# projects

application_id: 7684130
project_number: 5R42EY017518-03
project_title: Targeting drug delivery nanoparticles to sites of inflammation
administering_ic: NEI
award_notice_date: 2009-07-10
opportunity_number: PA-07-281
application_type: 5
activity_code: R42
ic: EY
serial_number: 017518
program_official: WUJEK, JEROME R
project_start_date: 2006-07-01
project_end_date: 2009-10-31
study_section: Special Emphasis Panel[ZRG1-BDCN-F(12)B]
contact_pi_person_id: 1898524
contact_pi: KAPLAN, HENRY JERROLD
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 144375263
duns_number: 144375263
fips: US
organization_id: 10002039
organization_name: POTENTIA PHARMACEUTICALS, INC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
budget_end_date: 2009-10-31
project_abstract:
DESCRIPTION (provided by applicant): The purpose of this Phase II STTR project is to develop a nanoparticle-based drug delivery system for use in the treatment of dry age-related macular degeneration (AMD). AMD is the leading cause of blindness for individuals over fifty-five years of age that live in the industrialized world affecting approximately 10 million people in the US and as many as 30 million worldwide. There are two forms of the disease both of which cause a loss of central vision. Approximately fifteen percent have wet or exudative AMD which causes rapid disabling blindness. The remaining eighty-five percent of patients have dry AMD a less severe form that produces gradual vision loss. At present there are no approved pharmacological agents approved for the treatment of dry AMD. This project seeks study to develop a "smart" poly-lactic glycolic acid (PLGA) nanoparticle drug delivery system that can home to sites of inflammation after intravenous injection. Homing is achieved through a mechanism similar to one used by lymphocytes recognize regions of inflammation. Once there the particles will release a complement inhibitor over a sustained period time. A growing body of research links excessive complement activation with several diseases of aging including AMD. The prototype nanoparticle developed in Phase I is able to selectively bind activated endothelial cells in cell culture. In vivo studies further show that the nanoparticles are able to bind inflamed blood vessels in the eye. In vitro studies showed that they are also able to release a complement inhibitor for periods in excess of 60 days. PUBLIC HEALTH RELEVANCE This application is critically concerned with developing a drug product that can be used to treat nonexudative age-related macular degeneration. There are currently no approved treatments for this disorder making it a major the issue of public health. In the longer term the goal of this work is to develop drug products that can selectively target and treat sites of disease action particularly those associated inflammation and degenerative disease.

project_terms:
Acute;Address;Affect;Age;Age related macular degeneration;Age-Years;Aging;Amino Acids;Area;Binding (Molecular Function);Biocompatible;Biodistribution;Blindness;Blood Vessels;Bypass;Cell Culture Techniques;Chronic;Complement;Complement Activation;Complement Inactivators;Complex;Conjunctival Hemorrhage;Cyclic Peptides;Data;Degenerative Disorder;Development;Diagnosis;Disease;Disorder by Site;Drug Delivery Systems;Drug Formulations;Drug Kinetics;Encapsulated;Endophthalmitis;Endothelial Cells;Environmental Risk Factor;Exudative age-related macular degeneration;Eye;Eye diseases;FDA approved;Frequencies (time pattern);Genetic;Glycolates;Goals;Home environment;Homing;In Vitro;Individual;Inflammation;Inflammatory;Injection of therapeutic agent;Lead;Legal Blindness;Life;Ligands;Link;Lymphocyte;Nonexudative age-related macular degeneration;Oryctolagus cuniculus;Pain;Pathogenesis;Patients;Peptides;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Play;Process;Research;Risk;Role;Selectins;Site;Small Business Technology Transfer Research;Staging;System;Therapeutic Agents;Time;Toxic effect;Toxicology;Vision;Work;base;density;in vivo;intravenous injection;meetings;nanoparticle;particle;programs;prototype;public health medicine (field);public health relevance;sialyl Lewis x;trafficking;vitreous floater


application_id: 7682979
project_number: 5R42HL079855-03
project_title: New anti-complement therapy to reduce reperfusion injury: Phase II
administering_ic: NHLBI
award_notice_date: 2009-07-20
opportunity_number: PA-07-281
application_type: 5
activity_code: R42
ic: HL
serial_number: 079855
program_official: LIANG, ISABELLA Y
project_start_date: 2005-05-01
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZRG1-BST-Z(10)]
contact_pi_person_id: 2129782
contact_pi: MALDONADO, CLAUDIO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 144667602
primary_uei: TGWXNHCYTTR3
duns_number: 144667602
uei: TGWXNHCYTTR3
fips: US
organization_id: 10004330
organization_name: ENDOPROTECH, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402041019
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Tissue and organ transplantation procedures save and/or improve the lives of hundred of thousands of patients annually in the US. The goal of this research is to develop a local anti-complement therapy for donor organ ex vivo application that will reduce complement-induced injury to the vascular endothelium. An unavoidable consequence of transplantation (allografts or autografts) is ischemia/reperfusion (IR) injury. Studies have shown that IR-induced complement activation leads to the formation of several key inflammatory mediators that alter vascular homeostasis and stimulate leukocyte activation and chemotaxis. After decades of neglect complement has been rediscovered as a potent mediator of inflammation and rejection in organ transplants. In Phase I of this proposal we successfully provided proof-of-concept that our novel therapy reduced complement deposition in vitro after activation of the classical pathway. Our therapy is based on a platform technology that allows the rapid display of protective exogenous proteins on the surface of cells during organ harvest. The goal in Phase II is to prepare the technology for clinical use. This will be accomplished by developing safe and stable lyophilized components which upon reconstitution are perfused into organs ex vivo to effectively reduce locally complement mediated injury in vivo. The technical objectives are: 1) Reduce cost of therapeutic formulations by using the most economical components without compromising anti-complement efficacy. 2) Determine potential toxicity of therapy and demonstrate its efficacy in a kidney rat model of IR. 3) Develop stable lyophilized therapeutic components for storage and demonstrate in vitro that reconstituted components are just as effective as freshly prepared components. 4) Demonstrate in kidney rat models of IR and transplantation that lyophilized products are effective in reducing antigen-independent and antigent-dependent IR injury. If successful these studies will demonstrate the potential clinical value of our therapy in enhancing natural anti-complement defenses in allografts. Our therapy will be applied during routine flushes of donor organs and will achieve therapeutic levels of drug locally without systemic adverse effects. Application of our therapy may extend the donor pool by allowing organ harvest from non-beating heart donors. Our approach is a faster alternative to gene therapy in that proteins can be displayed on the cell membranes in less than 1 hour. The economic implications for this novel therapeutic approach in transplantation are vast not only in terms of the potential benefits to patients but also in reducing health care costs associated with re-operations and complications arising from failed procedures.  
  
Public Health Relevance: The goal of this project is to develop a new targeted therapy that prevents damage to transplanted organs. An unavoidable inherent problem of transplantation is that blood flow during organ harvest must be cutoff and later reestablished during implantation. This process causes the activation of the immune component called the complement system which causes unintended tissue injury that ultimately leads to organ malfunction and failure. Anti-complement agents that are administered systemically have been developed but their use leaves transplant recipients vulnerable to viral and bacterial infections. EndoProtech Inc. is proposing to develop a novel safer anti-complement therapeutic agent that binds to cells of transplanted organs and eliminates systemic circulation of the agent. The therapy is applied during harvest while organs are outside the body before implantation. The objective is to protect tissues from complement-related injury with minimal side effects.

project_terms:
Adverse effects;Allografting;American;Antigens;Autologous Transplantation;Bacterial Infections;Binding (Molecular Function);Blood Circulation;Blood Vessels;Blood flow;Carcinogens;Cell Adhesion Molecules;Cell Transplants;Cell membrane;Cell surface;Cells;Chemotaxis;Clinical;Combined Modality Therapy;Complement;Complement Activation;Coupled;Coupling;Cultured Cells;Deposition;Drug Formulations;Edema;Effectiveness;Endothelial Cells;Extravasation;Failure (biologic function);Flushing;Functional disorder;Goals;Harvest;Health Care Costs;Heart;Homeostasis;Hour;Immune;In Vitro;Incubated;Inflammation;Inflammation Mediators;Inflammatory Response;Injury;Ischemia;Kidney;Left;Life;Lipids;Mediating;Membrane;Metals;Modeling;Operative Surgical Procedures;Organ;Organ Donor;Organ Harvestings;Organ Transplantation;Pathway interactions;Patients;Perfusion;Pharmaceutical Preparations;Phase;Phase II Clinical Trials;Plasma;Procedures;Process;Proteins;Rattus;Reactive Oxygen Species;Reperfusion Injury;Reperfusion Therapy;Research;System;Technology;Testing;Therapeutic;Therapeutic Agents;Time;Tissue Transplantation;Tissues;Toxic effect;Transplant Recipients;Transplantation;Treatment Efficacy;Vaccinia virus complement-control protein;Vascular Endothelium;Vesicle;Viral;Virus;analog;base;cell injury;commercialization;cost;economic implication;gene therapy;genetic regulatory protein;implantation;improved;in vivo;interstitial;leukocyte activation;neglect;new therapeutic target;novel;novel therapeutic intervention;pre-clinical;prevent;public health relevance;reconstitution


application_id: 7682926
project_number: 5R44HL090055-03
project_title: Development of a Personalized Medicine Interface for the Safe and Effective Treat
administering_ic: NHLBI
award_notice_date: 2009-08-13
opportunity_number: PA-07-280
application_type: 5
activity_code: R44
ic: HL
serial_number: 090055
program_official: LINK, REBECCA P
project_start_date: 2007-08-16
project_end_date: 2010-08-31
study_section: Special Emphasis Panel[ZRG1-GGG-J(10)B]
contact_pi_person_id: 8776872
contact_pi: REYNOLDS, KRISTEN KEELING
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 135412190
duns_number: 135412190
fips: US
organization_id: 10011008
organization_name: PHARMACOGENETICS DIAGNOSTIC LABORATORIES
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-08-01
budget_end_date: 2010-08-31
project_abstract:
DESCRIPTION (provided by applicant):  Warfarin is the most commonly used oral anticoagulant medication. Because an individual's proper warfarin dose is difficult to assess most physicians initiate therapy at a standard dose and follow up with an INR blood test to ensure the medicine is working properly. Unfortunately therapeutic warfarin doses vary significantly from patient to patient so that even a standard dose can cause life-threatening hemorrhaging. Genetic and non-genetic factors both influence an individual's warfarin dose requirement and response characteristics and although the importance of pharmacogenetics to warfarin therapy is understood clear guidance for how such information should be applied to patient therapy is woefully absent. The Personalized Medicine Interface (PerMIT) software utility supplies this critical guidance by modeling the dose requirements and response characteristics of individual patients based on their genotypic and physical characteristics. Using state-of-the-art multivariate computations PerMIT conveniently calculates a warfarin maintenance dose estimate and models the influence of repeated dosing on plasma drug concentration. PerMIT provides guidance during the transition from induction to maintenance therapy and limits the potential for misinterpretation of INR measurements by clearly displaying the relationship of the dosing regimen to the progress toward steady-state. The specific aim of Phase I was to develop a computational model that estimates the most appropriate warfarin maintenance dose for an individual accurately estimates the plasma concentration of S-warfarin following each warfarin dose and provides a visual estimate of the time to reach steady state. PGXL Laboratories has accomplished this specific aim with the creation of the graphical patient care interface PerMIT. The specific aim of Phase II is to demonstrate the power of PerMIT in guiding superior clinical management of patients taking warfarin. Three technical objectives will demonstrate that the software functions as intended that it is user friendly and that it is clinically effective: (1) Validate the analytical accuracy of computational algorithms which drive the PerMIT module; (2) Drive design improvements through Usability Testing; (3) Measure the clinical value of PerMIT in a prospective trial of PerMIT-guided therapy versus standard of care. Completion of the above-stated objectives will: (1) confirm that the computational basis of PerMIT is consistent with the state-of-the-art in warfarin dose estimation and plasma concentration modeling (2) assure the highest quality user interface based on a validated approach to Usability Testing and (3) demonstrate the utility of PerMIT for improved efficiency of patient care.  PUBLIC HEALTH RELEVANCE:  Warfarin is the most commonly prescribed oral anticoagulant but managing patients on warfarin is difficult due to variability in patients' response to the medication; indeed adverse reactions to warfarin are second only to insulin in frequency. Inherited differences account for approximately 40% of the variability in warfarin dose response between individuals but clinicians thus far have had no clear and easy methods or tools to help them understand and account for this variability when directing patient therapy. PerMIT:Warfarin provides muchneeded guidance to clinicians throughout the course of warfarin therapy and limits the potential for misinterpretation of blood test results (INR measurements) by clearly displaying the relationship between a patient's dosing regimen and their progress toward stable therapy.

project_terms:
Accident and Emergency department;Accounting;Adverse reactions;Age;Anticoagulants;Arts;Awareness;Blood Clot;Blood Tests;Blood coagulation;CYP2C9 gene;Characteristics;Clinical;Clinical Management;Computational algorithm;Computer Simulation;Computer software;Data;Development;Dose;Drug usage;Ensure;Event;Frequencies (time pattern);Gender;Genetic;Genotype;Hemorrhage;Hospital Costs;Individual;Inherited;Insulin;Label;Laboratories;Life;Maintenance;Maintenance Therapy;Measurement;Measures;Medicine;Methods;Modeling;Oral;Patient Care;Patient Care Management;Patients;Pharmaceutical Preparations;Pharmacogenetics;Phase;Physicians;Plasma;Risk;Small Business Innovation Research Grant;Test Result;Testing;Therapeutic;Time;Translating;Treatment Protocols;Update;Validation;Visit;Visual;Waran;Warfarin;Warfarin Sodium;Weight;Work;base;clinically relevant;design;dosage;follow-up;improved;non-genetic;prospective;public health relevance;response;standard of care;stroke;tool;usability;user-friendly


application_id: 7682850
project_number: 5R21AG032550-03
project_title: Effect of Antioxidants & Behavioral Enrichment on Gene Expression in Aged Canines
administering_ic: NIA
award_notice_date: 2009-08-17
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: AG
serial_number: 032550
program_official: WAGSTER, MOLLY V
project_start_date: 2008-09-01
project_end_date: 2010-08-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
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:
DESCRIPTION (provided by applicant): During aging there are a number of brain changes that may contribute to neuronal dysfunction and impaired cognition. Higher animal models are essential for understanding the molecular and cellular basis of brain aging. We have been using the aged canine (dog) model to identify key interventions and molecular mechanisms of brain aging. Age-dependent decline in memory and learning along with the progressive accumulation of oxidative damage neuron loss and 2-amyloid (A2) deposition occur in the aging dog brain similar to that in the human. Canine A2 is identical to human A2 accumulates endogenously at levels similar to human and A2 plaque loads are correlated with cognitive function. Thus this model system is useful for exploring links between aging oxidative damage A2 and cognition. We have used a dietary and an environmental enrichment intervention to determine if these can improve cognitive function singly and in combination. We have demonstrated that an antioxidant and mitochondrial co-factor dietary intervention improves learning and maintains cognitive function over a 2.8 year period of time in aged dogs. Along with improved learning we observe decreased A2 in antioxidant treated dogs and decreased oxidative damage using proteomics approaches. We have further shown that behavioral enrichment can also improve cognition but this occurs via a non- A2/plaque mechanism as A2 seems unaffected. Importantly beneficial cognitive effects of the antioxidant diet or behavioral enrichment treatments alone were further enhanced when combined. At present the molecular targets of each treatment and convergence points between the two treatments that lead to additive neuronal function improvements have yet to be established. The primary objective of this application is to take advantage of newly available technologies (Affymetrix Canine Genome Arrays) and utilize brain tissues from these same animals to further establish and map the neurobiological mechanisms underlying the cognitive improving effects of each treatment and the combined treatment. To accomplish these objectives the following aims are proposed: (1) To profile gene expression changes in the temporoparietal cortex as a function of age in dogs and; (2) To profile gene expression changes in aged dogs provided with either or both an antioxidant-enriched diet and behavioral enrichment. Further understanding of the pathways engaged by these two interventions may lead to new research hypotheses treatments and outcome measures that may be directly translated to human clinical trials. PUBLIC HEALTH RELEVANCE: Profiling gene expression changes as a consequence of antioxidant diet and behavioral enrichment interventions in aged canines will allow us to identify and optimize new therapeutics for improving cognition in both normal aging individuals and those with Alzheimer's disease.

project_terms:
Age;Aging;Aging-Related Process;Alzheimer's Disease;Amyloid;Amyloid beta-Protein;Amyloid beta-Protein Precursor;Amyloid deposition;Animal Model;Animals;Antioxidants;Apoptosis;Archives;Area;Base of the Brain;Behavioral;Bioinformatics;Biological Models;Brain;Canis familiaris;Carnitine;Categories;Clinic;Clinical Trials;Cognition;Cognitive;Combined Modality Therapy;Computer software;Data;Data Analyses;Deposition;Detection;Diet;Dietary Intervention;Dietary Supplementation;Dose;Down-Regulation;Employee Strikes;Exercise;Experimental Designs;Freezing;Funding;Future;Gene Expression;Genes;Genome;Growth Factor;Hippocampus (Brain);Human;Human Genome;Impaired cognition;Individual;Inflammation;Intervention;Intervention Studies;Laboratories;Lead;Learning;Link;Lipids;Maintenance;Maps;Measures;Memory;Metabolism;Mitochondria;Modeling;Molecular;Molecular Target;Nature;Nerve Degeneration;Neurobiology;Neuronal Dysfunction;Neuronal Plasticity;Neurons;Outcome Measure;Overlapping Genes;Pathology;Pathway interactions;Pattern;Process;Protein Precursors;Proteins;Proteomics;RNA;Reagent;Research;Reverse Transcriptase Polymerase Chain Reaction;Senile Plaques;Signal Transduction;Synaptic plasticity;Technology;Testing;Thioctic Acid;Time;Tissue Sample;Tissues;Translating;Treatment outcome;Up-Regulation (Physiology);Vitamin E;abeta accumulation;age related;aged;aging brain;base;beta amyloid pathology;brain tissue;cognitive function;cognitive training;combinatorial;environmental enrichment for laboratory animals;experience;feeding;fruits and vegetables;functional improvement;functional outcomes;improved;innovation;juvenile animal;neurobiological mechanism;neurogenesis;neuron loss;neuropathology;normal aging;novel therapeutics;oxidative damage;public health relevance;research study;response;social;treatment effect


application_id: 7681363
project_number: 3U01CA114622-04S2
project_title: Appalachia Community Cancer Network
administering_ic: NCI
award_notice_date: 2008-09-10
opportunity_number: RFA-CA-05-012
application_type: 3
activity_code: U01
ic: CA
serial_number: 114622
suffix: S2
program_official: OGUNBIYI, PETER
project_start_date: 2005-05-06
project_end_date: 2010-04-30
study_section: ZCA1-SRRB-Y(J1)
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  
A multidisciplinary team of collaborators from academic institutions and communities in Appalachian regions of Kentucky West Virginia Ohio Pennsylvania New York Maryland and Virginia are proposing to build on a strong foundation of previous activity of the Appalachia Cancer Network (ACN) an NCI-funded Special Populations Network and develop the Appalachia Community Cancer Network (ACCN).  The proposed ACCN will expand the previous ACN and expand to address cancer health disparities in seven areas in Appalachia areas that include some of the most medically underserved distressed and economically disadvantaged areas in the US. Cancer mortality rates are elevated in each of these areas as are the incidence rates for lung cervical and colorectal cancers suggesting that factors such as late stage diagnosis and barriers to cancer care must be addressed if disparities are to be reduced.  The long-term goal of the ACCN is to contribute to the reduction of cancer health disparities in Appalachia by developing implementing and evaluating community-based participatory research and providing training.  The specific aims of the AACN are to:  1) Build on a foundation established by the ACCN and develop and maintain community partnerships to facilitate research and action to reduce cancer health disparities; 2) Conduct community based participatory research ranging from focused needs assessments to intervention research to policy assessments; 3) Develop pilot research projects that focus on primary and secondary prevention of lung cervical and colorectal cancers in Appalachia; 4) Train researchers in community-based participatory research; and 5) Conduct evaluation of the ACCN including attention to processes short term impact and achievement of outcomes.  The ACCN will build on the ACN and develop programs in cancer education; community based participatory research and training.  Proposals for two pilot projects are also included. The pilot projects address cervical and colorectal cancer two cancers targeted by the ACCN

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


application_id: 7680746
project_number: 7R03HD049408-03
project_title: Driving neuroplasticity with nerve stimulation and modified CIT
administering_ic: NICHD
award_notice_date: 2008-09-04
opportunity_number: PA-03-108
application_type: 7
activity_code: R03
ic: HD
serial_number: 049408
program_official: NITKIN, RALPH M
project_start_date: 2006-04-01
project_end_date: 2010-02-28
study_section: Function, Integration, and Rehabilitation Sciences Study Section[CHHD-K]
contact_pi_person_id: 7375465
contact_pi: SAWAKI, LUMY
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Stroke is one the most devastating and prevalent diseases but efforts to limit the amount of tissue damaged in the acute phase have been disappointing highlighting the need for effective therapeutic interventions after neurological damage has occurred. A major goal of the research in stroke rehabilitation is to harness the capacity of the brain to reorganize after neurological damage has occurred and thus ultimately lead to successful recovery of function. Data from animal and human models have suggested that sensory input plays an important role in motor output possibly by influencing cortical plasticity. However in spite of the advances to date little is known about the extent to which sensory input in the form of peripheral nerve stimulation can be successfully combined to physical training. A new emerging approach called constraint induced therapy (CIT) is an intensive functional motor training and has produced promising results in the field of stroke rehabilitation. CIT involves restraining the unaffected arm with a sling or glove combined with intense task-oriented therapy of the affected side for six hours daily during 2 weeks. This pilot study will evaluate the effectiveness of sustained peripheral nerve stimulation coupled with functional motor training to improve hand motor function. While the functional motor training follows identical principles of CIT the length of daily training will be shortened to 4 hours daily and thus the PIs will refer to it in this proposal as a modified CIT. Preliminary data for this study demonstrated that peripheral nerve stimulation results in increased cortical motor excitability in normal subjects. In addition learning and use-dependent plasticity can be substantially enhanced by a single session of 2 hours of peripheral nerve stimulation in chronic stroke patients. The goal of this study is to test the hypothesis that stroke patients treated with upper extremity peripheral nerve stimulation preceding CIT (intervention group) will have improved hand motor function compared to a group receiving lower extremity peripheral nerve stimulation and CIT (control group). The PIs also expect that the degree of motor functional improvement will correlate with the increase of cortical motor map measured by transcranial magnetic stimulation. The long-range goals are: (a) to maximize the restoration of hand motor function after stroke and (b) to determine the impact of this intervention in activities of daily living and quality of life.

project_terms:
Activities of Daily Living;Acute;Adult;Affect;Animals;Brain;Clinical;Complex;Control Groups;Controlled Clinical Trials Randomized;Coupled;Daily;Data;Denervation;Disease;Driving neuroplasticity;Effectiveness;Goals;Hand;Hour;Human;Intervention;Lead;Learning;Leg;Length;Limb structure;Lower Extremity;Magnetic Resonance Imaging Functional;Maps;Measures;Modeling;Modification;Motor;Motor Activity;Motor Cortex;Motor Skills;Motor output;Muscle;Nerve;Nerve Block;Neurologic;Neuronal Plasticity;Neurons;Patients;Performance;Peripheral;Peripheral Nerve Stimulation;Phase;Pilot Projects;Plastics;Play;Property;Quality of life;Range;Recovery of Function;Rehabilitation therapy;Research;Role;Science of neurophysiology;Score;Sensory;Side;Synapses;System;Testing;Therapeutic Effect;Therapeutic Intervention;Thinking function;Tissues;Training;Transcranial magnetic stimulation;Trauma Nervous System;Upper Extremity;Upper arm;Week;animal data;axonal sprouting;chronic stroke;constraint induced therapy;experience;functional improvement;improved;memory process;restoration;sensory cortex;skill acquisition;stroke;stroke rehabilitation


application_id: 7679538
project_number: 5R43AI074176-02
project_title: ApoVax104-TB as a Novel Vaccine for Tuberculosis
administering_ic: NIAID
award_notice_date: 2009-09-04
opportunity_number: PA-06-135
application_type: 5
activity_code: R43
ic: AI
serial_number: 074176
program_official: JACOBS, GAIL G
project_start_date: 2008-09-01
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZRG1-IMM-K(12)B]
contact_pi_person_id: 8392573
contact_pi: MACLEOD, KATHRYN J
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 140646345
duns_number: 140646345
fips: US
organization_id: 4350801
organization_name: APOVAX, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-09-01
budget_end_date: 2011-08-31
project_abstract:
DESCRIPTION (provided by applicant): The objective of this NIAID Advanced STTR Phase I proposal is to combine the strengths of academic investigators from the fields of immunology and animal disease modeling with the resources of ApoImmune Inc. to develop a novel vaccine ApoVax104-TB" targeting both active and latent Tuberculosis (TB) infections. ApoVax104-TB" uses a novel proprietary vaccine based on ApoImmune's chimeric protein consisting of streptavidin and the costimulatory ligand 4-1BBL conjugated with known Mycobacterium tuberculosis T-cell antigens. This vaccine concept bears significant potential as a preventive and therapeutic vaccine against TB since the 4-1BBL component of the vaccine has been shown to induce adaptive (CD4+ and CD8+ T cell responses) and innate (dendritic cells macrophages and NK cells) immunity and overcome various immune evasion mechanisms (CD4+CD25+FoxP3+ Treg cells and clonal anergy). This application proposes to develop a subunit vaccine against TB based on a triple antigen strategy consisting of recombinant Ag85B ESAT-6 and Mpt83 TB proteins. Ag85B and ESAT-6 are expressed by actively growing bacteria and Mpt83 is expressed in non-dividing bacteria thereby targeting both subpopulations in the lung. These antigens will be biotinylated and conjugated to chimeric 4-1BBL via biotin- streptavidin interaction and delivered in vivo specifically to dendritic cells constitutively expressing the 4-1BB receptor. The underlying hypothesis is that 4-1BBL interaction with 4-1BB on dendritic cells will activate these cells for antigen uptake processing and presentation to T cells thereby generating potent adaptive immunity. At a second stage 4-1BBL may directly work on activated CD4+ and CD8+ T cells with upregulated 4-1BB receptor to expand these cells and augment the memory response. At a third stage 4-1BBL may overcome various immune evasion mechanisms such as clonal anergy and CD4+CD25+FoxP3+ Treg cells implicated in persistent TB. These combined effects are expected to result in protective as well as therapeutic effects against TB. This hypothesis is supported by our strong preliminary data demonstrating better efficacy of ApoVax104 than two bench-mark adjuvants Monophosphoryl Lipid A and CpG as components of a therapeutic vaccine against cervical cancer. The efficacy of ApoVax104-TBTM will be tested in preventive and therapeutic settings of TB in an animal model. If proven effective these studies will be followed by a Phase II STTR application to further develop the vaccine for testing in a Phase I clinical trail. The development of a vaccine against TB will have tremendous societal benefits as well as target a global market in the billions of dollars. PUBLIC HEALTH RELEVANCE: This project will establish the necessary fundamental parameters to develop a novel vaccine against tuberculosis (TB). Using ApoImmune's lead vaccine ApoVax104" we will develop a vaccine that will suppress the spread of TB by acting as a preventative as well as a therapeutic vaccine. ApoImmune's novel immunotherapy ApoVax104 TM vaccine is a new innovative approach to treating infectious diseases.

project_terms:
Adjuvant;Animal Disease Models;Animal Model;Antigen Presentation;Antigen Targeting;Antigen-Presenting Cells;Antigens;Bacteria;Binding (Molecular Function);Biotin;C57BL/6 Mouse;CD8B1 gene;Cells;Chimeric Proteins;Chronic;Clinical;Clonal Anergy;Communicable Diseases;Data;Dendritic Cells;Development;Dose;Down-Regulation;Drug Formulations;Effector Cell;Extracellular Domain;Figs - dietary;Generations;Head;Histocompatibility Antigens;Immune;Immune response;Immune system;Immunity;Immunology;Immunotherapy;Infection;Knockout Mice;Lead;Ligands;Lipopolysaccharides;Lung;Malignant neoplasm of cervix uteri;Marketing;Memory;Modeling;Mus;Mycobacterium tuberculosis;N-terminal;National Institute of Allergy and Infectious Disease;Natural Killer Cells;Phase;Preventive;Process;Protein Biochemistry;Proteins;Published Comment;Recombinants;Research Personnel;Resources;Signal Transduction;Small Business Technology Transfer Research;Staging;Streptavidin;Structure;Subunit Vaccines;T-Cell Proliferation;T-Lymphocyte;Techniques;Testing;Therapeutic;Therapeutic Effect;Treatment Efficacy;Tuberculosis;Tuberculosis Vaccines;Up-Regulation (Physiology);Upper arm;Ursidae Family;Vaccinated;Vaccination;Vaccines;Work;base;chemokine;clinical application;crosslink;cytokine;cytotoxicity;design;in vivo;innovation;interest;macrophage;monophosphoryl lipid A;mouse model;novel;novel vaccines;prevent;prophylactic;public health relevance;receptor;response;therapeutic vaccine;tumor;uptake;vaccine development;vaccine efficacy;vaccine evaluation


application_id: 7679402
project_number: 5R03OH008957-02
project_title: Safety and Injury Among Teens Enrolled in School-To-Work Apprentice Programs.
administering_ic: NIOSH
award_notice_date: 2009-07-06
opportunity_number: PAR-06-551
application_type: 5
activity_code: R03
ic: OH
serial_number: 008957
program_official: FREDERICK, LINDA J
project_start_date: 2008-09-01
project_end_date: 2011-08-31
study_section: Safety and Occupational Health Study Section[SOH]
contact_pi_person_id: 8476117
contact_pi: ZIEROLD, KRISTINA MARIE
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The School-To-Work Opportunities Act (STWOA) was passed in 1994 to support high school youth throughout the nation's public schools in transitioning from school to career-focused work. The Act created a work-based learning program that was modeled after the concept of an apprenticeship which would integrate school-based instruction with structured on-the-job training. Although federal funding for the STW program ended in 2001 many states continue to provide STW program activities for high school students. A report from the United States Department of Education showed that 71.8% of public high schools with 12th grades offered work-based learning programs for credit and 60% offered job shadowing opportunities. Since the inception of the Act limited research has been conducted to assess STW programs. To date no studies have investigated work- related injury and occupational safety and health training among students enrolled in work-based learning programs. The proposed study by a new investigator will generate information related to the safety and health of students involved in work-based learning programs. To document the occurrence of injury among students in STW programs data from the Wisconsin State Survey of Youth will be used to accomplish three specific aims: 1. Determine the prevalence severity and types of injury that students enrolled in STW programs are sustaining on the job and determine if the prevalence differs by gender age race/ethnicity and job tasks. 2. Delineate whether STW students have fewer injuries compared with other working students and determine if the findings differ based on the hours worked during the day the total number of hours worked per week and the job tasks completed. 3. Determine if students enrolled in the STW program are less likely to report being injured and less likely to have "near-miss" incidents compared to other working students who reported receiving OSH training. While there is a large body of information about safety training and injury in adult workers very little is known about safety training and injury in young workers and none at all in students enrolled in work-based learning programs. The questionnaire data to be analyzed in the proposed study presents the most detailed data available on: work-based learning programs injuries among the students enrolled in these programs and safety training and behavioral characteristics among the enrolled students. This proposed project offers the first opportunity to evaluate the occupational safety and health among work-based learning students and compare it to other working students.  Injury among working youth is a major public health problem. Many high school students participate in a School-to-Work program which combines school-based learning with on-the-job mentoring. Nothing is known about the occurrence and severity of injury among students enrolled in the program. This study will be the first to address the occurrence of injury among students enrolled in school-to-work programs.


application_id: 7679132
project_number: 5R01DA013519-09
project_title: Development of Novel Therapies or Methamphetamine Abuse
administering_ic: NIDA
award_notice_date: 2009-08-24
application_type: 5
activity_code: R01
ic: DA
serial_number: 013519
program_official: APPEL, NATHAN M
project_start_date: 2000-08-15
project_end_date: 2012-08-31
study_section: Medication Development Research Study Section[NIDA-L]
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
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
budget_start_date: 2009-09-01
project_abstract:
DESCRIPTION (provided by applicant):  Methamphetamine (METH) abuse continues to escalate and effective treatments are not yet available. METH interacts with the vesicular monoamine transporter (VMAT2) promoting both dopamine (DA) release into the cytosol and reversal of the DA transporter (DAT) to increase extracellular DA concentrations which is thought to be associated with its abuse liability. Importantly progress on the current project has shown that alpha-lobeline (LOB) has high affinity for the [3H]dihydrotetrabenazine binding site on VMAT2 and potently inhibits [3H]DA uptake into synaptic vesicles. We have also shown that LOB inhibits METH-evoked DA release in vitro and METH self-administration in rats. Thus LOB has potential as a new therapeutic agent for the treatment of METH abuse and has recently successfully completed Phase 1 a clinical trials. However LOB has been shown to interact with many different CMS targets (i.e. it is a relatively nonselective or "dirty" drug) including alpha4beta2* alpha6abeta2* and alpha3beta4* nicotinic acetylcholine receptors. In the current proposal we aim to develop LOB analogs with high affinity and selectivity for VMAT2 which we believe will have increased benefits over LOB as therapeutic candidates for the treatment of METH abuse. We chose VMAT2 as the target as it is a key point of regulation in DA synaptic transmission due to the high affinity of LOB for VMAT2 and due to METH's interaction with VMAT2 which results in increased extracellular DA that is associated with its reward and abuse. Thus our hypothesis focuses on VMAT2 as a novel therapeutic target for the treatment of METH abuse. Development of selective high affinity VMAT2 inhibitors will allow us to test the hypothesis that selective inhibition of VMAT2 decreases METH reward. We have identified lobelane as our lead compound due to its high affinity and relative selectivity for VMAT2 its ability to inhibit METH-evoked DA release and its ability to decrease METH self-administration. Thus the long-term goal of this research is to develop novel lobelane analogs as treatments for METH abuse pioneering the development of a novel class of therapeutic agents that selectively target VMAT2 and have potential as efficacious treatments for METH abuse.

project_terms:
3-Dimensional;Affinity;Binding (Molecular Function);Binding Sites;Biological Assay;Characteristics;Clinical Trials;Corpus striatum structure;Cytosol;Development;Dopamine;Dose;Drug Kinetics;Electronics;Evaluation;Exhibits;Goals;In Vitro;Kinetics;Lead;Length;Link;Lobeline;Metabolism;Methamphetamine;Modeling;Modification;Molecular Conformation;Molecular Models;Nicotinic Receptors;Pharmaceutical Preparations;Pharmacodynamics;Phase;Property;Rattus;Regulation;Relative (related person);Research;Research Personnel;Rewards;Self Administration;Series;Site;Slice;Specificity;Sucrose;Synaptic Transmission;Synaptic Vesicles;System;Testing;Therapeutic;Therapeutic Agents;Time;Vesicle;analog;comparative efficacy;dihydrotetrabenazine;dopamine transporter;effective therapy;extracellular;flexibility;inhibitor/antagonist;lipophilicity;methamphetamine abuse;methyllycaconitine;molecular modeling;new therapeutic target;novel;novel therapeutics;pharmacophore;piperidine;presynaptic;programs;stereochemistry;uptake;vesicular monoamine transporter


application_id: 7679055
project_number: 5R21AG031876-02
project_title: Aberrant Protein Complexes in CSF as Biomarkers of Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2009-08-05
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: AG
serial_number: 031876
program_official: HSIAO, JOHN
project_start_date: 2008-09-01
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZRG1-CND-E(90)S]
contact_pi_person_id: 2276639
contact_pi: LOVELL, MARK ANTHONY
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 major barriers to preventing or treating Alzheimer's disease (AD) are its unknown pathogenesis/etiology and the lack of a sufficiently sensitive and specific objective biomarker of the disease particularly at the early stages when therapeutic interventions would likely have the greatest efficacy. The basic hypothesis of this proposal is that levels of a novel protein-protein complex present in cerebrospinal fluid (CSF) are able to differentiate AD subjects from age-matched controls and subjects with non-AD neurologic disorders. In addition the biomarker complex appears to identify subjects with mild cognitive impairment (MCI) the earliest clinical manifestation of AD. Analysis of lumbar CSF from a small number of living probable AD and age-matched controls showed 100% sensitivity and 93% specificity in the identification of AD subjects. The proposed studies will enhance our understanding of the way in which the protein complex is generated and will further validate our initial findings by: 1) quantifying levels of the protein-protein complex in small volumes of ventricular CSF from autopsy-verified subjects with non-AD pathologies MCI LAD and age-matched control subjects using an enzyme linked immunoassay developed in our laboratory based on the trapping one component of the complex and quantifying the other component ; 2) quantifying levels of the protein-protein complex in lumbar CSF from living probable AD and age-matched control subjects using the ELISA and 3) using sequential immunoprecipitation SDS-PAGE and mass spectrometry to examine individual components of the protein complex in ventricular CSF from MCI LAD and age-matched control subjects. Together these studies will provide further validation of our preliminary findings and will provide support for wide scale testing of the protein-protein complex as a biomarker of AD and MCI. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the fourth leading cause of death in the United States and currently affects 4.5 million Americans. Two major barriers to treating and eventually preventing AD are: 1) the lack of understanding of the process of neuron degeneration and loss and 2) the lack of a sufficiently sensitive and specific biomarker of the disease. Preliminary and future studies described in this proposal show that a novel protein-protein complex present in cerebrospinal fluid can be quantified using an enzyme linked immunoassay (ELISA) and that this protein-protein complex is a sensitive and specific biomarker of AD including early stages of AD (mild cognitive impairment) when therapeutic interventions are most likely to have beneficial effects.

project_terms:
Affect;Age;Alzheimer disease prevention;Alzheimer's Disease;American;Amyloid;Amyloid beta-Protein Precursor;Antibodies;Apolipoprotein E;Autopsy;Binding Proteins;Biological Assay;Buffers;Cause of Death;Cerebrospinal Fluid;Chemicals;Clinic;Clinical;Cognitive;Communities;Complex;Coupled;Data;Dementia;Diagnosis;Diagnostic;Diagnostic Procedure;Diagnostic Sensitivity;Disease;Disease Progression;Early Diagnosis;Effectiveness;Electrophoresis;Enzyme Immunoassay;Enzymes;Etiology;Fractionation;Frontotemporal Dementia;Future;Gel;Genotype;Immunoassay;Immunoprecipitation;Individual;Intervention;Interview;Laboratories;Legal patent;Lewy Body Disease;Life;Link;Literature;Location;Mass Spectrum Analysis;Measures;Memory Disorders;Memory Loss;Modification;Molecular Weight;Nature;Nerve Degeneration;Pathogenesis;Pathologic;Pathology;Phase;Plasma;Population;Post-Translational Protein Processing;Prealbumin;Primary Health Care;Process;Progressive Supranuclear Palsy;Prostaglandins;Proteins;Research;Retinol Binding Proteins;Sampling;Senile Plaques;Sensitivity and Specificity;Series;Serotransferrin;Specificity;Specimen;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Staging;Staining method;Stains;Structure;Testing;Therapeutic Intervention;Time;United States;Validation;Ventricular;Western Blotting;base;beta-2 Microglobulin;biomarker;carbonate dehydratase;clinical Diagnosis;cognitive function;copper zinc superoxide dismutase;evidence base;improved;interest;liquid chromatography mass spectrometry;mental state;mild cognitive impairment;nervous system disorder;neurofibrillary tangle formation;neuroimaging;neuropathology;neuropsychological;novel;novel diagnostics;post gamma-globulins;pre-clinical;prevent;protein complex;public health medicine (field);public health relevance;tandem mass spectrometry;tau Proteins;two-dimensional


application_id: 7678679
project_number: 1R01CA139844-01
project_title: The role of MRP1 in Protection of Cardiac Injury
administering_ic: NCI
award_notice_date: 2008-09-25
application_type: 1
activity_code: R01
ic: CA
serial_number: 139844
program_official: SONG, MIN-KYUNG H
project_start_date: 2008-09-25
project_end_date: 2013-07-31
study_section: Special Emphasis Panel[ZCA1 RPRB-O (J1)]
contact_pi_person_id: 1862358
contact_pi: VORE, MARY
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-09-25
project_terms:
4 hydroxynonenal;ABCC1 gene;ATP-Binding Cassette Transporters;Adriamycin PFS;Alkylation;Antibodies;Biochemical;Biological Assay;Buthionine Sulfoximine;Cardiac;Cardiotoxicity;Cell Line;Cell membrane;Cells;Collaborations;Coupled;Cysteine;Development;Dose;Esters;Fractionation;Genes;Genotype;Glutathione;Goals;Heart;Histidine;Human;Immunohistochemistry;In Vitro;Injury;Lead;Localized;Lysine;Measures;Mediating;Mice Knockout;Mice Transgenic;Mitochondria;Modality;Morphology;Mus;Myocytes Cardiac;Normal tissue morphology;Oxidants;Oxidation-Reduction;Oxidative Stress;P-Glycoprotein;P-Glycoproteins;Production;Protein Isoforms;Protein Overexpression;Proteins;Proteomics;Quantitative Microscopy;RNA Messenger;Regulation;Role;Sarcolemma;Schiff Bases;Site;Stress;TNF protein human;Testing;Therapeutic;Time;Tissues;Toxic effect;Transgenic Organisms;Tumor Necrosis Factor-alpha;Tumor Necrosis Factors;Vesicle;Wild Type Mouse;adduct;base;cancer therapy;chemotherapeutic agent;cytotoxic;functional group;in vivo;novel;response;treatment effect;uptake


application_id: 7678676
project_number: 1R01CA139843-01
project_title: MbSOD in chemotherapeutic-Induced Cardiac Injury
administering_ic: NCI
award_notice_date: 2008-09-25
application_type: 1
activity_code: R01
ic: CA
serial_number: 139843
program_official: SONG, MIN-KYUNG H
project_start_date: 2008-09-25
project_end_date: 2013-07-31
study_section: Special Emphasis Panel[ZCA1 RPRB-O (J1)]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-09-25
project_terms:
ABCC1 gene;Acute;Adriamycin PFS;Animals;Anthracycline Antibiotics;Anthracyclines;Antibodies;Antioxidants;Apoptosis;Biochemical;Biological Assay;Brain;Cancer Patient;Cardiac;Cell Death;Cell Fractionation;Cessation of life;Chimeric Proteins;Chronic;Coupled;Data;Dose-Limiting;Drug Kinetics;Echocardiography;Enzymes;Gene Targeting;Generations;Genes;Goals;Heart;Heart Diseases;Immunoprecipitation;Injury;Intervention;Kinetics;Knock-out;Lead;Link;Living Wills;Malignant Neoplasms;Manganese;Manganese Superoxide Dismutase;Mediating;Methods;Mice Knockout;Microscopy Confocal;Mitochondria;Modeling;Morphology;Mus;Myocytes Cardiac;Nuclear;Numbers;Oxidation-Reduction;Oxidative Stress;P-Glycoproteins;Pathway interactions;Plasma;Polymerase Chain Reaction;Probability;Production;Protein Overexpression;Proteins;Proteomics;Protocols documentation;Protocols Treatment;Quality of life;RNA Messenger;Reactive Oxygen Species;Role;Signal Transduction;Source;Superoxide Dismutase;Superoxides;TP53 gene;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;Toxic effect;Transcription Genetic;Translations;Treatment Efficacy;Treatment-Related Cancer;Tumor Necrosis Factor-alpha;Wild Type Mouse;adduct;base;cancer therapy;chromatin immunoprecipitation;clinical application;cytokine;improved;in vivo;insight;mimetics;morphometry;novel;treatment effect;tumor


application_id: 7678029
project_number: 5R01DK081324-02
project_title: An Intergenerational CBPR Intervention to Reduce Appalachian Health Disparities
administering_ic: NIDDK
award_notice_date: 2009-07-20
opportunity_number: PAR-07-379
application_type: 5
activity_code: R01
ic: DK
serial_number: 081324
program_official: HUNTER, CHRISTINE
project_start_date: 2008-09-01
project_end_date: 2013-06-30
study_section: Special Emphasis Panel[ZRG1-RPHB-K(50)R]
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affect;Appalachian Region;Behavior;Behavioral Risk Factor Surveillance System;Body Weight decreased;Cardiovascular system;Cause of Death;Cessation of life;Characteristics;Chronic Disease;Communities;Dancing;Data;Death Rate;Development;Diabetes Mellitus;Diet;Diet good;Dietary intake;Educational workshop;Effectiveness of Interventions;Ensure;Equipment and supply inventories;Evaluation;Exercise;Goals;Health;Health care facility;Heart Diseases;Institution;Intake;Intervention;Interview;Kentucky;Life;Linguistics;Malignant Neoplasms;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Nutritionist;Obesity;Overweight;Participant;Phase;Physical activity;Population;Process;Protocols documentation;Psychologist;Questionnaires;Randomized;Reporting;Research;Research Personnel;Research Project Grants;Risk Factors;Rural;Solutions;Structure;Testing;Training;Translational Research;Treatment Protocols;Visit;Weight;Work;Youth;base;burden of illness;community based participatory research;cooking;design;energy balance;ethnographic method;fruits and vegetables;health disparity;improved;informant;innovation;instrument;intergenerational;meetings;member;motivational enhancement therapy;prevent;public health relevance;sedentary


application_id: 7677878
project_number: 5K12DA014040-10
project_title: BUILDING INTERDISCIPLINARY RESEARCH CAREERS IN WOMEN'S HEALTH IN KENTUCKY
administering_ic: NIDA
award_notice_date: 2009-08-10
opportunity_number: RFA-OD-05-002
application_type: 5
activity_code: K12
ic: DA
serial_number: 014040
program_official: FRANKENHEIM, JERRY
project_start_date: 2000-09-30
project_end_date: 2013-08-31
study_section: Special Emphasis Panel[ZRG1-EMNR-J(50)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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The primary goal of the proposed BIRCWH Program is to continue to provide Interdisciplinary Women's Health Research (IWHR) scholars with state-of-the-art multidisciplinary training in women's health research that will ensure that they successfully establish independent research careers in academic medicine. To achieve this goal we have refined and adapted our already successful organizational structure to provide scholars with in-depth training in 4 focused and interacting areas of women's health: 1) drug abuse and its relationship to sex and gender differences 2) cancer as it relates to women's health 3) hormonal regulation across a woman's lifespan and 4) oral health and its impact on cardiovascular and endocrine health and pregnancy outcomes. The 4 current focus areas were chosen as an extension of our previous research areas because research in these areas is of fundamental importance to improving the health of women. Also these 4 focus areas address the 4 overarching themes identified by NIH and ORWH as important for this proposal (interdisciplinary research sex/gender determinants lifespan and health disparities/differences and diversity). We will establish an innovative Shared Resource Laboratory called Advancing Research Through Support (ARTS) that will provide Scholars with skilled technical services that are unavailable elsewhere in the UK research environment. Finally we will establish an innovative program whereby former BIRCWH Scholars ("graduates") will act as Coaches by serving as members of research teams and providing an extensive and interactive support network for the IWRH Scholars. A unique feature and an important strength of our BIRCWH Program is its multidisciplinary cross departmental and interactive nature. This multidisciplinary structure allows us to address a broad range of issues related to public health including addictive behaviors aging cancer diabetes hormone action obesity oral health and pregnancy. During the previous funding period we used this interactive structure with considerable success. Therefore we propose to expand the opportunities afforded to each IWHR Scholar for rich concentrated and multidisciplinary experiences with a primary mentor a former BIRCWH Scholar (Coach) and many other faculty members that will enrich the IWHR Scholar's research experience and provide multiple role models to enhance the Scholar's career development.

project_terms:
Addictive Behavior;Address;Aging;Area;Arts;Cardiovascular system;Diabetes Mellitus;Drug abuse;Endocrine;Ensure;Environment;Faculty;Funding;Gender;Goals;Health;Hormones;Interdisciplinary Study;Kentucky;Laboratories;Longevity;Malignant Neoplasms;Medicine;Mentors;Nature;Obesity;Oral health;Pregnancy;Pregnancy Outcome;Research;Resource Sharing;Services;Sex Characteristics;Structure;Training;United States National Institutes of Health;Woman;Women's Health;career;career development;experience;health disparity;hormone regulation;improved;innovation;member;multidisciplinary;organizational structure;programs;public health medicine (field);role model;sex;success


application_id: 7676277
project_number: 2R56AA013388-04
project_title: Hippocampal neurotoxicity induced by ethanol withdrawal
administering_ic: NIAAA
award_notice_date: 2008-08-25
application_type: 2
activity_code: R56
ic: AA
serial_number: 013388
program_official: NORONHA, ANTONIO
project_start_date: 2001-08-01
project_end_date: 2009-08-31
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 8535960
contact_pi: PRENDERGAST, MARK 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
arra_indicator: N
budget_start_date: 2008-09-01
project_abstract:
Alcohol dependence and abuse likely cost more than $200 billion in lost productivity and healthcare annuallyin the United States. Brain injury is among the most prominent effects of prolonged alcohol use and appearsto contribute to the development of neurological abnormalities. Thus examination of biochemical pathwaysinvolved in this form of brain injury may be of value in identifying therapeutic targets to be exploited intreating alcohol-related brain injury. Excess activity of N-methyl-D-asparate (NMDA)-type glutamatereceptors has been implicated in both the behavioral and neurotoxic effects of alcoholism particularly duringalcohol withdrawal when excess release of glutamte and polyamines occurs. Polyamines are endogenoussubstances that among other things act as allosteric activators of NMDA receptors at NR 2 subunits.Substances that further promote activity of NMDA receptor systems such as glucocorticoids arehypothesized to exacerbate alcohol withdrawal effects. Indeed prolonged alcohol intake is associated withhypercortisolemia likely resulting from alcohol effects on hypothalamic corticotropin releasing hormone(CRH) receptors. However the consequences of elevated stress hormone release with regard to alcoholrelatedneuronal injury have been little studied. The proposed in vitro and in vivo rodent studies will test thehypothesis that alcohol-induced activation of the hypothalamic pituitary adrenal axis promotes NMDAreceptor-mediated seizure and neurotoxicity during alcohol withdrawal by: (1) stimulating the synthesis andrelease of polyamines via upregulation of the synthetic enzyme ornithine decarboxylase an effect dependentupon glucocorticoid receptor (GR) activation; and (2) upregulating the expression of polyamine-sensitiveNR2B subunits thus promoting NMDA channel opening and neuronal excitation and/or neurotoxicity in aGR-dependent manner. These studies will employ biochemical immunohistochemical confocal imagingand behavioral studies using an in vivo "moderate" binge-alcohol exposure paradigm that produces peakB.A.L.s of ~160 mg/dl and organotypic hippocampal slice cultures in parallel studies. It is the aim of thesestudies to elucidate the means by which glucocorticoids may exacerbate alcohol withdrawal behavioral andphysiological effects as these relevant biochemical pathways may represent therapeutic targets to beexploited in the treatment of alcohol withdrawal effects.

project_terms:
Abstinence;Acute;Adrenal Cortex Hormones;Alcohol consumption;Alcohol dependence;Alcohol withdrawal syndrome;Alcoholism;Alcohols;Anxiety;Attenuated;Behavioral;Biochemical;Biochemical Pathway;Blood;Blotting Western;Brain;Brain Injuries;Corticotropin-Releasing Hormone;Development;Elevation;Ethanol;Ethanol dependence;Exposure to;Funding;Glucocorticoid Receptor;Glucocorticoids;Glutamate Receptor;Healthcare;Hippocampus (Brain);Hormones;Hypothalamic structure;Image;In Vitro;Injury;Intake;Mediating;Methods;Modeling;Molecular Target;Neurologic;Neuronal Injury;Neurons;Ornithine Decarboxylase;Pathway interactions;Physiological;Polyamines;Productivity;Rattus;Receptor Activation;Receptors Corticotropin-Releasing Hormone;Research;Research Personnel;Rodent;Seizures;Slice;Stress;Structure of paraventricular nucleus;System;Testing;Tremor;United States;Up-Regulation (Physiology);Withdrawal;alcohol effect;alcohol exposure;clinically relevant;cost;craving;drinking;hypercortisolemia;hypothalamic-pituitary-adrenal axis;in vivo;in vivo Model;model design;neurotoxic;neurotoxicity;novel;receptor;receptor binding;response;synthetic enzyme;therapeutic target


application_id: 7676126
project_number: 5R21AG032567-02
project_title: Role of p62 in Protein Aggregation and Neurodegeneration in ALS
administering_ic: NIA
award_notice_date: 2009-08-14
opportunity_number: RFA-AG-08-001
application_type: 5
activity_code: R21
ic: AG
serial_number: 032567
program_official: ST HILLAIRE-CLARKE, CORYSE
project_start_date: 2008-09-01
project_end_date: 2012-08-31
study_section: ZAG1-ZIJ-5(M1)
contact_pi_person_id: 7875249
contact_pi: ZHU, HAINING
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Protein aggregates containing mutant copper-zinc superoxide dismutase (SOD1) are a hallmark of familial amyotrophic lateral sclerosis (ALS Lou Gehrig's disease) an age-related neurodegenerative disease. Conformational differences between wild-type (WT) and mutant SOD1 proteins have been demonstrated by many in vitro studies using a variety of biophysical techniques but in vivo details of the aggregation process remain to be defined. It is also unclear whether protein aggregates are toxic or beneficial. P62/Sequestome 1 (referred as p62 in this proposal) is a multifunctional protein involved in both of the two major protein degradation mechanisms ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway. We recently reported that the endogenous mouse p62 levels significantly increased prior to the disease onset in G93A SOD1 transgenic mice. In addition p62 was co-localized with mutant SOD1 and ubiquitin in the protein aggregates in spinal motor neurons in G93A SOD1 transgenic mice. We have established collaboration with Dr. Marie Wooten at Auburn University who is the leading scientist studying p62 in signaling cascades and who will provide the p62 knockout mice for the study. The long term goal of this collaborative project is to understand the role of p62 in protein aggregation caused by ALS-linked SOD1 mutants and motor neuron degeneration in ALS. The innovative aspect of this project is that the role of p62 in the ALS etiology is largely undefined. The central hypothesis to be tested in the project is that p62 can recognize misfolded mutant SOD1 and that p62 can ameliorate the mutant SOD1 induced toxicity by shuttling such misfolded proteins to the ubiquitin-proteasome system (UPS) and/or autophagy. Our preliminary studies demonstrate that p62 specifically recognizes mutant SOD1 and the ubiquitin-association (UBA) domain of p62 is not essential to such interaction. Our results also show that p62 enhances the formation of aggresome-like inclusion of mutant SOD1 but had little effect on WT SOD1. Recent results from other groups showed that p62 can directly bind to autophagy effector protein Atg8/LC3 and that the formation of autophagy was increased in the G93A SOD1 transgenic mice. These data strongly support the central hypothesis. Three specific aims are designed to determine the mechanisms by which p62 recognizes mutant SOD1 the downstream pathways activated by such interaction and the functional role of p62 in neuronal degeneration. Aim 1 is to map the domains of p62 essential for recognizing and interacting with mutant SOD1. Aim 2 is to determine whether and how p62 mediates the autophagy activation induced by mutant SOD1. Aim 3 is to study how p62 influences protein aggregation and ALS disease progression in vivo using p62 KO mice. The results from this study will provide invaluable insights into the role of p62 in protein aggregation and neurodegeneration in ALS which will result in better understanding of ALS etiology and potential discovery of new therapeutic target for ALS treatment. Project Narrative This collaborative project between Dr. Zhu at University of Kentucky and Dr. Wooten at Auburn University is to understand the role of p62 in mutant SOD1 induced protein aggregation and motor neuron degeneration in amyotrophic lateral sclerosis (ALS) an age-related neurodegenerative disease. The innovative aspect of this project is that the role of p62 in the ALS etiology is largely undefined. P62 is a multifunctional protein involved in both of the two major protein degradation mechanisms ubiquitin-proteasome system (UPS) and autophagy- lysosome pathway. The central hypotheses to be tested in the project are that p62 can recognize misfolded mutant SOD1 and that p62 can ameliorate the mutant SOD1 induced toxicity by shuttling such misfolded proteins to UPS and/or autophagy. We have obtained substantial amount of preliminary data that strongly support these hypotheses. Three specific aims are designed to further characterize the molecular details regarding the role of p62 in protein homeostasis (degradation and aggregation) and neuronal survival in ALS. Aim 1 is to map the domains of p62 essential for recognizing and interacting with mutant SOD1. Aim 2 is to determine whether and how p62 mediates the autophagy activation induced by mutant SOD1. Aim 3 is to study how p62 influences protein aggregation and ALS disease progression in vivo using p62 KO mice. The results from this study will provide invaluable insights into the role of p62 in protein aggregation and neurodegeneration in ALS which will result in better understanding of ALS etiology and potential discovery of new therapeutic target for ALS treatment.

project_terms:
Address;Amyotrophic Lateral Sclerosis;Animal Model;Autophagocytosis;Autophagosome;Binding (Molecular Function);Cessation of life;Collaborations;Cultured Cells;Data;Disease Progression;Electrons;Etiology;Familial Amyotrophic Lateral Sclerosis;Goals;Homeostasis;In Vitro;Kentucky;Knockout Mice;Length;Link;Lysosomes;Mediating;Microscopic;Molecular;Motor;Motor Neurons;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Onset of illness;Pathway interactions;Polyubiquitin;Precipitation;Process;Proteins;Reporting;Role;Scientist;Series;Signal Transduction;Spinal;System;Techniques;Testing;Time;Tissues;Toxic effect;Transgenic Animals;Transgenic Mice;Ubiquitin;Ubiquitination;Universities;Western Blotting;age related;copper zinc superoxide dismutase;design;domain mapping;in vivo;innovation;insight;motor neuron degeneration;multicatalytic endopeptidase complex;mutant;neuronal survival;new therapeutic target;overexpression;protein aggregate;protein aggregation;protein degradation;protein misfolding


application_id: 7675985
project_number: 5R21EY018952-02
project_title: To produce transgenic mice which express T cell receptors specific for (IRBP).
administering_ic: NEI
award_notice_date: 2009-08-05
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: EY
serial_number: 018952
program_official: SHEN, GRACE L
project_start_date: 2008-09-01
project_end_date: 2010-08-31
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 1863468
contact_pi: WOODWARD, JEROLD G
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Autoimmune posterior uveitis is a T cell mediated autoimmune disease characterized by mononuclear infiltrate into the retina and irreversible photoreceptor destruction. While the cause is unknown experimental autoimmune uveitis (EAU) can be induced in mice through immunization with interphotoreceptor retinoid binding protein (IRBP). Numerous studies in the EAU field as well as other autoimmune disease models suggest that the primary cause of autoimmune disease is a failure of immune tolerance mechanisms. T cell receptor (TCR) transgenic mice have provided and continue to provide a wealth of important information on mechanisms of tolerance induction as well as mechanisms of autoimmune tissue destruction particularly in the multiple sclerosis and diabetes fields. In this exploratory/developmental research grant application the applicant proposes to develop TCR transgenic mice with specificity for IRBP as a new model for EAU. The applicant has successfully cloned full length cDNAs encoding the alpha and beta chains of the TCR from three IRBP specific T cell clones and is in the process of cloning the receptor genes from two other T cell clones. In the first aim the applicant will generate two lines of transgenic mice from two different T cell clones. In the second aim the applicant will perform the initial characterization of the lines in order to establish them as useful models for EAU. These mice will be made available to the uveitis research community and create valuable new models for uveitis research. Studies using these mice may lead to new therapies for the treatment of uveitis.   
  
PUBLIC HEALTH RELEVANCE:  This project will generate new transgenic mouse models for autoimmune uveitis a severe sight threatening autoimmune disease. Similar mouse models have been produced for multiple sclerosis and diabetes and have been responsible for dramatic advances in those fields. These mice will be made available to the research community and thus foster new research into cures or treatment for autoimmune uveitis.

project_terms:
Adoptive Transfer;Antigens;Area;Autoantigens;Autoimmune Diseases;Autoimmune Process;Autoimmunity;Backcrossings;Biomedical Research;Breeding;Cell physiology;Cells;Cloning;Communities;Development;Diabetes Mellitus;Disease;Disease model;Effector Cell;Epitopes;Experimental Autoimmune Encephalomyelitis;Experimental Models;Exploratory/Developmental Grant;Eye;Failure (biologic function);Fluorescent Dyes;Fostering;Genes;Goals;Immune;Immune Tolerance;Immune response;Immunization;In Vitro;Knockout Mice;Label;Lead;Length;Mediating;Methods;Microinjections;Microtus;Modeling;Mononuclear;Multiple Sclerosis;Mus;Pancreas;Peripheral;Photoreceptors;Population;Posterior Uveitis;Pre-Clinical Model;Process;Production;Property;RIII Mouse;Receptor Gene;Research;Research Personnel;Research Project Grants;Retina;Risk;Role;Site;Source;Specificity;System;T-Cell Receptor;T-Cell Receptor Genes;T-Lymphocyte;Testing;Thymic epithelial cell;Thymus Gland;Tissues;Transfection;Transgenes;Transgenic Mice;Transgenic Organisms;Uveitis;Vision;alpha-beta T-Cell Receptor;autoimmune uveitis;beta Chain Antigen T Cell Receptor;design;in vivo;interstitial retinol-binding protein;intravital microscopy;model development;mouse interstitial retinol-binding protein;mouse model;novel;public health relevance;receptor;receptor expression;research study;success;zygote


application_id: 7675572
project_number: 4R00NS061803-03
project_title: Novel Model Systems Link Floridean Starch Metabolism to Lafora Disease
administering_ic: NINDS
award_notice_date: 2008-09-04
application_type: 4
activity_code: R00
ic: NS
serial_number: 061803
program_official: STEWART, RANDALL R
project_start_date: 2007-09-15
project_end_date: 2011-08-31
study_section: NSS
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-09-15
project_terms:
Animalia;Binding (Molecular Function);Biochemical;Biochemistry;Bioinformatics;Biological Models;CNS degeneration;Carbohydrates;Cellular biology;Cessation of life;Complement;Complex;Deterioration;Disease;Eimeria tenella;Energy-Generating Resources;Epilepsies Myoclonic;Eukaryota;Eukaryotic Cell;Event;Genes;Genetic;Glycogen;Grant;Human;Invertebrates;Knock-out;Lafora Disease;Life;Link;Mammalian Cell;Mammals;Metabolism;Modeling;Motor;Myoclonic Epilepsies Progressive;Neurodegenerative Disorders;Neurologic;Organism;Orthologous Gene;Paramecium tetraurelia;Patients;Phenotype;Phosphoric Monoester Hydrolases;Process;Protista;Reporting;Role;Seizure Focal;Seizures;Signal Transduction Pathway;Single Seizures;Starch;System;Testing;Tetrahymena thermophila;Tonic - clonic seizures;Tonic Seizures;Toxoplasma gondii;Transgenic Organisms;Vertebrates;carbohydrate metabolism;genome sequencing;glycogen metabolism;loss of function mutation;mRNA Expression;novel;novel therapeutics;particle;polyglucosan;protein expression;research study;therapeutic target;ubiquitin-protein ligase


application_id: 7675433
project_number: 5R01CA086412-26
project_title: Ligation of CR3 by Glucan and iC3b Links Innate and Adaptive Anti-tumor Immunity
administering_ic: NCI
award_notice_date: 2009-07-14
application_type: 5
activity_code: R01
ic: CA
serial_number: 086412
program_official: MCCARTHY, SUSAN A
project_start_date: 2000-02-23
project_end_date: 2012-07-31
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: Not Applicable
congressional_district: 03
department: PATHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-08-01
project_abstract:
DESCRIPTION (provided by applicant): Our strong preliminary data demonstrate a novel therapeutic strategy for tumor therapy by engaging leukocyte complement receptor 3 (CR3 CD11b/CD18 alphaMbeta2-integrin) to kill tumor cells opsonized with iC3b. Therapeutic efficacy is achieved by using yeast beta-glucan in combination with anti-tumor mAbs in multiple mouse syngeneic tumor models. The long-term goal has been to understand the molecular and cellular mechanisms of action within yeast beta-glucan mediated tumor immunotherapy and then promote it for clinical utilization with humanized anti-tumor mAbs or tumor vaccines eliciting a sufficient humoral response for activation of complement. We further demonstrate that yeast particulate beta-glucan stimulates dendritic cells for up-regulation of surface co-stimulatory molecules and MHC class II expression and secretion of IL-12 and TNF-alpha. Moreover combined therapy of beta-glucan and MUC1 vaccine exhibits a synergistic effect on tumor regression. The central hypotheses to be tested in this proposal are: 1) yeast particulate beta-glucan enhances the adaptive immunity via secretion of cytokines and the enhanced dendritic cell antigen presentation; and 2) yeast beta-glucan has a synergistically therapeutic effect on a B cell-mediated MUC1 vaccine in MUC1/MT double Tg mice developing spontaneous mammary carcinoma. Aim 1 determines whether beta-glucan mediated tumor immunotherapy promotes the adaptive T and B cell responses by using adoptively transferred OVA TCR transgenic OT-I (CDS) and/or OT-II T cells (CD4). The enhanced dendritic cell antigen presentation and subsequent enhanced antigen-specific T cell responses by beta-glucan will be determined. Aim 2 uses a B cell-mediated MUC1 vaccine in combination with beta-glucan to investigate the therapeutic efficacy in MUC1/MT double Tg mice developing spontaneous mammary carcinoma. Targeting tumor-associated antigen MUC1 to B cells breaks T and B cell tolerance in MUC1 Tg mice. The enhancing effect of beta-glucan on anti-MUd T and B cell responses will be determined. Beta-glucan mediated immunotherapy demonstrates promising results in the therapeutic setting and is potentially remedial for cancer patients.

project_terms:
Address;Antibodies;Antibody -dependent cell cytotoxicity;Antigen Presentation;Antigens;Asians;Award;B-Lymphocytes;Binding (Molecular Function);Biological Response Modifiers;Breast Carcinoma;C3bi;CD4 Positive T Lymphocytes;Cancer Patient;Cancer Vaccines;Cells;Centers for Disease Control and Prevention (U.S.);Clinical;Complement;Complement Activation;Complement Receptor;Data;Dendritic Cells;Effector Cell;Exhibits;FDA approved;Family;Glucans;Goals;Growth Factor Inhibition;Histocompatibility Antigens Class II;Human;ITGAM gene;Immune;Immunity;Immunoconjugates;Immunotherapy;Inflammatory;Integrins;Interleukin-12;Japan;Killings;Lectin;Leukocytes;Lewis Lung Carcinoma;Ligands;Ligation;Link;Macrophage-1 Antigen;Malignant Neoplasms;Mediating;Modeling;Molecular;Monoclonal Antibodies;Mucin-1 Staining Method;Mus;Natural Killer Cells;Ovalbumin;Particulate;Patients;Radioisotopes;Surface;T-Lymphocyte;Testing;Therapeutic;Therapeutic Effect;Toxin;Traditional Medicine;Transgenic Organisms;Treatment Efficacy;Tumor Antigens;Tumor Immunity;Tumor Necrosis Factor-alpha;Up-Regulation (Physiology);Vaccines;Yeasts;beta-Glucans;cancer care;cancer therapy;clinically relevant;cytokine;cytotoxic;cytotoxicity;human TNF protein;insight;macrophage;neoplastic cell;neutrophil;novel;novel strategies;novel therapeutics;prophylactic;response;success;tumor


application_id: 7674571
project_number: 5P01AG010836-15
project_title: LONG-TERM INTERVENTION CORE
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 010836
study_section: ZAG1
subproject_number: 9001
contact_pi_person_id: 7875396
contact_pi: PORTER, NADA MICOVIC
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: 2008-09-01
budget_end_date: 2009-08-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
This core is designed to establish a facility and procedures for definitively testing whether an intervention treatment alters the rate of brain aging in rodent models. Although the NIA supports a Consortium that runs intervention clinical trials for select agents there is growing recognition of a need for additional testing programs at the preclinical level.  However critical putative mechanisms and hypotheses of brain aging and AD are emerging from this PPG and elsewhere that warrant systematic testing. Long-term interventions are essentially the only way to test whether an experimental intervention alters the rate of gradual processes of aging and age-related pathology. Thus there is a need for an intervention program that focuses on animal models of brain aging and AD. The program project has two parallel longitudinal components (at Universities of Kentucky and Alabama) and will assess the effectiveness of "intervention treatments" in slowing the progression or alleviating aspects of brain aging and cognitive decline in a rat model of aging (F344 rats) and in a mouse model of AD (APP/PS1 mice). In F344 rats the long-term interventions will be initiated at middle age prior to the onset of cognitive decline. The same approach will be used in APP/PS1 mice. However because of the accelerated pathology of this model treatment will begin at 3 months prior to cognitive decline and the appearance of pathological markers. The treatments chosen are compatible with long-term exposure and have few side effects. The four initial agents (minocycline memantine vitamin D lipoic acid) test key hypotheses in various Projects of the PPG. All have compelling evidence for their potential efficacy against processes involved in aging and are currently approved for other indications in humans. A search of the clinical trials web site or the NIH CRISP database of sponsored grants reveals that none of these interventions are currently in clinicai/preciinical trial as aging interventions. Our use of these existing therapies as potential aging interventions therefore represents a novel use of these treatments. Thus these candidate interventions appear to be highly feasible and there is substantial evidence indicating potentially favorable outcomes. Importantly the selection of these agents for long-term tests is hypothesisdriven and will directly advance the aims of multiple Projects within the program project.

project_terms:
APP-PS1;Accounting;Adverse effects;Age;Aging;Aging-Related Process;Alabama;Animal Model;Animals;Appearance;Behavioral;Biological Markers;Caring;Cells;Classification;Clinical Trials;Compatible;Computer Retrieval of Information on Scientific Projects Database;Daily;Databases;Effectiveness of Interventions;Ensure;Environment;Grant;Head;Human;Ice;Impaired cognition;Individual;Inflammatory;Internet;Intervention;Kentucky;Left;Memantine;Minocycline;Modeling;Monitor;Mus;Outcome;Pathology;Personal Satisfaction;Principal Investigator;Procedures;Process;Rate;Rats Inbred F344;Rattus;Research Personnel;Rodent Model;Running;Site;Testing;Thioctic Acid;Training;United States National Institutes of Health;Universities;Vitamin D;Work;age related;aging brain;design;experience;intervention program;middle age;mouse model;multidisciplinary;novel;pre-clinical;programs


application_id: 7674570
project_number: 5P01AG010836-15
project_title: OXIDATIVE STRESS CALCIUM AND MITROCHONDRIAL DYSFUNCTION IN ALZHEIMER'S DISEASE
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 010836
study_section: ZAG1
subproject_number: 0011
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: 2008-09-01
budget_end_date: 2009-08-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Aging and age-related disorders such as Alzheimer's disease (AD) are associated withprogressive decreases in cognitive function. Markers of inflammation are also well-documented in both aging and AD brains but it is not known how inflammatory pathways are initiated nor are the cell types involved in the inflammatory cascade identified. In addition to inflammation calciumoverload oxidative stress and proteasome inhibition are all thought to participate in age-relateddeclines. New data from our laboratory suggests that these seemingly disparate phenomena may be linked; whereby changes in proteasome expression and activity in response to increased intracellular calcium and oxidative stress initiate inflammation in neurons. The focus of this proposal therefore is to test the hypothesis that oxidative stress- and calcium-induced alterations to the proteasome lead to inflammation in aging and AD brains. Studies will determine the effects of increasing doses of age- and AD-related stimuli on proteasome subunit expression proteasome activity and immune signaling in cultured neurons. The relationships between proteasome alterations calcium homeostasis inflammatory signaling and cell death will be determined. Studies will also be carried out in cultured astrocytes microglial cells and oligodendrocytes to determine cell-type specific components of proteasome-dependent inflammation and cytotoxicity. Additionally the role of preserved proteasome homeostasis and prevention of proteasome-dependent inflammation in the therapeutic effects of minocycline and estrogen will be tested in vitro and in vivo.Concurrently this project will serve as a Core for the PPG generating primary cultures of ratneurons and glial cells and providing quantitative assessments of inflammatory and proteasomehomeostasis in long-term intervention studies. Completion of these studies will greatly increase our understanding of the role of the proteasome in the aging brain and could aid in the development of novel therapies for brain aging by targeting inflammation.

project_terms:
3-nitrotyrosine;4 hydroxynonenal;Acids;Adult;Affect;Age;Age-Months;Aging;Alzheimer's Disease;Alzheimer's disease model;Amyloid beta-Protein;Animal Model;Animals;Antioxidants;Apoptosis;Astrocytes;Behavioral;Biological Assay;Biological Markers;Brain;Brain region;Caenorhabditis elegans;Calcium;Cell Death Signaling Process;Cells;Cerebellum;Collaborations;Complex;Creatine Kinase;Data;Deposition;Development;Disease;Dose;Electrophysiology (science);Elevation;Embryo;End Point;Enzymes;Estrogens;Fluorescence;Free Radicals;Functional disorder;Gene Mutation;Genes;Glutamate-Ammonia Ligase;Glutathione;Glycosylation End Products Advanced;Goals;Homeostasis;Human;Immune;Impairment;In Vitro;Inflammation;Inflammatory;Inherited;Intervention;Intervention Studies;Investigation;Knock-in Mouse;Laboratories;Lead;Life;Link;Lipid Peroxidation;Measures;Memory;Mice Mutant Strains;Microglia;Microscopy;Minocycline;Mitochondria;Modeling;Modification;Molecular;Mus;Mutation;Nerve Degeneration;Neuroglia;Neurons;Nitrates;Oligodendroglia;Oxidative Stress;Participant;Pathogenesis;Pathology;Pathway interactions;Persons;Prevention;Process;Production;Program Research Project Grants;Proteasome Inhibition;Protein Overexpression;Proteins;Proteomics;Rattus;Reactive Oxygen Species;Relative (related person);Reporting;Research;Rodent;Rodent Model;Role;Running;S-ethyl glutathione;Series;Signal Transduction;Source;Stimulus;Stress;Study Outcome;Sulfhydryl Compounds;System;Testing;Therapeutic;Therapeutic Effect;Thinking function;Thioctic Acid;Wild Type Mouse;Work;age related;aged;aging brain;base;cell type;cognitive function;cytochrome c;cytotoxicity;design;experience;familial Alzheimer disease;improved;in vivo;indexing;inhibitor/antagonist;insight;mature animal;mimetics;mind control;mitochondrial dysfunction;mouse model;multicatalytic endopeptidase complex;mutant;nitrate;normal aging;novel;oxidation;peptide A;presenilin-1;prevent;prototype;research study;response;rhod-2;success;xanthate D609


application_id: 7674569
project_number: 5P01AG010836-15
project_title: MITOCHONDRIA ROS CA2+ AND CAPLAIN IN THE AGING CNS
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 010836
study_section: ZAG1
subproject_number: 0010
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES 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: 2008-09-01
budget_end_date: 2009-08-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The underlying  hypothesis is that an age-related accumulation of oxidative damage tomitochondria causes increasing mitochondrial dysfunction resulting in impaired Ca 2+ regulation greater production of reactive oxygen species (Aim 1) and greater release of death-related proteins in response to insult (Aim 2). Calpains Ca2+-activated cysteine proteases are impacted by both Ca 2+ dysregulation and oxidative stress. Preliminary results suggest that m-calpain is associated with mitochondria where its substrates may include many cell-death related proteins (Aim 3). Mitochondrial calpain would be ideally situated for regulation by mitochondrial Ca 2+ release and redox mechanisms similar to the recently described mitochondrial nitric oxide synthase. The age-related alterations in mitochondrial function and cell death proteins are hypothesized to be exacerbated in vulnerable brain regions in AIzheimer's disease (AD) as compared to resistant brain regions and mitochondrial function in elderly individuals with less severe cognitive decline and neuropathology (Aim 4). However increased oxidative stress in aging and AD may limit the activity of calpain and other cysteine proteases possibly protecting against the consequences of Ca 2+ dysregulation but also limiting the proteolysis of substrate proteins (Aim 4). To examine the basic premise that an age-related accumulation of oxidative damage to mitochondria results in their dysfunction iwe will examine the efficacy of long-term anti-oxidant (lipoic acid) and NMDA receptor antagonism (memantine) intervention in attenuating the age-related alterations in mitochondrial function (Aim 5). The above studies of mitochondrial function will be performed on synaptic and non-synaptic mitochondrial fractions isolated from the cortex and cerebellum of rats of ages 1-24 months and from human brain autopsy tissues obtained from individuals with various levels of cognitive function and AD-related  europathology.The maximum postmortem interval is 5h. While many aspects of mitochondrial dysfunction have been examined in aging and AD few studies have examined isolated mitochondria and even fewer have evaluated synaptic vs. non-synaptic mitochondria. Together the studies outlined in this project will provide a comprehensive evaluation of mitochondrial function and dysfunction in aging and AD and the relationship of mitochondrial dysfunction to the age-related Ca2+ deregulation and oxidative stress.

project_terms:
3-nitropropionic acid;Age;Aging;Alzheimer's Disease;Animals;Antioxidants;Attenuated;Autopsy;Blotting Western;Brain;Brain region;CCL4 gene;Calpain;Cell Death;Cell Death Signaling Process;Cell Fractionation;Cells;Cerebellum;Cessation of life;Cysteine;Cysteine Protease;Disease;Elderly;Enzymes;Evaluation;Exhibits;Functional disorder;Funding;Homeostasis;Human;I Calpain;II Calpain;Impaired cognition;Individual;Intervention;Localized;Measurement;Memantine;Membrane;Mitochondria;Morphology;Mus;N-Methyl-D-Aspartate Receptors;Necrosis;Nerve Degeneration;Neurons;Nitric Oxide Synthase;Oxidation-Reduction;Oxidative Stress;Particulate;Production;Proteins;Proteolysis;Purpose;Rats Inbred F344;Rattus;Reactive Oxygen Species;Regulation;Research;Resistance;Sites Active;Staging;Superoxides;Swelling;Synapses;System;Thioctic Acid;Tissues;Toxin;age related;aged;aging brain;apoptosis inducing factor;apoptotic protease-activating factor 1;brain tissue;calpastatin;caspase;cognitive function;cytochrome c;endonuclease G;in vivo;inhibitor/antagonist;interest;juvenile animal;m-calpain;middle age;mitochondrial dysfunction;mitochondrial permeability transition pore;neuropathology;oxidation;response


application_id: 7674568
project_number: 5P01AG010836-15
project_title: CA2+ REGULATION AND MITOCHONDRIA IN BRAIN AGING AND ALZHEIMER'S DISEASE
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 010836
study_section: ZAG1
subproject_number: 0008
contact_pi_person_id: 2405844
contact_pi: LANDFIELD, PHILIP 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: 2008-09-01
budget_end_date: 2009-08-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Amyloid beta-peptide (Abeta) is central to the pathogenesis of Alzheimer's disease (AD) and the AD brain is under extensive oxidative stress. Previous research from our laboratory combined these two observations into a model for neurodegeneration in AD a model based on Abeta-associated free radical oxidative stress. In neurons Abeta-associated free radical oxidative stress and toxicity depend critically on methionine residue 35 of Abeta(1-42) and both are prevented or modulated by exogenous antioxidants. We have used the emerging techniques of proteomics coupled with immunoblottmg methods to identify specifically oxidatively modified proteins in AD brain. We now propose to extend these observations to sporadic and inherited AD and rodent models thereof to gain insight into the mechanisms of Abeta (1-42) in the oxidative stress and neurotoxic properties of this peptide. In Specific Aim # 1 we will use proteomics to test the hypothesis that there will be a common set of oxidized proteins in inherited and sporadic AD that differ from those of normal aging and that these oxidized proteins in common are important in the pathogenesis of AD. Similar studies in mice models of inherited AD are hypothesized to lead to the identity of the same common proteins. In Specific Aim #2 we will test the hypothesis that mitochondrial dysfunction and Ca 2+ accumulation in brain from genetic mutations relevant to AD will be found in adult brain mitochondria from the model chosen in Specific Aim #1 compared to adult brain from wild-type mice. Those proteins identified by proteomics in the systems studied will be expressed in SY5Y cells and challenged with Abeta(1-42) to determine if there is increased vulnerability to oxidative stress mitochondrial dysfunction Ca 2+ accumulation and cytotoxicity. In Specific Aim #3 we will use proteomics to test the hypothesis that Abeta(1-42)-induced oxidative stress in embryonic neuronal cultures obtained from the rodent model of familial AD chosen in Specific Aim # 1 leads to the same oxidatively modified proteins as exists in adult brain from this animal and in human familial AD brain. In Specific Aim #4 we will investigate whether oxidative stress induces mitochondrialalterations in neuronal cultures obtained from the rodent model of inherited AD chosen in Specific Aim #1 or whether mitochondrial alterations induced in these cultures leads to oxidative stress. In Specific Aim # 5 we will test the hypothesis that endogenous or exogenous antioxidants protect brain in-vivo against oxidative stress in the rodent model chosen in Specific Aim # 1. This is a comprehensive set of proposed studies employing novel approaches in systems ranging from sporadic and inherited AD brain to genetic animal models of AD to neuronal cultures designed to gain insight into Abeta-associated free radical oxidative stress and neurotoxicity and their modulation by endogenous and exogenous antioxidants. The increased understanding that will result from these studies will provide insight into potential therapeutic interventions in this important dementing disorder that affects millions of Americans.

project_terms:
Adult;Affect;Age;Age-Months;Aging;Agonist;Algorithms;Alzheimer's Disease;Alzheimer's disease model;American;Amyloid;Amyloid beta-Protein;Animal Model;Animals;Antioxidants;Astrocytes;Behavioral;Binding (Molecular Function);Binding Proteins;Biochemical;Bioinformatics;Brain;Caffeine;Calcineurin;Calcium;Cell Aging;Cells;Collaborations;Complement;Complex;Coupled;Cultured Cells;Data;Deposition;Disease;Embryo;Endoplasmic Reticulum;Estrogen Receptors;Event;Exhibits;Family;Free Radicals;Frequencies (time pattern);Gene Expression;Gene Expression Process;Gene Expression Profiling;Gene Mutation;Gene Transfer;Generations;Genes;Genetic;Genomics;Glial Fibrillary Acidic Protein;Glutamates;Goals;Green Fluorescent Proteins;Growth Factor;Hippocampus (Brain);Human;Image;Impaired cognition;Inflammatory;Inherited;Intervention;Laboratories;Lead;Learning;Mediating;Membrane;Methionine;Methods;Mice Transgenic;Microarray Analysis;Mitochondria;Modeling;Molecular;Mus;Myelin Proteins;Nerve Degeneration;Neuroglia;Neurons;Nimodipine;Oxidative Stress;Pathogenesis;Pathology;Pathway interactions;Pattern;Peptides;Phase;Physiological;Polymerase Chain Reaction;Positioning Attribute;Preparation;Procedures;Process;Property;Protein Overexpression;Proteins;Proteomics;RNA Small Interfering;Range;Rattus;Regulation;Regulatory Pathway;Reports Progress;Research;Resources;Rodent Model;Running;Signal Transduction;Slice;Source;Specificity;Steroids;Study Outcome;Synapses;System;Techniques;Testing;Therapeutic Intervention;Time;Toxic effect;Transgenic Organisms;Up-Regulation (Physiology);Ursidae Family;Validation;Viral;Wild Type Mouse;Work;age related;aged;aging brain;base;brain cell;cell age;cell type;cytotoxicity;density;design;familial Alzheimer disease;in vivo;inhibitor/antagonist;insight;interdisciplinary approach;knock-down;mature animal;mitochondrial dysfunction;mouse model;multidisciplinary;mutant;neurotoxic;neurotoxicity;normal aging;novel strategies;prevent;receptor;receptor expression;research study;response;steroid hormone;steroid hormone receptor;tool;transgenic model of alzheimer disease;voltage


application_id: 7674567
project_number: 5P01AG010836-15
project_title: GENE EXPRESSION AND CA2+ REGULATION IN BRAIN AGING AND ALZHEIMER'S DISEASE
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 010836
study_section: ZAG1
subproject_number: 0006
contact_pi_person_id: 6176244
contact_pi: CHEN, KUEY-CHU
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: 2008-09-01
budget_end_date: 2009-08-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The overall goal of this project is to identify genes/proteins that play a causal role in brain aging/risk for AD. We will test the hypothesis that interactions of steroids with Ca2+ signaling pathways are underlying causal factors that act in early mid-life using gene microarrays combined with sophisticated biostatistical analyses and real-time PCR protein assays and in situ hybridization. In the first three specific aims we will extend our previous work by determining which changes in gene expression take place earliest in normal aging rats and also in an animal model of AD the APP/PS1 mouse. Comparison of these two models will reveal how normal aging transitions into pathological aging and will identify risk factors for AD. In addition we will carry out microarray analyses of single neurons and gila to that test the hypothesis that aging is a process of neuronal involution and gUallmicroglial activation. We will coordinate this project closely with Project 3 in order to determine the temporal relationship between altered gene expression and Ca 2+ dysregulation assessed by physiological techniques. In the last twospecific aims we will test the hypothesis that steroid hormones and their coordinating transcription factors and Ca2+-regulated signaling molecules play a role in inducing changes in gene expression that mimic those in aging. These studies will be carried out using viral-mediatedoverexpression/knockdown of steroid hormone receptors or Ca2+-regulated signaling proteins in mixed cultures of hippocampal cells. Subsequent experiments will be carried out in cell-type specific cultures (neurons gila microglia) in order to identify where the changes in gene expression originate. Gene expression changes elicited by these treatments will be determined first using microarrays and subsequently real-time PCR of selected panels of aging biomarkers. Taken together these studies will elucidate the role of both factors previously implicated in brain aging (steroid hormones Ca 2+- regulating molecules) and will identify novel factors and pathways as well. Further this Project in collaboration with Project 3 and Cores A B and C will define more clearly the relationship of gene expression cascades to Ca 2+ dysregulation in aging/AD.

project_terms:
APP-PS1;Age;Age Group Unspecified;Age-Months;Aging;Alzheimer's Disease;Animal Model;Animals;Biological Assay;Biological Markers;Cells;Cognition;Collaborations;Collection;Data;Detection;Gene Expression;Gene Proteins;Genes;Goals;Hippocampus (Brain);Image Analysis;In Situ Hybridization;Measures;Mediating;Microglia;Modeling;Mus;Neuroglia;Neurons;Pathway interactions;Phase;Physiological;Play;Polymerase Chain Reaction;Preparation;Process;Protein Overexpression;Proteins;Proteomics;RNA Messenger;Rattus;Regulation;Relative (related person);Risk;Risk Factors;Role;Signal Pathway;Signaling Molecule;Signaling Protein;Slice;Steroids;Techniques;Testing;Time;Viral;Work;age related;aging brain;cell type;hippocampal pyramidal neuron;middle age;normal aging;novel;pathological aging;research study;steroid hormone;steroid hormone receptor;transcription factor


application_id: 7674545
project_number: 5R01DK069766-05
project_title: Tolerance Induction to Islet Transplants
administering_ic: NIDDK
award_notice_date: 2009-08-05
application_type: 5
activity_code: R01
ic: DK
serial_number: 069766
program_official: APPEL, MICHAEL C
project_start_date: 2005-09-01
project_end_date: 2011-08-31
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 1878929
contact_pi: ILDSTAD, SUZANNE T
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-09-01
project_abstract:
DESCRIPTION (provided by applicant): The focus of this proposal is to develop a novel "conditioning" approach that will replace myelotoxic agents to establish chimerism in NOD mice. We will induce immune deviation to promote host-versus-graft hyporesponsiveness thereby giving the hematopoietic stem cell (HSC) an opportunity to engraft and establish subsequent self-perpetuating deletional tolerance to islet allografts. Our recent studies in a mouse model suggest that the primary role for conditioning for HSC transplantation is to suppress host-versus-graft alloreactivity rather than to prepare vacant niches in the recipient's bone marrow compartment. This observation suggests that one could replace myelotoxic agents with antigen-specific approaches to induce host-versus-graft hyporeactivity or anergy at the time of HSC transplantation. As the mechanisms underlying T cell activation are defined highly specific approaches to suppress this alloreactivity have emerged. In AIM I. we will ESTABLISH CHIMERISM THROUGH IMMUNE DEVIATION OF THE RECIPIENT. We will immunomodulate the recipient: (a) targeting alloreactive cells in the host microenvironment; (b) inducing anergy and/or antigen-specific apoptosis of alloreactive host cells; and (c) through generation of regulatory T cells (Treg) and develop a novel nonmyeloablative conditioning regimen to induce antigen-specific hyporesponsiveness to the HSC and islet allografts. Cell-based therapies have great potential for inducing transplantation tolerance. Of greatest interest are the new subpopulations of bone marrow-derived dendritic cells (DC) that have recently been shown to be potently tolerogenic in vitro under certain circumstances. We are the first to demonstrate an in vivo engraftment-enhancing effect for precursor plasmacytoid DC (p-preDC). The exploitation of this discovery in vivo and its potential to reduce the need for myelotoxic conditioning has not yet been tested. Hematopoietic growth factors have also been used to drive the immune response to a tolerogenic T helper 2 (Th2) phenotype through production of p-preDC or other tolerance-promoting cells (graft facilitating cells {FC}) that in turn generate Treg. In AIM II we will USE PRE-TRANSPLANT IMMUNOMODULATION OF THE DONOR WITH HEMATOPOIETIC GROWTH FACTORS TO GENERATE TOLEROGENIC CELLS IN THE HSC ALLOGRAFT. We will use these factors and the cells they generate to modulate the tolerogenicity of the donor marrow inoculum in vivo to tip the immune milieu in favor of graft acceptance enhancing bone marrow chimerism without myelotoxic conditioning. We will examine the mechanism by which this occurs and identify which cell types in the graft are critical to tolerance induction. P-preDC exposed to apoptotic donor antigens are potently tolerizing in vitro through generation of Treg. The therapeutic application of this approach has not been tested in vivo. In AIM III we will USE EX VIVO IMMUNOMODULATION OF THE MARROW to expand p-preDC and FC and induce a tolerogenic inoculum for HSC transplantation.

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


application_id: 7674390
project_number: 3R01NS049126-05S1
project_title: Proteomic and Functional Studies of Mitochondria in ALS
administering_ic: NINDS
award_notice_date: 2008-09-02
application_type: 3
activity_code: R01
ic: NS
serial_number: 049126
suffix: S1
program_official: SUTHERLAND, MARGARET L
project_start_date: 2004-09-01
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZRG1-CDIN(01)Q]
contact_pi_person_id: 7875249
contact_pi: ZHU, HAINING
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS Lou Gehrig's disease) is an age-dependent neurodegenerative disorder characterized by the progressive selective death of motor neurons. Approximately 10% of ALS patients are familial cases and more than 90 mutations in the gene encoding copper-zinc superoxide dismutase (SOD1) have been linked with approximately 25% of familial ALS. The long term objective of this project is to understand how SOD1 mutants lead to motor neuron degeneration in familial ALS. It has been proposed that mitochondrial dysfunction and activation of apoptosis play a central role in motor neuron death. However the molecular mechanisms leading to mitochondrial dysfunction and apoptosis are incompletely understood. The innovative aspect of this project is to use a combination of proteomic and biochemical approaches to study mutant SOD1 mediated mitochondrial apoptosis. Specific Aim 1 is to identify mitochondrial proteins that are targets of the toxicity associated with SOD1 mutants by proteomics analysis of cellular models of ALS. Specific Aim 2 is to study the functional roles of the identified target proteins in mitochondrial dysfunction activation of apoptosis and neuron death. Our preliminary results have shown a mitochondrial outer membrane protein named "voltage dependent anion channel 2 (VDAC2)" as a promising target and this protein will be studied in detail. Similar experiments designed for this protein will be carried out for other proteins as more targets will be identified in Aim 1. Specific Aim 3 is to determine the functional differences in the identified target proteins between motor neurons and other cell types from the spinal cord of the ALS transgenic mice. The differences of target proteins such as VDAC2 between motor neurons and other types of cells from the mouse spinal cord will be measured in terms of mRNA levels protein abundances and modification state. The relationship between the changes in the target proteins and mitochondrial apoptosis age-dependent pathological changes and disease progression will also be investigated. The studies of functional differences of these proteins between motor neurons and other cell types are likely to provide insights into the mechanisms leading to selective motor neuron death.

project_terms:
Affect;Amyotrophic Lateral Sclerosis;Apoptosis;Biochemical;Cell Line;Cell Membrane Permeability;Cell model;Cells;Cessation of life;Disease Progression;Familial Amyotrophic Lateral Sclerosis;Genes;Homeostasis;Knowledge;Lead;Link;Measures;Mediating;Membrane Proteins;Mice Transgenic;Mitochondria;Mitochondrial Proteins;Modeling;Modification;Molecular;Motor Neurons;Mus;Mutation;Names;Neurodegenerative Disorders;Neuroglia;Neurons;Numbers;Patients;Play;Property;Protein Processing Post-Translational;Proteins;Proteome;Proteomics;Protons;RNA Interference;RNA Messenger;Reaction;Research Personnel;Resistance;Role;Site;Spectrum Analysis Mass;Spinal Cord;Techniques;Toxic effect;age related;cell type;copper zinc superoxide dismutase;design;innovation;insight;interest;mitochondrial dysfunction;mitochondrial membrane;motor neuron degeneration;mutant;neuron apoptosis;numb protein;programs;protein folding;research study;respiratory;voltage-dependent anion channel 2


application_id: 7673563
project_number: 5K01DK078648-03
project_title: Role of microRNAs in insulin production and secretion in pancreatic beta-cells
administering_ic: NIDDK
award_notice_date: 2009-08-21
opportunity_number: PAR-05-066
application_type: 5
activity_code: K01
ic: DK
serial_number: 078648
program_official: HYDE, JAMES F
project_start_date: 2007-09-10
project_end_date: 2011-08-31
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 8781988
contact_pi: TANG, XIAOQING
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  
The candidate has been previously studying the mechanisms of insulin-regulated glucose transport in 3T3-L1 adipocytes using RNAi technology and later focused on the mechanisms of RNAi and profiling of microRNAs in cancer cells and mouse tissues. To continue her training in the field of diabetes she has recently joined Dr. Sabire Ozcan's laboratory. Dr. Ozcan's research focuses mainly on glucose-regulated insulin gene transcription in pancreatic beta-cells. The immediate career goal of the candidate is to better acquaint herself with experimental procedures and applications in the regulation of insulin gene expression and glucose regulation of pancreatic beta-cell function. This training will allow her to pursue her long-term goal which is to study the role of miRNAs in regulating beta-cell function and to elucidate the role of miRNAs in the development of type-ll diabetes as an independent investigator.  
Recent studies indicate that a novel population of cellular small RNAs termed microRNAs (miRNAs) may play an important role in the development of type 2 diabetes. The expression of these miRNAs may be highly regulated under various environmental and physiological conditions; dysregulation of these small RNAs may lead to the development of type 2 diabetes. For example miR-375 has been discovered to be specifically expressed in pancreatic beta cells and be important in insulin secretion. The functions of most miRNAs in beta cells await to be investigated. The hypothesis of the P.I. is that miRNAs are not functioning alone but rather multiple miRNAs act in cohort to regulate beta cell development and insulin production and secretion in response to glucose. The specific aims of this project are: (1) To profile miRNA expression in pancreatic beta cells in order to identify novel cell-specific and glucose-regulated miRNAs with a recently developed rational miRNA microarray technology; (2) To study the function of the identified glucose-regulated and beta cell-specific miRNAs in MIN6 cells by transfecting with synthetic miRNAs to study overexpression effects and with 2-O-methyl RNA antagomirs to investigate the effects associated with their down-regulation. The results obtained from the proposed activities may lead to the discovery of novel miRNAs or new roles of miRNA network in the development of type 2 diabetes and potential therapeutic approaches to treat or prevent this disease.

project_terms:
Adipocytes;Aftercare;Application procedure;Beta Cell;Cardiovascular Diseases;Cell Line;Cell physiology;Cells;Development;Diabetes Mellitus;Disease;Down-Regulation;Gene Expression;Gene Silencing;Genetic Transcription;Glucose;Goals;Insulin;Laboratories;Lead;Membrane;MicroRNAs;Microarray Analysis;Molecular Profiling;Mus;Non-Insulin-Dependent Diabetes Mellitus;Oligonucleotides;Physiological;Play;Population;Production;RNA;RNA Interference;Rattus;Regulation;Research;Research Personnel;Role;Small RNA;Structure of beta Cell of islet;Technology;Therapeutic;Tissues;Training;blood glucose regulation;cancer cell;career;cohort;endocrine pancreas development;glucose transport;insight;insulin secretion;insulinoma;islet;novel;novel therapeutic intervention;overexpression;prevent;response


application_id: 7672413
project_number: 5R01AA012895-07
project_title: Mechanisms of Alcohol Tolerance and Priming in Humans
administering_ic: NIAAA
award_notice_date: 2009-07-21
application_type: 5
activity_code: R01
ic: AA
serial_number: 012895
program_official: MATOCHIK, JOHN A
project_start_date: 2001-09-01
project_end_date: 2011-08-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 6368360
contact_pi: FILLMORE, MARK T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-09-01
project_abstract:
DESCRIPTION (provided by applicant): Excessive alcohol use (i.e. a binge) contributes to many adverse health consequences (e.g. alcohol poisoning acute alcoholic hepatitis and live cirrhosis). Alcohol is well-known for its acute impairing effects on neurocognitive processes involved in the regulation of behavior and attention. Yet little research has examined how such disturbances might reduce self-control over actual alcohol use leading to patterns of abusive drinking (e.g. binge drinking). Given that even mild doses of alcohol impair control of behavior and attention it is important to understand how acute intoxication can reduce control over alcohol intake once a drinking episode has begun. The proposed project is based on the hypothesis that abuse potential of alcohol is determined by its reward-enhancing effects and its disruptive effects on control mechanisms. Experiments will examine non-dependent adults and will test the disruptive effects of alcohol on neurocognitive control mechanisms in relation to two characteristics associated with increased alcohol abuse: 1) alcohol-induced priming of self-administration; 2) the development of alcohol tolerance. Studies examine the effects of controlled doses of alcohol on neurocognitive performance tasks that measure inhibitory and activational aspects of control. The measures will be studied in relation to alcohol-induced priming of self-administration and in the development of learned alcohol tolerance. The findings will provide an understanding of how drinkers' susceptibility to alcohol's acute behavioral-impairing effects can pose an early-onset risk factor for later alcohol dependence by promoting a continued pattern of abusive binge drinking. The research strategies also will provide methods for testing the role of neurocognitive mechanisms in the treatment efficacy of existing pharmacotherapies such as naltrexone and acamprosate as well as some investigational medications that might operate via neurocognitive control mechanisms:

project_terms:
Accounting;Acute;Acute Alcoholic Hepatitis;Adult;Affect;Alcohol abuse;Alcohol consumption;Alcohol dependence;Alcohols;American Psychiatric Association;Attention;Behavior;Behavior Control;Behavioral;Behavioral Model;Characteristics;Cirrhosis;Consumption;Dependence;Development;Dose;Euphoria;Eye;Eye Movements;Funding;Goals;Health;Human;Impairment;Individual;Intoxication;Laboratories;Learning;Life;Measures;Methods;Modeling;Naltrexone;Neurocognitive;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Play;Predisposition;Principal Investigator;Procedures;Process;Recovery;Regulation;Research;Research Personnel;Rewards;Risk;Risk Factors;Role;Self Administration;Self-control as a personality trait;Series;Staging;Stimulus;Task Performances;Technology;Testing;Training;Treatment Efficacy;Withdrawal;Work;acamprosate;alcohol effect;alcohol poisoning;alcohol sensitivity;base;behavioral pharmacology;binge drinking;craving;drinking;early onset;programs;psychologic;research study;response;selective attention


application_id: 7672155
project_number: 1R41CA139802-01
project_title: Exosomal microRNA profiles as diagnostic biomarkers of ovarian cancer
administering_ic: NCI
award_notice_date: 2009-09-23
opportunity_number: PA-08-051
application_type: 1
activity_code: R41
ic: CA
serial_number: 139802
program_official: LOU, XING-JIAN
project_start_date: 2009-09-23
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZRG1 ONC-M (12)]
contact_pi_person_id: 1867564
contact_pi: TAYLOR, DOUGLAS DILLON
other_pis: GERCEL-TAYLOR, CICEK
congressional_district: 03
department: Unavailable
primary_duns: 829314298
duns_number: 829314298
fips: US
organization_id: 10021906
organization_name: TEKSHIFA, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402416405
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-09-23
budget_end_date: 2011-08-31
project_abstract:
DESCRIPTION (provided by applicant): Detection of ovarian cancer at Stage I results in 5-year survivals of greater than 90%; however only 23% of ovarian cancers are diagnosed early with 67% being diagnosed with metastatic disease. Thus new markers are being sought to accurate identify patients with ovarian cancer particularly in early stage. Emerging evidence suggests the potential involvement of altered regulation of microRNAs (microRNA) in the pathogenesis of human cancers. Several reports have recently demonstrated that microRNA are also active players in human oncogenic signaling pathways and that microRNA profiles from tumor biopsies can be used to diagnose tumour types and prognosis. microRNA-expression profiling of human tumors has identified signatures associated with diagnosis staging progression prognosis and response to treatment. In addition profiling has been exploited to identify microRNA genes that might represent downstream targets of activated oncogenic pathways or that target protein-coding genes involved in cancer. The over-expressions of hsa-miR-21 hsa-mir-141 hsa-miR-200a hsa-miR-200b hsa-miR-200c hsa-miR-203 hsa-miR-205 and hsa-miR-214 have been shown to diagnosis the presence of ovarian cancer and to correlate with poor survival in patients with ovarian cancer. While microRNA profiling has shown promise in the diagnosis of ovarian cancer at this time its application is limited to evaluation of tissue biopsies. To have utility as a diagnostic/screening tool tumor-associated microRNA needs to be identified prior to clinical symptoms or a demostrable mass. Our proposal to utilize circulating tumor exosome-associated microRNA as diagnostic/screening markers is based on our two observations: (1) the production and release of exosomes by tumor cells and (2) the presence of specific microRNAs associated with circulating tumor-derived exosomes. In our preliminary studies we have demonstrated that the microRNA signatures of circulating tumor-derived exosomes from ovarian cancer patients parallel the profiles of microRNAs expressed in the corresponding tumor. Our hypothesis is that identification of specific microRNA associated with circulating ovarian tumor-derived exosomes represent early markers for detection of ovarian cancer. They may also identify staging prognosis and response to therapy for patients with ovarian cancer. To address this hypothesis we will initially isolate and quantitate circulating exosomes from patients with ovarian serous adenocarcinoma at various stages and grades and compare with similar material isolated from women diagnosed with benign ovarian masses (and using material from women without cancer as controls). The microRNA associated with circulating tumor-derived exosomes will be profiled to define all microRNA associated with circulating exosomes. The presence of specific microRNA will be correlated with the presence or absence of malignant disease (and compared to CA125 levels as the "gold standard"). After identifying microRNAs associated with exosomes the presence of specific microRNAs will be defined for different stages to correlate the specific exosomal microRNAs with staging. PUBLIC HEALTH RELEVANCE: Detection of ovarian cancer at Stage I results in 5-year survivals of greater than 90%; however only 23% of ovarian cancers are diagnosed early with 67% being diagnosed with metastatic disease. While miRNA-expression profiling of human tumours has identified signatures associated with diagnosis staging prognosis and response to treatment its utility as a diagnostic tool is limited due to its application to tumor biopsies. Our proposal to utilize circulating tumor exosome-associated miRNA as early detection/screening markers is based on our two observations: (1) the production and release of exosomes by tumor cells and (2) the presence of specific oncogenic miRNA associated with circulating tumor-derived exosomes. Based on our data we propose that identification of specific miRNA associated with circulating ovarian tumor-derived exosomes are early markers for the presence of ovarian cancer and may also define stage prognosis and response to therapy.

project_terms:
3' Untranslated Regions;Address;Affect;Benign;Biopsy;Blood Circulation;CA-125 Antigen;Cancer Patient;Clinical;Code;Data;Diagnosis;Diagnostic;Disease;Early Diagnosis;Evaluation;Gene Expression;Gene Targeting;Genes;Gold;Human;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of ovary;Measures;MicroRNAs;Molecular Profiling;Oncogenic;Ovarian Diseases;Ovarian Mass;Ovarian Serous Adenocarcinoma;Pathogenesis;Pathway interactions;Patients;Peripheral;Production;Proteins;RNA Processing;Regulation;Reporting;Screening for Ovarian Cancer;Screening for cancer;Signal Pathway;Staging;Symptoms;Time;Tissues;Transcript;Tumor-Derived;Untranslated RNA;Woman;base;biomarker;cancer diagnosis;neoplastic cell;novel marker;outcome forecast;ovarian neoplasm;overexpression;public health relevance;response;tool;tumor

public_health_relevance:
Project NarrativeDetection of ovarian cancer at Stage I results in 5-year survivals of greater than 90%; however only23% of ovarian cancers are diagnosed early with 67% being diagnosed with metastatic disease.While miRNA-expression profiling of human tumours has identified signatures associated withdiagnosis staging prognosis and response to treatment its utility as a diagnostic tool is limited due toits application to tumor biopsies. Our proposal to utilize circulating tumor exosome-associated miRNAas early detection/screening markers is based on our two observations: (1) the production and releaseof exosomes by tumor cells and (2) the presence of specific oncogenic miRNA associated withcirculating tumor-derived exosomes. Based on our data we propose that identification of specificmiRNA associated with circulating ovarian tumor-derived exosomes are early markers for thepresence of ovarian cancer and may also define stage prognosis and response to therapy.


application_id: 7671879
project_number: 2R56AG024377-04A1
project_title: Characterization of the Sch9 -Longevity Pathway in Yeast
administering_ic: NIA
award_notice_date: 2008-08-20
opportunity_number: PA-07-070
application_type: 2
activity_code: R56
ic: AG
serial_number: 024377
suffix: A1
program_official: CHATTERJI, MINKI
project_start_date: 2004-09-01
project_end_date: 2008-12-31
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
project_abstract:
Project Summary/AbstractModel organisms such as Saccharomyces cerevisiae have proven effective in elucidatinggenes and metabolites that modulate lifespan and this knowledge forms a basis forunderstanding human aging and longevity. These studies have identified the Akt/PKBprotein kinases as conserved regulators of aging. However it is not entirely clear howthey work. One focus of our research is the S. cerevisiae Sch9 protein kinase an AKThomolog that regulates chronological life span (CLS). From in vitro studies we identifiedsphingolipid long chain bases (LCBs) and Pkh1 a homolog of human phosphoinositidedependentprotein kinase 1 (PDK1) as the first upstream regulators of Sch9. In additionwe identified the first Sch9 substrates Rli1 involved in translation initiation and ribosomebiogenesis and Ahp1 an alkyl hydroperoxide reductase that protects against oxidativestress. We will build upon these novel results and determine if phosphorylation of Rli1 andAhp1by Sch9 plays a role in CLS. We will also determine in vivo if LCBs and Pkh1 actupstream to regulate Sch9 during chronological aging. Published data suggest that theTOR proteins also regulate Sch9 during aging and we will determine if this hypothesis istrue. Although we have successfully identified Sch9 substrates there are likely to beothers and we propose to search for new substrates by classical biochemical strategiesand newer automated but complementary strategies. In summary the results of thesestudies will provide the much needed mechanistic understanding of how Akt (Sch9) activityis regulated in yeast and how it regulates CLS through downstream substrates. Thisknowledge will help to provide a molecular basis for understanding human aging andlongevity.

project_terms:
Aging;Alanine;Alleles;Animal Model;Binding (Molecular Function);Biochemical;Biogenesis;Biological Assay;Caloric Restriction;Cell Fractionation;Cells;Cellular Membrane;Centrifugation Density Gradient;Chimeric Proteins;Chromatin;Data;Enzymes;Genes;Glass;Homologous Gene;Human;In Vitro;Ion-Exchange Chromatography Procedure;Knowledge;Label;Libraries;Longevity;Longevity Pathway;Measures;Mediating;Mediator of activation protein;Molecular;Mutate;Organelles;Oxidative Stress;Pathway interactions;Phase;Phosphatidylinositols;Phosphorylation;Phosphorylation Site;Physiological;Play;Protein Binding;Protein Biosynthesis;Protein Kinase;Proteins;Proto-Oncogene Proteins c-akt;Publishing;RAC-Alpha Serine/Threonine Kinase;Radiolabeled;Rate;Research;Ribosomes;Role;Role playing therapy;Saccharomyces cerevisiae;Site;Slide;Spectrum Analysis Mass;Sphingolipids;Temperature;Testing;Translation Initiation;Work;Yeasts;abstracting;alkyl hydroperoxide reductase;analog;base;cell type;in vivo;mutant;novel;prevent;radiotracer;yeast protein


application_id: 7671142
project_number: 1R43AI079982-01A1
project_title: Potent antimicrobial peptides from carrion beetles
administering_ic: NIAID
award_notice_date: 2009-03-16
opportunity_number: PA-08-050
application_type: 1
activity_code: R43
ic: AI
serial_number: 079982
suffix: A1
program_official: HUNTLEY, CLAYTON C
project_start_date: 2009-03-16
project_end_date: 2010-09-15
study_section: Special Emphasis Panel[ZRG1 IDM-Q (10)]
contact_pi_person_id: 9710810
contact_pi: FATH-GOODIN, ANGELIKA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Antibiotic resistant pathogenic microbes are responsible for thousands of human fatalities worldwide each year. The heightening risk of emerging pathogen resistance in clinical settings promotes the need for discovery and development of new antibiotics with a high degree of activity potency and specificity. ParaTechs Corporation has identified proteinaceous antimicrobial components in the anal and oral secretions of carrion beetles from the family Silphidae. These beetles reproduce by processing and/or burying carrion from vertebrate carcasses upon which they lay their eggs and rear their young. Preservation of the carcass is accomplished through constant covering of the carrion with substances aggressively secreted by the beetles. Carrion treated by the beetles in this manner has shown little evidence of microbial decay over extended periods of time. Here we demonstrate that potent antimicrobial activity is present in proteinaceous secretions from three Silphid species: Nicrophorus marginatus Nicrophorus tomentosus and Silpha (recently revised to Necrophila) americana. Our data demonstrate that proteins within the secretions have varying degrees of potency specificity and activity against bacterial growth suggesting that different antimicrobial components of the secretions may be acting synergistically preventing bacterial decomposition of the carrion. In this Phase I NIH:SBIR proposal we seek funding for the genetic and functional characterization of the potent antimicrobial components discovered in the oral and anal secretions of N. marginatus and S. americana for utilization as novel model antimicrobial molecules for clinical testing and biopharmaceutical applications. PUBLIC HEALTH RELEVANCE: The rapidly increasing microbial resistance to antibiotics in clinical settings is one of the world's most pressing public health concerns. The progressive emergence of new resistant pathogenic bacterial strains demands that efforts be undertaken to seek novel powerful antimicrobial agents that are effective against antibiotic resistant pathogen strains. The potent antimicrobial peptides to be isolated from carrion beetles and characterized with this award possess significant potential utility as novel biopharmaceuticals and may serve as functional models for the development of new and powerful antimicrobial drugs and human therapeutics.

project_terms:
Antibiotic Resistance;Antibiotics;Anus;Award;Bacteria;Biological;Biological Preservation;Biological Products;Cadaver;Caring;Clinical;Collaborations;Complementary DNA;Data;Development;Drosophila genus;EST Library;Electrophoresis Gel Two-Dimensional;Engineering;Environment;Environmental Exposure;Exhibits;Expressed Sequence Tags;Family;Food;Food Preservatives;Funding;Genes;Genetic;Genetic Materials;Grant;Growth;Human;Insect Proteins;Insecta;Laboratories;Lead;Length;Literature;Livestock;Messenger RNA;Methodology;Microbe;Microbial Antibiotic Resistance;Modeling;N-terminal;Nature;Nomenclature;Oligonucleotide Primers;Oral;Order Coleoptera;Organ;Outcome Study;Peptides;Phase;Phase I Clinical Trials;Phase II Clinical Trials;Planets;Positioning Attribute;Predisposition;Process;Property;Proteins;Qualifying;Race;Recombinant Proteins;Reproduction;Research Proposals;Resistance;Resistance development;Resources;Risk;Salivary;Septic Shock;Source;Specificity;Structure;Temperature;Therapeutic;Therapeutic Human Experimentation;Time;Tissues;Transcript;Upper arm;Work;antimicrobial;antimicrobial drug;antimicrobial peptide;cDNA Library;commercialization;design;drug development;egg;evaluation/testing;expression vector;feeding;food resource;fungus;human disease;microbial;microbial genome;mimetics;model development;novel;pathogen;pathogen exposure;prevent;protein expression;public health medicine (field);public health relevance;rapid growth;research clinical testing;resistant strain;tool

public_health_relevance:
Project NarrativeThe rapidly increasing microbial resistance to antibiotics in clinical settings is one of theworld's most pressing public health concerns. The progressive emergence of newresistant pathogenic bacterial strains demands that efforts be undertaken to seek novelpowerful antimicrobial agents that are effective against antibiotic resistant pathogenstrains. The potent antimicrobial peptides to be isolated from carrion beetles andcharacterized with this award possess significant potential utility as novelbiopharmaceuticals and may serve as functional models for the development of newand powerful antimicrobial drugs and human therapeutics.


application_id: 7670115
project_number: 1R43RR025738-01A2
project_title: Creation of hyperactive transposons for mutagenesis in rodents
administering_ic: NCRR
award_notice_date: 2009-02-25
opportunity_number: PA-08-050
application_type: 1
activity_code: R43
ic: RR
serial_number: 025738
suffix: A2
program_official: O'NEILL, RAYMOND R
project_start_date: 2009-03-01
project_end_date: 2010-08-31
study_section: Special Emphasis Panel[ZRG1 GGG-J (10)]
contact_pi_person_id: 3075176
contact_pi: OSTERTAG, ERIC M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 145182338
duns_number: 145182338
fips: US
organization_id: 10004431
organization_name: TRANSPOSAGEN BIOPHARMACEUTICALS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405071112
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-03-01
project_abstract:
DESCRIPTION (provided by applicant): This project aims to rapidly produce rat mutants through a transposon-based method of mutagenesis. The rat is a favored model for many types of human disease for which mice are not suitable. The rat is the most relevant model for cardiovascular and hypertension disease with a heart rate much more similar to that of humans compared to mice. As opposed to the mouse rats and humans also share a more similar number of cytochrome P450 genes perhaps explaining why the rat has been a more useful model for toxicology and pharmacology studies. The rat is also a favored model for diabetes arthritis behavioral disorders (including drug addiction) and brain imaging. Unlike the acrocentric mouse genome the rat and human genomes are predominantly metacentric making chromosomal comparisons more relevant for modeling human genetic diseases. However rat mutants cannot be easily generated through traditional methods of homologous recombination in embryonic stem (ES) cells because rat ES cells cannot be cultured or manipulated. Alternative methods are inefficient and costly. While the rat has not had the ease of genetic manipulation that the mouse has had over the past twenty years it certainly possesses physiological anatomical and chromosomal similarities to humans that make for a more relevant model of human disease. Now this proposal seeks to rapidly produce rat mutants through the development of hyperactive transposons for germ line insertional mutagenesis. This approach uses randomly integrating transposons which enables the rapid identification of sequence-tagged mutation sites. The Aims will focus on synthesizing hyperactive transposases from three different families of transposons each with unique insertion characteristics. The current standard for mutagenesis in rodents using DNA transposons is a rate of 1-3 insertions per gamete in rats and mice. However to be commercially viable and produce at least one null allele in each offspring this transposition rate must be substantially improved. Our goal is to increase the mutation frequency to a level at least 25X greater than the transposons currently used for rodent mutagenesis. Hyperactive transposases will be the direct product from this study while the ultimate Phase II goal will be the generation of rat mutants (MutaRats) for modeling human disease. Offspring of MutaRats (MutaRat Knockout Rat Models) will not be phenotyped or mated to produce a breeding colony but sperm will be isolated from mutant males and cryogenically frozen for future retrieval and fertilization using already existing technology. Mutant animals will be distributed by the National Rat Resource and Research Center and shared with the academic community according to NIH policies for sharing model organisms for biomedical research.  
  
PUBLIC HEALTH RELEVANCE: About 89% of all compounds tested for drug use fail during the final stages of approval due to unacceptable side effects or a lack of efficacy. There is a clear need to screen drugs more effectively in animals during preclinical testing before entering the most expensive phases of drug testing in humans. This project is designed to employ a new method using mobile DNA elements (or "jumping genes") for the rapid and economical production of a large variety of mouse and rat models of human disease which will enable a greater scrutiny of candidate drugs and will facilitate more favorable testing in humans.

project_terms:
Adverse effects;Alleles;Amino Acid Substitution;Animal Model;Animals;Arthritis;Attenuated;Behavior Disorders;Biological Assay;Biomedical Research;Brain imaging;Breeding;Cardiovascular Models;Cell Line;Cells;Characteristics;Chemicals;Cloning;Code;Communities;Complement;Consensus;Culicidae;Custom;Cytochrome P450;DNA;DNA Shuffling;DNA Transposons;Development;Diabetes Mellitus;Disease;Drug Addiction;Drug usage;Elements;Engineering;Event;Family;Family suidae;Fertilization;Flow Cytometry;Freezing;Frequencies (time pattern);Future;Gene Deletion;Gene Delivery;Gene Transfer Techniques;Generations;Genes;Genetic Recombination;Genome;Genomics;Germ Cells;Germ Lines;Goals;Heart Rate;Hela Cells;Hereditary Disease;Human;Human Genetics;Human Genome;Human Pathology;Hyperactive behavior;Hypertension;Individual;Insertional Mutagenesis;Jumping Genes;Knock-out;Libraries;Malaria;Mammalian Cell;Methods;Mission;Modeling;Modification;Mus;Mutagenesis;Mutation;Organism;Partner in relationship;Paste substance;Performance;Pharmacologic Substance;Pharmacology and Toxicology;Phase;Phenotype;Phylogenetic Analysis;Physiological;Physiology;Policies;Preclinical Drug Evaluation;Preclinical Testing;Production;Property;Proteins;RNA;Rattus;Recombinants;Research;Resistance;Resources;Retrieval;Retrotransposon;Rodent;Ruminants;Sequence Alignment;Series;Site;Sleeping Beauty;Small Business Innovation Research Grant;Sperm Banks;Staging;System;Techniques;Technology;Testing;Time;Toxicology;Transgenic Animals;Transgenic Organisms;Transposase;Tribolium (beetle);United States National Institutes of Health;Variant;Work;Yeasts;base;cost;design;directed evolution;drug candidate;drug development;drug testing;embryonic stem cell;falls;genetic manipulation;genome-wide;high throughput screening;homologous recombination;human disease;improved;in vitro Assay;knockout gene;male;meetings;mouse genome;mouse model;mutant;novel;offspring;polypeptide;public health relevance;rat genome;sperm cell;therapeutic gene;tool;transposon/insertion element;vector

public_health_relevance:
Project Narrative About 89% of all compounds tested for drug use fail during the final stages of approval dueto unacceptable side effects or a lack of efficacy. There is a clear need to screen drugs moreeffectively in animals during preclinical testing before entering the most expensive phases ofdrug testing in humans. This project is designed to employ a new method using mobile DNAelements (or "jumping genes") for the rapid and economical production of a large variety ofmouse and rat models of human disease which will enable a greater scrutiny of candidatedrugs and will facilitate more favorable testing in humans.


application_id: 7669656
project_number: N01PC54403-13-0-1
project_title: Surveillance Epidemiology and End Results (SEER) Program - Kentucky
administering_ic: NCI
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
The Surveillance Epidemiology and End Results (SEER) Program of the National Cancer Institute (NCI) is an authoritative source of information on cancer incidence and survival in the United States. SEER currently collects and publishes cancer incidence and survival data from population-based cancer registries covering approximately 26 percent of the US population. SEER coverage includes 23 percent of African Americans 40 percent of Hispanic Americans 42 percent of American Indians and Alaska Natives 53 percent of Asians and 70 percent of Hawaiian and Pacific Island Americans. The current SEER data maintained at NCI includes records on 5.4 million cancers. The database serves as important resource for reporting on the burden of cancer and is utilized by researchers both within and outside of NCI for the purpose of conducting descriptive epidemiologic studies.The SEER Program is a core component of the NCI's surveillance activities which provide information used for planning cancer control and research programs and for evaluating the impact of such programs on cancer rates. The SEER Program was initiated in 1972 in response to requirements of the National Cancer Program for assessing the magnitude of the cancer burden in the United States and for identifying factors related to cancer risk and/or patient survival. The SEER Program has among its objectives: 1. To assemble and report on a periodic basis estimates of cancer incidence.2. To monitor annual cancer incidence trends to identify unusual changes in specific forms of cancer occurring in population subgroups defined by geographic demographic and social characteristics. 3. To provide continuing information on changes over time in extent of disease at diagnosis trends in therapy and changes in cancer patient survival. 4. To identify the occurrence of possible iatrogenic cancers i.e. cancers that are caused by cancer therapy. 5. To serve as a research resource to the National Cancer Institute and conduct studies dealing with current cancer control issues as well as problems related to the operation of the SEER Program.


application_id: 7669336
project_number: 5R44HL083586-03
project_title: Development of a Counterpulsation Therapy Device
administering_ic: NHLBI
award_notice_date: 2009-08-12
opportunity_number: PA-07-280
application_type: 5
activity_code: R44
ic: HL
serial_number: 083586
program_official: BALDWIN, TIM
project_start_date: 2006-02-20
project_end_date: 2011-06-30
study_section: Special Emphasis Panel[ZRG1-SBTS-E(10)B]
contact_pi_person_id: 8385495
contact_pi: SPENCE, PAUL A
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 610420817
duns_number: 610420817
fips: US
organization_id: 10006385
organization_name: SCR, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402022445
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-08-01
budget_end_date: 2011-06-30
project_abstract:
DESCRIPTION (provided by applicant):   SCR Inc. (Louisville KY) has developed a long-term implantable counterpulsation device (CPD) to treat heart failure (HF) patients who may be responsive to a milder form of cardiac assist. The CPD is 32-ml stroke volume valveless pneumatically-driven blood sac with a single inflow/outflow cannula. The sac fits ergonomically in a `pacemaker pocket' and the graft is connected to the arterial system by an anastomosis to the subclavian artery. The CPD can be operated by a standard clinical pneumatic drive console (iPulse) or a small wearable pneumatic driver (in development) connected to the sac by a percutaneous air line and timed to ECG. The CPD fills during native heart systole lowering ventricular workload and ejects during diastole augmenting myocardial and end-organ perfusion. In the phase I study the hemodynamic efficacy of the 32-ml CPD was comparable to a standard commercially-available 40-ml IABP in a large animal model (n=10) demonstrating feasibility. In this phase II study the development and testing of the implantable components of the CPD system will be completed to support a future FDA submission. This objective will be accomplished by (1) completing engineering development and surgical procedure (2) demonstrating reliability and hemocompatability and (3) demonstrating long-term safety and biocompatibility of the implantable components of the CPD system. Results of a pivotal Good Laboratory Practices (GLP) study will be completed with a summary report prepared for submission to the Food and Drug Administration (FDA) to request approval for clinical trials. The proposed study leverages the development work of SCR Inc and manufacturing and commercialization resources of Abiomed (Danvers MA). This partnership will be guided by an innovative group of physicians at Jewish Hospital (Louisville KY) and Advocate Christ Medical Center (Oak Lawn IL) and a world class research team in the Cardiovascular Innovation Institute (CII) at the University of Louisville (UofL). Our long- term objective is to successfully introduce the CPD as a viable long-term therapy to treat late NYHA class III and early NYHA class IV HF patients to restore their quality of life and promote myocardial recovery. PUBLIC HEALTH RELEVANCE is developing a long-term counterpulsation device (CPD) to treat early stage heart failure patients. The CPD has been developed for superficial implantation without the need to enter the chest and enables complete patient mobility.

project_terms:
Advocate;Agreement;Air;Anastomosis - action;Animal Model;Blood;Cannulas;Cardiac;Cardiovascular system;Carotid Arteries;Catheters;Chest;Chronic;Clinical;Clinical Trials;Coronary;Counterpulsation;Data;Development;Devices;Diastole;Electrocardiogram;Engineering;Functional disorder;Future;Goals;Heart;Heart failure;Hospitals;Implant;In Vitro;Institutes;Intra-Aortic Balloon Pumping;Location;Mechanics;Medical center;Modification;Myocardial;Operative Surgical Procedures;Organ;Pacemakers;Patients;Perfusion;Phase;Phase I Clinical Trials;Phase II Clinical Trials;Physicians;Quality of life;Recovery;Research;Resources;Safety;Sales;Staging;Stroke Volume;Structure of subclavian artery;Summary Reports;System;Systole;Testing;Thoracic aorta;Time;United States Food and Drug Administration;Universities;Ventricular;Work;Workload;biomaterial compatibility;commercialization;follower of religion Jewish;good laboratory practice;hemodynamics;implantation;in vivo;innovation;pre-clinical;programs;public health relevance;research study;verification and validation


application_id: 7668765
project_number: 2R44HL088760-02
project_title: Portable pneumatic driver for counterpulsation therapy
administering_ic: NHLBI
award_notice_date: 2009-05-14
opportunity_number: PA-08-050
application_type: 2
activity_code: R44
ic: HL
serial_number: 088760
program_official: MILLER, MARISSA A
project_start_date: 2007-08-01
project_end_date: 2011-04-14
study_section: Special Emphasis Panel[ZRG1 SBTS-E (10)]
contact_pi_person_id: 8385495
contact_pi: SPENCE, PAUL A
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 610420817
duns_number: 610420817
fips: US
organization_id: 10006385
organization_name: SCR, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402022445
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-05-15
budget_end_date: 2010-04-14
project_abstract:
DESCRIPTION (provided by applicant): SCR Inc. (Louisville KY) is developing a chronic implantable CPD system to treat HF patients who may be responsive to long-term counterpulsation support. The CPD has been developed for superficial implantation via a pacemaker incision without the need to enter the chest and enables complete patient mobility. The CPD is a 32-ml stroke volume polyurethane-lined blood chamber designed to fit comfortably in a subcutaneous pocket on the right anterior chest contralateral to an implantable cardioverter defibrillator (ICD) or biventricular pacer device implantation site. The pumping chamber is connected to the systemic circulation by a short ePTFE graft anastomosed to the axillary artery. The CPD is controlled by a small wearable pneumatic driver connected by a percutaneous air line and triggered by the patient's ECG. The CPD fills during native heart systole lowering ventricular workload and ejects during diastole augmenting myocardial and end-organ perfusion. In the phase I study the hemodynamic efficacy of the 32-ml CPD driver was equivalent to a standard commercially-available 40-ml IABP in a large animal model (n=12) over a range of physiologic conditions (hypotension hypertenstion and heart failure) demonstrating feasibility. In this phase II study the development and testing of the CPD driver will be completed to support a future FDA submission. This objective will be accomplished by (1) completing engineering development (2) demonstrating reliability and ergonomics and (3) demonstrating long-term safety of the CPD driver. Results of a pivotal Good Laboratory Practices (GLP) study will be completed with a summary report prepared for submission to the Food and Drug Administration (FDA) to request approval for clinical trials. The program detailed here leverages the development work of SCR and the engineering and development teams at Abiomed (Danvers MA). This partnership will be assisted and guided by an innovative group of physicians at Jewish Hospital (Louisville KY) and a world class research team in the Cardiovascular Innovation Institute (CII) at the University of Louisville (UofL). Our long-term objective is to successfully introduce the CPD system into the clinic as a long-term counterpulsation therapy to treat late NYHA class III and early NYHA class IV HF patients and help restore their quality of life. PUBLIC HEALTH RELEVANCE: SCR Inc. (Louisville KY) is developing a long-term counterpulsation device (CPD) to treat early stage heart failure patients. The CPD has been developed for superficial implantation without the need to enter the chest and a portable pneumatic driver that the patient can carry restores mobility.

project_terms:
Acute;Air;Anastomosis - action;Animal Model;Anterior;Blood;Blood Circulation;Cannulas;Cardiac;Cardiovascular system;Carotid Arteries;Catheters;Chest;Chronic;Clinic;Clinical;Clinical Trials;Contralateral;Coronary;Counterpulsation;Data;Development;Devices;Diastole;Electrocardiogram;Engineering;Functional disorder;Future;Goals;Heart;Heart failure;Hospitals;Hypertension;Hypotension;Implant;Implantable Defibrillators;In Vitro;Institutes;Intra-Aortic Balloon Pumping;Location;Mechanics;Modification;Myocardial;Operative Surgical Procedures;Organ;Pacemakers;Patients;Performance;Perfusion;Phase;Phase I Clinical Trials;Phase II Clinical Trials;Physicians;Physiological;Polyurethanes;Pump;Quality of life;Research;Right-On;Safety;Site;Staging;Stroke Volume;Summary Reports;Support System;Surgical incisions;System;Systole;Testing;Thoracic aorta;United States Food and Drug Administration;Universities;Ventricular;Weight;Work;Workload;axillary artery;biomaterial compatibility;clinically relevant;design;ergonomics;follower of religion Jewish;good laboratory practice;hemodynamics;implantation;improved;in vivo;innovation;pre-clinical;programs;public health relevance;research study;subcutaneous;verification and validation

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


application_id: 7667484
project_number: 5R01DE018215-02
project_title: NUTRITIONAL EPIGENETICS AND OROFACIAL DEVELOPMENT
administering_ic: NIDCR
award_notice_date: 2009-07-16
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DE
serial_number: 018215
program_official: SCHOLNICK, STEVEN
project_start_date: 2008-08-01
project_end_date: 2012-07-31
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 1861667
contact_pi: GREENE, ROBERT M
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Two Two major health care issues are inexorably intertwined: a woman's health and prenatal development of her unborn child. The nutritional value of a woman's diet is critical to both. Folate a water- soluble B vitamin is required for the growth of fetal tissues and normal development of the CNS and orofacial complex. In addition folate supplies the necessary methyl donors for DNA methylation one of the most common epigenetic modifications regulating gene expression in mammalian cells. Incorrect methylation patterns can result in developmental malformations including craniofacial defects. With a frequency of 1-2 in 1000 live births orofacial clefts represent nearly one-half of all craniofacial anomalies While methylation of DNA is a common epigenetic modification that contributes to the control of gene expression in mammalian cells the notion of tissue/cell-specific methylation of discrete CpG islands as a means of regulating morphogenesis of the orofacial region and as a molecular target of nutritional (folate) deficiency as outlined in the present proposal is novel. Thus the global hypothesis we plan to address in the current proposal is that folate deficiency can disrupt the normal methylation state of specific candidate genes and contribute to development of orofacial clefts.   
  
Specific aims/hypotheses addressed in the current application include:   
1 - CpG islands with tissue-dependent and differentially methylated regions (t-dmrs) exhibit distinct spatio- temporal methylation patterns during ontogeny of the 1st branchial arch.   
  
2 - Conditions of gestational folate deficiency that result in facial clefts elicit alterations in CpG island methylation patterns in the 1st branchial arch. These patterns can be reversed with folate supplementation regimens that rescue the phenotype.   
  
3 - Altered promoter CpG methylation patterns regulate expression of genes of the TGF( Signal Transduction Family in the embryonic 1st branchial arch from folate deficient (Folbp1-/-) mice.   
  
4 - Folate deficiency (Folbp1-/-) contributes to the genesis of orofacial clefts by inducing excess apoptosis within the developing 1st branchial arch.

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


application_id: 7666708
project_number: 7R01AG025273-05
project_title: Surgical Studies of Aging and the Gut
administering_ic: NIA
award_notice_date: 2009-09-16
opportunity_number: PA-03-147
application_type: 7
activity_code: R01
ic: AG
serial_number: 025273
program_official: MURTHY, MAHADEV
project_start_date: 2005-09-01
project_end_date: 2012-08-31
study_section: Gastrointestinal Cell and Molecular Biology Study Section[GCMB]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
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):  Medical advances over the last century have enabled people to live longer and remain healthy for a significantly greater amount of time. It is critical that clinicians understand the changes that occur in various organ systems with aging if we are to achieve improvements in the care of the elderly patient. Significant alterations occur in the gastrointestinal (Gl) tract with aging which can manifest as impairments in physiologic functions such as alterations in growth secretion motility and response to trophic factors. These changes have direct ramifications to diseases that are more common in the elderly such as the development of Gl malignancies. Relatively few studies have rigorously examined the changes that occur in the Gl tract with aging. In the past our laboratory has made great strides in the better understanding of the physiologic changes that occur in the Gl tract with aging. We have identified important functional alterations that occur with age such as dysregulation of gut mucosal function and growth in response to trophic factors. Recently we have shown that the basal proliferative rate of colonic mucosa is increased in aged mice. We have utilized gene array analysis and protein expression studies to demonstrate changes in the expression of components of the phosphatidylinositol-3 kinase (PI3K) pathway and insulin-like growth factor (IGF) proteins in the intestine with aging. In addition we have identified an important role for the PI3K/Akt pathway in normal intestinal function and proliferation. Based on our findings the central hypothesis of this proposal is that aging results in the increased activation of the PI3K/Akt pathway in the colon and this increased activity results in increased basal proliferation. We postulate that local changes in downstream protein expression and altered proliferative activity may predispose these colonic crypts to malignant transformation. To examine this hypothesis we have planned experiments with the following Specific Aims: 1) To define the age-associated alteration of colonic growth and PI3K/Akt pathway activation; 2) To determine alterations in proliferation and expression patterns of isolated colonic crypts and stem cells with aging; and 3) To elucidate the role of IGF-I and its receptor on altered PI3K/Akt expression and proliferation. Our studies utilizing novel in vitro models and molecular techniques will continue to challenge previous concepts and viewpoints regarding the aging process and address clinically relevant questions of Gl health and disease with aging which will translate to a better understanding of the effects of aging on the Gl tract and possibly lead to novel therapies.

project_terms:
1-Phosphatidylinositol 3-Kinase;Address;Affect;Age;Age-Years;Aging;Aging-Related Process;American;Caring;Cells;Colon;Colorectal;Colorectal Cancer;Development;Disease;Down-Regulation;Elderly;Feedback;Gene Expression;Gene Mutation;Genes;Growth;Health;Hormones;Impairment;Incidence;Insulin-Like Growth Factor I;Intestines;Laboratories;Lead;Life;Malignant - descriptor;Malignant Neoplasms;Medical;Molecular;Molecular Abnormality;Mucous Membrane;Mus;Mutation;Oncogenes;Operative Surgical Procedures;PTEN protein;Pancreas;Pathway interactions;Pattern;Physiological;Prevention;Process;Proteins;Published Comment;Publishing;Reporting;Role;Societies;Somatomedins;Stem cells;Techniques;Time;Tissues;Translating;age effect;aged;base;body system;cancer cell;carcinogenesis;cell motility;clinically relevant;colonic crypt;gastrointestinal;in vitro Model;innovation;kinase inhibitor;novel;older patient;protein expression;receptor;research study;response;tumor;tumorigenesis


application_id: 7666065
project_number: 5R01EY014821-06
project_title: Mechanisms of Intermediate Distance Space Perception
administering_ic: NEI
award_notice_date: 2009-07-09
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 014821
program_official: STEINMETZ, MICHAEL A
project_start_date: 2003-04-01
project_end_date: 2012-07-31
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 1965646
contact_pi: HE, ZIJIANG
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Visual space perception in the intermediate distance range (2-25 meters) serves a multi-faceted function. It allows the observer to perceive the 3D shapes sizes and locations of objects orient in space and guides our actions. Yet despite its importance in enabling the observer to interact in the natural environment knowledge of the mechanisms underlying space perception in the intermediate distance is incomplete. The long-term objectives of this project are to understand the basic mechanisms of space perception and to discover how these mechanisms mediate human space perception and action. Pertaining to the ability to locate an object on the ground previous work found that the visual system achieves this by constructing a representation of the ground surface and then uses it as a reference frame to localize an object on the ground. To localize a suspended object requires determining the relative position between the suspended object and the ground reference frame. Recent empirical studies have provided critical evidence for the notion of a ground-based space perception and led to the discovery of several fundamental mechanisms for representing the ground surface. This progress has motivated the formulation of a more comprehensive theoretical framework for understanding how the visual system forms the ground-based perceptual space in the current proposal. The specific aims are to seek quantifiable empirical proofs to substantiate and advance the framework. The following three broadly defined issues will be investigated: A. The Perceptual Mechanisms Used by the SSIP to Represent the Ground and Other Surfaces B. The Role of Top-Down Processing in Space Perception C. Locating an Object that Does Not Have a Direct Surface Contact with the Ground The research will employ the psychophysical method to test human observers predominantly in the real 3D environment. In addition to complement the research performed in the real 3D environment the proposed project will investigate space perception in the virtual environment by capitalizing on the virtual reality technology. This approach is not only useful for controlling the experimental stimulation but will also yield insights into how one can improve the immersive quality of virtual scenes. Overall the findings and insights gained from the proposed project will advance the science of human space perception in the intermediate distance range. It will also improve our understanding of the visual problems confronted by people with compromised visual functions.  PUBLIC HEALTH RELEVANCE: Research of space perception in the intermediate distance is important because a significant proportion of our daily activity such as locomotion and navigating are performed over this distance range. Besides its contribution to perceptual sciences the knowledge gained from this project can provide insights into the space perception and action problems of patients with visual deficits (e.g. in strabismus and amblyopia) and the problems encountered by ordinary people in non-optimal visual environments. The approach of using the virtual reality technology in the proposed project has the potential of being adapted into a useful tool for aiding people with space perception deficits.

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


application_id: 7665531
project_number: 5R44AI071618-03
project_title: ApoVax104-HPV as a Novel Vaccine for Cervical Cancer
administering_ic: NIAID
award_notice_date: 2009-07-20
opportunity_number: PA-06-134
application_type: 5
activity_code: R44
ic: AI
serial_number: 071618
program_official: PROGRAIS, LAWRENCE J
project_start_date: 2007-07-31
project_end_date: 2011-07-31
study_section: Special Emphasis Panel[ZRG1-IMM-G(10)B]
contact_pi_person_id: 8392573
contact_pi: MACLEOD, KATHRYN J
other_pis: SHIRWAN, HAVAL
congressional_district: 03
department: Unavailable
primary_duns: 140646345
duns_number: 140646345
fips: US
organization_id: 4350801
organization_name: APOVAX, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-08-01
budget_end_date: 2011-07-31
project_abstract:
DESCRIPTION (provided by applicant):  Cervical cancer is one of the most common cancers affecting women and is a worldwide health problem. Unlike most cancers cervical cancer is caused by a virus - the human papillomavirus (HPV). Two preventative vaccines against HPV were recently licensed in the United States. Merck & Co. developed a vaccine called Gardasil(tm) and GlaxoSmithKline has developed the vaccine Cervarix(tm). Although both appear to be effective at preventing HPV infection in women neither vaccine protects women already infected with HPV from developing cancer or afflicted with the disease. An estimated 20 million people are infected with HPV and worldwide cervical cancer is the third leading cause of cancer death affecting an estimated 500000 women each year. Consequently a therapeutic approach is still necessary to combat already existing HPV infection and cervical cancer.  
Regardless of significant advances in vaccinology the therapeutic potential of cancer vaccines remains to be realized partly due to an array of evasive and immunosuppressive mechanisms employed by progressing tumors4. Therefore the success of therapeutic vaccines is not only contingent upon their ability to generate new immune responses and/or boost the existing ones but also to overcome immune evasion mechanisms. Therapeutic vaccines based on well-defined universal tumor associated antigens (TAAs) represent an attractive approach because of their practicality as well as targeting broad range of cancer types. However the weak antigenic nature of TAAs combined with possible immune tolerance and evasion mechanisms in cancer patients present major hurdles that require potent adjuvants to achieve therapeutic efficacy.  
To overcome these obstacles ApoImmune has developed a proprietary novel HPV vaccine ApoVax104-HPV that constitutes i) a chimeric molecule containing the extracellular domain of costimulatory 4-1BBL fused C-terminus to core streptavidin (ApoVax104) and ii) biotinylated HPV 16 E7 oncoprotein as a TAA conjugated to the chimeric protein via biotin/streptavidin interaction. In the Phase I SBIR application we demonstrated that ApoVax104 component of the vaccine i) targets conjugated antigens into dendritic cells (DCs) constitutively expressing the 4-1BB receptor and activates DCs for antigen uptake and presentation leading to initiation of adaptive immunity ii) directly works on CD4+ and CD8+ T effector (Teff) cells further augmenting adaptive immunity and most importantly iiii) overcomes the suppressive function of CD4+CD25+FoxP3+ T regulatory (Treg) cells. Therefore the pleiotropic effects of 4-1BBL on innate adaptive and regulatory immunity provides a unique advantage over other vaccine approaches under development or in clinical settings. This notion is supported by our strong data obtained during Phase I SBIR studies demonstrating that vaccination with ApoVax104 with a synthetic peptide representing the dominant CD8+ T cell epitope for HPV E7 oncogene (E749-57) was more effective than 3 benchmark adjuvants (lipopolysaccharide (LPS) Monophosphoryl Lipid A (MPL) and CpG oligonucleotide (CpG) in the generation of primary and long- term T cell memory as well as in the eradication of established E7-expressing TC-1 tumors. In addition vaccination with ApoVax104 resulted in better efficacy and undetectable toxicity as compared an agonistic Ab against 4-1BB receptor currently being pursued for cancer clinical trials. Building on these strong preclinical studies obtained from Phase I the goal of this Phase II SBIR application is to develop a humanized ApoVax104-HPV vaccine containing full length HPV16 E6 and E7 oncoproteins to conform to the requirements of the Food and Drug Administration (FDA) for Phase I clinical trials.  
PUBLIC HEALTH RELEVANCE:  Unlike most cancers cervical cancer is caused by a virus - the human papillomavirus (HPV). Cervical cancer is one of the most common cancers affecting women and is a worldwide health problem. An estimated 20 million people are infected with HPV and worldwide cervical cancer is the third leading cause of cancer death affecting an estimated 500000 women each year. The overall goal of this project is to develop a therapeutic cervical cancer vaccine ApoVax104-HPV into a lead commercial product to test in a Phase I clinical trial.

project_terms:
Adjuvant;Affect;Agonist;Animals;Antigens;B-Lymphocytes;Benchmarking;Binding (Molecular Function);Biotechnology;Biotin;C57BL/6 Mouse;CD4 Positive T Lymphocytes;CD8B1 gene;Cancer Etiology;Cancer Patient;Cancer Vaccines;Cell Line;Cell physiology;Cells;Cervarix;Cervical cancer vaccine;Cessation of life;Chimeric Proteins;Clinical;Clinical Trials;Conjugate Vaccines;Data;Dendritic Cells;Development;Disease;Documentation;Dose;Drug Formulations;Effector Cell;Epitopes;Extracellular Domain;Failure (biologic function);Figs - dietary;Gardasil;Generations;Goals;Grant;Guidelines;Health;Homologous Gene;Human;Human Papilloma Virus Vaccine;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Immune;Immune Tolerance;Immune response;Immunity;Immunosuppressive Agents;Immunotherapeutic agent;Immunotherapy;Killings;Lead;Length;Licensing;Ligands;Lipopolysaccharides;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Modeling;Molecular;Monitor;Mus;Nature;Oligonucleotides;Oncogene Proteins;Oncogenes;Peptides;Phase;Phase I Clinical Trials;Phase II Clinical Trials;Preparation;Procedures;Process;Production;Protein Isoforms;Proteins;Quality Control;Recombinant Proteins;Role;Signal Transduction;Small Business Innovation Research Grant;Specificity;Staining method;Stains;Streptavidin;T memory cell;T-Lymphocyte;T-Lymphocyte Epitopes;Technology;Testing;Therapeutic;Toxic effect;Toxicology;Treatment Efficacy;Treatment Protocols;Tumor Antigens;Tumor Necrosis Factor Receptor;United States;United States Food and Drug Administration;Vaccinated;Vaccination;Vaccines;Validation;Virus;Woman;Work;base;cancer therapy;cancer type;clinical material;combat;crosslink;design;efficacy testing;in vivo;interest;long term memory;manufacturing process;member;monophosphoryl lipid A;novel;novel therapeutics;novel vaccines;preclinical study;prevent;protein purification;public health relevance;quality assurance;receptor;research study;response;safety study;success;synthetic peptide;therapeutic development;therapeutic vaccine;tumor;uptake;vaccine development;vaccinology


application_id: 7665352
project_number: 5P50NS039787-10
project_title: Restoration of Dopaminergic Function in Parkinson's Disease
administering_ic: NINDS
award_notice_date: 2009-07-31
opportunity_number: PAR-03-004
application_type: 5
activity_code: P50
ic: NS
serial_number: 039787
program_official: SIEBER, BETH-ANNE
project_start_date: 1999-09-30
project_end_date: 2012-01-31
study_section: ZNS1-SRB-M(17)
contact_pi_person_id: 8383539
contact_pi: GERHARDT, GREG A.
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
  
The neurorestorative and neuroprotective trophic actions of GDNF on midbrain dopamine (DA) neurons provide a promising but controversial therapeutic approach for the treatment of Parkinson's disease. We specifically plan to address the following major issues in the next 5 years of support for the University of Kentucky Udall Center: 1) We hypothesize that GDNF is affecting DA neurons through at least 3 major mechanisms: A) Upregulation of existing DA neurons - direct effects on tyrosine hydroxylase and related proteins (Project 1); B) Repair of DA neurons and connections - improved dendritic and neuronal fiber connections (Projects 2 and 3); and C) Neurogenesis and/or gliogenesis (Project 3). We will investigate these three mechanisms in the proposed experiments in nonhuman primate models of PD. 2) We propose to use a novel indwelling pump that can deliver GDNF chronically in the freely-moving MPTP-lesioned monkey to evaluate multisite delivery of GDNF (putamen vs. putamen + substantia nigra) to improve the functional restoration of DA systems. 3) Recent studies in PD patients involving a Phase 2 clinical trial have yielded controversial data regarding potential GDNF antibody formation and preliminary toxicology studies in rhesus monkeys support a potential toxicity of GDNF to cerebellar Purkinje cells and granule cells when chronically administered in high doses (100 Lig/day) and subsequently withdrawn. In conjunction with Projects 2 and 3 we will investigate the potential toxic effects of GDNF on dopamine and non-dopamine containing cells in the CNS. In addition we will investigate potential antibody formation from chronic GDNF administration. 4) Finally we will use an improved delivery approach to investigate the effects of GDNF infusion on milder parkinsonism in unilateral MPTP-treated monkeys to investigate if earlier intervention of GDNF treatment may contribute to better functional recovery of the nigrostriatal system. We will utilize a recently developed stable unilateral milder parkinsonian monkey model for these studies which may be an "earlystage" model of PD. The different highly integrated Projects and Cores will provide key data regarding the functional effects of chronic GDNF treatments to DA neurons mechanisms of action of GDNF both positive and negative and will provide data that may be useful to gain a better understanding of the effects of trophic factors on dead or dying neurons.    
  
  
Project 1  
  
Title:Neuropharmacological Studies  
  
PI:Greg Gerhardt PhD  
  
DESCRIPTION (provided by applicant):   
  
Quantitative Neuropharmacological .Studies of the Effects of Chronic Delivery of GDNF in Rhesus Monkeys. The neurorestorative and neuroprotective trophic actions of GDNF on midbrain DA neurons provide a promising but controversial therapeutic approach for the treatment of Parkinson's disease (PD).  Based on past work we hypothesize that GDNF is affecting DA neurons through at least 3 major mechanisms:  1) Upregulation of existing DA neurons - direct effects on tyrosine hydroxylase and related proteins; 2) Repair of DA neurons - improved dendritic and neuronal fiber connections; and 3) Neurogenesis and/or gliogenesis. Project 1 will investigate DA function and repair of DA neurons in conjunction with Projects 2 and 3. It is our central hypothesis that dual-site chronic intraputamenal/intranigral delivery of GDNF will improve function and restoration of damaged DA neurons with greater efficacy potency and reduced side effects. In addition we predict based on preliminary data that GDNF treatment in milder parkinsonian animals a model of early stage PD patients will lead to optimal restoration of the nigrostriatal DA neuronal system. We propose to use an indwelling pump that can deliver GDNF chronically in the freely-moving unilateral 1-methyl-4-phenyl- 1236-tetrahydropyridine (MPTP)-lesioned middle-aged female monkeys. Project 1 of this revised program project grant will perform quantitative neurochemical assessments using in vivo microdialysis Western immunoblot assays immunohistochemical studies and high performance liquid chromatography coupled with electrochemical detection (HPLC-EC) to study DA neuronal systems in the striatum (putamen and caudate nucleus) and substantia nigra of Rhesus monkeys that have received chronic GDNF infusions. These neurochemical changes to the monkey striatum during chronic delivery of GDNF will be performed in conjunction with behavioral immunohistochemical histological and functional MRI (fMRI) studies of the same monkeys in conjunction with Projects 2 and 3. In addition Project 1 will begin studies of glutamate regulation in the striatum substantia nigra and globus pallidus of 6-OHDA lesioned rats and the effects of GDNF infusion on glutamate regulation in the basal ganglia. This is as a new area of scientific growth of the Center. The investigation of the role of glutamate in relation of DA function will improve our understanding of the essential role of this neurotransmitter to basal ganglia function in PD.


application_id: 7665351
project_number: 5P50NS039787-09
project_title: Data Analysis and Management Core
administering_ic: NINDS
application_type: 5
activity_code: P50
ic: NS
serial_number: 039787
study_section: ZNS1
subproject_number: 9002
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
budget_end_date: 2009-07-31
funding_mechanism: Research Centers
project_abstract:
Core C- Data Analysis Data management and Data Entry CoreDr. Richard J. Kryscio Professor of Statistics and Director of the Biostatistics Consulting Unit will direct theData Analysis and Data Management Core. Dr. Kryscio has over 20 years of experience consulting onprojects in biomedicine. He is familiar with the analysis of behavioral neurochemical morphological andelectrochemical endpoints taken on rhesus monkeys that have parkinsonian symptoms that have beentreated with vehicle or GDNF. Dr. Anders H. Andersen will be in charge of the analysis of the fMRI data. Dr.Andersen has over 15 years of experience in biomedical signal and image data analysis especially in thearea of MRI and fMRI data. Mike Dunlap is responsible for data entry and for the daily maintenance of thedatabase shared by all projects and cores.The specific aims of the Data Analysis and Data Management Core are to:1. advise all investigators in the Udall Center on issues related to experimental design and data analysis.2. perform the statistical analysis of the main endpoints in each of the projects and cores.3. provide quantitative assessments of each fMRI session recorded in Project 2.4. correlate the findings among the projects.5. establish and maintain a centralized database for the studies on monkeys.

project_terms:
Area;Behavioral;Biometry;Charge;Consult;Daily;Data;Data Analyses;Databases;End Point;Experimental Designs;GDNF gene;Image;Macaca mulatta;Magnetic Resonance Imaging;Magnetic Resonance Imaging Functional;Maintenance;Monkeys;Parkinsonian Disorders;Research Personnel;Science of Statistics;Science of neurochemistry;Signal Transduction;Symptoms;data management;experience;professor


application_id: 7665350
project_number: 5P50NS039787-09
project_title: Animal Core
administering_ic: NINDS
application_type: 5
activity_code: P50
ic: NS
serial_number: 039787
study_section: ZNS1
subproject_number: 9001
contact_pi_person_id: 2154561
contact_pi: ZHANG, ZHIMING
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
budget_end_date: 2009-07-31
funding_mechanism: Research Centers
project_abstract:
Core B- Animal CoreThis Core will be in charge of taking care of the cohorts of monkeys that are to be used for the studies. Thebehavioral tests pump and cannula implant surgeries MPTP-lesions general care of the monkeys and thesurgeries for microdialysis recordings will be performed by this Core. Dr. Zhiming Zhang will coordinate theactivities of the animal Core.

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


application_id: 7665349
project_number: 5P50NS039787-09
project_title: Neuropharmacological Studies
administering_ic: NINDS
application_type: 5
activity_code: P50
ic: NS
serial_number: 039787
study_section: ZNS1
subproject_number: 0004
contact_pi_person_id: 8383539
contact_pi: GERHARDT, GREG A.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
budget_end_date: 2009-07-31
funding_mechanism: Research Centers
project_abstract:
Quantitative Neuropharmacoloqical.Studies of the Effects of Chronic Delivery of GDNF in Rhesus MonkeysThe neurorestorative and neuroprotective trophic actions of GDNF on midbrain DA neurons provide apromising but controversial therapeutic approach for the treatment of Parkinson's disease (PD).Based on past work we hypothesize that GDNF is affecting DA neurons through at least 3 major mechanisms:1) Upregulation of existing DA neurons - direct effects on tyrosine hydroxylase and related proteins; 2) Repairof DA neurons - improved dendritic and neuronal fiber connections; and 3) Neurogenesis and/or gliogenesis.Project 1 will investigate DA function and repair of DA neurons in conjunction with Projects 2 and 3. It is ourcentral hypothesis that dual-site chronic intraputamenal/intranigral delivery of GDNF will improve function andrestoration of damaged DA neurons with greater efficacy potency and reduced side effects. In addition wepredict based on preliminary data that GDNF treatment in milder parkinsonian animals a model of earlystage PD patients will lead to optimal restoration of the nigrostriatal DA neuronal system. We propose to usean indwelling pump that can deliver GDNF chronically in the freely-moving unilateral 1-methyl-4-phenyl-1236-tetrahydropyridine (MPTP)-lesioned middle-aged female monkeys. Project 1 of this revised programproject grant will perform quantitative neurochemical assessments using in vivo microdialysisWestern immunoblot assays immunohistochemical studies and high performance liquidchromatography coupled with electrochemical detection (HPLC-EC) to study DA neuronal systems inthe striatum (putamen and caudate nucleus) and substantia nigra of Rhesus monkeys that havereceived chronic GDNF infusions. These neurochemical changes to the monkey striatum during chronicdelivery of GDNF will be performed in conjunction with behavioral immunohistochemical histological andfunctional MRI (fMRI) studies of the same monkeys in conjunction with Projects 2 and 3. In addition Project 1will begin studies of glutamate regulation in the striatum substantia nigra and globus pallidus of 6-OHDA-lesioned rats and the effects of GDNF infusion on glutamate regulation in the basal ganglia. This is as a newarea of scientific growth of the Center. The investigation of the role of glutamate in relation of.DA function willimprove our understanding of the essential role of this neurotransmitter to basal ganglia function in PD.

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


application_id: 7665348
project_number: 5P50NS039787-09
project_title: Quantitative Morphological Studies
administering_ic: NINDS
application_type: 5
activity_code: P50
ic: NS
serial_number: 039787
study_section: ZNS1
subproject_number: 0003
contact_pi_person_id: 8535427
contact_pi: GASH, DON MARSHALL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
budget_end_date: 2009-07-31
funding_mechanism: Research Centers
project_abstract:
Intrastriatal infusion of the potent dopaminergic trophic factor GDNF promotes significant behavioralimprovements in animal models of Parkinson's disease. The mechanisms of action are not fullyunderstood but include the upregulation of nigrostriatal dopaminergic functions neuroprotectionagainst some neurotoxins and over a period of weeks to months structural restoration on thenigrostriatal dopaminergic system. Another possible mechanism with extraordinary implications ifsubstantiated is the neurogenesis of nigral dopamine neurons. The studies in Project 3 focuse onanswering three major questions. 1) What is the role of neurogenesis and/or gliogenesis in GDNF-induced functional recovery of the nigrostriatal system? Experiments are designed to critically test thehypothesis that neurogenesis is a principal component of functional recovery in the substantia nigra andputamen. 2) To what extent does GDNF therapy restore normal nigrostriatal dopaminergic circuitry?Structural restoration will be correlated with the measures of functional restoration quantified in Projects 1and 2 to critically test the hypothesis that the extent of motor behavior recovery in parkinsonian rhesusmonkeys receiving GDNF therapy is directly correlated to the structural restoration of the nigrostriataldopaminergic system. 3) To identify and analyze possible neuropatholoqical sequellae arising fromintracerebral GDNF treatment. Antibodies to GDNF have been detected in some advancedParkinson's disease patients receiving intracerebral administration of the trophic factor. The effectsof circulating GDNF antibodies on the adult primate nervous system are not known. Thehypothesisbeing tested in this specific aim is that there is not anautoimmune loss of GDNF-responsive neuronsin adult primates with circulating GDNF antibodies. Five populations of GDNF-responsive neuronswill be evaluated in rhesus monkeys receiving intracerebral infusions of GDNF or vehicle. Three ofthe neuronal populations are in the CNS: midbrain dopamine neurons Purkinje cells in thecerebellum and motor neurons in the cervical spinal cord. The other two neuronal types are in thePNS: dorsal root ganglion neurons and enteric neurons in the gastrointestinal system.

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


application_id: 7665347
project_number: 5P50NS039787-09
project_title: Behavioral and fMRI Studies
administering_ic: NINDS
application_type: 5
activity_code: P50
ic: NS
serial_number: 039787
study_section: ZNS1
subproject_number: 0002
contact_pi_person_id: 2154561
contact_pi: ZHANG, ZHIMING
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-08-01
budget_end_date: 2009-07-31
funding_mechanism: Research Centers
project_abstract:
PROJECT 2During the last funding period we demonstrated that programmable pump delivery of GDNF promotesimprovements in motor and nigrostriatal dopamine (DA)functions in nonhuman primate models ofParkinson's disease (PD). In the proposed studies Project 2 will use behavioral and functional magneticresonance imaging (fMRI) methods to determine conditions to further enhance GDNF actions on motor aridDA functions in MPTP-lesioned rhesus monkeys which best simulate the human parkinsonian state. Inconjunction with Projects 1 & 3 Project 2 will determine if combined putamenal and nigral delivery of GDNFvia programmable pumps and intraparenchymal catheters will produce better behavioral recovery of thenigrostriatal pathway than single-site putamenal delivery alone. Project 2 will also investigate if chronicintraparenchymal delivery of GDNF will more completely restore motor and DA functions in MPTP-lesionedanimals expressing milder but stable parkinsonism versus severely impaired animals. In Project 2 theanimals will be quantitatively characterized with apomorphine and levodopa/carbidopa pre- and post-GDNFadministration. To this end we will use a variety of behavioral measurements including: 1) an automatedvideo-tracking system for analyzing whole body movements 2) an automated hand-retrieval task forevaluating fine hand/coarse arm movements and 3) a nonhuman primate rating scale for evaluatingbehavioral features characteristic of PD: bradykinesia rigidity posture balance and tremor. In addition tobehavioral testing Project 2 will use fMRI techniques to noninvasively and simultaneously measureapomorphine-evoked blood oxygen level-dependent (BOLD) changes in basal ganglia functions of alertrhesus monkeys pre- and post-GDNF administration. Collectively these studies should contribute to animproved mechanistic understanding of the effects of chronic GDNF treatment on the nigrostriatal DA systemin nonhuman primates and improved approaches for the treatment of PD.

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


application_id: 7665097
project_number: 5R01CA091901-07
project_title: Novel Aureolic Acid-Type Antitumor Agents
administering_ic: NCI
award_notice_date: 2009-04-15
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 091901
program_official: FU, YALI
project_start_date: 2001-06-01
project_end_date: 2013-05-31
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 2257319
contact_pi: ROHR, JURGEN T
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): Aureolic acid-type anticancer agents such as mithramycin (MTM) or chromomycin (CMM) are potent anticancer drugs with a unique mode-of-action. They inhibit the growth of cancer cells by cross-linking GC-rich DNA thereby shutting down specificity-protein (Sp)-dependent pathways towards various proto-oncogenes including c-myc and c-src the latter being associated with the unique hypocalcemic activity found for these drugs. Particularly MTM is important and has become a popular biochemical tool to study Sp-dependent signal transduction pathways but  due to its toxic side effects  is rarely used as anticancer agent except for the treatment of tumor hypercalcemia refractory to other chemotherapy. However MTM was recently identified as a potential lead drug against neurological diseases arthritis and for the treatment of hematologic disorders. All these new applications require only very small less toxic concentrations of the drug although the mode-of- action in these contexts remains obscure. MTM's biosynthesis has been studied intensely during the previous funding period of this research project and consequently pursued combinatorial biosynthetic efforts revealed various biosynthetic intermediates and new MTM-analogues. Two of these analogues MTM SK and MTM SDK showed a much better anticancer activity profile with a greatly improved therapeutic index than MTM itself. These new drugs deserve further investigations. During the previous biosynthetic studies biosynthetic intriguing and interesting key enzymes were discovered which need to be further investigated particularly oxygenase MtmOIV Ketoreductase MtmW glycosyltransferases MtmGIV MtmGIII MtmGII MtmGI and other early acting post-polyketide synthase tailoring oxygenases and reductases. The goal is to understand the role and mechanisms of these enzymes in the MTM biosynthesis and to optimize them for the engineering of novel MTM derivatives. It is planned to (a) further investigate unclear biosynthetic steps and mechanisms of the MTM and CMM pathways and to generate new MTM analogues applying combinatorial biosynthesis (b) to analyze intriguing oxygenases and reductases (c) to investigate and improve the substrate specificity of glycosyltransferases (d) to study in vitro and in vivo MTM SK MTM SDK and other promising MTM analogues developed during the project.   
  
PUBLIC HEALTH RELEVANCE: The proposed work aims to develop and refine a new generation of aureolic acid type natural product analogues with significantly diminished toxicity that will be useful mainly as anticancer drugs but also as drugs to treat neurological diseases arthritis and hematologic disorders. To enable the production of these fine-tuned drugs through combinatorial biosynthesis in-depth research of the biosynthetic machinery including key enzymes will be explored.

project_terms:
Address;Adverse effects;Anabolism;Antineoplastic Agents;Arthritis;Biochemical;Biological Factors;Cancer Cell Growth;Chromomycin A3;Chromomycins;DNA;Disease;Engineering;Enzymes;Funding;Generations;Goals;Hypercalcemia;In Vitro;Investigation;Lead;Methods;Oxidoreductase;Oxygenases;Pathway interactions;Pattern;Pharmaceutical Preparations;Plicamycin;Process;Production;Property;Proteins;Proto-Oncogenes;Refractory;Research;Research Project Grants;Role;SRC gene;Signal Transduction Pathway;Specificity;Substrate Specificity;Therapeutic Index;Toxic effect;Work;analog;anticancer activity;antitumor agent;c-myc Genes;chemotherapy;chromomycin;combinatorial;crosslink;design;enzyme mechanism;follow-up;glycosyltransferase;improved;in vivo;interest;nervous system disorder;novel;olivomycin A;polyketide synthase;protein structure;public health relevance;research study;sugar;tool;tumor


application_id: 7664694
project_number: 1R41DE018839-01A2
project_title: Delivery of Polyphenols in Gum for Treatment of Gingivitis
administering_ic: NIDCR
award_notice_date: 2009-07-22
opportunity_number: PA-08-051
application_type: 1
activity_code: R41
ic: DE
serial_number: 018839
suffix: A2
program_official: ATKINSON, JANE C
project_start_date: 2009-07-23
project_end_date: 2010-06-30
study_section: Special Emphasis Panel[ZRG1 MOSS-K (11)]
contact_pi_person_id: 1883677
contact_pi: MILLER, CRAIG S
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 793506218
duns_number: 793506218
fips: US
organization_id: 10013455
organization_name: FOUR TIGERS, LLC
organization_city: PARIS
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403612425
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-23
project_abstract:
DESCRIPTION (provided by applicant):  Periodontitis represents a polymicrobial disease in which a complex microbial ecology that matures in biofilms in the subgingival sulcus triggers a chronic immunoinflammatory lesion that destroys soft and hard tissues of the periodontium. The ability to identify therapeutics to enable more effective control and/or prevention of gingival inflammation is a critical facet of current commercial strategies to improve oral health of the population. The goal of this Phase I proposal is to further develop a novel chewing gum containing blackberry extract that delivers bioactive phytochemicals to the oral cavity and test its efficacy in preventing gingivitis. The bioactive phytochemicals in the extract are polyphenols with the most notable being anthocyanins. Methods to prepare and stabilize the extract have already been developed as well as a prototype two gram blackberry extract chewing gum. In addition the extract has already been found to have anti-oxidant anti-cancer anti- inflammatory anti-bacterial and anti-viral properties. In this 12 month research plan four Specific Aims are proposed as follows: Aim 1: Refine the development of chewing gum as a delivery strategy for blackberry extract as a potent natural anti-gingivitis agent. To achieve this Aim the Investigators will i) complete development of qualified stability-indicating analytical method for anthocyanins and phenols in the blackberry extract and the gum prototype ii) develop methods to extract anthocyanins and phenols from the gum iii) determine the release rate of anthocyanins and phenols using a mechanical chewing device iv) perform an accelerated 1 month stability study and establish preliminary release specifications for the clinical batches. Aim 2: Test the hypothesis that bioactive phytochemicals in blackberry extract inhibit mechanisms associated with gingivitis. To achieve this Aim the Investigators will i) evaluate the anti-inflammatory properties of the blackberry extract in human oral epithelial cells and macrophages and ii) test the antimicrobial properties of the blackberry extract against periodontal pathogens and human herpes viruses. Four Tigers LLC and its wholly-owned subsidiary Berryceuticals LLC has partnered with WindStone Farms the largest blackberry farm in the eastern part of the United States to develop and commercialize health and medical products derived from blackberries. The investigators have assembled a highly interdisciplinary team of investigators encompassing expertise in pharmaceutics novel drug delivery systems for the oral cavity periodontics immunology and oral medicine. The chewing gum is an existing drug delivery approach that represents a practical and potentially highly versatile strategy to improve patient oral care. Specifically the gum formulation allows for the localized release of stabilized and highly potent anti-oxidant and anti- inflammatory phytochemicals within the oral cavity. The expected outcome may be improved treatments of gingivitis and periodontal disease as well as caries oral mucositis and other disorders and diseases of the oral cavity.   
  
PUBLIC HEALTH RELEVANCE: The ability to identify therapeutics to enable more effective control and/or prevention of gingival inflammation is a critical facet of current commercial strategies to improve oral health of the population. The goal of this Phase I proposal is to further develop a novel chewing gum delivery system containing blackberry extract that delivers bioactive natural compounds to the oral cavity and test its efficacy in preventing gingivitis. The bioactive compounds in the blackberry extract are polyphenols with the most notable being anthocyanins. These polyphenols have been shown to have very significant anti-inflammatory and anti-microbial properties among other biological activities. The expected outcome may be improved treatments of gingivitis and periodontal disease as well as caries oral mucositis and other disorders and diseases of the oral cavity. This product is being developed as one of the first "Botanical Drug Products" as defined by the FDA in their 2004 Guidance Document.

project_terms:
Address;Affect;Anogenital venereal warts;Anthocyanins;Anti-Bacterial Agents;Anti-Infective Agents;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Biological;Botanicals;Businesses;Cardiovascular system;Characteristics;Chemistry;Chewing Gum;Chronic;Clinical;Complex;Data;Dental caries;Development;Devices;Diabetes Mellitus;Disease;Drug Delivery Systems;Drug Formulations;Ecology;Epigallocatechin Gallate;Epithelial Cells;Event;Farming environment;Genetic;Gingiva;Gingivitis;Goals;Health;Herpesviridae;Human;Immune response;Immunology;Incidence;Infection;Inflammation;Inflammation Mediators;Inflammatory;Lead;Left;Lesion;Licensing;Low Birth Weight Infant;Malignant Neoplasms;Mastication;Measures;Mechanics;Medical;Methods;Microbial Biofilms;Mouth Diseases;Oral;Oral Medicine;Oral cavity;Oral health;Outcome;Patients;Periodontal Diseases;Periodontic specialty;Periodontitis;Periodontium;Pharmaceutical Preparations;Pharmacology;Pharmacy (field);Phase;Phenols;Phytochemical;Population;Predisposition;Prevalence;Prevention;Property;Qualifying;Reactive Oxygen Species;Research;Research Personnel;Risk;Risk Marker;Severities;System;Systemic disease;Testing;Therapeutic;Tigers;Tissues;Tooth Loss;Translational Research;Translations;United States;Viral;Water;analytical method;antimicrobial;cost;experience;improved;innovation;macrophage;microbial;novel;oral care;oral mucositis;pathogen;polyphenol;prevent;prototype;public health relevance

public_health_relevance:
The ability to identify therapeutics to enable more effective control and/or prevention of gingival inflammationis a critical facet of current commercial strategies to improve oral health of the population. The goal of thisPhase I proposal is to further develop a novel chewing gum delivery system containing blackberry extract thatdelivers bioactive natural compounds to the oral cavity and test its efficacy in preventing gingivitis. Thebioactive compounds in the blackberry extract are polyphenols with the most notable being anthocyanins.These polyphenols have been shown to have very significant anti-inflammatory and anti-microbial propertiesamong other biological activities. The expected outcome may be improved treatments of gingivitis andperiodontal disease as well as caries oral mucositis and other disorders and diseases of the oral cavity. Thisproduct is being developed as one of the first "Botanical Drug Products" as defined by the FDA in their 2004Guidance Document.


application_id: 7663910
project_number: 5R01DK071765-05
project_title: Mechanisms of S-adenosylmethionine in NASH
administering_ic: NIDDK
award_notice_date: 2009-08-07
application_type: 5
activity_code: R01
ic: DK
serial_number: 071765
program_official: DOO, EDWARD
project_start_date: 2005-09-15
project_end_date: 2011-07-31
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
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
budget_start_date: 2009-08-01
project_abstract:
DESCRIPTION (provided by applicant): S-adenosylmethionine (SAMe) is an important methyl donor and antioxidant. Depressed SAMe levels are observed in multiple forms of experimental liver injury and SAMe therapy is an effective hepatoprotective agent in diverse forms of experimental liver injury. SAMe is available as a complementary and alternative medicine and is widely used to treat several forms of liver disease as well as depression. Likely therapeutic properties of SAMe include its effects on methylation antioxidant status mitochondrial function hepatocyte differentiation cytokine metabolism and/or antidepressive functions. In this proposal we will evaluate potential benefits of SAMe in an emerging major health problem in the U.S. non-alcoholic steatohepatitis (NASH). While the etiology of NASH still remains unclear most investigators agree that a baseline of steatosis requires a second "hit" capable of inducing inflammation fibrosis or necrosis in order to develop NASH. The focus of our research group has been the interactions of cytokines oxidative stress with lipid peroxidation and mitochondrial dysfunction in the induction of steatohepatitis both alcoholic and nonalcoholic in origin. Recent research from other laboratories also supports increased cytokine activity oxidative stress and mitochondrial dysfunction in the pathogenesis of NASH. Our long-term goal is to further understand mechanism(s) of action of SAMe in liver disease. In this proposal we will evaluate specific mechanisms of action of SAMe in the human liver disease NASH. This is not a clinical trial but a mechanistic translational study. The specific objectives for this proposal are: 1 .Evaluate mechanisms for dysregulated TNF/cytokine production in patients with NASH and determine whether or not SAMe in vitro/ex vivo favorably modulates this abnormal cytokine metabolism; 2. Evaluate in vivo mechanisms of action of SAMe in NASH patients including antioxidant status cytokine metabolism liver function and quality of life issues; 3. Determine whether or not hepatic methyltransferases are decreased in NASH and improve with SAMe therapy; and 4. Determine by proteomic analysis of serum and liver biopsies the proteins (esp. oxidative stress oxidized and mitochondrial proteins) that may play a role in the diagnosis or etiology of NASH and which may be modified by SAMe therapy

project_terms:
Alcohol consumption;Alcoholic Hepatitis;Antioxidants;Applications Grants;Body Weight decreased;Choline Deficiency;Clinical;Clinical Trials;Coin;Complementary and alternative medicine;Development;Diabetes Mellitus;Diagnosis;Enzymes;Etiology;Evolution;FDA approved;Female;Fibrosis;Goals;Health;Hepatic;Hepatocyte;Hepatoprotective Agent;Human;Hyperlipidemia;Hypertension;In Vitro;Inflammation;Injury;Insulin Resistance;Knockout Mice;Knowledge;Laboratories;Lipid Peroxidation;Liver;Liver diseases;Liver neoplasms;Metabolic;Metabolic syndrome;Metabolism;Methionine;Methylation;Methyltransferase;Mitochondria;Mitochondrial Proteins;Mus;Necrosis;Obesity;Organ;Oxidative Stress;Pathogenesis;Patients;Pharmaceutical Preparations;Pharmacotherapy;Play;Polycystic Ovary Syndrome;Predisposition;Production;Property;Proteins;Proteomics;Protocols documentation;Quality of life;Research;Research Personnel;Role;S-Adenosylmethionine;Serum;Simulate;Steatohepatitis;Syndrome;Tamoxifen;Therapeutic;Therapeutic Agents;Toxin;Translational Research;Tumor Necrosis Factor-alpha;Tumor Necrosis Factors;base;cytokine;depressed;depression;diabetic;improved;in vivo;liver biopsy;liver function;methionine adenosyltransferase;mitochondrial dysfunction;non-alcoholic;nonalcoholic steatohepatitis;problem drinker;translational study


application_id: 7663173
project_number: 5R01DE015254-07
project_title: Pattern Recognition of P. gingivalis Virulence Factors
administering_ic: NIDCR
award_notice_date: 2009-07-16
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DE
serial_number: 015254
program_official: LUNSFORD, DWAYNE
project_start_date: 2004-07-01
project_end_date: 2013-07-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6712964
contact_pi: HAJISHENGALLIS, GEORGIOS
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Innate immunity plays a central role in infection-driven inflammatory conditions including periodontitis which is one of the most common chronic disorders of infectious origin in humans. However successful microbial pathogens such as the periodontopathogen Porphyromonas gingivalis have evolved mechanisms which proactively manipulate the innate immune response. Subversion of innate immunity may additionally undermine the overall host defense since the innate immune response plays an instructive role in adaptive immunity. This research proposal has been designed to investigate and elucidate molecular mechanisms whereby P. gingivalis modifies innate immune signaling pathways leading to increased virulence and persistence within the host. Although innate recognition and signaling in response to P. gingivalis is primarily mediated by the Toll-like receptor 2 (TLR2)-centered pattern recognition apparatus preliminary studies indicate that this periodontal pathogen instigates the association of the chemokine receptor CXCR4 with TLR2 resulting in cross-talk and altered signaling downstream of TLR2. On the basis of additional preliminary evidence the overall hypothesis is that P. gingivalis through its cell surface fimbriae exploits CXCR4 and manipulates TLR2 intracellular signaling in ways that suppress the proinflammatory/antimicrobial pathway but enhance a distinct proadhesive pathway; both of these activities have the potential to increase the survival capacity of the pathogen thereby prolonging P. gingivalis infection and potentiating its impact on periodontal disease. In vitro immunological approaches using transfected cell lines or primary macrophages will elucidate the mechanistic basis of TLR2/CXCR4 cross-talk which is hypothesized to involve the cAMP-dependent protein kinase A. Moreover the biological significance of the putative exploitation of CXCR4 by P. gingivalis will be investigated using a mouse periodontitis model in which a CXCR4 antagonist (AMD3100) is expected to suppress P. gingivalis virulence. The long-term objective of investigating CXCR4-dependent mechanisms whereby P. gingivalis manipulates TLR2 signaling is to identify effective antagonists for redirecting the innate response to benefit the host. The fight against HIV and AIDS has produced a number of drugs including CXCR4 antagonists which are available for investigation in other formidable diseases where CXCR4 may play a pathophysiological role. Such CXCR4 antagonists may find therapeutic application in human periodontitis.   
  
PUBLIC HEALTH RELEVANCE: Periodontitis is one of the most common chronic disorders of infectious origin in humans and is also associated with systemic diseases such as atherosclerosis. This research proposal presents evidence that the periodontal pathogen P. gingivalis exploits a host receptor namely CXCR4 for undermining host defense and promoting its virulence. We believe that CXCR4 antagonists may find therapeutic application in human periodontitis and in this context; we will test a CXCR4 antagonist (AMD3100) for its ability to inhibit P. gingivalis-induced periodontitis in a mouse model.

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


application_id: 7663142
project_number: 5P20RR017702-07
project_title: Molecular Determinants of Developmental Defects
administering_ic: NCRR
award_notice_date: 2009-05-20
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
program_official: DOUTHARD, REGINE
project_start_date: 2002-09-30
project_end_date: 2013-05-31
contact_pi_person_id: 1861667
contact_pi: GREENE, ROBERT M
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-06-01
project_abstract:
DESCRIPTION (provided by applicant): The present application represents a resubmission (01A1) of a COBRE application wherein we have addressed all concerns noted by reviewers (see "Introduction"). Revised individual project proposals are each preceded by an "Introduction" in which COBRE Investigators respond to Project Critiques provided by reviewers. The primary purpose of this renewal application continues to be fostering of health-related research and mentoring-enhanced competitiveness of junior unfunded investigators.   
  
In this renewal application we have included proposals from: 2 junior investigators who have not previously been a PI on a funded research project grant or program project grant; 2 early career investigators who were COBRE supported during our initial funding period and who were successful in obtaining independent funding from the NIH (R01 and K02); a senior investigator whose proposal will facilitate a mid-career research transition; and a pilot project from a clinical junior investigator seeking to redefine his academic career as a clinical research scientist. Two (2) new faculty lines representing sustained commitment from the university have been pledged as part of this competitive renewal application. Two junior faculty who complement the thematic scope of our COBRE will thus be recruited and will be COBRE-supported. Each of these investigators will be mentored by an established well-funded senior biomedical research scientist recognized for his/her scientific expertise in the area of the COBRE investigator's research proposal.  
  
The program continues to be led by Robert M. Greene Ph.D. an established biomedical research scientist well recognized for his extensive expertise central to the research theme of the proposal-molecular mechanisms underlying developmental defects. This renewal application if funded will 1) substantially enhance the research career development and research competitiveness of no less than five (5) junior investigators two early career investigators and one senior investigator and 2) promote the development and enhance the evolution of our Center such that it will be able to successfully compete for independent Center and/or program project funding. A detailed plan for each COBRE investigator's research career development has been formulated; expectations and objectives for achieving independent funding are clearly articulated; clear and tangible evidence of continuing and expanded institutional commitment is documented; excellent research resources and a supportive intellectual environment exists.


application_id: 7663058
project_number: 5R21EY019113-02
project_title: Zeb1 and epithelial-mesenchymal balance in the eye
administering_ic: NEI
award_notice_date: 2009-07-09
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: EY
serial_number: 019113
program_official: MARIANI, ANDREW P
project_start_date: 2008-08-01
project_end_date: 2011-07-31
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 1877760
contact_pi: DEAN, DOUGLAS CHASE
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Overexpression of zinc finger homeodomain 1 (Zeb1) triggers epithelial-mesenchymal transition (EMT) by repressing key epithelial specialization genes including E-cadherin. By contrast mutation of Zeb1 leads to mesenchymal-epithelial transition with ectopic expression of epithelial genes. Mutation of Zeb1 in patients is linked to epithelization of corneal endothelium and posterior polymorphous corneal dystrophy (PPCD). Mice null for Zeb1 exhibit PPCD characteristics late in embryogenesis whereas such pathologic changes are delayed until adulthood in heterozygous mice. Overexpression of Zeb1 occurs in dedifferentiation of retinal pigment epithelial (RPE) cells an EMT characterized by ectopic proliferation loss of pigment and transition to fibroblastic morphology. Such RPE dedifferentiation contributes to proliferative vitreoretinopathy the major complication in retinal detachment. Heterozygous mutation of Zeb1 prevents RPE dedifferentiation. We propose a series of experiments to begin examining the molecular basis for Zeb1 function in regulating epithelial-mesenchymal balance in eye cells. PUBLIC HEALTH RELEVANCE: Epithelial vs. mesenchymal balance is crucial for normal tissue formation in development and this balance is disrupted in eye diseases such as posterior corneal dystrophies and proliferative vitreoretinopathy. We provide evidence that the zinc finger E-box binding homeodomain1 (Zeb1) is important in regulating epithelial-mesenchymal balance in corneal endothelium and retinal pigmented epithelium.

project_terms:
Back;Binding (Molecular Function);Boxing;Cells;Characteristics;Complication;Corneal Endothelium;Corneal dystrophy;Development;E-Cadherin;Ectopic Expression;Embryonic Development;Epithelial;Equilibrium;Exhibits;Eye;Eye diseases;Gene Expression;Genes;Genetic Transcription;Human;Knockout Mice;Link;Mesenchymal;Molecular;Morphology;Mus;Mutant Strains Mice;Mutation;Normal tissue morphology;Pathologic;Patients;Phenotype;Pigments;Principal Investigator;Proliferative Vitreoretinopathy;Repression;Retinal Detachment;Retinal Pigments;Role;Series;Specific qualifier value;Structure of retinal pigment epithelium;Zinc Fingers;base;epithelial to mesenchymal transition;homeodomain;in vivo;overexpression;prevent;programs;public health relevance;research study;transcription factor


application_id: 7662572
project_number: 5R01CA122383-04
project_title: Tumor-Targeting Oligonucleotides
administering_ic: NCI
award_notice_date: 2009-07-31
application_type: 5
activity_code: R01
ic: CA
serial_number: 122383
program_official: LEES, ROBERT G
project_start_date: 2006-08-01
project_end_date: 2011-07-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 6663799
contact_pi: BATES, PAULA J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-09-01
project_abstract:
DESCRIPTION (provided by applicant): A major goal of translational cancer research is to develop targeted therapies that can specifically inhibit the expression or function of proteins that play an essential role in oncogenesis. There is considerable interest in using synthetic DNA or RNA oligonucleotides to achieve this goal because of their ability to recognize specified nucleic acid sequences or protein structures with high affinity. Several oligonucleotide-based strategies including antisense small interfering RNAs (siRNAs) protein-binding aptamers and immunostimulatory oligonucleotides have produced potent anti-cancer effects in pre-clinical studies. However clinical trials of therapeutic (antisense) oligonucleotides have been generally disappointing and this has been attributed in part to their inefficient uptake by cancer cells. The Principal Investigator and her collaborators have developed a novel antiproliferative oligonucleotide named AGRO100. This molecule has recently been tested in a clinical trial involving patients with advanced cancer and has demonstrated a remarkable lack of toxicity combined with promising clinical activity. Unlike most other oligonucleotides AGRO100 is taken up efficiently and selectively by cancer cells in culture and in vivo. We hypothesize that these extraordinary properties are related to the unusual G-quadruplex structure of AGR0100 and its ability to bind specifically to a protein that is expressed at high levels on the surface of cancer cells. The long-term goal of this project is to develop oligonucleotides that are avidly and selectively taken up by cancers in vivo. Such tumor-targeting sequences could be incorporated into oligonucleotide-based therapeutics or conjugated to chemotherapy drugs in order to enhance their efficacy and reduce unpleasant side effects. In this application we propose to elucidate the mechanism involved in the preferential uptake of AGRO100 by tumors and to identify sequence or structural motifs that lead to efficient oligonucleotide internalization by cancer cells. The first specific aim is to characterize the cellular internalization of AGRO100 and confirm the role of nucleolin in this process. The second aim is to use a SELEX approach to identify oligonucleotides (from combinatorial libraries) that have efficient and selective uptake by cancer cells. The third aim is to incorporate the optimal tumor-targeting sequences into antisense siRNA and immunomodulatory oligonucleotides in order to determine if this leads to superior uptake and activity.

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


application_id: 7660495
project_number: 5R01DK072032-05
project_title: Podocytes and oxidative stress in diabetic kidney
administering_ic: NIDDK
award_notice_date: 2009-06-26
application_type: 5
activity_code: R01
ic: DK
serial_number: 072032
program_official: NIHALANI, DEEPAK
project_start_date: 2005-09-01
project_end_date: 2011-07-31
study_section: Pathobiology of Kidney Disease Study Section[PBKD]
contact_pi_person_id: 1927079
contact_pi: EPSTEIN, PAUL N
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-08-01
project_abstract:
DESCRIPTION (provided by applicant): The single largest cause of end stage renal disease in the United States is diabetic nephropathy (DN). We have recently characterized the progression of DN in a transgenic mouse model of Type I diabetes called OVE26. This model is a significant improvement over previous DN models in that 9 month old OVE26 mice exhibit many characteristics of advanced DN. They show a 100 fold increase in albuminuria extensive interstitial fibrosis and a modest reduction in GFR. We will use this model to assess the role of reactive oxygen species (ROS) in the glomerular podocyte for development of DN. OVE26 mice will also allow us to assess changes in glomerular gene expression by laser capture and Affymetrix gene array analysis during the progression from early DN at two months of age to severe DN at fourteen months of age in OVE26 mice. In addition the severe DN in OVE26 animals will allow us to make the first test of the ability of oral antioxidant therapy to block advance DN.    ROS have been shown to be a critical component of DN. Systemic treatment with antioxidants or ubiquitously expressed antioxidant transgenes protect diabetic animals from early stage DN. However by systemic treatment it is not possible to identify which cells in the glomerulus are injured by ROS or protected by antioxidant treatment. Podocytes are an important candidate cell. They make up a critical component of the selective glomerular filtration membrane and many podocytes are lost during the progression of DN. In addition they have been shown to produce ROS. We developed transgenic mice that use the podocyte selective nephrin promoter to overexpress a transgene for the potent antioxidant protein metaliothionein. We demonstrated elevated podocyte expression of the metaliothionein transgene by immunohistochemistry and western blotting. Mice that overexpress metaliothionein in podocytes were bred to OVE26 Type I diabetic mice. Our initial results demonstrate that podocyte overexpression of metaliothionein dramatically reduces diabetes-induced macroalbuminuria and significantly reduces glomerular hypertrophy. These mice will be used to assess the role of ROS damage to the podocyte in the changing gene expression and deteriorating structure and function that lead to diabetic end stage renal disease.

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


application_id: 7659606
project_number: 5R03AG029304-02
project_title: Dynamics of Sleep Fragmentation in the Elderly
administering_ic: NIA
award_notice_date: 2009-07-09
opportunity_number: PA-06-180
application_type: 5
activity_code: R03
ic: AG
serial_number: 029304
program_official: MACKIEWICZ, MIROSLAW
project_start_date: 2008-08-01
project_end_date: 2011-06-30
study_section: Cardiovascular and Sleep Epidemiology Study Section[CASE]
contact_pi_person_id: 1918429
contact_pi: BRUCE, EUGENE N
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): Aging is associated with major changes in the structure and quality of sleep. Older subjects experience decreased sleep efficiency increased numbers of arousals and awakenings and sleep fragmentation which may well play a pivotal role in both the daytime sleepiness and the age-associated decline in neurocognitive function in the elderly. This application develops and tests an integrative hypothesis that relates arousals to the occurrence of transient EEG events indicative of subthreshold arousals and sleep consolidations. By applying this integrative framework to both middle-aged (40-49 yrs) and elderly (70-79 yrs) Caucasian and African-American men and women we expect to generate novel insights into the causes of sleep fragmentation in the elderly. Preliminary results show that Sample Entropy of the C3A2 EEG signal varies systematically with sleep state being highest in Wake and lowest in stage 3-4 and that this variation is age-dependent. Thus a conceptual model of temporal fluctuations of depth of sleep within a sleep state and a novel measure of depth of sleep EEG entropy (a measure of irregularity) are proposed. A core principle of the model is that depth of sleep is continuously graded. Three hypotheses derived from this model will be tested: (1) EEG entropy fluctuates in a given sleep state and arousals are more likely when entropy transiently increases; (2) in a given sleep state fluctuations of EEG entropy with time (which reflect short-lived events in the EEG such as microarousals and bursts of delta waves) are not entirely random; rather they also reflect the slow decay of the effects of prior events that perturbed the depth of sleep; and (3) the time course of decay of the effects of past sleep-disturbing events is slower in elderly than in middle- aged subjects; this factor contributes to the increased number of arousals in the elderly by prolonging the period of increased susceptibility to a subsequent sleep disturbance. This Small Research Grant will utilize existing data from the NHLBI-supported Sleep Heart Health Study (polysomnograms from >6400 subjects are available).  PUBLIC HEALTH RELEVANCE: We expect that the proposed studies will develop and validate a novel framework for understanding the time-varying relationship of transient EEG events to arousals and their increase with aging. Additionally Sample Entropy of EEG signals may find utility as a measure of depth of sleep for evaluating the effects of therapies. The goal of this study is to understand why the elderly awaken more frequently at night than younger individuals. To accomplish this objective we will analyze electroencephalogram (EEG) recordings obtained from middle-aged and elderly subjects while they are asleep to enhance our understanding of the changes that occur in these EEGs immediately before subjects wake up.

project_terms:
Accounting;Address;Adult;African American;Age;Aging;Applications Grants;Arousal;Categories;Caucasians;Caucasoid Race;Circadian Rhythms;Clinical;Complex;Data;Data Analyses;Development;Distant;Elderly;Electroencephalogram;Entropy;Evaluation;Event;Figs - dietary;Foundations;Frequencies (time pattern);Future;Gender;Goals;Health;Heart;Homeostasis;Incidence;Individual;Kale - dietary;Life;Measures;Methods;Modeling;National Heart Lung and Blood Institute;Nature;Neurocognitive;Pattern;Play;Predisposition;Prevalence;Race;Relative (related person);Reporting;Research Project Grants;Resolution;Role;Sampling;Signal Transduction;Sleep;Sleep Fragmentations;Sleep disturbances;Slow-Wave Sleep;Staging;Stimulus;Structure;Testing;Time;Variant;Woman;age effect;age related;base;clinically significant;experience;indexing;insight;men;middle age;neuromechanism;novel;public health relevance;relating to nervous system;sleep regulation;time use


application_id: 7659587
project_number: 5R03HD058850-02
project_title: Academic-Community Coalition for a School-based Obesity Prevention/Treatment Prog
administering_ic: NICHD
award_notice_date: 2009-06-26
opportunity_number: PA-06-416
application_type: 5
activity_code: R03
ic: HD
serial_number: 058850
program_official: HAVERKOS, LYNNE
project_start_date: 2008-08-01
project_end_date: 2011-06-30
study_section: ZHD1-DSR-M(HB)
contact_pi_person_id: 8535924
contact_pi: PERMAN, JAY A
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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The University of Kentucky College of Medicine proposes a pilot study to test the feasibility of a school-based program for the prevention and treatment of childhood obesity. The prevalence of childhood obesity has increased dramatically in the United States along with a host of obesity-related diseases. The human and economic costs of this epidemic and related illnesses are enormous and left unchecked they threaten to overwhelm the health care system of this country. Unfortunately there are relatively few studies that both document success in obesity prevention and treatment in children and identify "best practices" suitable for export to other communities and neighborhoods. Initial data from our earlier pilot program at a local elementary school demonstrated a significant improvement in Body Mass Index (BMI) endpoints after only six months of a universal intervention program consisting of physical activity nutrition instruction and behavioral modification. Therefore we propose to test the overall hypothesis that a coalition of academic and community partners can develop and implement a school-based obesity prevention and treatment program that is effective affordable scalable and sustainable. The study design is a parallel-group randomized controlled trial to compare an obesity prevention and treatment program consisting of tiered interventions of escalating intensity with conventional school programs and curricula. Cross-group contamination is minimized by designating an entire elementary school as the intervention group compared with a control elementary school of similar demographic characteristics and student profiles. Specific aim 1 will evaluate the effectiveness of module 1 (universal prevention) interventions aimed at the entire enrollment of the intervention school. They include daily in-class physical activities and nutritional instruction elimination of food rewards and improvements in the school menu. Specific aim 2 will evaluate the efficacy of module 2 (Jumpin' Jaguars program) interventions that are targeted to and tailored for children who are at risk or already overweight/obese (i.e. BMI = 85 percent) and at greatest risk for weight-related illnesses. This module includes individualized strategies to enhance physical activity nutritional education behavioral modification and caregiver involvement and participation. The outcomes for both intervention modules are weight height calculated BMI BMI percentile weight status category and will be obtained every 6-month for two years. We anticipate that the significant improvement in BMI endpoints in module 1 (universal) interventions seen in our earlier pilot will be maintained and extended after the two years of this study. We expect the trend in improvement in BMI endpoints in module 2 interventions (Jumpin' Jaguars) seen in our 6-month earlier pilot will reach significance with the two-year duration of this study. The coalition of academic and community partners enables the leveraging of personnel and material resources such that our program is affordable scalable and sustainable. Programs with these characteristics represent the future for the prevention of childhood obesity in this country. Project Narrative: Since childhood obesity and related illnesses have reached epidemic proportions in the United States effective programs for the prevention and treatment of obesity in children and adolescents are critical for the future health and well-being of the citizens of this nation. In this research application the University Of Kentucky College Of Medicine proposes to test the efficacy of a school-based childhood obesity prevention and treatment program that is built on a coalition of academic and community partners. This program has a high likelihood of identifying "best practices" that are both affordable and scalable and therefore transferable to other communities across the Commonwealth and nation.

project_terms:
Accounting;Address;Adolescent;Age;Behavior Therapy;Body mass index;Cardiovascular Diseases;Caregivers;Categories;Centers for Disease Control and Prevention (U.S.);Characteristics;Child;Child Support;Childhood;Communities;Country;County;Data;Diabetes Mellitus;Disease;Economic Burden;Educational Curriculum;Educational aspects;Effectiveness;Enrollment;Epidemic;Family;Food;Future;Gender;Growth;Health;Healthcare Systems;Height;Human;Human Resources;Instruction;Intervention;Kentucky;Left;Life;Life Expectancy;Malignant Neoplasms;Medical;Medicine;Neighborhoods;Non-Insulin-Dependent Diabetes Mellitus;Nutritional;Obesity;Obesity associated disease;Orthopedics;Outcome;Overweight;Panthera onca;Personal Satisfaction;Physical activity;Pilot Projects;Population;Prevalence;Prevention;Prevention program;Preventive Intervention;Probability;Quality of life;Randomized Controlled Trials;Research;Research Design;Resources;Rewards;Risk;Schools;Sleep Apnea Syndromes;Students;Testing;Underrepresented Minority;United States;Universities;Weight;Youth;base;college;cost;design;economic cost;efficacy testing;elementary school;group intervention;intervention program;nutrition;obesity in children;obesity prevention;programs;self esteem;success;treatment program;trend;universal prevention


application_id: 7658068
project_number: 5T32DK007778-10
project_title: Training Program in Oxidative Stress and Nutrition
project_terms: Oxidative Stress;Training Programs;nutrition
administering_ic: NIDDK
award_notice_date: 2009-07-27
opportunity_number: PA-02-109
application_type: 5
activity_code: T32
ic: DK
serial_number: 007778
program_official: DENSMORE, CHRISTINE L
project_start_date: 2000-08-15
project_end_date: 2010-07-31
study_section: Digestive Diseases and Nutrition C Study Section[DDK-C]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  
Poort dietary habits play an etiological role in 5 of the 10 leading causes of death in the United States. In spite of long-standing compelling arguments nutrition education in medical schools remains inadequate. This is a competing renewal of a training program in the area of "Oxidative Stress and Nutrition". Progress has been excellent during the previous funding period as evidenced by student qualifications honors and awards and productivity. Four areas of emphasis in nutritional sciences form the basis of the training program in the competing renewal: (1) Nutrition and Cardiovascular Disease (2) Nutrition and Cancer (3) Nutrition and Neuroscience/Aging and (4) Nutrition and Metabolic Disease. The training program is based in the Multidisciplinary Ph.D. Program in Nutritional Sciences which provides teaching and research. The research facilities of training faculty in Nutritional Sciences has been markedly improved during the previous funding period through allocation of dedicated space for research and graduate training. Faculty members sharing a common interest in nutrition have joint appointments in the Nutritional Sciences Ph.D. Program with primary appointments in multiple units including: Aging Anatomy/Neurobiology Agriculture Biochemistry Cardiology Chemistry Gastroenterology Microbiology/Immunology Neurosurgery Pediatrics Pharmacology Physiology Pharmaceutical Sciences and Radiation Medicine. There are 31 productive funded training faculty who are highly interactive in this training program. The training program for pre-doctoral includes 13 credit hours in nutrition-based courses 15 credit hours in biomedically based courses 4 credit hours in statistics and 1 credit hour in ethics in research. Students participate in laboratory rotations guided by the Director of Graduate Studies during the first year and subsequently are advised by a major professor and a 4 member advisory committee. Four Pre-doctoral students will be selected (after passing the qualifying examination) in the 4 broad areas of nutritional importance


application_id: 7655321
project_number: 5R01HL063760-07
project_title: Oxidative Stress and Heart Failure by Copper Restriction
administering_ic: NHLBI
award_notice_date: 2009-07-13
opportunity_number: PA-05-089
application_type: 5
activity_code: R01
ic: HL
serial_number: 063760
program_official: ERSHOW, ABBY
project_start_date: 2001-06-15
project_end_date: 2011-06-30
study_section: Integrative Nutrition and Metabolic Processes Study Section[INMP]
contact_pi_person_id: 1877629
contact_pi: KANG, Y JAMES
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Sustained pressure overload causes cardiac hypertrophy and the transition to heart failure. The aortic banding mouse model leads to hypertrophic cardiomyopathy and heart failure through the mechanism of sustained pressure overload but we have evidence that mineral imbalance may be involved. We have observed that increasing dietary copper (Cu) intake from 6 mg Cu/kg diet to 20 mg/kg diet can reverse the established hypertrophic cardiomyopathy in the aortic banding mouse model even in the presence of sustained pressure overload. Decreased cytochrome c oxidase (CCO) activity and mitochondriopathy are associated with heart failure in humans. The same CCO defect and mitochondriopathy are also found in the mouse model of pressure overload-induced cardiomyopathy and increasing dietary Cu intake recovered CCO activity and reversed mitochondriopathy. We propose this study to carry out the following aims: Aim 1 is to explore molecular mechanism by which sustained pressure overload causes Cu restriction to CCO in the heart. We will test the hypothesis that Cu mobilization and redistribution or efflux in response to oxidative stress generated by sustained pressure overload leads to Cu restriction to CCO resulting in altered CCO assembly and suppressed CCO activity. Aim 2 is to determine the essential role of recovery of suppressed CCO activity in Cu supplementation-induced regression of cardiomyopathy by sustained pressure overload. A cardiac COX10 conditional knockout mouse model in which cardiac CCO activity can be reduced by 50- 70% under the treatment with tamoxifen will be used. We hypothesize that Cu supplementation would not rescue the failing heart in the cardiac COX10-knockout or CCO-deficient mice if the recovery of CCO activity is essential even Cu supplementation can reverse alterations in other events including calcineurin/NFAT PI3K/Akt and ERK1/2 pathways or can activate other cardiomyopathy regression mechanisms. Aim 3 is to define potential application of Cu therapy to appropriate populations of heart failure patients by testing the hypothesis that Cu supplementation should be limited to pressure overload cardiomyopathy not applied to diabetic cardiomyopathy because diabetes causes liver dysfunction which in turn causes Cu retention in the system increasing the risk of Cu toxicity to the heart and other organs. Therefore Cu supplementation is not an appropriate approach to rescue diabetic cardiomyopathy.

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


application_id: 7655217
project_number: 2R01HL071071-06A2
project_title: Sphingolipid Signaling in Endothelial Function
administering_ic: NHLBI
award_notice_date: 2009-03-18
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: HL
serial_number: 071071
suffix: A2
program_official: GOLDMAN, STEPHEN
project_start_date: 2003-07-01
project_end_date: 2009-08-31
study_section: Vascular Cell and Molecular Biology Study Section[VCMB]
contact_pi_person_id: 6981385
contact_pi: LEE, MENQ-JER
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Sphingosine-1-phosphate (S1P) a serum-borne bioactive lipid regulates various biological activities of vasculature. Most if not all S1P functions are mediated by the S1P family of G-protein-coupled receptors (GPCRs). Five S1P receptor subtypes (S1P1-S1P5) have been identified. Previously we showed that S1P1 a Gi-coupled GPCR regulates endothelial cytoskeletal architectures chemotaxis formation of adherens junctions (AJs) and tight junctions (TJs) as well as morphogenic and angiogenic responses. The S1P/ S1P1 signaling enhances the transendothelial electrical resistance (TEER) an indicator of vascular barrier integrity. Moreover the S1P1-transduced signaling inhibits the histamine-induced vessel leakage in the Sprague-Dawley (SD) rat. Mechanistically S1P stimulation results in the formation of two distinct Zonula Occludens-1 (ZO-1) complexes which regulate the TJ formation and chemotactic response in endothelial cells (ECs). These results suggest that S1P signaling via the S1P1 receptor is important in the regulation of vascular functions. Importantly we recently observed that S1P1 receptor is present in the nuclear compartment of ECs. Furthermore we demonstrate that importin1 directly interacts with the third intracellular loop (i3) of S1P1 receptor and the nuclear translocation of S1P1 receptor is mediated by the importin 21-Ran nuclear transport machinery. Inhibition of nuclear translocation of S1P1 has no effect on the initial S1P-mediated TEER rise yet markedly diminishes its sustained rise. Furthermore endothelial nuclear S1P-S1P1 signaling axis stimulates the transcription of Cyr61 and CTGF two growth factors which are functionally important in angiogenesis. Together these results suggest the central hypothesis of this proposal: "both the plasma membrane (PM-) and nuclear (N)-S1P1 receptors play critical roles in regulating endothelial functions particularly in vascular integrity and angiogenesis". The main goal of this proposal is to characterize the respective signaling cascades and biological responses mediated by the PM- and N-S1P1 receptors with particular focus on the regulation of vessel integrity function and angiogenic response. Three specific aims are planned in this proposal and they are: (1) characterize the mechanisms of S1P1 receptor-mediated endothelial barrier integrity function (2) determine the functions of nuclear S1P1 receptor in ECs and (3) utilizing animal models to elucidate the physiological functions of S1P1 receptor in vivo. The success of this proposed research will not only lead to the discovery of novel mechanisms mediating GPCR signaling but may also develop into future therapeutic usages. PUBLIC HEALTH RELEVANCE: Sphingosine-1-phosphate receptor subtype 1 (S1P1) is abundantly present in both plasma membrane and nuclear compartments of vascular endothelial cells. Recent evidence strongly suggests that plasma membrane S1P1 receptors play a critical role in the regulation of vascular barrier function; however the function of nuclear S1P1 remains to be elucidated. The proposed research aims to characterize the molecular details and physiological relevance of plasma membrane and nuclear S1P1 receptor mediated signaling by using both in vitro and in vivo model systems.

project_terms:
Actins;Adherens Junction;Animal Model;Architecture;Area;Binding (Molecular Function);Biological;Biological Models;Blood Vessels;Cell Nucleus;Cell membrane;Chemotaxis;Complex;Cytoskeleton;Electrical Resistance;Elements;Endothelial Cells;Equilibrium;Event;Extracellular Matrix;Extravasation;Family;Figs - dietary;Focal Adhesion Kinase 1;Future;G Protein-Coupled Receptor Signaling;G-Protein-Coupled Receptors;Gene Silencing;Genetic Transcription;Goals;Growth Factor;Guanosine Triphosphate Phosphohydrolases;Histamine;Homeostasis;In Vitro;Integrins;Investigation;Lead;Ligation;Lipids;Mediating;Microfilaments;Modeling;Molecular;Mutate;Nuclear;Nuclear Translocation;Pathway interactions;Permeability;Physiological;Play;Rattus;Regulation;Research;Role;Running;Serum;Signal Transduction;Sphingolipids;Sphingosine-1-Phosphate Receptor;Sprague-Dawley Rats;Talin;Technology;Testing;Therapeutic;Tight Junctions;Transcriptional Activation;Translating;Vascular Endothelial Cell;angiogenesis;cadherin 5;connective tissue growth factor;human EMS1 protein;in vivo;in vivo Model;mutant;novel;nucleocytoplasmic transport;public health relevance;receptor;receptor-mediated signaling;response;rho;sphingosine 1-phosphate;success

public_health_relevance:
Sphingosine-1-phosphate receptor subtype 1 (S1P1) is abundantly present in both plasma membraneand nuclear compartments of vascular endothelial cells. Recent evidence strongly suggests thatplasma membrane S1P1 receptors play a critical role in the regulation of vascular barrier function;however the function of nuclear S1P1 remains to be elucidated. The proposed research aims tocharacterize the molecular details and physiological relevance of plasma membrane and nuclear S1P1receptor mediated signaling by using both in vitro and in vivo model systems.


application_id: 7655084
project_number: 2R01EY013632-05A1
project_title: Cannabinoid Receptors and Novel Antiglaucoma Drugs
administering_ic: NEI
award_notice_date: 2009-07-17
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: EY
serial_number: 013632
suffix: A1
program_official: AGARWAL, NEERAJ
project_start_date: 2003-08-01
project_end_date: 2011-07-31
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 2093529
contact_pi: SONG, ZHAO-HUI
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Glaucoma is one of the leading causes of blindness worldwide. Elevated intraocular pressure (IOP) is the primary riskfactor for optic nerve damage in glaucoma. Many studies conducted on human subjects and animal models have shownthat marijuana and its active components cannabinoids lower IOP. This project is focused on understanding themechanisms by which cannabinoids potential therapeutic agents for glaucoma lower intraocular pressure (IOP). In theprevious funding period we have established that CB1 and CB2 cannabinoid receptors are expressed on the trabecularmeshwork (TM) cells and cannabinoid agonists enhance aqueous humor outflow through both CB1 and CB2 receptors.For the competitive renewal application of this project we hypothesize that non-CB1/CB2 cannabinoid derivatives maycause an enhancement of aqueous humor outflow through a novel non-CB1/CB2 cannabinoid receptor and the novelcannabinoid receptor may mediates the IOP-lowering effects of the non-CB1/CB2 cannabinoid agonists throughmetalloprotease (MMP)-mediated mechanisms. Two specific aims are designed to test the above three hypotheses.Specific Aim 1: To study the effects of non-CB1/CB2 cannabinoid agonists and the role of GPR55 a novel non-CB1/CB2 cannabinoid receptor on aqueous humor outflow. Specific Aim 2: To study the mechanisms of actions for theaqueous humor outflow-enhancing effects of non-CB1/CB2 cannabinoid agonists. Completing this project should providemechanistic insight regarding cannabinoid-induced enhancement of aqueous humor outflow facility. These studies shouldalso contribute to our understanding of the homeostasis of aqueous humor outflow and may lead to the development ofbetter therapeutic agents for lowering IOP.

project_terms:
Address;Agonist;Animal Model;Anterior;Anti-glaucoma Agent;Aqueous Humor;Biological Assay;Blindness;Cannabinoids;Cells;Development;Funding;GTP Binding;Glaucoma;Homeostasis;Immunohistochemistry;Lead;Marihuana;Matrix Metalloproteinases;Mediating;Metalloproteases;Optic Nerve;Physiologic Intraocular Pressure;Play;Receptor Cannabinoid CB2;Risk Factors;Role;Signal Transduction;Testing;Therapeutic Agents;Trabecular meshwork structure;Western Blotting;antiglaucoma drug;cannabinoid receptor;design;human subject;insight;novel;research study

public_health_relevance:
Cannabinoids are potential novel anti-glaucoma agents. This proposal aims to study themechanisms underlying the aqueous humor outflow-enhancing effects of cannabinoids.These studies should provide mechanistic insight regarding the IOP-lowering effects ofcannabinoids. These studies should also contribute to our understanding of thehomeostasis of aqueous humor outflow and may lead to the development of bettertherapeutic agents for lowering IOP.


application_id: 7654745
project_number: 1R01DC009418-01A1
project_title: Neurotrophin receptor regulation of taste development
administering_ic: NIDCD
award_notice_date: 2009-03-23
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: DC
serial_number: 009418
suffix: A1
program_official: SULLIVAN, SUSAN L
project_start_date: 2009-04-01
project_end_date: 2013-03-31
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: MINICHIELLO, LILIANA
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Description (provided by applicant): During development sensory innervation to taste buds is tightly regulated by the actions of two neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4). Although both of these factors regulate gustatory innervation their specific functions are different from one another. BDNF is expressed in gustatory epithelium and determines whether gustatory neurons will locate and innervate taste placodes during development while NT4 does not. Both BDNF and NT4 regulate gustatory neuron and taste bud number but they have their influences at different times during development. The long range goal of this research is to understand the cellular and molecular mechanisms that regulate the neural innervation to and the maintenance of taste buds during development. The proposed studies focus on mechanisms by which these two neurotrophins BDNF and NT4 can influence various aspects of neural innervation through the same receptors TrkB and p75. The proposed studies use cell counting tract tracing immunohistochemistry and scanning electron microscopy in gene knockout mice to determine when TrkB and p75 are required for specific aspects of gustatory development including axonal extension into the tongue target selection and geniculate neuron/taste bud survival. Furthermore these studies combine these anatomical approaches with sophisticated genetic tools allowing the function of single phosphorylation sites on the TrkB receptor protein to be blocked in vivo. These experiments will determine which TrkB intracellular signaling pathways are required for axonal extension into the tongue target selection and geniculate neuron/taste bud survival. Together these studies test the hypotheses that TrkB mediates the effects of both BDNF and NT4 but that each function of these neurotrophins requires a different intracellular signaling pathway. While p75's more subtle role is to modulate the regulation of gustatory development by neurotrophins. Because these experiments examine the fundamental mechanisms of how neurotrophins regulate neuronal survival and axon targeting via Trk receptors this project has important implications for the therapeutic use of these signaling mechanisms in controlling neuron survival and axon targeting during regeneration. PUBLIC HEALTH RELEVANCE: The taste system is an ideal and commonly used system for examining axon regeneration following injury. We are examining the signaling mechanisms for two factors (neurotrophins) that influence axon targeting and neuron survival during development. By understanding of how these signaling mechanisms normally function techniques can be developed to manipulate these important signaling factors during nerve regeneration which will improve reinnervation and function following nervous system injury.

project_terms:
Afferent Neurons;Axon;Binding (Molecular Function);Birth;Brain-Derived Neurotrophic Factor;Cell Count;Cell Cycle;Computer Systems Development;Data;Development;Developmental Process;Docking;Embryonic Development;Epithelium;Fiber;Fungiform Papilla;Genes;Genetic;Goals;Growth;Growth Factor;Immunohistochemistry;Injury;Intracellular Signaling Proteins;Knockout Mice;Maintenance;Mediating;Microscopy Electron Scanning;Molecular;Mus;Mutate;NTF3 gene;Natural regeneration;Nerve;Nerve Growth Factor Receptors;Nerve Regeneration;Nervous System Trauma;Neurites;Neuronal Differentiation;Neurons;Neurotrophic Tyrosine Kinase Receptor Type 2;Palate;Pan Genus;Pathway interactions;Pattern;Peripheral;Phospholipase;Phosphorylation Site;Receptor Protein-Tyrosine Kinases;Receptor Signaling;Regulation;Research;Role;Sensory;Sensory Ganglia;Signal Pathway;Signal Transduction;Site;System;Taste Buds;Taste Perception;Techniques;Testing;Therapeutic Uses;Time;Tongue;Tyrosine;Wild Type Mouse;adapter protein;axon regeneration;improved;in vivo;nerve supply;neuron development;neuron loss;neuronal survival;neurotrophic factor;neurotrophin 4;postnatal;public health relevance;receptor;reinnervation;relating to nervous system;research study;response;somatosensory;synaptogenesis;tool;transcriptional coactivator p75


application_id: 7653706
project_number: 7R01AG017173-08
project_title: Genetics of Alzheimer's Disease in Israeli Arabs
administering_ic: NIA
award_notice_date: 2009-08-12
application_type: 7
activity_code: R01
ic: AG
serial_number: 017173
program_official: MILLER, MARILYN
project_start_date: 2000-09-30
project_end_date: 2013-07-31
study_section: Epidemiology of Clinical Disorders and Aging Study Section[ECDA]
contact_pi_person_id: 2056983
contact_pi: FRIEDLAND, ROBERT PAUL
other_pis: Not Applicable
congressional_district: 03
department: NEUROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-08-15
project_abstract:
DESCRIPTION (provided by applicant): We found a very high prevalence of Alzheimer disease (AD) (20% of those 60 years or older) in an inbred Arab community in northern Israel. This observation is apparently unrelated to the APOE c4 allele which has a frequency of <4% in demented and non-demented elders. A low resolution genome scan and fine mapping studies uncovered AD susceptibility loci in several chromosomal regions that have been implicated in previous studies of outbred Caucasian populations. We also found association between AD and several single nucleotide polymorphisms (SNPs) in the angiotensin converting enzyme gene on chromosome 17. During our investigation of the genetic etiology of AD in this community we discovered coincidentally a very high prevalence of hypertension which was associated with AD.  Going forward the primary focus of our project remains the genetic basis of AD. In light of emerging evidence for a vascular component to AD risk we plan to expand the scope of the study to investigate genetic pathways for hypertension and more specifically the relationship between the two disorders in this population. To accomplish these goals we will screen all persons residing in this community ages 65 and older (approximately 2163) for dementia and will obtain from a carefully selected subset of 750 cohort members (including 150 subjects meeting AD criteria 150 subjects with essential hypertension 150 subjects with both AD and hypertension and 300 non demented normotensivc controls) risk factor data and blood samples for biochemical and DNA studies and for establishing lymphoblastoid cell lines.  Our scientific aims are: 1) Identify 100000 base pair regions containing AD (and possibly hypertension) susceptibility genes on chromosomes 9 10 12 and 17 by profiling 600 SNPs spanning 15 million base pairs in each of the four previously implicated chromosomal regions using high throughput genotyping technology; and evaluate these data using allelic and haplotype association methods; 2) Fine-map disease loci in the 100 kb regions showing significant association in Aim 1 using a grid of SNPs in 20 kb intervals and repeating this process iteratively with a higher density of SNPs until the maximum linkage disequilibrium is attained; 3) Evaluate association between disease and 50 genes within the intervals showing the strongest signals in Aim 2 by genotyping additional SNPs and sequencing as necessary; 4) Evaluate association between disease and 100 genes with an emphasis on genes previously implicated in AD and genes involved in vascular functioning; and 5) Determine the relative contributions of SNPs showing significant association to disease susceptibility and investigate interactions among SNPs from multiple loci and with other factors including plasma homocysteine levels and education. The ultimate goal of this study is to find new targets (genetic and non-genetic) for therapy.

project_terms:
Age;Alleles;Alzheimer's Disease;Alzheimer's disease risk;Apolipoprotein E;Arabs;Attention;Base Pairing;Biochemical;Blood Pressure;Blood Vessels;Blood specimen;Candidate Disease Gene;Caucasians;Caucasoid Race;Censuses;China;Chromosomes Human Pair 17;Chromosomes Human Pair 2;Chromosomes Human Pair 9;Communities;Craniocerebral Trauma;DNA;Data;Dementia;Disease;Disease Association;Disease susceptibility;Educational Background;Educational aspects;Elderly;Enzyme Gene;Essential Hypertension;Europe;European;Family;Founder Effect;Frequencies (time pattern);Funding;Gender;Gene Order;Genes;Genetic;Genetic Polymorphism;Genetic Predisposition to Disease;Genome Scan;Genotype;Goals;Haplotypes;High Prevalence;Homocysteine;Homocystine;Hypertension;Inbreeding;Investigation;Israel;Light;Linkage Disequilibrium;Maps;Methods;Occupations;Pathway interactions;Peptidyl-Dipeptidase A;Persons;Pharmaceutical Preparations;Physical Education;Plasma;Population;Predisposition;Prevalence;Process;Psyche structure;Recording of previous events;Relative (related person);Research;Resolution;Risk;Risk Factors;Signal Transduction;Single Nucleotide Polymorphism;Smoking;Surveys;Susceptibility Gene;Time;Vascular Diseases;base;cohort;density;gene therapy;genetic pedigree;genotyping technology;informant;lymphoblastoid cell line;meetings;member;non-genetic;normotensive


application_id: 7653686
project_number: 1R01DC009434-01A2
project_title: Regulation of outer hair cell electromotility and noise-induced hearing loss
administering_ic: NIDCD
award_notice_date: 2009-02-18
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: DC
serial_number: 009434
suffix: A2
program_official: FREEMAN, NANCY
project_start_date: 2009-02-18
project_end_date: 2014-01-31
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
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;Face;GTP-Binding Proteins;Genes;Goals;Gramicidin;Hair Cells;Hearing;Image;In Situ;In Vitro;Intervention;Labyrinth;Lead;Lipid Peroxidation;Mediating;Methods;Molecular Motors;Motor;Motor Activity;Mus;Noise;Noise-Induced Hearing Loss;Operative Surgical Procedures;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;novel;prevent;public health medicine (field);rat Pres protein;response;sound;vibration


application_id: 7653527
project_number: 9R01HD060996-06A2
project_title: Effect of prior event on reward value
administering_ic: NICHD
award_notice_date: 2009-07-20
opportunity_number: PA-07-070
application_type: 9
activity_code: R01
ic: HD
serial_number: 060996
suffix: A2
program_official: FREUND, LISA S
project_start_date: 2009-07-20
project_end_date: 2011-06-30
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 7876951
contact_pi: ZENTALL, THOMAS R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
In the original 5-year proposal we had 3 specific aims. In order to compress some of the work such that it would accomplishable within a 24 month period we have deleted a part in aim 2 while retaining aims 1 and 3. We also combined parts of aim 2 with aim 3. In addition to accomplish this work in a shorter time frame we will need to hire 5 individuals (see Jobs saved or created below). We have selected aims that will contribute significantly to the base of scientific knowledge on this topic. The aims we can accomplish in are numbered and explained below.

project_terms:
Accounting;Address;Affect;Attention;Auditory;Bibliography;Binding (Molecular Function);Categories;Clinical;Cognitive;Communities;Correlation Studies;Development;Event;Exhibits;Exposure to;Funding;Goals;Heart Rate;Individual;Infant;Knowledge;Language;Learning;Link;Manuscripts;Measures;Methodology;Modality;Nature;Occupations;Ocular Fixation;Parents;Performance;Population;Positioning Attribute;Process;Relative (related person);Research;Research Personnel;Rewards;Role;Scientist;Speed (motion);Stimulus;Structure;Students;Testing;Time;Visual;Visual attention;Work;base;graduate student;infancy;innovation;lexical;novel;object recognition;research study;specific language impairment;teacher;visual information;visual process;visual processing;visual stimulus

public_health_relevance:
This proposal addresses a key question in early word learning: how do infants process and integrate simultaneously presented auditory and visual information. Results of this project will help researchers parents and teachers to better understand word learning in typical and atypical populations and the information gained from this research will be fundamental for understanding how exposure to a language influences the way infants perceive their world.


application_id: 7653274
project_number: 1R01GM085302-01A1
project_title: Enzyme Mis-Metallation Consequences and Opportunities
administering_ic: NIGMS
award_notice_date: 2009-06-05
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: GM
serial_number: 085302
suffix: A1
program_official: FABIAN, MILES
project_start_date: 2009-07-01
project_end_date: 2011-06-30
study_section: Macromolecular Structure and Function A Study Section[MSFA]
contact_pi_person_id: 1896479
contact_pi: MILLER, ANNE-FRANCES
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
project_abstract:
Aerobic organisms exploit O2 to extract large amounts of energy from oxidativemetabolism of food and employ oxidative reactions for a number of important chemicaltransformations involved in antibiotic biosynthesis metabolism of xenobioticsconstruction of biopolymers and more. In order to access this chemistry O2 must beactivated and this is often accomplished via Fe-containing enzymes. Free activated O2reacts with many components of cells and the damage that ensues contributes to manydiseases including diabetes arthritis neurodegenerative conditions cancer and thesymptoms of old age. A crucial biochemical defense against this array of ills is theenzyme superoxide dismutase (SOD) which catalyzes conversion of the parentactivated O2 species superoxide to O2 + H2O2. The current work focuses on theEscherichia coli SOD that is evolved to use Fe as its catalytic metal ion (FeSOD) withsupporting in-vivo experiments on a homologous yeast SOD that employs Mn instead(MnSODSc). The yeast enzyme is highly homologous to the human mitochondrialMnSOD and thus serves as a model for the human enzyme while also drawing onextensive genetic and physiological studies of yeast which cannot be performed onhumans. The major thrusts address mechanisms by which the Fe of FeSOD (and byextension the Fe of O2- activation enzymes) interacts with activated O2 withoutsuccumbing to it and means by which the active site of FeSOD tunes the reactivity of Fe(such that it will de-activate superoxide). The efforts on yeast SOD initiate investigationsof possible pathological consequences of Fesubstitution into human SOD via the yeastmodel and test a mutation by which this pathology could be prevented or corrected. Themajor thrust builds directly on past research in the applicant's lab using E. coli FeSODvariants that have been shown to be trapped in one of the two states employed byFeSOD's catalytic cycle but to retain otherwise native-like active sites. Because theycannot progress through the catalytic cycle they are ideal systems in which to generatemodels of enzyme-substrate and enzyme-product complexes to learn how the FeSODactive site binds and interacts with its substrate and products. Detailed studies by skilledspectroscopists as well as mechanistic and thermodynamic studies will provide anexceptionally complete picture of models of the intermediates of SOD turnover andinsights into how Fe enzymes handle their essential but dangerous substrate.Established enzymological and biophysical approaches will be blended with stopped-flow and freeze-quenched methods to extend the lab's ability to treat short-livedcomplexes. The yeast system will be launched. Initial studies of the reactions betweenperoxide and Fe-substituted MnSOD will evaluate the potential significance of Fesubstitution into SOD to human oxidative stress. A mutation developed in E. coli andcharacterized as part of the mechanistic work will also be tested for ability to reverse thepossible toxic effects of Fe substitution into yeast MnSOD thus carrying translatingmechanistic insights into potential treatments.

project_terms:
Active Sites;Address;Aerobic;Age;Anabolism;Antibiotics;Arthritis;Atherosclerosis;Binding (Molecular Function);Biochemical;Biopolymers;Cell Respiration;Chemicals;Chemistry;Complex;Coupled;Diabetes Mellitus;Disease;Electron Transport;Elements;Enzyme Activation;Enzymes;Escherichia coli;Food;Freezing;Genetic;Homologous Gene;Human;Hydrogen Peroxide;Hydroxyl Radical;Hypochlorous Acid;In Vitro;Individual;Investigation;Ions;Learning;Life;Longevity;Malignant Neoplasms;Manganese Superoxide Dismutase;Metals;Methods;Mitochondria;Modeling;Mutation;Nerve Degeneration;Organism;Oxidants;Oxidative Stress;Parents;Pathology;Peroxides;Peroxonitrite;Physiological;Production;Protons;Reaction;Reperfusion Injury;Research;Respiration;Specificity;Spectrophotometry;Structure;Superoxide Dismutase;Superoxides;Symptoms;System;Testing;Thermodynamics;Time;Toxic effect;Translating;Variant;Work;Xenobiotic Metabolism;Yeast Model System;Yeasts;attenuation;base;cell injury;enzyme substrate;gain of function;in vivo;insight;portability;prevent;research study

public_health_relevance:
Superoxide (O2 -) is produced as a byproduct of respiration and as part of theinflammatoryresponse. It goes on to produce a host of highly reactive and destructiveoxidants includinghydrogen peroxide (H2O2) hydroxyl radical (OH ) peroxynitrite(ONOO-) hypochlorous acid(HOCl) and more. These are important elements of thesymptoms and progression of arthritisreperfusion injury diabetes cancer severalneurodegenerative conditions atherosclerosis andthe symptoms of old age.Superoxide dismutases (SODs) are therefore central to our healthand longevity. Thecurrent work exploits bacterial and yeast homologues of mitochondrialMnSOD toelucidate the mechanism of superoxide dismutation Fe-based O2 activation andattenuation and a potential basis for Fe toxicity.


application_id: 7652486
project_number: 5R01DA018822-04
project_title: Gated Carbon Nanotube Membrane Transdermal Drug Delivery
administering_ic: NIDA
award_notice_date: 2009-06-30
application_type: 5
activity_code: R01
ic: DA
serial_number: 018822
program_official: AIGNER, THOMAS G
project_start_date: 2006-09-30
project_end_date: 2014-06-30
study_section: Gene and Drug Delivery Systems Study Section[GDD]
contact_pi_person_id: 7929219
contact_pi: HINDS, BRUCE JACKSON
other_pis: Not Applicable
congressional_district: 06
department: ENGINEERING (ALL TYPES)
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: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
project_terms:
Affinity;Alkanes;Alkanesulfonates;Binding (Molecular Function);Caliber;Carbon;Carbon Nanotubes;Cavia;Characteristics;Charge;Cigarette;Clonidine;Development;Devices;Dose;Drug Delivery Systems;Drug Kinetics;Electronics;Family suidae;Fentanyl;Film;Human;In Vitro;Incidence;Ionic Strengths;Iontophoresis;Ligands;Longitudinal Studies;Marketing;Membrane;Methods;Molecular;Nanotubes;Nicotine;Opiates;Patient-Controlled Analgesia;Pharmaceutical Preparations;Pharmacotherapy;Plasma;Polymers;Polystyrenes;Production;Reaction Time;Research Personnel;Role;Safety;Security;Skin;Smoker;Solutions;Solvents;System;Therapeutic;Transdermal substance administration;Treatment Protocols;Withdrawal;aqueous;base;biomaterial compatibility;carboxylate;chronic pain;cost;craving;dosage;flexibility;improved;in vivo;irritation;programs;prototype;skin irritation;smoking cessation;success;voltage


application_id: 7652359
project_number: 5U60OH008483-05
project_title: Kentucky Occupational Safety and Health Surveillance
administering_ic: NIOSH
award_notice_date: 2009-05-28
opportunity_number: PAR-04-106
application_type: 5
activity_code: U60
ic: OH
serial_number: 008483
program_official: FREDERICK, LINDA J
project_start_date: 2008-07-01
project_end_date: 2010-06-30
study_section: ZOH1-SBO(50)R
contact_pi_person_id: 7931539
contact_pi: BUNN, TERRY LEE
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (Provided by applicant):  Kentucky ranks as the 8th- worst state for fatal occupational injury rates and is also among the states with the highest nonfatal occupational injury and illness incidence rates (BLS 2006). This expanded project focuses on the population-based surveillance of fatal and nonfatal work-related injuries and illnesses in Kentucky a southeastern state. The objectives of the fundamental Kentucky Occupational Safety and Health Surveillance (KOSHS) and expanded Fatality Assessment and Control Evaluation (FACE) programs are to identify industry sectors occupations and worker populations at high risk for work injuries and illnesses to advance the usefulness of surveillance data for injury prevention and to develop and implement targeted strategies for dissemination of data utilizing a sector-based approach to reducing occupational injuries and illnesses. The methodology consists of conducting population-based surveillance of 20 occupational injury/illness indicators and in-depth focused multi-source surveillance of occupational fatalities to identify risk factors. Surveillance of occupational motor vehicle collisions will be expanded to include multiple data sources. A new indicator for occupational falls including older worker falls will be established. On-site investigations of selected fatality cases involving motor vehicle collisions in the transportation and logging sectors will be performed. A case-control study will be conducted to determine the association between the number of passengers and injury severity in older male driver motor vehicle collisions. Narratives of older worker occupational falls using Workers' Claims data will be coded. Fatality narratives of interpersonal violence-related occupational homicides will be developed and disseminated utilizing multiple sources of data The "Kentucky- Working to Save Lives" consortium will be sustained and charged with the development of a statewide occupational injury prevention plan. Nonparametric statistical analysis methods will be applied to the CRASH data set to identify geographic areas of Kentucky highways with the highest probability of commercial vehicle and coal truck crashes. Targeted worker and employer groups will be provided with a sound evidence basis for improved worker safety by analyzing and disseminating occupational injury and illness surveillance data and publications for impact at both the state and national levels. A process impact and outcome evaluation of the major activities conducted.


application_id: 7652018
project_number: 1R01AR055974-01A1
project_title: Respiratory Muscle Weakness in Chronic Inflammation
administering_ic: NIAMS
award_notice_date: 2009-03-14
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: AR
serial_number: 055974
suffix: A1
program_official: NUCKOLLS, GLEN H
project_start_date: 2009-04-01
project_end_date: 2014-02-28
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1869134
contact_pi: REID, MICHAEL B
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Animal Model;Animals;Antioxidants;Arachidonic Acids;Area;Binding (Molecular Function);Biological Assay;Breathing;Calcium;Cardiovascular Diseases;Cell Culture Techniques;Ceramides;Chronic;Chronic Disease;Chronic Obstructive Airway Disease;Clinical;Complement;Data;Diaphragm (Anatomy);Disease;Dyspnea;Esthesia;Event;Exercise;Exercise Tolerance;Extracellular Signal Regulated Kinases;Fiber;Functional disorder;Genetic;Goals;Heart failure;Hour;Human;Inflammation;Inflammatory;Intervention;Lead;Life;Ligand Binding;Link;Mediating;Mediator of activation protein;Microfilaments;Mitochondria;Mitogen-Activated Protein Kinase 3;Morbidity - disease rate;Mortality Vital Statistics;Muscle;Muscle Fibers;Muscle Weakness;Muscle function;Neurons;Nitric Oxide Synthase;Oxidants;Oxidation-Reduction;Pathway interactions;Patients;Peroxonitrite;Phospholipase;Phospholipase A2;Phosphotransferases;Physiologic intraventricular pressure;Post-Translational Protein Processing;Production;Protein Isoforms;Protein Kinase;Proteins;Publishing;Pulmonary Emphysema;Reactive Oxygen Species;Research;Respiratory Failure;Respiratory Muscles;Role;Serum;Signal Transduction;Source;Sphingolipids;Sphingomyelinase;Symptoms;Testing;Therapeutic Agents;Tumor Necrosis Factor Receptor;Tumor Necrosis Factor-alpha;Tumor Necrosis Factors;Work;depressed;drug development;gene therapy;mouse model;muscle strength;novel;premature;pressure;prevent;public health relevance;receptor;research study;response;therapeutic target;tool


application_id: 7650356
project_number: 5R01HL064894-08
project_title: Regulation and function of EC-SOD
administering_ic: NHLBI
award_notice_date: 2009-06-08
application_type: 5
activity_code: R01
ic: HL
serial_number: 064894
program_official: HARABIN, ANDREA L
project_start_date: 2000-09-01
project_end_date: 2012-06-30
study_section: Lung Cellular, Molecular, and Immunobiology Study Section[LCMI]
contact_pi_person_id: 1863574
contact_pi: FOLZ, RODNEY J
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
project_abstract:
DESCRIPTION (provided by applicant): Extracellular superoxide dismutase (EC-SOD) is the most abundant extracellular antioxidant enzyme in the lung and current studies indicates that EC-SOD plays a key role in the pathogenesis of oxidant-induced pulmonary and vascular injury and resulting inflammation. We and others have shown that EC-SOD overexpression in the lungs of mice protects the lungs against acute lung injury from hyperoxia exposure residual oil fly ash influenza pneumonia hemorrhage induced lung injury radiation pneumonitis bleomycin-induced lung fibrosis and preserves lung development in a neonatal model of hyperoxia. In cardiovascular disease models EC-SOD protects against ischemia-reperfusion injury attenuates hypertension and specific polymorphisms impart a significant increased risk for ischemic heart disease. Despite this work the precise mechanism of EC-SOD's protective role in these disease processes remains unclear. Recently we have begun to unravel factors important in regulating EC-SOD tissue and cell-specific expression. In this competing renewal application we will build on our most recent findings that have begun to explore molecular pathways that control EC-SOD gene expression. Based on our initial characterization of the human and mouse EC-SOD genes we now hypothesize that EC-SOD transcriptional expression is regulated by a family of transcription factors (Ets MZF-1 Kruppel and Sp1/Sp3) interacting at a proximal and distal promoter element located in the 5'-untranslated region of the murine EC-SOD gene. It is further proposed that the activity of these elements is modulated by epigenetic processes including histone acetylation and methylation. To test these hypotheses we propose 3 specific aims. Aim 1 will examine the contribution and identification of cis-elements and trans-activating factors regulating basal and cell specific EC-SOD expression in the lung. In Aim 2 we will identify and characterize transcription factor elements responsible for modulation of EC-SOD gene transcription. In Aim 3 will use a novel in vivo bioluminescence imaging system to examine the functional and spatial gene expression profile utilizing the newly discovered EC-SOD proximal and distal promoter elements in transgenic mice. It is anticipated that this work will provide new insights into our understanding of molecular mechanisms involved in the regulation of EC-SOD gene expression. This could lead to novel pharmacologic strategies for augmenting endogenous EC-SOD levels in the lungs and other tissues which would be predicted to reduce extracellular oxidative stress and attenuate lung disease processes.

project_terms:
5' Untranslated Regions;Affect;Animals;Antioxidants;Attenuated;Basal Cell;Be++ element;Beryllium;Bioluminescence;Bleomycin;Blood Vessels;Cardiac;Cardiovascular Diseases;Cells;Complex;Development;Disease;Disease model;Distal;Elements;Enzymes;Epigenetic Process;Event;Family;Fibrosis;Future;Gene Expression;Gene Expression Profile;Genes;Genetic Polymorphism;Genetic Transcription;Goals;Growth;Heart;Hemorrhage;Histone Acetylation;Human;Hyperoxia;Hypertension;Image;Indium;Inflammation;Inflammatory Response;Influenza;Injury;Ischemia;Knock-out;Kruppel-like transcription factors;Lead;Lung;Lung Injury Acute;Lung Neoplasms;Lung diseases;Manganese Superoxide Dismutase;Methylation;Modeling;Molecular;Mus;Muscle Smooth Vascular;Myocardial Ischemia;Neonatal;Oxidants;Oxidative Stress;Pathogenesis;Pathway interactions;Physiological;Play;Pneumonia;Process;Promotor (Genetics);Radiation Pneumonitis;Regulation;Reperfusion Injury;Reperfusion Therapy;Reporter;Respiratory physiology;Risk;Role;Structure of parenchyma of lung;Superoxide Dismutase;System;Testing;Time;Tissues;Transcriptional Regulation;Transgenic Mice;Transgenic Organisms;Work;base;expectation;extracellular;gene therapy;in vivo;insight;interest;lung development;lung injury;novel;novel therapeutics;oil fly ash;overexpression;prevent;transcription factor;tumor growth


application_id: 7650219
project_number: 5K01DK076743-03
project_title: Mass Spectrometry Analysis of Notch4 Networks in Diabetes-Related Tubule Injury
administering_ic: NIDDK
award_notice_date: 2009-06-30
opportunity_number: PA-06-001
application_type: 5
activity_code: K01
ic: DK
serial_number: 076743
program_official: RANKIN, TRACY L
project_start_date: 2007-07-01
project_end_date: 2011-06-30
study_section: Kidney, Urologic and Hematologic Diseases D Study Section[DDK-D]
contact_pi_person_id: 8638278
contact_pi: POWELL, DAVID W.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  
The Candidate's overall career goal is to establish and maintain an independent proteomic and molecular biology-based program focused on investigation of events that mediate diabetic nephropathy (DN). DN is the leading cause of end-stage renal disease (ESRD). There are no current treatments that completely prevent progression to ESRD. This emphasizes the health-related importance for discovery of novel regulatory events as potential therapeutic targets for the diagnosis prevention and treatment of DN. Tubulointerstitial fibrosis (TF) is a prominent feature of progressive DN that is mediated by transforming growth factor-beta (TGF-beta). Notch4 is a fascinating membrane-bound transcription regulator that was recently implicated in TGF signaling and renal disease. Our preliminary findings indicate that Notch4 activation inhibits TGF-beta signaling in cultured renal tubular cells and show decreased expression of Notch4 in tubular cells from diabetic mice as compared with controls. This suggests a hypothesis that down-regulation of Notch4 activity promotes the TGF-beta-mediated effects in DN. This project will develop Notch4-deficient diabetic mice. Renal pathophysiology experiments will be performed to delineate the in vivo role of Notch4 in diabetes-mediated TF and TGF signaling. It is anticipated that these animals will also provide a better model for the study of TF as none of the current diabetic animal models exactly mimic the TF observed in diabetic humans. Accumulating evidence suggests a key role of TGF-mediated epithelial to mesenchymal transition (EMT) in diabetes-associated TF. We have recently developed models for TGF-mediated EMT in human kidney (HK) tubule cell lines. We will also develop HK models for glucose and advanced glycation end product (AGE)-mediated EMT. We will use these cellular models in combination with active Notch4 transfection and RNAi-mediated Notch4 knockdown to dissect the role of Notch4 in different components of signaling and transcription activity in EMT. Lastly we will use state-of-the-art proteomic techniques with the Notch4-deficient diabetic mice to define Notch4-mediated protein expression and organelle localization in DN. In addition to molecular insight provided by these studies the animal model and pathophysiology training obtained during this Career Development Award will provide valuable resources for the Candidate to expand his diabetes-related program and obtain independent-level funding.

project_terms:
Address;Advanced Glycosylation End Products;Animal Model;Animals;Arts;Binding (Molecular Function);Cell Line;Cell model;Cells;Cellular biology;Diabetes Mellitus;Diabetic Nephropathy;Diabetic mouse;Diagnosis;Down-Regulation;End stage renal failure;Event;Fibrosis;Functional disorder;Funding;Genetic Transcription;Glucose;Goals;Human;Injury;Investigation;K-Series Research Career Programs;Kidney;Kidney Diseases;Mass Spectrum Analysis;Mediating;Membrane;Mentors;Modeling;Molecular;Molecular Biology;Molecular and Cellular Biology;Organelles;Prevention;Proteins;Proteomics;RNA Interference;Regulation;Renal tubule structure;Research;Resources;Role;Signal Transduction;Stimulus;Study models;Techniques;Training;Transfection;Transforming Growth Factor beta;Tubular formation;base;career;career development;diabetic;epithelial to mesenchymal transition;fascinate;improved;in vivo;insight;notch protein;novel;prevent;programs;protein expression;research study;therapeutic target;tool


application_id: 7650150
project_number: 5R01AI078756-03
project_title: IFN-gamma production by microglia for prevention of toxoplasmic encephalitis
administering_ic: NIAID
award_notice_date: 2009-09-28
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AI
serial_number: 078756
program_official: WALI, TONU M
project_start_date: 2008-07-03
project_end_date: 2013-06-30
study_section: AIDS-associated Opportunistic Infections and Cancer Study Section[AOIC]
contact_pi_person_id: 1882071
contact_pi: SUZUKI, YASUHIRO
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_terms:
Acquired Immunodeficiency Syndrome;Address;Antigen Presentation;Brain;Cell Adhesion Molecules;Cells;Chronic;Defense Mechanisms;Development;Disease;Disease Management;Encephalitis;Endothelial Cells;Goals;Growth;Host Defense;Host Defense Mechanism;Immune;Immune response;Immunity;Immunocompromised Host;Individual;Infection;Infiltration;Interferon Type II;Life;MHC Class I Genes;Mediator of activation protein;Microglia;Migration Assay;Modeling;Molecular;Mus;Neuroglia;Neurons;Organ;Parasites;Play;Prevention;Production;Recruitment Activity;Role;Source;Staging;System;T-Cell Activation;T-Lymphocyte;Toxoplasma gondii;Toxoplasmosis;brain cell;cerebrovascular;chemokine;cytokine;design;disorder prevention;improved;in vivo;macrophage;novel;prevent;public health relevance;response


application_id: 7648164
project_number: 5R01CA131059-02
project_title: Novel Modular Vascular Patterning Assay for HTS
administering_ic: NCI
award_notice_date: 2009-07-20
opportunity_number: PA-07-320
application_type: 5
activity_code: R01
ic: CA
serial_number: 131059
program_official: LI, JERRY
project_start_date: 2008-07-01
project_end_date: 2011-06-30
study_section: Instrumentation and Systems Development Study Section[ISD]
contact_pi_person_id: 1881039
contact_pi: MOHAN, ROYCE
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The vascular endothelial cells lining blood vessels in humans are one of the principle sites that become involved in inflammatory and proliferative responses to a diverse array of human diseases. Microvascular homeostasis is thus a vital component of human health; its inappropriate activation in response to inflammatory and angiogenic stimuli can become a pathogenic component fueling the growth and spread of cancers and contributing to debilitating arthritis age-related macular degeneration and multiple organ failure associated with underlying diseases such as diabetes. On the other hand impaired angiogenesis is also equally pathogenic and afflicts its victims by slowing down wound healing and contributing to heart diseases and stroke. Collectively given the complexity of the angiogenesis signaling system these major burdens of human health that arise from dysregulation of blood vessel growth need to be addressed by a more concerted effort in drug discovery. Biological assays that model the processes of angiogenic diseases can assist the process of drug discovery and disease target identification. However currently few assays represent the complexity of the diseased microvasculature as they typically focus on one pathogenic mechanism/pathway. With this in mind we propose to continue the development of a high content high throughput screening (HC-HTS) vascular patterning assay which we have recently validated as drug screening tool through a previously funded NIH Roadmap Initiative R21 grant. In this R01 proposal we plan to extend the scale and scope of the three dimensional endothelial cell sprouting assay (3D-ECSA) to promote its adoption for the HTS paradigm. Our innovative approaches bring in 1) modern automated robotic systems that allow us to improve efficiency and standardize production of spheroids 2) high content image analysis software to use with 3D-ECSA under HTS conditions and 3) development of a pilot scale chemical library focused on the immunoproteosome as a chemical enabling tool towards validation of the 3D-ECSA. The successful accomplishments of these goals will not only afford us a valuable tool for large scale biology but will help bring forward a technology advancement to identify new classes of chemical probes of protein function and drug leads for life saving therapeutics.

project_terms:
3-Dimensional;Address;Adoption;Age related macular degeneration;Arthritis;Biological;Biological Assay;Biology;Blood Vessels;Cardiovascular Diseases;Cell Line;Characteristics;Chemicals;Complex;Computer software;Controlled Study;Development;Diabetes Mellitus;Differentiation and Growth;Disease;Diversity Library;Endothelial Cells;FDA approved;Funding;Goals;Grant;Growth;Growth Factor;Hand;Health;Heart Diseases;Homeostasis;Human;Hyperglycemia;Hypoxia;Image;Image Analysis;Impaired wound healing;Individual;Inflammatory;Lead;Life;Malignant Neoplasms;Manuals;Mind;Modeling;Multicellular Process;Multiple Organ Failure;Optics;Pathway interactions;Pattern;Pharmaceutical Preparations;Preclinical Drug Evaluation;Principal Investigator;Process;Production;Quality Control;Research;Robotics;Running;Screening procedure;Signal Transduction;Simulate;Site;Stimulus;System;Technology;Therapeutic;United States National Institutes of Health;Validation;Vascular Endothelial Cell;Wound Healing;angiogenesis;drug discovery;high throughput screening;human disease;improved;innovation;novel;programs;protein function;prototype;response;small molecule libraries;stroke;tool


application_id: 7648101
project_number: 5R01GM070559-05
project_title: Molecular Analysis of Juvenile Hormone Action
administering_ic: NIGMS
award_notice_date: 2009-01-23
application_type: 5
activity_code: R01
ic: GM
serial_number: 070559
program_official: CHIN, JEAN
project_start_date: 2005-02-01
project_end_date: 2010-01-31
study_section: Special Emphasis Panel[ZRG1-TMP(99)]
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
budget_start_date: 2009-02-01
project_abstract:
DESCRIPTION (provided by applicant):  Some insects compete with us for food and transmit human and livestock diseases but other insects are beneficial. Therefore there has been a continuous demand for the development of insect control methods that are target-specific. Juvenile hormone (JH) and ecdysteroids are the major hormones that regulate molting metamorphosis 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. The main objective of this proposal is to identify genes that play critical roles in JH action. JH response elements (JHRE) identified in the promoter region of JH- and 20-hydroxyecdysone (20E)-responsive JH esterase (jhe) gene and ecdysone receptor (EcR) deficient Drosophila melanogaster cell line (L57) were used to develop a robust system that can be used for studying the molecular basis of JH action. In L57 cells a reporter gene placed under the control of JHRE is induced by JH and the JH induction was suppressed by 20E. The nuclear proteins isolated from L57 cells bind to JHRE and 20E in the presence of EcR can prevent this binding. In L57 cells EcR and DSP do not bind directly to JHRE and are not directly involved in JH induction of a reporter gene regulated by JHRE. Identification of proteins that bind to JHRE is critical for understanding JH action. The two specific aims of the proposal are: (1) to identify genes that play key roles in JH action; and (2) to determine the role of identified genes in JH action. The genes that are involved in JH induction of JHRE regulated reporter gene will be identified using RNAi and yeast assays. The identified gene will be characterized by studying the binding of expressed proteins to JHRE and labeled JH expression of their mRNA and proteins during D. melanogaster development and analysis of D. melanogaster mutants deficient in identified genes. 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 can also be used in medicine by developing gene switches for various applications such as gene therapy drug discovery and therapeutic protein production.

project_terms:
Adult;Aedes (genus);Agonist;Alkaline Phosphatase;Base Pairing;Binding (Molecular Function);Binding Proteins;Biological;Biological Assay;Biological Metamorphosis;Cell Line;Cells;Code;Collection;Complementary DNA;Complex;Culicidae;D Cells;Development;Direct Repeats;Disease;Disease Vectors;Dose;Double-Stranded RNA;Drosophila melanogaster;Ecdysone;Ecdysteroids;Ecdysterone;Elements;Esterase Gene;Event;Food;Gene Expression;Genes;Hormone Receptor;Hormones;Human;Insect Control;Insecta;Intestines;Juvenile Hormones;Label;Lead;Length;Life Cycle Stages;Livestock;Luc Gene;Mediating;Medicine;Messenger RNA;Methods;Molecular;Molecular Analysis;Molting;Mosquito Control;Nuclear Protein;Nuclear Proteins;Phosphorylation;Play;Production;Promoter Regions (Genetics);Protein Binding;Protein Dephosphorylation;Protein Kinase C;Proteins;RNA Interference;RNA chemical synthesis;Reporter;Reporter Genes;Reproduction;Research;Research Personnel;Resistance development;Response Elements;Role;Screening procedure;Signal Transduction;Switch Genes;System;Techniques;Time;Tissues;Vertebrates;Work;Yeasts;analog;base;drug discovery;ecdysone receptor;gene therapy;genome sequencing;hormone analog;hormone response element;insect disease;juvenile hormone esterase;mRNA Differential Displays;mutant;prevent;programs;receptor;response;therapeutic protein;vector control


application_id: 7648048
project_number: 5P20NR010679-03
project_title: Center for biobehavioral research in self-management of cardipulmonary disease
administering_ic: NINR
award_notice_date: 2009-07-27
opportunity_number: RFA-NR-07-004
application_type: 5
activity_code: P20
ic: NR
serial_number: 010679
program_official: HOSSEINI, JEANETTE M
project_start_date: 2007-09-29
project_end_date: 2012-06-30
study_section: ZNR1-REV-B(04)R
contact_pi_person_id: 1906318
contact_pi: MOSER, DEBRA KAY
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cardiovascular and pulmonary diseases are the major chronic illnesses requiring life-long self- management; they also are the conditions in which self-management may be the most difficult to sustain. The improvements in outcomes to be gained by optimal self-management however suggest that a research focus on self-management of cardiovascular and pulmonary diseases should be a priority. In this application we propose to establish an exploratory research center the Center for Biobehavioral Research on Self- Management of Cardiopulmonary Disease at the University of Kentucky College of Nursing (UKCON). The purpose of the Center is to: 1) develop the research infrastructure at the UKCON to promote and support research on processes interventions and outcomes of self-management of cardiovascular and ' pulmonary diseases; 2) expand the quality and quantity of self-management research projects using biobehavioral methods by centralizing methodological resources; 3) expand the number of nurse investigators doing interdisciplinary self-management research by supporting interdisciplinary exchange and linkages; 4) contribute to the scientific foundation for self-management by promotion and dissemination of systematic investigations of self-management processes interventions and outcomes; and 5) plan for and develop sustainability of interdisciplinary self-management research programs by building active and growing partnerships inside and outside of the University of Kentucky. The proposed Center will consist of three Cores: an Administrative Core a Self-Management Pilot/Feasibility and Biobehavioral Outcomes Core and a Research Program Development Data Analysis and Dissemination Core. In addition three pilot studies are included that focus on testing self-management interventions. The Administrative Core will coordinate center activities guide development of new resources supporting research and facilitate interdisciplinary collaboration in the study of self-management in the context of cardiovascular and pulmonary disease management and prevention. The Self-Management Pilot/Feasibility and Biobehavioral Outcomes Core will provide training mentorship and expertise to investigators conducting studies aimed at improving self-management among patients with cardiovascular and pulmonary diseases that includes collection of biobehavioral outcomes data. The Research Program Development Data Analysis and Dissemination Core that will provide mentorship infrastructure and resources to support development and sustainability of interdisciplinary programs of research directed at improving self-management of patients with cardiovascular and pulmonary diseases. The proposed Center will provide the UKCON with the support needed to sustain a center of excellence to promote research programs that focus on self-management of cardiovascular and pulmonary disease.  
  
CENTER AS A WHOLE INCLUDING ADMINISTRATIVE CORE AND EVALUATION PLAN


application_id: 7648047
project_number: 5P20NR010679-02
project_title: Data Analysis Research Program Development and Dissemination Core
administering_ic: NINR
application_type: 5
activity_code: P20
ic: NR
serial_number: 010679
study_section: ZNR1
subproject_number: 9002
contact_pi_person_id: 1903848
contact_pi: HALL, LYNNE ANDERSON
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
budget_end_date: 2009-06-30
funding_mechanism: Research Centers
project_abstract:
Chronic cardiovascular and pulmonary diseases adversely affect the quality of life of millions ofAmericans. Self-management is essential for disease management in those with these chronic conditions.In order to move into a new area of research focused on improving self-management of cardiovascular andpulmonary diseases and to support investigators in the development of extramural research proposalsjunior as well as established investigators need training and mentoring with research program development(e.g. establishing a research trajectory developing researchable problems conceptualizing theoreticalfoundations for hypothesis formation proposal development) data analysis (e.g. selection of appropriatestatistical methods interpretation of statistical output presentation of statistical findings) and disseminationof results via scientific presentations and publications in appropriate venues. The Research ProgramDevelopment Data Analysis and Dissemination Core will build on existing support services available inthe College of Nursing and extend services to support Center investigators in other ways.The purposes of the Research Program Development Data Analysis and Dissemination Coreare to: (1) provide support services to assist faculty in developing a focused ongoing funded program ofresearch related to evidence-based interventions to promote self-management in patients withcardiovascular and pulmonary diseases; (2) offer faculty development opportunities and mentoring inresearch proposal development psychosocial instrumentation and surveys research design and samplingdata management and analysis and data-based presentation and manuscript preparation; and (3) throughcollaboration with the Administrative Core the Self-management Pilot/Feasibility and BiobehavioralOutcomes Core the Executive Committee and the Advisory Committee provide the infrastructure andresources necessary for development of ongoing programs of research focused on improving selfmanagementof patients with cardiovascular and pulmonary diseases.

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


application_id: 7648046
project_number: 5P20NR010679-02
project_title: Self-Management Pilot/Feasibility and Biobehavioral Outcomes Core
administering_ic: NINR
application_type: 5
activity_code: P20
ic: NR
serial_number: 010679
study_section: ZNR1
subproject_number: 9001
contact_pi_person_id: 1906096
contact_pi: LENNIE, TERRY A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
budget_end_date: 2009-06-30
funding_mechanism: Research Centers
project_abstract:
Development of evidence-based strategies to improve self-management of cardiovascular and pulmonarydiseases requires that investigators develop scientifically sound rigorous research studies. Measuringbiobehavioral outcomes of self-management of cardiovascular and pulmonary diseases presents challenges toinvestigators entering this field of study. The University of Kentucky College of Nursing is doubling the size ofthe undergraduate program. Funding to hire eight additional faculty members who will have 50% release timefor research has been approved by the Board of Regents. These new members who will be investigators earlyin their research careers will be hired over three years. Three of these members will start in the Fall of 2007. Inaddition we have junior faculty (Darlene Welsh and Misook Chung) and established investigators (Ann Pedenand Lynne Hall) on our faculty who are planning to join our cardiovascular and pulmonary research team(RICH Heart Program). The proposed Center will be ideally suited to assist these faculty members to developprograms of research in self-management of cardiovascular and pulmonary diseases.To meet the needs of current and future faculty members the proposed Core will assist projectinvestigators in the development and conduct of pilot/feasibility studies aimed at improving self-management ofcardiovascular and pulmonary diseases that include measurement of biobehavioral outcomes. Advice trainingand mentorship will be provided in research design as well as measurement and interpretation of three types ofoutcomes: 1) biobehavioral variables that demonstrate effectiveness of interventions (e.g. knowledgepsychological status physiological status) 2) biobehavioral variables that demonstrate improvement in selfmanagementbehaviors (e.g. adherence nutritional status physiological status) and 3) biobehavioralvariables that demonstrate improvement in clinical outcomes (e.g. physiological status mortality morbidityand quality of life).

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


application_id: 7647290
project_number: 5P30AG028383-03
project_title: CLINICAL CORE - SATELLITE
administering_ic: NIA
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1
subproject_number: 9005
contact_pi_person_id: 1896068
contact_pi: SMITH, CHARLES B
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: 2008-07-01
budget_end_date: 2009-06-30
funding_mechanism: Research Centers
project_abstract:
The Kentucky Clinic North Minority Satellite (KYCN) represents a renewed effort to recruit minorities
particularly African Americans into the University of Kentucky Alzheimer's Disease Center ( UK ADC)
clinical and research programs. This application integrates KYCN into a unique comprehensive model of
dementia-related services and research in the local African American community. Resources of the
Administration on Aging (AOA) the Kentucky Cabinet for Health Services the Alzheimer's Association and
the UK ADC are combined in a multidisciplinary partnership. These efforts include direct minority
participation in recruitment education administration care delivery dementia awareness in-home safety
assessment and transportation services. KYCN under the auspices of UK ADC maintains an independent
research function distinct from the service orientation of the AOA state agencies and the Alzheimer's
Association. The success of this clinic and our research efforts in this population is based on developing
trust between the UK ADC and the African American community nurtured through the provision of quality
medical care and the stable on-going presence of a local clinic staffed by well-trained dedicated
multicultural professionals. Over the last several years we have met program goals providing 97 initial
dementia evaluations recruiting 51 of these individuals into our longitudinal research programs and
obtaining autopsy consent in 6 of these subjects. For this proposal the initial success of this clinic will be
expanded in order to meet the following goals: (1) To provide dementia diagnoses for 30 new patients per
year and to follow a cohort of 100 primarily African American patients longitudinally. (2) To collect data
reportable to NACC as a Uniform Data Set (UDS) for normal controls MCI AD and other non-AD
dementias in a central Kentucky African American population. (3) In conjunction with the Education and
Information Transfer Core to educate the African American community about AD and other dementias the
importance of early diagnosis and treatment and participation in dementia research. (4) To increase
participation by African Americans in AD research with prearranged autopsy including the BRAINS and
Dementia Research programs.

project_terms:
Adult;African American;Aging;Alzheimer's Disease;Autopsy;Awareness;Brain;Caring;Clinic;Clinical;Clinical Research;Communities;Consent;Control Groups;Data;Data Set;Dementia;Diagnosis;Early Diagnosis;Educational aspects;Ensure;Evaluation;Family;Goals;Health Services;Health Services Research;Home environment;Individual;Kentucky;Lead;Medical;Memory Disorders;Minority;Modeling;Neurologic;Patients;Population;Program Evaluation;Recruitment Activity;Reporting;Research;Resources;Safety;Services;Training;Training Support;Transportation;Trust;Universities;base;cohort;delivery of care;design;diagnosis evaluation;improved;multidisciplinary;neuropsychological;outreach;programs;success


application_id: 7647289
project_number: 5P30AG028383-03
project_title: EDUCATION AND INFORMATION CORE
administering_ic: NIA
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1
subproject_number: 9004
contact_pi_person_id: 8536107
contact_pi: WEKSTEIN, DAVID 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: 2008-07-01
budget_end_date: 2009-06-30
funding_mechanism: Research Centers
project_abstract:
The Education and Information Transfer Core (EITC) functions as a vital link between our Alzheimer's
Disease Center (ADC) and the local and state communities. Objectives for the EITC are: 1) to assist the
Clinical Core in the recruitment and retention of research subjects with a special emphasis on minorities; 2)
to enhance the development of AD-related research among faculty and students of the ADC and the
University; 3) to educate family caregivers and the local community about dementing disorders and to
increase the visibility of the ADC; 4) to provide training and educational opportunities on dementing illness to
health care and other professional audiences; and 5) to determine the needs of our target audiences and
evaluate the programs that we offer to them. To accomplish these goals the EITC will provide a range of
programs and services. Efforts developed at the Kentucky Clinic North Minority Satellite will be expanded so
that ADC research projects reflect greater participation by African Americans the largest minority group in
Kentucky. Programs for researchers will include a bibliographic service a scientific writing course seminars
and clinical research conferences. To increase disease awareness in the local community the EITC will offer
programs such as Alzheimer's Disease Awareness Day and Call the Doctor. The EITC participates in a
training grant on aging for family practice residents; an Administration on Aging grant focused on educating
African Americans about Alzheimer's disease and providing culturally sensitive dementia care; and a
Geriatric Education Center grant that provides training to health professionals in the geographic area. The
EITC and the local Alzheimer's Association jointly sponsor an annual community conference for family
members and others who provide care or support to AD families. In summary the EITC will work through
partnerships with national and statewide organizations to design and offer dementia-specific programs to
meet the needs of various target audiences. These offerings will be developed to promote improved health
and diversified services for patients and their family members suffering from dementia.

project_terms:
Adult;African American;Aging;Alzheimer's Disease;Attention;Awareness;Basic Science;Caring;Clinic;Clinical;Clinical Research;Collaborations;Communities;Dementia;Development;Discipline;Disease;Education Continuing;Educational aspects;Effectiveness Program;Elderly;Ensure;Evaluation;Faculty;Family;Family Caregiver;Family Practice;Family member;Fostering;Funding;General Population;Geographic Locations;Goals;Grant;Group Structure;Health;Health Education Community;Health Personnel;Health Professional;Health Services;Healthcare;Kentucky;Link;Minority;Minority Groups;Neurodegenerative Disorders;Neurologic;Nurses;Participant;Patients;Population;Primary Care Physician;Range;Research;Research Activity;Research Personnel;Research Project Grants;Research Subjects;Research Support;Schedule;Services;Students;Surveys;Techniques;Training;Training Support;Underserved Population;Universities;Update;Work;Writing;community organizations;day;design;improved;interest;mild cognitive impairment;multidisciplinary;outreach program;postdoctoral investigator;programs;research study;skills;symposium


application_id: 7647288
project_number: 5P30AG028383-03
project_title: NEUROPATHOLOGY CORE
administering_ic: NIA
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1
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: 2008-07-01
budget_end_date: 2009-06-30
funding_mechanism: Research Centers
project_abstract:
The overall objective of the Neuropathology Core of the University of Kentucky Alzheimer's Disease Center
is to support research on normal brain aging presymptomatic Alzheimer's disease (AD) mild cognitive
impairment (MCI) early and late AD mixed dementia syndromes and other dementing disorders. The core
will perform short postmortem interval (2-4 hr) autopsies by our Rapid Autopsy Team on longitudinally
followed subjects from our normal control BRAiNS Clinic Dementia Research Clinic and Kentucky Clinic
North Minority Satellite (KYCN) and provide brain specimens CSF and synaptosomes for investigators at
UK other ADCs and outside investigators. The core will also provide consensus conference determined
diagnoses quantitation of neurofibrillary tangles (NFT) neuritic plaques and diffuse plaques from 8 brain
regions Abeta 1-40 and 1-42 quantitation Braak staging CERAD and NIA-Reagan Institute staging on all
autopsied cases to investigators. The core will maintain a tissue bank of the above specimens and frozen
serum plasma buffy coats and CSF from living patients from the Dementia Research Clinic the normal
control BRAiNS Clinic and KYCN. Special emphasis will be placed on defining the neuropathological
findings in the brains of the oldest old (>85) and providing investigators with specimens from cognitively
normal control subjects with no Abeta and few NFT (Braak O-ll) (successful cerebral aging) and cognitively
normal control subjects with abundant Abeta and NFT. Monthly or more frequent consensus conferences will
be held with the Clinical Core to define clinical-pathological diagnoses on all autopsied subjects. Clinical-pathological
conferences will be held every two months and twice annually for the Ohio Valley Geriatric
Research Center. Support for the Nun Study the Honolulu Asian Aging study the UK Udall Parkinson's
Disease Research Center and the Georgia Centenarian Study will be provided by the Neuropathology Core.
This core's unique opportunity to conduct clinical-pathological correlative studies on longitudinally followed
subjects to better understand normal brain aging and the transition to dementia and the factors involved in
this transition could contribute to early interventions and possible preventive measures.

project_terms:
Age;Aged 80 and over;Aging;Alzheimer's Disease;Amygdaloid structure;Amyloid beta-Protein;Area;Asians;Autopsy;Biometry;Brain;Brain region;Centenarian;Cerebrospinal Fluid;Cerebrum;Clinic;Clinical;Consensus;Correlative Study;Data;Databases;Degenerative Disorder;Dementia;Deposition;Diagnosis;Disease;Early Intervention (Education);Educational aspects;Elderly;Evaluation;Faculty;Freezing;Funding;Georgia USA;Georgia Western Asia;Hippocampus (Brain);Individual;Inferior;Institutes;Institution;Kentucky;Life;Lobule;Measures;Middle frontal gyrus structure;Minority;Neurodegenerative Disorders;Neurofibrillary Tangles;Ohio;Parietal;Parkinson Disease;Participant;Pathologic;Pathology;Patients;Physicians;Plasma;Preparation;Preventive;Program Research Project Grants;Protocols documentation;Reporting;Research;Research Personnel;Senile Plaques;Specimen;Staging;Structure of entorhinal cortex;Structure of middle temporal gyrus;Students Medical;Support of Research;Synaptosomes;Syndrome;Technology;Tissue Banks;Universities;Visual;Work;age related;aging brain;association cortex;base;data management;human very old age (85+);interest;mild cognitive impairment;neurofibrillary tangle formation;neuropathology;normal aging;peptide A;pre-clinical;symposium


application_id: 7647287
project_number: 5P30AG028383-03
project_title: BIOSTATISTICS AND DATA MANAGEMENT CORE
administering_ic: NIA
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1
subproject_number: 9002
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
budget_end_date: 2009-06-30
funding_mechanism: Research Centers
project_abstract:
The Biostatistics and Data Management Core (BDMC) has become a major part of the infrastructure of
the University of Kentucky Alzheimer's Disease Center (ADC). It plays an increasingly important role in data
management especially in reporting multiple data sets to NACC. This Core also provides an important
service in experimental design and statistical analysis to the ADC and affiliated AD research. The BDMC
has two specific aims one related to quality data management and the other related to effective statistical
consultation.
The first specific aim is to maintain a centralized database of the information collected by all ADC cores
pilot projects and affiliated AD and aging studies in an integrated manner. Relevant activities that support
this specific aim include: ensuring confidentiality at the subject level and security at the database level with
appropriate backup; assisting in the development of data collection forms and entering all data into the
centralized relational database in an accurate manner; training ADC personnel to practice quality data
collection procedures and to meet BDMC standards; providing expertise on data management procedures to
all ADC personnel and affiliated investigators; monitoring the flow of data in the longitudinal normal control
and AD cohorts and the minority satellite clinic; providing monthly summaries to the ADC Executive
Committee on subject recruitment retention and follow up; creating appropriate subsets of the database for
approved investigators and collaborative projects and archiving all such requests; and reporting accurate
and complete datasets to NACC.
The second specific aim is to provide expertise on experimental design and statistical analysis to ADC
cores pilot projects and affiliated AD projects. Relevant activities that support this specific aim include:
consultation for investigators in the early stages of all projects grant submissions presentations and
manuscripts; reviewing all ADC pilot projects for statistical content; collaborating with other Alzheimer's
Disease Centers on special projects of mutual interest such as periodic conferences on quantitative
methodologies in AD research; and incorporating advances in statistical methodology for interpreting and/or
analyzing data collected.
In addition this Core continues to contribute to the literature with innovative studies on statistical
methodology in AD research. It also participates in the training of graduate students postdoctoral
researchers and young investigators.

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


application_id: 7647286
project_number: 5P30AG028383-03
project_title: CLINICAL CORE
administering_ic: NIA
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1
subproject_number: 9001
contact_pi_person_id: 1896068
contact_pi: SMITH, CHARLES B
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: 2008-07-01
budget_end_date: 2009-06-30
funding_mechanism: Research Centers
project_abstract:
The overall goal of the Clinical Core of the University of Kentucky Alzheimer's Disease Center (UK ADC)
is to provide thoroughly evaluated longitudinally followed normal control subjects and Alzheimer's disease
(AD) and other non-AD dementing disorders patients for innovative research studies at UK other ADCs and
institutions studying AD and aging.
This Core will maintain a normal control population of 500 initially normal aged subjects who will be
followed longitudinally to autopsy (all have prearranged autopsies). The major emphases will be on studies
of normal aging and transition to preclinical AD mild cognitive impairment (MCI) and early AD. Control
participants will be evaluated annually with medical neurologic and neuropsychological tests to define
subtle changes in cognitive and neurologic functions. A developmental study will be carried out to attempt to
define the theoretical entity preclinical AD in this population.
This Core will maintain a Dementia Research Clinic of 200 subjects with dementing disorders who will be
followed longitudinally to autopsy (all have prearranged autopsies). Emphasis will be placed on recruiting
MCI early AD and mixed dementia (AD/vascular dementia AD/DLB Parkinson's Disease Dementia)
patients. Dementia Research Clinic patients undergo the same thorough annual evaluation as our control
subjects. The detailed evaluation of control and dementia subjects provides a database for use by UK
investigators associated with our Center and investigators at other ADCs and institutions. Longitudinally
followed control subjects and MCI and early AD patients will provide important data about the course and
progression of AD.
The Clinical Core will expand and maintain a satellite clinic for African Americans the Kentucky Clinic
North Minority Satellite in Lexington to provide longitudinal follow and broadening research opportunities for
an understudied population.
This Core will also obtain serum plasma buffy coats and CSF from normal control subjects MCI and
early AD patients for use by investigators. The Core will participate in the NIA AD neuroimaging initiative
NACC funded studies ADCS trials and industry sponsored drug trials. The uniform data set and the
minimum data set are collected by this Core and submitted to NACC in a timely fashion by the Biostatistics
and Data Management Core. The close relationship between the Clinical Core and the Neuropathology
Core allows for unique clinical-pathological correlation studies on longitudinally followed subjects to better
understand normal aging and transition to MCI and AD.

project_terms:
Adult;African American;Age-Years;Aging;Alzheimer's Disease;Autopsy;Biometry;Brain;Cessation of life;Characteristics;Clinic;Clinical;Clinical Data;Cognitive;Consent;Control Groups;Correlation Studies;Data;Data Set;Databases;Dementia;Dementia Vascular;Development;Disease;Ensure;Evaluation;Funding;Goals;Grant;Guidelines;Image;Industry;Institution;International;Kentucky;Lewy Body Disease;Medical;Minority;Multicenter Studies;Names;Nervous System Physiology;Neurodegenerative Disorders;Neurologic;Neuropsychological Tests;Parkinson Disease;Parkinson's Dementia;Participant;Patients;Pharmaceutical Preparations;Pilot Projects;Plasma;Population;Population Control;Program Research Project Grants;Purpose;Range;Recruitment Activity;Research;Research Personnel;Research Project Grants;Staging;Techniques;Universities;cohort;data management;follow-up;healthy aging;innovation;mild cognitive impairment;neuroimaging;neuropathology;neuropsychological;normal aging;pre-clinical;research study;size;volunteer


application_id: 7647162
project_number: 5R01MH078228-04
project_title: Neuroimaging Studies of Depression in Parkinson's Disease
administering_ic: NIMH
award_notice_date: 2009-06-18
opportunity_number: RFA-MH-06-003
application_type: 5
activity_code: R01
ic: MH
serial_number: 078228
program_official: MEINECKE, DOUGLAS L
project_start_date: 2006-07-01
project_end_date: 2011-06-30
study_section: ZMH1-ERB-H(03)
contact_pi_person_id: 8273960
contact_pi: BLONDER, LEE XENAKIS
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:
DESCRIPTION (provided by applicant): Depression is a common and potentially serious complication of Parkinson's disease (PD). Studies show that approximately 40 percent of PD patients are depressed. There is evidence that these patients have deficits in verbal fluency set shifting confrontation naming and memory relative to non-depressed PD patients. Despite the widespread toll on emotional health posed by PD few studies have undertaken a comprehensive examination of the neural underpinnings of Parkinsonian depression. In this project we will compare depressed versus non-depressed Parkinson patients to a sample of demographically-matched healthy controls using neuropsychological assessment and magnetic resonance imaging (MRI). Our primary hypothesis is that depression in PD is linked to structural and functional abnormality in dorsal and ventral striatum amygdala orbitofrontal cortex medial frontal cortex and anterior cingulate. Based on this we predict that in comparisons with non-depressed PD patients PD patients with depression will show 1.) significant reductions in the volume of the caudate nucleus orbitofrontal cortex medial frontal cortex anterior cingulate and amygdala; and 2.) reduced activation on cognitive and emotional tasks known to engage these regions. Our secondary hypothesis is that anti-parkinsonian medications particularly D2/D3 receptor agonists will result in elevation in mood and increased activation in these brain regions among depressed PD patients during the performance of cognitive and emotional tasks. To delineate the neural substrates of Parkinsonian depression each patient and control will undergo neuropsychological testing and structural and functional MRI. We will compare regional brain volume in structures associated with depression and patterns of functional MRI activation during working memory and facial affect processing tasks. Neuropsychological testing and fMRI will be performed "on" and "off dopaminergic pharmacotherapy in PD patients and at two similar time points in the unmedicated control group. The research proposed herein will contribute to our understanding of the neural pathways that underlie depression in PD the relationship of dysphoria to cerebral activation during cognitive and affective processing and the effects of dopaminergic pharmacotherapy on brain response in prefrontal and limbic regions.

project_terms:
Affect;Affective;Agonist;Amygdaloid structure;Anterior;Brain;Brain region;Cerebrum;Cognitive;Complication;Control Groups;Dopamine Agonists;Dorsal;Emotional;Face;Functional Magnetic Resonance Imaging;Health;Human;Individual;Link;Magnetic Resonance Imaging;Medial;Memory;Moods;Names;Neural Pathways;Neuropsychological Tests;Parkinson Disease;Parkinsonian Disorders;Patients;Pattern;Performance;Pharmaceutical Preparations;Pharmacotherapy;Prefrontal Cortex;Prevalence;Process;Quality of life;Regulation;Relative (related person);Research;Sampling;Short-Term Memory;Structure;Time;Variant;Ventral Striatum;base;brain volume;caudate nucleus;depressed;depression;disturbance in affect;dysphoria;frontal lobe;neuroimaging;neuromechanism;neuropsychological;putamen;receptor;relating to nervous system;research study;response;reward processing


application_id: 7646667
project_number: 1R15GM087661-01
project_title: Genetic and Biochemical Analyses of Germline Development in Drosophila
administering_ic: NIGMS
award_notice_date: 2009-03-27
opportunity_number: PA-06-042
application_type: 1
activity_code: R15
ic: GM
serial_number: 087661
program_official: HAYNES, SUSAN R
project_start_date: 2009-04-01
project_end_date: 2012-03-31
study_section: Development - 1 Study Section[DEV1]
contact_pi_person_id: 9347733
contact_pi: ARKOV, ALEXEY
other_pis: Not Applicable
congressional_district: 01
department: BIOLOGY
primary_duns: 041980632
primary_uei: LHC2S92MXG63
duns_number: 041980632
uei: LHC2S92MXG63
fips: US
organization_id: 5591701
organization_name: MURRAY STATE UNIVERSITY
organization_city: MURRAY
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 420712393
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Genetic and Biochemical Analyses of Germline Development in Drosophila During development germline is originated from the embryonic germ cells. Eventually the primordial germ cells give rise to sperm and eggs and therefore are responsible for producing an entire organism in the next generation. The landmarks of the germline are special organelles which contain factors necessary for germ cell development including Oskar and Tudor. While there is significant knowledge about the mechanisms that determine differentiation of many somatic cells little is known about genetic factors involved in germ cell formation and specification. Moreover composition and function of germline organelles are poorly understood. This project focuses on the identification and characterization of new genes and genes' products essential for the assembly of germline organelles and germ cell development in Drosophila. Many Drosophila genes show striking similarity to human genes and many developmental processes follow the same rules in both fruit flies and humans. Therefore data obtained during the proposed research should be relevant to humans and may provide critical insight into the biological cause of germline diseases including germline cancers and infertility. In addition the proposed study should result in better understanding of the role that the Tudor protein plays during the assembly of germline organelles. Tudor contains 11 Tudor domains which have been evolutionary conserved. In particular mutations in Tudor domain of human SMN protein cause spinal muscular atrophy which is a leading genetic cause of early childhood mortality. The following specific aims are proposed: I. Identification of the Components of Germline Organelles. Tudor-containing protein complexes present in the ovarian germline organelles will be stabilized by chemical cross-linking and immunopurified. Proteins present in the cross-linked complexes will be identified using mass spectrometry. Localization of identified proteins to germline organelles will be verified in immunostaining experiments. In addition the effect of mutations in genes that code for the identified proteins on germline development will be examined. If however this biochemical approach will encounter technical difficulties due to high non-specific protein background an alternative genetic approach is proposed as follows. II. Genetic Screen to Identify New Genes Acting Upstream of tudor Gene during Assembly of Germline Organelles. This genetic approach will focus on isolation of the mutants that disrupt the localization of Tudor to ovarian germline organelles and should point to components of these organelles. During the screen localization of Tudor which is fused with Green Fluorescent Protein will be monitored in ovaries. The effect of the mutations on the germline development will be determined and mutant genes will be characterized. PUBLIC HEALTH RELEVANCE: The proposed study should enhance our knowledge of germline development and may provide important insight into the origin of defective sperm and eggs that can be responsible for birth defects. In addition the proposed research may shed light on the cause of human germline disorders including testicular and ovarian cancers and infertility. Furthermore the proposed experiments will result in a better understanding of Tudor protein's function during development. Tudor contains multiple repeat modules (called Tudor domains) which are found in various organisms including humans. Importantly genetic changes in Tudor domain of human SMN protein are responsible for spinal muscular atrophy which is a leading genetic cause of early childhood mortality (1).

project_terms:
Affect;Alleles;Antibodies;Antibody Affinity;Biochemical;Biological;Cell Nucleus;Cells;Chemicals;Chimeric Proteins;Code;Complex;Congenital Abnormality;Cytoplasm;Cytoplasmic Granules;Data;Development;Developmental Process;Disease;Drosophila genus;Embryo;Embryonic Development;Employee Strikes;Female;Genes;Genetic;Genetic Screening;Germ;Germ Cells;Green Fluorescent Proteins;Human;Infertility;Knowledge;Life;Light;Malignant Neoplasms;Malignant neoplasm of ovary;Mammals;Maps;Masks;Mass Spectrum Analysis;Monitor;Morphology;Mortality Vital Statistics;Mutation;Oocytes;Oogenesis;Organelles;Organism;Ovarian;Ovary;Pathway interactions;Peptides;Play;Proteins;Research;Role;Somatic Cell;Spinal Muscular Atrophy;Structure of primordial sex cell;Study Section;Techniques;Testing;Transgenes;Transgenic Organisms;crosslink;early childhood;egg;fly;insight;mutant;next generation;novel;protein complex;protein crosslink;protein function;public health relevance;research study;sperm cell

public_health_relevance:
Project NarrativeThe proposed study should enhance our knowledge of germline development and mayprovide important insight into the origin of defective sperm and eggs that can beresponsible for birth defects. In addition the proposed research may shed light on thecause of human germline disorders including testicular and ovarian cancers andinfertility. Furthermore the proposed experiments will result in a better understanding ofTudor protein's function during development. Tudor contains multiple repeat modules(called Tudor domains) which are found in various organisms including humans.Importantly genetic changes in Tudor domain of human SMN protein are responsiblefor spinal muscular atrophy which is a leading genetic cause of early childhoodmortality (1).


application_id: 7646391
project_number: 5R01DK074816-03
project_title: Albumin-AFP Gene Family Regulation in Fetal and Adult Liver
administering_ic: NIDDK
award_notice_date: 2009-06-10
application_type: 5
activity_code: R01
ic: DK
serial_number: 074816
program_official: SERRANO, JOSE
project_start_date: 2007-09-01
project_end_date: 2011-06-30
study_section: Gastrointestinal Cell and Molecular Biology Study Section[GCMB]
contact_pi_person_id: 1879406
contact_pi: SPEAR, BRETT
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
project_abstract:
DESCRIPTION (provided by applicant): Mammalian liver development requires the sequential activation of genes in a highly ordered manner. Once activated levels of gene expression in the liver must continually be responsive to extracellular signals in order for organisms to maintain physiological homeostasis. We have been studying the mouse alpha- fetoprotein (AFP) gene as a model of liver-specific gene regulation. These studies have focused on the AFP enhancer region. More recently we have become increasingly interested regulation of all genes in the albumin-AFP gene family. One main goal of this proposal is to investigate the role of the AFP enhancers in the control of this gene family in the liver. Since AFP is activated in the fetal liver shut-off at birth and reactivated in models of liver damage and liver cancer these studies should help elucidate the basis of transcriptional changes that occur during liver damage and hepatocarcinogenesis. We are also interested in studying the process of zonal regulation in the adult liver. Zonal gene expression is a mechanism that allows different subpopulations of hepatocyte in the liver to carry out distinct metabolic activities. The zonal gene regulation can be disrupted in damaged liver and in neoplastic liver cells. Since zonal gene regulation is essential for the liver to carry out its normal function it is important to understand the basis for this control in the normal and diseased liver.

project_terms:
Adult;Albumins;Binding (Molecular Function);Binding Proteins;Birth;Chromosomes;Complement 3c;Development;Elements;Enhancers;Family;Fetal Liver;Gene Activation;Gene Expression;Gene Expression Regulation;Gene Family;Genes;Genomics;Glutamate-Ammonia Ligase;Goals;Hepatocarcinogenesis;Hepatocyte;Homeostasis;Human;Indium;Link;Liver;Malignant neoplasm of liver;Mammals;Mediating;Metabolic;Methods;Modeling;Molecular;Molecular Conformation;Mus;Neoplastic liver;Nucleic Acid Regulatory Sequences;Organism;Positioning Attribute;Process;Promoter Regions (Genetics);Promotor (Genetics);Rattus;Regulation;Regulatory Element;Repression;Role;Signal Transduction;Testing;Time;Transgenic Organisms;Vitamin D-Binding Protein;alpha-Fetoproteins;base;comparative;extracellular;fetal;interest;member;postnatal;research study


application_id: 7646384
project_number: 5R44HD050006-03
project_title: Stimulation-Augmented Exercise and Neuromotor Therapy
administering_ic: NICHD
award_notice_date: 2009-04-01
opportunity_number: PA-07-280
application_type: 5
activity_code: R44
ic: HD
serial_number: 050006
program_official: SHINOWARA, NANCY
project_start_date: 2006-05-01
project_end_date: 2011-03-31
study_section: Special Emphasis Panel[ZRG1-MOSS-L(02)B]
contact_pi_person_id: 7771781
contact_pi: HARTMAN, ERIC C
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 129360637
duns_number: 129360637
fips: US
organization_id: 4168101
organization_name: CUSTOMKYNETICS, INC.
organization_city: NICHOLASVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403401290
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-01
budget_end_date: 2010-03-31
project_abstract:
DESCRIPTION (provided by applicant):  This Phase II SBIR project proposes to develop an electrical stimulation augmented exercise device for individuals with incomplete spinal cord injury (iSCI).  The device will provide a closed-chain load bearing lower extremity exercise that has the potential to condition muscles and reverse or slow the rate of loss of bone mineral density.  Users will be encouraged to voluntarily perform the exercise.  Client volitional efforts will be augmented by electrical stimulation and a servomotor drive such that the prescribed exercise range of motion is fulfilled with each movement cycle.  The adaptive stimulation controller will continuously adjust the stimulation profile based on movement errors and servomotor activity to provide only the stimulation that is necessary to complete the exercise while encouraging clients to contribute their best volitional effort on each exercise cycle.  A visual feedback infrastructure will be developed that encourages client participation emphasizes clinically relevant therapeutic exercise goals and rewards client achievements.  The visual environment will require clients to generate a series of appropriately timed and executed volitional trigger events (ranging from 'trace levels of applied force' to 'unassisted movements') which will be rewarded with a full range of motion movement cycle and success in a game.  We hypothesize that long-term use of the device in a comprehensive motor rehabilitation program may lead to functional improvements in addition to the localized and systemic benefits of exercise.  Phase I feasibility milestones were achieved including demonstration that: 1) client volitional effort could be synchronized with the stimulation controller; 2) functional stimulation levels could be well tolerated in this population where cutaneous sensation is in-tact (potentially hypersensitive); and 3) the stimulation controller could accommodate client volitional effort and generate only the stimulation that was needed to elicit the desired exercise movement.  We propose to build upon Phase I results through the following Phase II aims: 1) develop a servomotor drive that will improve exercise quality provide a wider range and better control of bodyweight loading allow use by individuals with advanced osteoporosis who are most in need of the exercise and accomplish the goal of coordinating volitional and stimulation-augmented efforts via haptic feedback rather than a real-time visual display; 2) develop intellectually engaging visual display environments that encourage and reward clinically relevant client volitional efforts; and 3) improve reliability and manufacturability.  We will demonstrate efficacy via a two-site clinical trial in which twenty (20) individuals with chronic incomplete spinal cord injury participate in a 12-week exercise paradigm using the device. Outcome measures will include assessment of functional improvements (i.e. FIM gait analysis) and a dynamometer test to assess improvements in volitional control independent of exercise-related improvements in torque generating capability. The target market for the device is clinics who serve individuals with neuromotor disabilities such as incomplete SCI traumatic brain injury or stroke.  The device will be competitively priced within the electrical stimulation-based exercise equipment market.  PUBLIC HEALTH RELEVENCE: The proposed work may benefit public health through development of a clinically viable electrical stimulation based therapeutic exercise device for use in motor rehabilitation following spinal cord injury or stroke. Compared to existing devices and techniques the adaptively controlled electrical stimulation servomotor assist and video game components and tight integration of instrumentation control stimulation visualization and reporting features may improve efficacy and availability of the therapeutic intervention for many affected individuals.

project_terms:
Achievement;Affect;Articular Range of Motion;Bone Density;Cardiovascular Diseases;Chronic;Client;Clinic;Clinical Trials;Craniocerebral Trauma;Cutaneous;Development;Devices;Diabetes Mellitus;Electric Stimulation;Electronics;Environment;Equipment;Esthesia;Event;Exercise;Feedback;Generations;Goals;Imagery;Individual;Joints;Lead;Leg;Lower Extremity;Marketing;Mechanics;Motor;Movement;Muscle;Osteoporosis;Outcome Measure;Paralysed;Pattern;Phase;Phase II Clinical Trials;Physical Fitness;Population;Positioning Attribute;Price;Range of motion exercise;Rehabilitation therapy;Reporting;Research Infrastructure;Rewards;Series;Site;Sledding;Small Business Innovation Research Grant;Spinal cord injury;Structure;System;Techniques;Testing;Therapeutic;Therapeutic Intervention;Time;Torque;Traumatic Brain Injury;Video Games;Visual;Weight-Bearing state;Work;base;clinically relevant;design;disability;foot;functional improvement;gait examination;haptics;improved;instrumentation;motor control;nervous system disorder;programs;prototype;public health medicine (field);respiratory;sensor;stroke;success;tool;visual feedback


application_id: 7646301
project_number: 5T32ES007266-20
project_title: MOLECULAR MECHANISMS OF TOXICITY TRAINING GRANT
project_terms: Grant;Molecular;Toxic effect;Training
administering_ic: NIEHS
award_notice_date: 2009-07-01
application_type: 5
activity_code: T32
ic: ES
serial_number: 007266
program_official: SHREFFLER, CAROL A
project_start_date: 1990-07-01
project_end_date: 2010-06-30
study_section: Environmental Health Sciences Review Committee[EHS(TG)]
contact_pi_person_id: 1862358
contact_pi: VORE, MARY
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant)  
  
The goal of the Molecular Mechanisms of Toxicity Training Program is to provide students with an education in toxicology that is based on an understanding of biochemistry physiology pharmacology and molecular/cell biology coupled with an in-depth research experience on the mechanisms by which specific agents induce toxicity and/or the basic cellular processes upon which environmental agents impact to cause toxicity.  The Training Program is based in the Graduate Center for Toxicology (GCT) which grants the Ph.D. in Toxicology and provides an administrative and teaching nucleus of 6 core faculty.  The diversity of training opportunities is enhanced by 24 joint faculty who have primary appointments in the Colleges of Medicine Pharmacy Agriculture and Arts & Sciences and Nutritional Sciences.  Numerous collaborations and multidisciplinary approaches to research problems among this group provide a rich research training environment.  This application requests support for 8 predoctoral trainees in five areas of strength which serve as a focus:  1) Oxidative Stress 2) DNA Repair 3) Biochemical Toxicology 4) Neurotoxicology and 5) Immunotoxicology. Current enrollment in the Toxicology Program is 35 predoctoral students including 5 minority students.  The University of Kentucky sponsors a program with the University of Puerto Rico to bring up to 10 students for summer research experiences as a means of increasing our recruitment of outstanding minority doctoral students; 6-7 of these students work in the laboratories of GCT faculty and 5 are supported by a T35 Environmental Toxicology/Short Term Research Grant (ES 10951). The predoctoral training program requires 23 credit hours in biomedical based coursework (i.e. biochemistry physiology cell biology pharmacology statistics) 13 in toxicology-based courses (including Ethics in Scientific Research) and two electives (3-4 credits) selected from courses germane to the research area (e.g. molecular biology neuroscience immunology).  Students are guided through the program initially by a Director of Graduate Studies followed by a Major Advisor and a 4-member Advisory Committee which supervises the student's Qualifying Examination research and thesis defense.  There continues to be strong University support for the GCT in the form of student fellowships supplementation of the Training Grant and new faculty lines space and equipment.  The program continues to grow in terms of the quality and breadth of the Training Program due to recruitment of new faculty with vigorous research programs increased funding of faculty and increased enrollment of excellent motivated predoctoral students.


application_id: 7645828
project_number: 5R01CA083237-09
project_title: Molecular Mechanisms of Metastasis Suppression by NM23
administering_ic: NCI
award_notice_date: 2009-07-21
application_type: 5
activity_code: R01
ic: CA
serial_number: 083237
program_official: WOODHOUSE, ELIZABETH
project_start_date: 1999-08-01
project_end_date: 2011-07-31
study_section: Cancer Genetics Study Section[CG]
contact_pi_person_id: 7875382
contact_pi: KAETZEL, DAVID M
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-08-01
project_abstract:
DESCRIPTION (provided by applicant): While mechanisms regulating oncogenesis have been elucidated substantially in recent years comparatively little is yet known about the mechanisms that underlie metastasis of tumor cells the ultimate cause of death in cancer. Metastasis suppressor genes play pivotal roles in controlling this process but only a handful have been identified. NM23 ("negative in metastasis") genes represent the first described metastasis suppressors and are recognized for their antimetastatic activity in melanoma breast and gastric carcinoma. The overall goal of this project to systematically dissect the molecular mechanisms and genomic pathways underlying the metastasis suppressor activity of NM23. We recently found that the NM23-H1 isoform is a 3'-5' exonuclease (3'5' EXO) an activity often associated with genome integrity apoptosis and chromatin remodeling. Although there is clear potential relevance of these processes to malignant progression we will also measure the extent to which the nucleoside diphosphate kinase (NDPK) and histidine kinase (hisK) activities of NM23-H1 contribute to its metastasis suppressor properties. In Specific Aim 1 we will complete a detailed structure-function analysis to delineate the active site of the 3'5 EXO and characterize a panel of mutants harboring lesions that selectively disrupt the 3'5' EXO NDPK and hisK functions of the NM23-H1 molecule. The mutants will be used as molecular tools to determine the relative contributions of each to suppression of the metastatic phenotype (Specific Aim 2) in human melanoma cells using cell culture and in vivo models to measure tumorigenic and metastatic potential. Gene expression changes elicited by expression of NM23-H1 variants will be determined by microarray analysis and real-time PCR (Specific Aim 3). Correlational analysis will identify NM23-regulated genes whose expression tracks with metastatic phenotype and metastatic progression. Functional relevance of identified genes will be validated by viral-mediated overexpression and knockdown approaches. In Specific Aim 4 we will directly test the DMA repair activity of NM23-H1 in mammalian and yeast cell models and identify the relevant enzymatic function. These studies should provide the first systematic analysis of pathways through which NM23 proteins oppose metastasis in multiple cancer types and therefore could suggest novel strategies to combat this final and intractable stage of the disease.

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


application_id: 7645788
project_number: 5R21DE017378-02
project_title: Oral H. pylori Prevalence in Intellectually/Developmentally Disabled Adults
administering_ic: NIDCR
award_notice_date: 2009-06-03
opportunity_number: PAR-06-246
application_type: 5
activity_code: R21
ic: DE
serial_number: 017378
program_official: NOWJACK-RAYMER, RUTH
project_start_date: 2008-07-01
project_end_date: 2011-06-30
study_section: ZDE1-SK(07)
contact_pi_person_id: 7034912
contact_pi: BINKLEY, CATHERINE J
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Helicobacter pylori (H. pylori) bacteria play a significant role in the etiology of gastric and duodenal ulcers gastro-esophageal reflux disease and gastric adenocarcinoma. Intellectually disabled/developmentally disabled (ID/DD) adults are reported to have H. pylori infection at approximately twice the rate of the general population and experience recurrence at a seven-fold higher rate contributing to increased mortality due to gastric cancer. The oral cavity may serve as a reservoir for H. pylori and subsequently contribute to the recurrence of gastric infection. Numerous studies have identified H. pylori in dental plaque an environment that is relatively resistant to systemic antibiotics. Systemic antibiotics are used to treat H. pylori infections but do not appear to eradicate H. pylori in the mouth. The oral status of ID/DD adults is reported to be poor due to inadequate oral hygiene leading to increased plaque caries and periodontal disease. Furthermore poor oral status (periodontal disease) has been associated with H. pylori seropositivity. While ID/DD adults have elevated rates of H. pylori gastric infections nothing is known about the prevalence of H. pylori in their oral cavities. The proposed exploratory research will address the following questions in this disadvantaged population: 1) What is the prevalence of H. pylori in the dental plaque in ID/DD adults? 2) Is poor oral status associated with H. pylori gastric infection? and 3) Does H. pylori persist in the dental plaque of ID/DD adults after systemic antibiotic treatment and if so is it associated with recurrence of gastric infection? This epidemiological study of 112 institutionalized ID/DD and 112 control subjects will involve oral examinations indices dental plaque sampling and C13 Urea Breath Tests at baseline to determine prevalence. Nested Polymerase Chain Reaction (PCR) analyses will be used to detect H. pylori in the dental plaque. For those ID/DD subjects who have a positive gastric H. pylori test at baseline repeated oral sampling and gastric tests will be performed over 1 year to determine persistence. If poor oral health status and oral H. pylori prevalence are correlated with gastric H. pylori infections a future pilot clinical trial will be conducted to investigate the concordance between genetic strains of H. pylori in the mouth and stomach the effect of various interventions on oral health oral H. pylori prevalence and H. pylori gastric infections in ID/DD adults. The proposed research responds to the Surgeon General's National Call to Action to conduct studies to elucidate underlying mechanisms and determine any causal associations between oral infections and systemic conditions. The proposed research also addresses the need to reduce health disparities improve quality of life and reduce morbidity and mortality in vulnerable populations. Project Narrative: Helicobacter pylori infections are a significant cause of morbidity in institutionalized intellectually and developmentally disabled (ID/DD) persons in the United States. There is reason to investigate whether there is an association between oral health and H. pylori infection and recurrence of H. pylori infection in ID/DD individuals. The proposed study would provide pilot data for a clinical trial and add to the knowledge concerning oral status and H. pylori infection. Our results may demonstrate that professional oral care is medically necessary for the reduction of morbidity and mortality caused by H. pylori infection in ID/DD persons. This research is consistent with the Healthy People 2010 overarching goal of eliminating health disparities. It is also consistent with the Surgeon General's National Call to Action to determine oral health care needs refine protocols of care for special needs patients and to conduct studies to determine associations between oral infections and systemic conditions.

project_terms:
Accounting;Address;Adult;Aftercare;Antibiotic Therapy;Antibiotics;Bacteria;Biological Assay;Breath Tests;Caregivers;Caring;Cessation of life;Clinical Research;Clinical Trials;Data;Dental Clinics;Dental Hygiene;Dental Plaque;Dental Plaque Index;Dental caries;Development;Disabled Persons;Disadvantaged;Disease;Duodenal Ulcer;Environment;Epidemiologic Studies;Etiology;Exploratory/Developmental Grant;Foundations;Frequencies (time pattern);Future;Gastric Adenocarcinoma;Gastroesophageal reflux disease;General Population;Genotype;Goals;Habits;Health Policy;Health Status;Healthcare;Healthy People 2010;Helicobacter Infections;Helicobacter pylori;Incidence;Individual;Infection;Intervention;Intestinal Diseases;Knowledge;Malignant Neoplasms;Morbidity - disease rate;Mortality Vital Statistics;Nested PCR;Oral;Oral Examination;Oral Hygiene Index;Oral cavity;Oral health;Patients;Pattern;Periodontal Diseases;Play;Polymerase Chain Reaction;Population;Prevalence;Preventive;Protocols documentation;Pylorus;Quality of life;Recurrence;Reporting;Research;Resistance;Risk;Risk Factors;Role;Route;Sampling;Site;Stomach;Stomach Diseases;Surgeon;Testing;Tooth structure;United States;Urea;Vulnerable Populations;developmentally disabled;experience;genetic strain;health disparity;improved;malignant stomach neoplasm;medically necessary care;oral care;oral infection;oral status


application_id: 7645784
project_number: 5R01AI069321-03
project_title: Modulation of apoptosis by Legionella Pneumophila
administering_ic: NIAID
award_notice_date: 2009-06-29
application_type: 5
activity_code: R01
ic: AI
serial_number: 069321
program_official: KORPELA, JUKKA K
project_start_date: 2007-07-15
project_end_date: 2012-06-30
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 1877865
contact_pi: ABU KWAIK, YOUSEF A
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
project_abstract:
DESCRIPTION (provided by applicant):  Legionella pneumophila is an intracellular pathogen that evades endocytic fusion and hijacks ER-to-golgi vesicle traffic to remodel its phagosome into an ER-derived compartment permissive for intracellular replication. The Dot/lcm type IV secretion system of L. pneumophila is essential for both modulation of phagosome biogenesis and modulation of the macrophage apoptotic pathways through robust early and novel activation of caspase-3 independent of the intrinsic and extrinsic pathways of apoptosis. The Dot/lcm- mediated activation of caspase-3 results in cleavage of Rabaptin-5 which is an effector of the early endosome regulator Rab5. Inhibition of caspase-3 using caspase-3 peptide inhibitors blocks intracellular replication of L. pneumophila and results in trafficking of the organism to phagolysosomes similar to dot/icm mutants. Our hypothesis is: Caspase-3-meditaed cleavage of Rabaptin-5 is central to the arrested biogenesis of the Legionella-containing phagosome (LCP) and to intracellular replication. To test this hypothesis our specific aims are to examine the following: Specific aim I. Role of caspase-3 activation in biogenesis of the LCP; Specific aim II: Role of caspase-3-mediated cleavage of Rabaptin-5 in biogenesis of the LCP; Specific aim III. Identification of the L. pneumophila effector involved in caspase-3 activation. Significance: Our proposed studies are the crux of our understanding of the molecular and cellular mechanisms by which this pathogen commandeer the host cell and will she light on the cellular mechanism by which this pathogen engages a cross talk between the apoptotic pathways and vesicle traffic in the host cell to remodel it to its liking. The bacterial effector involved in this process is a potential target for therapy and prevention of the disease.

project_terms:
Abbreviations;Adenylate Cyclase;Apoptosis;Apoptotic;Biochemical;Biogenesis;Biological Models;Biological Preservation;Biology;Caspase Inhibitor;Cell physiology;Cells;Cellular biology;Co-Immunoprecipitations;Disease;Early Endosome;Endoplasmic Reticulum;Ensure;Golgi Apparatus;Human;Infection;Knowledge;Lead;Legionella;Legionella pneumophila;Life Style;Light;Mediating;Molecular;Nuclear;Organism;Pan Genus;Pathway interactions;Peptides;Phagolysosome;Phagosomes;Prevention therapy;Process;Proteins;RNA Interference;Role;Small Interfering RNA;Staging;Testing;Type IV Secretion System Pathway;Vesicle;caspase-3;clinical application;disorder prevention;inhibitor/antagonist;macrophage;monocyte;mutant;novel;pathogen;programs;trafficking


application_id: 7645154
project_number: 5R03AI076714-02
project_title: PAR2 Bronchopulmonary Sensory Nerve and Pathogenesis of Asthma
administering_ic: NIAID
award_notice_date: 2009-06-30
opportunity_number: PA-06-180
application_type: 5
activity_code: R03
ic: AI
serial_number: 076714
program_official: DONG, GANG
project_start_date: 2008-07-01
project_end_date: 2011-06-30
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 8579171
contact_pi: GU, QIHAI
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): Protease-activated receptor-2 (PAR2) is expressed in various cells in the airways and lungs. Increasing evidence has suggested that activation of PAR2 contributes to airway inflammation and airway hyperresponsiveness the prominent features of many respiratory diseases including asthma. The mechanism underlying the potent actions of PAR2 in the airways and lungs remains to be elucidated; and an involvement of neurogenic mechanisms caused by the activation of bronchopulmonary sensory nerves particularly C-fiber afferents has been recently suggested. The long-range goal of this research project is to elucidate the mechanism that how the interaction between PAR2 and bronchopulmonary C-fibers is involved in the pathogenesis of asthma. Airway acidification occurs in asthmatic patients and affects airway functions by numerous pathways. One prominent consequence of acidification in the airways is the stimulation of bronchopulmonary C- fibers. The primary objective of this R03 pilot proposal is to investigate the effect of PAR2 activation on the acid stress-induced bronchopulmonary C-fiber responses. Our hypothesis is that when PAR2 is activated by endogenous (e.g. mast cell tryptase and trypsin-like proteases) or exogenous (e.g. airborne allergens) agonists the airway acidification-induced changes in airway functions may be amplified and collectively contributes to the disease process of asthma. Two specific aims have been proposed: 1) to determine the effect of PAR2 activation on vagal bronchopulmonary C-fiber responses to acid stress and to investigate the underlying cellular mechanisms; and 2) to determine the involvement of bronchopulmonary C-fibers in the PAR2 activation-induced airway hyperresponsiveness to acid stress and to differentiate the relative contributions of cholinergic reflex and tachykininergic mechanisms. The in-vivo respiratory recording and in-vitro whole-cell patch-clamping will be carried out in the proposed studies. The results obtained from this proposal should improve our understanding of the pathogenic role of the interaction between PAR2 and bronchopulmonary sensory nerves and offer novel therapeutic strategies for the treatment of airway inflammatory diseases such as asthma.   
  
PUBLIC HEALTH RELEVANCE: A decrease in airway luminal pH occurs in asthmatic patients and has diverse effect on airway functions. A receptor called protease-activated receptor-2 is known to play an important role in the pathogenesis of asthma. The proposed project will investigate how activation of this receptor regulates the pulmonary sensory nerve responses to low pH in the airways and how these interactions will affect the disease process of asthma.

project_terms:
Affect;Agonist;Airway Obstruction;Asthma;C Fiber;Cells;Chronic;Development;Disease;Goals;Immune;In Vitro;Inflammatory;Knowledge;Liquid substance;Lung;Lung diseases;Nervous system structure;Neuroimmunomodulation;Neuropeptides;PAR-2 Receptor;Pathogenesis;Pathway interactions;Peptide Hydrolases;Play;Process;Receptor Activation;Recurrence;Reflex action;Relative (related person);Research Project Grants;Role;Signal Transduction;Trypsin;Tryptase;acid stress;afferent nerve;airborne allergen;airway hyperresponsiveness;airway inflammation;asthmatic patient;base;cholinergic;cytokine;improved;in vivo;neurotrophic factor;novel therapeutics;patch clamp;public health relevance;receptor;respiratory;response;treatment strategy


application_id: 7644994
project_number: 5R01AG020941-07
project_title: Changes in myogenic progenitor potential with age
administering_ic: NIA
award_notice_date: 2009-06-26
opportunity_number: RFA-AG-06-003
application_type: 5
activity_code: R01
ic: AG
serial_number: 020941
program_official: WILLIAMS, JOHN
project_start_date: 2002-06-01
project_end_date: 2011-06-30
study_section: ZAG1-ZIJ-2(M1)
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   This project will explore a novel mechanism potentially contributing both to muscle atrophy and increased muscle lipid with age. Our work shows that in the mouse the progenitors present in muscle that are primarily responsible for postnatal muscle growth repair and maintenance activate an adipocyte-like gene program with age. The balance between myogenic and adipogenic potential appears to be regulated by Wnt signaling. In fact the constellation of Wnt ligands present and the signaling pathways activated appear to crosstalk to control muscle size and lipid content. Thus Wnt signaling may provide the mechanistic link whereby exercise influences both muscle properties. We hypothesize that Wnt signaling is altered in myogenic progenitors as a function of age contributing to impaired muscle function through loss of muscle mass and increased intramyocellular lipid following injury. In addition intermyocellular lipid increases with age and we will assess the cellular properties of myofibroblasts to test the hypothesis that changes in their potential through altered Wnt signaling may contribute to lipid accumulation surrounding myofibers. In Aim 1 we will identify the signaling pathways that account for the distinct function of WntlOb in repressing adipogenic gene expression compared to other Wnts that promote myogenic differentiation and hypertrophy and determine the role of changes in Wnt signaling in altering myogenic progenitor potential with age. Myofibroblasts will be characterized in vitro in Aim 2 to determine if adipogenic potential increases with age potentially contributing to intermyocellular lipid. Co-culture of myogenic progenitors and myofibroblasts from different aged mice will determine if age affects their interaction. In Aim 3 myogenic progenitors will be "exercised" in vitro with a Flexcell stretcher to attempt to alter adipogenic potential. Lipid accumulation and myotube size will be quantified to determine if the effects of exercise differ with age through altered signaling. Preliminary data in human myogenic progenitors suggest that age also increases their adipogenic potential and focused analyses will be translated into humans. In Aim 4 myogenic progenitors and myofibroblasts will be isolated from older compared to younger humans to characterize myogenic and adipogenic differentiation potential that will be correlated with age muscle adiposity size and strength. The effects of an exercise regimen on muscle properties in vivo will be assessed in relation to changes in myogenic progenitor potential in vitro. We will examine the underlying mechanisms involved and whether response differs with age. The long term goal of this research is to characterize changes in cell fate with age and determine their contribution to impaired muscle function in the elderly. Using this information rational new strategies for frailty prevention can be designed and tested.

project_terms:
Accounting;Adipocytes;Affect;Age;Aging;Area;Cells;Coculture Techniques;Collaborations;Data;Elderly;Equilibrium;Exercise;Gene Expression;Genes;Goals;Growth;Human;Hypertrophy;In Vitro;Injury;Intervention Studies;Knock-out;Ligands;Link;Lipids;Maintenance;Mus;Muscle;Muscle Fibers;Muscle function;Muscular Atrophy;Myoblasts;Myofibroblast;Obesity;Prevention;Property;Research;Research Personnel;Role;Signal Pathway;Signal Transduction;Skeletal muscle structure;Testing;Transgenic Organisms;Translating;Treatment Protocols;Work;aged;design;frailty;in vitro Model;in vivo;muscle aging;muscle form;novel;postnatal;progenitor;programs;repaired;response


application_id: 7644810
project_number: 1R15HL096463-01
project_title: Effect of soy isoflavone on cholesterol & SREBP-regulated gene expression.
administering_ic: NHLBI
award_notice_date: 2009-04-11
opportunity_number: PA-06-042
application_type: 1
activity_code: R15
ic: HL
serial_number: 096463
program_official: ERSHOW, ABBY
project_start_date: 2009-04-15
project_end_date: 2012-03-31
study_section: Integrative Nutrition and Metabolic Processes Study Section[INMP]
contact_pi_person_id: 9482332
contact_pi: MULLEN, EIMEAR M.
other_pis: Not Applicable
congressional_district: 04
department: BIOLOGY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Soy is known to lower cholesterol levels and this corresponds to a decrease in cardiovascular disease risk. However the mechanisms of this hypocholesterolemic effect as well as the components of soy that cause this effect are a source of controversy. It is also unknown whether soy protein containing endogenous isoflavones would have the same effect as soy protein containing low isoflavones with isoflavones supplemented back to the protein source. We have previously shown in a cell culture model that the isoflavones genistein and daidzein increase the processing of the Sterol Regulatory Element Binding Proteins (SREBPs) and the expression SREBP-regulated genes such as HMG CoA reductase HMG CoA synthase and the LDL receptor. This study will address whether isoflavones cause a similar increase in SREBP processing and SREBP-regulated gene expression in an in vivo model. We will use the C57BL/6J mouse and feed it an atherogenic diet for either 2 days 10 days or 6 weeks. The diets will contain soy protein with low endogenous amounts of isoflavones with or without isoflavone supplementation or soy protein with high amounts of endogenous isoflavones. The animals will be sacrificed and their plasma and liver tissue lipids will be analyzed. The processing of SREBP-2 and the protein levels of HMG CoA reductase will be measured by immunoblotting. The expression levels of SREBP-regulated genes will also be investigated by quantitative real time PCR. We hypothesize that there will be a decrease in plasma cholesterol and triglyceride levels and this will correspond to an increase in SREBP processing as well as SREBP-regulated gene expression. However we do not know if we will observe the same results for soy protein containing high amounts of endogenous isoflavones or soy protein containing low amounts of isoflavones with isoflavones supplemented back to the protein source. PUBLIC HEALTH RELEVANCE: Cardiovascular disease and hypercholesterolemia are one of the major causes of death in the United States. This project seeks to investigate the mechanisms by which an inexpensive dietary component soy isoflavones lowers cholesterol levels.

project_terms:
3-hydroxy-3-methylglutaryl-coenzyme A;Address;Animals;Atherogenic Diet;Back;Binding Proteins;Blood;Cardiovascular Diseases;Cause of Death;Cell Culture Techniques;Cholesterol;Diet;Dietary Component;Gene Expression;Gene Proteins;Genes;Genistein;Hepatic;Homeostasis;Hydroxymethylglutaryl-CoA reductase;Immunoblotting;Isoflavones;Lipids;Liver;Low Density Lipoprotein Receptor;Measures;Modeling;Mus;Organ;Pharmaceutical Preparations;Plasma;Play;Process;Proteins;Regulatory Element;Role;SRE-2 binding protein;Source;Soy Proteins;Sterols;Supplementation;Time;Tissues;Triglycerides;United States;Work;atorvastatin;cardiovascular disorder risk;cholesterol biosynthesis;daidzein;design;enzyme activity;feeding;hypercholesterolemia;in vivo;in vivo Model;mouse model;protein expression;public health relevance;soy;soy protein isolate

public_health_relevance:
Project narrativeRelevanceCardiovascular disease and hypercholesterolemia are one of the major causes of death in the United States.This project seeks to investigate the mechanisms by which an inexpensive dietary component soy isoflavoneslowers cholesterol levels.


