# projects

application_id: 8429732
project_number: 1R21AI103717-01
project_title: Targeting functional assembly of the bacterial multidrug efflux transporter
administering_ic: NIAID
award_notice_date: 2013-08-09
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: AI
serial_number: 103717
program_official: XU, ZUOYU
project_start_date: 2013-08-09
project_end_date: 2015-07-31
study_section: Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section[DDR]
contact_pi_person_id: 10386925
contact_pi: WEI, YINAN
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
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 World Health Organization has identified antimicrobial resistance as one of the top three threats to human health. In contrast with the fast
evolution and spreading of drug-resistant pathogens the number of effective antimicrobials that are available to healthcare workers is dwindling. The long-term goal of the research is to find solutions to treat bacterial infections caused by drug resistant pathogens. The biogenesis process of the primary multidrug efflux pump in bacterial pathogen will be used as a novel target. In Gram-negative bacteria such as Escherichia coli the triplex AcrA-AcrB-TolC pump is a major player in both intrinsic and acquired multidrug resistance. Mutant strains of E. coli deficient in the pump exhibit drastically decreased tolerance to many drugs. Therefore inhibitors that interrupt drug efflux should be very useful in reversing drug- resistance in pathogens. The central hypothesis is that the protein assembly process can be blocked to prevent or disrupt the production of functional MDR pumps. Specifically the objective of the proposed study is to identify inhibitors to block the oligomerization of AcrB which exists and functions as a homotrimer. The following Specific Aims will be pursued: 1) To develop an assay to identify compounds that promote AcrB trimer dissociation. 2) To develop an assay to identify compounds that prevent AcrB subunit association. 3) To screen a small collection of compounds to validate and optimize assays. In year one the work focus will be the development of assays (Aims 1 and 2). In year two approximately 5000 compounds will be screened to validate the assay and identify hit compounds. For identified active compounds we will confirm their activity using bacteria culture and measure binding parameters of their interaction with the target protein. Outcomes of the proposed study include the establishment of useful assays and methodologies to interfere with membrane protein oligomerization. Similar methodologies will be directly applicable to AcrB homologues in other Gram- negative pathogens. In addition the collection of hit compounds that will be obtained will serve as seed structures to generate follow up compound for future screening effort. Upon completion of the project we will seek additional funding and collaborate with the University of Cincinnati Drug Discovery Center to adapt our assay for high throughput screening using 384-well plates. It would also include a collaborative medicinal chemistry synthetic effort based on the results of this R21 and results from the expanded screening. These extended efforts would also involve development of a biology component to test compound efficacy including mammalian cellular toxicity. Another option is broader screening through a proposal to the NIH Molecular Libraries Program or partnering with an interested pharmaceutical company. We expect the proposed research will lead to new compound classes and validate novel target mechanisms for the development of effective antimicrobial treatments for drug-resistant E. coli and other Gram-negative bacterial pathogens.

project_terms:
Affinity;Amino Acids;Antibiotics;Antimicrobial Resistance;Bacteria;Bacterial Infections;Binding (Molecular Function);Biogenesis;Biological Assay;Biology;Cell membrane;Chimeric Proteins;Clinical Trials;Collaborations;Collection;Development;Dissociation;Drug Binding Site;Drug Efflux;Drug resistance;Escherichia coli;Escherichia coli drug resistance;Evolution;Exhibits;Fluorescence;Funding;Future;Goals;Gram-Negative Bacteria;Growth;Health;Health Personnel;Homologous Gene;Human;In Vitro;Incidence;Infection;Lead;Libraries;Link;Measures;Membrane Fusion;Membrane Proteins;Methodology;Methods;Microbe;Molecular Bank;Monitor;Multi-Drug Resistance;Outcome;Oxidation-Reduction;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacologic Substance;Process;Production;Proteins;Pump;Reporter;Research;Seeds;Site;Solutions;Staging;Structure;Testing;Toxic effect;United States National Institutes of Health;Universities;Work;World Health Organization;antimicrobial;assay development;base;design;disulfide bond;drug discovery;efflux pump;expectation;flexibility;follow-up;high throughput screening;inhibitor/antagonist;interest;monomer;mutant;novel;novel strategies;pathogen;pathogenic Escherichia coli;prevent;programs;protein protein interaction;public health medicine (field);public health relevance;screening;small molecule;success

public_health_relevance:
The rapid increase in the incidence of drug resistance in pathogenic strains of Gram-negative bacterium is an especially worrisome and critical global public health challenge. The goal of the proposed studies is to identify inhibitors to block the biogenesis of the major multidrug resistant pump AcrAB-TolC. Two assays will be developed to identify compounds that interfere with the trimerization of AcrB which will disable the efflux pump and drastically increase the potency of antimicrobial treatment.


application_id: 8428588
project_number: 5P30NS051220-08
project_title: MICROSCOPY CORE
administering_ic: NINDS
award_notice_date: 2012-11-21
opportunity_number: PAR-08-116
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: Neurological Sciences and Disorders A Study Section[NSD-A]
subproject_number: 7622
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-12-01
budget_end_date: 2013-11-30
project_abstract:
The Microscopy Image Analysis and Stereology Core located on the BBSRB fourth floor provides advanced instrumentation required for neurotrauma and other neuroscience research including two Olympus Provis AX70 Fluorescence Microscopes (Image Pro interfaced via MagnaFire Digital Camera) an Olympus BX 41 with Video Camera an Olympus BX 50 Epifluorescent Microscope (Bioquant Stereology package + 3D topographer interfaced with MagnaFire Digital Camera and Optronics Video Camera) a
Zeiss Axiovert 200 M microscope and a Nikon E400 teaching microscope with DAGE Video Camera. In addition to this existing equipment SCoBIRC recently invested in three new specialized microscopes with funding from the NIH. The first an Olympus FluoViewTM 300 point-scanning point-detection confocal laser scanning microscope designed for biology research applications has excellent resolution efficiency of
excitation and an intuitive user-friendly interface including preset parameters for individual users. The FluoViewTM 300 is also capable of 3D rendering and time-lapse observation and TTL I/O signals can be generated to coordinate experiments timed with external instrumentation. Additionally two high-sensitivity photomultiplier tubes (PMTs) are located directly within the FV300 confocal fluorescence emission light path for high sensitivity detection of the fluorescence signal. The second stereology microscope is an inverted
Olympus IX 81 outfitted with motorized stage encoders and the BioQuant Nova Prime software particulariy well suited for quantification using modern stereological tools. The core is staffed by a Core Director Patrick Sullivan Ph.D. SCoBIRC Associate Director and Associate Professor of Anatomy & Neurobiology and an Assistant Director Alexander Rabchevsky Ph.D. Associate Professor of Physiology both of whom are well
versed in the use of multiple image analysis endpoint measures and confocal imaging as endpoints in theirresearch. Both have expertise in developing protocols used to assess tissue sparing and cell loss in neurotrauma research.

project_terms:
Anatomy;Biology;Cell Count;Cells;Center Core Grants;Computer software;Computers and Advanced Instrumentation;Detection;Doctor of Philosophy;Educational process of instructing;Electrons;Equipment;Floor;Fluorescence;Funding;Housing;Human Resources;Image;Image Analysis;Individual;Lasers;Light;Measurement;Measures;Microscope;Microscopic;Microscopy;Neurobiology;Neurosciences Research;Physiology;Protocols documentation;Research;Resolution;Scanning;Signal Transduction;Staging;Time;Tissues;Tube;United States National Institutes of Health;design;digital;digital imaging;fluorescence microscope;instrumentation;light emission;method development;photomultiplier;professor;research study;spinal cord and brain injury;tool;transmission process;user-friendly


application_id: 8428587
project_number: 5P30NS051220-08
project_title: BEHAVIORAL TESTING
administering_ic: NINDS
award_notice_date: 2012-11-21
opportunity_number: PAR-08-116
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: Neurological Sciences and Disorders A Study Section[NSD-A]
subproject_number: 7621
contact_pi_person_id: 6875991
contact_pi: SAATMAN, KATHRYN E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-12-01
budget_end_date: 2013-11-30
project_abstract:
The Behavioral Testing Core is housed within two rooms in the basement of BBSRB. B028 is a dedicated room for behavioral assessment of rats in which the Core has the capability of performing a) cognitive testing of learning and memory using a Morris water maze system b) sensory testing using a whisker nuisance task c) nociceptive testing using a Hargreaves plantar device and d) locomotor function testing using the Basso Beattie Bresnahan (BBB) scale and the foot misplacement apparatus (horizontal ladder).
B030 is a dedicated room for behavioral assessment of mice in which the Core has the capability of performing cognitive testing of learning and memory using a white Morris water maze (for black mice) or a black maze (for white mice) in conjunction with an updated digital tracking system. Mice can also be evaluated for sensorimotor function using a corner turn test vestibulomotor ability using the rotarod apparatus and simple and complex motor function using the composite neuroscore neurological severity
score. Basso mouse scale (BMS) grip strength meter and string test. Specific instruments purchased with P30 funds include 2 AccuScan Instruments EzVideoDV Automated Tracking System Digital Systems a Columbus Instruments Rotamex-5 and Foot Misplacement Apparatus 2 analgesia meters and a wading pool for open field locomotor assessment. Kathryn Saatman Ph.D. directs the Behavioral Testing Core
along with Assistant Core Director Alexander Rabchevsky. Stephen Onifer Ph.D provide day-to-day management of core operations and overseeing training data storage and dissemination and core usage.
Two senior technicians who are trained in behavioral testing in rodent TBI models (Ms. Jennifer Pleasant 25% effort) and SCI models (Mr. Travis Lyttle 25% effort) assist and instruct new core users with the behavioral assessments.

project_terms:
Absence of pain sensation;Behavior assessment;Center Core Grants;Cognitive;Complex;Data Storage and Retrieval;Devices;Doctor of Philosophy;Equipment;Evaluation Methodology;Funding;Housing;Learning;Memory;Modeling;Motor;Mus;Neurologic;Nociception;Rattus;Research;Rodent;Sensorimotor functions;Sensory;Severities;System;Testing;Training;Update;Vibrissae;behavior test;digital;foot;grasp;improved;instrument;meter;morris water maze;operation;ranpirnase;spinal cord and brain injury


application_id: 8428585
project_number: 5P30NS051220-08
project_title: ANIMAL MODELING
administering_ic: NINDS
award_notice_date: 2012-11-21
opportunity_number: PAR-08-116
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: Neurological Sciences and Disorders A Study Section[NSD-A]
subproject_number: 7620
contact_pi_person_id: 1884283
contact_pi: SCHEFF, STEPHEN W
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-12-01
budget_end_date: 2013-11-30
project_abstract:
CORE B. Animal Modeling Core Plans: This core previously named the Animal Surgery & TBI/SCI Model Core will be renamed Animal Modeling Core to reflect the expansion of the capabilities of this widely used facility beyond its previous use as an animal surgery and neurotrauma modeling resource. While these functions will continue to constitute the central component of the core which will be the Surgery and In Vivo Models Component we request funding to add physiological (blood pressure heart rate arterial oxygenation body temperature and electrophysiological (e.g. somatosensory evoked potentials
magnetically-evoled inter-enlargement recordings) monitoring capability during the acute recovery period after experimental neurotrauma. In addition we request support to establish a Viral Vectors Component and a Genetically-Modified Mice Component. These latter two capabilities currently exist within individual SCoBIRC laboratories (Dr. George Smith's lab in the former instance and Dr. Geddes' in the latter case).
However the increasing need for the application of these across multiple laboratories has made it sensible to now expand and incorporate them under the umbrella of our Animal Modeling Core in order to improve access to them and to insure technical standardization across user laboratories.

project_terms:
Acute;Animal Model;Animals;Blood Pressure;Body Temperature;Breeding;Center Core Grants;Funding;Genes;Genotype;Heart Rate;Improve Access;Individual;Knock-out;Laboratories;Microinjections;Modeling;Monitor;Mus;Names;Operative Surgical Procedures;Physiologic Monitoring;Physiological;Recovery;Research;Resources;Rodent;Somatosensory Evoked Potentials;Standardization;Transgenic Organisms;Viral Vector;in vivo;in vivo Model;spinal cord and brain injury


application_id: 8427869
project_number: 1U01AA021901-01
project_title: Novel therapies in alcoholic hepatitis University of Louisville
administering_ic: NIAAA
award_notice_date: 2012-09-13
opportunity_number: RFA-AA-12-007
application_type: 1
activity_code: U01
ic: AA
serial_number: 021901
program_official: WANG, JOE
project_start_date: 2012-09-15
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZAA1 JJ (07)]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This application is the translational component of an overall UO1 application entitled "Novel therapies in alcoholic hepatitis - University of Louisvill." Alcoholic hepatitis (AH) has a high morbidity and mortality. In VA Cooperative Studies in which liver biopsies were performed only 35% of patients with AH and underlying cirrhosis and 60% of those with AH alone (no cirrhosis) were alive at the end of four years with most deaths occurring early in the study. There is no FDA-approved therapy for any stage of alcoholic liver disease (ALD). The most widely-used (off-label) drug therapies for AH are glucocorticoids and pentoxifylline. Both agents have anti-inflammatory activities and downregulate proinflammatory cytokines such as tumor necrosis factor (TNF). Unfortunately an important subset of AH patients treated with glucocorticoids have "steroid resistance" and some patients have contraindications to steroid therapy. Studies on pentoxifylline in AH are limited and efficacy appears highest in preventing/treating the hepatorenal syndrome. Thus new therapies as well as a better understanding of mechanisms/biomarkers for severity of disease and response to therapy are necessary. Our research team has been a leader in defining mechanisms of alcohol-induced liver injury using in vitro and animal models of ALD and in translating basic findings into the clinical setting. Our group is the first to describe dysregulated cytokine metabolism in AH. We have a long-standing interest in mechanisms of inflammation and liver injury. We also have extensive experience in the gut-liver axis and AH as well as in the development of novel therapies for AH.!!Building on the above translational research strengths of our program which focus on the gut-liver axis and inflammation in ALD we propose three highly translational Specific Aims which all relate to and utilize samples from our proposed UO1 clinical trial. Aim 1 will evaluate novel mechanisms for alcohol-induced alterations in gut integriy leading to endotoxemia and AH. We will study the therapeutic efficacy of both live probiotics and probiotic supernatants. Aim 2 will study the role of specific PDE4 inhibition in AH using animal models and our AH clinical patient population. There are recent data in the pulmonary literature showing that specific PDE4 inhibitors are effective in steroid resistant patients which may translate to AH. Lastly Aim 3 evaluates mechanisms for steroid resistance using both specimens from patients in our clinical trial and in vitro data. All three of our specific aims utiize specimens obtained from our U01 clinical trial and our protocol interacts with the two other translational protocols in our U01 consortium. Our goal is not only to better understand mechanisms for AH but also to develop new therapies (including those already available for other diseases) for AH either immediately transforming clinical practice or providing novel therapies for our clinical trial consortium.   
   
PUBLIC HEALTH RELEVANCE: This is a translational application portion of an overall UO1 application. Our goal is not only to better understand mechanisms for AH but also to develop new therapies (including those already available for other diseases) for AH.

project_terms:
Acute Alcoholic Hepatitis;Adenylate Cyclase;Alcohol consumption;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Amino Acids;Anabolic steroids;Animal Model;Anti-Bacterial Agents;Anti-Inflammatory Agents;Anti-inflammatory;Attenuated;Bacteria;Biological Assay;Cessation of life;Cirrhosis;Clinical;Clinical Trials;Cyclic AMP;Data;Development;Dinoprostone;Disease;Effectiveness;Endotoxemia;Endotoxins;FDA approved;Glucocorticoids;Goals;Hepatorenal Syndrome;Human;Hypoxia;Hypoxia Inducible Factor;In Vitro;Inflammation;Injury;Interleukin-1;Interleukin-10;Intestines;Label;Laboratories;Life;Literature;Liver;Lung;Metabolism;Misoprostol;Morbidity - disease rate;Mortality Vital Statistics;Mucins;Mucous body substance;Nutritional Support;Patients;Pentoxifylline;Peptides;Permeability;Pharmacotherapy;Phosphodiesterase Inhibitors;Placebos;Positioning Attribute;Prednisone;Probiotics;Production;Protocols documentation;Relative (related person);Research;Research Personnel;Resistance;Role;Sampling;Severities;Severity of illness;Signal Transduction;Site;Specimen;Staging;Steroid Resistance;Steroid therapy;Steroids;Stimulus;Supplementation;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Translating;Translational Research;Treatment Efficacy;Tumor Necrosis Factor-alpha;Universities;Zinc;analog;biomarker;clinical practice;cooperative study;cytokine;experience;improved;inhibitor/antagonist;interest;liver biopsy;monocyte;novel;novel strategies;patient population;peripheral blood;phosphoric diester hydrolase;prevent;prognostic indicator;programs;response;trefoil factor


application_id: 8427392
project_number: 5R01MH082762-04
project_title: 2/2-Computer-Assisted Cognitive-Behavior Therapy for Depression
administering_ic: NIMH
award_notice_date: 2013-01-10
opportunity_number: PAR-09-153
application_type: 5
activity_code: R01
ic: MH
serial_number: 082762
program_official: O'CONNOR, STEPHEN
project_start_date: 2010-06-16
project_end_date: 2015-01-31
study_section: Interventions Committee for Adult Disorders[ITVA]
contact_pi_person_id: 9075017
contact_pi: WRIGHT, JESSE H.
other_pis: Not Applicable
congressional_district: 03
department: PSYCHIATRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): We propose a two center randomized controlled trial evaluating the efficacy and cost-effectiveness of computer-assisted cognitive-behavior therapy (CCBT) for outpatients with major depressive disorder (MDD). Results of a preliminary study indicated that despite reducing the amount of therapist contact by about 50% CCBT was at least as effective as an 8 week course of conventional individual CBT on depression outcomes with greater effects on dysfunctional attitudes and knowledge about CBT. We now propose to conduct a more rigorous test of the therapeutic equivalence and cost-effectiveness of CCBT versus a full 16 week 20 session course of individual CBT which provides three times the amount of therapeutic contact. A total of 172 male and female outpatients (86 per site) meeting SCID/DSM-IV criteria for MDD will be randomized across five years. Outcomes will be assessed by independent evaluators without knowledge of the treatment received. The study is designed to have the statistical power to test the equivalence of CCBT and the full course of CBT at both the end of acute phase therapy and across 6 months of follow-up. In addition to effects on depressive symptoms and categorical outcomes (i.e. response and remission rates) dependent variables will include measures of dysfunctional attitudes social functioning quality of life and health care costs and utilization. It is predicted that: 1) CCBT will be equivalent to CBT at week 16 and across the 6 month follow-up; and 2) CCBT will be significantly more cost-effective than CBT. Secondary aims include testing potential moderators of treatment outcome and the predicted absence of site differences (as an indicator of disseminability). This trial has significant implications for the public health because it will provide a rigorous test the clinical utility of CCBT against a model of conventional individual therapy that offers three times as much clinical contact. If equivalence and cost- effectiveness are demonstrated the proposed research will set the stage for larger scale studies evaluating broader dissemination of CCBT.

project_terms:
Acute;Attitude;Characteristics;Clinical;Cognitive;Cognitive Therapy;Computer Assisted;Computer-Assisted Therapy;Control Groups;DSM-IV;Data;Data Analyses;Development;Disease remission;Elements;Female;Grant;Health Care Costs;Hour;Individual;Intervention;Investigation;Knowledge;Major Depressive Disorder;Measures;Mental Depression;Methods;Modeling;Multimedia;Outcome;Outpatients;Patient Preferences;Patients;Pennsylvania;Phase;Protocols documentation;Psychotherapy;Quality of life;Randomized;Randomized Controlled Trials;Recruitment Activity;Relapse;Research;Research Design;Research Methodology;Sampling;Services;Site;Social Functioning;Staging;Testing;Therapeutic;Thinking function;Time;Training;Treatment outcome;Universities;Waiting Lists;base;behavior change;clinically significant;comparative efficacy;conventional therapy;cost;cost effective;cost effectiveness;depressive symptoms;design;effective therapy;efficacy testing;experience;follow-up;health care service utilization;improved;male;meetings;programs;public health medicine (field);public health relevance;response

public_health_relevance:
Project NarrativeAlthough Cognitive Behavior Therapy (CBT) is an effective treatment for major depressivedisorder its utility is limited by cost and availability of trained therapists. Computer-assisteddelivery of this therapy (CCBT) has shown promise and may offer similar benefits as CBT withas little as one third the amount of therapist time. The proposed study will test the therapeuticequivalence and cost-effectiveness of CCBT versus CBT across a 16 week acute phase and a6 month follow-up.


application_id: 8426117
project_number: 5R01AG031764-05
project_title: Beta-Amyloid Immunization in a Canine Model of Aging
administering_ic: NIA
award_notice_date: 2013-04-04
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AG
serial_number: 031764
program_official: RYAN, LAURIE M
project_start_date: 2009-03-01
project_end_date: 2015-02-28
study_section: Clinical Neuroimmunology and Brain Tumors Study Section[CNBT]
contact_pi_person_id: 8662513
contact_pi: HEAD, ELIZABETH
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Alzheimer's disease (AD) is associated with progressive cognitive decline and the accumulation of senile plaques and neurofibrillary tangles. Senile plaques contain the beta-amyloid peptide (A) which is thought to play a causative role in the disease. Thus a number of therapeutics are being developed that may reduce the production deposition or enhance clearance of A in the brains of patients with AD. In transgenic mouse models of AD deposition of A may be prevented or reduced after immunization with fibrillar A1-42. Further learning and memory is improved by either active or passive immunization with anti-A antibodies. On the basis of work in transgenic mice a clinical trial (AN1792) was initiated in AD patients who were administered fibrillar A42. Cognitive benefits were reported in this study and autopsy studies show a reduction in brain A. We extended immunotherapy studies into the canine model of human brain aging that naturally develop human-type A and cognitive decline. Aged animals were actively immunized for over 2 years (25 injections in total). Our results in immunized aged beagles showed decreased brain A and improved executive function. We hypothesize that we can improve cognition to a greater extent and extend cognitive improvements to include multiple domains by combined treatment with an intervention that may restore neuron health after A removal. Thus we propose to combine immunotherapy with behavioral enrichment in aged dogs and target two molecular pathways that may converge to provide additive benefits. We predict aged dogs will show significant cognitive improvements maintenance of cognition and reduced neuropathology when we combine immunotherapy with behavioral enrichment. Further the combination treatment will provide larger benefits to cognition and neuropathology than either treatment alone. The canine provides a unique model system in which to develop combinatorial treatment approaches involving immunotherapy for reducing AD pathology and improving cognition that may be more directly translated into human clinical trials.

project_terms:
12 year old;AN-1792;Active Immunization;Adjuvant;Adverse event;Affect;Aftercare;Age;Aging;Alzheimer's Disease;Amyloid;Amyloid beta-Protein;Animal Model;Animals;Antibodies;Antigens;Attenuated;Autopsy;B-Lymphocytes;Behavioral;Biological Models;Brain;Brain Pathology;Brain-Derived Neurotrophic Factor;Bromodeoxyuridine;Canis familiaris;Cerebral Amyloid Angiopathy;Clinical Trials;Cognition;Cognitive;Combined Modality Therapy;Congo Red;Data;Deposition;Discrimination (Psychology);Discrimination Learning;Disease;Dot Immunoblotting;Dynamin I;Enzyme-Linked Immunosorbent Assay;Excision;Exercise;Experimental Designs;Female;Future;GDNF gene;Growth Factor;Head;Health;Hippocampus (Brain);Housing;Human;Immune response;Immunization;Immunotherapy;Impaired cognition;Individual;Infiltration;Injection of therapeutic agent;Intervention;Lead;Learning;Maintenance;Matched Group;Measures;Mediating;Memory;Memory impairment;Methods;Modeling;Molecular;NR2B NMDA receptor;Neurofibrillary Tangles;Neurons;Neuropsychological Tests;Outcome;Outcome Measure;Outcome Study;Passive Immunization;Pathogenesis;Pathology;Pathway interactions;Patients;Phase;Play;Polysorbate 80;Procedures;Production;Proteins;Prussian blue;Publishing;Reagent;Relative (related person);Reporting;Reversal Learning;Role;S-nitro-N-acetylpenicillamine;Sampling;Senile Plaques;Synapses;Synaptophysin;T-Lymphocyte;Techniques;Testing;Therapeutic;Time;Tissues;Toy;Transgenic Mice;Translating;Visual;Walking;Western Blotting;Work;aged;aging brain;aluminum sulfate;base;cognitive function;cognitive training;combinatorial;design;disability;drebrins;environmental enrichment for laboratory animals;executive function;improved;improved functioning;male;mild cognitive impairment;mouse model;neurogenesis;neuron loss;neuropathology;neurotrophic factor;normal aging;novel;prevent;research study;response;sex;social

public_health_relevance:
Project Narrative Alzheimer's disease (AD) is associated with progressive cognitive decline an the accumulation of brain pathology. We will use a combination treatment approach to improve cognition and reduce neuropathology in the canine model of aging through immunotherapy and behavioral enrichment which is an approach that may be directly translated into human clinical trials.


application_id: 8425042
project_number: 5R21AR062356-02
project_title: Non-contact Diffuse Optical Assessment of Pressure Ulcer and Therapy
administering_ic: NIAMS
award_notice_date: 2013-03-08
opportunity_number: PA-10-069
application_type: 5
activity_code: R21
ic: AR
serial_number: 062356
program_official: TSENG, HUNG H
project_start_date: 2012-02-15
project_end_date: 2015-01-31
study_section: Special Emphasis Panel[ZRG1-BMIT-J(01)S]
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Pressure ulcers affect 1-3 million American adults. Prolonged pressure results in poor peripheral circulation and tissue hypoxia and may cause significant tissue damage. As one of the adjunctive therapies electrical stimulation (ES) is less labor intensive with lower costs compared to conventional therapies for ulcer treatment. However ES parameters are often selected arbitrarily and treatment outcomes are evaluated by visible estimates of tissue mass and/or wound volume changes rather than intrinsic hemodynamic changes in ulcerous tissues. Early detection of pressure ulcers is the key for effective ulcer management and for reducing subsequent treatment costs. Since pressure ulcers usually originate from deep tissues attached to the bone (e.g. gluteal muscles surrounding the sacrum) measurement of deep tissue hemodynamics is essential for early diagnosis of ulcers and for optimization of ES treatment. However no easy methods exist yet that are able to detect the early stages of ulcer development in deep tissues. A new advanced technology near- infrared diffuse optics can noninvasively monitor blood flow and oxygenation in deep tissues (up to several centimeters) with fiber-optic probes that gently contact the skin surface and has recently been demonstrated in our preliminary studies. However measurements of tissue hemodynamics using contact probes are not appropriate for ulcerous tissues that are prone to infection. This proposed project is to develop and validate a novel non-contact diffuse optical system (Aim 1) for early hemodynamic assessment of ulcer development in deep tissues. This non-contact system will completely avoid tissue deformation and potential infections induced by probe-tissue contact. This study will also integrate the non-contact system with an ES stimulator for treatment and therapeutic monitoring of pressure ulcers. After the integrated non-contact system is validated in healthy muscles and ES treatment parameters are optimized to maximize tissue hemodynamic responses to ES (Aim 2) the non-contact optical system will be used to detect blood flow and tissue oxygenation in gluteal muscles surrounding the sacrum in patients with or without pressure ulcers (stages I-IV) before during and after ES treatments over 4 weeks (Aim 3). It is expected that measurement of deep tissue hemodynamics that affect tissue damage/healing will provide unique value for the early diagnosis of ulcer development the objective optimization of ES parameters and the longitudinal evaluation of ES treatment effects. Our long-term goal is to conduct extensive studies on statistically significant populations from multiple rehabilitation centers to translate and commercialize this innovative integrated system for the effective clinical management of pressure ulcers. Given the health burden of long-term care for pressure ulcers this translational technology project has the potential to significantly advance our understanding of pressure ulcer development and treatment ultimately leading to significant improvements in human health and substantial cost savings.

project_terms:
Accounting;Adult;Affect;American;Blood Circulation;Blood flow;Clinical Management;Computers;Cost Savings;Cutaneous;Decubitus ulcer;Development;Diffuse;Early Diagnosis;Early identification;Electric Stimulation;Evaluation;Fiber Optics;Forearm;Goals;Healed;Health;Healthcare;Heterogeneity;Human;Hypoxia;Impairment;Individual;Infection;Long-Term Care;Measurement;Measures;Methods;Monitor;Muscle;Optics;Pain Threshold;Patients;Peripheral;Population;Prevention;Procedures;Property;Recruitment Activity;Rehabilitation Centers;Sacral Region;Skin;Source;Spinal cord injury;Staging;Surface;System;Technology;Therapeutic;Tissues;Touch sensation;Translating;Treatment Cost;Treatment outcome;Ulcer;Validation;Variant;bone;conventional therapy;cost;detector;healing;hemodynamics;high risk;improved;innovation;lens;novel;patient population;pressure;response;sacrum;therapy development;tissue oxygenation;treatment effect;wound

public_health_relevance:
Early detection of pressure ulcers is the key for effective ulcer management and for reducing subsequent treatment costs. Measurement of deep tissue hemodynamics that affect tissue damage/healing is essential for the early diagnosis of ulcers and for the optimization of treatment (e.g. electrical stimulation (ES)) since pressure ulcers usually originate from deep tissues attached to the bone. The objective of this study is to develop and validate a novel non-contact near-infrared diffuse optical system which will allow us to probe blood flow and oxygenation in deep tissues during ES without touching vulnerable/ulcerous tissue surfaces.


application_id: 8424007
project_number: 7R01EB003730-08
project_title: Assembly of phi29 pRNA nanoparticles for siRNA delivery to prostate cancer cells
administering_ic: NIBIB
award_notice_date: 2012-03-06
opportunity_number: PA-08-052
application_type: 7
activity_code: R01
ic: EB
serial_number: 003730
program_official: ZULLO, STEVEN J
project_start_date: 2004-09-01
project_end_date: 2013-05-31
study_section: Nanotechnology Study Section[NANO]
contact_pi_person_id: 1878565
contact_pi: GUO, PEIXUAN
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 investigator): Nanotechniques involve the creation characterization and modification of organized nanomaterials to serve as building blocks for the construction of submicro or nanoscale devices and systems with applications in technology and medicine. Living systems contain a wide variety of ordered macromolecular structures and powerful bionanomachines. The ingenious novel design of the bacteriophage phi29 DNA packaging motor and its constituents has inspired the artificial synthesis and assembly of phi29 biomimetic motor and its components. The 30-nm nanomotor was geared by six copies of ATP-binding packaging RNAs (pRNAs). The structural versatility of pRNA coupled with its ability to form dimers trimers hexamers and patterned superstructures via interlocking loop interactions make it a promising tool for nanomachine fabrication pathogen detection and drug/gene delivery. The low-resolution global structures of the pRNA and its dimer trimer and hexamer have been probed by photoaffinity cross linking chemical modification interference compensatory modification Cryo-AFM and 3D computer modeling. The long-term objective is to introduce exogenous components nano-materials modules moieties drugs and other therapeutic reagents into the motor and develop it for various applications in nanotechnology and medicine. During the first four years of this grant we have demonstrated that pRNA can be used as a building block for bottom-up assembly of polyvalent nanoparticles to deliver siRNA ribozymes and other therapeutics to specific cells. A single molecule fluorescence dual-view imaging system was designed and constructed to count the number of pRNA copies within the constructed pRNA nanoparticles. The short-term objective of this application is to utilize prostate cancer as a model system to determine the feasibility of using the phi29 pRNA motor for targeted delivery of siRNA or other therapeutic molecules and treatment of cancerous diseases. Specifically the novel RNA nanotechnology approach previously developed for the bottom-up assembly of multimeric pRNA nanoparticles will be exploited to construct polyvalent pRNA vehicles carrying an RNA aptamer to specifically bind to prostate surface antigens and a therapeutic siRNA targeting an anti-apoptosis factor for the prostate cancer treatment. Methods for large scale production of pRNA nanoparticles and construction of stable pRNA therapeutic nanoparticles resistant to RNase digestion in vivo will be developed. Approaches designed to combine therapy with the simultaneous detection of the therapeutic effect will be developed by exploiting the polyvalent nature of the pRNA nanoparticles. The efficacy in prostate cancer therapy the biodistribution pharmacokinetics toxicity off-target effects as well as the double stranded RNA induced interference will be evaluate in both prostate cancer cells and mice models.     PUBLIC HEALTH RELEVANCE: The novel RNA nanotechnology of bottom-up assembly for phi29 motor pRNA nanoparticles will be used to construct polyvalent pRNA nanoparticles for siRNA delivery in prostate cancer therapy. Prostate cancer will be used as a model system to determine the feasibility of using the phi29 motor pRNA nanoparticles for the targeted delivery of siRNA or other therapeutic molecules and treatment of cancerous diseases.

public_health_relevance:
Project NarrativeThe novel RNA nanotechnology of bottom-up assembly for phi29 motor pRNA nanoparticles will be used toconstruct polyvalent pRNA nanoparticles for siRNA delivery in prostate cancer therapy. Prostate cancer will beused as a model system to determine the feasibility of using the phi29 motor pRNA nanoparticles for thetargeted delivery of siRNA or other therapeutic molecules and treatment of cancerous diseases.


application_id: 8423842
project_number: 7R01CA098664-08
project_title: Repair of oxidative DNA damage in mammalian cells
administering_ic: NCI
award_notice_date: 2012-05-09
opportunity_number: PA-07-070
application_type: 7
activity_code: R01
ic: CA
serial_number: 098664
program_official: OKANO, PAUL
project_start_date: 2003-03-10
project_end_date: 2014-05-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 6617337
contact_pi: IZUMI, TADAHIDE
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): DNA base excision repair (BER) is a ubiquitous and indispensable defense mechanism against cell death mutagenesis and carcinogenesis caused by spontaneously formed DNA damage such as oxidation and alkylation. Apurinic/apyrimidinic endonuclease (APE1 in mammals) arguably determines the BER rate in cells and thus plays a central role in the repair pathway. Recent findings indicate that APE1 is essential for cellular viability and that endogenous DNA damage is lethal if left unrepaired. Independently from its repair activity APE1 interacts with histone deacetylase 1 (HDAC1) to suppress expression of many genes including the parathyroid hormone gene. APE1 also regulates cJun/cFos and other crucial transcription factors. A high of APE1 is often in are expression observed malignant tumor cells which more resistant to radio- and chemotherapeutic treatments suggesting that APE1's repair function increases the chance of survival for cancer cells as well. Thus APE1 may be either beneficial or harmful to humans depending on the type of cells in which it is expressed. Understanding the mechanism for regulation of APE1 activity is therefore crucial for evaluating BER efficiency and its consequences in normal and cancer cells. Indeed cancer predisposition by APE1 deficiency is known and p53 is an upstream regulator of APE1. We have discovered that APE1 is ubiquitinated by mouse double minute 2 (MDM2) and that the ubiquitination is induced by genotoxic stress in a p53-dependent manner. Ubiquitination occurs at specific Lys residues in the APE1 polypeptide and appears to have significant effects on the functions of APE1 and other cellular proteins including XRCC1 (X-ray cross-complementation 1) p53 and HDAC1 that interact directly with APE1. The central hypothesis of this project is that APE1 ubiquitination regulated by MDM2 and p53 modulates the APE1 level and functions in DNA damage response. In order to elucidate the cellular defense mechanism involving this remarkably multifunctional protein we will: (1) determine the effect of APE1 ubiquitination on its enzymatic and DNA binding activities; (2) unravel interaction of ubiquitinated APE1 with factors in BER and p53 signaling network; and (3) establish the regulation of APE1 ubiquitination in vivo. These parameters are crucial to predict susceptibility of cancer cells against therapeutic drugs that generates genomic instability. With the research facilities provided by Louisiana Cancer Research Consortium (LCRC) this project in the long-term should provide insights for developing new modalities for adjuvant cancer therapies and organ preservation and for improving the management of other age-related pathophysiology. PUBLIC HEALTH RELEVANCE: DNA is continuously damaged by environmental toxicants like smoke and by reactive oxygen radicals generated inside of our bodies. Damaged DNA causes mutations and may ultimately lead to cancer and age- related diseases. This project will help us understand how to enhance natural healing of DNA damage and will help to improve the current methodology for non-surgical cancer treatments including radiotherapy and chemotherapy.

project_terms:
Adjuvant;Affect;Affinity;Alkylation;Base Excision Repairs;Cancer cell line;Cell Death;Cells;DNA;DNA Binding;DNA Damage;Defense Mechanisms;Disease;Double Minutes;Effectiveness;Functional disorder;Genes;Genomic Instability;Genotoxic Stress;Healed;Hormones;Human;Kinetics;Lead;Left;Louisiana;Malignant Neoplasms;Mammalian Cell;Mammals;Methodology;Modality;Monoubiquitination;Mus;Mutagenesis;Mutation;Normal Cell;Oncogene Proteins;Organ Preservation;Oxidative Stress;Parathyroid gland;Pathway interactions;Pharmaceutical Preparations;Play;Predisposition;Protein p53;Proteins;Radiation therapy;Reactive Oxygen Species;Reagent;Regulation;Regulator Genes;Reporting;Resistance;Roentgen Rays;Role;Signal Transduction;Smoke;Suppressor Genes;Testing;Therapeutic;Toxic Environmental Substances;Ubiquitination;age related;anticancer research;cancer cell;cancer therapy;carcinogenesis;cell type;chemotherapy;domain mapping;endonuclease;healing;human APEX1 protein;human HDAC1 protein;improved;in vivo;insight;neoplastic cell;oxidation;oxidative DNA damage;polypeptide;public health relevance;repaired;research facility;response;transcription factor

public_health_relevance:
NarrativeDNA is continuously damaged by environmental toxicants like smoke and by reactive oxygen radicalsgenerated inside of our bodies. Damaged DNA causes mutations and may ultimately lead to cancer and age-related diseases. This project will help us understand how to enhance natural healing of DNA damage andwill help to improve the current methodology for non-surgical cancer treatments including radiotherapy andchemotherapy.


application_id: 8423298
project_number: 5R01AR049010-09
project_title: Microsomal Prostaglandin E Synthase in Rheumatoid Arthritis
administering_ic: NIAMS
award_notice_date: 2012-12-14
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: 2013-06-30
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.

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: 8420476
project_number: 5R01NS045954-10
project_title: Neuropeptidergic Inhibition of Spinal Pain Transmission
administering_ic: NINDS
award_notice_date: 2013-01-17
opportunity_number: PA-07-282
application_type: 5
activity_code: R01
ic: NS
serial_number: 045954
program_official: OSHINSKY, MICHAEL L
project_start_date: 2002-09-10
project_end_date: 2015-01-31
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.

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: 8417013
project_number: 5R01DA022451-04
project_title: Enhancement of Sexual Motivation
administering_ic: NIDA
award_notice_date: 2013-01-16
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DA
serial_number: 022451
program_official: LYNCH, MINDA
project_start_date: 2010-02-01
project_end_date: 2015-01-31
study_section: Special Emphasis Panel[ZRG1-BBBP-T(03)M]
contact_pi_person_id: 7876913
contact_pi: AKINS, CHANA K.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): There is considerable evidence for a co-morbid relationship between cocaine abuse and risky sexual behavior. Clinical studies have shown a correlation between cocaine use and risky sexual practices such as increased frequency an increased number of partners and unprotected sex. These sexual practices have been linked to adverse health consequences including high prevalence rates for sexually-transmitted diseases. Controlled preclinical studies that utilize animal models have demonstrated that prior repeated exposure to cocaine enhances sexual motivation and behavior. However no parametric or systematic studies further investigating the basic mechanisms underlying this relationship have been conducted. The goal of the proposed experiments is to utilize an animal model whose sexual behavior system has been well-studied Japanese quail. In addition to the benefits of using quail to study sexual behavior the use of a visually-oriented species in studying drug effects may be of additional relevance to studying human drug addiction. We currently have preliminary evidence in male Japanese quail that preexposure to cocaine enhances sexual motivation. This finding ties in well with clinical observations that indicate that cocaine use in humans may increase sexual motivation thereby increasing the likelihood of the occurrence of high-risk sexual behavior. The overall working hypothesis of this proposal is that the magnitude of the sexual response depends on several cocaine preexposure parameters including dose amount of exposure time between exposures and the withdrawal period before sexual behavior testing. Additionally we hypothesize that cocaine preexposure increases the resistance to extinction (harder to eliminate) and facilitates the reacquisition of a sexual response that has been extinguished. The proposed research has the potential to contribute to our understanding of cocaine preexposure effects on sexual motivation using a visually-oriented animal model. For example in males sexual motivation may be enhanced by prior cocaine exposure. Such an enhancement might translate in humans as high risk or compulsive sexual behaviors such as increased frequency of sexual activity sex with multiple partners and unprotected sex. These risky sexual behaviors have been linked with considerable health consequences such as the transmission of HIV and hepatitis C. The goal of the proposed project is to contribute to understanding underlying mechanisms of cocaine's effects on sexual motivation.

project_terms:
Acute;Animal Model;Animals;Association Learning;Behavior;Brain region;Breeding;Chronic;Clinical;Clinical Research;Cocaine;Cocaine Abuse;Conditioned Stimulus;Coturnix japonica;Cues;Dependence;Dose;Drug Addiction;Drug abuse;Drug usage;Empirical Research;Ethics;Event;Extinction (Psychology);Female;Food;Frequencies (time pattern);Goals;HIV;Health;Hepatitis C;High Prevalence;Human;Investigation;Learning;Length;Light;Link;Long-Term Effects;Measures;Memory;Mentored Research Scientist Development Award;Methods;Modeling;Motivation;Multiple Partners;Partner in relationship;Performance;Pharmaceutical Preparations;Phase;Physiological Effects of Drugs;Pre-Clinical Model;Procedures;Property;Publishing;Quail;Recovery;Research;Research Training;Resistance;Rewards;Rodent;Saline;Seasons;Sensory;Sex Behavior;Sexually Transmitted Diseases;Signal Transduction;Simulate;Stimulus;System;Testing;Time;Translating;United States;Unsafe Sex;Visual;Withdrawal;Work;addiction;approach behavior;behavior test;clinically relevant;cocaine exposure;cocaine use;conditioning;drug of abuse;drug testing;experience;high risk;high risk sexual behavior;indexing;learned behavior;male;neural circuit;preclinical study;public health medicine (field);research study;response;sex;transmission process

public_health_relevance:
NarrativeClinical studies have shown a correlation between cocaine use and risky sexual practices such as increasedfrequency an increased number of partners and unprotected sex. These sexual practices have been linked toadverse health consequences including high prevalence rates for sexually-transmitted diseases. The currentapplication is a preclinical model used to investigate how drugs of abuse alter sexual motivation.


application_id: 8416997
project_number: 5R01NS073584-03
project_title: ER stress and oligodendrocyte survival after spinal cord injury
administering_ic: NINDS
award_notice_date: 2013-02-01
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: NS
serial_number: 073584
program_official: JAKEMAN, LYN B
project_start_date: 2011-02-01
project_end_date: 2016-01-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: HETMAN, MICHAL
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_terms:
Acute;Address;Apoptosis;Apoptotic;Cell Culture Techniques;Cell Death;Cell Survival;Cells;Cellular Stress;Cessation of life;Chemicals;Chemosensitization;Chronic;Coculture Techniques;Commit;Cytoplasm;Cytoprotection;Data;Defense Mechanisms;Disease;Endoplasmic Reticulum;Family;Functional disorder;Genes;Genetic;Grant;Hand;Hypoxia;In Vitro;Inflammation;Injury;Knockout Mice;Locomotor Recovery;Mediating;Mediator of activation protein;Membrane Proteins;Methods;Modeling;Molecular Chaperones;Mus;Neurons;Oligodendroglia;Organelles;Pathology;Pathway interactions;Patients;Phosphorylation;Protein Dephosphorylation;Proteins;Recovery of Function;Role;Signal Transduction;Small Interfering RNA;Spinal Cord;Spinal Ganglia;Spinal cord injury;TNFRSF10B gene;Translational Repression;Translations;Trauma;Traumatic CNS injury;Tunicamycin;Up-Regulation (Physiology);arm;biological adaptation to stress;cytotoxic;effective therapy;endoplasmic reticulum stress;excitotoxicity;improved;in vitro Assay;in vivo;inhibitor/antagonist;insight;loss of function;nervous system disorder;new therapeutic target;novel;oligodendrocyte precursor;oxidative damage;precursor cell;protective effect;public health relevance;research study;response;secretory protein;tauroursodeoxycholic acid;therapeutic target;transcription factor

public_health_relevance:
Project Narrative. Spinal cord injury (SCI) is a devastating injury for both patients and their families and atpresent there is no effective treatment either acutely or for chronic patients. This grant examines the role ofthe endoplasmic reticulum stress response a cellular defense mechanism induced in every spinal cord cellafter SCI in mediating survival or death of myelinating oligodendrocytes after SCI. We expect to identify newacute therapeutic targets that will hopefully extend beyond SCI to other CNS trauma and neurological diseasetreatment.


application_id: 8416985
project_number: 5R01AI051517-10
project_title: Paramyxovirus F protein mediated membrane fusion
administering_ic: NIAID
award_notice_date: 2013-01-11
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AI
serial_number: 051517
program_official: CASSETTI, CRISTINA
project_start_date: 2002-05-15
project_end_date: 2014-08-14
study_section: Special Emphasis Panel[ZRG1-IDM-S(02)S]
contact_pi_person_id: 8106840
contact_pi: DUTCH, REBECCA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Membrane fusion a process critical for viral entry is promoted by the paramyxovirus fusion (F) proteins. All F proteins contain a number of common features that play fundamental roles in fusion. However significant variations exist between F proteins related to protein activation and promotion of membrane fusion and many critical questions remain concerning the mechanism by which fusion is promoted by these important viral proteins. The long-term objective of our research is to understand the precise mechanism(s) of paramyxovirus F protein-promoted membrane fusion. Our overall hypothesis is that the function of domains critical for fusion promotion will be conserved in diverse F proteins but that interactions in these domains will modulate triggering mechanisms. To address this important hypothesis we will pursue the following specific aims: 1.) We will build on our exciting preliminary data which demonstrates trimer formation of isolated Hendra F transmembrane (TM) domains to define the role of TM-TM interactions in glycoprotein folding and fusion. We will therefore delineate the residues critical for TM-TM interactions and evaluate the role of this interaction in Hendra F folding trafficking and fusion; analyze the effect of HRB or cytoplasmic-tail additions on stability of TM-TM interactions; compare TM-TM interactions for the PIV5 and HMPV F proteins to those observed for the Hendra F TM; and determine if TM domains from paramyxovirus attachment proteins interact with themselves or with the F protein TM domains; 2.) We will define the role of low pH and endocytosis in HMPV viral entry and delineate the role of electrostatic repulsion in the HRB linker region in HMPV F low pH-induced conformational changes and entry of recombinant viruses and; 3.) We will analyze the role of stabilizing interactions between HRA and a conserved region of F2 which our studies of PIV5 F indicate can play a role in triggering by defining key interactions in this domain in PIV5 F assessing the stage of fusion which is affected analyzing the effect of mutations in this region on viral entry and analyzing the effect of mutations to this region in other F proteins. Accomplishing these goals will provide crucial information on the regions that control the molecular events involved in the F protein-promoted membrane fusion process and potentially identify new targets for antiviral therapy.

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

public_health_relevance:
Relevance: The paramyxovirus family contains both established human pathogens suchas measles virus and respiratory syncytial virus and newly emerged human pathogensincluding the highly pathogenic Hendra and Nipah viruses and the recently identifiedhuman metapneumovirus (HMPV). A detailed understanding of the fusion mechanismcould lead to development of new antiviral reagents.


application_id: 8416743
project_number: 1R01ES022191-01
project_title: Integrated Chemoselective and Informatic Platform for Large-Scale Metabolomics
administering_ic: NIEHS
award_notice_date: 2012-09-26
opportunity_number: RFA-RM-11-019
application_type: 1
activity_code: R01
ic: ES
serial_number: 022191
program_official: BALSHAW, DAVID M
project_start_date: 2012-09-26
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1 BST-P (50)]
contact_pi_person_id: 7213583
contact_pi: FAN, TERESA WHEI-MEI
other_pis: HIGASHI, RICHARD M;MOSELEY, HUNTER NATHANIEL;NANTZ, MICHAEL H
congressional_district: 03
department: CHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Recent advances in metabolomics technologies especially those that combine the complementarily of mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) enables rapid analysis of thousands of peaks representing hundreds of metabolites. Yet key barriers remain for large-scale metabolomics applications most notably: even higher throughput with robust metabolite assignment and quantification; identification of unknown metabolites; analysis of low abundance/labile metabolites; and reconstruction of metabolic networks and regulation. Here we propose an integrated approach that uses chemoselective (CS) tagging of key metabolite functional groups to boost the speed and accuracy of metabolite identification and enhance detection. Such tagged metabolites are inherently amenable for multiplexed analysis and reliable relative quantification via stable isotope encoding. This approach will accelerate analytical throughput while widening the classes of analytes including metabolically enriched isotopologues far beyond current limits. We will achieve our goals via the following specific aims: SA1. To develop CS probes for tagging metabolites by targeting functional groups: Hydrophobic quaternary ammonium (QA)-based CS probes will be developed for tagging carbonyl amino thiol & diol functional groups (FG) in metabolites optimized for direct infusion FT- ICR-MS detection & assignment; SA2. To develop a set of isotope-encoded CS probes for metabolite identification and multiplexed quantification by FT-ICR-MS and NMR: Developing 13C-encoded QA-CS probes will facilitate integrated structural analysis of metabolites by 13C edited 2D NMR and FT-ICR-MS & multiplexed analysis by FT-ICR-MS; SA3. To develop web-based software for large-scale CS-adducted metabolite assignment & pathway reconstruction: Algorithm for robust automated MS assignment of metabolite & labeled isotopologues will be developed based on isotopologue cliques FG profile & molecular formula (MF). NMR- derived substructure & MF will be combined with MS data for semi-automated assignment of metabolite isotopomers & unknowns. Atom-resolved human metabolic database will be refined and tools developed for pathway reconstruction based on labeled metabolite profiles; SA4. To demonstrate the integrated CS profiling and biochemo-informatic approach in three basic and translational projects: Metabolic reprogramming driven by oncogenic gene defects or enzyme deletion in human lung and kidney cancers will be mapped using Stable Isotope-Resolved Metabolomics (SIRM) enhanced by newly developed CS tagging chemistry and automated assignment tools. Our long-term goal is to decipher human disease metabolic networks for drug discovery & early diagnosis.   
   
PUBLIC HEALTH RELEVANCE: The proposed chemoselective tagging of metabolites with integrated informatics tools will enhance both metabolite profiling and elucidation of human disease metabolic networks far beyond current limits. The information gained from these tools will help accelerate at an unprecedented rate our functional understanding of human disease development and progression while improving our ability to diagnose prognose and treat intractable human diseases such as cancer.


application_id: 8415855
project_number: 5R01GM070559-09
project_title: Molecular analysis of juvenile hormone action
administering_ic: NIGMS
award_notice_date: 2013-01-28
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 070559
program_official: CHIN, JEAN
project_start_date: 2005-02-01
project_end_date: 2016-01-31
study_section: Vector Biology Study Section[VB]
contact_pi_person_id: 7355989
contact_pi: PALLI, SUBBA R
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): There has been a continuous demand for the development of insect control methods that are target-specific. Juvenile hormone (JH) and ecdysteroids (20-hydroxyecdysone 20E is the most active form) are the major hormones that regulate development and reproduction in insects. Since these hormones are not present in vertebrates they represent attractive targets for the development of insect control methods. Hindering this effort is the lack of understanding of the molecular basis of JH action. During the current grant period seven proteins that are components of multi-protein complexes involved in JH signal transduction and its cross-talk with 20E were identified. Ligand binding studies performed using labeled JH showed that none of these proteins bind to JH with high affinity. While these proteins are likely involved in JH action and its cross-talk with 20E none of them are JH receptors. Search for a better system to study JH action without interference from ecdysteroids discovered JH regulation of reproduction in Tribolium castaneum an ideal system to study JH action without interference from ecdysteroids. In this insect JH without the interference from ecdysteroids regulates vitellogenin gene expression in the fat body and vitellogenin uptake by the oocytes. These two systems provide a unique opportunity to study both genomic (fat body) and non-genomic (ovary) actions of JH in the same insect at the same time. Therefore the renewal application proposes to study mechanism of JH action in regulation of vitellogenin gene expression in the fat body and vitellogenin uptake into the oocytes with a major goal of identifying receptors transcription factors and protein modifiers critical for JH signal transduction. Completion of whole genome sequencing availability of microarrays functioning of systemic RNA interference (RNAi) and excellent response to JH and its analogs make T. castaneum an excellent model system for studies on JH action. In the first specific aim microarray RNAi qRT-PCR electrophoretic mobility shift assays and ligand-binding assays will be employed to identify and characterize receptors transcription factors and protein modifiers involved in JH regulation of vitellogenin gene expression. In the second specific aim a panel of in vivo cell culture and in vitro assays will be used to determine whether any of the 51 G- protein-coupled receptors indentified in T. castaneum as those required for egg production and embryogenesis are activated by JH to regulate vitellogenin uptake into the oocytes. JH analogs are being used for mosquito control but some mosquitoes are already developing resistance to these analogs. The results from these studies will aid in understanding the mode of action of JH analogs thus facilitating their judicious use. The genes identified will be useful to develop screening assays to identify new insect disease vector control agents. The receptors identified can also be used in medicine by developing gene switches for various applications such as gene therapy tissue engineering and therapeutic protein production.

project_terms:
Adult;Affinity;Agonist;Anabolism;Biological;Biological Assay;Biological Metamorphosis;Biological Models;Cell Culture Techniques;Code;Culicidae;Data;Development;Disease;Disease Vectors;Ecdysone;Ecdysteroids;Ecdysterone;Electrophoretic Mobility Shift Assay;Embryonic Development;Event;Extracellular Space;Fat Body;Female;Flour;Food;G-Protein-Coupled Receptors;Gene Expression;Genes;Genome;Genomics;Goals;Grant;Health;Homologous Gene;Hormone Receptor;Hormones;Human;Insect Control;Insecta;Juvenile Hormones;Label;Life Cycle Stages;Ligand Binding;Livestock;Medicine;Membrane;Messenger RNA;Methods;Methoprene;Molecular;Molecular Analysis;Molting;Mosquito Control;Oocytes;Oogenesis;Ovary;Play;Production;Promoter Regions (Genetics);Protein Binding;Protein Precursors;Proteins;RNA Interference;Regulation;Reproduction;Resistance development;Role;Set protein;Signal Transduction;Switch Genes;System;Time;Tissue Engineering;Tribolium (beetle);Vertebrates;Vitellogenesis;Vitellogenins;analog;base;egg;follicular epithelial cell;gene therapy;genome sequencing;hormone analog;hormone biosynthesis;hormone regulation;in vitro Assay;in vivo;insect disease;knock-down;non-genomic;prevent;protein complex;receptor;reproductive;research study;response;screening;therapeutic protein;transcription factor;uptake;vector control

public_health_relevance:
PROJECT NARRATIVEInsect juvenile hormone analogs are being used for mosquito control but some mosquitoes are alreadydeveloping resistance to these analogs. The results from these studies will aid in understanding the mode ofaction of JH analogs thus facilitating their judicious use. The genes identified will be useful to developscreening assays to identify new insect disease vector control agents and for developing gene switches usefulfor various applications such as gene therapy tissue engineering and therapeutic protein production.


application_id: 8415730
project_number: 1DP5OD012132-01
project_title: Exploring the role of dyssynchrony in pediatric heart disease with MRI
administering_ic: OD
award_notice_date: 2012-09-25
opportunity_number: RFA-RM-11-007
application_type: 1
activity_code: DP5
ic: OD
serial_number: 012132
program_official: MILLER, BECKY
project_start_date: 2012-09-25
project_end_date: 2017-08-31
study_section: Special Emphasis Panel[ZRG1 BBBP-E (53)]
contact_pi_person_id: 9404495
contact_pi: FORNWALT, BRANDON K
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Pediatric heart failure cost the United States an estimated $2 billion in 2006 and is increasing in prevalence and cost despite hospital mortality unfortunately remaining constant at 7%. The big-picture goal of our current research program is to attempt to address this problem by adapting a relatively new highly successful therapy for adult heart failure called cardiac resynchronization therapy (CRT) into a treatment option for children with heart failure. The most critical knowledge gap is identifying which children are most
likely to benefit from CRT. The current application addresses this challenge in a population of patients with a common serious congenital heart defect known as tetralogy of Fallot (TOF). Patients born with tetralogy of Fallot (TOF) the most common cyanotic congenital heart defect currently undergo surgical repair as children but later develop heart failure as adults. This research will investigate whether the surgical repair predisposes these patients to uncoordinated contraction in the heart as a result of disruption of electrical conduction pathways which occurs during surgery. If this uncoordination (or "dyssynchrony") proves to be a significant factor it can be treated with CRT thus yielding a new treatment for patients with heart failure due to TOF. We are able to explore the role of dyssynchrony in these patients because we recently developed unique methodology and software to derive indices of dyssynchrony in the heart from standard magnetic resonance images (MRI). We hypothesize that patients with surgically repaired TOF suffer from dyssynchronous contraction in the heart and that dyssynchrony contributes to the development of heart failure and eventual mortality in these patients. We propose to test our hypotheses with the following specific aims: 1) evaluate whether patients with repaired TOF suffer from dyssynchrony when compared to normal subjects 2) evaluate whether dyssynchrony leads to worsening ventricular function over time in patients with repaired TOF and 3) determine whether dyssynchrony is related to mortality in patients with repaired TOF. Completion of this application should therefore improve the health and care of patients with repaired TOF through identifying potentially lifesaving treatment options for them. Additionally our approach can be used in future work to explore the role of dyssynchrony in patients with other diseases associated with electrical conduction abnormalities such as dilated cardiomyopathy thus furthering our long-term goal to translate cardiac resynchronization therapy into a treatment option to improve the health of children with heart failure.   
   
PUBLIC HEALTH RELEVANCE: Pediatric heart failure cost the United States an estimated $2 billion in 2006 and is increasing in prevalence and cost with no corresponding improvement in hospital mortality. The big-picture goal of our research program is to attempt to address this problem by adapting a relatively new highly successful therapy for adult heart failure called cardiac resynchronization therapy into a treatment option to improve the health of children with heart failure.

project_terms:
Address;Adult;Age;Blood;Cardiac;Cessation of life;Child;Child health care;Childhood;Computer software;Congenital Heart Defects;Development;Dilated Cardiomyopathy;Disease;Failure (biologic function);Figs - dietary;Future;Goals;Healthcare;Heart;Heart Atrium;Heart Diseases;Heart failure;Hospital Mortality;Infant;Intervention;Investigation;Knowledge;Lead;Left;Left ventricular structure;Magnetic Resonance Imaging;Methodology;Modeling;Mortality Vital Statistics;Operative Surgical Procedures;Outcome;Output;Pacemakers;Pathway interactions;Patient Care;Patients;Prevalence;Research;Right ventricular structure;Role;Testing;Tetralogy of Fallot;Time;Translating;United States;Ventricular;Ventricular Ejection Fractions;Ventricular Function;Work;congenital heart disorder;cost;design;improved;indexing;patient population;programs;repaired;tool

public_health_relevance:
Pediatric heart failure cost the United States an estimated $2 billion in 2006 and is increasing in prevalence and cost with no corresponding improvement in hospital mortality. The big-picture goal of our research program is to attempt to address this problem by adapting a relatively new highly successful therapy for adult heart failure called cardiac resynchronization therapy into a treatment option to improve the health of children with heart failure.


application_id: 8415543
project_number: 5R01DA025032-05
project_title: Agonist Replacement Therapy for Methamphetamine Dependence: Human Lab Studies
administering_ic: NIDA
award_notice_date: 2012-11-16
opportunity_number: PA-07-333
application_type: 5
activity_code: R01
ic: DA
serial_number: 025032
program_official: HAMPSON, AIDAN
project_start_date: 2009-01-01
project_end_date: 2015-08-31
study_section: ZDA1-MXH-H(20)
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG 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): Methamphetamine dependence is a significant public-health concern. The results of clinical trials suggest that agonist replacement therapies (e.g. d-amphetamine) may be effective for methamphetamine dependence. The present project has three specific aims. The first specific aim is to demonstrate the safety tolerability and behavioral effects of intranasal methamphetamine in humans maintained on d-amphetamine. To accomplish this aim we will conduct one experiment in which non-treatment seeking volunteers with recent histories of illicit stimulant use will receive ascending doses of intranasal methamphetamine while maintained on increasing doses of d-amphetamine (Exp. 1). Cardiovascular indices will be used to determine the safety and tolerability of the d-amphetamine-methamphetamine combinations while subjective-effect questionnaires will be used to characterize the behavioral effects. The results of this experiment will guide the selection of doses to be tested in subsequent studies. The second specific aim is to demonstrate that d-amphetamine maintenance attenuates the reinforcing effects of methamphetamine. To accomplish this aim we will determine the reinforcing effects of intranasal methamphetamine during d-amphetamine maintenance using a progressive-ratio procedure (Exp. 2). Pharmacotherapies that attenuate the reinforcing effects of methamphetamine may be effective for initiating abstinence. The third specific aim is to demonstrate that d-amphetamine maintenance attenuates the discriminative-stimulus effects of methamphetamine. To accomplish this aim volunteers will learn to discriminate intranasal methamphetamine (Exp. 3). The discriminative effects of methamphetamine may be involved in relapse to drug-taking behavior in that an initial dose (i.e. a lapse) may function as a discriminative stimulus signaling the availability of more drug. Pharmacotherapies that attenuate the discriminative-stimulus effects of methamphetamine may be effective for preventing relapse. The proposed research will provide important additional clinical information regarding the efficacy of agonist replacement therapies for methamphetamine dependence. By using two sophisticated human laboratory procedures one to model abstinence initiation (i.e. drug self-administration) and the other to model relapse prevention (i.e. drug discrimination) the proposed research will determine the mechanisms that mediate the clinical efficacy of d-amphetamine for methamphetamine dependence. By inference then the proposed research will identify the optimal conditions under which d-amphetamine would be effective as a pharmacotherapy for methamphetamine dependence (i.e. initiate abstinence or prevent relapse). Finally because d-amphetamine reduces methamphetamine use these clinical findings can be used as a reference to determine the predictive validity of human laboratory procedures. Identifying procedures for assessing the efficacy of putative pharmacotherapies via a "beside-to-bench" or "reverse engineering" strategy is important because human laboratory studies can be conducted more rapidly and efficiently than clinical trials.

project_terms:
Abstinence;Admission activity;Agonist;American;Attenuated;Behavior;Behavioral;Behavioral Mechanisms;Cardiovascular system;Clinical;Clinical Trials;Cocaine;Cocaine Dependences;Cocaine Users;Dextroamphetamine;Dose;Educational process of instructing;Engineering;Epidemiology;Goals;Great Lakes Region;Health;Human;Institution;Intelligence;Kentucky;Laboratories;Laboratory Animals;Laboratory Procedures;Laboratory Study;Learning;Location;Maintenance;Mediating;Methadone;Methamphetamine;Methamphetamine dependence;Methods;Modeling;Nicotine Dependence;Opiate Addiction;Pharmaceutical Preparations;Pharmacotherapy;Placebos;Procedures;Psychostimulant dependence;Questionnaires;Recording of previous events;Relapse;Replacement Therapy;Reporting;Research;Safety;Self Administration;Signal Transduction;Stimulus;Testing;Uncertainty;bench to bedside;clinical effect;clinical efficacy;design;disorder later incidence prevention;drug abstinence;drug discrimination;effective therapy;indexing;methamphetamine abuse;nicotine replacement;novel;preclinical study;prevent;public health medicine (field);research study;volunteer

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Methamphetamine dependence is a significant public health concern. The proposed research will provide important clinical information regarding the efficacy of agonist replacement therapy for methamphetamine dependence. The proposed research will also identify the optimal conditions under which d-amphetamine would be effective as a pharmacotherapy for methamphetamine dependence (i.e. initiate abstinence or prevent relapse). Finally the proposed research will determine appropriate human laboratory procedures for testing pharmacotherapies for methamphetamine dependence. Identifying appropriate human laboratory procedures for assessing the efficacy of pharmacotherapies for methamphetamine dependence is important because laboratory studies can be conducted more rapidly and efficiently than clinical trials.


application_id: 8415060
project_number: 1P01CA163223-01A1
project_title: Systems Biochemistry in Lung Cancer: Toward a Mechanistic Understanding of NSCLC
administering_ic: NCI
award_notice_date: 2013-02-07
opportunity_number: PAR-12-005
application_type: 1
activity_code: P01
ic: CA
serial_number: 163223
suffix: A1
program_official: SPALHOLZ, BARBARA A
project_start_date: 2013-03-01
project_end_date: 2013-09-06
study_section: Special Emphasis Panel[ZCA1 RPRB-0 (O1)]
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
other_pis: FAN, TERESA WHEI-MEI;YAN, JUN
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):  

Deaths from lung cancer are the highest of all cancers in North America and elsewhere and because of the long incubation time are likely to remain so for the foreseeable future. Furthermore although the 5-year survival rate of stage I lung cancer is 60-70% later stage disease has a very poor prognosis. Accurate detection of asymptomatic early stage lung cancer in individuals at risk is currently unreliable. A better understanding of the basic biochemistry of lung cancers is a prerequisite to mechanism-based reliable early detection of the disease and to improved approaches to treatment. The very complexity of the transformed cells and the variable host-tumor interactions makes the problem refractory to any single approach. A systems biochemistry approach in which lung cancers are studied at the mechanistic level in the laboratory in mouse models and in human subjects offers the opportunity to address the complexity of cancer development and progression. The use of stable isotope resolved metabolomics provides the necessary direct biochemical information about lung cancer with minimal processing that is not otherwise available. This program will address the problem in a 3-pronged approach based on the following integrated projects: 
Project 1: Cellular Systems Biochemistry. Microenvironmental nutrient availability and immune modulation in lung cancer cells. 
Project 2; Preclinical Systems Biochemistry. Using SIRM in Human NSCLC xenograft mouse to determine biochemical mechanisms of immunomodulator B-glucan.    

Project 3: Translational Systems Biochemistry. Molecular mechanisms of NSCLC and response to B-glucan by SIRM. The three projects will use a common mechanistic approach to understanding cancer biochemistry namely stable isotope resolved metabolomics (SIRM) that we have been developing over the last eight years. The analytical requirements will be met in the SIRM Analytical Core which also supplies the necessary sample handling and bioinformatics support for the three projects. Core A provides overall administrative support.

project_terms:
Address;Analytical Biochemistry;Animal Model;Animals;Arginine;Benign;Biochemical;Biochemical Pathway;Biochemistry;Bioinformatics;Biological Factors;Cancer Biology;Cancer Gene Mutation;Cell Culture Techniques;Cell model;Cells;Cessation of life;Clinical Trials;Collaborations;Congresses;Data;Death Rate;Detection;Development;Disease;Early Diagnosis;Epithelial Cells;Fibroblasts;Food Interactions;Future;Generations;Genes;Glucans;Glucose;Glutamine;Goals;Human;Hypoxia;Immune;Immune system;Immunomodulators;Implant;In Situ;Individual;Informatics;Investigation;Knowledge;Label;Laboratories;Link;Lung;Lung Neoplasms;Macrophage Activation;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Mediating;Metabolic;Metabolic Pathway;Metabolism;Modeling;Molecular;Mus;Mutation Analysis;Nature;Non-Small-Cell Lung Carcinoma;North America;Nutrient;Pathway Analysis;Patients;Pattern;Phenotype;Physicians;Plasma;Process;Property;Proteomics;Refractory;Resected;Resolution;Risk;Role;Sampling;Scientist;Slice;Staging;Structure of parenchyma of lung;Survival Rate;System;Technology;Testing;Time;Tissues;Tumor-Derived;Xenograft procedure;arginase;base;cancer cell;cell transformation;cohort;host neoplasm interaction;human subject;human tissue;immune activation;immunoregulation;improved;insight;interest;macrophage;meetings;metabolomics;mouse model;neoplastic cell;novel strategies;oncology;outcome forecast;pre-clinical;programs;research study;response;stable isotope;subcutaneous;tool;transcriptomics;treatment strategy;tumor;tumor immunology;tumor metabolism;tumor microenvironment;tumor progression


application_id: 8413775
project_number: 5R01DC009434-05
project_title: Regulation of outer hair cell electromotility and noise-induced hearing loss
administering_ic: NIDCD
award_notice_date: 2013-01-15
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DC
serial_number: 009434
program_official: FREEMAN, NANCY
project_start_date: 2009-02-18
project_end_date: 2015-01-31
study_section: Auditory System Study Section[AUD]
contact_pi_person_id: 8360158
contact_pi: FROLENKOV, GREGORY I
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): Excessively loud sounds and noise are among the leading causes of deafness and hearing impairment in the US. Acoustic over-stimulation is likely to activate multiple physiological mechanisms most of which are poorly understood. Perhaps the first process that would be shut down in the face of acoustic over-stimulation is the cochlear amplification of sound-induced vibrations. Prestin a unique plasma membrane molecular motor of the outer hair cells is critical for the cochlear amplification. Although regulation of important cellular functions via signaling pathways is a fundamental property of the cells a signaling pathway that would "shut down" the operation of prestin is still unknown. Our preliminary data show that direct activation of TRPA1 channels by specific agonists inhibits the motor activity of prestin in the outer hair cells. This inhibition is not observed in mice lacking the TRPA1 channels (Trpa1-/-). Since TRPA1 could be a downstream target of a variety of second-messenger systems TRPA1-mediated inhibition of prestin may represent a general mechanism regulating cochlear amplification during various stresses including acoustic over-stimulation. Consistent with this idea our preliminary data show that moderate noise exposure results in a significantly larger elevation of hearing thresholds in Trpa1-/- mice as compared to wild type (Trpa1+/+) littermates. Although the signaling pathways that control TRPA1 in outer hair cells have yet to be identified we found that extracellular ATP can inhibit prestin motor activity in Trpa1+/+ but not in Trpa1-/- mice. The goal of this project is to determine how TRPA1 channels participate in the protection of the cochlea from over- stimulation. This study will test the following central hypothesis: The cochlea is protected from acoustic over-stimulation by activation of TRPA1 channels and inhibition of prestin motor activity a previously unknown mechanism that can be activated via metabotropic ATP receptors. The proposed study will determine: 1) specific intracochlear processes that are affected by a TRPA1 deficiency; 2) the mechanism of TRPA1 activation in outer hair cells; 3) the mechanism of TRPA1-mediated inhibition of outer hair cell electromotility. Identification of the cellular processes and key molecules regulating outer hair cell electromotility at high sound intensities will open a new avenue of research in the field of noise-induced hearing loss. It may also lead to pharmacological interventions that would prevent damage of the cochlea through the enhancement of natural protection mechanisms. Finally the genes encoding the proteins involved in this novel mechanism of cochlear regulation would represent attractive candidates to screen for genetic variants that are associated with susceptibility or resistance to noise-induced and perhaps other types of hearing loss. This research is relevant to public health because it investigates a previously unknown mechanism that protects the inner ear from damage due to acoustic over-stimulation. The experimental results should help scientists develop treatments for the noise-induced hearing loss which is one of the most common causes of deafness and hearing impairment.

project_terms:
4 hydroxynonenal;ATP Receptors;Acoustic Nerve;Acoustics;Action Potentials;Affect;Agonist;Calmodulin;Cell membrane;Cell physiology;Cells;Cochlear structure;Cyclic GMP;Data;Deafness;Evoked Potentials Auditory Brain Stem;GTP-Binding Proteins;Genes;Goals;Gramicidin;Hair Cells;Hearing;Image;In Situ;In Vitro;Intervention;Labyrinth;Lead;Lipid Peroxidation;Mediating;Methods;Modification;Molecular Motors;Motor;Motor Activity;Mus;Noise;Noise-Induced Hearing Loss;Organ of Corti structure;Outer Hair Cells;Pathway interactions;Physiological;Predisposition;Preparation;Process;Property;Proteins;Regulation;Research;Resistance;Scientist;Second Messenger Systems;Sensory;Signal Pathway;Signal Transduction Pathway;Spontaneous Otoacoustic Emissions;Stress;TRPA1 Channel;Techniques;Testing;base;cell type;extracellular;flash photolysis;genetic variant;hearing impairment;in vivo;mouse ANKTM1 protein;novel;operation;prevent;public health medicine (field);rat Pres protein;response;sound;vibration

public_health_relevance:
NARRATIVEThis research is relevant to public health because it investigates previously unknown mechanism thatprotects the inner ear from damage due to acoustic over-stimulation. The experimental results should helpscientist to develop treatments for the noise-induced hearing loss which is one of the most common causeof deafness and hearing impairment.


application_id: 8411149
project_number: 5K01ES017105-04
project_title: Ubiquitous pollutant acrolein inhibits IFN?? antiviral signaling: relevance to HC
administering_ic: NIEHS
award_notice_date: 2012-12-18
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.

project_terms:
Acrolein;Acrylates;Air Pollutants;Alcohol abuse;Aldehydes;Alzheimer's Disease;Amino Acids;Antiviral Agents;Atherosclerosis;Automobile Exhaust;Binding (Molecular Function);Biocide;Biological Markers;Biological Models;Biology;Biopsy Specimen;Cell Line;Cessation of life;Chemical Weapons;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;chronic liver disease;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

public_health_relevance:
Acrolein is one of the major reactive aldehydes ubiquitously present in foods water and in theenvironment. It is a major constituent of cigarette smoke. Recent data suggest that HCV-infected smokers have worse IFN therapeutic outcomes compared with non-smokers. Acroleinis also generated endogenously due to cellular metabolism and this may constitute a significantsource of intracellular acrolein in situations of oxidative stress and inflammation. Elevatedacrolein adducts have been detected in several disease conditions that are also known to beassociated with failure of IFN therapy. Hence based on available literature and our owncompelling preliminary results we have opted to use acrolein as the model compound for thisstudy. The aim of this study is to determine the contribution of acrolein to the mechanisms ofIFN resistance. We have preliminary evidence to demonstrate that acrolein at nontoxicconcentrations significantly down-regulates IFN signaling and antiviral/anti-HCV geneexpression.


application_id: 8411011
project_number: 1R01DA033862-01A1
project_title: Epidemiologic Study of the Effectiveness of an ADF in Reducing Opioid Abuse
administering_ic: NIDA
award_notice_date: 2012-08-13
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: DA
serial_number: 033862
suffix: A1
program_official: OBRIEN, MOIRA
project_start_date: 2012-09-01
project_end_date: 2015-08-31
study_section: Behavioral and Social Consequences of HIV/AIDS Study Section[BSCH]
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
project_abstract:
DESCRIPTION (provided by applicant): The overarching goal of this time-sensitive application is to measure the effectiveness of the new abuse deterrent formulation (ADF) for OxyContin(R) in decreasing abuse of OxyContin(R). Prescription opioid abuse is a major public health concern and has plagued the rural United States in particular. The Office of National Drug Control Policy (ONDCP) and the FDA have strongly encouraged the pharmaceutical industry to develop formulations that protect against abuse; however apart from clinical trials among pain patients demonstrating efficacy of the drug for treating pain there have been no epidemiologic studies to date that have examined whether ADFs are actually effective in reducing abuse of any drug. A longitudinal epidemiologic study of prescription opioid abuse is currently in the latter phase of follow-up in rural Kentucky (R01-DA024598) in which 94.8% of participants abused OxyContin(R) in their lifetime and 81% abused the drug in the 6-months prior to the formulation change. Given this high prevalence of OxyContin(R) abuse before the formulation change this study sample is ideal for detecting changes in signals of abuse with the new ADF for OxyContin(R). The specific aims include: 1) evaluation of the effectiveness of the ADF for OxyContin(R) in reducing abuse via oral intranasal and injection routes; 2) determining whether opioid users transitioned to abuse of other prescription opioids once the non-ADF version was no longer available on the street; and 3) examination of changes in prevalence and incidence of HIV and hepatitis C (HCV) as a result of changes in route of administration after the old formulation was no longer available. This time-sensitive study is highly significant given the paucity of epidemiologic data related to the effectiveness of ADFs in reducing abuse of prescription opioids. Further this study is uniquely positioned to measure the effectiveness of the ADF for OxyContin(R) expeditiously and without the potential bias that would result if abuse were assessed retrospectively. Given the importance that the ONDCP and the FDA have placed on further development of ADFs for prescription opioids the results from this study have vast implications for public policy in addition to public health. This highly relevant study will evaluae the effectiveness of a model ADF across multiple public health domains including changes in this product's abuse and misuse via the oral intranasal and injection routes of administration. The results from this study in turn will have vast implications for not only public health but aso policies surrounding development of ADFs in order to prevent abuse of prescription opioids.   
   
PUBLIC HEALTH RELEVANCE: Prescription opioid abuse is a significant public health problem in the United States. Abuse deterrent formulations (ADFs) are one strategy that are being used to combat the growing issue. However there is a paucity of longitudinal epidemiologic data on the effectiveness of ADFs in reducing opioid abuse. Therefore this study seeks to examine the effectiveness of the ADF for OxyContin(R) in reducing OxyContin(R) abuse via the oral intranasal and injection routes of administration and to determine whether drug users transition to abusing non-ADF opioids as well as whether rates of HIV and HCV differ as a result of changes in abuse patterns once the old formulation is off the street.

project_terms:
Accounting;Clinical Trials;Data;Data Correlations;Development;Dose;Drug Controls;Drug Formulations;Drug Industry;Drug abuse;Drug usage;Drug user;Effectiveness;Epidemiologic Methods;Epidemiologic Studies;Evaluation;Goals;HIV;Hepatitis C;Hepatitis C Transmission;Hepatitis C virus;High Prevalence;Hydrocodone;Incidence;Injection of therapeutic agent;Kentucky;Manufacturer Name;Marketing;Measures;Methadone;Modeling;Names;Opioid;Oral;Outcome;Outcome Measure;Overdose;Oxycodone;Pain;Participant;Patients;Pattern;Percocet;Pharmaceutical Preparations;Phase;Plague;Policies;Positioning Attribute;Prevalence;Public Policy;Recommendation;Research;Risk Behaviors;Route;Rural;Sample Size;Sampling;Sampling Studies;Serologic tests;Severities;Shares syringes;Signal Transduction;Time;United States;Visit;addiction;cohort;combat;design;disease transmission;drug efficacy;effectiveness measure;epidemiologic data;follow-up;indexing;opioid abuse;pill (pharmacologic);prescription opioid;prescription opioid abuse;prevent;primary outcome;public health medicine (field)

public_health_relevance:
Prescription opioid abuse is a significant public health problem in the United States. Abuse deterrent formulations (ADFs) are one strategy that are being used to combat the growing issue. However there is a paucity of longitudinal epidemiologic data on the effectiveness of ADFs in reducing opioid abuse. Therefore this study seeks to examine the effectiveness of the ADF for OxyContin(R) in reducing OxyContin(R) abuse via the oral intranasal and injection routes of administration and to determine whether drug users transition to abusing non-ADF opioids as well as whether rates of HIV and HCV differ as a result of changes in abuse patterns once the old formulation is off the street.


application_id: 8409992
project_number: 1R01DA033866-01A1
project_title: Brief intervention for drug-using rural women at high-risk for HIV/HCV
administering_ic: NIDA
award_notice_date: 2012-07-06
opportunity_number: PA-10-129
application_type: 1
activity_code: R01
ic: DA
serial_number: 033866
suffix: A1
program_official: JONES, DIONNE
project_start_date: 2012-07-15
project_end_date: 2017-06-30
study_section: Behavioral and Social Science Approaches to Preventing HIV/AIDS Study Section[BSPH]
contact_pi_person_id: 14909213
contact_pi: STATON, MICHELE
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF SOCIAL WELFARE/WORK
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The overall aim of this study is to reduce risk behaviors and increase health and behavioral health service utilization among disadvantaged drug-using rural women at high-risk for HIV and HCV. This project has potential to make a significant contribution to science by advancing knowledge about the health disparities high-risk behaviors (injection drug use sex risk) and service utilization of this high-risk vulnerable an understudied group of women during a time of emerging and significant public health risk in an Appalachian rural setting. This project will incorporate standardized screening (NIDA-modified ASSIST) to identify high-risk rural women drug users from jails including injectors. Consenting women (N=350) will be asked to participate in a baseline interview and will then be randomly assigned to one of two study groups: (1) HIV Education (HIV- Ed n=175) which includes the NIDA standard pre and post-test counseling HIV and HCV rapid testing and an information packet on existing community drug abuse and HIV/HCV resources; or (2) Motivational Interviewing- based HIV Risk Reduction (MI-HIV n=175) which in addition to what is received in the HIV-Ed group also includes an evidence-based brief intervention for high-risk women focused on an individualized plan for enhancing motivation to reduce risk behaviors and to use health and behavioral health services in the community. Specific aims include: (1) to compare the effectiveness of an evidence-based HIV risk reduction intervention (MI-HIV) to HIV Education (NIDA Standard) in reducing sex risk behaviors injection practices and drug use among a culturally unique sample of disadvantaged drug-using rural women at high-risk for HIV and HCV; and (2) to examine MI-HIV Intervention engagement as a predictor of community health and behavioral health service utilization (including drug treatment and mental health) at follow-up among disadvantaged drug- using rural women at high risk for HIV and HCV. This project is innovative because it 1) targets a high-risk and understudied group of women 2) uses brief intervention to not only reduce risk behavior but also to enhance motivation for using community health and behavioral health resources and 3) utilizes a real-world setting to identify high-risk women drug users. The long-term goal of this study is to increase access to health and behavioral health services in order to improve the quality of health of high-risk rural women.   
   
PUBLIC HEALTH RELEVANCE: The overall aim of this study is to reduce risk behaviors and increase health and behavioral health service utilization among disadvantaged drug-using rural women at high risk for HIV and HCV. This project has potential to make a significant contribution to science by providing knowledge about the health risk behaviors and service utilization of a vulnerable and understudied group of women during a time of emerging and significant public health risk in a rural Appalachian setting. Successful completion of the aims of
this project will advance the delivery of a low-cost potentially high impact intervention with implications for a number of other real world settings (such as criminal justice venues) where other disadvantaged high-risk drug users can be identified and targeted for intervention.

project_terms:
AIDS/HIV problem;Address;Appalachian Region;Area;Centers for Disease Control and Prevention (U.S.);Communities;Community Health;Community Services;Consent;Counseling;Country;Criminal Justice;Disadvantaged;Drug abuse;Drug usage;Drug user;Educational Intervention;Educational aspects;Evidence based intervention;Goals;HIV;Health;Health Resources;Health Services;Healthcare;Hepatitis C virus;High Risk Woman;Injection of therapeutic agent;Intervention;Interview;Jail;Kentucky;Knowledge;Mental Health;Motivation;National Institute of Drug Abuse;Opiates;Participant;Pattern;Pharmaceutical Preparations;Pre-Post Tests;Prevalence;Random Allocation;Randomized;Reporting;Research;Research Personnel;Resources;Risk;Risk Behaviors;Risk Reduction;Rural;Sampling;Science;Screening procedure;Services;Staging;Testing;Time;United States National Institutes of Health;Vulnerable Populations;Walkers;Woman;Women's Group;base;behavioral health;brief intervention;compare effectiveness;comparison group;cost;design;drug resource;evidence base;follow-up;health care service utilization;health disparity;high risk;high risk behavior;improved;innovation;motivational enhancement therapy;outreach;prescription opiate;public health medicine (field);response;rural area;service utilization;sex risk;treatment planning

public_health_relevance:
The overall aim of this study is to reduce risk behaviors and increase health and behavioral health service utilization among disadvantaged drug-using rural women at high risk for HIV and HCV. This project has potential to make a significant contribution to science by providing knowledge about the health risk behaviors and service utilization of a vulnerable and understudied group of women during a time of emerging and significant public health risk in a rural Appalachian setting. Successful completion of the aims of
this project will advance the delivery of a low-cost potentially high impact intervention with implications for a number of other real world settings (such as criminal justice venues) where other disadvantaged high-risk drug users can be identified and targeted for intervention.


application_id: 8403828
project_number: 5R01CA138410-04
project_title: Regulation of miRNA in breast cancer
administering_ic: NCI
award_notice_date: 2012-12-07
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: 2014-12-31
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.

project_terms:
3' Flanking Region;3' Untranslated Regions;4-Hydroxy-Tamoxifen;Affect;Aromatase Inhibitors;BCL2 gene;Binding (Molecular Function);Bioinformatics;Biological Assay;Biological Markers;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;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;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: 8403825
project_number: 5R01CA035635-26
project_title: Specificity of Intercalation Reactions
administering_ic: NCI
award_notice_date: 2012-11-29
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 035635
program_official: MISRA, RAJ N
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
arra_indicator: N
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.

project_terms:
Base Sequence;Basic Science;Beryllium;Binding (Molecular Function);Binding Proteins;Biology;Calorimetry;Cell Cycle;Coupled;Crystallography;DNA;DNA Intercalation;DNA Structure;Diffusion;Drug Kinetics;Drug Stability;Drug Targeting;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

public_health_relevance:
G-quadruplexes are four-stranded DNA structures that are thought to be functionallyimport elements in the human genome. Quadruplexes have emerged as potential drugtargets. The proposed project will use computational and biophysical methods to studythe structure stability and drug binding of functionally significant quadruplex structures.The results will be of fundamental use for guiding the design of new drugs targetedtoward quadruplexes.


application_id: 8403722
project_number: 5R01HL108621-03
project_title: Mitophagic and anti-angiogenic mechanism of heart failure
administering_ic: NHLBI
award_notice_date: 2012-12-23
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: HL
serial_number: 108621
program_official: ADHIKARI, BISHOW B
project_start_date: 2011-04-15
project_end_date: 2015-12-31
study_section: Special Emphasis Panel[ZRG1-VH-B(02)M]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Although heart failure is inevitable disease its management depends on the understanding of the mechanism of ailing to failing myocardium. During heart failure the heart undergoes compensatory remodeling (i.e. left ventricle hypertrophy (LVH) and vascular angiogenesis. Unfortunately during end-stage heart failure there is dis-coordination between the LVH and angiogenesis (i.e. LVH persists but angiogenesis declines). This leads to continue increase in LV wall stress leading to failure. Remodeling by its very nature implies synthesis degradation and re-arrangement of intra and inter cellular matrix. Matrix metalloproteinases (MMPs) are designer architecture and tailor. The long-term goal of this project is to understand the differential role of MMPs in structural and functional heterogeneity in myocardial remodeling. The selective MMP-2 gene ablation reduces survival and exacerbates cardiac failure-induced by myocardial inflammation. MMP-9 gene ablation is cardioprotective. In human heart end-stage failure MMP-9 activation supersedes the MMP-2 activation. The hypothesis of this proposal is that MMP-2 is constitutive and during compensatory phase activates proteinase activated receptor-1 (PAR-1 a GPCR) and releases growth factors via the activation of anti-stress (PKB/AKT). Chronic stress leads to mitochondrial mitophagy and activation of MMP-9 and MMP-13 (an interstitial collagenase in rodent and MMP-1 in human). TIMP-3 (an apoptotic/autophagic factor) and anti-angiogenic statins are released The hypothesis will be tested by following three specific aims: Specific Aim #1: To determine whether the induction of MMP-2 PAR-1 G1s and AKT causes compensatory hypertrophy and mitochondrial mitophagy causes MMP-9 activation and decreases G1s and AKT in de-compensatory heart failure. Specific Aim #2: To determine whether the MMP-2 releases angiogenic growth factors during compensatory remodeling and MMP-9 releases anti-angiogenic statins in de-compensatory heart failure. Specific Aim #3: To determine whether the mitochondrial mitophagy attenuates angiogenesis in part by activating MMP-9 releasing TIMP-3 and generating statins during de-compensatory heart failure. These studies will delineate the causative role of PAR-1 MMP TIMP G1s and mitophagy in switch from compensatory LVH and angiogenesis to de-compensatory LVH and anti-angiogenesis and will have therapeutic ramifications for chronic heart failure.

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

public_health_relevance:
Project NarrativeThese studies will delineate the differential role of mitochondrial mitophagy and anti-angiogenesis mechanisms in end-stage heart failure. The differential role of differentMMPs in angiogenesis and anti-angiogenesis in transition from compensatoryhypertrophy to de-compensatory heart failure will be determined. The positive outcomeof this project will have therapeutic ramifications for chronic heart failure.


application_id: 8403636
project_number: 5R01CA143428-03
project_title: Rel B mediated-redox regulation of radiation therapy
administering_ic: NCI
award_notice_date: 2012-12-21
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: CA
serial_number: 143428
program_official: BERNHARD, ERIC J
project_start_date: 2011-01-01
project_end_date: 2015-11-30
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: ST CLAIR, WILLIAM H
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): Accumulating data suggest that prostate cancers exist in an elevated state of oxidative stress and that reactive oxygen species (ROS) contribute importantly to the cytotoxic effect of ionizing radiation (IR). However ROS also participate in cellular signaling processes leading to adaptive responses that reduce the effectiveness of radiation therapy. Thus despite rapid advances in treatment techniques the outcome of radiation therapy especially for patients with tumors with unfavorable prognoses remains to be improved. The goal of this project is to identify novel mechanisms that could lead to the development of specific measures for effective treatment of aggressive prostate cancers. We have identified the alternative pathway of the redox sensitive nuclear factor kappa beta (NF-?B) as a major contributor to prostate cancer growth and progression. Preliminary data indicate that: 1) aggressive prostate cancers have high nuclear RelB a member of the alternative pathway of NF-:B and manganese superoxide dismutase (MnSOD) a critical antioxidant enzyme levels; 2) suppression of RelB in androgen independent-aggressive prostate cancer cells results in reduction of interleukin 8 (IL8) levels in tumor cells and reduced tumor growth in vivo; 3) overexpression of RelB in androgen responsive prostate cancer cells results in enhanced tumor growth and production of IL8 but reduced prostate specific androgen (PSA) production; and 4) suppression of RelB nuclear translocation enhances radiation sensitivity of prostate cancer. Based on these novel and important preliminary findings we hypothesize that RelB regulates prostate cancer response to radiation via a MnSOD dependent NF-?B switch to activate expression of IL8 and suppress expression of PSA in prostate cancer cells. We propose that clinical testing for recurrent tumor growth should involve measuring levels of IL8 in addition to employing the standard PSA test. Combining these tests will enhance accurate cancer detection and prognosis. To test this hypothesis and validate the proof-of-concept for the combined use of IL8 and PSA as prognostic factors three interrelated specific aims will be addressed. Aim 1 will elucidate the mechanism by which MnSOD modulates the effect of RelB on the transcription of IL8 and PSA in prostate cancer cells using biochemical and molecular biology approaches. Aim 2 will examine the role of IL8 in the protection against the effects of radiation therapy of prostate cancer. Aim 3 will determine whether serum IL8 level is a predictive marker of prostate cancer response to radiation therapy using samples from cancer patients.  These mechanistic based bench to bedside approaches should provide novel insights into the mechanisms of prostate cancer resistant to radiation therapy and may provide practical predictive measures for prostate cancer diagnostic treatment planning and surveillance.

project_terms:
Address;Affinity Chromatography;Androgens;Animal Model;Antioxidants;Basic Science;Binding (Molecular Function);Biochemical;Biological Assay;Cancer Center;Cancer Detection;Cancer Diagnostics;Cancer Etiology;Cancer Patient;Cancer Prognosis;Cessation of life;Clinical;Clinical Research;Cultured Cells;Data;Development;Diagnosis;Diagnostic Neoplasm Staging;Effectiveness;Enzymes;Family;Gene Expression;Genes;Genetic Transcription;Goals;Growth;Human;Immunoprecipitation;Interleukin-8;Ionizing radiation;Kentucky;Lead;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Manganese Superoxide Dismutase;Measures;Mediating;Modeling;Molecular Biology;NF-kappa B;Nuclear;Nuclear Translocation;Outcome;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Patients;Physicians;Play;Predictive Factor;Production;Prognostic Factor;Prostate;Prostate-Specific Antigen;Proteomics;Radiation;Radiation Tolerance;Radiation therapy;Reactive Oxygen Species;Recurrent tumor;Regulation;Resistance;Risk;Role;Sampling;Serum;Site-Directed Mutagenesis;Small Interfering RNA;Techniques;Testing;Time;Transcriptional Regulation;Translating;Tumorigenicity;Universities;Visit;base;bench to bedside;cancer diagnosis;cancer type;computerized data processing;cytotoxic;cytotoxicity;effective therapy;follow-up;improved;in vivo;inflammatory marker;insight;member;men;neoplastic cell;novel;outcome forecast;overexpression;prostate cancer cell;public health relevance;research clinical testing;research study;response;treatment planning;treatment strategy;tumor;tumor growth

public_health_relevance:
Project Narrative Prostate cancer is the most frequently diagnosed cancer in men and the number of men who die fromprostate cancer is unacceptably high. The results obtained from this study will provide insights into the novelmechanisms by which interleukin 8 (IL8) and prostate specific antigen (PSA) are differentially regulated andwill test a proof-of-concept for using their relationship to predict the efficacy of radiation therapy for treatingprostate cancer. Thus this study will enable physicians to tailor risk-adjusted strategies for treatment ofprostate cancer.


application_id: 8403585
project_number: 5R01AG024377-08
project_title: Characterization of the Sch9 -Longevity Pathway in Yeast
administering_ic: NIA
award_notice_date: 2012-12-13
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AG
serial_number: 024377
program_official: GUO, MAX
project_start_date: 2004-09-01
project_end_date: 2015-05-31
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 1879389
contact_pi: DICKSON, ROBERT CARL
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Model organisms such as Saccharomyces cerevisiae have proven effective in elucidating genes and metabolites that modulate life span and this knowledge forms a basis for understanding human aging and longevity. These studies have identified the Akt/PKB protein kinases as conserved regulators of aging. However it is not entirely clear how they work. One focus of our research is the S. cerevisiae Sch9 protein kinase an AKT homolog that regulates chronological life span (CLS). From in vitro studies we identified sphingolipid long chain bases (LCBs) and Pkh1 a homolog of human phosphoinositide-dependent protein kinase 1 (PDK1) as the first upstream regulator of Sch9. In addition we identified the first Sch9 substrates Rli1 involved in translation initiation and ribosome biogenesis and Ahp1 an alkyl hydroperoxide reductase that protects against oxidative stress. We will build upon these novel results and determine if phosphorylation of Rli1 and Ahp1 by Sch9 plays a role in CLS. We will also determine in vivo if LCBs and Pkh1 act upstream to regulate Sch9 during chronological aging. Although we have successfully identified Sch9 substrates there are likely to be others and we propose to search for new substrates by classical biochemical strategies newer automated but complementary strategies and a genetic screening strategy. In summary the results of these studies will provide the much needed mechanistic understanding of how Akt (Sch9) activity is regulated in yeast and how it regulates CLS through downstream substrates. This knowledge will help to provide a molecular basis for understanding human aging and longevity.

project_terms:
Affect;Aging;Alanine;Alleles;Animal Model;Binding (Molecular Function);Biochemical;Biogenesis;Biological Assay;Caloric Restriction;Cell Fraction;Cell Fractionation;Cells;Cellular Membrane;Chimeric Proteins;Chromatin;Density Gradient Centrifugation;Down-Regulation;Enzymes;Genes;Genetic;Genetic Screening;Glass;Health;Homologous Gene;Human;In Vitro;Ion-Exchange Chromatography Procedure;Knowledge;Label;Libraries;Longevity;Longevity Pathway;Mammals;Mass Spectrum Analysis;Measures;Mediator of activation protein;Membrane;Molecular;Mutate;Organelles;Oxidative Stress;Pathway interactions;Phase;Phosphatidylinositols;Phosphorylation;Physiological;Play;Protein Binding;Protein Biosynthesis;Protein Kinase;Proteins;Proto-Oncogene Proteins c-akt;Research;Ribosomes;Role;Saccharomyces cerevisiae;Serine;Signal Transduction Pathway;Slide;Sphingolipids;Temperature;Testing;Translation Initiation;Work;Yeasts;alkyl hydroperoxide reductase;analog;base;cell type;dihydroceramide desaturase;dosage;in vivo;mutant;novel;prevent;uptake;yeast protein

public_health_relevance:
Project NarrativeThe proposed research will determine how the Sch9 protein kinase a functional homologof mammalian Akts/PKBs regulates chronological life span in the Baker's yeastSaccharomyces cerevisiae. Signal transduction pathways that contain Akt/PKB typeprotein kinases play important roles in regulating aging and life span and these pathwayshave been conserved from yeasts to mammals. Thus information gained from thesestudies should provide a more mechanistic basis for understanding how aging and lifespan are regulated in humans.


application_id: 8401678
project_number: 1R21EY022871-01
project_title: Tectal influences on visual thalamic activity: an optogenetic approach
administering_ic: NEI
award_notice_date: 2012-09-21
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: EY
serial_number: 022871
program_official: STEINMETZ, MICHAEL A
project_start_date: 2012-09-30
project_end_date: 2014-09-29
study_section: Special Emphasis Panel[ZRG1 IFCN-L (02)]
contact_pi_person_id: 1864719
contact_pi: GUIDO, WILLIAM
other_pis: KRAHE, THOMAS E
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Much is known about how inputs from sources other than the retina affect the thalamic relay of retinal signals in route to the visual cortex. They arse from a variety of subcortical and cortical sources comprise the bulk of synapses onto thalamic relay cells and act as modulators to affect the gain of retinogeniculate signal transmission. The superior collliculus (SC) a primary retino-recipient structure also sends a prominent projection to the dorsal lateral geniculate nucleus (dLGN) the first order nucleus that conveys retinal signals to visual cortex. However whether SC input acts as a driver to help shape the receptive field structure of dLGN relay neurons or as a modulator to dampen or amplify the flow of thalamic information remains untested. To understand how information arising from the SC influences dLGN function and how particular SC cell types contribute to this we shall make use of mouse transgenics to visualize or target cell types and projections of the tectogeniculate pathway optogenetics to photo-activate SC inputs to evoke postsynaptic activity in dLGN cells and in vitro and in vivo recording techniques to assess whether SC inputs behave as drivers or modulators of dLGN activity. These combined approaches will allow us to selectively control the neuronal activity of the tecto-geniculate pathway and shed light on how interactions between two retino- recipient subcortical structures affect the processing and transfer of visual information.   
   
PUBLIC HEALTH RELEVANCE: These studies will provide valuable information about how first-order sensory nuclei of the thalamus receive and process information from peripheral sense organs. They shall also reveal how afferent input from central structures can modulate the flow of thalamic information in route to sensory cortical areas. Understanding the functional and structural organization of thalamic circuitry with optogenetic tools may offer further insight into
the study and treatment of neurological disorders that result from the formation of abnormal patterns of connectivity.

project_terms:
Action Potentials;Acute;Address;Affect;Area;Behavior;Cations;Cell Nucleus;Cells;Chimera organism;Chloride Ion;Chlorides;Data;Depressed mood;Dorsal;Electric Stimulation;Electrodes;Eye;Fiber;Fiber Optics;Glutamates;Halorhodopsins;Head Movements;Imagery;In Vitro;Lateral Geniculate Body;Lead;Light;Location;Mammals;Mus;Mutation;Neurons;Optic tract structure;Pathway interactions;Pattern;Peripheral;Physiologic pulse;Process;Property;Pump;Reporter;Retina;Retinal;Retinal Ganglion Cells;Route;Sense Organs;Sensory;Shapes;Signal Transduction;Slice;Source;Space Perception;Structure;Synapses;Techniques;Tectum Mesencephali;Thalamic structure;Transgenic Mice;Variant;Viral Vector;Visual;Visual Cortex;Whole-Cell Recordings;adeno-associated viral vector;biocytin;cell type;extracellular;image processing;in vivo;information processing;insight;loss of function;nerve supply;nervous system disorder;object recognition;optogenetics;polypeptide;postsynaptic;receptive field;recombinase;red fluorescent protein;research study;response;retinogeniculate;retinotectal;superior colliculus Corpora quadrigemina;tool;transmission process;vector;visual information;visual stimulus

public_health_relevance:
These studies will provide valuable information about how first-order sensory nuclei of the thalamus receive and process information from peripheral sense organs. They shall also reveal how afferent input from central structures can modulate the flow of thalamic information in route to sensory cortical areas. Understanding the functional and structural organization of thalamic circuitry with optogenetic tools may offer further insight into
the study and treatment of neurological disorders that result from the formation of abnormal patterns of connectivity.


application_id: 8401579
project_number: 2U10NS058967-06
project_title: UK NETT Clinical Site Hub
administering_ic: NINDS
award_notice_date: 2012-08-31
opportunity_number: PAR-11-342
application_type: 2
activity_code: U10
ic: NS
serial_number: 058967
program_official: JANIS, SCOTT
project_start_date: 2007-05-03
project_end_date: 2017-07-31
study_section: Special Emphasis Panel[ZNS1 SRB-N (01)]
contact_pi_person_id: 8686194
contact_pi: HUMPHRIES, ROGER LOYD
other_pis: Not Applicable
congressional_district: 06
department: EMERGENCY 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 proposal describes the re-establishment of a Neurological Emergencies Treatment Trials (NETT) Network Clinical Site Hub at the University of Kentucky Chandler Medical Center (UKCMC) in Lexington Kentucky in response to NIH/NINDS PAR-11-342. The overall goal of this proposal is to identify UKCMC as an academic medical facility with regional affiliate partners adept in "the evaluation of treatments for patiens with a broad spectrum of neurological emergencies." The NETT Clinical Hub Site at UKCMC (UK NETT) has been a vigorous participant in the NETT Network since its competitive selection as one of the original 17 Network sites in 2007. During the past 4 years as a participating Clinical Hub Site UK NETT has enrolled more than 50 subjects in the Phase 111 clinical trials undertaken within the NETT Network to include RAMPART (midazolam v. lorazepam in status epilepticus) ALIAS Part 2 (albumin v. placebo in acute ischemic stroke) POINT (clopidogrel loading for stroke prevention after transient ischemic attack) and ProTECT (progesterone v. placebo in traumatic brain injury). Emergency Medicine is well represented within this venture as the original and proposed UK NETT are based within the Department of Emergency Medicine at UKCMC. UK NETT is founded upon an intra-institutional collaboration that extends beyond Emergency Medicine to include physician faculty members in the Departments of Neurology Neurosurgery Surgery/Trauma Surgery and Anesthesiology/Intensive Care Medicine. Regional affiliate medical care facilities aligned with UK NETT include "spoke" community hospitals located within Kentucky. The following Specific Aims are proposed: 1) To demonstrate the existence of an infrastructure for high-volume subject recruitment in "large simple" clinical trials performed in acute-onset neurological disorders and 2) To demonstrate experience in successfully conducting clinical trials in acute-onset neurological disorders requiring Exception from Informed Consent as regulated by the United States Food & Drug Administration.   
   
PUBLIC HEALTH RELEVANCE: The relevance of this proposal for public health is to identify the University of Kentucky Chandler Medical Center in Lexington Kentucky as a regional center for clinical research in acute illnesses affecting the human nervous system. These conditions include stroke seizures traumatic brain or spinal cord injury and other disorders among the most common causes of death and serious disability affecting American citizens.


application_id: 8401004
project_number: 1R03CA171604-01
project_title: Apple peel extract inhibits Cr(VI)-induced lung cancer
administering_ic: NCI
award_notice_date: 2012-08-30
opportunity_number: PAR-11-079
application_type: 1
activity_code: R03
ic: CA
serial_number: 171604
program_official: SEIFRIED, HAROLD E
project_start_date: 2012-09-01
project_end_date: 2014-08-31
study_section: Special Emphasis Panel[ZCA1 SRLB-2 (M1)]
contact_pi_person_id: 10011919
contact_pi: ZHANG, ZHUO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Cr(VI)-containing compounds are well established environmental carcinogens. Although the mechanisms of Cr(VI) carcinogenesis remain to be investigated various studies indicate that Cr(VI)-induced generation of reactive oxygen species (ROS) plays a key role. Many naturally occurring substances present in the human diet have been identified as potential chemopreventive agents. Investigations using animal models and epidemiological studies indicate that consumption of phytochemicals might reduce the incidence of cancers and other chronic diseases. These plant-derived phytochemicals are rich sources of naturally occurring antioxidants. Our preliminary studies have shown that oral administration of apple peel extract decreased the number of nonmalignant and malignant skin tumors induced by 12-O-tetradecanolyphorbol-13-acetate (TPA) in 7 12-dimethyl Benz (a) anthracene-initiated mouse skin. Apple peel extract is able to directly scavenge hydroxyl radial (OH) and superoxide radical (O2-). Our preliminary studies have also shown that apple peel extract inhibited Cr(VI)-induced "OH radical generation in cellular system. The mechanisms involve direct scavenging of OH radical and chelation of Cr(V) by apple peel extract to make this chromium intermediate less reactive toward hydrogen peroxide(H2O2) for OH radical generation. Our preliminary data have shown that apple peel extract inhibited Cr(VI)-induced expressions of inflammatory proteins including NF-?B and TNF-. We hypothesize that apple peel extract may function as an antioxidant and as a chemopreventive agent against Cr(VI)-induced lung cancer via inhibition of Cr(VI)-induced oxidative stress. Aim 1 will use in vivo electron spin resonance (ESR) to investigate inhibition of Cr(VI)-generated free radicals by apple peel extract in living animals (BALB/c mice). Two approaches will be used: (a) to investigate the chelation of Cr(V)-NADPH complex or change of its structure by apple peel extract; and (b) to investigate the inhibition of apple peel extract on Cr(VI)-induced free radical generation. Aim 2 will investigate the protection
of apple peel extract against Cr(VI)-induced lung inflammation chronic oxidative lung tissue injury and cell proliferation using BALB/c mice. There are increasing studies supporting the association among oxidative stress chronic inflammation and cancer development. Because oxidative stress plays an important role in inflammation cell proliferation and tissue injury itis likely that inhibition of oxidative stress will protect Cr(VI)-induced chronic lung injury and an inflammatory microenvironment leading to the protection in Cr(VI)-induced lung cancer. In this aim we will Investigate the protection of apple peel extract against Cr(VI)-induced inflammation chronic oxidative lung injury and cell proliferation using female BALB/c mice.   
   
PUBLIC HEALTH RELEVANCE:  The Cr(VI)-containing compounds are well established environmental carcinogens. Oxidative stress is considered to play an important role in the mechanism of Cr(VI)-induced carcinogenesis. The goal of this proposal is to develop apple peel extract as an antioxidant and a protective agent against Cr(VI)-induced oxidative stress and lung cancer.

project_terms:
Acetates;Animal Model;Animals;Antioxidants;Apple;Benz(a)Anthracenes;California;Carcinogens;Cell Proliferation;Chemopreventive Agent;Chromium;Chronic;Chronic Disease;Complex;Consumption;Data;Development;Diet;Electron Spin Resonance Spectroscopy;Environmental Carcinogens;Epidemiologic Studies;Equilibrium;Exposure to;Female;Free Radicals;Frequencies (time pattern);Fruit;Generations;Glutathione Reductase;Goals;Human;Hydrogen Peroxide;Hydroxyl Radical;Inbred BALB C Mice;Incidence;Inflammation;Inflammatory;Inhalation Exposure;Injury;International Agency for Research on Cancer;Investigation;Life;Lung Inflammation;Malignant Neoplasms;Malignant neoplasm of lung;Measurement;Molecular;Mus;NADP;NADPH Oxidase;Non-Malignant;Nose;Occupational;Occupational Groups;Oral;Oral Administration;Oxidative Stress;Oxygen;Phytochemical;Plants;Play;Podophyllum peltatum;Process;Protective Agents;Proteins;Radial;Reaction;Reactive Oxygen Species;Reducing Agents;Role;Skin;Skin Cancer;Source;Structure;Structure of parenchyma of lung;Superoxides;System;TNF gene;Tissues;Water;benzanthracene;carcinogenesis;carcinogenicity;chelation;in vivo;instrument;lung injury;tumorigenesis

public_health_relevance:
The Cr(VI)-containing compounds are well established environmental carcinogens. Oxidative stress is considered to play an important role in the mechanism of Cr(VI)-induced carcinogenesis. The goal of this proposal is to develop apple peel extract as an antioxidant and a protective agent against Cr(VI)-induced oxidative stress and lung cancer.


application_id: 8400390
project_number: 5R37DE011111-20
project_title: P.gingivalis Interactions with Gingival Epithelial Cells
administering_ic: NIDCR
award_notice_date: 2012-11-28
opportunity_number: PA-07-070
application_type: 5
activity_code: R37
ic: DE
serial_number: 011111
program_official: LUNSFORD, DWAYNE
project_start_date: 1995-04-01
project_end_date: 2013-12-31
study_section: Special Emphasis Panel[ZRG1-MOSS-B(02)M]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Periodontal diseases are one of the most common bacterial infections of humans and impose a significant burden on the health care system. One of the predominant pathogens in periodontal disease is the gram- negative anaerobe P. gingivalis. However P. gingivalis can also inhabit the oral cavity in the absence of overt disease and can participate in a balanced interaction with host cells. Epithelial cells that line the gingival crevice function both as a physical barrier and as sensors of microbial colonization. The outcome of the interaction between P. gingivalis and gingival epithelial cells therefore makes a significant contribution to the degree of equilibrium between host and microbe and to overall gingival health status. P. gingivalis can manipulate epithelial cell signal transduction pathways in order to direct entry into the host cell and to reprogram host innate immunity. One of the effector molecules of P. gingivalis is the HAD family serine phosphatase SerB. The goal of this proposal is to define the mechanism of action of SerB as it relates to uptake of the organism by gingival epithelial cells and modulation of innate immunity. Firstly the ability of SerB to dephosphorylate and activate cofilin will be examined. Cofilin regulates actin dynamics through mediating the disassembly of actin filaments and our hypothesis is that activation of cofilin by SerB is required for P. gingivalis entry. This will be tested through up and down regulation of cofilin activity by siRNA and transfections with activation-altered cofilin. Secondly we shall determine the signaling pathways modulated by SerB that converge on suppression of the chemokine IL-8. The participation of MEK and NF-?B will be investigated by blotting mobility shift assays and dominant positive and negative mutations. Finally we shall characterize the interconnectivity between SerB-induced cytoskeletal signaling and IL-8 suppression by manipulation of actin filament structure and MEK activation status. These studies will provide a detailed molecular analysis of the targeting of host signal transduction by a specific effector phosphatase of P. gingivalis. Ultimately the knowledge gained could be developed into strategies that could be utilized to intervene in the P. gingivalis-epithelial cell interaction to ensure that the outcome is non-harmful to the host.

project_terms:
Actins;Address;American;Anaerobic Bacteria;Architecture;Bacteria;Bacterial Infections;Cell Communication;Cell Line;Cells;Choline phosphatase;Disease;Down-Regulation;Effector Cell;Electrophoretic Mobility Shift Assay;Ensure;Environment;Enzymes;Epithelial;Epithelial Cells;Equilibrium;Family;Genes;Genetic Transcription;Gingiva;Goals;Health Status;Healthcare Systems;Human;IL8 gene;Immune;Immune response;Immunologic Surveillance;Intercept;Knowledge;MAP Kinase Signaling Pathways;MEKs;Mediating;Microbe;Microfilaments;Molecular;Molecular Analysis;Mucous Membrane;Mutation;Natural Immunity;Oral cavity;Organism;Outcome;Periodontal Diseases;Periodontium;Phosphoric Monoester Hydrolases;Physiological;Porphyromonas gingivalis;Process;Production;Protein Dephosphorylation;Role;Serine;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Small Interfering RNA;Structure;Surface;System;Testing;Therapeutic Agents;Tissues;Transfection;Up-Regulation (Physiology);actin depolymerizing factor;adverse outcome;chemokine;cofilin;design;haloacid dehalogenase;insight;microbial colonization;microorganism;novel;pathogen;prevent;public health relevance;sensor;uptake

public_health_relevance:
P. gingivalis is a cause of periodontal diseases that afflict millions of Americans. In this study we will examinethe interactions between P. gingivalis and the human cells that are colonized by the organism. The informationto be gathered could be used to identify targets for novel therapeutic agents designed to interfere with thecolonization and survival strategies of P. gingivalis.


application_id: 8400086
project_number: 2R44DK089892-03A1
project_title: BIOMARKER FOR EARLY DETECTION OF CHRONIC KIDNEY DISEASE
administering_ic: NIDDK
award_notice_date: 2012-06-01
opportunity_number: PA-11-096
application_type: 2
activity_code: R44
ic: DK
serial_number: 089892
suffix: A1
program_official: MOXEY-MIMS, MARVA M
project_start_date: 2010-09-20
project_end_date: 2015-05-31
study_section: Special Emphasis Panel[ZRG1 DKUS-L (11)]
contact_pi_person_id: 1897474
contact_pi: CARRITHERS, STEPHEN L
other_pis: COUGHLIN, RICHARD THOMAS
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
project_abstract:
DESCRIPTION (provided by applicant): There are an estimated 26 million Americans with early chronic kidney disease (CKD). Early diagnosis and treatment are the only cost-effective means to reverse this growing problem. 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. Current methods and biomarkers that are used to assess CKD are effective once the disease is well established but are not reliable for the detection of early disease. Further many patients initially determined to
have a mild decline in kidney function by the current methods may actually be misclassified and possibly under-diagnosed resulting in a patient having undiagnosed moderate to severe kidney damage. We will produce a new ELISA for CKD to be employed as a diagnostic test based upon the use of a novel biomarker that reflects early events in the pathophysiology of kidney disease. Detection of this biomarker for CKD will give laboratory results and clinical insight that
are complementary to creatinine-based glomerular filtration rate (GFR) estimates as well as tests for urine albumin. This should result is a more reliable and earlier identification of CKD.  n addition our CKD-Assay would give physicians the ability to evaluate patients that have been recently diagnosed with hypertension or diabetes. In Phase I we evaluated the feasibility and proof-of principal of this test and found that the prototype assay in both populations was highly sensitive and specific. In Phase II we will look for the influence of comorbid conditions and medications on assay performance compare our results to the gold standard assay of GFR and follow up patients over at least 3 years to evaluate the ability of this biomarker to follow progression of CKD. Lastly we will evaluate whether patient characteristics such as age gender BMI ethnicity and other factors impact on assay performance. We request Phase II support so that we can evaluate the prototype assay and further test its feasibility to help identiy at-risk patients for early kidney disease and monitor therapy with the ultimate goal of obtaining FDA approval and reducing the societal impact of under-diagnosed CKD.   
   
PUBLIC HEALTH RELEVANCE: Chronic Kidney Disease affects nearly 26 million people in the United States which places them at higher risk of cardiovascular disease and hemodialysis. We will develop an assay for the identification of people with advanced kidney disease that are under-diagnosed by current methods and to aid physicians in earlier treatment and better assessment of chronic kidney disease.

project_terms:
Affect;Age;Albumins;American;Antibodies;Archives;Biological Assay;Blood Circulation;Cardiovascular Diseases;Characteristics;Chronic Kidney Failure;Clinical;Clinical Trials;Complement;Creatinine;Detection;Development;Diabetes Mellitus;Diagnosis;Diagnostic tests;Disease;Early Diagnosis;Early identification;Early treatment;Enzyme-Linked Immunosorbent Assay;Ethnicity aspects;Event;Filtration;Functional disorder;Gender;Glomerular Filtration Rate;Goals;Gold;Health;Hemodialysis;Homeostasis;Hypertension;Impairment;Individual;Kidney;Kidney Diseases;Laboratories;Linear Models;Measures;Medical;Methods;Microalbuminuria;Monitor;NHANES;Patients;Performance;Pharmaceutical Preparations;Phase;Physicians;Play;Population;Prevalence;Race;Reagent;Renal function;Risk;Role;Sampling;Serum;Sodium Chloride;Specificity;Staging;Testing;United States;United States National Institutes of Health;Urine;Variant;Water;base;biomarker;cardiovascular risk factor;case control;commercialization;cost effective;economic impact;follow-up;high risk;insight;novel;phase 1 study;post gamma-globulins;prevent;prohormone;prototype;prouroguanylin;research and development;research clinical testing;scale up

public_health_relevance:
Chronic Kidney Disease affects nearly 26 million people in the United States which places them at higher risk of cardiovascular disease and hemodialysis. We will develop an assay for the identification of people with advanced kidney disease that are under-diagnosed by current methods and to aid physicians in earlier treatment and better assessment of chronic kidney disease.


application_id: 8398919
project_number: 5F31DC010281-03
project_title: Deaf infants' cognitive skills and their post-cochlear implant language outcomes
administering_ic: NIDCD
award_notice_date: 2012-12-13
opportunity_number: PA-10-108
application_type: 5
activity_code: F31
ic: DC
serial_number: 010281
program_official: SKLARE, DAN
project_start_date: 2011-01-01
project_end_date: 2013-05-31
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 9702555
contact_pi: SHAFTO, CARISSA LYNN
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term research goal is to identify predictors of spoken language development in profoundly deaf children who receive a cochlear implant (CI). Decades of research have demonstrated that children with severe-to-profound deafness (including children who receive a CI) on average exhibit deficits in language and literacy as compared to their normally-hearing (NH) peers (e.g. Geers 2004; Miller 2009; Paul 1998). These literacy and spoken language deficits are thought to be responsible for the significant academic achievement gaps that are observed between deaf and NH children (e.g. Harris & Beech 1998). Further research is needed to determine the skills underlying spoken language development in deaf children so that more effective early intervention strategies can be developed.  The goal of the proposed project is to compare cognitive skills (known to be important for language acquisition) in children with profound hearing loss to those of children with NH and to examine the relationship between a nonverbal cognitive skill (VSL ability) and spoken language ability.  The first specific aim is to examine visual sequence learning (VSL) in infants aged 8 to 23 months with severe-to-profound deafness that will be undergoing cochlear implantation. Their performance on the VSL task will be compared to the performance of aged-matched infants with NH. Infants with CIs will be tested on the VSL task just prior to the initial activation of their CI (i.e. prior to auditory input). Differences in performance between the two groups will serve as an index of the effects of early auditory deprivation on VSL ability.  The second specific aim is to determine the relationship between VSL ability and later spoken language in deaf infants who use CIs. Correlational analyses will be conducted between scores on the VSL task prior to cochlear implantation and vocabulary and grammatical scores on the MacArthur-Bates Communicative Development Inventories (CDIs; Fenson et al. 2006) one year following cochlear implantation.  Because language development begins at birth infancy is an opportune time to investigate predictors of spoken language ability. A potential clinical implication of this work is the identification of early nonverbal predictors of spoken language outcome which may be used in the future to develop new early intervention strategies designed to promote spoken language development. These strategies may narrow the achievement gap between NH and deaf children. A strong positive correlation between VSL in infancy and spoken language ability one year later would suggest that early sequence learning skills are important for spoken language development. In contrast a weak correlation might suggest that VSL ability is not that important for spoken language development in deaf infants. Either pattern of results clarifies the effects of auditory deprivation on the development of cognitive skills that underlie spoken language development.

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

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


application_id: 8398731
project_number: 1R03CA165086-01A1
project_title: Maternal Exercise Enhances Cancer Protection in Offspring
administering_ic: NCI
award_notice_date: 2012-07-09
opportunity_number: PAR-11-079
application_type: 1
activity_code: R03
ic: CA
serial_number: 165086
suffix: A1
program_official: RISCUTA, GABRIELA
project_start_date: 2012-07-09
project_end_date: 2014-06-30
study_section: Special Emphasis Panel[ZCA1 SRLB-2 (M1)]
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
project_abstract:
DESCRIPTION (provided by applicant):  To date caloric restriction has shown itself to be the most reproducible and promising intervention to improve cancer outcomes in laboratory animals. An intense and expanding area of research is focused on discovering easily achievable interventions that can have long-lasting positive effects. This proposal will explore maternal exercise during pregnancy as a potential short-term intervention that can provide a lifetime of benefits for the next generation. In a small pilot study in mice offspring born to exercised dams had improved glucose regulation and enhanced stress protection compared to offspring born to sedentary dams. These preliminary findings contribute to the hypothesis that maternal exercise during pregnancy and nursing protects mature offspring against chemical carcinogens because of increased activities of antioxidant enzymes. The first aim is designed to test whether maternal exercise during pregnancy is a realistic intervention that can protect mature offspring from chemical carcinogens. The second aim will look to elucidate the role of the stress-induced transcription factor nuclear factor erythroid-2 related factor 2 as a potential mechanism for long-lasting protection by perinatal exercise. These studies will provide important information on the potential positive impact maternal exercise may have on offspring cancer protection.   
   
PUBLIC HEALTH RELEVANCE:  The benefits of exercise have been studied extensively but the effects of maternal exercise during pregnancy on long-term outcomes in offspring have been neglected. The goal is to use maternal exercise in mice as an intervention to increase cancer protection in the offspring through increased activity of antioxidant enzymes.

project_terms:
910-Dimethyl-12-benzanthracene;Acetates;Adopted;Adult Children;Anthracenes;Antioxidants;Area;Behavior;Binding (Molecular Function);Birth;Breeding;Caloric Restriction;Carcinogens;Cardiovascular Diseases;Cells;Chemicals;Commit;Development;Diabetes Mellitus;Diet;Discipline of Nursing;Drug Metabolic Detoxication;Enzymes;Epidemic;Exercise;Female;Future;Gene Targeting;Generations;Genetic Transcription;Goals;Health;Home environment;Housing;Inbred ICR Mice;Intervention;Laboratory Animals;Litter Size;Liver;Malignant Neoplasms;Measures;Modeling;Mus;Neonatal;Obesity;Outcome;Oxidative Stress;Papilloma;Parents;Partner in relationship;Pathway interactions;Perinatal;Phorbol;Phorbols;Pilot Projects;Pregnancy;Probability;Proteins;Research;Resistance;Response Elements;Role;Running;Signal Transduction;Skin;Skin Tissue;Staging;Stress;Testing;Topical application;Tumor Promoters;Ultraviolet Rays;Very Light Exercise;biological adaptation to stress;blood glucose regulation;carcinogenesis;chemical carcinogen;design;improved;keratinocyte;male;melanocyte;neglect;next generation;novel;nuclear factor-erythroid 2;offspring;response;sedentary;transcription factor;trend;tumor;unborn child

public_health_relevance:
The benefits of exercise have been studied extensively but the effects of maternal exercise during pregnancy on long-term outcomes in offspring have been neglected. The goal is to use maternal exercise in mice as an intervention to increase cancer protection in the offspring through increased activity of antioxidant enzymes.


application_id: 8397784
project_number: 1F31AA021028-01A1
project_title: Redundant Signal Effect and Alcohol Impairment of Behavioral Inhibition in ADHD
administering_ic: NIAAA
award_notice_date: 2012-06-28
opportunity_number: PA-11-111
application_type: 1
activity_code: F31
ic: AA
serial_number: 021028
suffix: A1
program_official: WITT, ELLEN
project_start_date: 2012-07-01
project_end_date: 2014-06-30
study_section: Epidemiology, Prevention and Behavior Research Study Section[AA-2]
contact_pi_person_id: 10629876
contact_pi: MILLER, MELISSA A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Alcohol has been reliably shown to impair performance on a wide range of behaviors relevant for everyday activities. This impairment is especially pronounced in environments that require dividing attention across multiple stimuli. However under certain circumstances the presentation of multiple stimuli can actually facilitate performance. The redundant signal effect refers to the phenomenon by which individuals respond  more quickly and accurately when information is presented as redundant bimodal stimuli (e.g. visually and  aurally) rather than as a single stimulus presented to either modalit alone. Moreover recent research has shown that the presence of redundant stimuli can reduce alcohol's impairing effects on the ability to execute responses. What is not known however is whether the presence of redundant inhibitory signals might reduce alcohol's impairing effects on inhibitory control. Alcohol is well-known for its disinhibiting effects on behavior and studies suggest that impaired inhibition might contribute to alcohol abuse by promoting excessive binge drinking. Therefore it is important to determine the degree to which redundant inhibitory signals reduce the effects of alcohol on inhibitory control. Moreover it is also important to determine th degree to which these signals might improve inhibitory control in individuals at-risk for alcohol abuse such as those characterized by chronic deficits in the ability to inhibit behavior such as those with attention deficit/hyperactivity disorder (ADHD). The proposed research will examine the effects of redundant inhibitory signals on inhibitory control in individuals with ADHD and a comparison group of healthy adults. Moreover the project will determine the degree to which redundant inhibitory signals reduce the disinhibiting effects of alcohol in these two groups.  Given that everyday perception is multisensory the present study provides a unique model of drinkers realworld environments by assessing alcohol's effects on inhibitory mechanisms of behavior in response to multisensory stimuli.   
   
PUBLIC HEALTH RELEVANCE:  Alcohol is known for its disinhibiting effects on behavior which is thought to contribute to excessive binge drinking and some clinical populations (i.e. individuals with ADHD) have been identified as being particularly sensitive to the disinhibiting effects of alcohol increasing their risk for alcohol abuse. The present study will examine the degree to which redundant inhibitory signals (signals presented both visually and aurally) can reduce alcohol's impairing effects on the ability to inhibit behavior. The project will provide a novel highly useful model to investigate how alcohol effects on inhibitory control might be altered in contexts that involve redundant inhibitory signals.

project_terms:
Accounting;Adult;Alcohol abuse;Alcohols;Attention;Attention deficit hyperactivity disorder;Auditory;Behavior;Behavior Control;Behavioral;Behavioral inhibition;Characteristics;Chronic;Clinical;Disease;Drug abuse;Drug usage;Environment;Impairment;Individual;Laboratories;Modality;Modeling;Participant;Perception;Performance;Pharmaceutical Preparations;Population;Reaction Time;Research;Risk;Sensory;Signal Transduction;Stimulus;Testing;Visual;Work;alcohol and other drug;alcohol effect;auditory stimulus;binge drinking;clinical application;comparison group;disinhibitory psychopathology;drinking behavior;improved;multisensory;novel;response;sobriety;visual information;young adult

public_health_relevance:
Alcohol is known for its disinhibiting effects on behavior which is thought to contribute to excessive binge drinking and some clinical populations (i.e. individuals with ADHD) have been identified as being particularly sensitive to the disinhibiting effects of alcohol increasing their risk for alcohol abuse. The present study will examine the degree to which redundant inhibitory signals (signals presented both visually and aurally) can reduce alcohol's impairing effects on the ability to inhibit behavior. The project will provide a novel highly useful model to investigate how alcohol effects on inhibitory control might be altered in contexts that involve redundant inhibitory signals.


application_id: 8396642
project_number: 3R01CA131075-03S1
project_title: The role of Mc1r in melanocytic UV-induced DNA damage and repair responses
administering_ic: NCI
award_notice_date: 2012-05-14
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: CA
serial_number: 131075
suffix: S1
program_official: OGUNBIYI, PETER
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;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: 8395774
project_number: 1F31NS077750-01A1
project_title: Effects of spinal cord injury on vagal afferents from the rat bladder and colon.
administering_ic: NINDS
award_notice_date: 2012-07-25
opportunity_number: PA-11-111
application_type: 1
activity_code: F31
ic: NS
serial_number: 077750
suffix: A1
program_official: LUDWIG, KIP A
project_start_date: 2012-07-01
project_end_date: 2015-06-30
study_section: Special Emphasis Panel[ZRG1 F01-F (20)]
contact_pi_person_id: 10717584
contact_pi: HERRITY, APRIL N
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Secondary health complications present a major concern for people living with spinal cord injury (SCI). Furthermore deficits in urological functin rank high as one of the most important factors affecting quality of life for SCI patients 6. A common complication of SCI is the development of a neurogenic bladder which involves lower urinary tract dysfunction and a loss of voluntary control. Complications include overactivity of th detrusor muscle leading to urinary incontinence sustained high pressure within the bladder tissue walls and sphincter-detrusor dyssynergia resulting in a loss of coordination 26. In previous years the leading cause of death in SCI patients was due to renal failure 76. However improvements in urological management have reduced mortality rates in this area but current urological treatment options for patients are often difficult to sustain and have low patient compliance 33. Some of the problems with current treatment options include: repeated infections and scarring from frequent catheterization sexual dysfunction side effects following surgical procedures adverse reactions to pharmaceuticals and failure to establish recommended guidelines and protocols for bladder management. Equally important in chronic SCI is a loss of conscious control of defecation. Patients develop a neurogenic bowel that includes constipation fecal impaction and incontinence and increased pain from abdominal distention 66; 68; 60. Patients
are able to defecate by either digital ano-rectal stimulation to initiate reflexive contractions or
through digital evacuation 68. Both urinary bladder dysfunction and colorectal problems are causes of significant morbidity and mortality in the SCI population 29; 67. Therefore in order to improve and better assist patients with bladder and bowel dysfunction a better understanding of the anatomy and physiology following chronic injury is needed. Evidence from anatomical tracing studies as well as preliminary electrophysiology recordings from our lab indicates that the bladder and colon are not only innervated by spinal afferents but by the vagus nerve as well. In pathological conditions such as SCI where central pathways are compromised the vagus nerve may take on a faciliatory role and actually contribute to dysfunction. In order to assess the degree of vagal involvement the purpose of this study is 1) to evaluate using neuroanatomical tracing techniques in male rats the extent of urinary bladder and colon sensory afferents in nodose ganglia the degree convergence with the colon and the histochemical phenotype of such neurons and 2) to identify using in vitro and in vivo electrophysiological recordings plasticity-related changes in nodose ganglion neuronal response properties of traced urinary bladder and colon sensory afferents under conditions of tissue irritation and/or chronic spinal transection relative to normal controls. This project aims o demonstrate that vagal afferents are conveyed directly from the rat bladder and colon to the caudal medulla and can be characterized based upon their histochemical signature and response properties to tissue irritation and/or SCI. The ultimate goal is to identify the vagus nerve as a potential source of phantom sensations that arise from below the level of a "clinically" (ASIA criteria) as well as an "anatomically" complete SCI with the hope of providing a
novel therapeutic target for SCI patients.   
   
PUBLIC HEALTH RELEVANCE: The goal of this project is to study the role of the vagus nerve with respect to bladder and bowel function with an emphasis on its contribution in a clinically relevant rodent spinal cord injury model. Determining the anatomical connections and physiological responses of the vagus with respect to the bladder and distal colon will aide in the development of novel therapeutic devices for urinary/bowel disorders including dysfunction after chronic spinal cord injury.

project_terms:
Abdominal Pain;Acute;Adverse effects;Adverse reactions;Affect;Afferent Neurons;Anatomy;Area;Ataxia;Bladder;Bladder Dysfunction;Bladder Tissue;Catheterization;Cause of Death;Cells;Cervical;Cervix Uteri;Chemical Stimulation;Chemicals;Chronic;Cicatrix;Colon;Colorectal;Compliance behavior;Complication;Conscious;Constipation;Data;Defecation;Development;Devices;Disease;Distal;Electrophysiology (science);Esthesia;Exhibits;Failure (biologic function);Fecal Impaction;Fecal Incontinence;Female;Functional disorder;Genital system;Goals;Guidelines;Health;In Vitro;Individual;Infection;Injury;Intestines;Intractable Pain;Kidney Failure;Label;Life;Lower urinary tract;Mechanical Stimulation;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Neurogenic Bladder;Neurons;Nodose Ganglion;Nucleus solitarius;Operative Surgical Procedures;Orgasm;Pathway interactions;Patients;Pharmacologic Substance;Phenotype;Physiological;Physiology;Population;Procedures;Property;Protocols documentation;Quality of life;Rattus;Rectum;Relative (related person);Reporting;Rodent;Role;Sensory;Sexual Dysfunction;Source;Sphincter;Spinal;Spinal Cord transection injury;Spinal cord injury;Spinal cord injury patients;Structure;Sympathectomy;Techniques;Tissues;Urinary Incontinence;Vagina;Vagus nerve structure;Viscera;Visceral;Visceral pain;Woman;afferent nerve;base;clinically relevant;detrusor muscle;digital;improved;in vivo;irritation;male;nerve supply;new therapeutic target;novel therapeutics;patch clamp;pressure;rectal;relating to nervous system;reproductive;response;urinary;urologic

public_health_relevance:
The goal of this project is to study the role of the vagus nerve with respect to bladder and bowel function with an emphasis on its contribution in a clinically relevant rodent spinal cord injury model. Determining the anatomical connections and physiological responses of the vagus with respect to the bladder and distal colon will aide in the development of novel therapeutic devices for urinary/bowel disorders including dysfunction after chronic spinal cord injury.


application_id: 8392846
project_number: 2R37AI052218-11
project_title: In vitro glycorandomization of natural products
administering_ic: NIAID
award_notice_date: 2012-06-19
opportunity_number: PA-11-260
application_type: 2
activity_code: R37
ic: AI
serial_number: 052218
program_official: TSENG, CHRISTOPHER K
project_start_date: 2002-06-03
project_end_date: 2017-05-31
study_section: Special Emphasis Panel[ZRG1 BCMB-B (02)]
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
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): The attachment of sugars to naturally-occurring and/or synthetic small molecules can dramatically influence the corresponding mechanism pharmacodynamics pharmacokinetics and even patent life of the parental structure. Yet due to the technical challenges associated with conventional glycosylation strategies the application of glycosylation in the context of drug discovery and/or development remains underexplored. An overarching aim of this program has been to develop simple and user-friendly chemoenzymatic methods for the differential glycosylation of target scaffolds to ultimately enable such drug discovery/development exploration. Toward this goal the first phase of this study (years 1-5) led to the key proof of concept for  chemoenzymatic glycorandomization (a one pot three enzyme strategy capable of activating and attaching free monosaccharides to complex natural product scaffolds) and also provided fundamental information regarding two critical but poorly understood enzyme classes (anomeric sugar kinases and sugar-1-phosphate nucleotidylyltransferases). The second phase of this project (years 6-10) dramatically expanded the attempted application of this first generation system toward a range of diverse scaffolds leading to success in many cases but also exposing key limitations of the platform. Importantly the work conducted during the second phase also led to fundamental new knowledge regarding glycosyltransferase (GT)-catalyzed reactions that serves as the basis from which to launch the third phase of this study. Specifically the proposed third phase of this study (years 11-15) takes
advantage of our recent abilities to evolve highly permissive GTs and also drive GT-catalyzed reactions in reverse to enable next generation single enzyme or dual enzyme transglycosylation strategies for differential glycosylation of an array of structurally-diverse scaffolds (including natural product-based or synthetic glycosylated or non-glycosylated parental scaffolds). We propose to take full advantage of the current state of the art to: i) narrow the gaps of knowledge in understanding functional GT structure-activity-relationships; ii) specifically develop a range o catalysts for the production of novel sugar nucleotides (anticipated to be of broad use to the glycobiology community); iii) develop a range of catalysts for the differential glycosylation of a key set of structurally diverse anti-infective and anticancer scaffolds; and iv)exploit the corresponding differentially glycosylated scaffolds as a novel source for the discovery of new antiinfective  and anticancer leads.   
   
PUBLIC HEALTH RELEVANCE:  We propose to develop simple and user-friendly chemoenzymatic methods for the differential glycosylation of complex target scaffolds to enable glycoconjugation as a tool for drug discovery and development. The models selected as part of the current study are anticipated to hold particularly high potential for the discovery of new antibacterial antiviral and anticancer leads.

project_terms:
Amino Acids;Anti-Bacterial Agents;Anti-Infective Agents;Antiviral Agents;Automobile Driving;Biological;Biological Assay;Biological Factors;Bufadienolides;Cardenolides;Catalysis;Cell Proliferation;Chemistry;Ciprofloxacin;Collaborations;Communities;Complement;Complex;Daptomycin;Development;Drug Kinetics;Enzymes;Equilibrium;Evaluation;Evolution;Generations;Glucose;Glycobiology;Glycosides;Goals;In Vitro;Investments;Knowledge;Legal patent;Libraries;Life;Macrolides;Methods;Minocycline;Modeling;Monosaccharides;Mutagenesis;National Institute of Allergy and Infectious Disease;Novobiocin;Nucleotides;Pharmacodynamics;Phase;Phosphotransferases;Positioning Attribute;Predisposition;Production;Pyrimidine;Reaction;Reagent;Screening procedure;Sirolimus;Source;Specificity;Structural Models;Structure;Structure-Activity Relationship;System;Thymidine;Toxic effect;Uridine;Ursidae Family;Variant;Vertebral column;Work;analog;anticancer activity;base;bufadienolide;catalyst;design;design and construction;directed evolution;drug development;drug discovery;functional group;glycosylation;glycosyltransferase;innovation;inorganic phosphate;liquid chromatography mass spectrometry;member;next generation;novel;pathogen;pre-clinical;progenitor;programs;research study;scaffold;small molecule;success;sugar;sugar nucleotide;tool;user-friendly


application_id: 8392450
project_number: 1R43AI098179-01A1
project_title: Biological vector control reducing arboviruses including Dengue and Chikungunya
administering_ic: NIAID
award_notice_date: 2012-05-24
opportunity_number: PA-11-096
application_type: 1
activity_code: R43
ic: AI
serial_number: 098179
suffix: A1
program_official: COSTERO-SAINT DENIS, ADRIANA
project_start_date: 2012-06-01
project_end_date: 2014-05-31
study_section: Special Emphasis Panel[ZRG1 IDM-V (12)]
contact_pi_person_id: 11545088
contact_pi: MAINS, JAMES WILLIAM
other_pis: DOBSON, STEPHEN LEONARD
congressional_district: 06
department: Unavailable
primary_duns: 780816091
primary_uei: F873ZJEX7615
duns_number: 780816091
uei: F873ZJEX7615
fips: US
organization_id: 10027931
organization_name: MOSQUITOMATE, INC.
organization_city: Lexington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40502
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): In the absence of effective approved vaccines or therapeutic measures against dengue and other mosquito borne pathogens public health efforts must focus on the control of mosquito vectors that are required for transmission. Unfortunately effective control measures are not available against the invasive and medically important Asian Tiger Mosquito (Aedes albopictus). This is due largely to its biology; the cryptic and inaccessible breeding sites of this mosquito prevent finding and treating a large proportion of the targeted mosquito population. This project will perform critical research required for the development of a self-delivering species specific biological control approach against Ae. albopictus without involving genetically modified organisms. In brief the strategy is to release Ae. albopictus males that are infected with Wolbachia bacteria which effectively sterilize the mates of the released males. Male mosquitoes do not bite blood feed or transmit disease. They can be reared inexpensively and can find indigenous female Ae. albopictus more effectively than a team of trained professionals using existing tools. Following mating the mated females are sterile for the remainder of their life. The Wolbachia-based approach can be integrated with existing insecticidal approaches allowing the simultaneous control of Ae. albopictus and additional important mosquitoes. In Phase I of this study we will (1) extend prior work characterizing the level of egg hatch resulting from the incompatible matings with USA-derived indigenous mosquitoes (2) assess the reproductive output of the laboratory colony which will allow for improved estimate of rearing cost (3) test methods for packaging and delivery and (4) assess competitiveness of the resulting males infected with the Wolbachia microbial pesticide. Each of these goals is important for the intended downstream economic model. The proposed scientific goals will occur in parallel with an EPA assessment that is in progress toward an Experimental Use Permit. Downstream the approach being developed is broadly applicable to additional important mosquitoes both within and beyond the USA.   
   
PUBLIC HEALTH RELEVANCE: Due to the lack of vaccines for prevention of dengue and additional mosquito borne pathogens in the USA controlling important mosquito populations is critical. This project supports further development of a self- delivering species specific biological control targeting Aedes albopictus an invasive mosquito for which effective controls are not available. The approach being developed will be compatible with and can be used simultaneously with existing insecticidal tools. A regulatory pathway is defined. Moreover the approach will be broadly applicable to additional mosquito vector species (e.g. Ae. aegypti Culex pipiens etc.) and appropriate for areas outside the USA.

project_terms:
Address;Aedes (genus);Affect;Arboviruses;Area;Asians;Bacteria;Biological;Biology;Bite;Blood;Breeding;California;Complement;Containment;Culex pipiens;Culicidae;Dengue;Development;Disease;Disease Vectors;Economic Models;Embryo;Encephalitis;Excision;Failure (biologic function);Female;Fertility;Genetic;Genetically Modified Organisms;Goals;Government;Indigenous;Infection;International;Kentucky;Laboratories;Legal patent;Letters;Licensing;Life;Marketing;Measures;Methods;Modification;Mosquito Control;Output;Partner in relationship;Pesticides;Phase;Population;Preparation;Prevention;Procedures;Process;Production;Regulatory Pathway;Relative (related person);Research;Resistance;Rivers;Rosa;Scientist;Site;Sorting - Cell Movement;Sterility;Technology;Testing;Therapeutic;Tigers;Training;United States Environmental Protection Agency;Universities;Vaccines;Wolbachia;Work;base;chikungunya;cost;egg;feeding;hatching;improved;male;meetings;microbial;novel;pathogen;phase 1 study;prevent;public health medicine (field);reproductive;research study;tool;transmission process;vector;vector control;vector mosquito

public_health_relevance:
Due to the lack of vaccines for prevention of dengue and additional mosquito borne pathogens in the USA controlling important mosquito populations is critical. This project supports further development of a self- delivering species specific biological control targeting Aedes albopictus an invasive mosquito for which effective controls are not available. The approach being developed will be compatible with and can be used simultaneously with existing insecticidal tools. A regulatory pathway is defined. Moreover the approach will be broadly applicable to additional mosquito vector species (e.g. Ae. aegypti Culex pipiens etc.) and appropriate for areas outside the USA.


application_id: 8392203
project_number: 1R43CA165300-01A1
project_title: PFK-015: An inhibitor of PFKFB3 to treat Glioblastomas
administering_ic: NCI
award_notice_date: 2012-09-17
opportunity_number: PA-11-096
application_type: 1
activity_code: R43
ic: CA
serial_number: 165300
suffix: A1
program_official: HAIM, TODD E
project_start_date: 2012-09-17
project_end_date: 2013-10-16
study_section: Special Emphasis Panel[ZRG1 OTC-T (10)]
contact_pi_person_id: 9851336
contact_pi: TAPOLSKY, GILLES HUGUES
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 809099836
duns_number: 809099836
fips: US
organization_id: 10020411
organization_name: ADVANCED CANCER THERAPEUTICS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021959
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-09-17
project_abstract:
DESCRIPTION (provided by applicant): Amongst the different cancer types afflicting the US population glioblastoma multiforme (GBM) is a dreadful disease with an overall average survival of 10 months. With about 8000 new cases per year representing only about 2% of new cancer patients this disease benefits from an Orphan drug designation. Also new therapies are needed to prolong patients' survival.  New therapies based on novel mechanisms of action or inhibiting new biological pathways are required to improve cancer patients' survival. The Warburg effect the higher rate of glucose metabolism of cancer cells was identified as a potential cancer target many decades ago. PFKFB3 is a key enzyme involved in the glycolytic pathway and is also required for tumor growth in animal models. Thus inhibiting PFKFB3 may prove to be a useful strategy for the development of novel anti-neoplastic agents targeting the energy needs of cancer cells.  Advanced Cancer Therapeutics (ACT) in collaboration with Jason Chesney MD PhD at the Brown Cancer Center University of Louisville KY who validated preclinically PFKFB3 as a potential cancer target proposes to complete the characterization of PFK-015 in GBM preclinical models. PFK-015 is a potent inhibitor of PFKFB3 and preliminary results in a U87GM xenograft model have shown that PFK-015 has comparable activity to Temozolomide and that PFK-015 crosses the blood brain barrier.  The work proposed in this application encompasses 1) completion of the in vitro characterization of PFK-015 by screening its activity in 7 glioblastoma cell lines and synergies with Temozolomide; 2) characterization of the PK profile of PFK-015 in mice including determining brain and plasma levels; and 3) tumor growth inhibition studies in several orthotopic models.  Positive results in the studies described above would warrant additional preclinical studies (i.e. efficacy toxicology) in order to determine if PFK-015 should undergo IND enabling testing to initiate a Phase I study in GBM cancer patients.   
   
PUBLIC HEALTH RELEVANCE: Amongst the different cancer types afflicting the US population glioblastoma multiforme (GBM) is a dreadful disease with an overall average survival of 10 months. While it constitutes only approximately 2% of all new cancer patients with about 8000 new cases per year new therapies are clearly needed for this disease that benefits from an Orphan drug designation. This application proposes to investigate the use of a novel class of anticancer agents in GBM preclinical models.  PFKFB3 is a protein involved in the glycolytic pathway and commonly over expressed in many cancers (pancreatic lung breast brain ovarian...) including glioblastomas. Preliminary results obtained with PFK-015 a potent inhibitor of PFKFB3 in a glioblastoma xenograft model have shown that it has tumor growth inhibition activity comparable to that of Temozolomide the drug currently used as first line therapy for the treatment of glioblastoma multiforme. Furthermore PFK-015 inhibits glucose uptake by tumors as shown by PET imaging and crosses the blood brain barrier.  In this application additional PK and in vitro experiments will be done to further understand the properties of PFK-015 and determine if it has synergy with Temozolomide. Efficacy studies in several glioblastoma models will be performed including combinations studies. A therapeutic agent based on a novel mechanism of action that would have activity as a single agent and synergies with the compound currently used as first line therapy would be extremely valuable and cancer patients would tremendously benefit from such an opportunity.

project_terms:
6-Phosphofructokinase;Advanced Malignant Neoplasm;Animal Model;Animals;Antineoplastic Agents;Astrocytes;Biological;Blood;Blood - brain barrier anatomy;Brain;Brain Neoplasms;Breast;Cancer Center;Cancer Patient;Cancer cell line;Cell Line;Cells;Clinical;Collaborations;Data;Development;Diagnosis;Disease;Doctor of Philosophy;Dose;Drug Kinetics;Enzymes;Female;Glioblastoma;Glycolysis;Hour;Human;Human Cell Line;Hypoxia;Image;Imaging Techniques;Implant;In Vitro;Inhibitory Concentration 50;Injection of therapeutic agent;Lung;Malignant Neoplasms;Malignant neoplasm of pancreas;Modeling;Mus;Names;Orphan Drugs;Ovarian;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Plasma;Population;Positron-Emission Tomography;Pre-Clinical Model;Process;Program Development;Property;Proteins;Publishing;Sampling;Screening procedure;Small Business Innovation Research Grant;Solid;Staging;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;Toxic effect;Toxicology;U251;Universities;Warburg Effect;Work;Xenograft Model;Xenograft procedure;base;cancer cell;cancer type;chemotherapeutic agent;combinatorial;glucose metabolism;glucose uptake;improved;in vivo;inhibitor/antagonist;neoplastic;novel;novel strategies;novel therapeutic intervention;outcome forecast;phase 1 study;preclinical study;research study;small molecule;temozolomide;therapy development;tumor;tumor growth;tumor xenograft;uptake

public_health_relevance:
Amongst the different cancer types afflicting the US population glioblastoma multiforme (GBM) is a dreadful disease with an overall average survival of 10 months. While it constitutes only approximately 2% of all new cancer patients with about 8000 new cases per year new therapies are clearly needed for this disease that benefits from an Orphan drug designation. This application proposes to investigate the use of a novel class of anticancer agents in GBM preclinical models.  PFKFB3 is a protein involved in the glycolytic pathway and commonly over expressed in many cancers (pancreatic lung breast brain ovarian...) including glioblastomas. Preliminary results obtained with PFK-015 a potent inhibitor of PFKFB3 in a glioblastoma xenograft model have shown that it has tumor growth inhibition activity comparable to that of Temozolomide the drug currently used as first line therapy for the treatment of glioblastoma multiforme. Furthermore PFK-015 inhibits glucose uptake by tumors as shown by PET imaging and crosses the blood brain barrier.  In this application additional PK and in vitro experiments will be done to further understand the properties of PFK-015 and determine if it has synergy with Temozolomide. Efficacy studies in several glioblastoma models will be performed including combinations studies. A therapeutic agent based on a novel mechanism of action that would have activity as a single agent and synergies with the compound currently used as first line therapy would be extremely valuable and cancer patients would tremendously benefit from such an opportunity.


application_id: 8391729
project_number: 5R01CA129015-05
project_title: The role of Pdcd4 in colorectal tumor progression
administering_ic: NCI
award_notice_date: 2012-11-28
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 129015
program_official: JHAPPAN, CHAMELLI
project_start_date: 2009-01-01
project_end_date: 2014-11-30
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 8737920
contact_pi: YANG, HSIN-SHENG
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): Colorectal cancer is the second leading cause of cancer-related deaths in the United States largely due to invasion and metastasis to the liver and lymph nodes. Thus a thorough understanding of invasion/metastasis is necessary for prevention and treatment of colon cancer. Over- expression of programmed cell death 4 (Pdcd4) a novel tumor suppressor inhibits invasion and AP-1 dependent transcription in colon tumor cells. Pdcd4 expression is frequently down-regulated in colon tumor tissues as compared to adjacent normal tissues. The objective of the proposed study is to define the function of Pdcd4 in tumor invasion/metastasis and elucidate the molecular mechanisms involved in these processes. We knocked down Pdcd4 expression in colon tumor GEO and HT29 cells and found that Pdcd4 knock-down triggers morphological changes induces invasion and activates 2-catenin/Tcf and AP-1 dependent transcription. Our preliminary results further demonstrated that a decrease in E-cadherin expression correlates with an increase in the protein level of Slug a transcription repressor for E-cadherin expression. We therefore hypothesize that Pdcd4 knock-down promotes colon tumor cell invasion/metastasis through down-regulation of E-cadherin and activation of 2-catenin/Tcf and AP-1 dependent transcription. To test our hypothesis four Specific Aims are proposed. Aim 1: determine whether Pdcd4 functions as a metastasis inhibitor in colon tumor cells. Epithelial-to-mesenchymal transition and metastasis in mice will be assayed using Pdcd4 knock- down and over-expressed cells. Aim 2: examine whether activation of 2-catenin/Tcf dependent transcription led by E-cadherin down-regulation in Pdcd4 knock-down cells promotes invasion/metastasis. We will test activation of 2-catenin/Tcf dependent transcription by knocking down E-cadherin reversion of the invasive/metastatic ability by inhibiting 2-catenin/Tcf dependent transcription verification of uPAR and c-Myc as the target genes of 2-catenin/Tcf dependent transcription and inhibition of 2-catenin/Tcf4 dependent transcription and its target gene expression by over-expressing Pdcd4. Aim 3: determine whether activation of 2-catenin/Tcf4 dependent transcription in Pdcd4 knock-down cells up-regulates MAP4K1 expression and AP-1 activity through c-Myc. We will establish the c-Myc as a regulator of MAP4K1 expression and activation of 2- catenin/Tcf dependent transcription causing up-regulation of MAP4K1 expression JNK activation and AP-1 dependent transcription. Aim 4: determine whether Pdcd4 translationally inhibits transcription repressor Slug expression resulting in up-regulation of E-cadherin and suppression of invasion/metastasis. Translation inhibition and the inhibitory mechanism will be analyzed using in vitro and in vivo translation assays followed by an examination of E-cadherin expression level and the ability of invasion/metastasis in Slug knock-down and Pdcd4 expressing cells. This work will provide a comprehensive understanding of how Pdcd4 modulates colon tumor progression and holds great promise for novel interventions for preventing and treating colon cancer.

project_terms:
5' Untranslated Regions;Address;Apoptosis;Binding (Molecular Function);Binding Sites;Biological Assay;Cancer Etiology;Cancerous;Cells;Cessation of life;Colon;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Colorectal Neoplasms;Complex;Cultured Cells;Dominant-Negative Mutation;Down-Regulation;E-Cadherin;Epithelial;Fibroblasts;Fractionation;Free Energy;Gene Expression;Gene Targeting;Genetic Transcription;HT29 Cells;Health;In Vitro;Injection of therapeutic agent;Intervention;Knowledge;Liver;MAPK8 gene;Malignant Neoplasms;Measures;Mesenchymal;Messenger RNA;Methods;Molecular;Mus;Mutate;Mutation;Neoplasm Metastasis;Normal tissue morphology;Nude Mice;Oncogene Activation;Polyribosomes;Prevention;Primary Neoplasm;Process;Promotor (Genetics);Proteins;Publications;Reagent;Reverse Transcription;Role;Site-Directed Mutagenesis;Slug protein;Staining method;Stains;Structure;Testing;Tissues;Transcription Factor AP-1;Transcription Repressor/Corepressor;Translational Repression;Translations;Tumor Cell Invasion;Tumor Suppressor Proteins;Tumor Tissue;Tumor-Suppressor Gene Inactivation;United States;Up-Regulation (Physiology);Work;base;c-myc Genes;cancer cell;chromatin immunoprecipitation;design;epithelial to mesenchymal transition;implantation;in vivo;inhibitor/antagonist;insight;knock-down;lymph nodes;mutant;neoplastic cell;novel;novel therapeutics;prevent;slug;translation assay;tumor progression

public_health_relevance:
Project NarrativeColorectal cancer is the second most fatal cancer in the United States largely due to invasion and metastasisto the liver and lymph nodes. In this proposal we intend to understand the effects of a novel tumor suppressorPdcd4 on colon tumor metastasis and the molecular mechanism involved in this process. This work willprovide a comprehensive understanding of how Pdcd4 modulates colon tumor progression and holds greatpromise for novel interventions for preventing and treating colon cancer.


application_id: 8391225
project_number: 5R01NS062306-06
project_title: PPAR Inhibition of Spinal Pain Transmission
administering_ic: NINDS
award_notice_date: 2012-11-22
opportunity_number: PA-07-282
application_type: 5
activity_code: R01
ic: NS
serial_number: 062306
program_official: OSHINSKY, MICHAEL L
project_start_date: 2008-12-18
project_end_date: 2014-11-30
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:
PROJECT DESCRIPTIONPeroxisome proliferator-activated receptor gamma (PPAR ) is well-characterized as a key target of thethiazolinedione (TZD) class of anti-diabetic drugs. Our preliminary results describe the existence of PPAR mRNA and protein in the dorsal horn. Furthermore we demonstrate that the mechanical and thermalhypersensitivity associated with inflammation or nerve injury was rapidly reduced by intrathecal administrationof rosiglitazone (a TZD) and 15d-PGJ2 (an endogenous PPAR  ligand) in a dose- and PPAR -dependentmanner and by systemic administration of pioglitazone a BBB-permeant FDA-approved ligand. The centralhypothesis of this proposal is that ligand-dependent activation of PPAR in the dorsal horn decreases injury-induced activation of spinal neurons and glia that then dampens behavioral signs of inflammatory andneuropathic 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 ourresearch program is to harness the therapeutic potential of PPAR signaling to alleviate chronic pain in humans.AIM 1 will test the hypothesis that PPAR  agonists reduce allodynia and hyperalgesia. We will usepharmacological agents and nervous system-specific PPAR  deletion mutants to determine the contribution ofPPAR  signaling in the spinal cord to the induction and maintenance of chronic pain. First we will determinewhether single intrathecal or systemic administration of pioglitazone and 15d-PGJ2 reduces behavioral signs ofinflammatory and neuropathic pain. We predict that their analgesic actions will be blocked with PPAR antagonists. Second we will determine whether chronic intrathecal or oral administration of PPAR  agonistsbegun 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  knockdown.AIM 2 will test the hypothesis that PPAR  ligands reduce injury-induced activation of neurons andmicroglia in the dorsal horn. Somatosensory stimulation of injured rats induces the expression of theimmediate early gene c-fos in the superficial laminae of the dorsal horn. We predict that intrathecalpioglitazone will reduce inflammation- and nerve injury-induced expression of Fos immunoreactive neurons aswell as the expression of OX-42 a marker of microglia activation.AIM 3 will test the hypothesis that endogenous PPAR  systems tonically inhibit allodynia. First we willdetermine if PPAR expression occurs in neurons and/or glia that are activated during pain. Second in anextension of Aims 1-2 we will determine whether receptor antagonists and genetic deletion increase allodyniaand neuronal/glial activation. If affirmative then we will determine whether the PPAR signaling elements co-vary with allodynia. At various times after nerve injury or persistent inflammation we will evaluate: behaviorand A) PPAR  mRNA and protein; B) phosphorylated PPAR ; and C) 15d-PGJ2 levels with LC/MS/MS.

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: 8389560
project_number: 5R01AI033481-19
project_title: Yersiniabactin and plague pathogenesis
administering_ic: NIAID
award_notice_date: 2012-11-09
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: 2015-11-30
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:
Yersinia pestis causes a zoonotic disease plague with well established reservoirs on everyinhabited continent except Australia. Although humans are an accidental dead-end hostbubonic and pneumonic plague has caused widespread loss of human life during recurrentpandemics. Nearly 2000 human plague cases occur yearly and outbreaks in Africa SouthAmerica and Southeast Asia are common. In addition Y. pestis is a category A select agentwith potential use for bioterrorism. The ability of pathogens to acquire iron from their hosts is acritical requirement for the development of nearly all infectious disease processes. Y. pestisencodes 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 bubonicplague. In a mouse model of bubonic plague the Ybt system is essential in the early phases ofdisease while the Yfe system plays an important role in the later stages of plague. Mutations inybt but not yfe affect the pathogenesis of pneumonic plague. Our studies indicate that Yfe andFeo (a ferrous iron transporter) play somewhat redundant roles in iron uptake - mutants lackingboth systems show more severe phenotypes for in vitro growth intracellular growth andpathogenesis in bubonic and pneumonic plague. All these genes are regulated by Fur and ironavailability. In addition the Ybt system is activated by the AraC-type regulator YbtA and the Ybtsiderophore. The ultimate goals of my laboratory are to 1) genetically and biochemicallycharacterize the iron transport systems of Y. pestis; 2) determine the mechanisms regulatingexpression of these systems; 3) assess the relative importance of these systems in bubonic andpneumonic plague; and 4) explore the potential for new antimicrobial therapies and vaccinecomponents 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 Ybttransport and iron utilization and 3) examine Ybt roles in bubonic and pneumonic plaguepathogenesis.

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;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: 8387023
project_number: 5R01DK090460-03
project_title: Maternal Exercise Protects Offspring from Obesity and Insulin Resistance
administering_ic: NIDDK
award_notice_date: 2012-11-15
opportunity_number: PA-10-067
application_type: 5
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.

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;public health relevance;response;sedentary;stem;trend;unborn child

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


application_id: 8386896
project_number: 5R01DK080901-05
project_title: Glucocorticoids and endocannabinoids in vagal complex
administering_ic: NIDDK
award_notice_date: 2012-11-23
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: 2014-11-30
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:
The experiments in this research grant proposal will identify the cellular and synaptic effects ofendogenous cannabinoid (eCB) ligands and of glucocorticoid-induced release of eCBs in the dorsal motornucleus of the vagus (DMV). Neurons in the DMV regulate parasympathetic output to most of thesubdiaphragmatic viscera and therefore critically control feeding digestion glucose and insulin secretionand other metabolic functions. Their activity is largely controlled by synaptic input to the DMV which ismodulated by locally released chemicals and circulating hormones. Regulation of DMV neurons bycannabinoids vanilloids and glucocorticoids has been suggested; when applied centrally thesecompounds profoundly alter parasympathetic function. Several eCB ligands which are thought to bereleased 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 enhancesneurotransmitter release whereas CB1R tends to inhibit synapses. Both effects occur by activation ofreceptors on presynaptic terminals. Preliminary evidence suggests that eCB ligands are released fromDMV neurons and that glucocorticoids or depolarization can induce this release. Thus eCB activity in theDMV may modulate both TRPV1 and CB1R activity. Neither the type(s) of eCB ligands released theeffects of most eCB ligands on synaptic activity nor the trigger or mechanism of eCB release in the DMVare known. We will use whole-cell patch-clamp recordings from DMV neurons in brainstem slices toidentify effects of eCB ligands on cellular activity in the DMV and will also identify the compounds releasedby cells in the area using pharmacological and biochemical methods. The experiments will be guided bythree specific aims: 1) Differentiate effects of eCB ligands on CB1R and TRPV1 in the DMV; 2) Determinethe 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 alterTRPV1 and CBR1 activity in the DMV in specific and predictable spatial temporal functionally relevantand activity-dependent patterns and that glucocorticoids induce eCB release from DMV cells by acting atmembrane-bound G protein-coupled receptors on DMV neurons. Drugs based on the eCB system arebeing investigated for therapeutic use in a variety of nervous system pathologies including disordersrelated to feeding digestion and obesity. Glucocorticoids which release eCBs in some systems arewidely prescribed and are also released by stressful stimuli. Results of these studies will be critical topredicting and understanding how these compounds interact with each other and affect parasympatheticfunction. Possible translational benefits also exist because of the benefit in controlling eCB levels in thevagal system of patients with elevated glucocorticoids.

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;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: 8386609
project_number: 5F32DK089717-03
project_title: Insulin effects in the vagal complex
administering_ic: NIDDK
award_notice_date: 2012-11-16
opportunity_number: PA-10-110
application_type: 5
activity_code: F32
ic: DK
serial_number: 089717
program_official: CASTLE, ARTHUR
project_start_date: 2010-12-01
project_end_date: 2013-11-30
study_section: ZDK1-GRB-W(O1)S
contact_pi_person_id: 10299496
contact_pi: KASERMAN, CAMILLE BLAKE
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 dorsal vagal complex (DVC) is essential to integrating visceral sensory afferents and various other inputs in order to produce appropriate parasympathetic motor outputs via the vagus nerve which is vital for energy homeostasis. Certain pathologies such as diabetes can cause disruption of this circuit. Diabetes mellitus is a metabolic disorder that results in dysfunctional glucose regulation by insulin deficiency (type-1) or resistance (type-2). Hyperglycemia a condition of diabetes significantly alters central vagal function and diabetics often experience gastric dysfunction gastroparesis and other visceral symptomatology. Insulin crosses the blood brain barrier and is transported into the brainstem over twice as rapidly as into whole brain and neuronal insulin receptors are expressed in the DVC. Neuronal insulin and insulin receptors are required for normal control of glucose homeostasis and the regulation of peripheral energy homeostasis and glucose metabolism. Despite the importance of the DVC and the evidence that insulin action in the brain is critical for homeostasis very little is known about insulin's action in the brain specifically the DVC. This proposal will test the effects of insulin on cellular communication within the DVC. The general hypothesis is that insulin is inhibiting neurons in the dorsal motor nucleus (DMV). I predict that this occurs directly and indirectly by acting on glutamatergic neurons of in the nucleus of the solitary tract (NTS) that project to the DMV. Electrophysiological studies will be conducted in brainstem slice preparations from adult mice. Gastric-related neurons of DMV and NTS will be identified by their anatomical connection with the proximal stomach. With whole-cell patch clamp recordings the effects of insulin will be examined on: 1) input to DMV neurons and 2) glutamatergic neurons of the NTS identified with RT-PCR that project to the DMV by "uncaging" glutamate in these neurons and examining paired-pulse responses in the DMV to electric stimulation of the NTS. These results will be coordinated with pharmacological and molecular biological analyses to generate models of insulin action in the vagal complex in mice.

project_terms:
Adult;Affect;Area;Binding (Molecular Function);Biological;Blood - brain barrier anatomy;Blood Circulation;Brain;Brain Part;Brain Stem;Brain region;Cells;Communication;Complex;Data;Diabetes Mellitus;Disease;Dorsal;Eating;Electric Stimulation;Event;Frequencies (time pattern);Functional disorder;Gastric Emptying;Gastrointestinal tract structure;Gastroparesis;Glutamates;Homeostasis;Hormones;Hyperglycemia;Hypothalamic structure;In Vitro;Insulin;Insulin Receptor;Label;Lead;Mediating;Metabolic Diseases;Methods;Modeling;Molecular;Motor output;Mus;Neurons;Nucleus solitarius;Output;Pathology;Peripheral;Phosphotransferases;Physiologic pulse;Physiology;Potassium Channel;Preparation;Regulation;Resistance;Reverse Transcriptase Polymerase Chain Reaction;Satiation;Sensory;Signal Transduction;Slice;Stomach;Synapses;Testing;Vagus nerve structure;Visceral;blood glucose regulation;cell body (neuron);diabetic;diabetic patient;dorsal motor nucleus;experience;glucose metabolism;hepatic gluconeogenesis;insight;male;patch clamp;postsynaptic;presynaptic;public health relevance;receptor;research study;response;therapy design

public_health_relevance:
Project Narrative This proposal will test the effects of insulin on the dorsal vagal complex which controls gastric function.Because this region is located in the brainstem which is adjacent to an incomplete portion of the blood brainbarrier hormones found in the bloodstream such as insulin can readily access this part of the brain. Diabeticpatients often experience gastric dysfunction; thus the actions of insulin in this brain region are important to ourunderstanding of the physiology of this disease. The results of this study will provide a clearer understanding ofhow insulin regulates autonomic function which could lead to new insights in designing treatments fordiabetes.


application_id: 8386581
project_number: 5F31NS071804-03
project_title: Calpastatin overexpression as a therapeutic approach to traumatic brain injury
administering_ic: NINDS
award_notice_date: 2012-12-20
opportunity_number: PA-10-108
application_type: 5
activity_code: F31
ic: NS
serial_number: 071804
program_official: HICKS, RAMONA R
project_start_date: 2011-01-05
project_end_date: 2013-05-31
study_section: Special Emphasis Panel[ZRG1-F01-L(20)L]
contact_pi_person_id: 9791904
contact_pi: SCHOCH, KATHLEEN MARIE
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): Traumatic brain injury (TBI) afflicts approximately 1.4 million individuals in the U.S. each year. Following TBI a variety of cellular mediators contribute to neuronal death and dysfunction including the cysteine proteases calpains. Prolonged activation of calpains occurs within neurons due to a rapid and sustained rise of intracellular free calcium. Although an endogenous inhibitor of calpains calpastatin is co- expressed the sustained activation of these calcium-dependent proteases suggests endogenous calpastatin levels may be insufficient. The overall hypothesis of this proposal is that overexpression of calpastatin will reduce the proteolytic activity of calpains and associated neuronal death after trauma thereby attenuating motor and cognitive deficits. Calpastatin overexpression will be induced in two ways-transgenic overexpression of human calpastatin (hCAST) (Aim 1) and calpastatin expression via lentiviral vector delivery into brain regions vulnerable to TBI (Aim 2).  Aim 1 will use a novel transgenic mouse line with human calpastatin under control of the ubiquitous prion promoter. This mouse line exhibits a 9-fold greater expression of calpastatin in the cortex and hippocampus compared to wildtype mice. hCAST transgenic and wildtype littermates will be subjected to severe controlled cortical impact (CCI) injury or sham treatment. To confirm that calpastatin overexpression decreases calpain activity cortical and hippocampal homogenates will be evaluated for calpain-mediated cytoskeletal and membrane protein breakdown via immunoblot. Both motor and cognitive functions will be assessed after injury after which mice will be euthanized for analysis of hippocampal neurodegeneration and cortical tissue damage to assess the neuroprotective actions of hCAST overexpression. The expectation is that hCAST transgenic mice will have reduced posttraumatic calpain proteolytic activity offering a neuroprotective advantage. Aim 2 establishes an alternative approach to hCAST overexpression through lentiviral vector delivery. After injection of control lentivirus or calpastatin lentivirus into the cortex or hippocampus mice will be subjected to 1.0mm CCI brain injury or sham treatment and assessed as in Aim 1. Targeting of calpastatin to vulnerable neuronal regions prior to injury should spare affected neurons and reduce behavioral deficits.

project_terms:
Address;Affect;Area;Attenuated;Behavior;Behavioral;Brain Injuries;Brain region;C-terminal;Calcium;Calpain;Cells;Cessation of life;Cleaved cell;Cognitive;Cognitive deficits;Convection;Cysteine Protease;Cytoskeletal Proteins;Diffusion;Elements;Exhibits;Functional disorder;Genes;Goals;Hippocampus (Brain);Human;Image;Immunoblot Analysis;Immunoblotting;Immunohistochemistry;Individual;Infusion procedures;Injection of therapeutic agent;Injury;Lentivirus Vector;Location;Measurement;Mediating;Mediator of activation protein;Membrane;Membrane Proteins;Methods;Mitochondrial Proteins;Motor;Mus;Nerve Degeneration;Neurologic;Neurons;Pathogenesis;Peptide Hydrolases;Performance;Placebos;Prions;Promotor (Genetics);Proteolysis;Regulatory Element;Research;Role;Severities;Subfamily lentivirinae;Testing;Therapeutic;Tissues;Transgenic Mice;Transgenic Organisms;Trauma;Traumatic Brain Injury;Variant;Viral;behavior measurement;brain tissue;calpain inhibitor;calpastatin;cognitive function;cohort;controlled cortical impact;effective therapy;expectation;improved;inhibitor/antagonist;injured;morris water maze;motor deficit;novel;overexpression;public health relevance;receptor;response;treatment strategy

public_health_relevance:
8. Project NarrativeGiven the scope of traumatic brain injury it is imperative to understand the mechanisms of neuronal damageand death in order to develop effective treatment strategies. My research aims will not only seek to establish afunctional neuroprotective role for calpastatin in brain trauma but also advance translational efforts for thetreatment of brain injury.


application_id: 8386082
project_number: 1R21AA020849-01A1
project_title: Dietary Fat in Ethanol-Induced Intestinal Barrier Dysfunction in ALD
administering_ic: NIAAA
award_notice_date: 2012-07-27
opportunity_number: PA-10-069
application_type: 1
activity_code: R21
ic: AA
serial_number: 020849
suffix: A1
program_official: GAO, PETER
project_start_date: 2012-08-01
project_end_date: 2014-07-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 10484237
contact_pi: KIRPICH, IRINA A.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This application will evaluate Gut-Liver and Diet-Alcohol interactions with respect to the critical role of intestinal barrier integrity/function in he development and progression of alcoholic liver disease (ALD). ALD remains one of the leading causes of liver diseases and a major cause of morbidity and mortality in the United States and worldwide. Why some heavy drinkers develop ALD and other are spared is unclear (we postulate dietary effects-see below). Gut-derived lipopolysaccharide (LPS) plays a crucial role in the development of ALD. Increased intestinal permeability resulting from the disruption of intestinal integrity is a major cause of alcohol-induced endotoxemia. Dietary fat is an important cofactor for the development of ALD. It has been shown that diets enriched in saturated fatty acids protect against alcohol-induced liver disease in rodents whereas dietary polyunsaturated fatty acids (e.g. linoleic acid LA) promote liver damage. Our working hypothesis is that dietary LA potentiates pro-oxidative and pro-inflammatory effects on intestinal epithelial cells with consequent NF-kB activation. These events lead to alterations of intestinal tight junctions through an MLCK-dependent mechanism and contribute to the ethanol-associated disruption of intestinal integrity. We hypothesize that the combined deleterious effects of LA and EtOH on intestinal barrier integrity occur through a common NF-kB-MLCK-mediated mechanism. Increased gut permeability leads to elevated blood endotoxemia and consequent liver injury. Thus inhibition of MLCK will attenuate intestinal tight junction disruption decrease gut leakines and blood endotoxemia and attenuate ethanol/dietary linoleic acid induced liver damage. The Specific Aims of our application are: 1. To determine: a) if linoleic acid induces oxidative stress activates NF-kB and increases pro-inflammatory cytokine production in Caco-2 cells an in vitro model of the intestinal epithelial barrier; b) if linoleic acid enhances ethanol- mediated disruptin of intestinal barrier integrity by deregulation and redistribution of the major tight junctions proteins through an NF-kB-MLCK-mediated mechanism and if this effect is additive or synergistic. 2. To determine: a) whether dietary linoleic acid potentiates intestinal oxidative stress and promotes intestinal inflammation through NF-kB activation in an animal model of ALD; b) whether dietary linoleic acid-mediated intestinal inflammation contributes to ethanol-associated intestinal tight junction dysfunction through the MLCK-mediated mechanism in vivo; and c) if pharmacological inhibition/genetic deletion of MLCK can attenuate tight junction alterations decrease gut permeability and blood endotoxemia and consequently attenuate liver injury in a mouse model of ALD. Dietary modulation may represent a novel preventive/therapeutic approach in ALD and MLCK could be a specific novel therapeutic target.

project_terms:
Acetaldehyde;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Animal Model;Attenuated;Blood;Caco-2 Cells;Chronic;Development;Diet;Dietary Fats;Endotoxemia;Endotoxins;Epithelial;Epithelial Cells;Ethanol;Event;Fatty Acids;Fatty acid glycerol esters;Functional disorder;Genetic;Goals;Immune system;In Vitro;Individual;Inflammation;Inflammatory;Inflammatory disease of the intestine;Injury;Interleukin-1;Intestines;Joints;Lead;Linoleic Acids;Lipopolysaccharides;Liver;Liver diseases;Mediating;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Myosin Light Chain Kinase;NF-kappa B;Organ;Oxidative Stress;Pathogenesis;Permeability;Play;Polyunsaturated Fatty Acids;Preventive;Production;Proteins;Rodent;Role;Saturated Fatty Acids;TNF gene;Therapeutic;Tight Junctions;Tissues;Transcriptional Activation;United States;Unsaturated Fats;Unsaturated Fatty Acids;Work;alcohol effect;base;cell type;chronic alcohol ingestion;claudin-1 protein;cofactor;cytokine;in vitro Model;in vivo;mouse model;new therapeutic target;novel;novel therapeutic intervention;occludin;prevent

public_health_relevance:
ALD remains one of the leading causes of liver diseases and a major cause of morbidity and mortality in the United States and worldwide. Why some heavy drinkers develop ALD and other are spared is unclear (we postulate dietary effects-see below). Interactions between the gut immune system and the liver are critical components of ALD. Diet may represent a novel therapeutic approach in ALD and this is the goal of this proposal.


application_id: 8386060
project_number: 1R03HD071291-01A1
project_title: The Role Of CCL20 In Ovulation: A Novel Mediator Of Ovarian Leukocyte Recruitment
administering_ic: NICHD
award_notice_date: 2012-09-24
opportunity_number: PA-10-064
application_type: 1
activity_code: R03
ic: HD
serial_number: 071291
suffix: A1
program_official: TAYMANS, SUSAN
project_start_date: 2012-09-24
project_end_date: 2014-06-30
study_section: Reproduction, Andrology, and Gynecology Study Section[CHHD-R]
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  The preovulatory LH surge sets in motion a chain of events that culminate in breakdown of the ovarian follicle wall and release of the egg in a process known as ovulation. Ovulation involves an inflammatory process that is characterized by a massive influx of white blood cells known as leukocytes to the ovary. This influx of leukocytes is critical for fertility as removal of leukocytes in experimental models blocks oocyte release. However the factor(s) underlying the recruitment of leukocytes to the ovary are unknown. The present proposal will examine a newly identified candidate chemokine ligand 20 (CCL20). Our preliminary data shows that mRNA for CCL20 is massively induced in the human during the early and late preovulatory stage in the granulosa and theca cells from the ovarian follicle. Yet other than our preliminary data nothing is known as to temporal patterns of expression the regulation or function of CCL20 and its receptor CCR6 in the ovary. The present proposal builds on these provocative findings and will test the overall hypothesis that the LH surge stimulates an increase in CCL20 and the increase in this chemokine results in recruitment of leukocytes that impact events necessary for ovulation. This hypothesis will be addressed using a unique model where the granulosa and theca from human periovulatory follicles will be collected prior to and at three designated times after hCG to induce ovulation (early late and postovulatory). These human samples will be compared and contrasted to changes in CCL20 and CCR6 in the rat ovary using a well characterized rodent model for ovulation. This will be accomplished by the following three Aims. Aim 1 will determine the changes in the expression of the CCL20 and CCR6 system in both the human and rat ovary. This Aim will also determine how CCL20 and CCR6 expression is regulated via the major ovulatory pathways induced by LH. Aim 2 will explore the role of CCL20 in leukocyte recruitment into the ovary using well-characterized migration and invasion models. Due to the potential role of CCL20 to regulate cellular differentiation Aim 3 will investigate the role of CCL20 on ovarian cell function specifically the ability of granulosa cells to survive differentiate and make sterid hormones. Additionally the impact of CCL20 on ovarian cells will be assessed using microarray technology. The major strengths of the current proposal lie in the use of well characterized human preovulatory follicles as a foundation to understand the cellular expression regulation and the impact of CCL20 on the events associated with ovulation in the human and our integrated comparative approach across species to elucidate the role that this chemokine plays in the ovulatory process. Nothing is known about CCL20 and its receptor in the ovary. As such the proposed studies are extremely timely to elucidate the role that this chemokine system plays in the coordinated processes of follicular rupture and oocyte release which are fundamental aspects of normal human ovarian physiology.   
   
PUBLIC HEALTH RELEVANCE: The proposed studies will investigate the underlying mechanism involved in human ovulation which is a process where the egg is released from the follicle in the ovary. These studies will focus on a protein chemokine ligand 20 (CCL20) that we believe serves to attract white blood cells into the ovary to help breakdown the wall of the ovarian follicle to allow the egg to be released. Only by fully understanding such basic tenets of ovarian function will we be able to promote or inhibit the events associated with the ovulatory process thereby facilitating and increasing fertility or acting in a contraceptive manner to decrease fertility.

project_terms:
Address;Animals;Apoptosis;Biological Assay;CCR6 gene;Cell Cycle Kinetics;Cell physiology;Cells;Contraceptive Agents;Data;Epidermal Growth Factor;Event;Excision;Experimental Models;Fertility;Figs - dietary;Foundations;Genes;Hormones;Human;Human Chorionic Gonadotropin;In Vitro;Inflammatory;Inflammatory Response;Leukocytes;Ligands;Matrix Metalloproteinases;Mediator of activation protein;Messenger RNA;Microarray Analysis;Modeling;Motion;Oocytes;Ovarian;Ovarian Follicle;Ovarian Tissue;Ovary;Ovulation;Pathway interactions;Pattern;Physiology;Play;Process;Progesterone;Prostaglandins;Proteins;Rattus;Reaction;Recruitment Activity;Regulation;Reporting;Rodent;Rodent Model;Role;Rupture;Sampling;Signal Pathway;Signal Transduction;Staging;Steroid biosynthesis;Stimulus;System;Testing;Time;Tissues;chemokine;comparative;egg;granulosa cell;migration;novel;receptor;research study;theca cell

public_health_relevance:
The proposed studies will investigate the underlying mechanism involved in human ovulation which is a process where the egg is released from the follicle in the ovary. These studies will focus on a protein chemokine ligand 20 (CCL20) that we believe serves to attract white blood cells into the ovary to help breakdown the wall of the ovarian follicle to allow the egg to be released. Only by fully understanding such basic tenets of ovarian function will we be able to promote or inhibit the events associated with the ovulatory process thereby facilitating and increasing fertility or acting in a contraceptive manner to decrease fertility.


application_id: 8385921
project_number: 1R03DE021460-01A1
project_title: Integrated Analysis: Epigenetic Regulation of Gene Expression During Orofacial De
administering_ic: NIDCR
award_notice_date: 2012-08-28
opportunity_number: PAR-10-041
application_type: 1
activity_code: R03
ic: DE
serial_number: 021460
suffix: A1
program_official: HARRIS, EMILY L
project_start_date: 2012-09-01
project_end_date: 2014-08-31
study_section: Special Emphasis Panel[ZDE1 JR (11)]
contact_pi_person_id: 7842814
contact_pi: MUKHOPADHYAY, PARTHA
other_pis: BROCK, GUY
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The long-term objectives of this proposal are to elucidate the role of epigenetic regulation of gene expression during mammalian orofacial development. Formation of the mammalian orofacial tissue is a multifaceted synchronized developmental process involving cell migration proliferation differentiation apoptosis and synthesis of extracellular matrix. All these critical cellular processes are under the control of a
variety of genes encoding growth and differentiation factors signaling mediators transcription factors and extracellular matrix proteins whose expression is controlled in turn by epigenetically-modulated regulatory elements. Disruption of any one of these processes can lead to orofacial clefting. Emerging evidence strongly supports the importance of epigenetic mechanisms controlling the expression of key genes critical for orofacial ontogenesis. Recent studies from our lab have demonstrated that precise patterns of differential gene methylation and expression occur in embryonic orofacial tissue. Preliminary data revealed several epigenetically regulated genes which have documented critical roles in orofacial morphogenesis. We thus propose to test the hypothesis that regulation of differentially-expressed genes via differentially methylated regions is essential for proper development of the embryonic orofacial region. Three hypothesis-driven specific aims will be pursued: 1) Differentially expressed genes encoding mRNAs are epigenetically regulated during orofacial development. 2) Differentially expressed and epigenetically regulated gene transcripts are essential for the regulation of specific biological processes as well as phenotypic outcomes associated with orofacial development and 3) Selected differentially-expressed target genes are epigenetically regulated via differentially methylated regions during orofacial development.   
   
PUBLIC HEALTH RELEVANCE: Orofacial clefts are amongst the most prevalent birth defects in humans which can lead to difficulties in infant feeding breathing and speech impairment. Studies proposed in the current application are designed to advance our understanding of the complex mechanisms that control development of the orofacial region. This research proposal will adopt a novel bioinformatic approach and will utilize a mouse model that mimics human orofacial development to investigate the role of epigenetic regulation of gene expression during mammalian orofacial development. Successful completion of the proposed studies will provide a better insight of the specific control mechanisms that are important in orofacial development and will ultimately reveal potential mechanisms of clefting.

project_terms:
Adopted;Apoptosis;Back;Bioinformatics;Biological;Biological Process;Breathing;Candidate Disease Gene;Cell physiology;Cleaved cell;Complex;Congenital Abnormality;CpG dinucleotide;Data;Development;Developmental Process;Differentiation and Growth;Embryo;Embryonic Development;Epigenetic Process;Extracellular Matrix;Extracellular Matrix Proteins;Gene Expression;Gene Expression Regulation;Gene Targeting;Genes;Global Change;Goals;Human;Impairment;Infant;Investigation;Lead;Mediator of activation protein;Messenger RNA;Methods;Methylation;Modification;Molecular;Morphogenesis;Outcome;Pathway interactions;Pattern;Process;Regulation;Regulatory Element;Research Proposals;Role;Signal Pathway;Signal Transduction;Speech;Testing;Time;Tissues;Transcript;base;bisulfite;cell motility;design;feeding;insight;mRNA Expression;mouse model;novel;novel strategies;orofacial;transcription factor

public_health_relevance:
Orofacial clefts are amongst the most prevalent birth defects in humans which can lead to difficulties in infant feeding breathing and speech impairment. Studies proposed in the current application are designed to advance our understanding of the complex mechanisms that control development of the orofacial region. This research proposal will adopt a novel bioinformatic approach and will utilize a mouse model that mimics human orofacial development to investigate the role of epigenetic regulation of gene expression during mammalian orofacial development. Successful completion of the proposed studies will provide a better insight of the specific control mechanisms that are important in orofacial development and will ultimately reveal potential mechanisms of clefting.


application_id: 8385354
project_number: 1R21AA020848-01A1
project_title: Probiotics and HIF signaling in Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2012-12-13
opportunity_number: PA-10-069
application_type: 1
activity_code: R21
ic: AA
serial_number: 020848
suffix: A1
program_official: RADAEVA, SVETLANA
project_start_date: 2012-12-10
project_end_date: 2014-11-30
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 8029790
contact_pi: FENG, WENKE
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The pathogenesis of alcoholic liver disease (ALD) is multi-factorial. Animal and human studies suggest that gut-derived endotoxin is a critical factor contributing to ALD. Endotoxins are derived from the cell wall of Gram-negative bacteria and normally penetrate the gut epithelium in only trace amounts due to tightly regulated intestinal barrier function. However endotoxin leakiness is increased under pathological conditions such as alcohol abuse. The barrier function of the intestinal epithelium is provided by paracellular apical junction complexes including tight junctions and adherens junctions located at the apical end of epithelial cells and by mucus layers. Protection of the mucus layer involves mucins and a number of regulatory peptides such as intestinal trefoil factors (ITFs) which play critical rols in formation and stabilization of the barrier enhancement of rapid intestinal repair ('restitution) modulation of mucosal differentiation processes and modulation of the mucosal immune response. Formation and restitution of the barrier is also dependent on uninterrupted mucosal blood flow and ongoing glycolysis. Intestinal epithelial cells are positioned between an anaerobic lumen and a highly metabolic lamina propria forming a steep physiologic oxygen gradient. Physiological and pathological hypoxia induces hypoxia-inducible factor (HIF) -1 and -2 which represent a major adaptation response by upregulating a variety of gene products such as intestinal ITF mucins and glycolytic enzymes. Our preliminary studies showed that chronic alcohol feeding decreased intestinal HIF-2 ITF and tight junction expression leading to increased endotoxemia and ultimately liver injury. Supplementation of a probiotic strain lactobacillus rhamnosus GG (LGG) attenuates those deleterious effects and ALD. However the mechanisms are unknown. Our central hypothesis is that alcohol feeding causes a change favoring oxidative stress inflammation and mitochondrial damage which reduces HIF responsive signaling and the targeted proteins leading to disruption of gut barrier function increased endotoxemia and subsequent ALD and that probiotic supplementation will attenuate alcohol-induced liver injury by potentiating HIF regulated responses. To test this hypothesis we will carry our following specific aims: Specific Aim 1. Determine the effects of ethanol and probiotics on intestinal HIF signaling and mechanisms in ALD. Specific Aim 2. Determine whether HIF signaling is required for the protective effect(s) of probiotic supplementation against
alcohol-induced liver injury. We will use intestine-specific HIF-1 and HIF-2 knockout mice to evaluate and compare the role of HIF-1 and HIF-2 in ALD. We will then use prolyl-4 hydroxylase-1 PH.D.1 knockout mice for a gain-of-function strategy to determine whether an increase HIF attenuates alcohol-induced mucus layer dysfunction in ALD. This study will have a major impact on the development of new therapeutic targets for the prevention and treatment of ALD.

project_terms:
Adherens Junction;Affect;Alcohol abuse;Alcohol consumption;Alcoholic Liver Diseases;Alcohols;Animals;Apical;Attenuated;Blood flow;Caco-2 Cells;Cell Wall;Chronic;Cirrhosis;Complex;Development;Endotoxemia;Endotoxins;Enzymes;Epithelial Cells;Fatty Liver;Figs - dietary;Functional disorder;Glycolysis;Goals;Gram-Negative Bacteria;Human;Hypoxia;Hypoxia Inducible Factor;Inflammation;Intestines;Knockout Mice;Lactobacillus casei rhamnosus;Lamina Propria;Liver diseases;Metabolic;Mitochondria;Mucins;Mucosal Immune Responses;Mucous body substance;Mus;Oxidative Stress;Oxygen;Pathogenesis;Pathway interactions;Peptides;Physiological;Play;Positioning Attribute;Prevention;Probiotics;Process;Procollagen-Proline Dioxygenase;Proteins;Proto-Oncogene Proteins c-akt;Role;Signal Transduction;Supplementation;Testing;Tight Junctions;alcohol effect;alcohol exposure;bHLH-PAS factor HLF;chronic liver disease;feeding;gain of function;gastrointestinal epithelium;hypoxia inducible factor 1;intestinal epithelium;liver injury;loss of function;new therapeutic target;prevent;protective effect;public health relevance;repaired;response;trefoil factor

public_health_relevance:
Excessive alcohol drinking is a leading cause of chronic liver disease worldwide which results in a spectrum of liver disorders that range from fatty liver to cirrhosis. The goals of this project are to investigate the effects of probiotic supplementation on
alcohol-induced liver injury and the mechanisms related to hypoxia-inducible factor. This study will have a major impact on the development of new therapeutic targets for the prevention and treatment of ALD.


application_id: 8385076
project_number: 1R21HD069897-01A1
project_title: Consortium to Evaluate a Novel Violence Prevention Program on College Campuses
administering_ic: NICHD
award_notice_date: 2012-08-10
opportunity_number: PAS-10-226
application_type: 1
activity_code: R21
ic: HD
serial_number: 069897
suffix: A1
program_official: BURES, REGINA M
project_start_date: 2012-08-10
project_end_date: 2014-06-30
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 8001935
contact_pi: WILLIAMS, CORRINE M
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): Up to 25% of women may be sexually assaulted during college and one-third of college students have experienced physical aggression from dating partners. While most students neither participate in nor condone violence many respond passively to a campus culture that may tacitly support violence as evidenced by violent media images jokes trivializing violence against women and sexual harassment. Growing awareness that all members of the campus community can play a significant role in ending dating and sexual violence (DV/SV) has led to an increase in violence prevention interventions for college students. However very few of these programs have been empirically evaluated. A significant barrier to progress in intervention research is the infrastructure required to implement and evaluate interventions across multiple sites. For this project the intervention will be Green Dot
an innovative primary prevention intervention to reduce DV/SV among college students which was developed at the University of Kentucky. The intervention consists of one-hour persuasive speeches followed by a six to either hour bystander intervention training called Students Educating and Empowering to Develop Safety (SEEDS). In addition we are creating booster sessions that will be provided to all students who have completed SEEDS training to assist with additional skills-building that may be required. As a developmental project the proposed research will consist of three phases: 1) pilot work to create survey modules resulting in a questionnaire that contains measures which are standardized across campuses to evaluate the effectiveness of the intervention and is a manageable length; 2) data collection at UK to streamline data collection procedures when other colleges are brought on; and 3) recruitment of additional implementation and control college sites. The University of Kentucky will operate as the coordinating center for the multi-site evaluation and will continue to serve as the pilot site or data collection and refinement of study methodology. The University of South Carolina has agreed to serve as an implementation site and the University of Cincinnati has agreed to serve as a control site. We will recruit an additional eight colleges (four control and four intervention
sites) during the project period. By beginning with this R21 to conduct developmental work and begin problem solving we can help to ensure the success of subsequent projects. If Green Dot is then determined to be effective across multiple campuses in preventing violence and the associated sequelae of adverse academic as well as physical and mental health outcomes experienced by so many college students then the potential impact of this study is indeed groundbreaking. Additionally the lessons learned from establishing a multi-site public health intervention trial with one coordinating center responsible for all data collection via online surveys has implications for the study of other health issues.   
   
PUBLIC HEALTH RELEVANCE: Preventing dating and sexual violence among college students is a public health priority due to adverse academic and physical and mental health consequences. This study will create the foundation for a large multi-site evaluation of the violence prevention intervention Green Dot which will have a revolutionary impact if Green Dot is ultimately determined to be effective in preventing violence across multiple campuses. Additionally the lessons learned from establishing a multi-site public health intervention trial with one coordinating center responsible for all data collection via online surveys has implications for the study of other health issues.

project_terms:
Address;Awareness;Behavior;Behavioral Risk Factor Surveillance System;Communities;Data Collection;Development;Diffuse;Diffusion of Innovation;Educational Intervention;Effectiveness of Interventions;Ensure;Ethnicity aspects;Evaluation;Evaluation Studies;Faculty;Forcible intercourse;Foundations;Funding;Goals;Health;Hour;Image;Institutional Review Boards;Intervention;Intervention Studies;Intervention Trial;Kentucky;Learning;Length;Measures;Mental Health;Methodology;Modeling;Monitor;Outcome;Participant;Phase;Physical aggression;Play;Positioning Attribute;Pregnancy;Prevention program;Preventive Intervention;Primary Prevention;Problem Solving;Procedures;Questionnaires;Race;Randomized;Recruitment Activity;Research;Research Infrastructure;Risk Assessment;Role;Safety;Selection Criteria;Sexual Harassment;Site;South Carolina;Speech;Structure;Students;Surveys;System;Testing;Training;United States;Universities;Violence;Woman;Women's Health;Work;base;binge drinking;college;dating violence;dating violence prevention;empowered;experience;high school;innovation;interest;member;novel;peer;physical conditioning;programs;public health medicine (field);public health priorities;sexual assault;sexual violence;skills;success;theories;tool;university student;violence against women;violence prevention;willingness

public_health_relevance:
Preventing dating and sexual violence among college students is a public health priority due to adverse academic and physical and mental health consequences. This study will create the foundation for a large multi-site evaluation of the violence prevention intervention Green Dot which will have a revolutionary impact if Green Dot is ultimately determined to be effective in preventing violence across multiple campuses. Additionally the lessons learned from establishing a multi-site public health intervention trial with one coordinating center responsible for all data collection via online surveys has implications for the study of other health issues.


application_id: 8384461
project_number: 1R21AG040542-01A1
project_title: Muscle Fat and NK Lymphocytes in Aging
administering_ic: NIA
award_notice_date: 2012-07-27
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: AG
serial_number: 040542
suffix: A1
program_official: WILLIAMS, JOHN
project_start_date: 2012-08-01
project_end_date: 2014-07-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 1882143
contact_pi: LUTZ, CHARLES T.
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): We propose that both sarcopenia (loss of muscle mass) and obesity contribute to age-related immunosenescence by negatively regulating natural killer (NK) lymphocyte number and function. Preliminary studies showed an inverse correlation between body mass index and NK cell number in elderly women but not in young adult women. Therefore the interplay between skeletal muscle and adipose tissue may contribute to control of human NK cell development survival and function in the elderly. Skeletal muscle and fat are known to regulate each other via cytokines including adipose-derived tumor necrosis factor (TNF) and IL-6 which negatively impact NK cells. Muscle produces lower levels of these cytokines but produces abundant IL-15 which controls fat and is both absolutely required and rate-limiting for NK cell development and survival. Based on our observations we propose two hypotheses:  Muscle promotes NK development and survival and fat negatively regulates NK cells.  Muscle supports NK cells via IL-15 and fat inhibits NK cells via TNF and IL-6.  Our novel hypotheses lead to two predictions that will be tested in the elderly. 1) NK cell number and function will correlate directly with skeletal muscle strength and mass and correlate inversely with visceral fat mass. 2) Plasma IL-15 will correlate directly with muscle strength and mass and NK cell number and function but correlate inversely with visceral fat.  Our interdisciplinary team
has expertise in muscle biology NK immunity body composition measurement and biostatistics. Our highly innovative work will address for the first time whether skeletal muscle affects NK cells and whether IL-15 has a role in this process. Our work will have a highly significant impact because it will open completely new areas of investigation and may suggest novel ways to treat both sarcopenia and declining immunity in aging.   
   
PUBLIC HEALTH RELEVANCE: We will investigate a new idea that muscle is good for the immune system and fat is bad for the immune system in elderly people. Specifically we will test the effects of muscle and fat on natural killer (NK) lymphocytes that are important in fighting infections and cancer. If this idea is correct it could open up new ways to treat fat accumulation muscle loss and immune system weakness in old age.

project_terms:
Abbreviations;Address;Adipocytes;Adipose tissue;Affect;Age;Aging;Area;Biological Assay;Biology;Biometry;Body Composition;Body mass index;Cell Count;Cell physiology;Cessation of life;Clinical Research;Coin;Communicable Diseases;Communication;Complex;DNA Nucleotidylexotransferase;Development;Dose-Limiting;Dual-Energy X-Ray Absorptiometry;Elderly;Elderly woman;Enzyme-Linked Immunosorbent Assay;Fatty acid glycerol esters;Goals;Human;Immune system;Immunity;Immunoglobulins;In Situ Nick-End Labeling;Individual;Infection;Inflammatory;Interferons;Interleukin-15;Interleukin-6;Investigation;Kentucky;Killer Cells;Label;Lead;Link;Lymphocyte;Lymphocyte Count;Lymphocyte Function;Malignant Neoplasms;Measurement;Measures;Medical;Membrane;Monoclonal Antibodies;Morbidity - disease rate;Mortality Vital Statistics;Muscle;Muscle Fibers;Natural Killer Cells;Obesity;Peripheral;Peripheral Blood Mononuclear Cell;Plasma;Process;Research Personnel;Role;Skeletal muscle structure;Surface;Techniques;Testing;Thick;Time;Tumor Necrosis Factor-alpha;Universities;Visceral;Woman;Work;X-Ray Computed Tomography;age related;base;cell body (neuron);college;cytokine;fighting;healthy aging;human subject;immune function;immunosenescence;improved;innovation;interleukin-15 receptor;loss of function;monocyte;muscle form;muscle strength;novel;operation;receptor;receptor expression;research and development;sarcopenia;wasting;young adult

public_health_relevance:
We will investigate a new idea that muscle is good for the immune system and fat is bad for the immune system in elderly people. Specifically we will test the effects of muscle and fat on natural killer (NK) lymphocytes that are important in fighting infections and cancer. If this idea is correct it could open up new ways to treat fat accumulation muscle loss and immune system weakness in old age.


application_id: 8384076
project_number: 1R21OH010195-01A1
project_title: Aging Neuromuscular Behavior and Risk of Occupational Low Back Pain
administering_ic: NIOSH
award_notice_date: 2012-07-31
opportunity_number: PAR-09-139
application_type: 1
activity_code: R21
ic: OH
serial_number: 010195
suffix: A1
program_official: FREDERICK, LINDA J
project_start_date: 2012-07-01
project_end_date: 2014-06-30
study_section: Safety and Occupational Health Study Section[SOH]
contact_pi_person_id: 10388308
contact_pi: BAZRGARI, BABAK
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): Low back disorders and low back pain (LBP) in particular remain as the most common and debilitating work-related musculoskeletal disorder. An increasing LBP prevalence with aging along with an increasing participation of older individuals at work motivates a better understanding of underlying mechanisms linking aging with LBP. Abnormal mechanics of the spinal column (i.e. higher spinal loads and lower stability) under various work activities/events can eventually result in LBP. Spine biomechanics depend on the physical demands of a task/event (e.g. external loading) passive trunk mechanical characteristics (e.g. stiffness and damping) and active mechanical neuromuscular response to equilibrium and stability requirements. Despite current knowledge on the age-related degradation of trunk tissues the overall resultant changes in trunk mechanical behaviors (TMB - both active and passive) are unknown. It is also unknown how changes in TMB with age can influence spine biomechanics under various work activities/events. On the basis of contemporary causal biomechanical theory and our pilot data two hypotheses were shaped and will be investigated in the present application. Particularly linking aging with LBP via causal biomechanical theory suggests that: 1) there are age-related changes in TMB and 2) that these changes adversely affect spine biomechanics. Adverse effects on spine biomechanics are increases in spinal loads and decreases in spine stability for a given task/event (e.g. lifting/slp). Changes in TMB that could adversely affect spine biomechanics may include stiffer trunk reduced damping increased reflex latency and decreased reflex response. The aim of present application is to explore such relationships between aging and spine biomechanics by addressing two specific aims: Aim 1: How does TMB change with age? Aim 2: Do such age-related changes in TMB adversely affect spine biomechanics? TMB and spine biomechanics will be evaluated using a novel set of in vivo experimental methods including passive torso tests (i.e. stress-relaxation) and sudden loading experiments coupled with finite element modeling and a series of system identification techniques. The emphasis here is on aspects of the biomechanical theory that link a risk factor (i.e. aging) to abnormal spine mechanics specifically via the influences of the risk factor on TMB and spine mechanics and which have not yet been explored. Availability of a new set of powerful tools to comprehensively assess TMB and spine biomechanics will enable us to explore these facets of the causal biomechanical theory for the first time. A better understanding of potential causal mechanisms not only contributes to prevention but also is critical for efficient rehabilitation and safe return-to-wor of workers with occupational LBP. By quantifying age-related alterations in TMB and the resultant effects on spine biomechanics we expect to establish a foundation from which to develop and implement age-appropriate controls for LBP.   
   
PUBLIC HEALTH RELEVANCE: The potential role of age-related changes in mechanical behaviors of the human trunk and in the development of low back pain via their adverse effects on spine biomechanics will be explored in this application. Consistent with the research objectives of NIOSH the project seeks to investigate and identify the relationships between a risk factor here aging and associated occupational diseases and injuries. It also addresses the strategic goal to reduce the incidence and severity of low back pain which is present within most sectors in the recent National Occupational Research Agenda and with particular emphasis on older workers.

public_health_relevance:
The potential role of age-related changes in mechanical behaviors of the human trunk and in the development of low back pain via their adverse effects on spine biomechanics will be explored in this application. Consistent with the research objectives of NIOSH the project seeks to investigate and identify the relationships between a risk factor here aging and associated occupational diseases and injuries. It also addresses the strategic goal to reduce the incidence and severity of low back pain which is present within most sectors in the recent National Occupational Research Agenda and with particular emphasis on older workers.


application_id: 8382178
project_number: 5U54CA153604-03
project_title: Training Program
administering_ic: NCI
award_notice_date: 2012-09-12
opportunity_number: RFA-CA-09-032
application_type: 5
activity_code: U54
ic: CA
serial_number: 153604
study_section: ZCA1-PCRB-G
subproject_number: 7550
contact_pi_person_id: 6192172
contact_pi: LENGERICH, EUGENE J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-09-01
budget_end_date: 2013-08-31
project_abstract:
There is a growing awareness in the academic and public health communities that biologic social and environmental factors all affect cancer risks and outcomes. In Appalachia residents tend to value individualism and self-reliance traditionalism family and place and religious fundamentalism.^^" Appalachian families often have a multigenerational character that influences all aspects of life. For example the health of family members across generations often is closely linked with lifestyle factors such as eating and physical activity habits. In the states comprising the ACCN there is a high prevalence of inadequate fruit and vegetable consumption among adult men (range 52-89%) and women (range 36-80%).Similariy residents reports of no physical activity within a month's time ranges from 24-37% for adult males and 29-41% for adult females.(211) Thus it is not surprising that almost one-third of residents in each of the ACCN states are obese. Obesity and inactivity has been associated with increased risk of cancers of the breast (postmenopausal) endometrium colon kidney gallbladder ovaries pancreas and esophagus.(212) Explanations for these linkages vary and are inconclusive but include limited education and lack of risk awareness higher illness burden associated with obesity low self-perception and body image social discrimination and poor patient-physician relationships and communication all of which may influence participation in screening and other cancer prevention activities. To further understanding of cancer risk factors such obesity and inactivity as well as the implementation of evidence-based prevention and intervention programs to promote cancer awareness screening and behavioral change requires a well-trained cadre of researchers and community professionals working together to develop test and disseminate new and culturally appropriate strategies that lead to improved outcomes and reduced cancer risk in Appalachia. The Appalachian Cancer Scholars Program (ACSP) will build upon the solid foundation of individual ACCN senior investigators and their collaborative efforts as a team dedicated to using CBPR to reduce the cancer burden in Appalachia. The previous ACCN had four pilots funded by the National Cancer Institute [Project Directors: Drs. Curry (Penn State University) Vanderpool (University of Kentucky) Kluhsman (Penn State University) and Demian (West Virginia University)]. The ACCN has provided a framework for promotion in rank of two investigators: Dr. Kluhsman Penn State University from Senior Research Associate to Assistant Professor and Dr. Katz Ohio State University from Assistant Professor to Associate Professor. Dr. Kluhsman's 2008 dissertation was an investigation of factors associated with adoption of evidence-based strategies by ACCN cancer coalitions to increase cancer screening. While Kluhsman was based at Penn State University and her PhD was awarded from the University of Colorado her dissertation committee was chaired by Dr. Dignan at University of Kentucky. Dr. Raup-Krieger the principal investigator of the proposed pilot project received her PhD from Penn State University with a dissertation supported by the ACCN. After her dissertation. Dr. Raup-Krieger accepted a position as Assistant Professor at Ohio State University and continued her research with ACCN. Dr. Oralia Dominic received her PhD in Biobehavioral Health from Penn State University in 2008 and then became a post-doctorate scholar with ACCN scholar funded by a Minority Supplement from the National Cancer Institute to ACCN. Based upon pilot data collected through ACCN Dr. Dominic submitted a KOI application to the National Cancer Institute in October 2009. These individual training successes demonstrate the solid foundation in training that ACCN has already created and the successful background of the individual investigators in training and mentoring post-doctoral scholars and junior faculty to use CBPR for cancer prevention and control research in Appalachia.

project_terms:
Adoption;Adult;Advisory Committees;Affect;Appalachian Region;Applications Grants;Award;Awareness;Behavioral;Body Image;Cancer Burden;Cancer Control Research;Cancer Research Network;Colon;Colorado;Communication;Communities;Community Outreach;Community Participation;Computer software;Consumption;Data;Development;Doctor of Philosophy;Eating;Educational aspects;Endometrium;Environment;Environmental Risk Factor;Esophagus;Evaluation;Faculty;Family;Family member;Feedback;Female;Foundations;Funding;Gallbladder;Generations;Habits;Health;High Prevalence;Individual;Institution;Investigation;Kentucky;Kidney;Lead;Life;Link;Malignant Neoplasms;Mentors;Methods;Minority;NCI Scholars Program;National Cancer Institute;Obesity;Ohio;Outcome;Ovary;Pancreas;Physical activity;Physician-Patient Relations;Pilot Projects;Policy Maker;Positioning Attribute;Postdoctoral Fellow;Postmenopause;Prevention program;Primary Cancer Prevention;Principal Investigator;Process;Recording of previous events;Recruitment Activity;Religion and Spirituality;Reporting;Research;Research Personnel;Research Training;Risk;Risk Factors;Screening for cancer;Screening procedure;Self Perception;Site;Social Discrimination;Solid;Structure;Technology;Testing;Time;Training;Training Programs;Training and Education;United States National Institutes of Health;Universities;West Virginia;Woman;Work;anticancer research;base;biobehavior;burden of illness;cancer health disparity;cancer prevention;cancer risk;evidence base;experience;fruits and vegetables;improved;innovation;intervention program;investigator training;lifestyle factors;male;malignant breast neoplasm;medically underserved population;meetings;member;men;outreach program;professor;public health medicine (field);self reliance;social;success;surveillance strategy;trend


application_id: 8382175
project_number: 5U54CA153604-03
project_title: Research Project
administering_ic: NCI
award_notice_date: 2012-09-12
opportunity_number: RFA-CA-09-032
application_type: 5
activity_code: U54
ic: CA
serial_number: 153604
study_section: ZCA1-PCRB-G
subproject_number: 7548
contact_pi_person_id: 1878622
contact_pi: PASKETT, ELECTRA D.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-09-01
budget_end_date: 2013-08-31
project_abstract:
Project SummaryiA transdisciplinary heaith disparities research team in ACCN will partner with churches in the 5-state ACCN region to refine and test a previously piloted faith-based intervention program "Walk by Faith" to address obesity by focusing on environmental and individual level changes. Community-based participatory research strategies will be used in all phases of this inten/ention that will target two behavioral causes of obesity a sedentary lifestyle and an unhealthy diet. The proposed project will be implemented in 5 Appalachian regions which are mainly rural have medically underserved populations characterized by low incomes deficits in education poor health increased rates of obesity and increased cancer incidence and mortality rates. Additionally adults living in these areas have higher rates of no leisure activity and higher rates of eating less than 5 servings of fruits and vegetables daily compared to adults living in the U.S. In addition to individual causes of obesity an obesogenic environment promotes obesity on a population level by encouraging physical inactivity and limiting healthy food choices. The goal of the application is to test a faithbased intervention from 10 intervention churches compared to a comparison program (cancer screening tests) in 10 additional churches. The specific aims ofthis proposal are to: 1) Refine a previously piloted faith-based intervention focused on environmental and individual level changes to increase physical activity and to improve consumption of healthy food choices among members of male and female church members; 2) implement and test the intervention program using a group-randomized design to decrease BMI among members of 10 randomly selected churches vs. a comparison condition in 10 churches; 3) Utilize process and outcome evaluation strategies to assess the effectiveness of the different components of the intervention including an ehealth computer program that will track the number of steps per day and provide tailored message and letters to intervention participants; and 4) utilize the results to plan the dissemination of the inten/ention to churches located in other Appalachian states. The results of this proposed project will have immediate impact among the members of participating churches and the successful strategies could be used to improve the health of residents of other Appalachian states in the future.

project_terms:
Address;Adult;Appalachian Region;Area;Behavior;Behavioral;Blood Pressure;Body mass index;Cancer Control;Centers for Disease Control and Prevention (U.S.);Cessation of life;Church;Colon Carcinoma;Communities;Community Networks;Computer Programs and Programming;Consumption;Country;County;Data;Diet;Direct Costs;Eating;Educational Status;Educational aspects;Effectiveness;Environment;Evaluation;Facilities and Administrative Costs;Female;Food;Frequencies (time pattern);Future;Goals;Health;Health Food;Height;High Prevalence;Incidence;Individual;Intervention;Leisure Activities;Letters;Life;Life Style;Link;Low income;Malignant Neoplasms;Measures;Mortality Vital Statistics;Obesity;Outcome;Participant;Phase;Physical activity;Planets;Population;Process;Questionnaires;Randomized;Reporting;Research;Research Project Grants;Rural;Screening for cancer;Screening procedure;Technology;Testing;United States;Walking;Weight;Woman;base;community based participatory research;cost;design;disorder prevention;environmental change;faith-based intervention;follow-up;fruits and vegetables;health disparity;improved;intervention effect;intervention program;low socioeconomic status;male;medically underserved population;member;men;posters;prevent;programs;public health medicine (field);rural area;sedentary;social health determinants


application_id: 8380568
project_number: 5P30AG028383-07
project_title: Neuropathology Core
administering_ic: NIA
award_notice_date: 2012-06-18
opportunity_number: RFA-AG-11-005
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_start_date: 2006-07-15
study_section: ZAG1-ZIJ-5
subproject_number: 6077
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-07-01
project_terms:
Address;Aged 80 and over;Aging;Alzheimer's Disease;Autopsy;Biochemical;Biometry;Biostatistics Core;Brain;Brain Diseases;Brain region;Caring;Centenarian;Cerebrospinal Fluid;Cerebrum;Clinical;Clinical Data;Cognition Disorders;Collaborations;Complement;Consensus;Correlation Studies;Correlative Study;Country;Data;Databases;Degenerative Disorder;Dementia;Deposition;Diagnosis;Diagnostic;Disease;Down Syndrome;Elderly;Enrollment;Ensure;Freezing;Frontotemporal Dementia;Genomics;Goals;Hippocampus (Brain);Individual;Institutes;Instruction;Investigation;Kentucky;Lesion;Lewy Body Disease;Life;Measures;Methodology;Methods;Metric;MicroRNAs;Mission;National Institute on Aging;Neurodegenerative Disorders;Neurofibrillary Tangles;Oxidative Stress;Parkinson Disease;Pathology;Patients;Plasma;Preparation;Preventive;Process;Protocols documentation;Relative (related person);Religion and Spirituality;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Sampling;Sclerosis;Senile Plaques;Services;Specimen;Staging;Synapses;Synaptosomes;Syndrome;Therapeutic;Tissue Banking;Tissue Banks;Tissue Sample;Universities;age related;aged;aging brain;amyloid precursor protein processing;brain tissue;cohort;data management;experience;genome wide association study;innovation;meetings;mild cognitive impairment;neuroinflammation;neuropathology;normal aging;pre-clinical;symposium;synucleinopathy;tau Proteins;tool


application_id: 8380566
project_number: 5P30AG028383-07
project_title: Biostatistics and Data Management Core
administering_ic: NIA
award_notice_date: 2012-06-18
opportunity_number: RFA-AG-11-005
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_start_date: 2006-07-15
study_section: ZAG1-ZIJ-5
subproject_number: 6075
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-07-01
project_terms:
Advisory Committees;Aging;Alzheimer's Disease;Applications Grants;Area;Attention;Autopsy;Biometry;Clinical;Clinical Trials Data Monitoring Committees;Collaborations;Commit;Communities;Computer Assisted;Consult;Consultations;Data;Data Analyses;Data Collection;Data Quality;Data Set;Databases;Dementia;Development;Elderly;Elements;Enrollment;Ensure;Epidemiology;Equipment and supply inventories;Experimental Designs;Extramural Activities;Faculty;Funding;Gerontology;Image;Instruction;Kentucky;Laboratories;Leadership;Link;Logic;Manuscripts;Methodology;Methods;Mission;Modeling;Outcome;Pathology;Pilot Projects;Policies;Postdoctoral Fellow;Procedures;Process;Psychology;Publications;Quality Control;Records;Reporting;Research;Research Design;Research Personnel;Research Project Grants;Resources;Role;Seasons;Series;Serum;Services;Students;Study Section;System;Time;Tissue Sample;Training;Translations;Universities;Vision;Work;cohort;data management;graduate student;high standard;improved;innovation;meetings;neuropathology;novel;outreach;programs;public health medicine (field);relational database;statistics;success


application_id: 8380565
project_number: 5P30AG028383-07
project_title: Clinical Core
administering_ic: NIA
award_notice_date: 2012-06-18
opportunity_number: RFA-AG-11-005
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_start_date: 2006-07-15
study_section: ZAG1-ZIJ-5
subproject_number: 6071
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-07-01
project_terms:
Age;Aging;Alzheimer's Disease;Area;Autopsy;Biometry;Cell Line;Cessation of life;Clinic;Clinical;Clinical Data;Clinical Trials;Cognition;Cognitive;Collaborations;Commit;Correlative Study;Data;Data Collection;Data Set;Dementia;Detection;Development;Diagnosis;Diagnostic;Disease;Education and Outreach;Ensure;Environment;Funding;Future;Health;Healthcare Systems;Image;Impaired cognition;Industry;Instruction;International;Investigation;Kentucky;Leadership;Life;Measures;Minority;Mission;Pathologic;Patients;Pharmaceutical Preparations;Phase;Pilot Projects;Play;Positioning Attribute;Prevention;Productivity;Psychometrics;Publications;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Subjects;Role;Sampling;Therapeutic;Translational Research;Translations;United States National Institutes of Health;Universities;Work;base;biomarker;cohort;data management;drug development;drug discovery;genome wide association study;high risk;innovation;mild cognitive impairment;multidisciplinary;neuropathology;normal aging;novel;pre-clinical;programs;research clinical testing;research study;stem;success;therapeutic development;tool;translational study


application_id: 8379699
project_number: 5P01HL078825-07
project_title: Regulation of CPC Function via Protein O-GlcN Acylation
administering_ic: NHLBI
award_notice_date: 2012-06-18
opportunity_number: PAR-10-285
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
project_start_date: 2005-04-15
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7458
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-06-01
project_abstract:
The myocardium is largely unable to effecfively repair itself following an infarcfion. Recent work indicatesthat resident cardiac progenitor cells (CPCs) represent an under-developed therapeutic target.Unfortunately the post-ischemic myocardium is an unfavorable environment for the survival and potenfialcardiomyogenic differentiation of CPCs thereby limlfing effective post-ischemic myocardial repair ofexogenously administered CPCs. Project 3 will address the biological regulation of stress signaling and itsimpact on CPC function. Recently several reports indicated a unique stress response (0-GlcNAc) in theheart that allows differenfiated cardiac myocytes to withstand the violent environment of the post-ischemicmyocardium. Protein 0-GlcNAcylafion occurs in every mulficellular organism that has been examined; yetnothing is known about the role of this stress signal in CPCs. This Project will directly address thisdeficiency to create new biological insights. Project 3 will test the central hypothesis that a unique alarmsignal (0-GlcNAc) plays a fundamental role in regulafing CPC function and that it promotes CPC survivalbut may limit bona fide post-ischemic cardiomyogenesis by maintaining CPCs in a persistent state of alarm.Project 3 will establish the impact of the pro-adaptive stress signal 0-GlcNAc on CPC function byspecifically focusing on proliferation (Aim 1) survival (Aim 2) and differenfiafion (Aim 3). This Project willuse an exhausfive series of carefully controlled loss- and gain-of-function approaches. Regardless of thespecific outcomes of the Alms this Project will provide completely novel Insights into an exclfing area ofcardiovascular medicine because of the significance of the quesfions being pursued. Project 3 will confinueto collaborate with Projects 1 2 and 4 to understand innovafive inter-regulatory mechanisms between O-GlcNAcylation and: the NO-CO axis (Project 1) TNF-NFkB induced inflammation (Project 2) andhyperglycemic suppression of CPC function (Project 4). The role of protein 0-GlcNAcylafion in CPCs iscompletely unknown. This Project will undoubtedly establish new biological insights by assuming aninnovative approach to understanding CPC regulation and pathophysiology.RELEVANCE (See instructions):Project 3 will establish completely innovafive insights into the regulation of the proliferation survival anddlfferenfiation of primitive cells in the heart and translate the findings into a clinically relevant model of heartfailure. Regardless of the specific outcomes of the Aims Project 3 will provide completely novel insights intoa unique form of stress signaling as a previously unrecognized regulator of progenitor cell function.

project_terms:
Acylation;Address;Area;Attenuated;Biological;Biology;Cardiac;Cardiac Myocytes;Cardiovascular system;Cell Count;Cell Death;Cell Differentiation process;Cell Proliferation;Cell Survival;Cell physiology;Cellular Stress;Cessation of life;Characteristics;Defect;Doctor of Medicine;Environment;Eukaryota;Functional disorder;Heart;Heart failure;Hyperglycemia;Hypoxia;Infarction;Inflammation;Instruction;Maintenance;Mechanics;Medicine;Modeling;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Organism;Outcome;Play;Principal Investigator;Process;Proteins;Regulation;Reporting;Research;Role;Series;Shelter facility;Signal Transduction;Staging;Stem cells;Stress;System;TNF gene;Testing;Therapeutic;Translating;Violence;Work;base;biological adaptation to stress;cell injury;cell type;clinically relevant;experience;gain of function;innovation;insight;novel;oxidant stress;paracrine;primitive cell;repaired;response;restoration;therapeutic target


application_id: 8379695
project_number: 5P01HL078825-07
project_title: Role of the NO-CO Module in Regulating CPC Function
administering_ic: NHLBI
award_notice_date: 2012-06-18
opportunity_number: PAR-10-285
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
project_start_date: 2005-04-15
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7456
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-06-01
project_abstract:
The discovery of cardiac progenitor cells (CPCs) provides a potential new approach to the treatment of heartfailure (HF) The initial results of our first-in-humans clinical study of CPCs in patients with HF (SCIPIO) areencouraging. However CPC-based therapies are severely limited by the fact that almost all (at least 97%)of the transplanted CPCs die shortly after transplantafion. This implies that increasing the survival oftransplanted cells by prevenfing apoptosis will enhance the efficacy of CPC therapy. In the current fundingperiod of this Program Project we have found that carbon monoxide (CO) and nitric oxide (NO) exertpowerful anti-apoptotic actions and form a closely inter-related functional module (CO-NO module) which isregulated by heme oxygenase-1 (HO-1) extracellular superoxide dismutase (ecSOD) and inducible NOsynthase (iNOS). We will exploit this discovery to enhance cell-based therapies. The overall goal of Proiect1 is to elucidate the role of the CO-NO module in regulating CPC function and to evaluate its therapeuticutility after myocardial infarction (Ml). We propose that augmenting this module will greatly potentiate theeffectiveness of transplanted CPCs and dramaticallv enhance CPC-mediated cardiac repair. This Projectrepresents the natural evolution of our previous work in this Program Project; having discovered that the CO-NO module affors powerful protection against mmyocardial ischemia we will now build on this work toenhance the reparative ability of CPCs. In Aim 1 we will determine the roles of HO-1 and CO in modulatingCPC function. In Aim 2 we will establish the role of ecSOD in regulating CPC function and mediating HO-1-induced protection of CPCs. In Aim 3 we will determine the role of NO in modulating CPC function and therole of HO-1 and ecSOD in mediating the effects of NO on CPCs. Using both gain- and loss-of-functionapproaches in all three Aims we will systematically evaluate fundamental parameters of CPC competence invitro and the ability of CPCs to repair cardiac damage in vivo in a murine model of post-MI LV remodelingand dysfunction. In Aim 4. we will elucidate the molecular mechanisms whereby CO and NO upregulateecSOD and NO upregulates HO-1 and ecSOD in CPCs focusing on the transcription factor Nrf2. These willbe the first studies to examine the role of CO and NO and their supporting proteins HO-1 ecSOD andINOS in modulating CPC function. The results will be entirely new and will add a new dimension to ourunderstanding of CPC biology. In addition these studies will provide proof-of-principle for the therapeuticutility of manipulations that potentiate the CO-NO module in CPCs which may lay the groundwork for futuretrials of genetically or pharmacologically enhanced CPCs in patients with HF.RELEVANCE (See instructions):In 2009 we started SCIPIO a study of c-kit+ cardiac progenitor cells (CPCs) in patients with heart failureand the initial results are encouraging. Project 1 builds on SCIPIO. We will test a new therapy - genetically-modified or preconditioned CPCs which promise to be superior to the cells currently being used in SCIPIO.If the results confirm our working hypothesis these studies will lay the groundwork for testing more effectiveCPCs for the treatment of heart failure and thus may facilitate translation of cell therapies to humans.

project_terms:
Apoptosis;Apoptotic;Carbon Monoxide;Cardiac;Cell Survival;Cell Therapy;Cell Transplants;Cell physiology;Cells;Cellular biology;Chemotaxis;Clinical Research;Competence;Deet;Dimensions;Doctor of Medicine;Effectiveness;Evolution;Functional disorder;Funding;Future;Gene Transfer;Generations;Genetic;Genetic Transcription;Goals;Heart failure;Heme;Heme Oxygenase (Decyclizing);Human;In Vitro;Instruction;Ischemia;Left Ventricular Remodeling;Length;Measures;Mediating;Mediator of activation protein;Minority;Modeling;Molecular;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Nitric Oxide;Nitric Oxide Donors;Nitric Oxide Synthase;Oxidative Stress;Patients;Phase I Clinical Trials;Principal Investigator;Proteins;Proto-Oncogene Protein c-kit;Reactive Oxygen Species;Resistance;Role;Stem cells;Structure;Superoxide Dismutase;Telomerase;Testing;Therapeutic;Translations;Transplantation;Up-Regulation (Physiology);Work;cardiac repair;clinical application;cytokine;extracellular;gain of function;human NOS2A protein;in vivo;inhibitor/antagonist;loss of function;novel strategies;oxidative damage;phase 1 study;pre-clinical;preconditioning;prevent;programs;senescence;telomere;transcription factor


application_id: 8377273
project_number: 5P42ES007380-16
project_title: Core E: Superfund Inter-Disciplinary Training Core
administering_ic: NIEHS
award_notice_date: 2012-03-30
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_end_date: 2014-03-31
study_section: ZES1-JAB-C
subproject_number: 9008
contact_pi_person_id: 8534462
contact_pi: BACHAS, LEONIDAS G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-04-01
project_abstract:
The environmental challenge posed by Superfund chemicals is of high magnitude and affects severalaspects of human life. The aim of the University of Kentucky Superfund Program is studying the effects ofnutrition on the toxicity of Superfund chemicals detection of these chemicals and their remediation. To solveany environmental problems the emerging researchers should have specific scientific training broadknowledge of different disciplines and be effective communicators. The Training Core plans to address thisneed through cross-disciplinary graduate education and a training program in environmental sciences. Thecollaboration of the Training Core with the individual projects and the other Cores of the UK-SBRP willexpose our trainees to both basic and applied research. In addition to their involvement in individualprojects trainees will be introduced to (a) proteomics EPA methods and Bioinformatics and SystemsBiology in Toxicology though workshops organized by the Research Support Core (Core B); (b) ResearchTranslation strategies through workshops and participation in the activities of the Research Translation Core(Core C); and (c) real environmental problems through participation in the activities of the CommunityOutreach Core in communities residing close to Superfund sites. The goals of the Training Core are (i) toprovide thorough training of students in their specific field (ii) to instill basic knowledge about socioeconomiclaw engineering and science aspects (iii) to enhance the ability of students to communicate with scientistsas well as non-scientists. In addition to providing student stipents the Training Core will make availabletravel funds to student trainees and postdoctoral scholars to present their Superfund-related research atscientific conferences. Emphasis will be placed on identifying and recruiting motivated individuals andstudents from underrepresented groups through brochures web page and presentations at minorityinstitutions. The Training Core program will be evaluated on a regular basis to assess the progress inmeeting the goals of the program. This will be accomplished by first evaluating the progress of the traineestoward their educational goals and second in terms of how the trainees view and value the program.

project_terms:
Address;Affect;Applied Research;Basic Science;Bioinformatics;Chemicals;Collaborations;Collection;Communication;Communities;Community Outreach;Complex;Detection;Dimensions;Discipline;Ecology;Economics;Educational Activities;Educational workshop;Effectiveness;Engineering;Environment;Ethics;Evaluation;Evaluation Methodology;Faculty;Funding;Generations;Goals;Graduate Education;Human;Individual;Institution;Interdisciplinary Study;Interview;Kentucky;Knowledge;Laws;Learning;Legal;Life;Mentors;Methods;Minority;Monitor;Nutritional;Pamphlets;Postdoctoral Fellow;Principal Investigator;Problem Solving;Process;Proteomics;Published Comment;Recruitment Activity;Research;Research Activity;Research Personnel;Research Project Grants;Research Support;Science;Scientist;Series;Societies;Students;Superfund;System;Systems Biology;Toxic effect;Toxicology;Training;Training Programs;Translational Research;Travel;Universities;base;college;environmental toxicology;interest;knowledge base;meetings;member;next generation;nutrition;outreach;programs;remediation;research and development;skills;social;socioeconomics;superfund chemical;superfund site;symposium;web page


application_id: 8377271
project_number: 5P42ES007380-16
project_title: Core D: Community Outreach Core (SCAN)
administering_ic: NIEHS
award_notice_date: 2012-03-30
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_end_date: 2014-03-31
study_section: ZES1-JAB-C
subproject_number: 9007
contact_pi_person_id: 8535399
contact_pi: GAETKE, LISA M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-04-01
project_abstract:
Since 2000 UK's SBRP's Community Outreach Core has provided support and guidance through criticalinformation on nutrition and health-related issues to meet the needs of individuals and communities affectedby environmental contaminants. This purpose is underscored through its title Superfund Community Actionthrough Nutrition (SCAN). During previous funding SCAN established a close collaboration with communitygroups in eastern and western Kentucky and SCAN programs endorsed by these two communitiesprovided a new service resource for nutrition and scientific information. The aim of SCAN is to empoweraffected individuals and communities to take proactive steps toward their own health by drawing on thestrength of the nutrition-related research from UK's SBRP. The specific aims of SCAN include: 1) furtherdevelop and present SCAN nutrition and environmental health education programs for a new third site incentral Kentucky and the previously established community constituents; 2) further define SCAN's nutritioneducation message and enhanced recommendations that diets low in fat and high in phytonutrients mayreduce the toxicity of RGB's and related compounds as reported by UK SBRP's biomedical researchers; 3)develop new tangible qualitative outcome measures of SCAN programs as to improved knowledge andattitudes of health risks associated with exposure to environmental contaminants and the influence ofnutrition on these risks with consideration of sensitive issues such as community characteristics andpending litigation that may impede quantitative measures; 4) further establish trust with identified communityconstituents in order to provide advanced SCAN programs which show changes in nutrition and healthrelatedbehaviors. Results of SCAN programs will be used to assess the differences that diet and geo-socialcharacteristics play on nutrition and health issues and to design new diet strategies for individuals familiesand communities to enable them to optimize their health in the face of exposure to Superfund contaminants.Exposure to Superfund chemicals has been shown to affect public health by contributing to an increasedrisk for chronic diseases especially in combination with poor diet. UK's nutrition education programsdesigned with input from participants empower affected individuals to make more informed decisions abouttheir diet and health and are an important community service for Kentuckians in proximity to Superfund sites.

project_terms:
Affect;Anthropometry;Attitude to Health;Behavior;Body Composition;Characteristics;Chronic Disease;Collaborations;Communities;Community Actions;Community Outreach;Community Services;Diet;Diet Records;Dietitian;Educational aspects;Environmental Health;Environmental Pollution;Exercise;Exposure to;Family;Fatty acid glycerol esters;Fiber;Food;Funding;Hazardous Waste Sites;Health;Health Knowledge Attitudes Practice;Health Professional;Health education;Individual;Intake;Kentucky;Knowledge;Litigation;Measures;Metabolic;Nutrition Assessment;Nutritional status;Outcome Measure;Participant;Pharmacists;Physicians;Play;Quality of life;Questionnaires;Recommendation;Reporting;Research;Research Personnel;Research Project Grants;Resources;Risk;Services;Site;Social Characteristics;Superfund;Testing;Toxic effect;Trust;design;empowered;improved;insight;interest;meetings;nutrition;nutrition education;programs;public health medicine (field);superfund chemical;superfund site


application_id: 8377270
project_number: 5P42ES007380-16
project_title: Core B: Research Support Core
administering_ic: NIEHS
award_notice_date: 2012-03-30
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_end_date: 2014-03-31
study_section: ZES1-JAB-C
subproject_number: 9005
contact_pi_person_id: 8260644
contact_pi: TOBOREK, MICHAL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-04-01
project_abstract:
The Research Support Core (Core B) of the Superfund Basic Research Program at the Universityof Kentucky (UK-SBRP) will perform the vital role of supporting the research activities of all biomedicaland non-biomedical projects. The main objective of Core B is to provide a central facility that willenhance and develop the research capabilities of the University of Kentucky SBRP (UK SBRP)particularly in the areas of systems biology bioinformatics/biostatistics proteomics and PCBanalysis. Creation of a central facility in these research areas is critical to study the impact of nutritionon the toxicity of environmental pollutants (primarily PCBs). Establishment of a coordinated effort in theform of one Research Support Core will maximize both the research and cost effectiveness of UKSBRP.Core B consists of four entities (namely Systems Biology Bioinformatics/Biostatistical AnalysisProteomics and Analytical Components) directed by an expert in each area. The Aims of Core B are:1. Cross-link the individual research projects by developing a unified data managementinfrastructure and by providing feedback information to guide the process of discoveringcommon pathways and mechanisms of modulatory effects of diets on vascular pathology ofPCBs.2 Integrate diverse biological data from the individual research projects in order to generate acomprehensive systems biology model of the effects of nutrition on PCB-induced vasculartoxicity.3. Develop and provide analytical services expertise and technical support in the areas ofbioinformatics proteomics and PCB analysis.4. Provide training and support on using bioinformatics and systems biology tools as well asanalytical chemistry approaches for toxicology research to all investigators involved in theUK-SBRP.Core B will bind together critical research activities of individual projects to enhance the overallresearch potential and success of UK-SBRP. Thus it will not only offer research services but will alsobe critical for integration of individual research projects into a unified entity. In addition to providing auniform platform for generation and computational analysis of high-throughput data (microarrays andproteomics) the Core will employ the systems biology approaches to create predictive models to betteranticipate the effects of nutrition on toxicity of superfund chemicals.

project_terms:
Address;Analytical Chemistry;Area;Basic Science;Binding (Molecular Function);Bioinformatics;Biological;Biometry;Blood Vessels;Computer Analysis;Consultations;Data;Data Analyses;Databases;Diet;Disease;Educational workshop;Ensure;Environmental Pollutants;Equipment;Experimental Designs;Feedback;Generations;Genomics;Human Resources;Individual;Kentucky;Mediating;Modeling;National Institute of Environmental Health Sciences;Pathology;Pathway interactions;Polychlorinated Biphenyls;Procedures;Process;Proteomics;Quality Control;Research;Research Activity;Research Infrastructure;Research Personnel;Research Project Grants;Research Proposals;Research Support;Role;Sampling;Services;Software Tools;Structure;Superfund;Surveys;Systems Biology;Technical Expertise;Technology;Toxic effect;Toxicology;Training;Training Support;Universities;cost effectiveness;crosslink;data management;innovative technologies;new technology;nutrition;predictive modeling;programs;success;superfund chemical;tool


application_id: 8377268
project_number: 5P42ES007380-16
project_title: Core C: Research Translation Core
administering_ic: NIEHS
award_notice_date: 2012-03-30
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_end_date: 2014-03-31
study_section: ZES1-JAB-C
subproject_number: 9004
contact_pi_person_id: 8535916
contact_pi: ORMSBEE, LINDELL E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-04-01
project_abstract:
The University of Kentucky Superfund Basic Research Program will focus on the environmental healthimpacts of chlorinated organics with a more specific focus on RGBs and TCE. The Program will include fiveseparate biomedical research projects that seek to better understand the biochemical and cellularmechanisms associated with exposure to such chemicals as well as the associated impacts on suchdiseases as cancer diabetes hypertension and cardiovascular disease i.e. diseases common in Kentucky.One of the unique aspects of the research program will be the investigation of the role of nutrition inmitigating the impacts associated with such exposures. In addition separate projects will examine the use ofnanotechnologies and biosensors in detecting such chemicals in the environment and will explore noveltechniques for remediation with a particular focus on groundwater contaminated by TCE. The latter projectwill have specific potential for application as a result of ongoing remediation studies associated with theGaseous Diffusion Plant in Paducah Kentucky. The Research Translation Core will translate Programresearch to five targeted audiences: Government Industry Broad Audiences Health Professionals andAcademia. Consistent with the guidelines of the RFA the specific aims of the Research Translation Core aresummarized as follows:1. Communicate important research outcomes to specific targeted audiences to ensure the accurate andtimely use of the knowledge and technologies generated by individual research projects thus contributing tothe reduction of environmental contamination and the improvement of public health. Specific targetaudiences include: a) government b) academia industry and health professionals and c) broad audiences(including the general public and impacted communities).2. Leverage research translation activities and targeted research translation projects through effectivepartnerships and other communication tools. Specific partnerships include: 1) The Kentucky WaterResources Research Institute 2) The Kentucky Research Consortium for Energy and Environment 3) TheKentucky Cooperative Extension Service 4) UK College of Communications and Information Studies 5) UKCenter for Clinical and Translational Science and 6) Other SBRP Research Translation Cores (seeattached letters of support)3. Develop and implement a mechanism for tracking and evaluating the effectiveness of the translatedresearch to confirm the utility and appropriateness of the communication tools selected.These efforts promoted through eight specific translation projects will contribute to a reduction inenvironmental contamination an increase in target audiences' knowledge about the relationship betweenSuperund chemical exposure and health outcomes and a subsequent improvement in human health.

project_terms:
Academia;Basic Science;Biochemical;Biomedical Research;Biosensor;Cardiovascular Diseases;Chemical Exposure;Chemicals;Clinical Sciences;Communication;Communication Tools;Communities;Diabetes Mellitus;Diffusion;Disease;Effectiveness;Ensure;Environment;Environmental Health;Environmental Pollution;Exposure to;General Population;Government;Guidelines;Health;Health Professional;Human;Hypertension;Individual;Industry;Investigation;Kentucky;Knowledge;Letters;Malignant Neoplasms;Nanotechnology;Outcome;Outcomes Research;Plants;Research;Research Institute;Research Project Grants;Resources;Role;Services;Superfund;Targeted Research;Techniques;Technology;Toxic effect;Translating;Translational Research;Translations;Universities;Water;college;novel;nutrition;programs;public health medicine (field);remediation;superfund chemical


application_id: 8377267
project_number: 5P42ES007380-16
project_title: Project 7: Chloro-Organic Degradation by Nanosized Metallic Systems and by Chelat
administering_ic: NIEHS
award_notice_date: 2012-03-30
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_end_date: 2014-03-31
study_section: ZES1-JAB-C
subproject_number: 0010
contact_pi_person_id: 8534525
contact_pi: BHATTACHARYYA, DIBAKAR
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-04-01
project_abstract:
Chlorinated organics bring toxicity from water soil and sediment phases and exert a cumulativedeleterious effect on the environment. Various Superfund sites contain mixtures of RGBs chloroethylenesand other compounds. The degradation of of chloro-organics to nontoxic non-chlorinated and easilybiodegradable products will require integrated approaches involving "combined" (reductive and oxidative)remediation technologies. Our proposed approach to use combined technologies should lead to significantimprovement over current remediation practices by the elimination of the production of chloro-organicintermediates. Our research will focus on the degradation of selected RGBs TCE and RGB mixtures. Athorough understanding of the reaction kinetics for both steps (reductive and oxidative) the potential role ofsurfactants and material (such as doping catalyst metals chelates) characteristics will be important for theintegration of the steps. The approaches taken for reductive dechlorination by bimetallic nanoparticles inpolymer media and nanotubes will allow the development of highly controlled structures for high reactivityand stability. The proposed technology will have a significant impact on the role of nanostructured materialsand hydroxyl radical /superoxide radical anion reaction pathway in the environmental field for current andfuture needs. The technique for potential on-site generation of hydrogen peroxide and gluconic acid (ironchelate) provides enzyme (glucose oxidase) immobilization using an innovative approach of layer- by-layerassembled membranes and this should enhance application opportunities in various Superfund sites.Kinetic modeling of both oxidative and reductive systems should establish an excellent foundation forfundamental understanding of bimetallic nanotechnology-based systems and for chelate-modifiedhydroxyl/superoxide radical-based reactions. Another important aspect of this proposal is that pollutanttoxicity will be reduced significantly for both the dechlorination step and the combined reaction systems.Relevance: The proposed research is expected to have significant positive impact on pollution remediationthrough flexible dechlorination technology developments with significant reduction of material usage andhighly improved health benefits through toxicity reduction.

project_terms:
Advanced Development;Anions;Carbon;Characteristics;Chelating Agents;Chemicals;Chlorine;Development;Educational workshop;Effectiveness;Environment;Enzymes;Equilibrium;Flushing;Foundations;Free Radicals;Future;Generations;Glucose;Health Benefit;Hydrogen;Hydrogen Peroxide;Hydroxyl Radical;Immobilization;In Situ;Iron;Iron Chelating Agents;Kinetics;Lead;Life;Maps;Membrane;Metals;Methods;Modeling;Monitor;Morphology;Nanostructures;Nanotechnology;Nanotubes;National Institute of Environmental Health Sciences;Natural regeneration;Parents;Pathway interactions;Phase;Phenols;Pollution;Polychlorinated Biphenyls;Polymers;Production;Property;Reaction;Reagent;Research;Roentgen Rays;Role;Salts;Sampling;Site;Soil;Solvents;Spectrum Analysis;Structure;Superoxides;Surface;System;Techniques;Technology;Testing;Toxic effect;Trichloroethylene;Vascular Endothelial Cell;Vinyl Chloride;Water;Work;base;biodegradable product;catalyst;cost effective;dechlorination;diphenyl;enzyme immobilization;flexibility;gluconate;glucose oxidase;improved;innovation;membrane assembly;nanoparticle;nanosized;nanostructured;novel strategies;nutrition;operation;organic acid;oxidation;particle;pollutant;reaction rate;remediation;superfund chemical;superfund site;surfactant;technology development


application_id: 8377265
project_number: 5P42ES007380-16
project_title: Project 3: Vascular Mechanisms of PCB-Induced Brain Metastases
administering_ic: NIEHS
award_notice_date: 2012-03-30
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_end_date: 2014-03-31
study_section: ZES1-JAB-C
subproject_number: 0009
contact_pi_person_id: 8260644
contact_pi: TOBOREK, MICHAL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-04-01
project_abstract:
RGBs have both tumor promoting and vascular effects; however little is known about their influenceon the development of metastatic disease. We indicated that selected non-coplanar PCB congenersaccumulate in the brain stimulate dysfunction of brain microvascular endothelial cells (BMEC) andfacilitate the interaction of tumor cells with the vascular endothelium. Our new data provide evidence thatPCBs localize to caveolae in endothelial cells. This is an important finding because a variety of cellsurface receptors and signaling pathways are also localized in these membrane domains. Thuscaveolae may provide the crucial signaling platform for cerebral vascular toxicity of PCBs. Wehypothesize that PCB-induced stimulation of caveolar-associated pathways such as the Ras andRho cascades underlie the mechanisms of PCB-induced injury to BMEC disruption of the bloodbrainbarrier (BBB) integrity and the development of brain metastases. Mechanistically we willfocus on the involvement of the Ras and Rho pathways in PCB-induced alterations of expression of tightjunction proteins which are associated with caveolae and are detrimental for the normal functions of thebrain endothelium and regulate the barrier properties of the BBB. Diet is one of the most powerfulmodifiable behavioral factors which can influence cancer development and progression. Moreover ourdata indicate that exposure to PCBs can upregulate expression of CD36 a receptor which is localized incaveolae and is involved in cellular uptake of fatty acids. Therefore we will also study the influence ofdietary polyunsaturated fatty acids (namely fatty acids of the omega-6 and omega-3 family) on thevascular toxicity of PCBs and PCB-induced brain metastases. Specifically we hypothesize that omega-6 fatty acids (e.g. linoleic acid) potentiate the pro-metastatic properties of selected PCBs and thatomega-3 fatty acids (e.g. alpha-linolenic acid) protect against these effects.The proposed research combines elements of clinical and translational approaches (brainmetastases) with environmental toxicology and molecular biology. In addition it is based on a variety ofmodel systems such as unique cultures of brain endothelial cells Transwell systems and in vivo studiesbased on genetically altered mice (caveolin-1 deficient mice). The long term goals of this application areto determine molecular mechanisms of metastatic events induced by PCBs. However an even moreimportant goal of this proposal is to evaluate how dietary factors can influence the development of tumormetastases induced by Superfund chemicals. Therefore our application has strong clinical implicationsand can significantly contribute to the improvement of public health.

project_terms:
Advocate;Animal Model;Behavioral;Biological Models;Blood - brain barrier anatomy;Blood Vessels;Brain;CD36 gene;Cancer Patient;Caveolae;Caveolins;Cell Surface Receptors;Cerebrum;Clinical;Data;Development;Diet;Dietary Factors;Dietary Fatty Acid;Dietary Intervention;Disease;Elements;Endothelial Cells;Endothelium;Event;Exposure to;Family;Fatty Acids;Functional disorder;Funding;Goals;Hazardous Substances;Health;Human;Inflammatory Response;Injury;Knowledge;Linoleic Acids;Malignant Neoplasms;Manuscripts;Mediating;Membrane;Membrane Microdomains;Metastatic malignant neoplasm to brain;Modeling;Molecular;Molecular Biology;Mus;Neoplasm Metastasis;Neurologic;Omega-3 Fatty Acids;Omega-6 Fatty Acids;Pathology;Pathway interactions;Play;Polychlorinated Biphenyls;Polyunsaturated Fatty Acids;Property;Proteins;Publishing;Receptor Signaling;Research;Research Proposals;Risk;Role;Signal Pathway;Signal Transduction;System;Tight Junctions;Toxic effect;Unsaturated Fats;Vascular Endothelium;abstracting;alpha-Linolenic Acid;base;caveolin 1;environmental toxicology;in vivo;innovation;neoplastic cell;nutrition;outcome forecast;polyunsaturated fat;protein expression;public health medicine (field);receptor;rho;superfund chemical;translational approach;tumor;uptake


application_id: 8377262
project_number: 5P42ES007380-16
project_title: Project 4: The Impact of Obesity on PCB Toxicity
administering_ic: NIEHS
award_notice_date: 2012-03-30
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_end_date: 2014-03-31
study_section: ZES1-JAB-C
subproject_number: 0008
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-04-01
project_abstract:
Obesity predisposes to cardiovascular disease which is the primary cause of death in the obese population.During the current period of support results demonstrate that coplanar PCB ligands of the arylhydrocarbonreceptor (AhR) which accumulate markedly in adipose tissue increase adipocyte differentiation andproinflammatory gene expression. Administration of PCB77 to apolipoprotein E (apoE)-/- mice resulted in anincrease in body weight adipose mass and macrophage imrnunostaining in adipose tissue. Importantlymice administered PCB77 exhibited a marked increase in their susceptibility to angiotensin II (Angll)-inducedabdominal aortic aneurysm (AAA) formation. We have previously demonstrated that Angll-induced AAAsare associated with marked inflammation in vascular and surrounding peri-aortic adipose tissue and thatobesity increases the susceptibilty to Angll-induced AAAs. The working hypothesis of this proposal is thatadiposity and proinflammatory adipokine expression in response to coplanar PCBs promotes Angll-inducedAAAs. Moreover we hypothesize that dietary manipulation of fat content will modulate the adverse effects ofcoplanar PCBs on Angll-induced AAAs. In aim 1 we will identify mechanisms for coplanar PCB-inducedregulation of proinflammatory gene expression in adipocytes focusing on oxidative stress and NFkappaB assignaling intermediates. Given that adipocytes store fatty acids we will examine the interplay betweenpolyunsaturated fatty acids (PUFA) of the n-6 versus n-3 family in their ability to promote or abrogate theeffects of coplanar PCBs. In aim 2 we will define the role of the adipocyte AhR in the effects of PCB77 onproinflammatory adipokine expression body weight and Angll-induced AAAs. In aim 3 we will determinethe effect of diets enriched with linoleic acid (n-6) or linolenic acid (n-3) on PCB77-induced regulation of bodyweight ectopic lipid deposition and the formation and progression of Angll-induced AAAs. Results fromthese studies will directly relate to all projects of this superfund through elaboration of mechanisms wherebydietary intervention through fatty acids can mitigate or augment the toxicity of PCBs on the vascular systemon the ability to measure and detect PCBs in biological samples and on the pathophysiologic effects of PCBremediation products on adipocyte and vascular function. The long-term health benefits of this researchrelate to definition of contribution of PCBs to obesity and to obesity-associated cardiovascular disease.

project_terms:
Abdominal Aortic Aneurysm;Acute-Phase Proteins;Adipocytes;Adipose tissue;Adverse effects;Agonist;Angiotensin II;Apolipoprotein E;Biological;Blood Vessels;Body Weight;Cardiovascular Diseases;Cause of Death;Chronic;Data;Deposition;Diet;Dietary Intervention;Disease;Employee Strikes;Exhibits;Experimental Models;Family;Fatty Acids;Fatty acid glycerol esters;Gene Expression;Greater sac of peritoneum;Health Benefit;In Vitro;Incidence;Infiltration;Inflammation;Inflammatory;Laboratories;Ligands;Linoleic Acids;Linolenic Acids;Lipids;Measures;Mortality Vital Statistics;Mus;Obesity;Obesity associated cardiovascular disease;Obesity associated disease;Omega-3 Fatty Acids;Oxidative Stress;Polychlorinated Biphenyls;Polyunsaturated Fatty Acids;Predisposition;Production;Regulation;Research;Role;Sampling;Severities;Signal Pathway;Signal Transduction;Superfund;Toxic effect;Translating;Vascular Diseases;Vascular System;Weight Gain;Work;abdominal aorta;adipocyte differentiation;adipokines;base;cytokine;in vivo;lipophilicity;macrophage;male;nutrition;receptor;remediation;response;superfund chemical


application_id: 8377260
project_number: 5P42ES007380-16
project_title: Project 6: Sensing Superfund Chemicals with Recombinant Systems
administering_ic: NIEHS
award_notice_date: 2012-03-30
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_end_date: 2014-03-31
study_section: ZES1-JAB-C
subproject_number: 0004
contact_pi_person_id: 1964876
contact_pi: DAUNERT, SYLVIA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-04-01
project_abstract:
There is an on-going need for simple rapid and cost-effective analytical methods capable of detecting toxicsubstances in the environment and in biological samples. Among these toxic compounds polychlorinatedbiphenyls (PCBs) have been extensively studied and proven to be harmful to humans and the environmentand consequently classified as Superfund chemicals. More recently hydroxylated PCBs (OH-PCBs) havealso been more closely examined as potentially exhibiting significant toxic health effects. Due to the toxicityand environmental and biological persistence of PCBs and OH-PCBs it is necessary to have efficient andeconomical methods to detect and quantify them. Currently employed traditional analytical methods arecostly time- and labor-consuming not amenable to field analyis and not appropriate for extensivemonitoring of target analytes in biological samples. To that end the long-term objective of this proposal is todesign and develop molecular biosensors employing genetic engineering tools which are selectivesensitive portable and inexpensive and propose them as a viable alternative to traditional analyticalmethods for the detection of PCBs and OH-PCBs in biological and environmental samples. Specificallywhole-cell biosensors will be constructed that are based on bacteria engineered to harbor a plasmidcontaining the genes encoding for the proteins involved in the catabolic pathways of Superfund chemicalscoupled to those of a signal-producing reporter protein. Additionally the regulatory proteins of bacterialresistance operons will be redesigned to improve their binding selectivity to target analytes and will beincorporated as the recognition elements in a new biosensing format. These redesigned proteins should beable to act like molecular switches to detect the presence of the target compounds in samples. Furthermorethe newly developed biosensing systems will be miniaturized and integrated into enabling technologies for insitu detection and field studies. As part of the enabling technologies the transformation of bacterial wholecellsensors into spores as long-term highly rugged storage and transport elements will be explored.These spore-based biosensors as well as the molecular switches will then be incorporated into portableminiaturized microfluidic platforms for field sensing. These biosensing systems provide with new tools formonitoring of human health and the environment therefore they are of high relevance for public health.

project_terms:
Bacteria;Bacterial Transformation;Binding (Molecular Function);Biological;Biosensing Techniques;Biosensor;Cells;Chemicals;Coupled;Detection;Development;Ecology;Elements;Emerging Technologies;Engineering;Environment;Environmental Monitoring;Exhibits;Funding;Genes;Genetic Engineering;Goals;Health;Human;In Situ;Indium;Methods;Microfluidic Analytical Techniques;Microfluidics;Molecular;Molecular Biology;Monitor;Nanotechnology;Nature;Operon;Pathway interactions;Plasmids;Poisons;Polychlorinated Biphenyls;Proteins;Recombinants;Reporter;Reproduction spores;Research Personnel;Sampling;Signal Transduction;System;Technology;Time;Toxic effect;Trademark;Work;analytical method;bacterial resistance;base;cost effective;design;field study;genetic regulatory protein;improved;miniaturize;nutrition;pollutant;public health relevance;sensor;success;superfund chemical;tool


application_id: 8377258
project_number: 5P42ES007380-16
project_title: Project 1: Superfund Chemicals Nutrition and Endothelial Cell Dysfunction
administering_ic: NIEHS
award_notice_date: 2012-03-30
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_end_date: 2014-03-31
study_section: ZES1-JAB-C
subproject_number: 0002
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-04-01
project_abstract:
Atherosclerosis a chronic inflammatory disease is still the number one cause of death in the United States.Numerous risk factors for the development of atherosclerosis have been identified including obesityhypertriglyceridemia and exposure to Superfund chemicals such as persistent organic pollutants (e.g.RGBs). Plant-based bioactive food components are reported to have antioxidant and anti-inflammatoryproperties. Our preliminary data suggest that endothelial cell dysfunction and inflammatory events inducedby exposure to coplanar PCBs can be markedly down-regulated by bioactive compounds such as flavonoidsevents which also can be modified by the cellular lipid milieu. Little is known about mechanisms of nutritionalmodulation of environmental toxicity. Membrane lipid domains such as caveolae are particularly abundant inendothelial cells where they are believed to play a major role in the regulation of endothelial vesiculartrafficking. More recently caveolae have also been implicated in the regulation of cell signal transductions.Thus we hypothesize that caveolae are critical in the cellular responses to Superfund pollutants lipids andlipophilic bioactive compounds such as flavonoids. We also hypothesize that the anti-inflammatoryproperties of flavonoids against chemical insults may be enhanced by omega-3 fatty acids and antagonizedor lessened by omega-6 fatty acids. These hypotheses will be tested in vitro as well as in vivo by studyingthe interactions of PCBs with dietary components such as fatty acids and flavonoids. Importantly we willuse cell and mouse models lacking the caveolin gene to determine the involvement of caveolae ininflammatory outcome. We propose to explore novel mechanisms of nutrient-mediated modulation ofSuperfund chemical toxicity and the outcome of our proposed study will lead to novel nutritionalrecommendations and therapeutic interventions in populations exposed to Superfund chemicals. Superfundchemical exposure specifically persistent organic pollutants like PCBs has been linked to a heightened riskof cardiovascular disease to the public. Project 1 intends to investigate the mechanisms used by thesechemicals resulting in disease specifically signaling pathways controlled by the membrane domainscaveolae. Project 1 will focus on means of nutritional intervention by blocking these targets and thusproposing means of protecting the public from the harmful effects of Superfund chemical exposure.

project_terms:
Anti-Inflammatory Agents;Anti-inflammatory;Antiatherogenic;Antioxidants;Atherosclerosis;Blood Vessels;CAV1 gene;Cardiovascular Diseases;Cause of Death;Caveolae;Caveolins;Cell model;Chemical Exposure;Chemicals;Chronic;Critical Pathways;Data;Development;Diet;Dietary Component;Dietary Fats;Dietary Fatty Acid;Dietary Intervention;Disease;Endothelial Cells;Event;Exposure to;Fatty Acids;Flavonoids;Functional disorder;Genes;Health;Hypertriglyceridemia;Incidence;Inflammatory;Inflammatory Response;Intervention;Lead;Link;Lipids;Low-Density Lipoproteins;Mediating;Membrane;Membrane Lipids;Mus;Nutrient;Nutritional;Obesity;Omega-3 Fatty Acids;Omega-6 Fatty Acids;Outcome;Pathology;Plants;Play;Polychlorinated Biphenyls;Population;Process;Property;Recommendation;Regulation;Reporting;Risk;Risk Factors;Role;Signal Pathway;Signal Transduction;Superfund;Testing;Therapeutic Intervention;Toxic effect;United States;base;bioactive food component;cardiovascular disorder risk;in vitro testing;in vivo;mouse model;novel;nutrition;pollutant;prevent;response;superfund chemical;trafficking;uptake


application_id: 8376722
project_number: 5P01AG005119-24
project_title: ANIMAL CORE
administering_ic: NIA
award_notice_date: 2012-03-19
application_type: 5
activity_code: P01
ic: AG
serial_number: 005119
project_end_date: 2014-03-31
study_section: ZAG1-ZIJ-4
subproject_number: 9005
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-04-01
budget_end_date: 2013-03-31
project_abstract:
This program project will primarily use genetic modified mice. The Animal Core will provide essential
genetically modified mice and control wild-type mice to support the research of all four projects. To
accomplish this objective the Animal Core will be responsible for: 1) establishing maintaining and breeding
the required numbers and ages of knock-in knockout and transgenic mice; 2) characterizing gene altered
mice using molecular biochemical and pathological methods to ensure genotype and phenotypes; 3)
performing the complex genetic crosses required to obtain mice with the desired combinations of mutations;
and 4) providing pups at the desired gestation stages and ages to establish primary culture cells. By
coordinating and standardizing animal and cell use among projects animals money and time will be saved.
Providing every project with animals and cells derived in the same manner will make it possible to crosscorrelate
information from the projects which will result in synergistic use of the animals and the data
generated. The Animal Core will also work closely with the Administrative Core and Core B to help the
project leaders plan and/or define their studies.

project_terms:
APP-PS1;Age;Age-Months;Alzheimer's Disease;Amyloid;Amyloid beta-Protein;Animal Model;Animals;Biochemical;Brain;Breeding;Cell Culture Techniques;Cells;Clinical;Complex;Consultations;Deposition;Development;Disease;Embryo;Ensure;Excision;Funding;Generations;Genes;Genetic;Genetic Crosses;Genotype;Histologic;Histopathology;In Vitro;Individual;Knock-in Mouse;Knock-out;Knockout Mice;Leucine;Mediating;Methionine;Methods;Microglia;Molecular;Monitor;Mus;Mutate;Mutation;NADP;NADPH Oxidase;Neurons;Newborn Infant;Oxidative Stress;Pathologic;Phenotype;Pregnancy;Primary Cell Cultures;Rattus;Research Design;Research Methodology;Research Personnel;Research Support;Rodent;Role;Schedule;Source;Southern Blotting;Staging;Techniques;Time;Transgenic Mice;Transgenic Organisms;Wild Type Mouse;Work;animal data;base;brain cell;postnatal;prevent;programs;pup;research study;success


application_id: 8376721
project_number: 5P01AG005119-24
project_title: BETA-AMYLOID CORE
administering_ic: NIA
award_notice_date: 2012-03-19
application_type: 5
activity_code: P01
ic: AG
serial_number: 005119
project_end_date: 2014-03-31
study_section: ZAG1-ZIJ-4
subproject_number: 9004
contact_pi_person_id: 8425703
contact_pi: MURPHY, PAUL M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-04-01
budget_end_date: 2013-03-31
project_abstract:
A major problem in amyloid-p peptide (A(3) related research is the inconsistency introduced by the
multiple and varied protocols employed by different laboratories for isolating analyzing quantifying
preparing and handling Af3; the centralization of procedures within this Core will circumvent these
inconsistencies. This Core thus has two specific aims: to provide an A(3 index to each project and to supply
A(3 to each project.
Ap index: Different aspects of Ap (concentration physiological properties deposition etc.) are often
measured in isolation. To date a comprehensive assessment of these aspects has not been performed in
the same tissue. For each project Core B will collect and collate from both human and rodent tissues the
following data: (a) the amounts of Ap (including AP40 and A042) and its solubility (b) the amounts of
oligomeric and fibrillar Ap and (c) the number of neuritic and non-neuritic plaques. These data will allow the
determination of the relationship(s) between individual changes in Ap and the various neurochemical end
point measures studied in the different projects.
Supply Ap: Evaluation of the physiological properties and toxicity of Ap has been hampered by
inconsistencies caused by variability in every possible aspect of Ap handling. Core B will maintain
consistency between projects by controlling each of these different variables (peptide acquisition and
storage preparation and quantification of oligomers and fibrils quantification of toxicity) through adherence
to established standardized protocols and through maintenance of rigid quality control. The novelty of this
Core is its thoroughness. We have assembled a unique group of investigators who together possess
proven expertise for each function of Core B. Utilizing methods that are well characterized and established in
their respective laboratories this team-oriented approach will allow the first comprehensive multifaceted
analysis of Ap in vivo and in vitro. Ultimately this will provide an unprecedented level of thoroughness and
rigor to Ap analysis imparting much needed fidelity and continuity to project data. First and foremost the
data and materials generated in Core B will allow the individual projects to correlate each of their individual
neurochemical alterations to different aspects of Ap assembly deposition and toxicity.

project_terms:
AP40;Adherence (attribute);Alzheimer's Disease;Amyloid;Amyloid beta-Protein;Data;Deposition;Evaluation;Human;In Vitro;Individual;Laboratories;Maintenance;Measures;Methodology;Methods;Oxidative Stress;Peptides;Physiological;Preparation;Procedures;Property;Protocols documentation;Quality Control;Research;Research Personnel;Rodent;Senile Plaques;Solubility;Tissues;Toxic effect;in vivo;indexing;neurochemistry;peptide A


application_id: 8376719
project_number: 5P01AG005119-24
project_title: ADMINISTRATIVE CORE
administering_ic: NIA
award_notice_date: 2012-03-19
application_type: 5
activity_code: P01
ic: AG
serial_number: 005119
project_end_date: 2014-03-31
study_section: ZAG1-ZIJ-4
subproject_number: 9003
contact_pi_person_id: 1894359
contact_pi: MARKESBERY, WILLIAM R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-04-01
budget_end_date: 2013-03-31
project_abstract:
The Administrative Core's major function is to provide leadership and facilitate the research aims of all cores
and projects of the program project with the long-term objective being to learn more about the role of beta
amyloid peptide and oxidative damage in the pathogenesis of Alzheimer's disease. The goal of these efforts
is to develop knowledge that will lead to the prevention or slowing of AD. This core will promote integration
of the cores and projects and facilitate communication between cores and projects by organizing monthly
scientific meetings of all investigators and staff. It will provide supervision of all fiscal matters including a
monthly financial report to each core and project leader. Scientific and administrative review of the program
project will be provided by an Internal Advisory Committee organized by this core. In addition an External
Advisory Committee composed of scientists with expertise that matches the individual projects will be
named and organized by this core. It will meet annually. These two advisory committees will provide
scientific review of accomplishments and future directions of the program project. Another important function
of this core is acting as a liaison between the University of Kentucky's Alzheimer's Disease Center and the
program project to obtain clinical and neuropathological data and specimens from normal control subjects
preclinical AD subjects and patients with mild cognitive impairment late Alzheimer's disease and
frontotemporal dementia (disease control). The Administrative Core provides statistical support for all cores
and projects including consultation on research design power analysis and statistical analyses. The Core
will also maintain a centralized database for all data from cores and projects.

project_terms:
Advisory Committees;Alzheimer's Disease;Amyloid beta-Protein;Animal Welfare;Animals;Archives;Biometry;Clinical;Communication;Consensus;Consult;Consultations;Data;Databases;Endowment;Ensure;Equipment;Ethics;Evaluation;Frontotemporal Dementia;Funding;Future;Goals;Guidelines;Individual;Kentucky;Knowledge;Lead;Leadership;Learning;Measures;Modeling;Names;Oxidative Stress;Pathogenesis;Patients;Prevention;Preventive;Program Reviews;Reporting;Research;Research Design;Research Personnel;Role;Sample Size;Scientist;Specialist;Specimen;Structure;Supervision;Therapeutic;Universities;base;data management;disorder control;indexing;meetings;mild cognitive impairment;neurochemistry;neuropathology;oxidative damage;patient oriented;pre-clinical;programs


application_id: 8376717
project_number: 5P01AG005119-24
project_title: AB AND NADPH OXIDASE IN MILD COGNITIVE IMPAIRMENT AND ALZHEIMER'S DISEASE
administering_ic: NIA
award_notice_date: 2012-03-19
application_type: 5
activity_code: P01
ic: AG
serial_number: 005119
project_end_date: 2014-03-31
study_section: ZAG1-ZIJ-4
subproject_number: 0012
contact_pi_person_id: 2306174
contact_pi: BRUCE-KELLER, ANNADORA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-04-01
budget_end_date: 2013-03-31
project_abstract:
Alzheimer's disease (AD) is the major age-related dementia and is expected to take an increasing toll on
society as the population ages. Histopathologically while the diagnostic criterion for AD is the presence of
amyloid-containing plaques and neurofibrilliary tangles AD brains are typified by increased oxidative stress
and focal neuronal death. While the exact relationship between beta amyloid (AP) deposition oxidative
stress and neuronal injury is still unresolved increasing evidence suggests that the NADPH oxidase system
may be altered in AD and in response to Ap. NADPH oxidase (NOX) originally described as the main
component of the leukocyte oxidative burst produces reactive oxygen species (ROS) that are involved in
both intracellular signaling and oxidative stress. NOX expression has been established in neurons thus
raising the possibility that aberrant activation of neuronal NOX by toxic forms of A(3 could contribute to ADrelated
neuronal alterations. The focus of this project is to test the hypothesis that sustained activation of
NOX by Ap triggers a pernicious cascade linking increases in ROS production to altered intracellular redoxbased
signaling and oxidative stress culminating in neuron degeneration and death. The specific aims to
test this hypothesis are as follows: 1) To test the hypothesis that NOX activity is increased during the
progression of AD; 2) To test the hypothesis that NOX activity is increased in response to increasing Ap
deposition in a specific APP/PS1 knock-in mouse model of amyloidogenesis; 3) To test the hypothesis that
toxic forms of Ap increase neuronal oxidative stress and cell death via NOX; 4) To test the hypothesis that
microglial NOX activation exacerbates neuronal responses to AP; and 5) To test the hypothesis that genetic
or pharmacologic ablation of NOX in the APP/PS1 transgenic mice attenuates oxidative stress and Ap
pathogenesis in vivo. The proposed experiments will make use of our extensive and well-characterized
tissue bank of human brain specimens as well as a novel and highly relevant mouse model of beta amyloid
pathogenesis. Finally studies will determine the specific effects of distinct physiological forms of AP(1-40/1-
42/oligomer/fibrillar) on NOX activation both in vitro and in vivo. Completion of these studies will result in a
more thorough understanding of the relationship between Ap deposition and AD-related neuronal pathology
and could highlight an innovative and highly promising target for therapeutic intervention in AD.

project_terms:
4 hydroxynonenal;APP-PS1;Ablation;Affect;Age;Age-Months;Alzheimer's Disease;Amyloid;Amyloid beta-Protein;Amyloid deposition;Attenuated;Automobile Driving;Biochemical;Brain;Brain region;Cell Death;Cerebellum;Cessation of life;Characteristics;Clinical;Data;Dementia;Deposition;Diagnostic;Dose;Free Radicals;Frontotemporal Dementia;Future;Genetic;Genetic Techniques;Hippocampus (Brain);Histological Techniques;Human;Impairment;In Vitro;Inferior;Inflammation;Inflammatory;Injury;Knock-in Mouse;Link;Lobule;Measures;Mediating;Methods;Microglia;Mitochondria;Modeling;Monitor;Mus;NADPH Oxidase;Nerve Degeneration;Neurofibrillary Tangles;Neuroglia;Neuronal Injury;Neurons;Oxidation-Reduction;Oxidative Stress;Parietal;Pathogenesis;Pathology;Patients;Physiological;Population;Production;Proteins;RNA;Reactive Oxygen Species;Regulation;Respiratory Burst;Role;Senile Plaques;Signal Transduction;Societies;Specimen;Staging;Structure of middle temporal gyrus;Sum;System;Testing;Therapeutic Intervention;Time;Tissue Banking;Tissue Banks;Tissues;Transgenic Mice;acetovanillone;age related;amyloidogenesis;attenuation;base;disorder control;in vivo;indexing;inhibitor/antagonist;innovation;mild cognitive impairment;mind control;mouse model;neuron loss;neuropsychological;neurotoxic;neurotoxicity;nitration;novel;novel strategies;oxidation;pre-clinical;research study;response


application_id: 8376714
project_number: 5P01AG005119-24
project_title: AB AND RAGE INTERACTIONS IN ALZHEIMER'S DIESEASE
administering_ic: NIA
award_notice_date: 2012-03-19
application_type: 5
activity_code: P01
ic: AG
serial_number: 005119
project_end_date: 2014-03-31
study_section: ZAG1-ZIJ-4
subproject_number: 0011
contact_pi_person_id: 7875104
contact_pi: KELLER, JEFFREY NEIL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-04-01
budget_end_date: 2013-03-31
project_abstract:
The receptor for advanced glycosylation end products (RAGE) has been implicated in mediating beta
amyloid (A(3) toxicity and contributing to Alzheimer's disease (AD) pathogenesis although the specifics on
many aspects of RAGE biology and toxicity remain to be elucidated. Recent reports have demonstrated
that in contrast to the transmembrane RAGE receptor the secreted or soluble forms of RAGE (sRAGE) are
capable of suppressing several aspects of Ap pathogenesis in vivo. Pilot studies from our laboratory
demonstrate that sRAGE suppresses the formation of assembled A(3 species and Ap -induced neurotoxicity
with sRAGE interacting with the oligomeric forms of Ap at higher apparent affinity than monomeric Ap.
However it is currently not known which regions of sRAGE are responsible for mediating each of these
observations. The goal of this proposal is to test two related hypotheses. The first hypothesis is that
increases in RAGE-ligand interactions occur during the progression of AD and in a transgenic
mouse model of Ap pathogenesis with oligomeric Ap representing a significant portion of the overall
RAGE-ligand interactions. The second hypothesis is that sRAGE inhibits the formation of pathogenic
p and the effects of pathogenic Ap via specific and related domains within the sRAGE protein. The
specific aims to test each of these hypotheses are as follows: 1) To define the alterations in RAGE-ligand
interactions in AD and APP/PS-1 mice 2) To elucidate the functional domains responsible for RAGE- Ap
interactions 3) To determine the mechanism by which sRAGE suppresses Ap-induced neurotoxicity and 4)
To determine the mechanism by which sRAGE suppresses Ap assembly and Ap deposition. Cumulatively
these data will advance the field by potentially identifying novel therapeutic strategies that could lead to
eventual treatments for AD. Additionally these findings will be critical in clarifying the current gaps that exist
in our understanding of RAGE with Ap-assembly Ap-deposition and Ap-induced neurotoxicity.

project_terms:
Affinity;Alzheimer's Disease;Amyloid beta-Protein;Biology;Data;Deposition;Goals;Laboratories;Lead;Ligands;Mediating;Mus;Oxidative Stress;Pathogenesis;Pilot Projects;Proteins;Reporting;Testing;Toxic effect;Transgenic Mice;amyloidogenesis;in vivo;mouse model;neurotoxicity;novel therapeutics;receptor;receptor for advanced glycation endproducts


application_id: 8376712
project_number: 5P01AG005119-24
project_title: BRAIN PROTEIN OXIDATION IN AD MCI AND PCAD: ROLES OF AB AND PIN1
administering_ic: NIA
award_notice_date: 2012-03-19
application_type: 5
activity_code: P01
ic: AG
serial_number: 005119
project_end_date: 2014-03-31
study_section: ZAG1-ZIJ-4
subproject_number: 0010
contact_pi_person_id: 8329002
contact_pi: BUTTERFIELD, D. ALLAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-04-01
budget_end_date: 2013-03-31
project_abstract:
Oxidative stress is present in Alzheimer's disease (AD) brain and we recently provided evidence that protein
oxidation and lipid peroxidation are also present in brains of persons with mild cognitive impairment (MCI).
Our lab first used redox proteomics to identify oxidatively modified proteins in AD and MCI brain. One
protein that is oxidatively modified and dysfunctional in both AD and MCI is Pin1 a regulatory protein of
many functions relevant to neurodegeneration. One source of oxidative stress in AD is amyloid beta-peptide
(AP). The single methionine (Met) of Ap appears to be critical to the oxidative stress induced by Ap. Our
overall hypothesis is A(3-mediated oxidative modification of brain Pin1 is fundamental to the progression of
AD and occurs via mechanisms involving the single Met of AfJ. To test this overall hypothesis a series of
Specific Aims are proposed. In Specific Aim 1 oxidative stress indices and redox proteomics of preclinical
AD (PCAD) brain will be undertaken to test the hypothesis that Pin 1 is oxidatively modified and must be
important in the progression of AD. In Specific Aim 2 to determine the temporal role of toxic aggregated AP
in the in vivo oxidative modification of Pin 1 we will use redox proteomics to test the hypothesis that in
human mutant APP/PS-1 knock in mice oxidative modification and dysfunction of Pin1 will occur. In Specific
Aim 3 we will test the hypothesis that Pin 1 in neuronal cultures will be oxidatively dysfunctional by
aggregated toxic forms of Ap. In Specific Aim 4 we will test the hypothesis that in vivo elevation of Pin 1 will
result in decreased levels of phospho-tau and Ap in brain of APP/PS-1 mice. In Specific Aim 5 we will test
the hypothesis that mechanisms involving the single Met residue of Ap are paramount in the in vivo toxic
properties of Ap including the oxidative modification of Pin1. In each Aim correlation of the status of Ap
(type solubility oligomerization etc. determined by Core B) will be made. This proposal reflects a set of
comprehensive and integrated studies that utilizes a variety of novel methodologies and that takes
advantage of our expertise in oxidative stress Ap and redox proteomics applied to AD. Dr. K.P. Lu
(Harvard) an acknowledged leader in Pin 1 research will serve as a Senior Investigator and provide
additional expertise. New insights into the oxidative stress neurodegeneration and progression of AD are
envisaged as are insights into a potential treatment to slow or disrupt progression of MCI to AD.

project_terms:
Accounting;Affect;Affinity;Age-Months;Alanine;Alzheimer's Disease;Alzheimer's disease model;Amyloid beta-Protein;Amyloid beta-Protein Precursor;Autopsy;Binding (Molecular Function);Binding Sites;Biological Assay;Brain;Brain region;Caenorhabditis elegans;Cerebellum;Cerebral cortex;Cessation of life;Codon Nucleotides;Collaborations;Cysteine;Data;Dementia;Dependovirus;Deposition;Depressed mood;Digestion;Disease;Electrospray Ionization;Ensure;Environment;Event;Free Radicals;Functional disorder;Human;Hydrophobicity;In Vitro;Individual;Institutes;Isomerase;Knock-in Mouse;Laboratories;Lead;Length;Leucine;Lipid Peroxidation;Measures;Mediating;Mediator of activation protein;Methionine;Methodology;Methods;Microtubules;Modeling;Modification;Mus;Mutate;N-terminal;NADPH Oxidase;Nerve Degeneration;Neurofibrillary Tangles;Neurons;Norleucine;Oxidation-Reduction;Oxidative Stress;Pathogenesis;Pathology;Peptides;Peptidylprolyl Isomerase;Persons;Play;Positioning Attribute;Process;Production;Progress Reports;Proline;Property;Protein Binding;Protein Biosynthesis;Protein Dephosphorylation;Proteins;Proteomics;RNA;Recombinants;Research;Research Personnel;Role;Senile Plaques;Series;Serine;Side;Site;Small Interfering RNA;Solubility;Source;Specificity;Staging;Tauopathies;Testing;Therapeutic Intervention;Threonine;Time;Toxic effect;Transgenic Mice;Triose-Phosphate Isomerase;Western Blotting;Wild Type Mouse;aging brain;base;disorder control;genetic regulatory protein;human DNA;in vivo;in vivo Model;indexing;insight;knock-down;mild cognitive impairment;mind control;mutant;nervous system disorder;neurotoxic;neurotoxicity;novel;oxidation;oxidative damage;pre-clinical;protein aminoacid sequence;success;tandem mass spectrometry;tau Proteins;tau phosphorylation;therapeutic target


application_id: 8376709
project_number: 5P01AG005119-24
project_title: BETA AMYLOID-INDUCED RNA OXIDATION AS A MEDIATOR OF AD PATHOGENESIS
administering_ic: NIA
award_notice_date: 2012-03-19
application_type: 5
activity_code: P01
ic: AG
serial_number: 005119
project_end_date: 2014-03-31
study_section: ZAG1-ZIJ-4
subproject_number: 0009
contact_pi_person_id: 1894359
contact_pi: MARKESBERY, WILLIAM R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-04-01
budget_end_date: 2013-03-31
project_abstract:
Alzheimer's disease (AD) is one of the major health problems in the United States and as our population
ages it will become more prominent unless measures to treat or prevent it are found. Understanding the
pathogenesis of selective neuron degeneration in AD is the key to defining preventive or therapeutic
measures. There is a rapidly increasing body of knowledge that indicates free radical-mediated oxidative
damage is involved in the pathogenesis of AD. Our recent studies have demonstrated significant oxidative
damage to brain lipids proteins DMA and RNA in amnestic mild cognitive impairment the earliest
detectable phase of AD indicating that oxidative damage is an early event in AD and not secondary to
neurodegeneration. The major hypothesis of this proposal is that RNA oxidation in early AD is mediated in
part by amyloid-beta peptide (AP) that promotes impairment of protein synthesis and neuron dysfunction. In
Specific Aims 1 and 2 we will quantify RNA oxidation and aldehydic modifications in neurons in the
progression of AD from normal to MCI to late AD (LAD) and in the APP/PS1 knock-in transgenic mice over
time using immunohistochemistry confocal microscopy and antibodies against 8-OHG acrolein/guanine
adducts and MC-1. In the same brain regions of normal controls disease controls (frontotemporal
dementia) MCI and LAD and brain specimens from APP/PS-1 mice we will quantify RNA oxidation in
purified pools of rRNA tRNA and mRNA by GC-MS-SIM and acrolein-modified guanine in these pools using
LC-MS-MS. In Specific Aim 3 we will determine the ability of toxic and non-toxic Ap from Core B to define
RNA oxidation and acrolein/guanine adducts in cultured neurons and compare this with the RNA oxidation
observed in vivo in Specific Aims 1 and 2. In Specific Aim 4 we will determine if the individual mRNAs
oxidized in response to Ap in vitro are also oxidized in the brains of control subjects and MCI LAD and
frontotemporal dementia patients. We will then determine whether the predicted proteins encoded by the
oxidized mRNAs exhibit decreased expression and function in the progression from normal to MCI to LAD.
Specific Aim 5 will define the ability of histone deacetylase inhibitors to ameliorate Ap-induced neurotoxicity
in vitro and in the APP/PS1 transgenic mice. We have preliminary data in all specific aims indicating the
feasibility of these studies. By conducting these studies in an unbiased manner and allowing the neurons
and brain specimens to guide us we will define how Ap promotes neuron dysfunction in AD. This study has
the potential of identifying molecular targets for development of therapeutic agents aimed at reducing neuron
injury and slowing the progression of or potentially preventing AD.

project_terms:
APP-PS1;Acrolein;Affect;Age;Age-Months;Alzheimer's Disease;Amino Acid Substitution;Amyloid beta-Protein;Antibodies;Antioxidants;Attenuated;Autopsy;Brain;Brain region;Cerebellum;Cerebral cortex;Confocal Microscopy;DNA;Data;Deposition;Development;Enzymes;Event;Exhibits;Feasibility Studies;Free Radicals;Frontotemporal Dementia;Functional disorder;Guanine;Health;Hippocampus (Brain);Histone Deacetylase Inhibitor;Human;Immunohistochemistry;Impairment;In Vitro;Individual;Inferior;Injury;Ions;Knock-in Mouse;Knowledge;Link;Lipid Peroxidation;Lipids;Lobule;Manganese Superoxide Dismutase;Mass Fragmentography;Measures;Mediating;Mediator of activation protein;Messenger RNA;Methods;Mitochondria;Modification;Molecular Target;Monitor;Motor Cortex;Mus;Mutant Strains Mice;NADPH Oxidase;Nerve Degeneration;Neuronal Injury;Neurons;Nuclear;Oxidative Stress;Parietal;Pathogenesis;Pathology;Patients;Pattern;Peptides;Phase;Play;Population;Preventive;Property;Protein Biosynthesis;Proteins;RNA;Relative (related person);Ribosomal RNA;Rodent;Role;Rotenone;Secondary to;Selenomethionine;Specificity;Specimen;Staging;Structure of middle temporal gyrus;Study Section;Testing;Therapeutic;Therapeutic Agents;Time;Toxin;Transfer RNA;Transgenic Mice;Translations;United States;Wild Type Mouse;Yeasts;adduct;amyloidogenesis;base;biomarker;copper zinc superoxide dismutase;disorder control;enzyme activity;glutathione peroxidase;in vivo;in vivo Model;indexing;inhibitor/antagonist;male;mild cognitive impairment;mind control;mouse model;neurotoxicity;novel therapeutics;oxidation;oxidative DNA damage;oxidative damage;pre-clinical;prevent;programs;response;stressor;time use;usability


application_id: 8374647
project_number: 5P30NS051220-07
project_title: MOLECULAR MECHANISMS
administering_ic: NINDS
award_notice_date: 2012-02-15
opportunity_number: PAR-08-116
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: Neurological Sciences and Disorders A Study Section[NSD-A]
subproject_number: 7623
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-12-01
budget_end_date: 2012-11-30
project_abstract:
CORE E. Molecular Mechanisms Core Plans: This core represents an expansion of the role of the previous Pharmacokinetics & Biomarker Core into what we now will call a Molecular Mechanisms Core in order to better meet the needs of the SCoBIRC faculty and other neuroscience investigators who use the SCoBIRC Core Facilities. In its former role the core managed by Core Director Dr. Edward D. Hall and Assistant Core Director and Supervisor Dr. Jeff Bosken primarily employed GC-MS and HPLC technologies
for bioanalytical measurements of drugs and potential injury-related biomarker compounds in biofluids (e.g blood urine cerebrospinal fluid). However the core's scope was expanded very eariy during the current funding period to include equipment (LiCor Odyssey Infrared Image Analyzer) and expertise for highly sensitive analysis of immunoblots using infrared-emitting secondary anfibodies. This technology has been heavily employed by several SCoBIRC and other BBSRB neuroscience investigators. More recently the
core has added an Applied Biosystem StepOnePlus quantitative RT-PCR capability for gene expression analysis studies which is growing in use. However going forward we intend to add another functional component to the Core to support the large number of SCoBIRC and other neuroscience faculty who are studying changes in mitochondrial bioenergetics in in vitro and in vivo models of acute and chronic neurodegenerative disease models. The growing interest in mitochondrial functional studies across several
funded and pilot projects has made it desirable to centralize this capability into the core to insure methodological consistency and quality control and comparability of data across laboratories. We plan to provide this centralized capability by first of all shifting existing equipment used for mitochondrial preparation and bioenergetic analyses of ex vivo mitochondrial isolates into the core and secondly to add new Seahorse technology for highly sensitive imaging of mitochondrial bioenergetics and dysfunction and
whole cells in culture models.
Requested Molecular Mechanisms Core Equipment and Supplies: We are specifically requesting funding for purchase of the following. Note: all equipment quotes are listed in Appendix I
 Seahorse Bioscience XF96 Dual Analyte Extracellular Analyzer- Justification: This state of art technology is capable of detecting real time changes in up to 3 analytes of cellular metabolism in a non-destructive manner in both energy producing pathways. $171636
Molecular Mechanisms Core Usage: The following SCoBIRC and other neuroscience invesfigators who have and will continue to use the core include: Cambi Geddes Gerhardt Gash Guttman Hall Rabchevsky Saatman Smith Snow Springer Sullivan Zhang and Zhu.
Molecular Mechanisms Core Staffing: The Center Core Grant PI Dr. Edward D. Hall (5% effort) will confinue to serve as Core Director for the Molecular Mechanisms Core. Dr. Jeff Bosken (100% effort) will also continue to serve as Core Supervisor. He will also be specifically responsible for conduct and training in regards to the bioanalytical instrumentation (GC-MS HPLC) functional component. Dr. Indrapal Singh
(25% effort) a Research Assistant Professor who is highly expert in mitochondrial bioenergetic studies will be responsible for the mitochondrial bioenergetics component of the core in regards to equipment maintenance training and pilot study conduct. . He will be responsible for maintenance pilot studies and training of laboratory personnel in regards to the immunoblotting (western slot infra-red imaging) and quantitative RT-PCR gene expression functions of the core.

project_terms:
Acute;Bioenergetics;Blood;Cells;Center Core Grants;Cerebrospinal Fluid;Chronic;Core Facility;Data;Disease model;Drug Kinetics;Energy Metabolism;Equipment;Equipment and Supplies;Faculty;Functional disorder;Funding;Gases;Gene Expression;Genus Hippocampus;High Pressure Liquid Chromatography;Image;Immunoblot Analysis;In Vitro;Injury;Laboratories;Laboratory Personnel;Life;Liquid substance;Maintenance;Measurement;Metabolism;Mitochondria;Modeling;Molecular;Neurodegenerative Disorders;Neurosciences;Pathway interactions;Performance;Pharmaceutical Preparations;Pilot Projects;Preparation;Quality Control;Research;Research Personnel;Reverse Transcriptase Polymerase Chain Reaction;Role;Snow;Technology;Testing;Time;Training;Urine;Western Blotting;biomarker;extracellular;in vivo Model;instrumentation;interest;meetings;method development;professor;spinal cord and brain injury


