pancreatic islets using various biochemical molecular and cell biological and immunological techniques to identify the critical pathways and players involved in glucose regulation of beta-cell specific transcription factors. The information obtained from our studies will be instrumental in the design of new therapies to treat and prevent diabetes associated with defects in insulin production.

project_terms:
Acetylation;Address;Affinity Chromatography;Beta Cell;Binding (Molecular Function);Biochemical;Biological;Blood Glucose;Calcium;Cell Line;Cell Nucleus;Cell physiology;Cells;Chimeric Proteins;Critical Pathways;Cytoplasm;Data;Defect;Development;Diabetes Mellitus;EP300 gene;Ensure;Event;Exposure to;Funding;Gene Expression;Genetic Transcription;Glucose;Goals;Hexosamines;Immunologic Techniques;Incubated;Insulin;Islets of Langerhans;Link;Mass Spectrum Analysis;Mediating;Modification;Molecular;Natural regeneration;Non-Insulin-Dependent Diabetes Mellitus;Pathway interactions;Phosphorylation;Post-Translational Protein Processing;Process;Production;Promotor (Genetics);Protein Glycosylation;Proteins;Publishing;Regulation;Research;Role;Site;Structure of beta Cell of islet;System;Techniques;Testing;base;blood glucose regulation;design;novel;novel strategies;prevent;research study;response;transcription factor

public_health_relevance:
Decreased or lack of insulin production leads to the development of diabetes. The major goal of this proposal is to understand how insulin production is regulated in the pancreatic beta cells. The results obtained from these studies may help in the development of novel strategies to enhance insulin production or regeneration of pancreatic beta cells.


application_id: 8001020
project_number: 1R43DK089892-01
project_title: Biomarker for Early Detection of Chronic Kidney Disease
administering_ic: NIDDK
award_notice_date: 2010-09-20
opportunity_number: PA-09-080
application_type: 1
activity_code: R43
ic: DK
serial_number: 089892
program_official: GOSSETT, DANIEL ROBERT
project_start_date: 2010-09-20
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZRG1 DKUS-G (11)]
contact_pi_person_id: 1897474
contact_pi: CARRITHERS, STEPHEN L
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 189577070
primary_uei: DJ6WUEKKFBM8
duns_number: 189577070
uei: DJ6WUEKKFBM8
fips: US
organization_id: 10001287
organization_name: SEQUELA
organization_city: PEWEE VALLEY
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400569116
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal is submitted in response to the program announcement PA-09-080 "Omnibus Solicitation of the NIH CDC and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44])" and intended to be directed to the NIDDK with a potential dual assignment to the NHLBI. There are an estimated 14 million Americans with early chronic kidney disease (CKD). Early diagnosis and treatment of CKD are the only cost-effective means to reverse this growing problem. Current methods and biomarkers that are used to assess CKD are effective once the disease is well established but none thus far are reliable for the detection of early renal disease. Existing tests used by physicians today are all essentially markers of kidney filtration function. NIH recognizes the challenge to diagnose CKD early during its initiation and development phases in order to prevent further renal damage reduce cardiovascular risk and minimize the economic impact of CKD through program announcements such as PA-09-204 (Development and Validation of Disease Biomarkers) and PA-09-181 (Non-Invasive Methods for Diagnosis and Progression of Diabetes Kidney Urological Hematological and Digestive Diseases). We will produce a new ELISA for CKD based upon the use of a novel biomarker that reflects in part the pathophysiology of kidney disease. Detection of this biomarker for CKD will give laboratory results and clinical insight that is complementary to creatinine-based GFR estimates (eGFR) as well as tests for urine albumin. Development of this test should result in a more reliable identification and detection of early CKD patients. In addition our CKD ELISA would give physicians the ability to evaluate patients that have been recently diagnosed with hypertension or diabetes the two leading causes of CKD. In turn this Phase I proposal will evaluate the prototype assay in both populations. We will look for the influence of comorbid conditions and medications on assay performance. Lastly we will evaluate whether patient characteristics such as age gender BMI ethnicity and other factors impact on assay performance. The information gained from this test will also lead to a better basic understanding of the biological mechanisms underlying CKD. Sequela requests Phase I support so that we can evaluate a prototype assay and test its feasibility to help identify at-risk patients for early kidney disease and monitor therapy with the ultimate goal of obtaining FDA approval.  
  
PUBLIC HEALTH RELEVANCE: Chronic Kidney Disease affects nearly 26 million people in the United States which places them at higher risk of renal failure and hemodialysis. We will develop an ELISA to aid in the diagnosis of early kidney disease to aid physicians in earlier treatment and better assessment of chronic kidney disease.

project_terms:
Affect;Age;Albumins;American;Antihypertensive Agents;Award;Biochemical Markers;Biological;Biological Assay;Blood Circulation;Cardiovascular Diseases;Cardiovascular system;Centers for Disease Control and Prevention (U.S.);Cessation of life;Characteristics;Chronic Kidney Failure;Clinical;Clinical Trials;Collaborations;Collection;Complement;Confusion;Creatinine;Data;Detection;Development;Diabetes Mellitus;Diagnosis;Diagnostic;Diagnostic tests;Dialysis procedure;Diet;Digestive System Disorders;Disease;Disease Outcome;Early Diagnosis;Early treatment;Effectiveness;End stage renal failure;Endocrinology;Enzyme-Linked Immunosorbent Assay;Erythrocytes;Essential Hypertension;Ethnicity aspects;Evaluation;Exclusion Criteria;Excretory function;Filtration;Freezing;Functional disorder;Gender;Glomerular Filtration Rate;Goals;Gold;Health;Hemodialysis;Homeostasis;Hormonal;Hospitals;Human;Hypertension;Impairment;Indiana;Institutes;Intervention;Iothalamate;Israel;Kidney;Kidney Diseases;Kidney Failure;Kidney Transplantation;Laboratories;Lead;Letters;Life;Location;Measurement;Measures;Metabolism;Methods;Microalbuminuria;Modeling;Monitor;NIH Program Announcements;National Heart Lung and Blood Institute;National Institute of Diabetes and Digestive and Kidney Diseases;Nephrology;Nephrons;Parents;Participant;Patients;Performance;Pharmaceutical Preparations;Phase;Physicians;Plasma;Play;Population;Population Control;Prevention;Production;Proteins;Protocols documentation;Receiver Operating Characteristics;Recording of previous events;Renal Glycosuria;Renal function;Research Ethics Committees;Risk;Risk Factors;Role;Sampling;Series;Serum;Site;Small Business Innovation Research Grant;Sodium;Sodium Chloride;Staging;Technology;Testing;Therapeutic Intervention;Transplant Recipients;Transplantation;Transport Process;Tube;United States;United States National Institutes of Health;Universities;Urine;Validation;Waiting Lists;Water;Weight;Work;base;biomarker;cardiovascular disorder risk;cardiovascular risk factor;cost;diabetic;diabetic patient;economic impact;high risk;improved;inorganic phosphate;insight;medical schools;novel;novel diagnostics;post gamma-globulins;prevent;prohormone;prototype;prouroguanylin;public health medicine (field);public health relevance;receptor;response;tool;urologic

public_health_relevance:
PROJECT NARRATIVE Chronic Kidney Disease affects nearly 26 million people in the United States which places them athigher risk of renal failure and hemodialysis. We will develop an ELISA to aid in the diagnosis of early kidneydisease to aid physicians in earlier treatment and better assessment of chronic kidney disease.


application_id: 8000652
project_number: 7R01CA116812-03
project_title: Lung extracellular matrix and tumor progression
administering_ic: NCI
award_notice_date: 2010-04-01
opportunity_number: PA-07-070
application_type: 7
activity_code: R01
ic: CA
serial_number: 116812
program_official: JHAPPAN, CHAMELLI
project_start_date: 2008-07-02
project_end_date: 2013-05-31
study_section: Special Emphasis Panel[ZRG1-RES-B(02)M]
contact_pi_person_id: 1876531
contact_pi: ROMAN, JESSE
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This project will investigate the signaling mechanisms that control non-small cell lung carcinoma (NSCLC) cell growth and resistance to therapy and will explore the anti- cancer effects of novel strategies designed to modulate these signals. It addresses this area by focusing on the growth promoting signaling mechanisms triggered in NSCLC by aberrant extracellular matrices deposited in the lung. It is generally well-accepted that tumor cells interact with their surrounding matrix and that this and related host factors contribute to carcinoma development and progression. Unfortunately this idea has not translated into clinically useful strategies for the management of lung cancer. This project will test the hypothesis that host cell- and tumor cell-derived fibronectin a matrix molecule highly expressed in tobacco-related lung disease is an important factor that stimulates NSCLC cell growth and survival through signals related to the mTOR pathway that are elicited by activation of the integrin a51. This hypothesis is supported by our own work showing that exposure to tobacco-related products stimulates fibronectin expression in lung fibroblasts both in vitro and in vivo and that fibronectin stimulates the growth of NSCLC by triggering a51 integrin receptor-mediated signals that appear mediated via mTOR. Fibronectin also inhibits NSCLC apoptosis induced by chemotherapeutic agents. Interestingly the relative expression of fibronectin isoforms seems to play a role in tumor proliferation. Finally we have generated data in vivo showing that strategies able to affect fibronectin expression or recognition and mTOR signaling inhibit tumor progression. These data suggest that an "altered" lung matrix characterized by a relative increase in fibronectin content stimulates NSCLC proliferation. This hypothesis will be tested in specific aims designed to: 1) determine the role of Akt/mTOR/S6K1 related pathways in fibronectin-induced proliferation/survival and chemotherapy-induced apoptosis of NSCLC and 2) examine the role of fibronectin 1521 and the Akt/TOR/S6K1 pathway in NSCLC using the K-ras and Lewis Lung Carcinoma models of lung cancer. Project Narrative: This project will investigate how alterations in the connective tissue matrix of the lung promotes lung cancer progression and how agents that affect the lung matrix may inhibit this process.

project_terms:
Address;Affect;Apoptosis;Area;Carcinoma;Cell Cycle Progression;Cell Proliferation;Cells;Cessation of life;Chronic lung disease;Connective Tissue;Data;Deposition;Development;Environment;Event;Exposure to;Extracellular Matrix;Fibroblasts;Fibronectins;Glycoproteins;Growth;Human;In Vitro;Integration Host Factors;Integrins;Knowledge;Lewis Lung Carcinoma;Lung;Lung diseases;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Modeling;Molecular Biology;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Oncogenic;Pathway interactions;Play;Process;Protein Isoforms;Relative (related person);Resistance;Role;Signal Transduction;Sirolimus;Survival Rate;Testing;Tobacco;Translating;Tumor-Derived;United States;Woman;Work;cell growth;chemotherapeutic agent;chemotherapy;design;in vivo;lung Carcinoma;lung carcinogenesis;mTOR protein;men;neoplastic cell;novel strategies;receptor;receptor-mediated signaling;therapy resistant;tumor;tumor progression


application_id: 7999941
project_number: 1R43GM090342-01A1
project_title: Novel methods for improving virion production in baculovirus
administering_ic: NIGMS
award_notice_date: 2010-08-23
opportunity_number: PA-09-080
application_type: 1
activity_code: R43
ic: GM
serial_number: 090342
suffix: A1
program_official: EDMONDS, CHARLES G
project_start_date: 2010-09-01
project_end_date: 2012-02-28
study_section: Special Emphasis Panel[ZRG1 IMST-D (13)]
contact_pi_person_id: 9710810
contact_pi: FATH-GOODIN, ANGELIKA
other_pis: WEBB, BRUCE A
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
project_abstract:
DESCRIPTION (provided by applicant): Baculovirus expression vectors have been successfully used to produce thousands of proteins for vaccines therapeutics and structure-function studies. Baculoviruses have also been adapted for use as mammalian expression systems and potential gene therapy agents. This proposal explores a novel strategy for purification quantitation and storage of high titer baculovirus stocks that are needed for mammalian transduction.  Baculovirus infection of tissue culture cells is mediated by a form of virus that buds from cells. These viruses are highly infectious due to the presence of fusion proteins in their envelopes. Most of the replicative potential of the cell however is directed toward packaging of occlusion-derived viruses (ODV) which lack fusion peptides and have low infectivity in cell culture. The recent discovery of a peptide sequence that directs proteins to the envelope of ODV suggests that it should be possible to increase infectivity of these viruses. This would offer a number of advantages because ODV are not only more numerous they are simpler to purify concentrate and titer. ODV are also highly stable and do not lose titer over time unlike budded virus.  To test this idea recombinant viruses will be produced with the baculovirus GP64 or VSV-G fusion protein linked to a sorting motif that targets heterologous proteins to ODV membranes. These recombinants will be screened for correct targeting of the fusion proteins and their infectivity relative to non-recombinant virus determined in vertebrate and invertebrate tissue culture systems. Experiments will also be conducted to discern whether Vankyrin-enhanced (VE) technology currently marketed by ParaTechs as a method to increase baculovirus-mediated gene expression would further boost yields of ODV and their infectivity. If successful Phase II experiments would focus on producing an engineered viral backbone containing appropriate mammalian promoters and offering simple strategies for producing viral recombinants. Phase II would also expand the range of mammalian cells and explore animal models for gene therapy applications.  This strategy of producing ODV that is highly infectious in tissue culture will add value to baculoviruses as mammalian expression vectors and gene therapy agents. The potential advantages offered with respect to simple concentration of viral stocks rapid determination of titer and long term storage without loss of infectivity represents a significant commercial opportunity and fully warrants undertaking this research.  
  
PUBLIC HEALTH RELEVANCE: Baculoviruses have been successfully adapted for use as mammalian expression systems; these BacMam vectors have allowed functional analyses of proteins not previously possible using other approaches. Whole viral genomes can also be delivered by baculovirus transduction thus enabling the development of anti-viral drugs and examination of the mechanisms of drug resistance for significant human disease agents. This proposal seeks to develop new strategies for the production purification quantitation and storage of infectious baculovirus which will add value to these expression systems.

project_terms:
Accounting;Animal Model;Baculoviruses;Cell Culture Techniques;Cells;Chimeric Proteins;Cytolysis;Data;Development;Drug resistance;Engineering;Environment;Gene Expression;Gene Therapy Agent;Genes;Goals;Health;Horizontal Disease Transmission;Human Resources;Infection;Insecta;Invertebrates;Laboratories;Link;Literature;Mammalian Cell;Marketing;Mediating;Membrane;Membrane Fusion;Methods;Mutation;Nature;Nuclear Inner Membrane;Nucleocapsid;Peptides;Pharmaceutical Preparations;Phase;Phenotype;Production;Promotor (Genetics);Proteins;Protocols documentation;Recombinant Proteins;Recombinants;Relative (related person);Research;Sorting - Cell Movement;Structure;System;Technology;Testing;Time;Vertebral column;Viral;Viral Genome;Virion;Virus;cell transformation;experience;expression vector;gene therapy;human disease;improved;novel;novel strategies;protein aminoacid sequence;public health relevance;recombinant virus;research study;systems research;therapeutic vaccine;tissue culture;tissue/cell culture;vector;virus envelope

public_health_relevance:
Baculoviruses have been successfully adapted for use as mammalian expression systems;these BacMam vectors have allowed functional analyses of proteins not previously possibleusing other approaches. Whole viral genomes can also be delivered by baculovirustransduction thus enabling the development of anti-viral drugs and examination of themechanisms of drug resistance for significant human disease agents. This proposal seeks todevelop new strategies for the production purification quantitation and storage of infectiousbaculovirus which will add value to these expression systems.


application_id: 7999255
project_number: 5R01DK080901-03
project_title: Glucocorticoids and endocannabinoids in vagal complex
administering_ic: NIDDK
award_notice_date: 2010-11-15
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 080901
program_official: MALOZOWSKI, SAUL N
project_start_date: 2009-02-15
project_end_date: 2013-11-30
study_section: Neuroendocrinology, Neuroimmunology, and Behavior Study Section[NNB]
contact_pi_person_id: 1911523
contact_pi: SMITH, BRET N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The experiments in this research grant proposal will identify the cellular and synaptic effects of endogenous cannabinoid (eCB) ligands and of glucocorticoid-induced release of eCBs in the dorsal motor nucleus of the vagus (DMV). Neurons in the DMV regulate parasympathetic output to most of the subdiaphragmatic viscera and therefore critically control feeding digestion glucose and insulin secretion and other metabolic functions. Their activity is largely controlled by synaptic input to the DMV which is modulated by locally released chemicals and circulating hormones. Regulation of DMV neurons by cannabinoids vanilloids and glucocorticoids has been suggested; when applied centrally these compounds profoundly alter parasympathetic function. Several eCB ligands which are thought to be released from cell membranes in a retrograde fashion activate both cannabinoid type 1 receptors (CB1R) and transient receptor potential vanilloid type 1 (TRPV1). In the DMV activation of TRPV1 enhances neurotransmitter release whereas CB1R tends to inhibit synapses. Both effects occur by activation of receptors on presynaptic terminals. Preliminary evidence suggests that eCB ligands are released from DMV neurons and that glucocorticoids or depolarization can induce this release. Thus eCB activity in the DMV may modulate both TRPV1 and CB1R activity. Neither the type(s) of eCB ligands released the effects of most eCB ligands on synaptic activity nor the trigger or mechanism of eCB release in the DMV are known. We will use whole-cell patch-clamp recordings from DMV neurons in brainstem slices to identify effects of eCB ligands on cellular activity in the DMV and will also identify the compounds released by cells in the area using pharmacological and biochemical methods. The experiments will be guided by three specific aims: 1) Differentiate effects of eCB ligands on CB1R and TRPV1 in the DMV; 2) Determine the eCB involvement in mediating rapid effects of glucocorticoids on local circuitry in the DMV; and 3) Identify the cellular pathway of the glucocorticoid effect. We will test the hypotheses that eCBs alter TRPV1 and CBR1 activity in the DMV in specific and predictable spatial temporal functionally relevant and activity-dependent patterns and that glucocorticoids induce eCB release from DMV cells by acting at membrane-bound G protein-coupled receptors on DMV neurons. Drugs based on the eCB system are being investigated for therapeutic use in a variety of nervous system pathologies including disorders related to feeding digestion and obesity. Glucocorticoids which release eCBs in some systems are widely prescribed and are also released by stressful stimuli. Results of these studies will be critical to predicting and understanding how these compounds interact with each other and affect parasympathetic function. Possible translational benefits also exist because of the benefit in controlling eCB levels in the vagal system of patients with elevated glucocorticoids. PUBLIC HEALTH RELEVANCE Endogenous cannabinoid compounds have particularly complex actions in the area of the brainstem most responsible for maintaining functions of organ systems and a number of drugs therapies based on altering these compounds in the brain are being developed without knowledge about their effects in this critical brain area. The experiments in this research grant proposal will identify the characteristics of these drugs how they are released by glucocorticoid hormones and what actions they have on the neurons. Results of these studies will be critical for predicting and understanding how these compounds interact to affect digestive functions and they will also be applicable to multiple other neuronal systems.

project_terms:
Accounting;Affect;Agonist;Anxiety;Applications Grants;Area;Binding (Molecular Function);Biochemical;Blood;Brain;Brain Stem;Calcium;Cannabinoids;Cell membrane;Cells;Characteristics;Complex;Data;Dependence;Digestion;Disease;Endocannabinoids;Enzymes;Ethanolamines;G-Protein-Coupled Receptors;Glucocorticoids;Glucose;Glutamates;Health;Hormones;Hypertension;Hypothalamic structure;Knowledge;Ligand Binding;Ligands;Lipase;Mediating;Membrane;Metabolic;Methods;Moods;Movement;Multiple Sclerosis;Nervous system structure;Neurons;Obesity;Output;Pathology;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Phosphotransferases;Presynaptic Terminals;Rattus;Receptor Activation;Reflex action;Regulation;Research Project Grants;Slice;Stimulus;Synapses;System;Testing;Therapeutic Uses;Time;Transgenic Mice;Vanilloid;Viscera;Visceral;anandamide;base;body system;chemical release;dorsal motor nucleus;endogenous cannabinoid system;feeding;gamma-Aminobutyric Acid;insulin secretion;neurotransmission;neurotransmitter release;painful neuropathy;patch clamp;postsynaptic;receptor;research study;response

public_health_relevance:
Endogenous cannabinoid compounds have particularly complex actions in the area of the brainstem mostresponsible for maintaining functions of organ systems and a number of drugs therapies based on alteringthese compounds in the brain are being developed without knowledge about their effects in this criticalbrain area. The experiments in this research grant proposal will identify the characteristics of these drugshow they are released by glucocorticoid hormones and what actions they have on the neurons. Results ofthese studies will be critical for predicting and understanding how these compounds interact to affectdigestive functions and they will also be applicable to multiple other neuronal systems.


application_id: 7998803
project_number: 1F31DA028018-01A1
project_title: A Translational Model of Mood-Based Drug Abuse
administering_ic: NIDA
award_notice_date: 2010-09-09
opportunity_number: PA-09-208
application_type: 1
activity_code: F31
ic: DA
serial_number: 028018
suffix: A1
program_official: GRANT, STEVEN J
project_start_date: 2010-09-09
project_end_date: 2010-11-15
study_section: Special Emphasis Panel[ZRG1 F02A-J (20)]
contact_pi_person_id: 9706320
contact_pi: GIPSON-REICHARDT, CASSANDRA D
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
project_abstract:
DESCRIPTION (provided by applicant): Urgency or mood-based rash action is one of four facets of impulsivity defined in human clinical literature (Whiteside & Lynam 2001; Cyders Smith Spillane Fischer Annus & Peterson 2007). An animal model of urgency may allow further understanding of the role of specific brain systems in mood-based rash action. By manipulating reward expectancy behavioral outcomes (such as a reinforcement omission effect or ROE) can be measured in laboratory rats (Gipson Zentall & Bardo in preparation). Gipson et al. sought to develop an operant animal analogue of urgency using an operant task in rats. Animals received an initial Pavlovian component in which a conditioned stimulus (a key light) was paired with the delivery of one sucrose pellet. A terminal operant component followed in which animals were able to repeatedly complete a fixed-ratio (FR)-10 schedule of reinforcement for one sucrose pellet. Infrequently no sucrose pellet was delivered in the Pavlovian component (omission trials). Response rates were measured on both trial types - rates were increased during omission trials (an ROE effect). This procedure allowed individual differences in level of urgency to be quantified. The first proposed study is designed to examine the effects of omission of expected non-drug reward (sucrose pellets) on d-amphetamine self-administration in rats. The second proposed set of studies is designed to examine the cross-species generality of the ROE by examining individual differences in urgency using an analog performance task in humans and to determine if these individual differences reflect urgency scores on the UPPS personality scale. Using a variation of the nonhuman animal procedure described above individuals will be tested for response rates following unexpected omission of reward. Monetary reward will be used in both human studies as the non-contingent expected reward in the initial component. Subjects will be allowed to click a computer mouse on a FR-100 schedule in a terminal component and will receive money (study 2a) or points that can be exchanged for capsules of d-amphetamine (study 2b). To better understand how to reduce risk for mood-based rash action in humans it is important to quantify individual differences in urgency. While there is little information on the neural systems involved in human urgency a valid animal model of rash action would provide a foundation upon which these systems can be better studied. If the neurobehavioral causes of urgency are better understood risk can be reduced in a more effective way and impulsivity in predisposed individuals may be reduced if drugs can be developed to specifically target these brain areas implicated in urgency.  
  
PUBLIC HEALTH RELEVANCE: Impulsivity is known to be a risk factor for various negative health-related behaviors including drug abuse. This project will assess a behavioral model of impulsivity in both rat and human subjects to determine its usefulness in relation to personality questionnaires that are typically used to assess impulsivity in humans. This work will advance our basic knowledge about the neural mechanisms of impulsive behavior and drug abuse.

project_terms:
Animal Model;Animals;Area;Behavior;Behavioral;Behavioral Model;Brain;Clinical;Computers;Conditioned Stimulus;Dextroamphetamine;Drug abuse;Exanthema;Expectancy;Foundations;Human;Impulsive Behavior;Impulsivity;Individual;Individual Differences;Knowledge;Laboratory Rat;Light;Literature;Measures;Modeling;Moods;Mus;Outcome;Personality;Pharmaceutical Preparations;Preparation;Procedures;Psychological reinforcement;Questionnaires;Rattus;Reinforcement Schedule;Rewards;Risk;Risk Factors;Role;Schedule;Self Administration;Sucrose;System;Task Performances;Testing;Variant;Work;analog;base;capsule (pharmacologic);design;drug reward;human subject;neurobehavioral;neuromechanism;non-drug;public health relevance;relating to nervous system;response

public_health_relevance:
Impulsivity is known to be a risk factor for various negative health-related behaviors including drug abuse.This project will assess a behavioral model of impulsivity in both rat and human subjects to determine itsusefulness in relation to personality questionnaires that are typically used to assess impulsivity in humans.This work will advance our basic knowledge about the neural mechanisms of impulsive behavior and drugabuse.


application_id: 7998178
project_number: 5R01CA124630-05
project_title: PTTG Role in Ovarian Tumorigenesis and Matastasis
administering_ic: NCI
award_notice_date: 2010-12-09
application_type: 5
activity_code: R01
ic: CA
serial_number: 124630
program_official: SATHYAMOORTHY, NEERAJA
project_start_date: 2007-03-26
project_end_date: 2012-12-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1858952
contact_pi: KAKAR, SHAM S.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-01-01
project_abstract:
Ovarian cancer is the fifth most commonly diagnosed cancer among women and the most frequent cause ofdeath from gynecologic malignancies in the United States. Molecular mechanisms that initiate and supportovarian tumorigenesis are not well defined. We cloned a novel oncogene "PTTG" also known as securin fromhuman testis and ovarian tumors and studied its function in tumorigenesis. PTTG is a multifunctional proteinand is highly expressed in many tumors including tumors of ovary. Introduction of PTTG into NIH3T3 andHEK293 cells induces cellular transformation and promotes tumor formation in nude mice suggesting itsstrong oncogenic function. Notably PTTG has been shown to inhibit separation of sister chromatids and toincrease the synthesis and secretion of bFGF VEGF and IL-8 as well as activate the expression of theoncogene c-myc and PI3K/AKT signaling pathway suggesting that the oncogenic activity of PTTG mayinvolve induction of aneuploidy and chromosomal instability increased angiogenesis and production ofgrowth promoting oncogene products. Down-regulation of PTTG expression in ovarian tumor cells in vitroand its deletion in animals (Knockout) results in reduction of tumor development suggesting its importantrole in maintenance of cancer phenotype. The long-term objectives of this application are to understand therole of PTTG in ovarian tumorigenesis and validate PTTG as a molecular target for the development of anti-neoplastic agents. In this application we propose: i) to determine the effect of overexpression of PTTG inovarian epithelial cells on cellular transformation and tumor development in nude mice; ii) to determine theeffect of overexpression of PTTG in ovarian surface epithelial cells on ovarian tumor initiation progressionand metastasis in transgenic animals and determine mechanisms that support tumor growth and metastasis;and iii)to determine the effect of down-regulation of PTTG expression in ovarian tumor cells on tumorsuppression and metastasis and determine mechanisms that lead to suppression of tumor growth andmetastasis. These studies will provide critical information regarding the mechanisms of PTTG in ovariantumorigenesis and metastasis and set up basis for the development of small molecules to inhibit PTTGfunction as anti-neoplastic agents. In addition transgenic animal model developed from our studies couldenhance efforts aimed at developing new methods for detection prevention and treatment of ovarian cancer.

project_terms:
5q35.1;Address;Adenoviruses;Aneuploidy;Animal Model;Antineoplastic Agents;Base Sequence;Boxing;Cancer Model;Cause of Death;Cell Proliferation;Cell Survival;Cells;Cessation of life;Chromosomal Instability;Chromosome abnormality;Chromosomes;Complementary DNA;Crossbreeding;Cytoplasm;Data;Detection;Developed Countries;Development;Down-Regulation;Endometrium;Enzyme-Linked Immunosorbent Assay;Epithelial Cells;Epithelium;Fetal Kidney;Fetal Liver;Fibroblast Growth Factor 2;Gene Expression;Genes;Genetic;Genetically Engineered Mouse;Genomic Instability;Growth;Gynecologic;Health;Human;IL8 gene;In Vitro;Laboratories;Lead;Maintenance;Malignant Neoplasms;Malignant neoplasm of ovary;Mediating;Messenger RNA;Methods;Modeling;Molecular;Molecular Cloning;Molecular Target;Mortality Vital Statistics;Mus;Mutation;Neoplasm Metastasis;Nuclear;Nuclear Proteins;Nude Mice;Oncogene Proteins;Oncogenes;Oncogenic;Ovarian;Ovarian Surface Epithelial-Stromal Tumor;Ovary;PI3K/AKT;PTTG1 gene;Phenotype;Preclinical Testing;Prevention;Process;Production;Proline-Rich Domain;Promotor (Genetics);Protein Sequence Analysis;Proteins;Reporting;Research Personnel;Role;Signal Pathway;Sister Chromatid;Sister Chromatid Exchange;Small Interfering RNA;Staging;Structure;Surface;System;Testicular Neoplasms;Testis;Time;Transgenic Animals;Transgenic Mice;Tumor Suppression;United States;Vascular Endothelial Growth Factors;Woman;angiogenesis;base;c-myc Genes;cancer diagnosis;cell type;expression vector;gene function;human PTTG1 protein;human tissue;in vivo;indexing;knockout animal;loss of function;malignant breast neoplasm;metaplastic cell transformation;neoplastic;neoplastic cell;novel;ovarian neoplasm;overexpression;pituitary tumor-transforming proteins;programs;small molecule;therapy development;tumor;tumor growth;tumor initiation;tumorigenesis;tumorigenic


application_id: 7997154
project_number: 2R42AG030239-02A2
project_title: Commercialization of a Diagnostic Test for Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2010-08-26
opportunity_number: PA-09-081
application_type: 2
activity_code: R42
ic: AG
serial_number: 030239
suffix: A2
program_official: HSIAO, JOHN
project_start_date: 2007-06-15
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZRG1 ETTN-C (11)]
contact_pi_person_id: 2276639
contact_pi: LOVELL, MARK ANTHONY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 614763006
duns_number: 614763006
fips: US
organization_id: 10010025
organization_name: SCOUT DIAGNOSTICS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402431805
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-09-01
project_abstract:
DESCRIPTION (provided by applicant): The major barriers to preventing or treating Alzheimer's disease (AD) are its unknown pathogenesis/etiology and the lack of an objective sensitive and specific biomarker of the disease particularly at the early stages when therapeutic interventions would likely have the greatest efficacy. The basic hypothesis of this project is that levels of a unique high molecular weight protein/protein complex consisting of 1 molecule of lipocalin (brain-specific) prostaglandin-d-synthase (PDS) and 1 dimer of transthyretin (TTR) quantified in cerebrospinal fluid (CSF) using an enzyme linked immunoassay (ELISA) developed and characterized by Scout Diagnostics will serve as an effective biomarker to identify Alzheimer's disease (AD) subjects early in disease progression. To convert the basic science developed during Phase I funding to a commercially viable product we propose to: a). synthesize and purify authentic PDS/TTR complex using recombinant human proteins generated in our laboratory for use as a standard for ELISA calibration and quantification; b) evaluate product storage and shipping requirements and prepare a horseradish peroxidase labeled probe antibody to decrease analysis time and; c) prepare and field test an instruction manual for use in independent diagnostic laboratories. To more fully characterize the PDS/TTR ELISA we propose to analyze CSF specimens from an additional 150 AD and 150 control subjects from three geographically distinct Alzheimer's disease centers (ADCs) and to carry out inter-laboratory validation studies by providing those ADCs with ELISA kits instructions and representative CSF specimens for analysis of duplicate aliquots of the same samples in their laboratories. In addition we will further determine the specificity of the biomarker for AD patients by analyzing CSF from 50 subjects with non-AD neurologic disorders including frontotemporal dementia corticobasal degeneration and parasupranuclear palsy. Overall our preliminary data suggest that use of the PDS/TTR complex either in CSF or in serum may provide an objective biomarker with sufficient sensitivity/specificity for the identification of AD subjects.  
  
PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the fourth leading cause of death in the United States and currently affects 4.5 million Americans. Two major barriers to treating and eventually preventing AD are: 1) the lack of understanding about the process of neuron degeneration and loss and 2) the lack of a sensitive and specific biomarker of the disease. Preliminary and future studies described in this proposal show that a novel protein-protein complex present in cerebrospinal fluid can be quantified using an enzyme linked immunoassay (ELISA). This protein-protein complex is a sensitive and specific biomarker of AD including early stages of AD (mild cognitive impairment) when therapeutic interventions are most likely to have beneficial effects.

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

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


application_id: 7996597
project_number: 5R01HD060915-03
project_title: Latexin's role in parsing stem cells
administering_ic: NICHD
award_notice_date: 2010-11-05
opportunity_number: RFA-AG-08-003
application_type: 5
activity_code: R01
ic: HD
serial_number: 060915
program_official: WINER, KAREN
project_start_date: 2008-12-15
project_end_date: 2012-11-30
study_section: ZAG1-ZIJ-2(M2)
contact_pi_person_id: 7673209
contact_pi: VAN ZANT, GARY
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): Juvenile factors that have potential effects on aging are myriad but fall into two broad categories: conscious and unconscious. An example of the former is taking up smoking as a pre-teen or adopting other dangerous lifestyles when young that are known at least on a statistical basis to shorten lifespan. Of course not all conscious decisions have detrimental effects. Many decisions about diet for example could promote healthy aging and a longer lifespan. This application is concerned with the "unconscious" category of factors detectable at early developmental stages that influence either positively or negatively not only overall lifespan but the quality of life with accumulating years. We focus on the number and functional capabilities of adult stem cells and the factors that parse their limited numbers and functional properties over a lifetime. Our underlying hypothesis is that quantitative and qualitative alterations in stem cells influence lifespan and successful aging. We study hematopoietic stem cells as a paradigm adult stem cell population and have shown age-related changes in stem cell number and function in mice. Moreover we have sought genetic determinants of stem cell properties that have an effect during aging. This proposal narrowly focuses on a quantitative trait the number of stem cells at a young age also correlated with lifespan. By utilizing the tools afforded by modern mouse genetics we have identified a quantitative trait gene and its protein product latexin that is important in mammals in parsing stem cells. In this application we propose to investigate the pattern of latexin expression in hematopoietic stem cells during embryonic development and at multiple points during adulthood and correlate these data with quantitative and qualitative parameters of stem cells and organismal longevity. An important tool we will make use of in these studies is latexin knockout mice which we are currently generating. In constitutive knockout animals we will study the effects on stem cells and aging when latexin is absent throughout development and adulthood. In conditional knockout mice we will determine when during development and young adulthood the presence of latexin is critical. Moreover the conditional knockouts will enable us to study the tissues in which latexin's expression is important and when. Lastly we investigate the genetic and epigenetic regulation of latexin expression segmentally at different stages of organismal development and adulthood. Preliminary data demonstrate in specific mouse strains that latexin expression is differentially regulated by both polymorphisms in the promoter and differential methylation of CG dinucleotides comprising a CpG island in the latexin promoter. In aggregate these descriptive and mechanistic studies will provide definitive information on the basic premise that adult stem cells influence aging and in particular the role that latexin plays as a mechanistic factor in this pathway. The median age of the U.S population continues to increase and will accelerate in the upcoming few decades. Healthy aging is thus a national priority especially given the rapidly rising costs of health care. Yet many of the physiological events occurring during development and early in childhood that have serious repercussions on the quality of life later are poorly understood. We believe that the regulation of stem cells and particularly the parsing of these populations chronologically is an important and neglected aspect of this quest. The proposed studies based on firm preliminary results specifically focus on the role of a novel stem cell regulator latexin on the hematopoietic stem cell population in a mammalian species the mouse.

project_terms:
Accounting;Adolescent;Adopted;Adult;Age;Aging;Apoptosis;Bone Marrow;C57BL/6 Mouse;Categories;Cell Aging;Cell Count;Cell physiology;Cells;Childhood;Chronology;Conscious;CpG Islands;CpG dinucleotide;DNA Damage;Data;Development;Diet;Elderly;Embryo;Embryonic Development;Ensure;Epigenetic Process;Event;Genes;Genetic;Genetic Determinism;Genetic Polymorphism;Health Care Costs;Hematopoiesis;Hematopoietic;Hematopoietic System;Hematopoietic stem cells;Knock-out;Knockout Mice;Life;Life Style;Longevity;Mammals;Methylation;Modeling;Mouse Strains;Mus;Organ;PC3.1 antigen;Pathway interactions;Pattern;Physiological;Play;Population;Population Sizes;Promotor (Genetics);Property;Proteins;Quality of life;Reactive Oxygen Species;Regulation;Relative (related person);Role;Smoking;Specificity;Staging;Stem Cell Factor;Stem cells;Teenagers;Tissues;Transgenic Mice;Uncertainty;Unconscious State;adult stem cell;age effect;age related;base;cell age;emerging adult;falls;fetal;functional decline;healthy aging;knockout animal;neglect;novel;progenitor;stem cell population;tool;trait;young adult


application_id: 7995212
project_number: 5R01NS054708-04
project_title: Genetic approaches to functional remyelination after SCI
administering_ic: NINDS
award_notice_date: 2010-12-03
opportunity_number: PAS-05-092
application_type: 5
activity_code: R01
ic: NS
serial_number: 054708
program_official: KLEITMAN, NAOMI
project_start_date: 2008-01-01
project_end_date: 2012-12-31
study_section: Special Emphasis Panel[ZRG1-BDCN-J(05)M]
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Our recent work shows that glial restricted precursor cells (GRPs) grafted into a demyelinating or contusive spinal cord injury (SCI) partially restore electrophysiological conduction and hindlimb locomotor recovery. We will build on those data and determine the potential of human embryonic stem cells (hESC) to restore function after engraftment into the damaged spinal cord. Aim 1. Using the focal VLF? demyelinating lesion and grafting D15A-GRPs (A2B5???) we will determine whether inhibition of BMP and Notch signaling pathways demonstrated in vitro to inhibit oligodendrocyte differentiation can enhance the remyelination capacity of the engrafted cells. We will examine a number of genetic and molecular biological approaches to inhibiting BMP and Notch signaling. Aim 2. Determine whether delivery of CNTF or NRG1 types I or III neurotrophic factors known to potentiate oligodendrocyte proliferation and maturation in vitro and in vivo will enhance remyelination by engrafted GRPs. Aim 3. Using optimal parameters established in Aims 1 and 2 and the more clinically relevant contusion SCI we will ask whether remyelination can result in enhanced recovery of function. We hypothesize that both remyelination and enhanced white matter sparing are needed for optimal recovery and will distinguish between those effects in these animals.

project_terms:
Address;Adult;Animals;Axon;Behavioral;Biological;Brain-Derived Neurotrophic Factor;CSPG4 gene;Cells;Chest;Ciliary Neurotrophic Factor;Contusions;Data;Demyelinations;Dominant-Negative Mutation;Engraftment;Environment;Failure (biologic function);Functional disorder;GRP gene;Gene Deletion;Genetic;Heterozygote;Hindlimb;Impairment;In Vitro;Injury;Intervention;Lentivirus Vector;Lesion;Locomotor Recovery;Magnetism;Measures;Methods;Modeling;Modification;Molecular Genetics;Monitor;Motor Evoked Potentials;Mus;NRG1 gene;Natural regeneration;Neuregulins;Notch Signaling Pathway;Oligodendroglia;Play;Publications;Publishing;Rattus;Recovery;Recovery of Function;Research Personnel;Retroviridae;Role;Signal Pathway;Signal Transduction;Small Interfering RNA;Spinal Cord;Spinal cord damage;Spinal cord injury;Stem cells;Work;cell type;clinically relevant;combinatorial;functional restoration;human embryonic stem cell;in vivo;injury prevention;insight;mouse model;myelination;neurotrophic factor;nicastrin protein;notch protein;partial recovery;precursor cell;response;success;treatment strategy;vector;white matter


application_id: 7994778
project_number: 5R01EY012974-09
project_title: The role of costimulatory molecules in uveitis
administering_ic: NEI
award_notice_date: 2010-11-23
application_type: 5
activity_code: R01
ic: EY
serial_number: 012974
program_official: MCKIE, GEORGE ANN
project_start_date: 2001-08-01
project_end_date: 2012-11-30
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 6193432
contact_pi: SHAO, HUI
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-12-01
project_abstract:
The identification of costimulatory molecules has provided important insights into molecular mechanisms forthe regulation of the immune response andmore importantly into several novel approaches for autoimmuneor tumor immunotherapy. The growing number of known T cell costimulatory pathways together with thedynamic nature of the immune response suggests that there may be a functional hierarchy of costimulatorymolecules regulating responses of naive effector and memory T cells. With the support of the current grantmy laboratory has made significant progress in understanding the role of costimulatory molecules inautoimmune uveitis. However our studies have also raised two important questions: (1) why are effectoruveitogenic T cells more resistant than naive T cells to treatment by costimulatory molecule blockers? (2) Dopathogenic and regulatory T cells rely on different costimulation so that a specific treatment regimen can beidentified to maximally suppress the pathogenic response with a minimal inhibitory effect on regulatory T cellactivation?For human disease immunotherapies that can interfere with an ongoing autoimmune disease are moreimportant than those preventing the development of disease since disease has already started by the time thepatient visits the doctor. Thus the long-term goal of this proposal is to explore therapeutic approachesinhibiting already activated autoreactive effector T cells. We will therefore determine whether CD28/B7costimulatory molecules are crucial for the pathogenic effect of uveitogenic T cells specifically: (1) whethereffector and regulatory T cells use CD28/B7 differently in terms of time and quantity and whether blockade of acombination of costimulatory molecules favors the treatment of ongoing autoimmune disease; (2) whether wecan identify therapeutic regimens that have a limited impact on regulatory T cell activity while inhibitingpathogenic activity; and (3) whether a combined treatment acting on costimulation of autoreactive T cell andocular inflammation can provide better control of ongoing disease. To provide a working model that will allowbetter understanding of the pathogenesis of recurrent uveitis we have established chronic recurrent models inthe rat and mouse. These studies should provide insights into the pathogenic mechanism leading to diseaseprogression and help in the development of supplementary therapies for this devastating disease.

project_terms:
Acute;Animals;Anti-Inflammatory Agents;Antibodies;Autoimmune Diseases;Autoimmune Process;CD28 gene;CTLA4 gene;CTLA4-Ig;Cells;Chronic;Clinical Treatment;Combined Modality Therapy;Complex;Data;Development;Disease;Disease Progression;Disease model;Disease remission;Dose;Environmental Risk Factor;Eye;Generations;Genetic;Goals;Grant;Guanine Nucleotide Dissociation Inhibitors;Human;IL2RA gene;Immune response;Immunotherapy;Inflammation;Inflammatory;LTB4R gene;Laboratories;Leukotriene B4;Ligation;MHC antigen;Mediating;Modeling;Molecular;Mus;Nature;Onset of illness;Pathogenesis;Pathway interactions;Patients;Pattern;Phase;Rattus;Reaction;Recruitment Activity;Recurrence;Regimen;Regulation;Regulatory T-Lymphocyte;Relapse;Research Personnel;Resistance;Rodent;Role;Signal Transduction;Study models;T memory cell;T-Cell Activation;T-Lymphocyte;Therapeutic;Therapeutic Effect;Time;Treatment Protocols;Uveitis;Visit;Work;autoimmune uveitis;autoreactive T cell;cell motility;chemokine;cytokine;disorder control;human disease;insight;novel strategies;prevent;programs;protective effect;receptor;response;treatment effect;tumor


application_id: 7994032
project_number: 7K22CA123104-03
project_title: The role of EP4 in fibronectin-induced human lung cancer cell growth
administering_ic: NCI
award_notice_date: 2010-03-30
opportunity_number: PAR-06-455
application_type: 7
activity_code: K22
ic: CA
serial_number: 123104
program_official: JAKOWLEW, SONIA B
project_start_date: 2008-06-01
project_end_date: 2011-05-31
study_section: Transition to Independence Study Section (I)[NCI-I]
contact_pi_person_id: 10244449
contact_pi: HAN, SHOUWEI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  In the U.S. over 90% of lung cancers are detected in patients with tobacco-related and other chronic lung disorders. These disorders are characterized by alterations in the content and composition of the lung extracellular matrix. One matrix glycoprotein highly expressed in chronic lung disease is fibronectin (Fn) and we firmly believe that relative increases in the content of Fn in lung might promote lung carcinogenesis. Consistent with this idea we have reported that Fn stimulates non small cell lung carcinoma (NSCLC) proliferation and reduces apoptosis suggesting that Fn may serve to promote tumor growth and survival. Further work revealed that these effects were related to increased expression of the pro-oncogene COX-2 and secretion of PGE2 a mitogen for lung carcinoma cells. More recently we found that the stimulatory effect of Fn could be enhanced by its ability to induce the expression of EP4 a PGE2 receptor that mediates its mitogenic effects. Based on our preliminary data we hypothesize that in addition to inducing COX-2 expression and PGE2 biosynthesis Fn binding to its integrin (5(1 receptor leads to activation of PI3-K/Akt/GSK-3 kinase signaling and induction of the transcription factor AP-2 which in turn leads to increased EP4 receptor expression thereby enhancing the mitogenic effect of PGE2 in tumor cells in vitro and in vivo. This hypothesis will be tested in the following specific aims.  Aim 1:  Explore the role of EP4 in Fn-induced lung carcinoma cell proliferation and determine the cellular and molecular mechanism(s) by which Fn upregulates EP4 expression.  Aim 2:  Determine the role of Fn/(5(1 and EP4 receptors in experimental models of lung carcinogenesis using established model of lung carcinogenesis related to k-ras mutation and Lewis Lung Carcinoma (LLC) mouse models.   
  
This research program will be accompanied by comprehensive didactic sessions and strengthened by mentor/ collaborators and consultants that will enhance the investigator's skills and promote an independent career in academia.

project_terms:
1-Phosphatidylinositol 3-Kinase;Academia;Affect;Anabolism;Apoptosis;Area;Binding (Molecular Function);Cancer Cell Growth;Carcinoma;Cell Proliferation;Cells;Cessation of life;Chronic;Chronic lung disease;Clinical;Cyclin D1;Cyclins;Data;Deposition;Dinoprostone;Disease;Down-Regulation;EP4 receptor;Event;Experimental Models;Extracellular Matrix;Fibronectins;Genes;Genetic Transcription;Glycoproteins;Growth;Human;In Vitro;Incidence;Integrins;Knowledge;Lead;Lewis Lung Carcinoma;Link;Lung;Lung diseases;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Mentors;Mitogens;Modeling;Molecular;Molecular Biology;Mus;Mutation;Non-Small-Cell Lung Carcinoma;Oncogenes;Oncogenic;Outcome;PTGS2 gene;Paper;Patients;Phosphorylation;Phosphotransferases;Process;Production;Prostaglandin E Receptor;Publishing;Regulation;Relative (related person);Reporting;Research;Research Personnel;Role;Signal Induction;Signal Pathway;Signal Transduction;Survival Rate;TFAP2A gene;Testing;Tobacco;Tumor Suppressor Genes;United States;Up-Regulation (Physiology);Woman;Work;base;career;cell growth;cell transformation;chemotherapeutic agent;enhancer-binding protein AP-2;human WFDC2 protein;in vivo;lung Carcinoma;lung carcinogenesis;men;mouse model;neoplastic cell;programs;protein expression;receptor;receptor expression;skills;tumor growth


application_id: 7993593
project_number: 5R01HL074351-07
project_title: Hypercholesterolemia in Cardiac Function Survival and Repair
administering_ic: NHLBI
award_notice_date: 2010-11-15
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 074351
program_official: SCHWARTZ, LISA
project_start_date: 2003-07-01
project_end_date: 2012-11-30
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 7372371
contact_pi: TANG, XIAN-LIANG
other_pis: ROKOSH, GREGG
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): Mounting mechanistic and translational studies support the use of cell-based therapies to repair myocardial tissue destroyed by infarction and to restore cardiac function. Several phenotypically distinct subsets of adult primitive cell populations have been shown to improve cardiac structure and function in animal models of myocardial infarction (MI) and heart failure. Small clinical trials of stem cell therapy have recapitulated these beneficial effects in patients with ischemic cardiomyopathy. Recent discovery of cardiac stem cells (CSCs) has sparked intense hope for the development of promising stem cell therapies for cardiac repair/regeneration because CSCs are inherently programmed to reconstitute cardiac tissue. In recent studies we found that intracoronary delivery of CSCs to rats with either acute or chronic MI and to pigs with chronic MI ameliorated cardiac function and regenerated new cardiac cells. However human patients needing cardiac reparative therapies generally possess an array of cardiovascular risk factors such as hypercholesterolemia (HC) diabetes hypertension etc. With the recent surge of interest in cell therapies for patients it is important to understand the impact of these risk factors on cell-mediated cardiac repair. In particular HC is a highly prevalent risk factor and contributes to a range of pathophysiological consequences. Hence the overall goal of this proposal is to investigate the impact of HC on CSC-mediated cardiac repair. Our fundamental hypothesis is that depending on the specific conditions cholesterol can be beneficial or detrimental in CSC-mediated cardiac repair. We propose that mild elevations of plasma cholesterol or the presence of the minimally oxidatively modified form of LDL-cholesterol precondition both the myocardium and the CSCs; the resulting combination of a primed myocardial microenvironment for cell engraftment and enhanced paracrine signaling mechanisms of preconditioned CSCs work in concert to enhance CSC-mediated cardiac repair. We further propose that marked elevations of plasma cholesterol or the presence of the completely oxidized form of LDL- cholesterol provoke oxidative injury to both the CSCs and the myocardium leading to loss of efficacy of cell therapies for cardiac repair. We will test these hypotheses under 3 specific aims using both in vitro cultured CSCs and cardiomyocytes in the presence of differently modified LDLs and in vivo rat models of MI with different levels of plasma cholesterol. Aim 1 will determine the effects of HC on CSC-mediated cardiac repair in vivo; Aim 2 will determine the effects of LDLs on CSC function and reparative capability in vitro; and Aim 3 will determine whether pretreatment of CSCs with differently modified LDLs in vitro alters the efficacy of cardiac reparative therapy in vivo. Given that plasma cholesterol is a modifiable risk factor but is also essential for cellular function understanding the effects of this prevalent risk factor on stem cell-based therapies will have translational and mechanistic importance. This project will provide novel insights into a much-needed preclinical framework to develop cell-based therapies for cardiac repair in patients with cardiovascular risk factors.

project_terms:
Acute;Address;Adult;Affect;Animal Model;Animals;Arterial Fatty Streak;Atherosclerosis;Biochemical;Blood Vessels;Cardiac;Cardiac Myocytes;Cardiomyopathies;Cardiovascular Diseases;Cardiovascular Physiology;Catheterization;Caveolae;Cell Communication;Cell Therapy;Cell physiology;Cells;Cholesterol;Chronic;Clinic;Clinical;Clinical Trials;Complex;Confocal Microscopy;Coronary Occlusions;Data;Development;Diabetes Mellitus;Diet;Dose;EFRAC;Echocardiography;Endoplasmic Reticulum;Engraftment;Evaluation;Experimental Models;Family suidae;Funding;Goals;Health;Heart;Heart failure;Homing;Human;Hypertension;Immunohistochemistry;In Vitro;Infarction;Injury;Integrins;Ischemic Preconditioning;LDL Cholesterol Lipoproteins;Low Density Lipoprotein oxidation;Low-Density Lipoproteins;Matrix Metalloproteinases;Measures;Mediating;Membrane Microdomains;Modeling;Molecular Biology;Morphology;Motion;Muscle Cells;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardial perfusion;Myocardial tissue;Myocardium;Natural regeneration;Outcome;Paracrine Communication;Pathology;Patients;Performance;Physiology;Plasma;Population;Preparation;Process;Proteins;Rattus;Reperfusion Therapy;Research;Risk;Risk Factors;Role;Signal Transduction;Specimen;Stem cells;Stromal Cell-Derived Factor 1;Structure;Testing;Tissue Extracts;Tissues;Transplanted tissue;Work;base;biological adaptation to stress;biological systems;cardiovascular risk factor;cell type;endoplasmic reticulum stress;extracellular;feeding;hemodynamics;hypercholesterolemia;improved;in vitro testing;in vivo;insight;interdisciplinary approach;interest;light microscopy;low density lipoprotein inhibitor;migration;modifiable risk;novel;oxidation;pre-clinical;preconditioning;pressure;primitive cell;programs;reconstitution;repaired;research study;response;stem;stem cell therapy;translational study

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Increasing evidence has demonstrated that adult stem/progenitor cells can repair myocardium with functional benefits in animal models of myocardial infarction and heart failure. Small clinical trials of stem cell therapy in human patients with myocardial infarction and ischemic cardiomyopathy have recapitulated these beneficial effects. Recent discovery that heart itself contains cardiac stem cells (CSCs) has sparked intense hope for the development of most promising stem cell therapies for cardiac repair because CSCs are inherently programmed to reconstitute cardiac tissue. However in the clinical arena patients who need cardiac reparative therapies are mostly associated with cardiovascular risk factors such hypercholesterolemia diabetes hypertension etc. With the recent surge of interest in cell therapies for patients it is important to understand the impacts of these risk factors on stem cell-mediated cardiac repair. Hypercholesterolemia is a most prevalent risk factor and imposes various pathophysiological impacts in the biological system. In this application we will conduct experiements to investigate the impacts of hypercholesterolemia on CSC-mediated cardiac repaie. We will use both normocholesterolemic and hypercholesterolemic rat models of myocardial infarction. Rats with myocardial infarction will receive CSC therapy. The efficacy of CSC therapy for cardiac repair will be assessed using comprehensive evaluation of myocardial performance including echocardiography and hemodynamic pressure-volume catheterization and tissue structure repair including morphology immunohistochemistry light and confocal microscopy. Regardless our results are "positive" or "negative" this project will provide novel insights into preclinical framework to develop effective cell-based therapies for cardiac repair in patients with cardiovascular risk factors. Given that plasma cholesterol is a modifiable risk factor and essential for cellular function understanding the effects of this prevalent risk factor on stem cell- based cardiac repair will have translational and mechanistic importance.


application_id: 7993448
project_number: 1R01CA153132-01
project_title: Oncopigs as a better model for human cancer
administering_ic: NCI
award_notice_date: 2010-08-05
opportunity_number: RFA-GM-10-009
application_type: 1
activity_code: R01
ic: CA
serial_number: 153132
program_official: MIETZ, JUDY
project_start_date: 2010-08-05
project_end_date: 2014-05-31
study_section: Special Emphasis Panel[ZCA1 SRLB-R (M1)]
contact_pi_person_id: 8801334
contact_pi: CLARK, GEOFFREY J.
other_pis: RUND, LAURETTA ;SCHOOK, LAWRENCE B.
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This project is driven by the hypothesis that current in vivo models for evaluating cancer therapies are too non-predictive of the human condition for efficient use. This may become a major impediment to the translation of new potential drugs into effective therapies for patients. The project proposes to determine if transgenic pigs may serve as a novel and more human-like model for cancer. Although pigs have been used extensively in biomedical research to date there is no reported transgenic swine model for cancer. Like humans pigs can live for decades and have a very low rate of spontaneous cancer. This is in contrast to common rodent-based cancer models where life span is limited to a few years and the spontaneous development of cancer is quite high. We now know that 5-6 to six genetic defects are required to convert a normal pig cell into a tumor cell. This is the same as in humans. However mouse cells can be transformed into tumor cells by as little as two genetic lesions. These simple yet profound genetic observations point to pigs as a far superior model system for the human condition.  We propose to use state of the art technology to generate transgenic pigs that can be induced to lose the expression of three major tumor suppressors simultaneously in the breast. These alterations will be coupled with an up-regulation of a growth hormone receptor. These genetic defects are often found in breast cancer and particularly in Triple Negative (TN) breast cancer. TN breast cancer is an especially aggressive and difficult to treat form of breast cancer with a high morbidity rate. We will include a far red fluorescent protein in the system which will allow non-invasive imaging of the status of the induced breast cells.  The project will involve the collaboration of laboratories with extensive experience in the molecular and cellular biology of human breast cancer and laboratories with world renown in the production and husbandry of transgenic pigs.  Animals will be tested to determine if these lesions are sufficient to provoke breast cancer and whether any such cancers have the characteristics of TN breast cancer. We will also use the population to test the effectiveness of cancer chemopreventative agents and whether the pigs respond to front line therapy for TN breast cancer in a similar manner to humans.  
  
PUBLIC HEALTH RELEVANCE: This project will establish a novel model system for evaluating new therapeutic approaches to cancer. The system should be much more predictive for the human condition thus enhancing the ability to identify and characterize effective novel therapeutics. It may also establish a unique model for the study of cancer preventative strategies that cannot be realistically modeled at present. The model is targeted towards breast cancer as over 40 thousand women are expected to die in the United states each year from this disease due to lack of sufficiently effective therapies.

project_terms:
African American;Animal Model;Animals;Arteriosclerosis;Arts;BRCA1 gene;Biological Assay;Biological Factors;Biological Models;Biomedical Research;Breast;Cancer Model;Cells;Characteristics;Clinical Trials;Collaborations;Controlled Study;Coupled;Development;Diabetes Mellitus;Disease;Disease model;Effectiveness;Epidermal Growth Factor Receptor;Failure (biologic function);Family suidae;Genetic;Growth Hormone Receptor;Hand;Human;Image;Laboratories;Lesion;Life;Lipids;Lipoproteins;Longevity;Malignant Neoplasms;Metabolism;Metastatic malignant neoplasm to brain;MicroRNAs;Modeling;Molecular;Molecular and Cellular Biology;Monitor;Morbidity - disease rate;Mus;Mutation;Neoplasm Metastasis;Patients;Pharmaceutical Preparations;Pilot Projects;Population;Production;Proteins;Reporting;Rodent;Series;Staging;Study models;System;TP53 gene;Technology;Testing;Therapeutic;Time;Tissues;Transgenic Organisms;Translations;Tumor Suppressor Proteins;United States;Up-Regulation (Physiology);Variant;Woman;Work;arterial lesion;base;cancer genetics;cancer prevention;cancer therapy;design;effective therapy;experience;expression vector;genome sequencing;human disease;in vivo;in vivo Model;inhibitor/antagonist;interest;loss of function;malignant breast neoplasm;model development;mouse model;neoplastic cell;novel;novel therapeutic intervention;novel therapeutics;predictive modeling;public health relevance;red fluorescent protein;research study;success;triple-negative invasive breast carcinoma;tumor;tumorigenesis;tumorigenic;vector

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


application_id: 7993335
project_number: 1R01CA149274-01A1
project_title: Diffuse Optical Monitoring of Head and Neck Tumor Therapy
administering_ic: NCI
award_notice_date: 2010-05-27
opportunity_number: PA-07-279
application_type: 1
activity_code: R01
ic: CA
serial_number: 149274
suffix: A1
program_official: BAKER, HOUSTON
project_start_date: 2010-07-01
project_end_date: 2015-04-30
study_section: Biomedical Imaging Technology Study Section[BMIT]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Treatment with radiation or chemo-radiotherapy is the standard therapy for head and neck cancers but this treatment is well known to be less efficacious in patients with hypoxic tumors. Furthermore cancer therapy may alter tumor physiological status thus impacting treatment efficacy. Factors that modulate tumor oxygenation include blood flow blood oxygenation oxygen metabolism and nicotine levels (i.e. tobacco use). Tumor hemodynamics and metabolism however are not routinely measured during cancer therapy due to the lack of appropriate technologies. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are the best currently available and reproducible methods to measure target lesions selected for objective response assessment but these modalities require large and costly instrumentation that severely limits their routine use in clinics. The capabilities of diffuse optics for continuously monitoring tumor hemodynamics and metabolism during therapy at the clinical bedside have recently been demonstrated in our preliminary studies. The objective of this project is to develop and optimize a noninvasive versatile multi-modality clinical optical instrument to aid in evaluating and predicting tumor responses at the most early stage possible. More specifically this optical instrument will monitor and predict hemodynamic and metabolic responses to chemo- radiotherapy in head and neck tumors. We hypothesize that functional assessment of tumor physiological status and dynamic changes during therapy will provide information for early prediction of long-term treatment outcomes thus enabling clinicians to optimize therapy for each patient in a time sensitive fashion. To achieve this goal we will assemble a hybrid flow and oxygen system that combines a newly developed diffuse correlation spectroscopy (DCS) flowmeter with a commercial tissue-oximeter for simultaneous measurement of tumor blood flow oxygenation and oxygen metabolism (derived from the flow and oxygenation data). The instrument including optical probes and a software platform will be tested and optimized for continuous and longitudinal monitoring of tumor physiological status and hemodynamic/metabolic changes before during and after therapy in patients including smokers and nonsmokers (n=125). It is anticipated that significant correlations will be observed between therapy outcomes (e.g. tumor volume change tumor toxicity time to disease recurrence survival) and tumor physiological status and changes as well as nicotine levels. Different types of physiological parameters may show different sensitivities to cancer therapy in each patient which could reveal the primary factor(s) affecting individual therapy outcomes. Our novel hybrid optical system will provide hemodynamic and metabolic imaging contrasts complementary to those of CT and MRI and holds unique potential for early evaluating and predicting cancer therapy responses. Our long-term goal is to develop robust scientific collaborations to optimize and individualize cancer therapy at early stages with noninvasive optical technologies.  
  
PUBLIC HEALTH RELEVANCE: Treatment with radiation alone or in combination with chemotherapy is standard therapy for the head and neck cancers but this treatment is well known to be less efficacious in patients with poorly-vascularized/hypoxic tumors. The objective of this project is to develop and test a low-cost clinical-level optical instrument that can quickly assess tumor hemodynamic and metabolic status and responses to cancer therapy in the early stages. This in depth assessment of tumor hemodynamic and metabolic properties will provide essential information for the early prediction and evaluation of treatment outcomes thus enabling clinicians to optimize individual treatment.

project_terms:
Accounting;Acute;Affect;Aftercare;Blood;Blood Volume;Blood flow;Cessation of life;Clinic;Clinical;Collaborations;Computer software;Cotinine;Data;Data Collection;Devices;Diffuse;Disease;Drug Delivery Systems;Evaluation;Exhibits;Fiber Optics;Flowmeters;Forearm;Goals;Head and Neck Cancer;Head and Neck Neoplasms;Hybrids;Hypoxia;Image;Individual;Lesion;Location;Magnetic Resonance Imaging;Malignant Neoplasms;Measurement;Measures;Metabolic;Metabolism;Methods;Modality;Monitor;Muscle;Nicotine;Non-smoker;Optical Instrument;Optical Methods;Optics;Outcome;Oxygen;Patient Care;Patients;Physiological;Progressive Disease;Property;Radiation;Radiation therapy;Recurrence;Reporting;Research;Roentgen Rays;Scanning;Serum;Smoker;Smoking;Spectrum Analysis;Stable Disease;Staging;System;Technology;Testing;Time;Tissues;Tobacco use;Toxic effect;Treatment Efficacy;Treatment outcome;Tumor Oxygenation;Tumor Volume;Ultrasonography;Withdrawal;X-Ray Computed Tomography;base;blood flow measurement;cancer therapy;chemotherapy;cost;design;follow-up;hemodynamics;improved;insight;instrument;instrumentation;novel;prognostic;prototype;public health relevance;response;simulation;therapy outcome;tissue phantom;tool;treatment duration;treatment planning;tumor


application_id: 7993288
project_number: 1R01HD061617-01A2
project_title: Function of RUNX transcription factors in COCs
administering_ic: NICHD
award_notice_date: 2010-09-21
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: HD
serial_number: 061617
suffix: A2
program_official: TAYMANS, SUSAN
project_start_date: 2010-09-24
project_end_date: 2014-05-31
study_section: Cellular, Molecular and Integrative Reproduction Study Section[CMIR]
contact_pi_person_id: 8244639
contact_pi: JO, MISUNG
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of the present proposal is to determine the molecular/cellular mechanism(s) involved in the maturation process of cumulus oocyte complexes (COCs). Proper maturation of the COC is critical to reproductive success in vivo and in vitro. Our lack of a complete understanding of this maturation process restricts our ability to manage fertility in vivo and hinders implementation of ART such as in vitro fertilization and in vitro maturation. Recent studies by our laboratory and others have begun to shed light on a small family of nuclear transcription factors RUNX1 and RUNX2 as key transcriptional regulators involved in COC expansion. Our preliminary data demonstrated that Runx1 and Runx2 expression is highly induced in cumulus cells of periovulatory follicles. We also found that RUNX1 and RUNX2 regulate the expression of Ptgs2 (a rate-limiting enzyme in the biosynthesis of prostaglandins) and Hapln1 (a stabilizer of cumulus matrix) in mural granulosa cells and/or cumulus cells. Both gene products are known to play crucial roles in COC expansion. Most importantly our pilot study demonstrated that over-expression of dominant negative RUNX in cumulus cells blocked COC expansion. Based on these novel findings we hypothesized that RUNX1/2 are essential transcriptional regulators necessary for the gonadotropin surge-induced COC expansion. This hypothesis will be tested by first demonstrating the functional significance of Runx1/2 expression in cumulus cells (Aim #1). Secondly we will determine the regulation action(s) of RUNX1 and RUNX2 on their target genes (Aim #2). Next we will determine the regulatory mechanism(s) of Runx1 and Runx2 expression in cumulus cells (Aim #3). These 3 Aims will be studied using rat COCs. To insure that the data obtained from rat studies is translatable to humans RUNX1/2 and their target gene expression profile will be also verified using human cumulus cells collected throughout the periovulatory period. We will also examine the correlation of the cumulus expression of RUNX1/2 and their target genes to oocyte quality fertilization and embryo development using COCs obtained from women undergoing IVF (Aim #4). These human studies will serve as a foundation for future translational/clinical application. The information obtained from the proposed studies will not only advance our understanding of the mechanism involved in COC maturation but also be instrumental for future translational/clinical application(s) thus leading to improved management of fertility in vivo and in vitro.  
  
PUBLIC HEALTH RELEVANCE: Proper maturation of COCs is requisite for successful ovulation and fertilization. Appropriate COC expansion induced by the preovulatory gonadotropin surge is directly linked to oocyte quality and developmental competence. There are still huge gaps in our understanding of how the preovulatory gonadotropin surge induces the maturation process in COCs. Previous studies and our preliminary data suggest that RUNX transcription factor(s) plays a critical role in cumulus expansion by regulating the transcription of specific periovulatory cumulus genes. Building upon these findings the present proposal will determine the molecular/cellular mechanism(s) involved in COC expansion by elucidating the functional role(s) of RUNX transcription factors during maturation of COCs. Information derived from the present proposal will provide new insight into the mechanisms involved in COC maturation. Such knowledge can be applied for promoting and inhibiting this critical facet of ovarian physiology thereby allowing us to better manage fertility in vivo and in vitro.

project_terms:
Adenoviruses;Anabolism;Animal Model;Cells;Collecting Cell;Competence;Complex;Data;Development;Dominant-Negative Mutation;Embryonic Development;Enzymes;Female;Fertility;Fertilization;Fertilization in Vitro;Foundations;Future;GDF9 gene;Gene Expression;Gene Expression Profile;Gene Targeting;Genes;Genetic Transcription;Goals;Gonadotropins;Hormonal;Human;In Vitro;Knowledge;Laboratories;Light;Link;Mediating;Mediator of activation protein;Molecular;Molecular Profiling;Mus;Nuclear Family;Oocytes;Ovarian;Ovulation;Peptides;Physiology;Pilot Projects;Play;Process;Promotor (Genetics);Prostaglandins;Proteins;RUNX1 gene;Rattus;Regulation;Role;Signal Transduction;Small Interfering RNA;Testing;Woman;base;clinical application;combinatorial;cytokine;granulosa cell;implantation;improved;in vivo;insight;novel;public health relevance;reproductive success;runx proteins;success;time interval;transcription factor

public_health_relevance:
Project Narrative Proper maturation of COCs is requisite for successful ovulation and fertilization. Appropriate COCexpansion induced by the preovulatory gonadotropin surge is directly linked to oocyte quality anddevelopmental competence. There are still huge gaps in our understanding of how the preovulatorygonadotropin surge induces the maturation process in COCs. Previous studies and our preliminary datasuggest that RUNX transcription factor(s) plays a critical role in cumulus expansion by regulating thetranscription of specific periovulatory cumulus genes. Building upon these findings the present proposal willdetermine the molecular/cellular mechanism(s) involved in COC expansion by elucidating the functional role(s)of RUNX transcription factors during maturation of COCs. Information derived from the present proposal willprovide new insight into the mechanisms involved in COC maturation. Such knowledge can be applied forpromoting and inhibiting this critical facet of ovarian physiology thereby allowing us to better manage fertility invivo and in vitro.


application_id: 7993205
project_number: 3R01DK067581-05S2
project_title: Histone Acetylation and Insulin Gene Expression
administering_ic: NIDDK
award_notice_date: 2009-12-28
opportunity_number: PA-02-100
application_type: 3
activity_code: R01
ic: DK
serial_number: 067581
suffix: S2
program_official: SATO, SHERYL M
project_start_date: 2010-01-01
project_end_date: 2011-09-30
study_section: Cellular Aspects of Diabetes and Obesity Study Section[CADO]
contact_pi_person_id: 7875121
contact_pi: OZCAN, SABIRE
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Normal regulation of insulin gene transcription by glucose is essential for the maintenance of glucose homeostasis and requires the beta-cell specific transcription factors Pdx-1 MafA and NeuroD1. However the exact mechanism(s) by which glucose increases insulin gene expression by modulating the function of these transcription factors remains unknown. We found that glucose regulates the DNA binding activity of Pdx-1 and that Pdx-1 is modified by acetylation. Furthermore we discovered that glucose stimulates insulin gene transcription by causing hyperacetylation of histone H4 at the insulin promoter via the recruitment of the histone acetylase p300 by Pdx-1. Modification of core histones by acetylation has been shown to alter gene expression but the mechanisms that direct histone acetylation to specific gene promoters are not well understood. Based on our preliminary data we hypothesize that high blood glucose levels stimulate insulin gene transcription via modulation of histone H4 acetylation mediated by the beta-cell specific transcription factor Pdx-l. This hypothesis will be further investigated by addressing the following questions: 1) Is the glucose-regulated acetylation of Pdx-1 important for Pdx-1 activity and/or DNA binding? 2) What role do the histone acetyltransferases p300/CBP and GCN5/PCAF play in glucose regulation of insulin gene expression? 3) Do the beta-cell specific transcription factors MafA and NeuroD1 regulate insulin gene transcription by recruiting histone acetyltransferases?     Although most of the experiments will be carried out using the mouse insulinoma MIN6 cell line the key findings will be confirmed using primary rat islets. Recent data indicate that defects in histone acetylation are associated with the pathogenesis of diabetes. Several of the diabetes-causing mutations in the MODY genes HNF-1alpha and HNF-4alpha interfere with their interaction with histone acetylases. Patients with Huntington's disease are prone to type II diabetes due to decreased insulin gene expression caused by degradation of histone acetylases. Information on how high blood glucose levels regulate beta-cell specific gene expression in the pancreas will help to understand how defects in this process result in diabetes. In addition the data obtained will contribute to our understanding of Pdx-1 MafA and NeuroD1 function in the regulation of pancreas development and glucose-stimulated insulin gene transcription.

project_terms:
Acetylation;Acetyltransferase;Address;Beta Cell;Binding (Molecular Function);Blood Glucose;Cell Line;Cells;Complex;DNA Binding;Data;Defect;Development;Diabetes Mellitus;Doctor of Philosophy;EP300 gene;Gene Expression;Genes;Genetic Transcription;Glucose;Goals;HNF-1alpha;Histone Acetylation;Histone H4;Homeodomain Proteins;Huntington Disease;Hyperglycemia;Incidence;Insulin;Maintenance;Mediating;Modification;Mus;Mutation;Non-Insulin-Dependent Diabetes Mellitus;Pancreas;Pathogenesis;Patients;Play;Process;Production;Promotor (Genetics);Rattus;Recruitment Activity;Regulation;Research Personnel;Role;Small Interfering RNA;Structure of beta Cell of islet;Techniques;Testing;Transgenic Mice;Up-Regulation (Physiology);base;blood glucose regulation;histone acetyltransferase;human HAT1 protein;human HNF4A protein;in vivo;insulinoma;islet;pancreas development;programs;research study;response;transcription factor


application_id: 7992399
project_number: 5R01NS053905-05
project_title: PLP alternative splicing and oligodendrocyte differentiation
administering_ic: NINDS
award_notice_date: 2010-11-25
application_type: 5
activity_code: R01
ic: NS
serial_number: 053905
program_official: MORRIS, JILL A
project_start_date: 2007-01-03
project_end_date: 2012-12-31
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: N
budget_start_date: 2011-01-01
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 Tissue;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;acrosome stabilizing factor;cell injury;in vivo;innovation;knock-down;nervous system disorder;novel;progenitor


application_id: 7992377
project_number: 5R01NS062306-04
project_title: PPAR Inhibition of Spinal Pain Transmission
administering_ic: NINDS
award_notice_date: 2010-11-25
opportunity_number: PA-07-282
application_type: 5
activity_code: R01
ic: NS
serial_number: 062306
program_official: PORTER, LINDA L
project_start_date: 2008-12-18
project_end_date: 2013-11-30
study_section: Special Emphasis Panel[ZRG1-IFCN-E(02)M]
contact_pi_person_id: 1879170
contact_pi: TAYLOR, BRADLEY K.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Peroxisome proliferator-activated receptor gamma (PPAR 3) is well-characterized as a key target of the thiazolinedione (TZD) class of anti-diabetic drugs. Our preliminary results describe the existence of PPAR 3 mRNA and protein in the dorsal horn. Furthermore we demonstrate that the mechanical and thermal hypersensitivity associated with inflammation or nerve injury was rapidly reduced by intrathecal administration of rosiglitazone (a TZD) and 15d-PGJ2 (an endogenous PPAR 3 ligand) in a dose- and PPAR 3-dependent manner and by systemic administration of pioglitazone a BBB-permeant FDA-approved ligand. The central hypothesis of this proposal is that ligand-dependent activation of PPAR3 in the dorsal horn decreases injury- induced activation of spinal neurons and glia that then dampens behavioral signs of inflammatory and neuropathic pain. The objective of the present application is to identify the mechanisms underlying PPAR- mediated inhibition of inflammatory or neuropathic pain with a focus on pioglitazone. The long-term goal of our research program is to harness the therapeutic potential of PPAR signaling to alleviate chronic pain in humans. AIM 1 will test the hypothesis that PPAR 3 agonists reduce allodynia and hyperalgesia. We will use pharmacological agents and nervous system-specific PPAR 3 deletion mutants to determine the contribution of PPAR 3 signaling in the spinal cord to the induction and maintenance of chronic pain. First we will determine whether single intrathecal or systemic administration of pioglitazone and 15d-PGJ2 reduces behavioral signs of inflammatory and neuropathic pain. We predict that their analgesic actions will be blocked with PPAR 3 antagonists. Second we will determine whether chronic intrathecal or oral administration of PPAR 3 agonists begun before or after tissue or nerve injury reduces behavioral signs of inflammatory and neuropathic pain. Third we predict that anti-allodynic actions will not occur in mice with neuron-specific PPAR 3 knockdown. AIM 2 will test the hypothesis that PPAR 3 ligands reduce injury-induced activation of neurons and microglia in the dorsal horn. Somatosensory stimulation of injured rats induces the expression of the immediate early gene c-fos in the superficial laminae of the dorsal horn. We predict that intrathecal pioglitazone will reduce inflammation- and nerve injury-induced expression of Fos immunoreactive neurons as well as the expression of OX-42 a marker of microglia activation. AIM 3 will test the hypothesis that endogenous PPAR 3 systems tonically inhibit allodynia. First we will determine if PPAR3 expression occurs in neurons and/or glia that are activated during pain. Second in an extension of Aims 1-2 we will determine whether receptor antagonists and genetic deletion increase allodynia and neuronal/glial activation. If affirmative then we will determine whether the PPAR3 signaling elements co- vary with allodynia. At various times after nerve injury or persistent inflammation we will evaluate: behavior and A) PPAR 3 mRNA and protein; B) phosphorylated PPAR 3; and C) 15d-PGJ2 levels with LC/MS/MS. PUBLIC HEALTH RELEVANCE Chronic pain management is a major scientific and health care challenge as current analgesic drugs rarely provide sufficient efficacy in the absence of serious side effects. We propose that ligands for peroxisome proliferator-activated receptor gamma (PPAR 3) such as rosiglitazone and pioglitazone represent a novel class of analgesic / anti-allodynic compounds. These conceptually innovative experiments are important and timely because TZDs are commercially available for diabetes and are in clinical trials for CNS neurodegenerative diseases. Thus confirmation of our hypothesis could lead to rapid translation to the clinical treatment of chronic pain.

project_terms:
9-deoxy-delta-9-prostaglandin D2;Adverse effects;Agonist;Analgesics;Antidiabetic Drugs;Astrocytes;Basic Science;Behavior;Behavioral;Chronic;Clinical Treatment;Clinical Trials;Cobalt;Diabetes Mellitus;Dose;FDA approved;FOS gene;Genetic;Goals;Healthcare;Human;Hyperalgesia;Hypersensitivity;Immediate-Early Genes;Immunohistochemistry;Inflammation;Inflammatory;Injury;Lead;Ligands;Maintenance;Mass Spectrum Analysis;Mechanics;Mediating;Messenger RNA;Microglia;Mus;Nervous system structure;Neurodegenerative Disorders;Neuroglia;Neurons;Oral Administration;PPAR gamma;Pain;Pain management;Peripheral;Peripheral nerve injury;Peroxisome Proliferator-Activated Receptors;Pioglitazone;Protein Isoforms;Proteins;Rattus;Receptor Inhibition;Receptor Signaling;Regulation;Research;Signal Transduction;Spinal;Spinal Cord;Stimulus;System;Testing;Therapeutic;Thiazolidinediones;Time;Tissues;Transgenic Mice;Translations;Western Blotting;allodynia;chronic pain;dorsal horn;inflammatory neuropathic pain;inflammatory pain;injured;innovation;liquid chromatography mass spectrometry;mutant;nerve injury;novel;painful neuropathy;programs;public health relevance;receptor;research study;rosiglitazone;somatosensory;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE STATEMENTChronic pain management is a major scientific and health care challenge as current analgesic drugsrarely provide sufficient efficacy in the absence of serious side effects. We propose that ligands forperoxisome proliferator-activated receptor gamma (PPAR ) such as rosiglitazone and pioglitazonerepresent a novel class of analgesic / anti-allodynic compounds. These conceptually innovativeexperiments are important and timely because TZDs are commercially available for diabetes and arein clinical trials for CNS neurodegenerative diseases. Thus confirmation of our hypothesis could leadto rapid translation to the clinical treatment of chronic pain.


application_id: 7991865
project_number: 5R25ES016248-04
project_title: Summer Education Experience for Research
administering_ic: NIEHS
award_notice_date: 2010-11-30
opportunity_number: RFA-ES-06-009
application_type: 5
activity_code: R25
ic: ES
serial_number: 016248
program_official: HUMBLE, MICHAEL C
project_start_date: 2008-01-01
project_end_date: 2012-11-30
study_section: ZES1-LKB-A(R5)
contact_pi_person_id: 1862358
contact_pi: VORE, MARY
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant)  
  
The primary objective of the Summer Education Experience in Research (SEER) in Toxicology is to provide 6 students with an opportunity to participate actively in ongoing research together with an educational seminar series that provides a background in research in environmental health sciences. The immediate goals are to provide a research experience for students at a critical time of career decision-making and to develop the research skills and expose the students to the potential and excitement of research careers. The long-term goal is to recruit these students into the Toxicology doctoral program. Students will have hands-on responsibilities in research projects in which reasonable conclusions can be obtained in a 9-week period and will spend 85% of their time in the laboratory. Research opportunities in specialty areas of Oxidative Stress DNA Repair and Mutagenesis Biochemical Toxicology and Chlorinated Organics and Cardiovascular Toxicity are provided by a group of 17 faculty members with experience in mentoring graduate and undergraduate students. Students will work with faculty who are primarily Core and Joint Faculty in the Graduate Center for Toxicology and who are Training Grant Faculty on the Molecular Mechanisms of Toxicity NIEHS T32 Training Grant or the Superfund Training Core. Students will be recruited from the University of Puerto Rico (UPR) as the continuation of a program for students from UPR that has been cosponsored by the University of Kentucky (UK) and UPR for about 9 years and was supported by an NIEHS T35 program from 2001 - 2006. The investigators will work with experienced faculty from the UPR to identify and recruit students for the SEER Toxicology program. Applicants must provide their student transcripts and will be interviewed by the UPR faculty to identify those with the maturity and academic excellence to succeed in a summer research experience. The UPR faculty will send the applications of the best students to Dr. Vore who will review them along with 2 other UK faculty mentors and select the top 6 applicants. This group will also match the interests of the applicants with those of the faculty who are able to work with the students in any given summer. A seminar series that exposes students to the broader issues in the environmental health sciences is also provided along with seminars on the responsible conduct of research and a presentation of how to prepare and apply for Graduate School. Students will make a 15-minute presentation of their research findings in a symposium-type format at the end of the summer. A plan for evaluating student satisfaction the effectiveness of mentors and the program has been developed and will be used to enhance the program in ensuing years.

project_terms:
Area;Biochemical;Cardiovascular system;DNA Repair;Decision Making;Educational aspects;Effectiveness;Environmental Health;Faculty;Goals;Grant;Interview;Joints;Kentucky;Laboratories;Mentors;Molecular;Mutagenesis;National Institute of Environmental Health Sciences;Oxidative Stress;Puerto Rico;Recruitment Activity;Research;Research Personnel;Research Project Grants;Schools;Series;Students;Superfund;Time;Toxic effect;Toxicology;Training;Transcript;Universities;Work;career;experience;interest;medical specialties;member;programs;responsible research conduct;satisfaction;skills;symposium;university student


application_id: 7991774
project_number: 5R01HL062846-07
project_title: Sources and effects of angiotensin peptides in atherosclerosis
administering_ic: NHLBI
award_notice_date: 2010-11-30
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 062846
program_official: THRASHER, TERRY N
project_start_date: 2000-09-20
project_end_date: 2012-11-30
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8378256
contact_pi: DAUGHERTY, ALAN
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This is a revised application for which we have now developed the mice that were requested in the previous reviews: floxed angiotensinogen and AT1a receptors. Therefore all the critical reagents to the proposed studies are now available. Evidence has evolved primarily in the last decade demonstrating that the renin angiotensin system (RAS) has a profound effect on atherogenic mechanisms. However many questions remain regarding the origin of the bioactive peptides and the mechanisms of the effects. Based on the findings of the previously funded period and others the focus of the proposed research is to determine the relative importance of the systemic versus local RAS to the development of atherosclerosis. The central hypothesis of this proposal is that macrophage-derived RAS components are responsible for the local generation of angiotensin peptides that propagate atherosclerosis primarily via stimulation of AT1a receptors expressed on endothelial cells. To determine the validity of this hypothesis the following specific aims are proposed. Aim 1: Determine the contribution of angiotensinogen from the liver (systemic) versus macrophages (local) to lesion size and characteristics of hypercholesterolemia-induced atherosclerosis. Aim 2: Determine the contribution of ACE1 and ACE2 expression on bone marrow-derived cells to the development of atherosclerotic lesion size and characteristics. Aim 3: Determine the cellular location of AT1a receptor expression that influences the atherogenic process.  
  
PUBLIC HEALTH RELEVANCE: Atherosclerotic diseases are the major cause of morbidity and mortality in the US population. Therefore investigations to prevent these diseases have vast public health implications.

project_terms:
Abdominal Aortic Aneurysm;Adhesions;Aneurysm;Angiotensin II;Angiotensinogen;Angiotensins;Area;Arterial Fatty Streak;Atherosclerosis;Blood Vessels;Bone Marrow;Breeding;Cells;Characteristics;Chemicals;Data;Development;Diet;Disease;Endothelial Cells;Enzymes;Funding;Generations;Genetic;Hepatocyte;In Vitro;Inflammatory;Investigation;Laboratories;Lesion;Liver;Location;Low Density Lipoprotein Receptor;Morbidity - disease rate;Mortality Vital Statistics;Mus;Pathology;Peptides;Population;Process;Production;Promotor (Genetics);Reagent;Relative (related person);Renin;Renin-Angiotensin System;Reporting;Research;Role;Series;Smooth Muscle Myocytes;Source;Tissues;Uncertainty;aortic arch;base;blood pressure regulation;cell type;enzyme deficiency;feeding;hypercholesterolemia;insight;macrophage;monocyte;prevent;public health medicine (field);public health relevance;receptor;receptor expression;saturated fat

public_health_relevance:
Atherosclerotic diseases are the major cause of morbidity and mortality in the USpopulation. Therefore investigations to prevent these disease have vast public healthimplications.


application_id: 7990514
project_number: 7U10HL080543-06
project_title: Emory Clinical Research Center in IPF
administering_ic: NHLBI
award_notice_date: 2009-11-23
opportunity_number: RFA-HL-04-021
application_type: 7
activity_code: U10
ic: HL
serial_number: 080543
program_official: REYNOLDS, HERBERT Y
project_start_date: 2005-05-01
project_end_date: 2011-04-30
study_section: ZHL1-CSR-M(F1)
contact_pi_person_id: 1876531
contact_pi: ROMAN, JESSE
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  
  
Idiopathic Pulmonary Fibrosis (IPF) is an idiopathic interstitial pneumonia characterized by the rapid replacement of the lung parenchyma with fibrosis which results in progressive deterioration of lung function.  This process often leads to respiratory failure and death.  Although several drugs are under investigation currently there are no effective means of treating this devastating disease.  This proposal is submitted in response to the NIH-sponsored RFA titled "IPF Clinical Research Network" with the intention of becoming one of the clinical research centers within this network.  Our site will be based at the Emory Center for the Treatment and Study of Interstitial Lung Disease (The Emory ILD Center).  The Emory ILD Center is considered a premier center for the diagnosis treatment and research of patients with IPF and related disorders because:  1) it currently serves as a referral base for patients with interstitial lung disease identified at any of five Emory hospitals at several academic institutions in metro Atlanta and through a network of private practice physicians located throughout the state of Georgia and the Southeastern region of the country; 2) it has served as a site for clinical-based investigations related to IPF and other interstitial lung diseases and as such has developed extensive experience in clinical trials and translational research related to IPF; 3) it is staffed by a multidisciplinary team of clinical investigators translational researchers research coordinators and other staff with expertise in the diagnosis and management of patients with IPF; and 4) it is directed by a team of investigators recognized in the field for their work in elucidating the mechanisms of lung tissue remodeling and fibroproliferation.  The proposal describes two clinical trials to be considered by the Network that target pro-fibrotic pathways and the lung fibroblast/myofibroblast the key effector cell responsible for fibroproliferation and tissue remodeling in pulmonary fibrosis.  It also includes a Clinical Research Skills Core that will mentor junior investigators into developing the necessary skills to become independent clinician scientists involved in research related to IPF.  The team of investigators leading the clinical research center and the Clinical Research Skills Core are currently engaged in clinical research related to IPF and have developed a reputation for mentoring young investigators into careers in academia.  (End of Abstract)

project_terms:
Academia;Angiotensin Receptor;Area;Basic Science;Belief;Cessation of life;Characteristics;Cicatrix;Clinical;Clinical Investigator;Clinical Research;Clinical Trials;Consensus;Country;Deposition;Deterioration;Diagnosis;Disease;Disease Progression;Drug Combinations;Effectiveness;Effector Cell;Event;Extracellular Matrix;Fibroblasts;Fibrosis;Functional disorder;Funding;Generations;Growth Factor;Half-Life;Hamman-Rich syndrome;Hospitals;Institution;Intention;Interstitial Lung Diseases;Investigation;Lead;Lung;Macrolides;Mentors;Myofibroblast;New Agents;Oral Administration;Pathway interactions;Patients;Pharmaceutical Preparations;Phase II Clinical Trials;Phenotype;Physicians;Private Practice;Process;Pulmonary Fibrosis;Research;Research Personnel;Research Project Grants;Respiratory Failure;Respiratory physiology;Safety;Scientist;Site;Structure of parenchyma of lung;Tissues;Training;Translational Research;Work;abstracting;base;career;clinical research site;drug testing;effective therapy;experience;lung injury;multidisciplinary;next generation;novel;pre-clinical;response;skills;treatment center


application_id: 7989839
project_number: 3R01AR055974-02S1
project_title: Respiratory Muscle Weakness in Chronic Inflammation
administering_ic: NIAMS
award_notice_date: 2010-08-15
opportunity_number: RFA-AR-10-001
application_type: 3
activity_code: R01
ic: AR
serial_number: 055974
suffix: S1
program_official: NUCKOLLS, GLEN H
project_start_date: 2009-04-01
project_end_date: 2011-02-28
study_section: Special Emphasis Panel[ZAR1 KM (M1)]
contact_pi_person_id: 1869134
contact_pi: REID, MICHAEL B
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): In this supplemental project we seek to capitalize on a confluence of exciting new data innovative technology and the unique expertise of three new collaborators. Data from our parent project have identified an obscure sphingomyelinase isoform -- neutral sphingomyelinase-3 (nSMase-3) -- as a potential mediator of diaphragm weakness stimulated by TNF or severe heart failure. We propose to test this thesis by a multidisciplinary strategy. The experimental approach includes cell culture systems a newly-created transgenic mouse line and diaphragm biopsies from humans with heart failure. The project is made possible by a powerful team of three new collaborators who are experts in molecular biology transplantation surgery and human genetics. The goal of our project is to evaluate nSMase-3 as a potential mediator of diaphragm weakness in heart failure and a target for future therapeutic development. We have two specific aims: Aim 1. To evaluate nSMase-3 as a mediator of TNF-induced oxidant activity and weakness. Experiment 1.1 will test the hypothesis that nSMase-3 is constitutively expressed by murine skeletal muscle and is upregulated by TNF. Experiment 1.2 will test the hypothesis that muscle-specific nSMase-3 deficiency will abolish TNF effects on diaphragm oxidant activity and specific force. Aim 2. To test for associations between nSMase-3 and cardiovascular disease in humans. Experiment 2.1 will test the hypothesis that nSMase-3 mRNA nSMase-3 protein and SMase activity are elevated in diaphragm and pectoralis muscles of patients undergoing surgery for heart failure. Experiment 2.2 will test the hypothesis that single nucleotide polymorphisms (SNPs) in the Smpd4 gene that codes for nSMase-3 will modulate expression or splicing of the gene in human tissue.    
  
PUBLIC HEALTH RELEVANCE:  Weakness and fatigue of the respiratory muscles cause exercise intolerance breathlessness and respiratory failure in patients with chronic heart and lung diseases.  This supplemental project tests a novel enzyme neutral sphingomyelinase-3 as a possible cause of respiratory muscle dysfunction in chronic disease and a potential target for future therapies.

project_terms:
Animals;Area;Biology;Biopsy;Breeding;Cardiac;Cardiovascular Diseases;Cell Culture System;Ceramides;Chronic;Chronic Disease;Code;Data;Depressed mood;Diaphragm (Anatomy);Dyspnea;Engineering;Enzymes;Exercise;Faculty;Fatigue;Freezing;Functional disorder;Future;Gene Expression;Gene Expression Regulation;Gene Targeting;Genes;Genetic;Goals;Heart;Heart failure;Human;Human Genetics;Inflammation;Inflammatory Response;International;Kentucky;Lung diseases;Manuscripts;Mediating;Mediator of activation protein;Messenger RNA;Molecular;Molecular Biology;Mus;Muscle;Muscle Weakness;Muscle function;National Institute of Arthritis and Musculoskeletal and Skin Diseases;Northern Blotting;Operative Surgical Procedures;Organ Donor;Organ Transplantation;Oxidants;Paper;Patients;Pectoralis Muscles;Pectoralis major muscle structure;Pilot Projects;Protein Isoforms;Proteins;PubMed;Recruitment Activity;Reporting;Research Personnel;Respiratory Failure;Respiratory Muscles;Risk Factors;Rodent Model;Role;Signal Transduction;Signaling Molecule;Single Nucleotide Polymorphism;Skeletal muscle structure;Sphingomyelinase;Sphingomyelins;Spliced Genes;Staging;Striated Muscles;TNF gene;Tamoxifen;Testing;Transgenic Mice;Transgenic Organisms;Transplant Surgeon;Tumor Necrosis Factor Receptor;Universities;Work;authority;falls;genetic analysis;human disease;human tissue;innovation;innovative technologies;interest;multidisciplinary;novel;parent project;public health relevance;research study;respiratory;skeletal;therapeutic development

public_health_relevance:
NARRATIVEWeakness and fatigue of the respiratory muscles cause exercise intolerance breathlessness and respiratory failure in patients with chronic heart and lung diseases.  This supplemental project tests a novel enzyme neutral sphingomyelinase-3 as a possible cause of respiratory muscle dysfunction in chronic disease and a potential target for future therapies.


application_id: 7989822
project_number: 1R01CA138797-01A2
project_title: Targeting AR and Akt for the Treatment of Prostate Cancer
administering_ic: NCI
award_notice_date: 2010-05-03
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: CA
serial_number: 138797
suffix: A2
program_official: ARYA, SURESH
project_start_date: 2010-07-01
project_end_date: 2011-04-30
study_section: Developmental Therapeutics Study Section[DT]
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): The androgen receptor (AR) plays an important role in the development and progression of prostate cancer (PCa). Most PCa specimens express high levels of AR which is necessary and sufficient to convert androgen-dependent (AR+) PCa to the clinically more aggressive androgen-independent (AR-) PCa. Although inhibition of AR activity is a mainstay of AR+ PCa treatment there are no effective therapies for AR- PCa which is uniformly lethal. Studies reveal AR and Akt mutually activate one another and that together AR and Akt inhibit pro-apoptotic signaling and enhance the conversion of AR+ to AR- PCa. Targeting both AR and Akt signaling represents a powerful therapeutic approach for treating AR+ PCa and preventing the emergence of AR- PCa. We recently demonstrated Withaferin-A (WA) a natural compound specifically targets AR- PCa cells by inhibiting phosphorylated Akt; this inhibition leads to the activation of prostate apoptosis response-4 (Par-4)-dependent apoptosis in cell culture and in animal models. Similarly inhibition of AR in AR+ PCa cells facilitates WA-induced Par-4 activation and apoptosis. Over-expression of either Akt or AR inhibits WA-mediated Par-4 activation and blocks apoptosis in AR+ PCa suggesting both AR and Akt negatively regulate the pro-apoptotic functions of Par-4 in PCa cells. We hypothesize that WA in combination with hormone ablation is an effective strategy to control the progression of PCa. To address this hypothesis we will: Aim 1. Characterize the molecular link between AR signaling and Par-4 and determine the effects of WA on AR+ PCa cells (investigating AR binding to the Par-4 promoter via reporter constructs ChIP assays using AR antibodies and Western analysis of pro- and anti-apoptosis proteins); Aim 2. Examine the relationship between Par-4 and FOXO 3a which is regulated by Akt and how WA modulates this interaction in AR+ PCa (studying FOXO3a binding to the Par-4 promoter via reporter constructs ChIP assays using FOXO3a antibodies mobility shift assays Western analysis of pro- and -anti-apoptosis proteins and TUNEL and annexin-V assays following FOXO3a over-expression); and Aim 3. Determine the chemotherapeutic effects of WA on the development of PCa in prostate specific PTEN knockout mice (PS PTEN-KO; performing in vivo WA efficacy studies on PCa histopathology immunohistochemistry of pro-survival and pro-apoptotic proteins proliferation index apoptosis and serum WA levels). We anticipate these studies will provide molecular insight into the mechanism of WA action against AR+ PCa and will ultimately lead to novel therapeutic strategies for the treatment of PCa.  
  
PUBLIC HEALTH RELEVANCE: This proposal focuses on the effect of a non-toxic dietary compound Withaferin-A (WA) on androgen-dependent (AR+) prostate cancer (PCa) and how WA in combination with androgen inhibitors selectively kills AR+ PCa. Establishing an effective and safe approach for treating AR+ PCa is an important health issue as AR+ PCa frequently transitions to AR-independent PCa which is a lethal cancer that is uniformly refractory to known therapeutics. In this proposal we will further characterize the therapeutic merit of WA which is used in traditional medicine for the prevention and treatment of cancer.

project_terms:
Ablation;Address;Adenocarcinoma;Androgen Antagonists;Androgen Receptor;Androgens;Animal Model;Antibodies;Apoptosis;Apoptotic;Area;Binding (Molecular Function);Bioavailable;Biological Assay;CWR22Rv1;Cell Culture Techniques;Cell Death;Cells;Development;Disease Progression;Dominant-Negative Mutation;Dose;Electrophoretic Mobility Shift Assay;Hand;Health;Histopathology;Hormonal;Hormones;Immunohistochemistry;In Situ Nick-End Labeling;In Vitro;Induction of Apoptosis;Killings;Knockout Mice;LNCaP;Lead;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Modeling;Molecular;Mus;PAWR gene;PTEN gene;Pattern;Play;Prevention;Promotor (Genetics);Prostate;Prostatic Neoplasms;Proteins;Radiation;Receptor Cell;Receptor Signaling;Refractory;Regulation;Reporter;Research;Role;S-Phase Fraction;Sampling;Serum;Signal Transduction;Small Interfering RNA;Specimen;Therapeutic;Traditional Medicine;Transgenic Organisms;Tumor Tissue;Xenograft procedure;androgen independent prostate cancer;annexin A5;base;cancer cell;cancer therapy;effective therapy;in vivo;in vivo Model;inhibitor/antagonist;insight;novel therapeutics;prevent;pro-apoptotic protein;public health relevance;receptor binding;research study;response;treatment strategy;tumor;tumor growth

public_health_relevance:
This proposal focuses on the effect of a non-toxic dietary compound Withaferin-A (WA)on androgen-dependent (AR+) prostate cancer (PCa) and how WA in combination withandrogen inhibitors selectively kills AR+ PCa. Establishing an effective and safeapproach for treating AR+ PCa is an important health issue as AR+ PCa frequentlytransitions to AR-independent PCa which is a lethal cancer that is uniformly refractory toknown therapeutics. In this proposal we will further characterize the therapeutic merit ofWA which is used in traditional medicine for the prevention and treatment of cancer.


application_id: 7989401
project_number: 5F31DE020240-02
project_title: AI-2-dependent quorum sensing in Aggregatibacter actinomycetemcomitans
administering_ic: NIDCR
award_notice_date: 2010-10-27
opportunity_number: PA-07-002
application_type: 5
activity_code: F31
ic: DE
serial_number: 020240
program_official: FRIEDEN, LESLIE A
project_start_date: 2009-12-01
project_end_date: 2012-11-30
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 9851704
contact_pi: NOVAK, ELIZABETH ANN
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): Dental plaque is a complex oral biofilm comprised of a diverse microbial community which necessitates that bacteria coordinate their behavior and function based on the environment and other organisms in the biofilm. In the oral pathogen Aggregatibacter actinomycetemcomitans this intimate cell-to- cell communication potentially occurs via the quorum sensing circuit dependent upon the soluble signaling molecule autoinducer-2 (AI-2). Previous results suggest that the response circuits of A. actinomycetemcomitans differ from the established paradigms for AI-2 signaling. Thus we hypothesize that the AI-2-mediated quorum sensing response circuit in A. actinomycetemcomitans is tailored towards the specific survival strategies employed by this organism in the oral biofilm and contributes to its in vivo persistence and virulence through AI-2 regulation of iron acquisition. To address this hypothesis we will further characterize the molecular mechanisms of AI-2-dependent quorum sensing in A. actinomycetemcomitans. Our first specific aim is to determine the importance of AI-2-dependent quorum sensing in the persistance and virulence of A. actinomycetemcomitans. Since periodontal diseases are mixed bacterial infections of the oral cavity it is theorized that populational shifts in the biofilm that leads to overrepresentation of certain organisms rather than their absence or presence is a major contributing factor to the onset and progression of oral diseases. Using the Baker model of periodontitis we will determine if AI-2-mediated quorum sensing is important in vivo during single infections with either wild type or AI-2 receptor-deficient strains of A. actinomycetemcomitans. Our second specific aim is to identify the component that links AI-2 detection to downstream gene regulation. Initial studies suggest that the two- component system QseBC may link detection and gene regulation. To address our hypothesis we will determine if QseBC regulates biofilm formation in A. actinomycetemcomitans. This will be accomplished by constructing QseBC mutants and analyzing their ability to form biofilms in vitro. We will also determine if QseBC influences the expression of AI-2-regulated genes such as iron acquisition by utilizing quantitative PCR.   
  
Public Health Relevance: Determining the extra- and intracellular physiologic roles of AI-2 will provide rationale for the development of novel quorum sensing inhibitors as a way to prevent the growth of A. actinomycetemcomitans biofilms associated with oral diseases as well as other diseases (e.g. cardiovascular disease). Furthermore innovative methods to control biofilm formation in the oral cavity would have a major impact on healthcare costs

project_terms:
Actinobacillus actinomycetemcomitans;Address;Bacteria;Bacterial Infections;Behavior;Cardiovascular Diseases;Cell Communication;Cell physiology;Cells;Communication;Communities;Complex;Dental Plaque;Detection;Development;Disease;Disease Progression;Environment;Escherichia coli;Event;Exhibits;Gene Expression Regulation;Genes;Goals;Growth;Health Care Costs;In Vitro;Infection;Iron;Link;Mediating;Methods;Microbial Biofilms;Modeling;Molecular;Mouth Diseases;Onset of illness;Operon;Oral cavity;Organism;Outcome;Periodontal Diseases;Periodontitis;Physiological;Porphyromonas gingivalis;Regulation;Research;Role;Salmonella;Signal Transduction;Signaling Molecule;System;Therapeutic Intervention;VAI-2;Vibrio;Virulence;base;extracellular;in vivo;inhibitor/antagonist;innovation;microbial;microbial community;mutant;novel;oral biofilm;oral pathogen;periplasm;prevent;public health relevance;quorum sensing;receptor;response;uptake


application_id: 7989190
project_number: 1R21AG036875-01A1
project_title: Novel assay identifies all microRNA targets in Alzheimer and normal aged brains
administering_ic: NIA
award_notice_date: 2010-06-04
opportunity_number: PA-09-164
application_type: 1
activity_code: R21
ic: AG
serial_number: 036875
suffix: A1
program_official: REFOLO, LORENZO
project_start_date: 2010-06-15
project_end_date: 2012-05-31
study_section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): We hypothesize that microRNAs (miRNAs) play important roles in the human brain during healthy aging and in Alzheimer's disease (AD). MiRNAs are small RNAs that regulate gene expression. Most miRNAs act through hybridization with "target" mRNAs. We and others have observed an altered pattern of miRNA expression in AD brain tissue. In various models where miRNAs are reduced neurodegeneration ensues quickly. The mechanisms of miRNA-mediated neuroprotection and neurodegeneration are poorly understood partly because most of the mRNA targets of miRNAs are still unknown. Unfortunately there has been no suitable technique to indicate experimentally which mRNAs are miRNA targets. We developed a high-throughput assay to identify miRNA targets in human brain tissue. Here we propose to use this novel assay to better understand the neurochemistry of AD. Our research program has the following Specific Aims: 1. Obtain brain tissue from the University of Kentucky Alzheimer's Disease Center Brain Bank that is thoroughly characterized including clinical evaluations near death short post-mortem intervals and state-of-the-art neuropathology. Clinical cohorts will include brain tissue of non- demented controls mild cognitive impairment controls AD and non-AD dementia controls. 2. Optimize a novel biochemical assay for accurate specific and direct miRNA target identification. This assay the Co-immunoprecipitation MicroRNA Assay Procedure (CoMAP) has been optimized in cell culture and preliminarily in brain tissue. CoMAP will be performed on the brain tissue described in Specific Aim #1. 3. Analyses of CoMAP data will incorporate data from mRNA microarray miRNA microarray clinical data and pathological data referent to the same specimens. These analyses will focus on discovering miRNA targets relevant to AD treatment and diagnosis and on elucidating the mRNA targets that subserve the neuroprotective functions of miRNA. The raw and analyzed datasets and the CoMAP assay itself will be shared freely with other investigators. These Specific Aims are intended to answer the following fundamental questions: 7 What mRNAs are miRNA targets in healthy brain aging? 7 What mRNAs are miRNA targets in Alzheimer's disease and other altered brain states? 7 How do changes in mRNA targets correlate with changes in expression of miRNAs?  
  
PUBLIC HEALTH RELEVANCE: The objective of this project is to use a novel technique to better understand the causes of Alzheimer's disease and why some people remain Alzheimer's disease-free during aging. We will characterize in human brains a newly-discovered high impact level of gene regulation which are called microRNAs using a method called a Co-immunoprecipitation MicroRNA Assay Procedure (CoMAP). We think that we can produce information that directly or indirectly contributes to diagnostics and therapeutics for Alzheimer's disease patients.

project_terms:
Aging;Alzheimer's Disease;Arts;Biochemical;Biological Assay;Biology;Brain;Cell Culture Techniques;Cessation of life;Clinical;Clinical Data;Co-Immunoprecipitations;Data;Data Set;Dementia;Diagnosis;Diagnostic;Evaluation;Future;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Human;Investigation;Journals;Kentucky;Link;Mediating;Medicine;Messenger RNA;Methods;MicroRNAs;Modeling;Nerve Degeneration;Nobel Prize;Patients;Pattern;Physiology;Play;Prize;Procedures;Research;Research Personnel;Role;Sampling;Science;Small RNA;Specimen;Techniques;Therapeutic;Tissues;Universities;aging brain;brain tissue;cohort;healthy aging;high throughput screening;mild cognitive impairment;neurochemistry;neuropathology;neuroprotection;normal aging;novel;programs;public health relevance;research clinical testing

public_health_relevance:
PROJECT SUMMARY / PROJECT NARRATIVE The objective of this project is to use a novel technique to better understand the causes of Alzheimer's disease and why some people remain Alzheimer's disease-free during aging.  We will characterize in human brains a newly-discovered high impact level of gene regulation which are called microRNAs using a method called a Co-immunoprecipitation MicroRNA Assay Procedure (CoMAP).  We think that we can produce information that directly or indirectly contributes to diagnostics and therapeutics for Alzheimer's disease patients.


application_id: 7989139
project_number: 5R01AI033481-17
project_title: Yersiniabactin and plague pathogenesis
administering_ic: NIAID
award_notice_date: 2010-11-15
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AI
serial_number: 033481
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 1993-07-01
project_end_date: 2013-11-30
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 1864186
contact_pi: PERRY, ROBERT DONALD
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Yersinia pestis causes a zoonotic disease plague with well established reservoirs on every inhabited continent except Australia. Although humans are an accidental dead-end host bubonic and pneumonic plague has caused widespread loss of human life during recurrent pandemics. Nearly 2000 human plague cases occur yearly and outbreaks in Africa South America and Southeast Asia are common. In addition Y. pestis is a category A select agent with potential use for bioterrorism. The ability of pathogens to acquire iron from their hosts is a critical requirement for the development of nearly all infectious disease processes. Y. pestis encodes a large number of proven or putative iron transport systems but the siderophore- dependent yersiniabactin (Ybt) and Yfe systems are the most important for causing bubonic plague. In a mouse model of bubonic plague the Ybt system is essential in the early phases of disease while the Yfe system plays an important role in the later stages of plague. Mutations in ybt but not yfe affect the pathogenesis of pneumonic plague. Our studies indicate that Yfe and Feo (a ferrous iron transporter) play somewhat redundant roles in iron uptake - mutants lacking both systems show more severe phenotypes for in vitro growth intracellular growth and pathogenesis in bubonic and pneumonic plague. All these genes are regulated by Fur and iron availability. In addition the Ybt system is activated by the AraC-type regulator YbtA and the Ybt siderophore. The ultimate goals of my laboratory are to 1) genetically and biochemically characterize the iron transport systems of Y. pestis; 2) determine the mechanisms regulating expression of these systems; 3) assess the relative importance of these systems in bubonic and pneumonic plague; and 4) explore the potential for new antimicrobial therapies and vaccine components based on these transport systems. In this proposal we will focus on the Ybt system. The specific aims of this proposal are to 1) characterize Ybt regulation 2) investigate Ybt transport and iron utilization and 3) examine Ybt roles in bubonic and pneumonic plague pathogenesis. PUBLIC HEALTH RELEVANCE: Most bacterial pathogens require iron in order to grow and cause disease. Yersinia pestis the causative agent of plague produces a small molecule called a siderophore that can remove the iron that it needs from host iron-binding compounds and plays a very important role in both bubonic and pneumonic plague. Understanding how the bacterium makes this siderophore and how its production is regulated may eventually lead to the development of either a vaccine or new drugs against plague and other bacterial diseases.

project_terms:
Affect;Africa;Australia;Bacteria;Bacterial Infections;Binding (Molecular Function);Bioterrorism;Bubonic Plague;Categories;Cells;Communicable Diseases;Development;Disease;Disease Outbreaks;Genes;Genetic Transcription;Goals;Growth;Health;Human;In Vitro;Investigation;Iron;Laboratories;Lead;Life;Manganese;Microarray Analysis;Mutation;Pathogenesis;Periplasmic Binding Proteins;Pharmaceutical Preparations;Phase;Phenotype;Plague;Play;Pneumonic Plague;Principal Investigator;Process;Production;Proteins;Recurrence;Regulation;Regulon;Relative (related person);Role;Siderophores;Signal Transduction;Site;South America;Southeastern Asia;Staging;Subcutaneous Injections;System;Techniques;Tissues;Transcriptional Activation;Vaccine Therapy;Vaccines;Yersinia pestis;antimicrobial;base;member;mouse model;mutant;pandemic disease;pathogen;permease;programs;receptor;small molecule;uptake;yersiniabactin

public_health_relevance:
Project NarrativeMost bacterial pathogens require iron in order to grow and cause disease. Yersinia pestis the causative agentof plague produces a small molecule called a siderophore that can remove the iron that it needs from hostiron-binding compounds and plays a very important role in both bubonic and pneumonic plague.Understanding how the bacterium makes this siderophore and how its production is regulated may eventuallylead to the development of either a vaccine or new drugs against plague and other bacterial diseases.


application_id: 7987278
project_number: 1R01CA131075-01A2
project_title: The role of Mc1r in melanocytic UV-induced DNA damage and repair responses
administering_ic: NCI
award_notice_date: 2010-06-01
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: CA
serial_number: 131075
suffix: A2
program_official: OKANO, PAUL
project_start_date: 2010-07-01
project_end_date: 2015-04-30
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 8508402
contact_pi: D'ORAZIO, JOHN A
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): We seek to understand the molecular responses that occur when skin is exposed to UV radiation in order to devise novel strategies to protect against damage and carcinogenesis. In this proposal we will examine two major risk factors for skin cancer: UV radiation and pigment (melanin) phenotype. Our studies focus on the melanocyte and its cell surface receptor the melanocortin-1 receptor (Mc1r) which regulates melanin synthesis. We hypothesize that Mc1r protects melanocytes against UV-mediated mutagenesis and transformation by modulating melanization and recovery from UV-mediated cellular injury. Loss-of-function polymorphisms in Mc1r correlate with fair skin and a high incidence of melanoma while robust Mc1r function correlates with darker skin and UV resistance. We have developed a novel genetically-matched murine model of human skin as well as a protocol for growing primary melanocytes from these mice. These isogenic melanocytes span eumelanotic pheomelanotic and amelanotic melanin composition will serve a unique and potent tool to delineate the role of Mc1r function in response to UV. Using our unique animal model and primary melanocytes derived thereof we propose the following aims: Aim 1. Characterize the mechanism of Mc1r-mediated enhancement of nucleotide excision repair (NER); Aim 2. Determine whether Mc1r signaling protects against UV-mediated oxidative damage; and Aim 3. Determine the ability of pharmacologic Mc1r rescue to protect against UV damage. With respect to Aim 1 we will examine the role of Mc1r in the repair of UV-induced photolesions by southwestern and flow cytometric analysis and determine the influence of Mc1r on cellular levels of nucleotide excision repair enzymes by qRT-PCR and Western analysis. We will investigate a molecular link between Mc1r signaling and enhanced repair enzyme levels by examining expression of the NER enzymes basally and in the setting of UV irradiation and by investigating the ability of cAMP-responsive transcription factors downstream of Mc1r signaling (namely Mitf and CREB) to bind to and induce transcription of NER enzyme promoters. In Aim 2 we will study whether pheomelanin which is produced as a result of low Mc1r function promotes oxidative damage in melanocytes by complementary measures of oxidative load (DCF-mediated fluorescence flow cytometry Southwestern blotting hOGG1-adapted Comet assay TBARS assay and direct quantification of oxidative DNA adducts by GC/MS). Importantly we will directly test whether  
pheomelanin functions as a pro-carcinogen by an HPRT-based forward mutagenesis approach in primary melanocytes. Finally we will directly test the ability of forskolin an activator of adenylyl cyclase to bypass defective Mc1r function to enhance recovery from UV-mediated DNA damage and to rescue UV protection in melanocytes and in whole skin. Together these studies will lay the foundation for future translational studies designed to develop novel small molecule-based approaches for UV and cancer protection to prevent many cases of melanoma.  
  
PUBLIC HEALTH RELEVANCE:  Though it has long been known that people with functional defects of the melanocortin 1 receptor (Mc1r) protein are at high risk of developing melanoma the way(s) in which Mc1r protects against melanoma are not understood. Using pigment cells known as melanocytes we will study how the Mc1r protein influences UV- mediated DNA and cellular damage in melanocytes and contributes to melanoma resistance. Our goal is to develop the strategy of pharmacologic Mc1r rescue toward translational applicability so that many cases of melanoma can be prevented.

project_terms:
Address;Adenylate Cyclase;Animal Model;Automobile Driving;Binding (Molecular Function);Biological Assay;Bypass;CREB1 gene;Carcinogens;Cell Line;Cell Surface Receptors;Cells;Comet Assay;Cyclic AMP;DNA;DNA Adducts;DNA Damage;DNA Repair;Defect;Exposure to;Figs - dietary;Flow Cytometry;Fluorescence;Forskolin;Foundations;Future;Genes;Genetic Polymorphism;Genetic Transcription;Goals;Human;In Vitro;Incidence;Individual;Injury;Link;Malignant - descriptor;Malignant Neoplasms;Measures;Mediating;Melanins;Melanocyte stimulating hormone;Methods;Modeling;Molecular;Monophenol Monooxygenase;Mus;Mutagenesis;Nucleotide Excision Repair;Phenotype;Pigmentation physiologic function;Pigments;Primary Cell Cultures;Promotor (Genetics);Protocols documentation;Receptor Signaling;Receptor Melanocortin Type 1;Recovery;Research Design;Resistance;Risk Factors;Role;Skin;Skin Cancer;Skin Pigmentation;Southwestern Blotting;Sun Exposure;Surface;System;Testing;The Sun;UV induced;UV induced DNA damage;UV protection;UV response;Ultraviolet B Radiation;Ultraviolet Rays;Variant;alpha-Melanocyte stimulating hormone;base;carcinogenesis;cell injury;congenic;defined contribution;eumelanin;high risk;loss of function;melanocyte;melanoma;novel;novel strategies;oxidative damage;pheomelanin;photolesion;prevent;public health relevance;receptor;receptor binding;receptor function;repair enzyme;repaired;research study;response;small molecule;synthetic enzyme;tool;transcription factor;translational study;ultraviolet damage;ultraviolet irradiation


application_id: 7987096
project_number: 1R01EY019891-01A1
project_title: Role of 14-3-3o in development and repair of corneal epithelium
administering_ic: NEI
award_notice_date: 2010-08-09
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: EY
serial_number: 019891
suffix: A1
program_official: SHEN, GRACE L
project_start_date: 2010-09-01
project_end_date: 2014-08-31
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 8891723
contact_pi: LI, QIUTANG
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Exposure of the corneal epithelium to the environment leaves this important barrier susceptible to injury. Accordingly the corneal epithelium has a remarkable self-renewal capacity. This self renewal is mediated by a reservoir of limbal stem cells which migrate to sites of injury where they proliferate and differentiate to replace the damaged epithelium. This proposal is directed toward understanding the role of 14-3-3C in corneal epithelial differentiation. 14-3-3 is a family of proteins that bind phosphoproteins and regulate their subcellular localization. 14-3-3C is the epithelial-specific family member and using a mouse genetic model we demonstrate its crucial role in corneal epithelial differentiation Mutation of both copies of the gene leads to defective corneal epithelial development in the embryo. Heterozygous mutation allows for normal embryonic development; however the corneal epithelial differentiation in response to injury remains impaired. Thus 14-3-3C gene dosage distinguishes corneal epithelial development embryologically from corneal epithelial differentiation following injury. This defect in differentiation leads to outgrowth of undifferentiated cells which eventually form an opaque corneal plaque with associated inflammation and neovascularization. This plaque forms spontaneously as the heterozygous mice age and we provide evidence that this is linked to a dry eye-like effect resulting from a defective meibomian gland which fails to secrete lipid. Notch1 is essential for corneal epithelial differentiation via its activation of genes important for both differentiation (including genes in the vitamin A pathway) as well as cell cycle arrest and we have found that 14-3-3C mutant cells fail to activate Notch1. Expression of activated Notch1 restores differentiation in mutant cells and accordingly the defective differentiation phenotype and the resulting corneal plaque formation closely resemble that seem with tissue-specific knockout of the Notch1 gene. We link 14-3-3C to cell surface expression of the EGF receptor (EGFR) and thus to the Erk signaling pathway which is activated by binding of EGF to this receptor. This is important because EGF signaling represses Notch1 and this signaling must be extinguished for Notch1 expression and subsequent corneal epithelial differentiation. We propose studies to further characterize the linkage between 14-3-3C EGFR and Notch1 (and its target genes) in corneal epithelia differentiation. These studies involve both cell culture and genetic cross using 14-3-3C mutant mice.  
  
PUBLIC HEALTH RELEVANCE: The integrity of the cornea the most anterior part of the eye is indispensable for vision. Forty-five million individuals worldwide are bilaterally blind and another 135 million have severely impaired vision in both eyes because of the loss of corneal transparency. Our proposed experiments aim to elucidate the essential role of 14-3-3C in corneal epithelial homeostasis and wound healing and to understand the molecular network that controls the process. We shall study the cornea epithelium development and wound healing process barrier integrity and the molecular/genetic properties of 14-3-3C mutant mice. We hope to better understand corneal disease development and provide new strategies for prevention and treatment.

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


application_id: 7986980
project_number: 1R01CA133171-01A2
project_title: The role of the Ras effector Nore1a in tumor suppression
administering_ic: NCI
award_notice_date: 2010-07-01
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: CA
serial_number: 133171
suffix: A2
program_official: WATSON, JOANNA M
project_start_date: 2010-07-01
project_end_date: 2015-04-30
study_section: Cancer Molecular Pathobiology Study Section[CAMP]
contact_pi_person_id: 8801334
contact_pi: CLARK, GEOFFREY 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
project_abstract:
DESCRIPTION (provided by applicant): Nore1a is a member of the RASSF family of tumor suppressors. It is frequently down- regulated in primary human tumors and is genetically linked to a familial human cancer syndrome. Over-expression of Nore1a can promote apoptosis cell cycle arrest and senescence. Restoration of Nore1a expression to physiological levels blocks the tumorigenic phenotype and shRNA mediated inactivation of Nore1a enhances the transformed phenotype. Thus the evidence that Nore1a is an important human tumor suppressor is strong. Nore1a also directly binds the Ras oncoprotein and appears to serve as a novel effector mediating some of the pro-apoptotic and pro-senescent effects of oncogenic Ras. Thus loss of function of Nore1a may be particularly important to Ras dependent tumors allowing oncogenic Ras to circumvent its apoptotic and senescent functions. However the signaling pathways controlled by Nore1a have not been defined and no animal model for Nore1a function has been investigated. Furthermore the effects of loss of Nore1a function on the transforming effects of oncogenic Ras have not been characterized.  Nore1a lacks obvious enzymatic activity and little is known about its mechanism of action. However it has been hypothesized that it may serve as a scaffolding protein to modulate the formation of tumor suppressor complexes. We have now identified two tumor suppressors in endogenous complex with Nore1a: the Homeodomain Interacting Protein Kinase 2 (HIPK2) protein and the Von Hippel-Lindau protein (VHL) a notorious tumor suppressor which plays a critical role in the development of the majority of Renal Cell Carcinomas (RCC). Both HIPK2 and VHL act in part by directly modulating the master tumor suppressor p53. Defects in p53 have been detected in approximately 50% of human tumors and it may be argued that p53 is the most critical tumor suppressor yet identified. Thus Nore1a may function by modulating p53 by dual pathways and could serve as part of the well known but poorly characterized link between Ras and p53.  We propose a series of experimental aims designed to determine the precise role of Nore1a loss of function in the development of the tumorigenic phenotype and in Ras mediated transformation. This includes a proposal to determine the role of the Nore1a/Ras interaction in vivo using a novel Nore1a knockout mouse model. We will then determine if the mechanism of action of Nore1a involves the modulation of the HIPK2 or VHL tumor suppressors and whether Nore1a acts to integrate their effects upon p53. We anticipate that these experiments will identify Nore1a as an important novel diagnostic and therapeutic target for cancer.  
  
PUBLIC HEALTH RELEVANCE: These studies will serve to define the role of a novel potential tumor suppressor Nore1a in human cancer. They will determine if Nore1a is an important diagnostic/prognostic marker for cancer. They will also determine if Nore1a may be a suitable candidate for the development of epigenetic therapy to restore its normal function in tumor cells.

project_terms:
Animal Model;Apoptosis;Apoptotic;Binding (Molecular Function);Cell Cycle Arrest;Complex;Defect;Development;Diagnostic;Epigenetic Process;Family;Human;Knockout Mice;Link;Malignant Neoplasms;Mediating;Oncogene Proteins;Oncogenic;Pathway interactions;Phenotype;Physiological;Play;Prognostic Marker;Protein Kinase;Protein p53;Proteins;Renal Cell Carcinoma;Role;Scaffolding Protein;Series;Signal Pathway;Signal Transduction;Syndrome;TP53 gene;Tumor Suppression;Tumor Suppressor Proteins;VHL protein;Von Hippel-Lindau Tumor Suppressor Protein;design;homeodomain;in vivo;loss of function;member;mouse model;neoplastic cell;novel;novel diagnostics;public health relevance;research study;restoration;senescence;small hairpin RNA;therapeutic target;tumor;tumorigenic

public_health_relevance:
These studies will serve to define the role of a novel potential tumor suppressor Nore1ain human cancer. They will determine if Nore1a is an important diagnostic/prognosticmarker for cancer. They will also determine if Nore1a may be a suitable candidate forthe development of epigenetic therapy to restore its normal function in tumor cells.


application_id: 7986445
project_number: 1R01ES018883-01A1
project_title: HIF-alphia in Cr(VI) carcinogenesis
administering_ic: NIEHS
award_notice_date: 2010-08-09
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: ES
serial_number: 018883
suffix: A1
program_official: QUINN, ASHLINN KO
project_start_date: 2010-08-09
project_end_date: 2015-03-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 10011919
contact_pi: ZHANG, ZHUO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Although the carcinogenicity of Cr(VI) has been well documented by studies both in vitro and in vivo its mechanism of action remains to be investigated. Our recent studies indicate that Cr(VI) induces HIF-11 activation. MAP kinase p38 and reactive oxygen species (ROS) are involved in this process. HIF-11 is a key regulatory protein for angiogenesis which is a physiological process involving the growth of new blood vessels from pre-existing vessels. Solid tumors of smaller than 1 to 2 cubic millimeters are not vascularized. To spread they need to be supplied by blood vessels that bring oxygen and nutrients and remove metabolic wastes. Inhibition of HIF-11 decreases cell transformation capacity in hypoxia and tumor growth in vivo while overexpression of HIF-11 allows anchorage-independent growth in normoxia and development of more aggressive tumors. Since HIF-11 is important in cancer initiation and progression it is likely that HIF-11 activation and angiogenesis could be important in Cr(VI)-mediated carcinogenesis. We hypothesize that ROS and HIF-11 activation play an important role in Cr(VI)-induced carcinogenesis. Human bronchial epithelial BEAS-2B cells and athymic female nude mice (3-4 weeks old) deficient in thymus-dependent (T-cell) immunological functions will be used in the present study. Three specific aims are proposed. Aim 1 will investigate the mechanism of Cr(VI)-induced ROS generation and the role of ROS in activation of HIF-11 and angiogenesis in vitro. The regulation of HIF-1 activity could occur at multiple levels: transcription translation and post-translational modifications. The questions remain open concerning at what level Cr(VI) induces HIF-11 activation. Aim 2 will answer that question in cell system. Aim 3 will investigate the roles of ROS and HIF-1 signaling in Cr(VI)-induced cell transformation in vitro tumorigenesis tumor growth and metastasis in vivo. We anticipate that Cr(VI) induces angiogenesis via HIF-11 activation through ROS and MAP kinase p38 promoting Cr(VI)-induced cell transformation tumorigenesis tumor growth and metastasis. .  
  
PUBLIC HEALTH RELEVANCE: Hexavalent chromium [Cr(VI)] is a known human carcinogen. The carcinogenicity of Cr(VI) has been well documented by studies both in vitro and in vivo. We hypothesize that Cr(VI) induces oxidative stress and activate HIF-1 angiogenesis signalling pathway leading to cell transformation tumorigenesis tumor growth and metastasis. The goal of this proposal is to test that hypothesis.

project_terms:
Anchorage-Independent Growth;Blood Vessels;Carcinogens;Cell Hypoxia;Cell Line;Cells;Development;Diffuse;Dominant-Negative Mutation;Environmental Carcinogens;Epithelial;Exposure to;Female;Generations;Genetic Transcription;Goals;Human;Hydrogen Peroxide;Hydroxyl Radical;Hypoxia;In Vitro;Incidence;Inhalation Exposure;International Agency for Research on Cancer;MAPK14 gene;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Metabolic;NADPH Oxidase;Neoplasm Metastasis;Nose;Nude Mice;Nutrient;Occupational;Occupational Groups;Oxidative Stress;Oxygen;Pathway interactions;Physiological Processes;Play;Post-Translational Protein Processing;Process;Proteins;Reactive Oxygen Species;Regulation;Reporting;Role;Signal Pathway;Signal Transduction;Small Interfering RNA;Solid Neoplasm;Source;Superoxides;System;T-Lymphocyte;Testing;Thymus Gland;Translations;Vascular Endothelial Growth Factors;Writing;angiogenesis;cancer initiation;carcinogenesis;carcinogenicity;cell transformation;chromium hexavalent ion;genetic regulatory protein;in vivo;insight;millimeter;mitogen-activated protein kinase p38;new growth;overexpression;public health relevance;tumor;tumor growth;tumorigenesis;wasting


application_id: 7986010
project_number: 2R01HL078663-05A1
project_title: Lysolipid Signaling in Cardiovascular Disease
administering_ic: NHLBI
award_notice_date: 2010-07-12
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: HL
serial_number: 078663
suffix: A1
program_official: HASAN, AHMED A K
project_start_date: 2004-09-24
project_end_date: 2014-06-30
study_section: Special Emphasis Panel[ZRG1 VH-E (02)]
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are essential bioactive lysolipid mediators that regulate a range of developmental and physiological processes and are emerging as targets for a new class of molecular therapeutics. In the cardiovascular system LPA is poised to serve as a mediator of atherothrombotic disease: it is abundant in atherosclerotic plaque present in the blood produced by activated platelets triggers phenotypic responses in smooth muscle cells and potentiates platelet activation. Exposure of LPA during atherosclerotic plaque rupture/erosion has been proposed as a key modulator of platelet thrombosis. We report a novel pathway for regulation of platelet LPA responses that involves recruitment of the lysophospholipase D enzyme autotaxin responsible for LPA production to activated platelets. We have also found that LPA inhibits mouse platelet function and that approximately 20% of human volunteers also lack a stimulatory response to LPA. We have evidence that this inhibitory LPA-signaling pathway confers vascular protection from thrombosis in mice and potentially from atherosclerotic disease in humans. We suggest that a therapeutic strategy directed at blocking stimulatory platelet LPA responses while promoting inhibitory ones could result in beneficial anti-thrombotic effects. Implementation of this strategy requires the molecular characterization of platelet LPA responses and proof of a role for circulating or locally produced LPA in regulating hemostasis and thrombosis. The broad goal of this proposal is to provide mechanistic insight essential for establishing LPA signaling as a viable anti-thrombotic target. We will take advantage of the differences in murine and human platelet LPA responses to identify the receptor(s) responsible for LPA signaling in mice and humans and then generate a transgenic mouse with platelet-specific expression of a stimulatory LPA receptor that phenocopies the human LPA response so that processes of relevance to human disease can be studied in a small animal mode. We are uniquely well-prepared to achieve these goals based on our expertise in bioactive lipid signaling and the tools we have amassed to study LPA in the vasculature. Completion of these studies promises to provide valuable insight into regulation of platelet function and may have exciting implications for the development of novel anti-thrombotic strategies that target LPA signaling.  
  
PUBLIC HEALTH RELEVANCE: Atherothrombotic vascular disease is a leading cause of death in the United States. Blood platelets are essential for acute thrombotic events such as heart attacks and strokes and also contribute to local and systemic inflammation. This research project seeks to understand how the production of a class of pro-inflammatory lipid molecules is influenced by platelets and how the lipids affect platelet function. Completion of the work will provide new insights into pathways that could be targeted to prevent and treat arterial thrombosis.

project_terms:
Acute;Adenylate Cyclase;Affect;Agonist;Animal Model;Animals;Arterial Fatty Streak;Atherosclerosis;Binding (Molecular Function);Biological Models;Blood;Blood Platelets;Blood Pressure;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Cell physiology;Cell surface;Cells;Cyclic AMP;Data;Development;Diagnosis;Dinoprostone;Disease;Dose;Enzymes;Event;Exposure to;Funding;G-Protein-Coupled Receptors;Genetic;Goals;Hemostatic function;Human;Human Volunteers;Hyperplasia;In Vitro;Inflammation;Inflammation Mediators;Inflammatory;Integrins;Investigation;Knowledge;Lipids;Lysophosphatidic Acid Receptors;Lysophospholipids;Mediator of activation protein;Molecular;Mortality Vital Statistics;Mus;Myocardial Infarction;Myocardial Ischemia;Nuclear Receptors;Pathway interactions;Peroxisome Proliferators;Phenocopy;Physiological;Physiological Processes;Physiology;Platelet Activation;Play;Positioning Attribute;Process;Production;Property;Prostaglandins;Regulation;Reporting;Research;Research Project Grants;Risk Factors;Role;Rupture;Signal Pathway;Signal Transduction;Smooth Muscle Myocytes;Surface;System;Testing;Therapeutic;Thrombosis;Transgenic Mice;United States;Vascular Diseases;Work;alkylglycerophosphoethanolamine phosphodiesterase;base;cell growth;cell motility;human disease;improved;in vitro Model;in vivo;innovation;insight;lysophosphatidic acid;novel;novel therapeutics;prevent;programs;prostaglandin EP3 receptor;public health relevance;receptor;receptor function;research study;response;sphingosine 1-phosphate;stroke;tool

public_health_relevance:
PROJECT NARRATIVEAtherothrombotic vascular disease is a leading cause of death in the United States. Blood platelets areessential for acute thrombotic events such as heart attacks and strokes and also contribute to localand systemic inflammation. This research project seeks to understand how the production of a class ofpro-inflammatory lipid molecules is influenced by platelets and how the lipids affect platelet function.Completion of the work will provide new insights into pathways that could be targeted to prevent andtreat arterial thrombosis.


application_id: 7985874
project_number: 7R01DK071976-04
project_title: GKLF/Beta-catenin crosstalk in the intestine
administering_ic: NIDDK
award_notice_date: 2010-02-19
application_type: 7
activity_code: R01
ic: DK
serial_number: 071976
program_official: CARRINGTON, JILL L
project_start_date: 2007-09-01
project_end_date: 2012-06-30
study_section: Special Emphasis Panel[ZRG1-DIG-C(02)M]
contact_pi_person_id: 7013090
contact_pi: LIU, CHUNMING
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: 2009-07-15
project_abstract:
DESCRIPTION (provided by applicant): The majority of colorectal cancers have mutations of the ARC (adenomatous polyposis coli) tumor supressor gene or the ?-catenin oncogene causing ?-catenin accumulation that activates other oncogenes. This project will investigate the interaction of ?-catenin and other signaling molecules in the intestine. Gut-enriched Krppel-like transcriptional factor (GKLF now called KLF4) is down-regulated in many colon cancer cells and considered to be a candidate tumor suppressor protein; it inhibits intestinal cell proliferation and induces cell differentiation. In contrast ?-catenin induces intestinal cell proliferation and inhibits differentiation. KLF4 expression is APC-dependent and its function and expression are inversely correlated with those of ?-catenin. The central hypothesis of this project is that KLF4 inhibits ?-catenin signaling in the differentiated cells; conversely ?-catenin inhibits KLF4 expression in proliferating cells so KLF4/??-catenin crosstalk defines the proliferating and differentiating compartments in the intestine. Up- regulation of ?-catenin and down-regulation of KLF4 together contribute to the initiation of colon cancers. To address this hypothesis we will pursue three Specific Aims to: 1) Delineate the mechanisms by which KLF4 inhibits ?-catenin signaling using cell-based assays or in vitro-binding assays; 2) Determine the mechanisms of APC-regulated KLF4 expression in colon cancer cells and in the intestines of APC-deleted mice; and 3) assess the functional effects of KLF4/??-catenin interactions in human colorectal cancers and in nude mice injected with colon cancer cells with altered KLF4/??-catenin signaling. These experiments should elucidate the role of this important signaling axis in the development and progression of colorectal cancers and eventually lead to new clinical markers and treatment approaches for this important class of cancers. Health Relevance: Colorectal cancer is the second leading cause of cancer-related deaths in the U.S. with -150000 new cases and 57000 deaths annually (about 10% of all cancer deaths) at an estimated annual economic cost greater than $3.5 billion. A better understanding of the signaling pathways contributing to colorectal cancer progression should provide targets for novel therapeutic agents to treat this disease.

project_terms:
Address;Adenomatous Polyposis Coli;Binding (Molecular Function);Binding Proteins;Biological Assay;C-terminal;Cancer Etiology;Casein Kinase Ialpha;Cell Adhesion;Cell Differentiation process;Cell Nucleus;Cell Proliferation;Cells;Cessation of life;Chromatin Structure;Clinical;Clinical Markers;Colon Carcinoma;Colorectal Cancer;Complex;Cyclin D1;DNA;Data;Development;Disease;Down-Regulation;E-Cadherin;Epithelial Cells;Family;GKLF protein;Gene Targeting;Genes;Genetic Transcription;Glycogen Synthase Kinase 3;Hand;Health;Homeostasis;Human;In Vitro;Intestines;Kruppel-like transcription factors;Lead;Malignant Neoplasms;Mammalian Cell;Membrane;Messenger RNA;Methods;Molecular;Mus;Mutation;Natural regeneration;Neoplasm Metastasis;Nuclear Translocation;Nude Mice;Oncogenes;Pathway interactions;Phosphorylation;Process;Proliferating;Proteins;Proto-Oncogene Proteins c-myc;Publishing;Recruitment Activity;Repression;Research Personnel;Role;Sampling;Signal Pathway;Signal Transduction;Signaling Molecule;Stem cells;TCF Transcription Factor;Testing;Therapeutic Agents;Tissues;Transact;Transcription Coactivator;Tumor Suppressor Proteins;Up-Regulation (Physiology);base;beta catenin;c-myc Genes;cancer cell;colon cancer cell line;colon carcinogenesis;economic cost;gastrointestinal;insight;mouse model;multidisciplinary;novel therapeutics;overexpression;programs;research study;tumor;tumor growth;tumor progression;tumor xenograft;tumorigenesis;ubiquitin ligase


application_id: 7985358
project_number: 1R01CA133257-01A2
project_title: Exercise-mediated protection against brain metastases
administering_ic: NCI
award_notice_date: 2010-04-23
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: CA
serial_number: 133257
suffix: A2
program_official: EMENAKER, NANCY J
project_start_date: 2010-07-01
project_end_date: 2015-05-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 8260644
contact_pi: TOBOREK, MICHAL
other_pis: Not Applicable
congressional_district: 06
department: NEUROSURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Clinical evidence indicates that moderate to vigorous exercise is a powerful means to reduce metastatic cancer incidence. However the mechanisms of this beneficial influence are not fully understood. Our present application is specially focused on the mechanisms of tumor cell extravasation into the brain. Such an emphasis on brain metastases is consistent with our interest in the blood-brain barrier physiology and pathology. In addition brain metastases are one of the leadings causes of cancer-related morbidity and mortality. The central hypothesis of the present application is that exercise protects against the development of blood- borne brain metastases by increasing antioxidant capacity and modulating redox- regulated responses in the capillary endothelium. To study this hypothesis we will employ an animal model of wheel running mice that mimics the voluntary pattern of human exercise. We will specifically focus on the exercise-mediated protection against vascular mechanisms of tumor cell extravasation via disruption of tight junction proteins of the endothelium. Tight junctions are the critical components of the brain capillaries which regulate the integrity of the blood-brain barrier. Mechanistically the main emphasis will be placed on the involvement of the Ras and Rho signaling in alterations of phosphorylation and expression of tight junction proteins.  The proposed research combines elements of exercise physiology clinical approaches (namely tumor dissemination and growth) cancer progression and molecular and vascular biology. In addition we will employ advanced systems biology approaches. Novelty and significance of the present proposal are related to our focus on the blood-brain barrier in brain metastasis as tumor extravasation occurs at the level of the cerebrovasculature endothelium and the evaluation of the protective effects of physical activity on tumor dissemination and growth. We believe that the data obtained from this proposal will provide evidence that even moderate exercise can significantly protect against the development of blood-brain metastases. Furthermore a better understanding of the pathophysiological regulation of BBB molecular and functional properties is critical in assessing brain metastasis etiology and in identifying future drug targets to develop more effective therapeutic approaches.  
  
PUBLIC HEALTH RELEVANCE:  We propose that exercise can attenuate the formation of brain tumor metastases at the level of the blood-brain barrier (BBB) via antioxidant related mechanisms. Specifically we will explore the link between exercise and the protection against disruption of tight junction proteins alterations of caveolae-associated redox signaling and transcapillary dissemination of tumor cells. We believe that the data obtained from this proposal will provide evidence that exercise can significantly protect against the development of blood-brain metastases.

project_terms:
Abbreviations;Actins;Address;Animal Model;Animals;Antioxidants;Attenuated;Biological Models;Biology;Blood;Blood - brain barrier anatomy;Blood Vessels;Blood capillaries;Brain;Brain Neoplasms;C57BL/6 Mouse;Cancer Etiology;Caveolae;Caveolins;Cell Surface Receptors;Cerebrum;Clinical;Cytoskeleton;Data;Development;Dextrans;Disseminated Malignant Neoplasm;Drug Delivery Systems;Elements;Endothelial Cells;Endothelium;Equilibrium;Etiology;Evaluation;Event;Exercise;Exercise Physiology;Extravasation;Functional disorder;Future;GTP-Binding Proteins;Glutathione;Goals;Growth;Human;In Situ;Incidence;Injection of therapeutic agent;Integral Membrane Protein;Intercellular Junctions;Internal carotid artery structure;Label;Lewis Lung Carcinoma;Link;Malignant Epithelial Cell;Malignant Neoplasms;Manganese Superoxide Dismutase;Mediating;Membrane;Membrane Microdomains;Metastatic malignant neoplasm to brain;Modeling;Moderate Exercise;Molecular;Monomeric GTP-Binding Proteins;Morbidity - disease rate;Mortality Vital Statistics;Mus;Neoplasm Metastasis;Nuclear;Oxidases;Oxidation-Reduction;Oxidative Stress;Pathology;Pathway interactions;Pattern;Permeability;Phosphorylation;Physical activity;Physiology;Process;Property;Proteins;Proteomics;Regulation;Research;Rodent;Role;Running;Signal Pathway;Signal Transduction;Solid;Staining method;Stains;Systems Biology;Techniques;Therapeutic;Tight Junctions;Tissues;Very Light Exercise;advanced system;base;brain tissue;capillary;caveolin 1;dextran;in vivo Model;interest;junctional adhesion molecule;mitochondrial dysfunction;neoplastic cell;novel;occludin;oxidation;prevent;protective effect;protein expression;public health relevance;research study;response;rho;sedentary;tissue processing;tumor;tumor progression

public_health_relevance:
PROJECT NARRATIVE We propose that exercise can attenuate the formation of brain tumor metastases at thelevel of the blood-brain barrier (BBB) via antioxidant related mechanisms. Specifically we willexplore the link between exercise and the protection against disruption of tight junction proteinsalterations of caveolae-associated redox signaling and transcapillary dissemination of tumorcells. We believe that the data obtained from this proposal will provide evidence that exercisecan significantly protect against the development of blood-brain metastases.


application_id: 7984204
project_number: 1R01CA140605-01A2
project_title: Dietary prevention of prostate cancer
administering_ic: NCI
award_notice_date: 2010-07-26
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: CA
serial_number: 140605
suffix: A2
program_official: MALONE, WINFRED F
project_start_date: 2010-08-01
project_end_date: 2011-05-31
study_section: Special Emphasis Panel[ZRG1 OTC-B (02)]
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 natural compounds that possess chemotherapeutic and/or chemopreventive properties with respect to cancer. In the proposed study we will characterize the mechanism of action of the compound Withaferin-A (WA) a bioactive compound of Withania somnifera which is extensively used in Asian and African traditional medicine. WA displays impressive and selective activity against androgen- dependent and androgen-independent prostate cancer (ADPC and AIPC respectively) of which the latter is refractory to all current forms of treatment. Our preliminary in vitro and in vivo data indicate WA targets ADPC and AIPC cells by inhibiting the activity of Akt a protein kinase that activates cell survival pathways. Our preliminary data demonstrate that concomitant to Akt inhibition in ADPC and AIPC cells WA activates FOXO3a which in turn activates prostate apoptosis response-4 (Par-4) a protein that selectively induces apoptosis in cancer cells Based on our results we hypothesize WA overrides the negative effects of Akt on CREB/Par-4 signaling to achieve chemopreventive and/or chemotherapeutic effects on AIPC. To address this hypothesis we propose the following aims: investigate the interaction between Akt/CREB and Par-4 signaling (Aim 1); and how WA modulates the pro-apoptotic signaling in AIPC (Aim 2); evaluate the effects of WA on androgen- -independent prostate tumor growth in the transgenic adenocarcinoma of mouse prostate (TRAMP) model (Aim 3); and examine the mechanisms of WA-mediated tumor inhibition in TRAMP and/or TRAMP cell lines (Aim 4). For the in vitro arm of our studies we will use a variety of approaches (immunoprecipitation siRNA strategies immunofluorescence Western blot Northern blots Chip assays siRNA strategies pull down assays pharmacological blocking) in order to determine the molecular junction at which Akt/CREB 3aand Par-4 converge. For our in vivo studies we will conduct tumor regression studies yet we will also examine histopathology cell death expression patterns of pro-survival proteins and pro-apoptotic proteins in the tumor tissues and WA levels in the serum and prostate tissue. Our long term goal is to promote natural compounds to a clinical environment where these agents can be thoroughly assessed for their chemopreventive and chemotherapeutic properties. Our preliminary data indicate WA is a potential candidate for such clinical evaluation and our proposed studies will elucidate at a mechanistic level its potency against prostate cancer both from a chemopreventive and chemotherapeutic standpoint.  
  
PUBLIC HEALTH RELEVANCE: Prostate cancer (PCa) remains a major cause of cancer-related death and at advanced stages current therapy is ineffective. Intervention with dietary compounds for the prevention and/or treatment of prostate cancer is a relatively new area of research focused on signal transduction pathways which has resulted in the development of important new therapeutics for specific malignancies. The proposed study of dietary supplement Withaferin-A (WA) the major bioactive compound from Withania somnifera) is designed to provide essential insights at the molecular level into the mechanism of action of Withaferin-A against prostate cancer and may ultimately lead to clinical evaluation of its potential for chemoprevention and/ or chemotherapy in prostate cancer.

project_terms:
Address;Adenocarcinoma;African Traditional Medicine;Age;Androgens;Animal Model;Apoptosis;Apoptotic;Area;Asians;Binding (Molecular Function);Biological Assay;Cancer Etiology;Cancer Model;Cell Culture Techniques;Cell Death;Cell Line;Cell Survival;Cells;Cessation of life;Chemoprevention;Chemopreventive Agent;Clinical;Clinical Trials;Cyclic AMP Response Element;Cyclic AMP-Responsive DNA-Binding Protein;Data;Development;Diet;Dietary Supplements;Environment;Event;Exposure to;Gap Junctions;Goals;Growth;Histopathology;Immunofluorescence Immunologic;Immunoprecipitation;In Vitro;Induction of Apoptosis;Inhibition of Apoptosis;Intervention;Lead;Lesion;Lipids;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Modality;Modeling;Molecular;Mus;Northern Blotting;Outcome;Outcome Study;PAWR gene;PTEN gene;Pathway interactions;Pattern;Phosphoric Monoester Hydrolases;Phosphorylation;Prevention;Prevention approach;Promotor (Genetics);Property;Prostate;Prostatic Neoplasms;Protein Kinase;Proteins;Refractory;Research;Resistance;Role;S-Phase Fraction;Serum;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Small Interfering RNA;Specimen;Staging;Tissues;Trans-Activation (Genetics);Transgenic Animals;Transgenic Organisms;Tumor Suppressor Proteins;Tumor Tissue;Western Blotting;Withania somnifera;androgen independent prostate cancer;angiogenesis;arm;base;cancer cell;cell growth;chemotherapy;design;feeding;in vivo;insight;novel therapeutics;prevent;pro-apoptotic protein;prostate cancer prevention;public health relevance;research clinical testing;research study;response;tumor;tumor growth;tumor progression

public_health_relevance:
Project narrative:Prostate cancer (PCa) remains a major cause of cancer-related death and at advanced stages current therapyis ineffective. Intervention with dietary compounds for the prevention and/or treatment of prostate cancer is arelatively new area of research focused on signal transduction pathways which has resulted in thedevelopment of important new therapeutics for specific malignancies. The proposed study of dietarysupplement Withaferin-A (WA) the major bioactive compound from Withania somnifera) is designed toprovide essential insights at the molecular level into the mechanism of action of Withaferin-A against prostatecancer and may ultimately lead to clinical evaluation of its potential for chemoprevention and/ or chemotherapyin prostate cancer.


application_id: 7983086
project_number: 2R01CA035635-23A2
project_title: Specificity of Intercalation Reactions
administering_ic: NCI
award_notice_date: 2010-06-30
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: CA
serial_number: 035635
suffix: A2
program_official: LEES, ROBERT G
project_start_date: 1984-03-01
project_end_date: 2014-12-31
study_section: Macromolecular Structure and Function B Study Section[MSFB]
contact_pi_person_id: 1863983
contact_pi: CHAIRES, JONATHAN B.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): DNA is an underrepresented target for small molecule therapeutic agents. One reason for the dearth of DNA targeted drugs is that the fundamental molecular mechanisms that govern sequence- and structural-selective ligands to DNA remain poorly understood. In order to develop design principles for targeting specific DNA sites a thorough understanding of the binding mechanisms of existing compounds that bind to DNA with unique types of selectivity is needed. The long-range goal of this project is to understand the mechanism of DNA intercalation reactions with particular emphasis on the energetic basis of sequence- and structural-selective binding. Renewal is sought for a successful and highly productive basic science program that has produced several promising avenues for DNA-targeted drug development. Four-stranded G-quadruplex DNA structures have emerged as important functional elements within the genome and represent important new targets for therapeutic drugs. G-quadruplexes are functional elements that are important in telomere biology and are emerging as important control elements in the expression of many genes particularly oncogenes. Research in the next funding period will focus on biophysical studies of G-quadruplex structure folding and stability and on their selective interactions specific quadruplex structures with drug-like molecules. Specific aims include: 1. Determination of the structure of the 200 nt single-stranded DNA overhang that is a conserved feature of human telomeres. 2. Determination of the thermodynamic stability of higher-order quadruplex structures and the kinetics of the folding. 3. Determination of the thermodynamics and kinetics of drug binding to specific quadruplex structures including the higher-order structures in telomeric DNA and the G-quadruplex "silencer" element found in the c-myc promoter. The results of these proposed studies will deepen our understanding of the structure and stability of functionally important G-quadruplexes and will provide fundamental mechanistic information of use in the rational design of new small molecules to selectively target functionally important quadruplex structures.  
  
PUBLIC HEALTH RELEVANCE: G-quadruplexes are four-stranded DNA structures that are thought to be functionally import elements in the human genome. Quadruplexes have emerged as potential drug targets. The proposed project will use computational and biophysical methods to study the structure stability and drug binding of functionally significant quadruplex structures. The results will be of fundamental use for guiding the design of new drugs targeted toward quadruplexes.

project_terms:
Base Sequence;Basic Science;Binding (Molecular Function);Binding Proteins;Biology;Calorimetry;Cell Cycle;Coupled;Crystallography;DNA;DNA Intercalation;DNA Structure;Diffusion;Drug Delivery Systems;Drug Kinetics;Drug Stability;Elements;Fluorescence;Foundations;Funding;G-Quartets;Gene Expression;Genes;Genome;Goals;Higher Order Chromatin Structure;Human;Human Genome;In Vitro;Indium;Kinetics;Ligand Binding;Ligands;Methods;Molecular;New Agents;Oncogenes;Pharmaceutical Preparations;Process;Promotor (Genetics);Property;Proteins;Radial;Reaction;Refractory;Regulatory Element;Research;Research Design;Resolution;Sedimentation process;Single-Stranded DNA;Site;Specificity;Structural Models;Structure;Telomerase;Testing;Therapeutic Agents;Thermodynamics;Time;Transcriptional Silencer Elements;base;c-myc Genes;design;dimer;driving force;drug development;innovation;intercalation;light scattering;molecular dynamics;new therapeutic target;programs;public health relevance;sedimentation velocity;small molecule;telomere


application_id: 7980997
project_number: 1R21EY021016-01
project_title: Pulvinar Influence on Striate Cortex Activity
administering_ic: NEI
award_notice_date: 2010-09-14
opportunity_number: PA-09-164
application_type: 1
activity_code: R21
ic: EY
serial_number: 021016
program_official: STEINMETZ, MICHAEL A
project_start_date: 2010-09-30
project_end_date: 2012-09-29
study_section: Special Emphasis Panel[ZRG1 IFCN-L (02)]
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant):  While advances have been made in characterizing the synaptic organization and visual response properties of the pulvinar nucleus its' exact contributions to the coding of visual signals have remained elusive. The proposed experiments are designed to answer fundamental questions regarding the projection from the pulvinar nucleus to the striate cortex. Using novel combinations of optogenetics tract tracing and in vitro whole cell recordings we will determine which cortical cell types are activated by pulvinocortical terminals and the frequency dependency of pulvinocortical responses. We will then use optogenetics and in vivo intrinsic optical imaging to determine whether inputs from the pulvinar nucleus change cortical receptive field properties. Tree shrews (tupaia belangeri) will be used as the experimental model because the circuitry of tree shrew striate cortex is well defined and similar to that of primates and in vivo intrinsic optical imaging of the tree shrew striate cortex provides a convenient method to monitor global changes in receptive field properties. The proposed experiments should contribute to our understanding of the construction and modulation of striate cortex response properties and how the pulvinar nucleus contributes to vision.  
  
PUBLIC HEALTH RELEVANCE:  The proposed experiments should contribute to our basic scientific understanding of the construction and modulation of V1 response properties relevant to the treatment of disorders such as strabismus and amblyopia. The experiments should also reveal fundamental information regarding the function of the pulvinocortical projections relevant to the treatment of disorders that are known to affect the pulvinar nucleus such as schizophrenia.

project_terms:
Affect;Amblyopia;Animals;Cations;Cell Nucleus;Cells;Collaborations;Complex;Dependency (Psychology);Disease;Experimental Models;Frequencies (time pattern);Functional Magnetic Resonance Imaging;Global Change;Green Fluorescent Proteins;Homologous Gene;Image;In Vitro;Inferior;Label;Lateral posterior nucleus of thalamus;Lesion;Light;Maps;Methods;Microspheres;Monitor;Motion;Patients;Pattern;Physiological;Population;Primates;Property;Pulvinar structure;Pyramidal Cells;Rhodamine;Rhodamines;Rodent;Schizophrenia;Signal Transduction;Slice;Strabismus;Structure of inferior part of pulvinar;Surface;Synapses;Tupaia;Tupaiidae;Universities;V1 neuron;Viral Vector;Virginia;Vision;Visual;Whole-Cell Recordings;area striata;cell type;design;in vivo;nonhuman primate;novel;optic imaging;orientation selectivity;postsynaptic;receptive field;research study;response;retinotopic;visual coding;visual stimulus;ward

public_health_relevance:
The proposed experiments should contribute to our basic scientific understanding of the constructionand modulation of V1 response properties relevant to the treatment of disorders such as strabismus andamblyopia. The experiments should also reveal fundamental information regarding the function of thepulvinocortical projections relevant to the treatment of disorders that are known to affect the pulvinar nucleussuch as schizophrenia.


application_id: 7980368
project_number: 2R01CA049797-19
project_title: Mechanisms of MnSOD expression in normal and tumor cells
administering_ic: NCI
award_notice_date: 2010-07-01
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: CA
serial_number: 049797
program_official: MIETZ, JUDY
project_start_date: 1989-12-01
project_end_date: 2015-04-30
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 long-term goal of this project is to identify novel redox base mechanisms that lead to the development of cancer. Our studies have identified the mitochondrial antioxidant enzyme manganese containing superoxide dismutase (MnSOD) as an important regulator that can both modulate the development of cancer and be modulated during the progression of cancer. Our studies in the previous funding period demonstrate that reduction of MnSOD levels occurs very early in the development of skin cancer and that the level of p53 regulates the expression of MnSOD. We also found that the level of the mitochondrial uncoupling protein 1 (UCP1) is significantly increased in skin tissues of MnSOD-deficient mice. We hypothesize that the activities of p53 MnSOD and UCP1 are regulated to minimize reactive oxygen species (ROS) production in mitochondria.  We propose that: 1) as a critical transcription factor p53 cooperates with transcriptional activators and suppressors to regulate MnSOD transcription (Aim 1) and 2) the reduction of MnSOD levels in mitochondria leads to UCP1 induction as a result of compromised mitochondrial function which induces transcriptional responses to reduce superoxide production from mitochondrial respiration (Aim 2). The positive and negative feedback loops between nuclei and mitochondria help to ensure that superoxide levels are minimized to prevent mitochondrial dysfunction and subsequent neoplastic transformation. We will use state-of-the-art molecular biology biochemistry and free radical biology approaches to address these specific aims.  Because mitochondria are major sites of cellular energy production and cellular ROS homeostasis and are integrators of apoptosis signaling that are altered in cancer cells understanding the regulation of mitochondrial ROS levels is important and will provide a unique opportunity to design novel interventions that maximize the benefits to normal tissues and prevent cancer development. Given that cellular redox status contributes to almost all aspects of biological function and that MnSOD and p53 are critical for normal cellular function and for cancer prevention the results from this study of cancer will have a broad impact on human health and the prevention of other diseases including obesity and metabolic disorders.  
  
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 found that the mitochondrial antioxidant enzyme manganese containing superoxide dismutase (MnSOD) is an important regulator that can modulate the development of cancer as well as be modulated during the progression of cancer. Our studies demonstrate that reduction of MnSOD levels occurs very early in the development of skin cancer and that expression of MnSOD is regulated by p53. We also found that the levels of the mitochondrial uncoupling protein (UCPs) are altered in skin tissue of MnSOD-deficient mice. In this application we will extend from this novel finding to determine how UCPs 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/or alteration of mitochondrial function.

project_terms:
Address;Antioxidants;Apoptosis;Arts;Binding (Molecular Function);Binding Sites;Biochemistry;Biogenesis;Biological Process;Biology;Cell Nucleus;Cell physiology;Cells;Chemicals;DNA Structure;Data;Development;Disease;Ensure;Enzymes;Exhibits;Family;Feedback;Free Radicals;Funding;Gene Expression;Genes;Genetic Transcription;Goals;Health;Homeostasis;Human;In Vitro;Intervention;Knowledge;Lead;Learning;Link;Luciferases;Malignant - descriptor;Malignant Neoplasms;Manganese;Manganese Superoxide Dismutase;Mediating;Messenger RNA;Metabolic;Metabolic Diseases;Mitochondria;Mitochondrial Proteins;Molecular Biology;Monitor;Mus;Neoplastic Cell Transformation;Normal tissue morphology;Obesity;Oxidation-Reduction;Oxidative Phosphorylation;Physiological;Prevention;Prevention strategy;Production;Promotor (Genetics);Proteins;RNA-Binding Proteins;Reactive Oxygen Species;Regulation;Regulatory Element;Reporter Genes;Reporting;Respiration;Ribonucleoproteins;Role;SOD2 gene;Signal Transduction;Site;Skin Cancer;Skin Carcinogenesis;Skin Tissue;Structure;Superoxide Dismutase;Superoxides;TP53 gene;Testing;Transcription Coactivator;Transgenic Mice;Tumor Suppressor Proteins;UV Radiation Exposure;Ultraviolet Rays;United States;base;cancer cell;cancer prevention;design;disorder prevention;fascinate;in vivo;insight;link protein;liposarcoma;member;mitochondrial dysfunction;mitochondrial uncoupling protein;mouse model;neoplastic cell;novel;nucleophosmin;prevent;programs;public health relevance;research study;response;skin cancer prevention;transcription factor;tumor progression;uncoupling protein 1

public_health_relevance:
Program NarrativeSkin cancer is the most common human malignancy in the United States. Many chemicals andUltraviolet radiation (UV) are well-established agents that cause skin cancer. We have found that themitochondrial antioxidant enzyme manganese containing superoxide dismutase (MnSOD) is animportant regulator that can modulate the development of cancer as well as be modulated during theprogression of cancer. Our studies demonstrate that reduction of MnSOD levels occurs very early inthe development of skin cancer and that expression of MnSOD is regulated by p53. We also found thatthe levels of the mitochondrial uncoupling protein (UCPs) are altered in skin tissue of MnSOD-deficientmice. In this application we will extend from this novel finding to determine how UCPs acts to preventskin cancer and will perform proof-of-concept experiments to verify the feasibility of using theknowledge to be learned to prevent the development of skin cancer resulting from exposure to UVand/or alteration of mitochondrial function.


