# projects

application_id: 8313863
project_number: 5R01NS077284-02
project_title: Role of FUS in ALS
administering_ic: NINDS
award_notice_date: 2012-03-26
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: NS
serial_number: 077284
program_official: GUBITZ, AMELIE
project_start_date: 2011-08-15
project_end_date: 2015-04-30
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD-M]
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 also known as Lou Gehrig's disease) is a progressive and fatal neurodegenerative disease. A general symptom of ALS is muscle weakness and wasting triggered by denervation at neuromuscular junctions. The majority of ALS cases are sporadic and approximately 10% are familial. Several ALS genes have been identified as their mutation can lead to familial ALS including two genes encoding RNA processing proteins TDP-43 and fused in sarcoma/translocated in liposarcoma (FUS/TLS). FUS is a ubiquitously expressed multi-domain RNA-binding protein. In neurons and glial cells FUS is almost exclusively localized to the nucleus but is also reported to transport mRNA for local translation in dendrites in neurons. In addition FUS plays a role in a variety of processes including nucleocytoplasmic shuttling of mRNA transcriptional regulation and mRNA splicing. However little is known regarding how FUS mutations cause motor neuron degeneration and ALS which is the focus of this study.  We recently published that the C-terminus of FUS where the ALS-causing mutations are clustered functions as an effective nuclear localization sequence (NLS). Our newly generated data suggest that a FUS- interacting protein Gemin3 plays a critical role in the perturbations caused by FUS mutations. Gemin3 can be sequestered by ALS mutant FUS which causes reduced Gemin3-positive nuclear structures (Gems) decreased assembly of snRNPs and attenuated spliceosome activity. The Drosophila model we established showed motor function deficiency when FUS was over-expressed in motor neurons. Interestingly Gemin3 was also reported to be required for larval motor function in Drosophila. Moreover we generated FUS/Gemin3 double transgenic flies and showed that expression of Gemin3 rescued the phenotypes of FUS transgenic flies. We thus hypothesize that the ALS-related FUS mutants or WT FUS with deregulated over-expression can accumulate in cytoplasm and sequester Gemin3 which results in decreased assembly of snRNPs in cytoplasm and compromised spliceosome function in the nucleus. To test the central hypothesis three specific aims have been designed to determine the role of FUS in ALS.  Aim 1 is to understand the regulation of FUS subcellular localization by the localization sequence elements within FUS as well as by its RNA binding ability. In Aim 2 we will first determine the molecular mechanism how FUS and Gemin 3 interact. We will further characterize how FUS mutations disturb Gemin 3- mediated snRNP assembly and spliceosome activity. Aim 3 will test the molecular mechanisms defined in Aims 1 and 2 using the Drosophila model. We will first determine whether motor neuron death and neuromuscular denervation are prominent in the transgenic flies with motor neuron-specific FUS expression. FUS-mediated Gemin3 sequestering and subsequent spliceosome changes will be especially tested in flies since Gemin3 over-expression rescued the motor function deficit phenotype caused by FUS. Furthermore the significance of FUS subcellular localization and RNA binding in producing toxicity in motor neurons will be investigated. Lastly we will carry out RNA-Seq experiment to determine the FUS-mediated splicing alterations.  This project will utilize the combination of cellular and Drosophila models to investigate the FUS- mediated ALS etiology. The findings are expected to provide critical insights into the mechanisms by which FUS mutations perturb the RNA processing pathways and ultimately lead to the disease.

project_terms:
Amyotrophic Lateral Sclerosis;Attenuated;C-terminal;Cell Nucleus;Cells;Cessation of life;Collaborations;Complex;Cytoplasm;DNA Repair;Data;Dendrites;Denervation;Disease;Drosophila genus;Elements;Etiology;Familial Amyotrophic Lateral Sclerosis;Future;Gemin3;Genes;Knowledge;Lead;Locomotion;Mediating;Messenger RNA;Modeling;Molecular;Motor;Motor Neurons;Muscle Weakness;Mutation;Names;Neurodegenerative Disorders;Neuroglia;Neuromuscular Junction;Neurons;Nuclear;Nuclear Structure;Outcome;Pathology;Pathway interactions;Phenotype;Physiological;Play;Process;Proteins;Proteomics;Publishing;RNA;RNA Binding;RNA Processing;RNA Splicing;RNA-Binding Proteins;Reagent;Regulation;Reporting;Research;Role;Small Nuclear Ribonucleoproteins;Spliceosome Assembly Pathway;Spliceosomes;Symptoms;Testing;Toxic effect;Transcriptional Regulation;Transgenic Organisms;Translations;design;fly;in vivo;insight;interest;liposarcoma;mRNA Precursor;motor neuron degeneration;mutant;nerve supply;neuromuscular;novel;nucleocytoplasmic transport;protein TDP-43;research study;sarcoma;tool;wasting

public_health_relevance:
Several amyotrophic lateral sclerosis (ALS) genes have been identified as their mutation can lead to familial ALS including two genes encoding RNA processing proteins TDP-43 and fused in sarcoma (FUS). The major challenge in the field is that little is known how FUS mutations cause motor neuron degeneration in ALS. We propose to test the hypothesis that the ALS-related FUS mutants or WT FUS with deregulated over- expression can accumulate in cytoplasm and sequester Gemin3 which results in decreased assembly of snRNPs in cytoplasm and compromised spliceosome function in the nucleus. To test the central hypothesis three specific aims have been designed to determine the role of FUS in ALS. We have produced novel preliminary data developed unique tools generated nearly all critical reagents and established collaborations with leading experts. We propose to use the combination of cellular and Drosophila models to test the hypothesis. The findings are expected to provide critical insights into the mechanisms by which FUS mutations perturb the RNA processing pathways and ultimately lead to the disease. The knowledge generated in the proposed research will also provide much-needed future direction for developing ALS treatment.


application_id: 8313808
project_number: 1R43AA021331-01
project_title: Device for Delivery of Rolipram to Liver for Treatment of Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2012-07-23
opportunity_number: PA-11-096
application_type: 1
activity_code: R43
ic: AA
serial_number: 021331
program_official: RADAEVA, SVETLANA
project_start_date: 2012-07-25
project_end_date: 2013-12-30
study_section: Special Emphasis Panel[ZRG1 DKUS-A (10)]
contact_pi_person_id: 10119089
contact_pi: BAUER, PHILIP
other_pis: GOBEJISHVILI, LEILA
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): Alcoholic Liver Disease (ALD) remains a leading cause of death from liver disease in the U.S. and there is still no FDA-approved therapy. Abnormal cytokine metabolism is a major feature of ALD. Elevated serum concentrations of tumor necrosis factor (TNF-) and TNF--inducible proinflammatory cytokines/chemokines such as IL-8 and IL-18 have been reported in patients with alcoholic hepatitis and/or cirrhosis and levels correlated with markers of the acute phase response reduced liver function and poor clinical outcome. The focus of this application is the delivery of an available drug using a unique
carrier system that targets liver and corrects the dysregulated cytokine production. Preliminary studies in isolated cells indicate that cyclic AMP (cAMP) decreases when cells are exposed to alcohol and is associated with an increase in pro- inflammatory cytokine levels. Increased cellular cAMP levels were observed to attenuate alcohol-mediated upregulation in pro-inflammatory cytokines. We also have preliminary data demonstrating the causal role of increased expression of phosphodiesterase 4 (PDE4) in the decreased cAMP concentrations observed in alcohol-exposed cells. Our working hypothesis is that altered PDE4 and cAMP metabolism cause abnormal cytokine production/activity which plays a critical role in the development and perpetuation of ALD. Our long-term goal is to develop therapeutic interventions based on this research in order to provide much needed drug therapy for ALD. We have identified a highly effective PDE4 inhibitor to treat ALD but in humans systemic administration of the inhibitor induces severe nausea when the drug crosses the blood-brain-barrier. The goal of this proposal is to develop a carrier system that targets liver and minimizes
release of free drug systemically while circulating in route to the organ. We will evaluate efficac of low-doses of PDE4 inhibitor in blocking cytokine production in the liver after challenging with lipopolysaccharide and we will evaluate efficacy of therapy in reducing alcohol induced liver injury in a rat model. We predict that our carrier system "loaded" with PDE4 inhibitor will not block PDE4 activity in brain but will concentrate in the liver. This will increase local bioavailability of inhibitor (blocking PDE4 activity in liver cells and selectively inhibiting production of pro-inflammatory cytokines) and will greatly enhance the protective effect albeit with a smaller amount of drug that does not cause toxic side effects.   
   
PUBLIC HEALTH RELEVANCE: Alcoholic Liver Disease (ALD) remains a leading cause of death from liver disease in the U.S. and there is still no FDA-approved therapy. We have identified a highly effective inhibitor of proinflammatory factors to treat ALD but in humans oral
systemic administration of the inhibitor induces severe nausea when it reaches the brain. We propose to develop a carrier system that minimizes release of free-drug while circulating and concentrates drug in the liver thereby maximizing the therapeutic effect while minimizing severe side effects.

project_terms:
Abstinence;Acute-Phase Reaction;Adverse effects;Alcoholic Hepatitis;Alcoholic Liver Cirrhosis;Alcoholic Liver Diseases;Alcohols;Anti-Tumor Necrosis Factor Therapy;Antibodies;Attenuated;Biological Availability;Blood;Blood - brain barrier anatomy;Brain;Cause of Death;Cells;Chronic;Cirrhosis;Clinical;Complex;Crohn's disease;Cross Circulation;Cyclic AMP;Data;Development;Devices;Disease;Dose;Drug usage;Endotoxins;Enteral;Enzymes;Ethanol;FDA approved;France;Goals;Hepatic;Hepatocyte;Hepatotoxicity;Human;IL8 gene;Inflammation;Inflammatory;Injury;Interleukin-10;Interleukin-18;Intestines;Kupffer Cells;Label;Ligation;Lipids;Lipopolysaccharides;Liver;Liver Regeneration;Liver diseases;Mediating;Metabolism;Modeling;Mortality Vital Statistics;Multicenter Trials;Mus;Nausea;Nausea and Vomiting;Oral;Organ;Outcome;PDE4B;Patients;Peripheral;Permeability;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacotherapy;Phosphodiesterase Inhibitors;Physicians;Play;Prednisone;Process;Production;Psoriasis;Rattus;Reporting;Research;Rheumatoid Arthritis;Role;Rolipram;Route;Serum;Severity of illness;Staging;Stimulus;Stomach;Surrogate Markers;Survival Rate;System;TLR4 gene;TNF gene;TNFR-Fc fusion protein;Testing;Therapeutic Effect;Therapeutic Intervention;Therapeutic Uses;Treatment Efficacy;Tumor Necrosis Factor-alpha;Up-Regulation (Physiology);Vesicle;Work;alcohol exposure;base;bile duct;chemokine;cost;cytokine;feeding;inhibitor/antagonist;injured;liver function;macrophage;monocyte;novel;nutrition;phosphodiesterase IV;protective effect;receptor;response

public_health_relevance:
Alcoholic Liver Disease (ALD) remains a leading cause of death from liver disease in the U.S. and there is still no FDA-approved therapy. We have identified a highly effective inhibitor of proinflammatory factors to treat ALD but in humans oral
systemic administration of the inhibitor induces severe nausea when it reaches the brain. We propose to develop a carrier system that minimizes release of free-drug while circulating and concentrates drug in the liver thereby maximizing the therapeutic effect while minimizing severe side effects.


application_id: 8313740
project_number: 2R44HL102981-02A1
project_title: Counterpulsation Device with Integrated EKG System for Chronic Partial Circulator
administering_ic: NHLBI
award_notice_date: 2012-05-08
opportunity_number: PA-11-096
application_type: 2
activity_code: R44
ic: HL
serial_number: 102981
suffix: A1
program_official: ADHIKARI, BISHOW B
project_start_date: 2010-06-01
project_end_date: 2014-02-28
study_section: Special Emphasis Panel[ZRG1 SBIB-V (12)]
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: 2012-05-15
project_abstract:
DESCRIPTION (provided by applicant): Heart failure (HF) remains one of the largest unsolved problems in health care today and continues to increase in incidence and cost ($34.8 billion in US in 2008). Prognosis remains limited especially in patients with advanced heart failure. Transplantation is often the best option for patients with advanced HF whose hearts are not recoverable but is limited by many factors primarily the small number of available donor hearts (<2500/yr in US). Use of current mechanical circulatory support (MCS) devices though increasing has also been limited due to the need for a major operation restriction to Class IV patients prolonged convalescence and cost (over $100000 US for the device itself). We have developed a novel MCS device (Symphony) that works synchronously with the heart can be placed with a minor operation and takes advantage of the proven benefits of counterpulsation. Symphony provides partial circulatory support to augment (not replace) native heart function. Recent clinical studies have provided strong evidence for the benefits of partial support. Also experimental data strongly supports the benefits of partial support rather than complete unloading of the heart to promote myocardial recovery. The Symphony device is placed through an 8-cm infraclavicular incision similar to that used for placement of a permanent pacemaker. A short graft is sewn to the subclavian artery connected to the pump and then positioned superficial to the pectoralis muscle. Symphony is timed with the EKG to fill during systole and eject during diastole. Recent work in a Phase 1 study demonstrated subcutaneous EKG leads were as effective as epicardial leads for QRS detection and triggering. In this phase II study we will complete development of the subcutaneous EKG lead system with integration to the Symphony device and lightweight portable driver and demonstrate efficacy safety and reliability of all system components. The development of a device that works synchronously with the heart provides partial support (thereby promoting recovery) and can be placed with a "pacemaker pocket" operative approach may have a significant impact in expanding the role of circulatory support in the treatment of HF patients. The additional advantage of low cost (due to simplicity of design and a limited operative approach) may further expand the use of mechanical support with this device to currently large unrealized global markets.   
   
PUBLIC HEALTH RELEVANCE: Heart failure is a major and growing health care concern for which there are limited treatment options in advanced stages. A novel circulatory support device is being developed that works synchronously with the heart (thereby promoting recovery) can be placed without a major operation and uses a proven mechanism of circulatory support (counterpulsation). This device may significantly increase the use of circulatory support for patients with advanced heart failure and possibly lead to earlier use in less ill patients with the
potential for myocardial recovery.

project_terms:
Adoption;Blood Circulation;Bypass;Cardiovascular system;Caring;Cattle;Chest;China;Chronic;Clinical;Clinical Research;Clinical Trials;Convalescence;Counterpulsation;Data;Detection;Development;Device Designs;Devices;Diastole;Early treatment;Electrocardiogram;Engineering;Exercise;Failure (biologic function);Fatigue;Fracture;Goals;Government Agencies;Healthcare;Heart;Heart Transplantation;Heart failure;Implant;Implantation procedure;Incidence;India;Infection;Infraclavicular region structure;Institutes;Intra-Aortic Balloon Pumping;Lead;Legal patent;Lung;Marketing;Mechanics;Medical;Methods;Metric;Mind;Minor;Modeling;Morphologic artifacts;Motion;Myocardial;Operative Surgical Procedures;Organ Donor;Outcome;Pacemakers;Patients;Pectoralis Muscles;Perfusion;Phase;Positioning Attribute;Predictive Value;Pump;Quality of life;Recovery;Research Personnel;Resources;Role;Safety;Sensitivity and Specificity;Signal Transduction;Staging;Sternotomy;Stroke Volume;Structure of subclavian artery;Study models;Support System;Surface;Surgical incisions;System;Systole;Testing;Therapeutic;Time;Transplantation;Ventricular;Work;Workload;biomaterial compatibility;clinical practice;commercialization;computerized data processing;conditioning;cost;design;heart function;hemodynamics;improved;industry partner;innovation;interest;migration;miniaturize;novel;operation;outcome forecast;patient population;phase 1 study;phase 2 study;product development;programs;prototype;research study;subcutaneous

public_health_relevance:
Heart failure is a major and growing health care concern for which there are limited treatment options in advanced stages. A novel circulatory support device is being developed that works synchronously with the heart (thereby promoting recovery) can be placed without a major operation and uses a proven mechanism of circulatory support (counterpulsation). This device may significantly increase the use of circulatory support for patients with advanced heart failure and possibly lead to earlier use in less ill patients with the
potential for myocardial recovery.


application_id: 8312757
project_number: 2R42DE018839-02A1
project_title: Delivery of Polyphenols in Gum for Treatment of Gingivitis
administering_ic: NIDCR
award_notice_date: 2012-08-31
opportunity_number: PA-09-114
application_type: 2
activity_code: R42
ic: DE
serial_number: 018839
suffix: A1
program_official: ATKINSON, JANE C
project_start_date: 2009-07-23
project_end_date: 2014-08-31
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: 2012-09-01
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 immune-inflammatory lesion that destroys soft and hard tissues of the periodontium. Despite the great improvement in oral health in recent years gingivitis and periodontal disease remain prominent and affect about half of all adults above the age of 30 years in the U.S. with an even higher prevalence in the underserved and developing and undeveloped countries. 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. To address the unmet need for safe cost-effective anti-gingivitis product/technology that promotes high patient compliance and could be incorporated into daily use we have developed a novel direct compression chewing gum formulation that contains freeze-dried blackberry powder (FBP) which is anti-inflammatory antibacterial and antiviral. Our preliminary findings suggested this gum product is commercially viable and potentially effective for the prevention and/or treatment of gingivitis. The goal of this Phase II STTR proposal is to manufacture the chewing gum containing FBP that delivers bioactive phytochemicals to the oral cavity and test its efficacy in preventing biofilm formation and gingivitis in humans. Studies will
determine the final gum product specifications and manufacturing method. A cGMP batch will be manufactured and Quality Control testing and Quality Assurance release will be performed. Submission and approval of an Investigational New Drug Application (IND) for an initial clinical study will be pursued based on guidance from our pre-IND meeting with FDA. In a randomized double-blind single center clinical efficacy study we will assess the chewing gum's ability to reduce i) levels of several plaque-forming bacteria species on enamel and in saliva using the retrievable enamel chip model and ii) clinical gingival inflammation oral microbial burden and saliva biomarkers of inflammation in humans. These studies if successful will lead to a subsequent IND submission to complete multi-center trials and eventual NDA submission of the product for registration as a "Botanical Drug Product" as addressed under the FDA Guidance Document of the same title. Four Tigers 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 encompassing collaborations between the agriculture industry oral biologists small business and Tom's of Maine a large healthcare company that focuses on all-natural products that together will lead to the manufacture and commercial availability of an innovative blackberry chewing gum that releases and delivers natural bioactive substances from freeze-dried fruit powder that will help prevent/treat gingivitis.   
   
PUBLIC HEALTH RELEVANCE:  This project presents the unique collaboration between the agriculture industry oral biologists small business and a large healthcare company that will lead to the manufacture and commercial availability of an innovative blackberry chewing gum that releases and delivers natural bioactive substances from freeze-dried fruit powder that will help prevent/treat gingivitis. Use of this novel adjunctive oral hygiene aid could greatly reduce the cost of dental care by preventing oral disease before it occurs and can be used by those who lack access to conventional oral hygiene measures.

project_terms:
Address;Adult;Affect;Age;Agriculture;Anthocyanins;Anti-Bacterial Agents;Anti-Infective Agents;Anti-Inflammatory Agents;Anti-inflammatory;Antiviral Agents;Bacteria;Berry;Biological Assay;Biological Factors;Botanicals;Businesses;Cardiovascular system;Characteristics;Chewing Gum;Chronic;Clinical;Clinical Research;Clinical Trials;Collaborations;Complex;Compliance behavior;Country;Data;Dental Care;Dental Enamel;Dental Hygiene;Dental Plaque;Development;Diabetes Mellitus;Disease;Double-Blind Method;Drug Delivery Systems;Drug Formulations;Ecology;Event;Exhibits;Farming environment;Freeze Drying;Fruit;Fusobacterium nucleatum;Genetic;Gingiva;Gingivitis;Goals;Health;Healthcare;High Prevalence;Human;Immune;Immune response;Immunology;In Vitro;Incidence;Industry;Infection;Inflammation;Inflammation Mediators;Inflammatory;Investigational New Drug Application;Lead;Lesion;Low Birth Weight Infant;Maine;Mastication;Measures;Medical;Methods;Microbial Biofilms;Military Personnel;Modeling;Mouth Diseases;Oral;Oral Medicine;Oral cavity;Oral health;Pattern;Periodontal Diseases;Periodontic specialty;Periodontitis;Periodontium;Pharmaceutical Preparations;Pharmacy (field);Phase;Phytochemical;Population;Porphyromonas gingivalis;Powder dose form;Predisposition;Prevention;Property;Protocols documentation;Quality Control;Randomized;Reactive Oxygen Species;Reporting;Research;Research Personnel;Resources;Risk;Risk Marker;Saliva;Severities;Simulate;Small Business Technology Transfer Research;Streptococcus mutans;Systemic disease;Technology;Testing;Therapeutic;Tigers;Tissues;Tooth Loss;Translational Research;Underserved Population;United States;antimicrobial;bactericide;base;biomarker;clinical efficacy;commercialization;cost;cost effective;improved;innovation;meetings;microbial;novel;polyphenol;prevent;quality assurance

public_health_relevance:
This project presents the unique collaboration between the agriculture industry oral biologists small business and a large healthcare company that will lead to the manufacture and commercial availability of an innovative blackberry chewing gum that releases and delivers natural bioactive substances from freeze-dried fruit powder that will help prevent/treat gingivitis. Use of this novel adjunctive oral hygiene aid could greatly reduce the cost of dental care by preventing oral disease before it occurs and can be used by those who lack access to conventional oral hygiene measures.


application_id: 8312261
project_number: 1R43CA162417-01A1
project_title: Sustained target delivery for treatment of cervical pathologies
administering_ic: NCI
award_notice_date: 2012-07-16
opportunity_number: PA-11-096
application_type: 1
activity_code: R43
ic: CA
serial_number: 162417
suffix: A1
program_official: LOU, XING-JIAN
project_start_date: 2012-07-16
project_end_date: 2013-12-31
study_section: Special Emphasis Panel[ZRG1 OTC-T (10)]
contact_pi_person_id: 2081643
contact_pi: SPENCER, WENDY A
other_pis: GUPTA, RAMESH C
congressional_district: 04
department: Unavailable
primary_duns: 831172668
primary_uei: HSCNW2K7VN97
duns_number: 831172668
uei: HSCNW2K7VN97
fips: US
organization_id: 10023330
organization_name: 3P BIOTECHNOLOGIES, INC.
organization_city: PROSPECT
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400598574
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Cervical cancer which is caused by HPV infection is characterized by the progressive formation of dysplastic lesions known as cervical intraepithelial neoplasia (CIN). Although vaccinations for the prevention of cervical cancer have been developed the current vaccine has a high cost targets only two-thirds of HPV strains and is effective only when administered prior to HPV infection. In the U.S. alone 1.2 million cases of
low-grade CIN and 0.2-0.3 million cases of high-grade CIN are diagnosed annually; yet no FDA- approved drug therapies are available for its treatment. For women diagnosed with low-grade CIN the standard approach is "watchful waiting;" women with high-grade CIN are treated with the loop electrosurgical excision procedure (LEEP). Despite this treatment a significant recurrence rate of high-grade CIN occurs. What is needed is a medical treatment option for resolving these lesions during the early stages of CIN.  Project Goal and Technological Innovation. This project will develop continuous-release implants containing a natural compound - specifically withaferin A - for the prophylactic treatment of high-risk patients with cervical cancer and other cervical pathologies. The implant to be used at the target site promises a significant advance in cancer prevention and treatment. Natural compounds administered orally are often accompanied by limited bioavailability while chemotherapeutics administered intravenously result in undesirable large spikes in the blood. The development of polymeric implants to provide continuous delivery of therapeutic agents directly to the target site
would substantially lower its effective dose and minimize toxicity concerns generally associated with high oral and i. v. doses.  The main objective of this project is to optimize polymeric implants ("cervical inserts") for continuous ("24/7") release of withaferin A at the target site (ie. the cervix) using a large animal model the goat. The studies described represent the necessary pre-clinical efforts to examine potential toxicity and rate of release of withaferin A from the cervical implants. In addition the concept of continuous local delivery of cancer chemopreventives is a novel and innovative concept that has the potential to revolutionize the clinical management of high-risk individuals. The new patient-friendly device would be an economic treatment. Furthermore prophylactic treatment with natural compounds delivered locally may obviate the need for LEEP. The implant delivery device is currently under a pending patent with one of the PIs (Dr. Gupta) as the inventor.  Hypothesis and Specific Aims. We hypothesize that withaferin A a triterpenoid which has no known toxicity and has significant antiproliferative and anti-viral activities against human cervical cancer cells in vitro and in viv when embedded in polymeric implants will be released continuously at the target site for extended periods and that no tissue or systemic toxicity associated with either the drug or the polymeric materials will be produced. The specific aims are to (1) optimize the formulation of polymeric cervical inserts and determine rate of drug release in vitro; and (2) using a large animal (goat) model determine the rate of drug release from cervical inserts any systemic and tissue toxicity and the levels of the drug in plasma and local surrounding and distal tissues. Future efforts will involve examining still longer-term drug release and potential longer-term or delayed toxicity obtaining FDA approval and conducting a clinical trial with cervical dysplasia patients.   
   
PUBLIC HEALTH RELEVANCE:  The overall goal of this research project is to develop polymeric cervical implants ("cervical inserts") that can provide continuous release of compounds with therapeutic activity against cervical pre-cancer and cancer directly to the target site. When placed in the cervix these implants can deliver drugs continuously ("24/7") for months potentially obviate the need for electrosurgical excision of pre-cancerous lesions and ultimately prevent the development of cervical cancer. This prophylactic treatment will benefit hundreds of thousands of women in the United States alone who otherwise would require a surgical procedure. Worldwide the benefits of this approach will be far greater because cervical cancer is the second most common cancer among women after breast cancer. In this pilot project we will optimize cervical inserts and assess any potential toxicity associated with both the implant materials and with a naturally-occurring compound (withaferin A) with potent anticancer activity against cervical pre-cancer/cancer using a large animal (goat) model.

project_terms:
Affect;Animal Model;Animals;Ashwagandha;Biological Availability;Biopsy;Blood;Breast;Cancer cell line;Cancerous;Cervical;Cervical Intraepithelial Neoplasia;Cervical dysplasia;Cervix Neoplasms;Cervix Uteri;Cessation of life;Chemopreventive Agent;Clinical Management;Clinical Research;Clinical Trials;Data;Data Analyses;Development;Devices;Diagnosis;Distal;Dose;Drug Delivery Systems;Drug Formulations;Dysplasia;Economics;Excision;Exhibits;FDA approved;Future;Goals;Goat;Hormones;Human;Human Papillomavirus;Human papilloma virus infection;Implant;In Vitro;Individual;Intravenous;Legal patent;Lesion;Loop electrosurgical excision procedure;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Measures;Medical;Medicinal Plants;Modeling;Mortality Vital Statistics;Operative Surgical Procedures;Oral;Organ;Pancreas;Pathology;Patient observation;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phase;Pilot Projects;Plants;Plasma;Preparation;Procedures;Prophylactic treatment;Prostate;Reaction;Recurrence;Reporting;Research;Research Project Grants;Screening procedure;Site;Spermatocidal Agents;Staging;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;Toxic effect;United States;Vaccination;Vaccines;Vagina;Viral;Viral Physiology;Vulva;Withania;Woman;Work;anticancer activity;cancer cell;cancer prevention;cancer therapy;cervical cancer prevention;commercial application;controlled release;cost;high risk;implant material;implantation;in vivo;innovation;malignant breast neoplasm;meetings;novel;pre-clinical;prevent;targeted delivery;technological innovation;tumor;tumor progression;tumor xenograft

public_health_relevance:
The overall goal of this research project is to develop polymeric cervical implants ("cervical inserts") that can provide continuous release of compounds with therapeutic activity against cervical pre-cancer and cancer directly to the target site. When placed in the cervix these implants can deliver drugs continuously ("24/7") for months potentially obviate the need for electrosurgical excision of pre-cancerous lesions and ultimately prevent the development of cervical cancer. This prophylactic treatment will benefit hundreds of thousands of women in the United States alone who otherwise would require a surgical procedure. Worldwide the benefits of this approach will be far greater because cervical cancer is the second most common cancer among women after breast cancer. In this pilot project we will optimize cervical inserts and assess any potential toxicity associated with both the implant materials and with a naturally-occurring compound (withaferin A) with potent anticancer activity against cervical pre-cancer/cancer using a large animal (goat) model.


application_id: 8311904
project_number: 1F31DE022679-01
project_title: MicroRNAs and Parotid Acinar Cell Differentiation
administering_ic: NIDCR
award_notice_date: 2012-08-15
opportunity_number: PA-11-111
application_type: 1
activity_code: F31
ic: DE
serial_number: 022679
program_official: FRIEDEN, LESLIE A
project_start_date: 2012-09-01
project_end_date: 2016-08-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 11005944
contact_pi: METZLER, MELISSA A
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long term goal of this fellowship project is to be able to provide clinical intervention to patients suffering from salivary gland loss of function. Parotid gland dysfunction affects millions of people across the nation and stems from several causes. Sjogren's syndrome (which affects 2 - 4 million Americans) for instance results in hypofuction of the gland. Also radiation damage severely affects the parotid gland and is common among patients receiving treatment for head and neck carcinomas. Loss of function in patients results in chronic xerostomia. This leads to a reduction in quality of life for these patients as well as a reduction in overall oral health as the incidence of dental caries and periodontal disease increases. The ability to regenerate or restore function to damaged parotid glands would greatly increase patient health and quality of life. This requires further knowledge of how the gland develops and differentiates into its different cell types. Defining the molecular mechanisms of parotid differentiation is a significant goal. Specifically the parotid acinar cells
are responsible for producing and secreting the salivary proteins amylase parotid secretory protein (PSP) and others in response to parasympathetic nerve stimulation. Parotid salivary proteins contribute to defense against bacteria and yeast and initiation of digestion. These cells are highly specialized; however the terminal differentiation of this cell type is poorly understoo. Within the last decade the importance of microRNAs on the process of development and differentiation has been identified in many cell types. This suggests that microRNAs are a common mechanism used by the cell to control differentiation. However the role of microRNAs in acinar terminal differentiation has yet to be explored. It remains to be investigated if microRNA levels correlate with acinar differentiation in vivo and which microRNAs are important. This project addresses the hypothesis that microRNA expression drives gene networks that are important for parotid acinar differentiation through two separate aims. Aim one is to determine if microRNAs are differentially expressed during parotid acinar differentiation in vivo and as compared to undifferentiated acinar cells. And to identify potential microRNA target genes and networks. MicroRNA (and well as mRNA) levels will be measured throughout the course of parotid acinar differentiation in the rat with the goal of using bioinformatics techniques to identify potentially biologically relevant miRNA:mRNA interactions and gene regulatory networks. Aim 2 will experimentally test the function of the predicted interactions by determining if microRNAs drive expression of differentiation associated gene networks in parotid acinar cells. This project contributes to the long term goal of understanding salivary gland biology to the point that clinical interventions can be developed to regenerate or restore glands to those patients suffering from parotid hypofunction.

project_terms:
Acinar Cell;Address;Affect;American;Amylases;Bacteria;Bioinformatics;Biological Assay;Biology;Cell Differentiation process;Cell Line;Cells;Chronic;Clinical;Dental caries;Development;Digestion;Fellowship;Functional disorder;Gene Expression;Gene Targeting;Genes;Gland;Goals;Head and Neck Squamous Cell Carcinoma;Health;Incidence;Intervention;Knowledge;Lead;Luciferases;Measures;Messenger RNA;MicroRNAs;Molecular;Natural regeneration;Nerve;Oral health;Parotid Gland;Pathway interactions;Patients;Periodontal Diseases;Process;Publications;Quality of life;Radiation;Rattus;Regulator Genes;Relative (related person);Research;Role;Salivary;Salivary Glands;Salivary Proteins;Sjogren's Syndrome;Small RNA;Staging;Symptoms;System;Techniques;Testing;Transfection;Translational Repression;Undifferentiated;Untranslated Regions;Work;Xerostomia;Yeasts;base;cell type;functional restoration;gene interaction;in vivo;interest;knock-down;laser capture microdissection;loss of function;mRNA Transcript Degradation;member;parotid secretory protein;protein expression;response;stem;transcription factor


application_id: 8310941
project_number: 5R21HL108190-02
project_title: Exploring Culture Community Communication and F&V Intake in Black Kentuckians
administering_ic: NHLBI
award_notice_date: 2012-02-29
opportunity_number: PA-08-240
application_type: 5
activity_code: R21
ic: HL
serial_number: 108190
program_official: BOYINGTON, JOSEPHINE
project_start_date: 2011-08-02
project_end_date: 2014-02-28
study_section: Health Disparities and Equity Promotion Study Section[HDEP]
contact_pi_person_id: 10491209
contact_pi: DELLA, LINDSAY J
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): In the U.S. there is a higher prevalence of cardiovascular disease in minority communities and in particular African American (AA) communities than white communities. Additionally being overweight or obese has been scientifically linked to increased risk for cardiovascular disease (CVD). African Americans tend to weigh more on average than whites and other minorities groups and therefore are at increased risk for developing CVD. A healthy diet composed of high fiber foods such as fruit and vegetables has been shown (along with physical activity) to help manage weight and thereby decrease risk for CVD. Research has shown that environmental socio-cultural and psychological factors can affect diet. Given that Kentucky has the second highest prevalence rate of CVD in the nation current prevention efforts in African American communities need to be adapted to the culture geography and individual beliefs of the population. This study proposes a multi-level investigation of environmental community and individual level correlates of fruit and vegetable (F&V) consumption in two Kentucky cities with large African American populations - Louisville and Hopkinsville. Our transdisciplinary approach which leverages data collection and analysis techniques from sociology communication public health and marketing is grounded in the social-ecological model. As such our aims for this study include: 1) identifying documenting and exploring environmental community familial and intrapersonal-level determinants of F&V consumption 2) implementing a cross- sectional quantitative assessment based on data uncovered in Aim 1 to identify important audience segments and salient predictors of each segment and 3) designing a tailored intervention to positively impact F&V consumption in West Louisville and Hopkinsville. To achieve Aim 1 we will use an innovative combination of participatory inquiry (e.g. transect walks) and in- depth interviews interviewing 20 individuals in each city (N=40). Knowledge gained from these research activities will then be used to address Aim 2 and inform the development of the cross-sectional survey which will be collected from 150 individuals in each city (N = 300). These data will be used to identify important segments of the African American audiences in each city. Finally intervention design options will be tested using an approach borrowed from commercial marketing- Adaptive Conjoint Analysis (ACA). In the private- sector ACA is often deemed superior to focus group testing because it allows product/campaign designers to understand the relative importance of various product (or intervention) attributes. This study will be the first translation of ACA to a public health intervention development context.

project_terms:
Achievement;Address;Adult;Affect;African American;American;Area;Behavior;Behavior Therapy;Belief;Cardiovascular Diseases;Cities;Communication;Communities;Comorbidity;Consumption;Cross-Sectional Studies;Data;Data Analyses;Data Collection;Development;Diet;Diet good;Discipline;Elements;Environment;European Economic Community;Family;Fiber;Focus Groups;Food;Geography;Goals;Health behavior;High Prevalence;Individual;Intake;Intervention;Interview;Investigation;Kentucky;Knowledge;Life;Life Style;Link;Location;Market Research;Marketing;Methodology;Methods;Minority;Minority Groups;Modeling;Motivation;Obesity;Overweight;Physical activity;Population;Population Density;Preparation;Prevalence;Prevention;Price;Private Sector;Psychological Factors;Publishing;Qualitative Research;Relative (related person);Reporting;Research;Research Activity;Research Methodology;Research Personnel;Risk;Rural;Social Marketing;Sociology;Taste Perception;Techniques;Testing;Translating;Translations;Walking;Weight;base;cardiovascular disorder risk;design;disorder risk;fruits and vegetables;innovation;metropolitan;preference;programs;public health medicine (field);social;therapy design;therapy development;tool

public_health_relevance:
The prevalence of cardiovascular disease (CVD) is higher in African Americans (AA) than other American populations. Therefore we need to better understand how the environment culture family and intrapersonal factors combine to impact behavior related to lessened cardiovascular disease risk - specifically increased fruit and vegetable (F&V) consumption. To that end the main purpose of this project is to use a formative research approach that incorporates participatory and qualitative research methods from sociology conceptual underpinnings from a cultural communication perspective and an intervention design method that borrows an analytic technique used by market researchers in the private sector in order to design a culturally congruent intervention to positively affect fruit and vegetable consumption among African American Kentuckians.


application_id: 8310769
project_number: 5R42AT006639-04
project_title: Novel estrogen receptor ligands from plant genomics
administering_ic: NCCIH
award_notice_date: 2012-08-14
opportunity_number: PA-09-081
application_type: 5
activity_code: R42
ic: AT
serial_number: 006639
program_official: HOPP, CRAIG
project_start_date: 2010-09-01
project_end_date: 2014-08-31
study_section: Special Emphasis Panel[ZRG1-EMNR-E(10)]
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Human nuclear receptor (HNR) ligands have potential value as pharmacotherapies or chemopreventive agents for many hormone-responsive cancers. The primary aim of this STTR is to transfer an "academic" plant genomics technology into drug discovery targeting HNR ligands. Estrogen receptor (ER) ligands in plants will be used for proof of application because these have clear commercial and therapeutic value in their own right. In phase1 transgenic Arabidopsis thaliana seedlings expressing a human ERalpha/GFP construct were used to screen extracts from a native plant library for ER ligands. 9 previously uninvestigated aquatic species were identified including species with agonist or antagonist activity at ERs in mammalian cell-based screens. In phase 2 representatives of these species will be investigated further using assay-guided HPLC fractionation to isolate active compounds which will be tested on breast cancer cells in vitro and in vivo. However the major aim in phase 2 is to apply the novel plant genomics technology to optimize the production of ER ligands in two plant species. In this technology transgenic hairy root cultures of a plant species are generated expressing either the ERalpha/GFP construct or a novel ERbeta/GFP construct. These cultures are then subjected to activation tagging mutagenesis (ATM) which induces random gain-of-function mutations in the genome. Now any individual mutant in which the production of ER ligands is increased should be identifiable by bright green fluorescence. This rapidly screens the "genomic capability" of the species to generate ligands for either ERalpha or ERbeta. In phase 1 proof of concept for this approach was achieved in a mutant population of transgenic A thaliana seedlings expressing ERalpha/GFP and in phase 2 we propose initially to apply this approach to hairy root cultures of Glycine max (soybean - known to contain high levels of ER ligands) and Cacalia plantaginea (a native plantain with high levels of ERalpha/beta agonist activity). Positive cultures will be characterized by their GFP expression and on the activity of culture extracts in conventional screens for ER activity. Attempts will also be made to regenerate intact mutant plants with the same over-producing phenotype and active fractions from mutant cultures or plants evaluated on breast cancer cells as above. The approach can be used with any HNR target and the major aim is to show that the technology can be transferred to anti-cancer natural product discovery.  The commercialization plan is aimed at licensing the technology or partnering with major companies to apply the technology to targets specified by the partner.    PUBLIC HEALTH RELEVANCE: The technology transfer in this STTR promises to rapidly evaluate plant species for appropriate therapeutic activity at human nuclear receptors. The example chosen is for plant compounds with activity at the two types of human estrogen receptors (ERalpha and beta) which have different therapeutic implications particularly for breast cancer. This is the most common form of cancer in women and is the major cause of death for women under 60 in the USA. Many breast cancers are (initially at least) "hormone responsive" in that drugs which inhibit ERs markedly slow the growth of the cancer cells and this is a very active research area in the pharmaceutical industry. Plants are a known rich source of ligands for the ER but it has proven difficult to exploit this source because conventional plant drug discovery is often time-consuming and expensive. This technology promises to change this by applying genomics approaches to plant drug discovery in this area.

project_terms:
Agonist;Area;Binding (Molecular Function);Biological Assay;Biological Factors;Biotechnology;Breast Cancer Cell;Breast Cancer Treatment;Businesses;Cancer Cell Growth;Cause of Death;Cells;Chemopreventive Agent;Climate;Data;Development;Drug Industry;Estrogen Receptor alpha;Estrogen Receptor beta;Estrogen Receptors;Fluorescence;Fluorescence Microscopy;Foundations;Fractionation;Genome;Genomics;Glycine max;Green Fluorescent Proteins;High Pressure Liquid Chromatography;Hormone Responsive;Human;Image;In Situ;In Vitro;Individual;Intellectual Property;Legal patent;Libraries;Licensing;Ligands;Link;Malignant Neoplasms;Mammalian Cell;Marketing;Methodology;Mouse-ear Cress;Mutagenesis;Natural regeneration;Nuclear Receptor Gene;Nuclear Receptors;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacotherapy;Phase;Phenotype;Plant Extracts;Plant Genes;Plant Roots;Plantago;Plants;Population;Process;Production;Promotor (Genetics);Reporter Genes;Research;Screening procedure;Seedling;Small Business Technology Transfer Research;Source;Soybeans;Specific qualifier value;Specificity;Stream;Switch Genes;Technology;Technology Transfer;Testing;Therapeutic;Time;Transgenes;Transgenic Organisms;United States National Institutes of Health;Woman;base;cancer therapy;combinatorial chemistry;commercial application;commercialization;design;drug discovery;gain of function mutation;high throughput screening;in vivo;interest;malignant breast neoplasm;mutant;novel;phase 1 study;protein expression;public health relevance;research and development;success

public_health_relevance:
Project narrative (rewritten)The technology transfer in this STTR promises to rapidly evaluate plant species for appropriate therapeuticactivity at human nuclear receptors. The example chosen is for plant compounds with activity at the two typesof human estrogen receptors (ERalpha and beta) which have different therapeutic implications particularly forbreast cancer. This is the most common form of cancer in women and is the major cause of death for womenunder 60 in the USA. Many breast cancers are (initially at least) "hormone responsive" in that drugs whichinhibit ERs markedly slow the growth of the cancer cells and this is a very active research area in thepharmaceutical industry. Plants are a known rich source of ligands for the ER but it has proven difficult toexploit this source because conventional plant drug discovery is often time-consuming and expensive. Thistechnology promises to change this by applying genomics approaches to plant drug discovery in this area.


application_id: 8310566
project_number: 4R00HL087924-03
project_title: Granule exocytosis and neutrophil activation
administering_ic: NHLBI
award_notice_date: 2011-08-24
opportunity_number: PA-07-297
application_type: 4
activity_code: R00
ic: HL
serial_number: 087924
program_official: MONDORO, TRACI
project_start_date: 2011-09-01
project_end_date: 2014-07-31
study_section: NSS
contact_pi_person_id: 8652094
contact_pi: URIARTE, SILVIA M
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The postulated role of exocytosis in mediating various functional response associated with neutrophil activation has not been directly tested. We will use a novel approach; generating TAT-fusion proteins containing the coiled-coil domains of different SNARE proteins; to test the hypothesis that blocking exocytosis of distinct granule subsets will prevent specific neutrophil phenotypic changes and this strategy may be used to prevent neutrophil-mediated tissue damage in vivo. The two years of mentored phase of this ^ward allowed the applicant to generate TAT-SNAP-23 and TAT-Syntaxin-4 fusion proteins and test the ability of these fusion proteins to block neutrophil granule exocytosis both in vitro and in vivo. Additionally the state-of-the-art techniques acquired during the mentored phase of the award allowed the applicant to increase her expertise in molecular biology techniques animal models of neutrophil-dependent inflammation and perform proteomic analysis; which will allow the PI to become a successful independent investigator. For the independent phase the specific objectives are: 1) To determine the specific functional responses that are regulated by neutrophil granule exocytosis; 2) To define the mechanisms by which inhibition of neutrophil exocytosis in vivo blocks the inflammatory response; and 3) To investigate the molecular mechanisms by which exocytosis is stimulated. The training the applicant received through out her K99 phase make her unique in the combination of experience interest and state-of-the-art technology and will maximize her potential to become an independent NIH-funded investigator.

project_terms:
Acute;Animal Model;Award;Chimeric Proteins;Chronic;Coiled-Coil Domain;Cytoplasmic Granules;Development;Exocytosis;Funding;Human;In Vitro;Inflammation;Inflammatory Response;Instruction;Knowledge;Mediating;Mentors;Modeling;Molecular;Molecular Biology Techniques;Neutrophil Activation;Phase;Proteins;Proteomics;Rattus;Reperfusion Injury;Research Personnel;Rheumatoid Arthritis;Role;S-nitro-N-acetylpenicillamine;SNAP receptor;Techniques;Technology;Testing;Tissues;Training;United States National Institutes of Health;Vasculitis;experience;in vivo;interest;neutrophil;novel strategies;novel therapeutics;prevent;response;syntaxin;syntaxin 4;ward

public_health_relevance:
RELEVANCE (See instructions): Neutrophils participate in a number of acute and chronic human illnesses including ischemia/reperfusion injury vasculitis and inflammatory arthritis. The new knowledge developed from this proposal will have a significant impact on the development of novel therapeutic strategies for these illnesses.


application_id: 8309953
project_number: 5R03DE021438-02
project_title: Genetic Markers Associated with Epithelial Ovarian Cancer and Hypodontia
administering_ic: NIDCR
award_notice_date: 2012-07-25
opportunity_number: PAR-07-418
application_type: 5
activity_code: R03
ic: DE
serial_number: 021438
program_official: HARRIS, EMILY L
project_start_date: 2011-08-01
project_end_date: 2014-07-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 9768371
contact_pi: MORFORD, LORRI A.
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Epithelial ovarian cancer (EOC) known as the silent killer in women is difficult to diagnosis due to a lack of effective early screening markers for the disease. Without improvements in the current early detection protocols over 70% of women diagnosed with EOC will be identified in late stage disease with a significantly reduced chance of survival. Interestingly recent work at the University of Kentucky has demonstrated that subjects diagnosed with EOC were 8.1 times more likely to also have hypodontia the lack of formation of 1 to 6 permanent teeth when compared to age-matched control subjects without EOC. Hypodontia which can be diagnosed as early as age 9 by radiograph in the dental clinic may be the earliest known marker of EOC- risk today. If hypodontia alone was utilized as a risk marker in the medical or dental clinic however many women could undergo increased testing for EOC with great cost and anxiety and may not truly be at risk. If specific markers (changes in a person's genetic code) could be identified which more frequently associate with EOC patients who have hypodontia (compared to healthy controls) these markers could be utilized for the early screening of young women with hypodontia to identify women at the highest risk for developing EOC in their lifetime. This could lead to earlier screening protocols for women at highest risk of developing EOC increased numbers of early stage diagnoses and the saving of countless numbers of lives. This study will create a DNA (genetic code) resource bank from the saliva of a population of Caucasian women in Central Kentucky who have either been diagnosed with EOC or are healthy control subjects. Every subject's DNA sample will be accompanied with the subject's complete dental history and an extensive family medical/cancer history covering three generations. Markers (small changes in the DNA code) will be studies using a process called Taqman genotyping to identify markers which most frequently associate with the subjects having EOC and hypodontia but not the control subjects. The markers to be studies are found within genes (DNA code) of the Activin/Inhibin and RUNX cell-to-cell signaling pathways. These two pathways have important roles for tooth development and reproductive tissue development and/or maintenance. In summary this study will identify specific markers which when combined with the observation of hypodontia in women could result in earlier screenings for highest EOC risk individuals an increase number of early stage diagnoses and the saving of many lives.

project_terms:
Accounting;Activins;Affect;Age;Alleles;Anxiety;Cancer Patient;Caucasians;Caucasoid Race;Cause of Death;Cells;Cessation of life;Code;Collection;DNA;Dental;Dental Clinics;Development;Diagnosis;Disease;Disease Marker;Early Diagnosis;Eligibility Determination;Epithelial ovarian cancer;Family;Female;Foundations;Future;Generations;Genes;Genetic Code;Genetic Markers;Genotype;Health;High Risk Woman;Hypodontia;Individual;Kentucky;Lead;Maintenance;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant Reproductive System Neoplasm;Malignant neoplasm of ovary;Medical;Methods;Nature;Neoplasm Metastasis;Oral health;Ovarian Tissue;Ovary;Pathway interactions;Persons;Population;Process;Protocols documentation;Recording of previous events;Research;Resources;Risk;Risk Marker;Role;Saliva;Sampling;Screening procedure;Shapes;Signal Pathway;Signal Transduction;Single Nucleotide Polymorphism;Staging;Survival Rate;Symptoms;Testing;Time;Tissues;Tooth structure;Universities;Variant;Woman;Women's Health;Work;aged;base;cancer risk;cost;genetic association;high risk;inhibin;novel;outcome forecast;permanent tooth;reproductive development;young woman

public_health_relevance:
Epithelial Ovarian Cancer (EOC) accounts for 3% of all cancers in women. As the deadliest reproductive system cancer that afflicts women and the fifth leading cause of death due to cancer in women it is an important health issue. Less than 20% of all EOC cases are diagnosed in stage I when the cancer is confined to the ovaries and the 5 year survival rate is 93%. Without improvements in the current screening methods for early detection over 70% of women diagnosed with EOC will be diagnosed after the cancer has metastasized (i.e. in Stages III and IV) with 5 year survival rates of only 34% and 18% respectively. This project will explore the novel observation that missing teeth (teeth that never properly formed) and EOC appear to be associated. We will identify genetic markers which when combined with the presence of missing teeth will identify women at greatest risk of developing EOC in their lifetime at much younger ages than previously possible. Identification of these high risk individuals should result in earlier screening regiments for the individuals an increased number of early stages diagnoses and the saving of many lives.


application_id: 8309922
project_number: 5R01MH092226-02
project_title: A Clinic-Based Safer Sex Program for Young Black Men Who Have Sex with Men
administering_ic: NIMH
award_notice_date: 2012-05-09
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: MH
serial_number: 092226
program_official: KAMATH, SUSANNAH M A
project_start_date: 2011-08-01
project_end_date: 2016-05-31
study_section: Behavioral and Social Science Approaches to Preventing HIV/AIDS Study Section[BSPH]
contact_pi_person_id: 8234905
contact_pi: CROSBY, RICHARD A
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_terms:
Acquired Immunodeficiency Syndrome;African American;Age-Years;Anal Sex;Anus;Attention;Behavior;Biological Assay;Centers for Disease Control and Prevention (U.S.);Chlamydia;Clinic;Clinical;Counseling;Development;Enrollment;Epidemic;Evidence based intervention;Funding;Future;Gays;Glare;Gonorrhea;HIV;Health;Heart;Hispanics;Incidence;Intervention;Laboratories;Methods;Modeling;National Institute of Mental Health (U.S.);Outcome;Patient Self-Report;Phase;Population;Prevention program;Randomized;Randomized Controlled Trials;Recruitment Activity;Relative (related person);Reporting;Research;Research Design;Risk;Sampling;Science;Sexual Partners;Swab;Syphilis;Target Populations;Testing;Translating;Trichomonas Infections;Urine;Vagina;Vulnerable Populations;arm;base;biomarker;clinical practice;condoms;design;disorder prevention;effective intervention;efficacy testing;efficacy trial;evidence base;experience;flexibility;follow-up;high risk men;inclusion criteria;intervention effect;intervention program;male;men;men who have sex with men;novel;post intervention;prevent;programs;public health medicine (field);randomized trial;rectal;response;safer sex;sex;skills;standard of care;theories;therapy design;transmission process;two-arm study


application_id: 8309139
project_number: 5R01AG039732-02
project_title: The Role of Adipose Tissue in Age-dependent Sensitivity to Critical Illness
administering_ic: NIA
award_notice_date: 2012-07-09
opportunity_number: PA-10-042
application_type: 5
activity_code: R01
ic: AG
serial_number: 039732
program_official: FRANKOWSKI, DAVID WITT
project_start_date: 2011-08-01
project_end_date: 2016-07-31
study_section: Special Emphasis Panel[ZRG1-BDCN-M(02)M]
contact_pi_person_id: 8163817
contact_pi: SAITO, HIROSHI
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
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:
Abbreviations;Acute;Adipose tissue;Age;Age Reporting;Aging;Animal Model;Blood Coagulation Factor;Body fat;Burn Trauma;Cessation of life;Coagulants;Coagulation Process;Complication;Critical Illness;Death Rate;Development;Disease Resistance;Disseminated Intravascular Coagulation;Elderly;Endotoxemia;Endotoxins;Excision;Foundations;Functional disorder;Gene Expression;Genes;Genetic;Goals;Growth Factor;Health Care Costs;Hormones;In Vitro;Incidence;Inflammation;Inflammatory;Inflammatory Response;Injection of therapeutic agent;Injury;Interleukin-1 Receptors;Interleukin-6;Intra-abdominal;Knockout Mice;Ligation;Link;Lipopolysaccharides;Lung;Measures;Mediating;Mediator of activation protein;Methods;Modeling;Mortality Vital Statistics;Mus;Operative Surgical Procedures;Organ;Organ Culture Techniques;Pathway interactions;Patients;Pattern;Plasminogen Activator Inhibitor 1;Plasminogen Activator Inhibitor 2;Plasminogen Inactivators;Play;Predisposition;Preventive;Process;Production;Puncture procedure;Role;Sepsis;Sepsis Syndrome;Severities;Signaling Protein;Source;Stress;System;TNF gene;Testing;Therapeutic;Thromboplastin;Thrombosis;Transgenic Organisms;Transplantation;Visceral;Visit;Wild Type Mouse;acute pancreatitis;age related;aged;biological adaptation to stress;cytokine;dietary restriction;effective therapy;improved;insight;middle age;mouse model;mutant;neglect;older patient;public health medicine (field);research study;therapy development


application_id: 8308282
project_number: 5U18FD003984-03
project_title: ENHANCING AND BUILDING THE CAPABILITY OF FEED SAFETY IN KENTUCKY
administering_ic: FDA
award_notice_date: 2012-06-21
opportunity_number: RFA-FD-10-002
application_type: 5
activity_code: U18
ic: FD
serial_number: 003984
project_start_date: 2010-09-17
project_end_date: 2013-06-30
study_section: ZFD1-SRC(99)
contact_pi_person_id: 10581876
contact_pi: WEBB, SHARON F.
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: UNIVERSITY-WIDE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-07-01
project_abstract:
Project SummaryThis project will seek to increase the capacity and capability of the feed program within theKentucky Division of Regulatory Services to enhance the safety of feeds for livestock andcompanion animals. This will increase the ability to track and identify any prohibited ruminantproteins in animal and pet food with the latest technology determine if non-nutritive elementsexist in ingredients and feeds at levels above either National Research Council listed values orFDA guidelines and assess the levels of mycotoxin contaminants in animal and pet food. Thesewill be accomplished through adding new detection and analytical equipment and adding acapable analyst and increased training for three analysts.

public_health_relevance:
PROJECT NARRATIVEOur overall strategy is to strengthen the total capability of the Kentucky feed program to morecompletely monitor animal and pet foods by increasing analytical capabilities in the laboratoryfor animal proteins non-nutritive elements and mycotoxins.


application_id: 8307977
project_number: 5R01DK056132-10
project_title: Neural Circuitry in the Dorsal Vagal Complex
administering_ic: NIDDK
award_notice_date: 2012-06-15
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 056132
program_official: HYDE, JAMES F
project_start_date: 2001-06-01
project_end_date: 2014-06-30
study_section: Neuroendocrinology, Neuroimmunology, and Behavior Study Section[NNB]
contact_pi_person_id: 1911523
contact_pi: SMITH, BRET N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Neuronal communication in the dorsal vagal complex (DVC) is critical for integrating visceral afferent and other inputs and translating that integrated signal into a coordinated parasympathetic motor output via the vagus nerve. In particular GABAergic inhibition is a dominant regulator of neuronal function in the area. Despite the recognized importance of this circuitry in controlling feeding and digestion relatively little is known about local cellular interactions in the DVC. The general hypothesis of this proposal is that activity of neurons in the dorsal motor nucleus of the vagus (DMV) that control gastric function is prominently controlled by inhibitory GABAergic inputs arising from neurons in the nucleus tractus solitarius (NTS). The activity of NTS GABA neurons is regulated by both glutamatergic excitatory and GABAergic inhibitory synaptic inputs. We propose that GABAergic control of preganglionic vagal motor output is accomplished by both phasic and tonic postsynaptic GABAA receptor-mediated inhibition and that specific cellular interactions in the DVC are organized in a manner that consistent with the concept well developed in other sensory-motor systems that local inhibitory circuitry coordinates responses between functional areas of the solitary complex. Gastrointestinal and other autonomic dysfunction affects people with diabetes mellitus and hyperglycemia significantly alters central vagal motor function. We further propose that GABAA receptor-mediated currents in gastric-related DMV neurons are functionally altered in a model of type 1 diabetes mellitus. We will use a multidisciplinary approach to examine GABA-mediated synaptic transmission between neurons in the DVC focusing particularly on inhibitory synaptic control of identified GABAergic neurons in the NTS as well as on neurons in the DMV in the context of gastrointestinal control. Electrophysiological experiments will be done in vitro using brain slice preparations from mature male mice in which DMV and NTS neurons can be identified by their anatomical connection with the stomach their GABA content or both. With whole-cell patch-clamp recordings we will use photoactivation of caged glutamate to stimulate selectively the soma-dendritic regions of local neurons in order to analyze GABA-mediated connections within the solitary complex. We aim to determine: 1) the contribution of tonic GABAergic currents to neuronal activity in the DMV; 2) how identified gastric-related GABAergic neurons in the NTS are regulated by GABA input; and 3) effects of hyperglycemia on GABA currents in a model of type 1 diabetes. We will correlate electrophysiological results with pharmacological and molecular biological analyses to construct a cellular model of local GABAergic control of DMV neuron activity. PUBLIC HEALTH RELEVANCE: Inhibitory connections between neurons that regulate the gastrointestinal system are critical to feeding and digestion but how they control output to the stomach is largely unknown. We have uncovered evidence of a heretofore unstudied and powerful means of regulating how the brain controls the gut and that this mechanism is altered in a model of type 1 diabetes mellitus. The experiments here will examine the synaptic mechanisms controlling gut-related neuron activity and will point to new ways of modifying activity of the gastrointestinal system in response to specific triggers associated with feeding and under pathological conditions of metabolic dysregulation.

project_terms:
Affect;Amino Acids;Area;Autonomic Dysfunction;Binding (Molecular Function);Biological;Brain;Cell model;Cells;Characteristics;Chronic;Communication;Complex;Data;Diabetes Mellitus;Diabetic mouse;Digestion;Dorsal;Event;Glucose;Glutamates;Health;Hyperglycemia;In Vitro;Insulin-Dependent Diabetes Mellitus;Label;Mediating;Membrane Potentials;Messenger RNA;Metabolic;Methods;Modeling;Molecular;Motor;Motor Neurons;Motor output;Mus;Neurons;Noise;Nucleus solitarius;Output;Preparation;Proteins;Regulation;Rest;Signal Transduction;Slice;Stomach;Synapses;Synaptic Transmission;Testing;Transgenic Mice;Translating;Vagus nerve structure;Viscera;Visceral Afferents;base;cell body (neuron);dorsal motor nucleus;feeding;gamma-Aminobutyric Acid;gastrointestinal;gastrointestinal system;interdisciplinary approach;male;mind control;neural circuit;patch clamp;photoactivation;photolysis;postsynaptic;receptor;research study;response;sensorimotor system

public_health_relevance:
Inhibitory connections between neurons that regulate the gastrointestinal system are critical to feeding anddigestion but how they control output to the stomach is largely unknown. We have uncovered evidence ofa heretofore unstudied and powerful means of regulating how the brain controls the gut and that thismechanism is altered in a model of type 1 diabetes mellitus. The experiments here will examine thesynaptic mechanisms controlling gut-related neuron activity and will point to new ways of modifying activityof the gastrointestinal system in response to specific triggers associated with feeding and underpathological conditions of metabolic dysregulation.


application_id: 8307823
project_number: 5R01GM083187-04
project_title: Regulation of alternative pre-mRNA processing by small nucleolar RNAs
administering_ic: NIGMS
award_notice_date: 2012-07-30
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 083187
program_official: BENDER, MICHAEL T
project_start_date: 2009-08-01
project_end_date: 2014-01-31
study_section: Molecular Genetics B Study Section[MGB]
contact_pi_person_id: 8899488
contact_pi: STAMM, STEFAN
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): There is a fundamental gap in understanding the function of small RNAs that constitute a large part of human gene expression. For example we do not know how the loss of small nucleolar RNA (snoRNA) expression contributes to the Prader-Willi syndrome the most frequent genetic cause for life-threatening obesity. Our long-term goal is to elucidate the regulation of alternative splicing by small RNAs that are estimated to comprise more than 40% of human gene expression. The objective of this application is to determine which alternative splicing patterns are influenced by the snoRNAs missing in individuals with Prader-Willi syndrome and to understand the molecular basis by which one of these snoRNAs HBII-52 influences alternative splicing patterns. The central hypothesis is that snoRNAs missing in individuals with Prader- Willi syndrome regulate alternative splicing by masking splicing regulatory elements on pre- mRNAs. Thus these snoRNAs regulate expression of numerous genes by changing their alternative splicing patterns. The rationale for the proposed research is that the genes regulated by these snoRNAs represent drug targets for treatment of the Prader-Willi syndrome. This proposal is therefore relevant to the NIH's mission that pertains to developing fundamental knowledge that will potentially help to reduce the burdens of human disease. Guided by our first published report that the snoRNA HBII-52 influences alternative splicing and additional strong preliminary data this hypothesis will be tested by pursuing two specific aims: 1) Identify the pre-mRNAs that are regulated by the snoRNAs missing in people with Prader-Willi syndrome; and 2) Determine how HBII-52 regulates alternative splice site usage and test alternatives for its expression. Under the first aim changes in pre-mRNA processing will be determined after ectopically expressing individual snoRNAs using bioinformatic predictions and splice-site sensitive DNA arrays. Under the second aim we will identify the repressor activity that competes with the snoRNA HBII-52 and determine its mode of action using an established in vitro system. The proposed work is innovative because it shows a complete new role for snoRNAs in the regulation of alternative pre-mRNA splicing. It may well change the current `textbook knowledge' that snoRNAs only regulate non-mRNAs. The proposed research is significant because it would show a novel role of snoRNAs identify the molecular defects in Prader-Willi syndrome and help to predict the influence of small RNAs on splice site selection.    PUBLIC HEALTH RELEVANCE: The proposed studies delve into an under-investigated area of gene expression and have the potential applicability to understand the molecular cause of the Prader-Willi Syndrome and potentially other forms of inherited obesity. The proposed research is relevant for public health because it investigates a new mechanism of human gene expression. Understanding this mechanism is the basis to improve diagnostics and therapeutic options for human diseases caused by defects in pre-mRNA processing.

project_terms:
Affinity;Alternative Splicing;Area;Binding (Molecular Function);Biochemical;Bioinformatics;Biology;Boxing;Cell Culture Techniques;Code;Collaborations;Complex;DNA;Data;Defect;Diagnostic;Drug Delivery Systems;Exons;Failure (biologic function);Fostering;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Genome;Goals;Human;In Vitro;Individual;Inherited;Knockout Mice;Knowledge;Life;Link;Masks;Mass Spectrum Analysis;Messenger RNA;Methods;Mission;Molecular;Molecular Target;Obesity;Orphan;Outcome;Pattern;Peptide Nucleic Acids;Peptides;Prader-Willi Syndrome;Process;Property;Proteins;Publishing;RNA;RNA Sequences;RNA Splicing;Receptor Serotonin 5-HT2C;Regulation;Regulatory Element;Reporter Genes;Reporting;Research;Resources;Ribosomal RNA;Role;SNRPN;Science;Site;Small Nuclear RNA;Small Nucleolar RNA;Small Nucleolar Ribonucleoproteins;Small RNA;System;Techniques;Testing;Textbooks;Therapeutic;Transcript;Transfer RNA;Work;base;human disease;improved;in vivo;innovation;mRNA Precursor;novel;prevent;public health medicine (field);public health relevance;success

public_health_relevance:
Project narrativeThe proposed studies delve into an under-investigated area of gene expression and have thepotential applicability to understand the molecular cause of the Prader-Willi Syndrome andpotentially other forms of inherited obesity. The proposed research is relevant for public healthbecause it investigates a new mechanism of human gene expression. Understanding thismechanism is the basis to improve diagnostics and therapeutic options for human diseasescaused by defects in pre-mRNA processing.


application_id: 8307009
project_number: 5R01HD053509-05
project_title: Transcriptional Coactivators and Pregnancy Outcomes
administering_ic: NICHD
award_notice_date: 2012-05-30
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HD
serial_number: 053509
program_official: HENKEN, DEBORAH B
project_start_date: 2008-07-01
project_end_date: 2015-06-30
study_section: Pregnancy and Neonatology Study Section[PN]
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 major medical health care issues are inexorably intertwined: a woman's health and prenatal development of her unborn child. Maternal folate status is one condition that has a profound influence on development of the central nervous system (CNS) and the incidence and recurrence of certain developmental disorders of the CNS (neural tube defects NTDs). While NTDs are amongst the most common human malformations the mechanisms by which folate exerts its ameliorative effect on these malformations or its role in normal morphogenesis of the CNS is not well understood. Extant data argue for interactions between folate status and developmental pathways controlled by specific transcriptional regulators. This proposal explores the nature of such interactions and consists of five hypothesis-driven specific aims linked together in order to present a cohesive picture of the molecular mechanisms by which specific translational coactivators mediate signal transduction in and contribute to development of the developing CNS. The overall hypothesis to be tested by the proposed specific aims is that normal CNS development in the mammalian embryo requires folate-mediated activation of a transcriptional complex functionally dependent on proper expression and integration of specific transcriptional coactivators. Specifically we propose that not only is proper expression of Folbp and transcriptional coactivators such as CBP p300 Cited2 Cart1 and AP-2 requisite for CNS formation but the integration of these molecules into a functional regulon is critical to normal CNS morphogenesis. Investments in research designed to reveal the causes of congenital anomalies such as NT defects provide excellent opportunities to meet Public Health Service requirements that biomedical science must pay social dividends. Experiments proposed in the current application seek to identify genes genetic variations and molecular pathways associated with susceptibility to NT defects and to understand signaling mechanisms associated with such disorders.NARRATIVE: In the United States every three minutes a baby is born with a birth defect! While neural tube defects (NTDs) are amongst the most common human malformations the mechanisms by which folic acid exerts its ameliorative effect on these malformations or its role in normal development of the neural tube is not well understood. Studies proposed in the current application should provide a better understanding of prenatal factors influencing the nutritional/health status of pregnant women and their impact on the health of the developing fetus particularly as it relates to NTDs. NARRATIVE:In the United States every three minutes a baby is born with a birth defect! While neural tube defects (NTDs)are amongst the most common human malformations the mechanisms by which folic acid exerts itsameliorative effect on these malformations or its role in normal development of the neural tube is not wellunderstood. Studies proposed in the current application should provide a better understanding of prenatalfactors influencing the nutritional/health status of pregnant women and their impact on the health of thedeveloping fetus particularly as it relates to NTDs.

project_terms:
Complex;Congenital Abnormality;Data;Defect;Development;Disease;E1A-associated p300 protein;EP300 gene;Embryo;Fetus;Folate;Folic Acid;Folic Acid Deficiency;Genes;Genetic Polymorphism;Genetic Transcription;Health;Health Status;Healthcare;Human;Incidence;Investments;Link;Mediating;Medical;Molecular;Morphogenesis;Nature;Neural Tube Defects;Neural Tube Development;Neuraxis;Nuclear;Nutritional;Pathway interactions;Pattern;Predisposition;Pregnancy Outcome;Pregnant Women;Proteins;Recurrence;Regulon;Research Design;Risk;Role;Science;Signal Transduction;TFAP2A gene;Testing;Transcription Coactivator;Transcription Factor AP-2 Alpha;United States;United States Public Health Service;Variation (Genetics);Women's Health;developmental disease/disorder;genetic association;malformation;meetings;nervous system development;prenatal;research study;social;unborn child


application_id: 8306213
project_number: 5R01AG033649-04
project_title: Metabolic syndrome and hippocampal Ca2+ dysregulation in aging memory decline
administering_ic: NIA
award_notice_date: 2012-07-13
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AG
serial_number: 033649
program_official: PETANCESKA, SUZANA
project_start_date: 2009-08-01
project_end_date: 2014-07-31
study_section: Neurobiology of Learning and Memory Study Section[LAM]
contact_pi_person_id: 8361727
contact_pi: THIBAULT, OLIVIER
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Increasing epidemiological and experimental evidence shows that factors associated with metabolic syndrome including glucose dysregulation insulin insensitivity and/or obesity are linked to cognitive decline in aging. Moreover the incidence of obesity and metabolic syndrome are approaching epidemic proportions. The thiazolidinediones (TZD) selective peroxisome proliferator-activated receptor-gamma (PPAR3) agonists improve several aspects of metabolic syndrome including lowering insulin resistance glucose and cholesterol levels in Type 2 diabetics and have also been linked to decreased inflammation and 2-amyloid load in models of Alzheimer's disease (AD). However the mechanisms that link peripheral metabolic syndrome to brain dysfunction are still poorly understood and few studies have analyzed these periphery-brain relationships in aged animals. Over the past years we and others have found considerable electrophysiological and imaging evidence that hippocampal Ca2+ dysregulation with aging correlates with cognitive decline. Recently our gene microarray studies also revealed downregulation of hippocampal insulin and glucose signaling that correlated with aging-related memory impairment. Here we will test the working hypothesis that peripheral components of metabolic syndrome induce alterations in Ca2+ homeostasis in the hippocampus by acting on L-type voltage-gated Ca2+ channels (L-VGCCs) NMDARs Ca2+-induced Ca2+ release (CICR) and the Ca2+-dependent afterhyperpolarization (AHP) thereby negatively affecting synaptic plasticity (LTP) and cognitive function. We will also test the hypothesis that these actions are mediated in part by changes in brain insulin/glucose signaling pathways and can be counteracted by TZDs. Specific Aim # 1 will study F344 male rats fed a normal diet and determine at 7-8 and 18-20 months of age which component of metabolic dysregulation most closely associates with measures of cognitive function and hippocampal electrophysiological/imaging function (L-VGCCs NMDARs CICR AHPs and LTP). Specific Aim #2 will test whether diet-induced obesity (DIO) exacerbates neurobiological cognitive gene expression and neuropathological indices of brain aging and whether interventions with TZDs can slow or reverse this process. Specific Aim #3 will analyze the effects of insulin on hippocampal slices testing for direct effects on electrophysiological markers of aging and will test the sub-hypothesis that neurons from aged animals exhibit insulin resistance. Together these multidisciplinary studies will provide one of the first systematic analyses of links between variables contributing to peripheral metabolic syndrome and cellular mechanisms of brain aging. Therefore even if the central hypothesis is rejected the studies proposed will provide more definitive evidence for the impact o metabolic syndrome as well as the actions of TZDs on the brain. PUBLIC HEALTH RELEVANCE Metabolic syndrome and diabetes are age- and obesity-related diseases that are rapidly approaching epidemic proportions in our society. Recent studies indicate that there may be a link between metabolic syndrome and cognitive decline. The underlying mechanisms through which individual components of peripheral metabolic dysregulation can negatively impact brain function are not known. Our research will identify new links between brain aging diabetes and obesity. If successful our project could impact public health by providing strong clues to help identify novel therapeutic targets and prevent cognitive decline in aging.

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

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


application_id: 8305138
project_number: 5R01CA073599-13
project_title: Redox Regulation of Tumor Suppression by MnSOD
administering_ic: NCI
award_notice_date: 2012-07-13
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 073599
program_official: JOHNSON, RONALD L
project_start_date: 1998-09-01
project_end_date: 2015-07-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this research is to elucidate the mechanisms by which the mitochondrial antioxidant enzyme manganese containing superoxide dismutase (MnSOD) modulates the carcinogenesis action of tumor promoters and UV radiation. Our studies in the previous funding period indicate that overexpression of MnSOD suppresses the incidence and multiplicity of papillomas in the 7-12-dimethylbenz (a) anthracene (DMBA)/ 12-O tetradecanoylphorbol-13-acetate (TPA) multistage skin carcinogenesis model. MnSOD- mediated tumor suppression is in part mediated by reduction of AP-1 activation and expression of proliferation related genes. Unexpectedly reduction of MnSOD by heterozygous knockout of the MnSOD gene does not result in increased tumor incidence or multiplicity using the DMBA/TPA model. The lack of increased susceptibility to DMBA/TPA-induced tumors in the MnSOD knockout mice is due in part to an increase in both apoptosis and proliferation after TPA treatment. Administration of MnSOD mimetic without interfering with TPA-induced apoptosis is very effective in reducing DMBA/TPA-induced skin papillomas in MnSOD-deficient mice. We also found that the increased apoptosis in MnSOD-deficient mice is associated with increased p53 accumulation in the mitochondria and reduced MnSOD expression. Based upon these novel findings we propose that activation of p53 enhances apoptosis in part via modulation of mitochondrial antioxidant defense capacity and that the tumor suppression effect of MnSOD is mediated in part by p53. Two specific aims are designed to test these hypotheses using TPA and UV radiation as the prototype oxidative stress generating carcinogens. The results of the proposed studies will provide insights into the common mechanisms by which MnSOD levels modulate apoptosis induced by chemical or UV radiation during an early stage of skin carcinogenesis. They will also enhance our understanding of the p53-dependent and -independent tumor suppression role of MnSOD. Identification of a common mechanism by which tumor promoter and UV radiation cause apoptosis would provide a means for developing a mechanistic based intervention that would prevent the development of skin cancers caused by a wide range of carcinogens. Thus this timely and important study will likely have a large scale impact on human health. PUBLIC HEALTH RELEVANCE:  Skin cancer is the most common human malignancy in the United States. Many chemicals and Ultraviolet radiation (UV) are well-established agents that cause skin cancer. We have recently found that by modulating the interaction between an essential antioxidant enzyme MnSOD and a key tumor suppressor protein p53 the incidence of skin tumors can be drastically reduced. In this application we will extend from this novel finding to determine how this interaction acts to prevent skin cancer and will perform proof-of-concept experiments to verify the feasibility of using the knowledge to be learned to prevent the development of skin cancer resulting from exposure to UV and other oxidative stress generating chemical carcinogens.

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


application_id: 8304907
project_number: 5R43AI096605-02
project_title: A transfollicular nanovaccine against leishmaniasis
administering_ic: NIAID
award_notice_date: 2012-06-15
opportunity_number: PA-10-123
application_type: 5
activity_code: R43
ic: AI
serial_number: 096605
program_official: MO, ANNIE X Y
project_start_date: 2011-07-20
project_end_date: 2015-06-30
study_section: Special Emphasis Panel[ZRG1-IMM-N(12)B]
contact_pi_person_id: 6721291
contact_pi: GHOROGHCHIAN, PAIMAN PETER
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 808379072
duns_number: 808379072
fips: US
organization_id: 10020780
organization_name: VINDICO NANOBIOTECHNOLOGY, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405072003
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-07-01
budget_end_date: 2015-06-30
project_abstract:
DESCRIPTION (provided by applicant): The World Health Organization estimates that over 350 million people are at risk of developing leishmaniasis and infection prevalence is 14 million people in the world. Annually 2 million people are infected with Leishmania species and 270000 will die. Leishmaniasis is one of the most important parasitic diseases affecting the U.S. military today with over 2500 U.S. military personnel diagnosed with cutaneous leishmaniasis (CL). Current non-immunization based treatments are variably effective highly toxic expensive and there are no vaccines in clinical use. Significant evidence has supported the role of the immune system in controlling Leishmania infection. Thus a vaccination remains an attractive disease prevention strategy. Two significant scientific knowledge gaps must be addressed: 1) a vaccine that can access the skin resident dendritic cells (DCs) and 2) the identification of Leishmania antigens that are biologically relevant in humans. Needle based vaccines bypass these immunopotent skin cells.  The long-term objective of this proposal is to develop a nanoscale polymersome-based vaccine that delivers an antigen and adjuvant to skin dendritic cells through transfollicular immunization (TFI). We will characterize the feasibility of integrating the Toll-like receptor 7/8 agonist resiquimod (RSQ) into the polymersome membrane and encapsulating a model Leishmania antigen Leishmania homolog of receptors for activated C kinase (LACK) into the aqueous core. We will then evaluate its functional properties in generating a TH1-type cytokine profile and functional cytotoxic CD8+ T cells in vivo. We hypothesize that co-encapsulation of LACK and RSQ into the nanovaccine can be achieved in a stepwise manner and that the resulting nanovaccine will penetrate the follicle and activate skin DCs. We also hypothesize that the topical administration of this nanovaccine will induce a LACK-specific T cell response. Finally we hypothesize that this nanovaccine will protect against challenge with a visceral Leishmania strain in a hamster model. AIM 1 Construct a nanovaccine encapsulating the antigen LACK and TLR7/8 agonist RSQ (LACK/RSQ-NPS). AIM 2 Determine the optimal physicochemical properties of LACK/RSQ-nanovaccine to penetrate the follicular duct activate skin DCs and induce a LACK-specific adaptive immune response. AIM 3 Determine if the LACK/RSQ-nanovaccine induces protective immune responses in vivo.  We anticipate the data generated from this proposal will result in a commercially viable topical nanovaccine that can access skin DCs via the transfollicular route. The NIAID supports basic preclinical and clinical research on immune-mediated diseases such as leishmaniasis and the development of effective vaccines. The aims proposed in this SBIR Phase I program are consistent with the mission statement of the NIAID.

project_terms:
Activities of Daily Living;Address;Adjuvant;Affect;Agonist;Antibodies;Antigens;Area;Basic Science;Biotechnology;Bypass;CD8B1 gene;Cells;Child;Clinical;Clinical Research;Communicable Diseases;Conflict (Psychology);Contracts;Country;Cream;Cutaneous Leishmaniasis;Data;Dendritic Cells;Dendritic cell activation;Department of Defense;Development;Diagnosis;Disease;Dose;Drug Formulations;Duct (organ) structure;Encapsulated;Generations;Goals;Government;Hair follicle structure;Hamsters;Heating;Homologous Gene;Human;Immune;Immune response;Immune system;Immunity;Immunization;Infection;Infectious Skin Diseases;International;Killings;Kinetics;Knowledge;Lead;Leishmania (genus);Leishmaniasis;Life;Mediating;Membrane;Methods;Military Personnel;Mission;Modeling;Monitor;Mus;National Institute of Allergy and Infectious Disease;Needles;Occupations;Parasites;Parasitic Diseases;Pathway interactions;Penetration;Phase;Prevalence;Prevention strategy;Property;Regimen;Resolution;Risk;Rodent Model;Role;Route;Skin;Small Business Innovation Research Grant;Solubility;System;T cell response;T-Lymphocyte;TLR7 gene;Technology;Testing;Topical application;Translating;Vaccination;Vaccine Adjuvant;Vaccine Design;Vaccines;Visceral;Visceral Leishmaniasis;World Health Organization;aqueous;base;cancer prevention;cytokine;cytotoxic;design;disorder prevention;human TLR7 protein;immunogenic;in vivo;nanomaterials;nanoparticle;nanoscale;novel;pre-clinical research;programs;prophylactic;receptors for activated C kinase;resiquimod;subcutaneous;vaccine delivery

public_health_relevance:
The World Health Organization estimates that over 350 million people are at risk of developing leishmaniasis and infection prevalence is 14 million people in the world. Annually 2 million people are infected with Leishmania species and 270000 will die. Leishmaniasis is one of the most important parasitic diseases affecting the U.S. military today. We plan to develop a nanovaccine against Leishmania that delivers the vaccine payload through the hair follicle duct to stimulate skin immune cells all without a needle. This major advance in Leishmania vaccine design may provide the first effective vaccine against Leishmania and would create biotechnology jobs in the US via US military contracts and international government contracts in countries suffering from leishmaniasis.


application_id: 8304539
project_number: 4R21DC010806-02
project_title: Exogenous growth factors for reversal of age-related laryngeal muscle denervation
administering_ic: NIDCD
award_notice_date: 2011-08-22
opportunity_number: PAR-08-018
application_type: 4
activity_code: R21
ic: DC
serial_number: 010806
program_official: SHEKIM, LANA O
project_start_date: 2010-09-13
project_end_date: 2013-05-31
study_section: ZDC1-SRB-Q(63)
contact_pi_person_id: 8274830
contact_pi: MCMULLEN, COLLEEN A
other_pis: STEMPLE, JOSEPH
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):  This application is in response to the NIDCD Research Grants for Translating Basic Research into Clinical Tools for Human Health (R21) (PAR-08-018). As individuals age muscle weakness and neuromuscular disorders have the potential to diminish the quality of life increase healthcare costs and lead to institutionalization. The larynx is part of a complex motor system that serves as a vibratory source of phonation and as a regulator that separates and protects the airway from the digestive tract. In the elderly age-related changes in the intrinsic laryngeal muscles may compromise voice quality thus impair the ability to communicate and diminish the ability to remain socially engaged. Laryngeal muscle dysfunction may also cause dysphagia and increase the risk of aspiration factors that lead to higher mortality and morbidity. Our preliminary findings indicate that the intrinsic laryngeal muscles have a unique phenotype that is significantly altered by age. More specifically the neuromuscular junctions (NMJs) become smaller and less abundant in aging rat laryngeal muscles and there is evidence of functional denervation. Therefore this project has two major objectives:(1) it will test the efficacy of exogenous neurotrophins as treatment to reverse denervation in the aging intrinsic laryngeal muscles; (2) it will provide the background to extend these findings to clinical treatments. The studies will test the central hypothesis that age related laryngeal muscle denervation is corrected by treatment with exogenous neuronal growth factors. Using the Fisher 344-Brown Norway F1 hybrid rat model of aging the studies will examine to what extent neurtrophins correct NMJ disorganization in the posterior cricoarytenoid (PCA vocal fold abductor) and thyoarytenoid (TA vocal fold adductor) muscles. Specific Aim I will examine whether systemic administration of the exogenous neurotrophins brain-derived nerve growth factor (BDNF) and neurotrophin-4 (NT-4) changes determinants of NMJ assembly in the aging PCA and TA. Specific Aim 2 will test whether local infiltration with the two growth factors influences NMJ structure and abundance in the aging PCA and TA muscles. This will be a first test of pharmacological interventions intended to reverse age-related neuromuscular dysfunction in the laryngeal muscles. This project will generate novel data on interventions aimed at preventing or reversing age-related neuromuscular dysfunction in these small muscles a first step to testing their efficacy in the clinical setting.  
  
PUBLIC HEALTH RELEVANCE:  Laryngeal dysfunction in the elderly is a major cause of disability from voice disorders to dysphagia and loss of airway protective reflexes. Few if any therapies exist that target age-related laryngeal muscle dysfunction. This project will test the efficacy of exogenous growth factors as treatment for functional denervation of laryngeal muscles in aging subjects.

project_terms:
Address;Age;Aging;Basic Science;Biochemical;Brain;Brain-Derived Neurotrophic Factor;Clinical;Clinical Treatment;Complex;Data;Deglutition Disorders;Denervation;Elderly;Experimental Designs;Functional disorder;Gastrointestinal tract structure;Growth Factor;Health;Health Care Costs;Human;Hybrids;Individual;Infiltration;Institutionalization;Intervention;Language;Laryngeal muscle structure;Larynx;Lead;Maintenance;Messenger RNA;Modality;Modeling;Molecular;Morbidity - disease rate;Morphology;Mortality Vital Statistics;Motor;Muscle;Muscle Weakness;Muscle denervation procedure;Muscle function;National Institute on Deafness and Other Communication Disorders;Nerve;Nerve Growth Factors;Nerve Regeneration;Neuromuscular Diseases;Neuromuscular Junction;Norway;Outcome Study;Pathologist;Performance;Phenotype;Phonation;Physiological;Proteins;Quality of life;Rattus;Rattus norvegicus;Recovery;Reflex action;Research Personnel;Research Project Grants;Risk;Rodent;Route;Scientist;Signal Transduction;Source;Specialist;Speech;Staging;Structure;System;Testing;Translating;Translations;Voice Disorders;Voice Quality;age effect;age related;base;density;design;disability;effective therapy;efficacy testing;experience;improved;nerve supply;neuromuscular;neuronal growth;neurotrophic factor;neurotrophin 4;novel;prevent;public health relevance;reinnervation;research clinical testing;research study;response;tool;vocal cord

public_health_relevance:
PROJECT NARRATIVE Laryngeal dysfunction in the elderly is a major cause of disability from voice disorders to dysphagia andloss of airway protective reflexes. Few if any therapies exist that target age-related laryngeal muscledysfunction. This project will test the efficacy of exogenous growth factors as treatment for functionaldenervation of laryngeal muscles in aging subjects.


application_id: 8303925
project_number: 1R21DA031439-01A1
project_title: Microneedle-enhanced codrug delivery for smoking cessation and appetite suppressi
administering_ic: NIDA
award_notice_date: 2012-07-11
opportunity_number: PA-10-069
application_type: 1
activity_code: R21
ic: DA
serial_number: 031439
suffix: A1
program_official: PARK, MOO KWANG
project_start_date: 2012-07-15
project_end_date: 2014-04-30
study_section: Gene and Drug Delivery Systems Study Section[GDD]
contact_pi_person_id: 1866585
contact_pi: STINCHCOMB, AUDRA L.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178031683
primary_uei: EKBZRSBPS8A3
duns_number: 178031683
uei: EKBZRSBPS8A3
fips: US
organization_id: 10006751
organization_name: ALLTRANZ, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Tobacco addiction is a multi-factorial process regulated by a number of pharmacological and physiological effects of tobacco smoke exposure. In addition to the well-known effects of tobacco derived nicotine on brain dopaminergic systems other secondary reinforcers such as body mass regulation are also involved with the compulsive tobacco use. Cigarette smoking is known to reduce appetite and increase the rate of cellular metabolism leading to body mass stabilization or reduction. Current smoking cessation treatments fail in up to 70% of cases for a variety of individualized reasons. One of the main reasons for recidivism especially in females is the potential for weight gain. The problem of weight gain during smoking cessation is well documented and studies consistently recommend incorporation of body weight management strategies to patient management plans. The proposed studies will use a novel microneedle-enhanced transdermal codrug delivery approach to test a new pharmacological approach that we hypothesize will enhance smoking cessation efforts. Bupropion is considered a first-line treatment for smoking cessation but the efficacy of this drug is relatively low. Hydroxybupropion (BUPOH) is an active metabolite of bupropion that may have significant drug delivery and therapeutic effect advantages over bupropion including better chemical stability reduced metabolic drug interaction potential and an equal or higher potency at relevant drug targets. BUPOH itself does not have the essential physicochemical properties that would allow a therapeutic dose of the drug to cross the human skin barrier. Microneedle-enhanced transdermal delivery is an efficient and painless method for increasing the skin permeation of many drugs. The proposed studies will test whether chemical modification optimization of the BUPOH codrug will enhance its microneedle-assisted skin permeation making it suitable for transdermal delivery. Hydroxybupropion will be chemically combined with phentermine (PHEN) a widely used appetite suppressant. PHEN should have a more tolerable side-effect profile if delivered at a constant rate through transdermal delivery. We hypothesize that a transdermal codrug (mutual prodrug or hybrid drug) of PHEN linked to the smoking cessation drug BUPOH will make an effective microneedle-enhanced transdermal pharmacotherapy for smoking cessation and weight loss. The specific aims of this project are to: 1 - synthesize a series of PHEN and BUPOH codrugs designed to elucidate quantitative structure-permeability relationships (QSPR) for microneedle-enhanced transdermal flux and subsequent bioconversion rates. 2 - to measure the drugs' penetration and concurrent bioconversion in skin in vitro with microneedle use and 3 - to characterize the pharmacokinetics of the drugs in guinea pigs in vivo with microneedle use. Correlation of our in vitro data with the in vivo model will aid in the creation of a reliable QSPR
database for transdermal codrugs with microneedle use as well as help to identify the most promising codrug/microneedle system for eventual human use.   
   
PUBLIC HEALTH RELEVANCE: The leading cause of preventable deaths in the United States is cigarette smoking with over 440000 premature deaths occurring each year. Cigarette smoking is known to reduce appetite and increase the rate of cellular metabolism leading to body mass stabilization or reduction. One of the main reasons for recidivism in persons trying to quit smoking is the potential for weight gain especially in women. Regardless of the varied findings of the many studies on smoking cessation and weight gain the primary recommendation has been to incorporate weight loss treatment with smoking cessation. A transdermal codrug (mutual prodrug or hybrid drug) of the popular weight-loss drug phentermine linked to a smoking cessation drug hydroxybupropion could be the ideal pharmacotherapy for the comorbidity.

project_terms:
6 beta-hydroxynaltrexone;Adjuvant;Adverse effects;Appetite Depressants;Area;Body Weight;Body Weight decreased;Brain;Bupropion;Cancer Etiology;Cardiovascular system;Cavia;Centers for Disease Control and Prevention (U.S.);Cessation of life;Chemicals;Clinical;Comorbidity;Data;Databases;Desire for food;Dose;Drug Delivery Systems;Drug Interactions;Drug Kinetics;Female;Heating;Human;Human Volunteers;Hybrids;Hydrogen Bonding;Hydrolysis;In Vitro;Kinetics;Link;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Metabolic;Metabolism;Methods;Modification;Molecular;Naltrexone;Nicotine;Painless;Patients;Penetration;Permeability;Persons;Pharmaceutical Preparations;Pharmacodynamics;Pharmacotherapy;Phentermine;Physiological;Process;Prodrugs;Property;Recommendation;Regulation;Route;Series;Skin;Smoking;Solubility;Solvents;Structure;Synthesis Chemistry;System;Testing;Therapeutic;Therapeutic Effect;Time;Tobacco;Tobacco Dependence;Tobacco smoke;Tobacco use;Toxicity Tests;Translating;United States;Weight Gain;Weight maintenance regimen;Weight-Loss Drugs;Withholding Treatment;Woman;chemical stability;cigarette smoking;cost effective;design;drug efficacy;improved;in vivo;in vivo Model;increased appetite;lipophilicity;malignant breast neoplasm;melting;novel;premature;recidivism;reinforcer;smoking cessation;water solubility

public_health_relevance:
The leading cause of preventable deaths in the United States is cigarette smoking with over 440000 premature deaths occurring each year. Cigarette smoking is known to reduce appetite and increase the rate of cellular metabolism leading to body mass stabilization or reduction. One of the main reasons for recidivism in persons trying to quit smoking is the potential for weight gain especially in women. Regardless of the varied findings of the many studies on smoking cessation and weight gain the primary recommendation has been to incorporate weight loss treatment with smoking cessation. A transdermal codrug (mutual prodrug or hybrid drug) of the popular weight-loss drug phentermine linked to a smoking cessation drug hydroxybupropion could be the ideal pharmacotherapy for the comorbidity.


application_id: 8303224
project_number: 5R03CA162520-02
project_title: Bionanoconjugates for Detection of Circulating Tumor Cells in Lung Cancer
administering_ic: NCI
award_notice_date: 2012-08-09
opportunity_number: PAR-08-055
application_type: 5
activity_code: R03
ic: CA
serial_number: 162520
program_official: YOUNG, MATTHEW R
project_start_date: 2011-07-18
project_end_date: 2014-06-30
study_section: ZCA1-SRLB-F(M1)
contact_pi_person_id: 7875285
contact_pi: HIRSCHOWITZ, EDWARD A.
other_pis: KNECHT, MARC
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):  Measurement of circulating tumor cells (CTC) has potential to fill major gaps in the clinical care and management of lung cancer patients. Validation of CTC as a prognostic marker in breast cancer patients set an important precedent for CTC measurement; however histochemical CTC enumeration now used as a clinical correlate in breast and prostate cancer has proven to be neither robust nor reliable enough for application to lung cancer. This is due in large part to the phenotypic heterogeneity and high antigen variability associated with lung tumors as compared to other solid tumors. PCR amplification of cancer protein transcripts is a conceptually appealing alternative approach to CTC measurement that offers sensitivity and unlimited capabilities for multiple antigen measurements. Although literature indicates that PCR detection of CTC correlates with lung cancer stage disease recurrence and survival this approach remains investigational. Since mRNA transcript is used as a surrogate for tumor protein expression PCR is criticized for lack of specificity. We have devised an approach that combines the specificity of immuno-histochemistry with the sensitivity of PCR. This application details testing and optimization of a novel nanoparticle-based system to overcome technical and biological hurdles encountered in lung cancer CTC measurement. Specifically bio-nanoconjugates are constructed to carry one antigen specific monoclonal antibody and a conjugate-specific double stranded DNA tag sequence for nano-specific identification. When conjugates bind antigen on a cell surface a single strand of the DNA tag can be released into suspension by briefly heating the complex mixture; liberated DNA strands amplified by PCR provide a highly sensitive and quantifiable measure of cellular binding and corresponding antigen expression. Signal amplification of the antigen-bound bio-nanoconjugate allows detection of low frequency proteins on low concentration CTC in peripheral blood and multiplexing capabilities inherent to the technology offer increasing sensitivity without reduced specificity making this particularly well suited for the measurement of lung cancer CTC. Sensitivity of the approach will be determined with peripheral blood spiked at various concentrations with cultured tumor cells with known antigen expression. CTC enrichment using antibody-mediated separation of CTC from peripheral blood mononuclear cells is expected to further increase the limits of detection while also reducing the potential for false positive results. We anticipate being able to achieve unrivaled detection limits with high degrees of specificity for lung cancer CTC. This application details the comparative and systematic phases of initial development and testing of this promising initiative.

project_terms:
Antibodies;Antigens;Binding (Molecular Function);Biological;CTAG1 gene;Cancer Patient;Cell Adhesion Molecules;Cell surface;Cells;Clinical;Clinical Management;Complex;Complex Mixtures;Coupling;Cultured Tumor Cells;DNA;DNA Sequence;Detection;Development;Diagnostic Neoplasm Staging;Disease;Epithelial Cells;Fluorescence;Foundations;Frequencies (time pattern);Future;Gold;Heating;Heterogeneity;Histocytochemistry;Imagery;Literature;Logic;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Measurement;Measures;Mediating;Messenger RNA;Methodology;Methods;Microscopy;Monoclonal Antibodies;Nanoconjugate;Non-Small-Cell Lung Carcinoma;Peripheral Blood Mononuclear Cell;Phase;Population;Prognostic Marker;Proteins;Recurrence;Reverse Transcriptase Polymerase Chain Reaction;Sampling;Signal Transduction;Single-Stranded DNA;Solid Neoplasm;Solutions;Specificity;Staining method;Stains;Surface;Suspension substance;Suspensions;System;TACSTD2 gene;Techniques;Technology;Testing;Transcript;Tumor Antigens;Validation;Visual;Whole Blood;antigen antibody binding;antigen binding;base;clinical application;clinical care;comparative;cost;cost effective;design;ds-DNA;improved;malignant breast neoplasm;nano;nanoparticle;neoplastic cell;novel;particle;peripheral blood;protein expression;research study;surface coating;survivin;tumor

public_health_relevance:
Measurement of circulating tumor cells (CTC) has potential to fill major gaps in the clinical care and management of lung cancer patients. There is not a currently reliable method for clinical application in lung cancer. This application details testing and optimization of a novel nanoparticle-based system to overcome technical and biological hurdles encountered in lung cancer CTC measurement.


application_id: 8301728
project_number: 5F32DC011427-03
project_title: The role of cAMP signaling in OSN axon convergence in the olfactory bulb
administering_ic: NIDCD
award_notice_date: 2012-08-09
opportunity_number: PA-10-110
application_type: 5
activity_code: F32
ic: DC
serial_number: 011427
program_official: SKLARE, DAN
project_start_date: 2010-09-01
project_end_date: 2013-08-31
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 10351735
contact_pi: HERON, PAULA MICHELLE
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): This postdoctoral F32 Kirschstein NRSA proposes a comprehensive research and training plan in the study of neurogenesis and axon guidance in the olfactory system with relevance to neural regeneration therapies. Failure of the damaged nervous system to repair itself has debilitating consequences for millions of people worldwide. Regeneration therapies are focused on restoring damaged circuitry by regrowth and guidance of the axons of spared neurons or replacement of dead neurons. The olfactory system provides a useful model to study cell replacement and axon targeting in a mature nervous system. Although the mechanisms by which olfactory sensory neuron (OSN) axons are targeted to the olfactory bulb remain largely unknown the anterior-posterior patterning of glomerular convergence in the bulb correlates with neuronal levels of cAMP and altered expression of activity-dependent guidance cues. However direct evidence of the involvement of cAMP in axon targeting and the genetic mechanisms involved are lacking. The specific aims of this proposal will test the hypothesis that cAMP plays a definitive role in glomerular convergence of axons in the bulb. If this idea is correct then transgenic mice exhibiting sustained increases in cAMP in immature OSNs should show altered glomerular convergence and position. Aim 1 will use transgenic mice that express a constitutively active G-protein-coupled receptor GPR12 in immature OSNs. GPR12 couples to Gas adenylyl cyclase and cAMP production. To follow specific populations of OSN axons GPR12 transgenic mice will be crossed with OR-tauLacZ mice such as the M71-tauLacZ strain. This will allow visualization of the coalescence of OSN axons. Aim 2 will investigate changes in cAMP-mediated downstream signaling events that lead to alterations in gene expression. Identification of cAMP driven signal transduction in immature OSNs will help to elucidate mechanisms that control the position of OSN axon convergence in the olfactory bulb. Aim 3 will test whether cAMP over expression will rescue the lack of target innervation in mice lacking the emx2 gene. The results from these studies will provide novel insight into the role of cAMP signaling in OSN axon growth and convergence in the olfactory bulb.    PUBLIC HEALTH RELEVANCE: Cell replacement as a regenerative approach to repair the injured nervous system remains promising. My research aims will contribute to understanding the processes that allow normal cellular replacement and appropriate target innervation in the olfactory system. This understanding of endogenous neural replacement can only help advance the design of effective regenerative therapies for brain and spinal cord injuries.

project_terms:
Adenylate Cyclase;Affect;Afferent Neurons;Anterior;Axon;Behavior;CREB1 gene;Cells;Coupled;Couples;Cues;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Data;Event;Exhibits;Failure (biologic function);G-Protein-Coupled Receptors;Gases;Gene Expression;Genes;Genetic;Genetic Transcription;Growth;Imagery;Internal Ribosome Entry Site;Lead;Link;Location;MAP Kinase Gene;Measures;Mediating;Modeling;Mus;National Research Service Awards;Natural regeneration;Nerve Regeneration;Nervous System Trauma;Nervous system structure;Neurons;Neurophysiology - biologic function;Neuropilin-1;Olfactory Epithelium;Olfactory Nerve;Pattern;Penetration;Physiological Processes;Play;Population;Positioning Attribute;Process;Production;Proto-Oncogene Proteins c-akt;Research;Research Training;Role;Signal Pathway;Signal Transduction;System;Testing;Therapeutic;Transduction Gene;Transgenic Mice;axon growth;axon guidance;design;emx2 protein;injured;insight;knockout animal;nerve supply;neural circuit;neurogenesis;novel;offspring;olfactory bulb;overexpression;public health relevance;reconstruction;regenerative;regenerative therapy;relating to nervous system;repaired;spinal cord and brain injury;success

public_health_relevance:
PROJECT NARRATIVECell replacement as a regenerative approach to repair the injured nervous systemremains promising. My research aims will contribute to understanding the processes thatallow normal cellular replacement and appropriate target innervation in the olfactorysystem. This understanding of endogenous neural replacement can only help advancethe design of effective regenerative therapies for brain and spinal cord injuries.


application_id: 8301646
project_number: 8P20GM103492-05
project_title: Center of Excellence in Diabetes and Obesity Research
administering_ic: NIGMS
award_notice_date: 2012-06-18
opportunity_number: PAR-07-229
application_type: 8
activity_code: P20
ic: GM
serial_number: 103492
program_official: CANTO, MARIA TERESA
project_start_date: 2008-09-26
project_end_date: 2013-07-31
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-07-01
project_abstract:
This proposal is to promote the initiation and the development of a multi-disciplinary thematic Center of Excellence in Diabetes and Obesity Research at the University of Louisville. The primary objective and the central focus of the Center are to enable promote and support scientific research related to the cardiovascular causes and consequences of diabetes and obesity. The second major aim of program is to provide mentoring and guidance to junior investigators in the Center with the overall goal of discovering new therapies for the treatment and prevention of diabetes and obesity. Specific objectives of the program are to: [1) Build and develop a thematic multi-disciplinary research center focused on diabetes and obesity research; (2) Develop basic and clinical understanding of the molecular mechanisms of diabetes and obesity and how they contribute to the burden of cardiovascular disease (3) Expand and bridge on-going research programs to integrate current expertise into a thematically coherent program (4) Promote collaborative interactions to build complementary individual and multi-investigator research projects; (6) Foster research careers of junior investigators leading to their development as independent principal investigators; (7) Build upon our existing research capabilities and core facilities to provide the state-of-the-art infrastructure support; (8) Develop a nationally-competitive program that will attract the best clinical cardiology fellows graduate students postdoctoral fellows and new faculty; and most importantly to discover new and effective means for preventing and treating diabetes and obesity. The five related projects of junior investigators for the first phase of the Center are to: (1) delineate the contribution of oxidative stress to hyperglycemic injury and test whether antioxidant interventions prevent vascular injury in diabetes; (2) to investigate whether hyperglycemia impairs the cardiac reparative potential of mesenchymal stem cells and whether transplantation of stem cells with greater potential for cardiac repair will result in greater improvement of function in diabetic hearts following infarction; (3) delineate the mechanisms contributing to premature senescence and death of cardiac progenitor cells leading to non-ischemic diabetic cardiomyopathy; (4) examine whether hyperglycemic stimulation of foam cell formation is mediated by ER stress and the unfolded protein response and if drug that act as chemical chaperone ameliorate accelerated atherogenesis in diabetic animals; and (5) identify the regulation of high glucose-triggered inflammatory signaling (NF-kB activation) by specific micro RNAs. These investigations will be supported by establishing state-of-the-art core facilities in confocal microscopy flow cytometry cardiovascular pathology animal models and imaging and function. We believe that a Center focused on diabetes and obesity will add to the academic success of the University and will have a positive impact on the field of diabetes and obesity research in the nation.

project_terms:
Address;Animal Model;Animals;Antioxidants;Area;Arterial Fatty Streak;Atherosclerosis;Award;Biochemistry;Biology;Blood Vessels;Cardiac;Cardiac Death;Cardiology;Cardiovascular Diseases;Cardiovascular Pathology;Cardiovascular Physiology;Cardiovascular system;Cellular biology;Centers of Research Excellence;Chemicals;Clinical;Clinical Trials;Confocal Microscopy;Core Facility;Development;Diabetes Mellitus;Diabetes prevention;Diabetic mouse;Echocardiography;Environment;Epidemiology;Extramural Activities;Faculty;Flow Cytometry;Foam Cells;Fostering;Foundations;Funding;Future;Glucose;Goals;Grant;Heart;Heart failure;Hyperglycemia;Image;Image Cytometry;Imaging Techniques;Individual;Infarction;Inflammation;Inflammatory;Injury;Intervention;Investigation;Knockout Mice;Laboratories;Measurement;Mediating;Mentors;Mentorship;Mesenchymal Stem Cells;Metabolism;Methodology;MicroRNAs;Modality;Modeling;Molecular;Molecular Biology;Molecular Chaperones;Monitor;Myocardial;NF-kappa B;Obesity;Oxidation-Reduction;Oxidative Stress;Pharmaceutical Preparations;Phase;Physiology;Postdoctoral Fellow;Principal Investigator;Proteins;Records;Regulation;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Role;Science;Scientist;Signal Transduction;Smooth Muscle Myocytes;Stem Cell Research;Stem cell transplant;Stem cells;Stress;Students;Sum;Sustainable Development;Talents;Techniques;Technology;Testing;Time;Tissue Sample;Tissues;Training;Transgenic Organisms;United States National Institutes of Health;Universities;Work;atherogenesis;cardiac repair;cardiovascular imaging;career;diabetic;diabetic cardiomyopathy;experience;flexibility;functional improvement;graduate student;in vivo;interest;macrophage;member;novel therapeutics;peer;premature;prevent;programs;response;senescence;stem cell biology;success


application_id: 8301402
project_number: 1R21AI095811-01A1
project_title: Genetic Regulation of Macrophage Polarization
administering_ic: NIAID
award_notice_date: 2012-08-23
opportunity_number: PA-10-069
application_type: 1
activity_code: R21
ic: AI
serial_number: 095811
suffix: A1
program_official: PALKER, THOMAS J
project_start_date: 2012-08-23
project_end_date: 2014-07-31
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 1901005
contact_pi: MCGILLIS, JOSEPH P.
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
project_abstract:
DESCRIPTION (provided by applicant): The long term objective of this research is to understand the genetic regulatory networks that orchestrate macrophage Mf polarization. A specific goal in this proposal is to identify and characterize 'master genetic regulators' that determine which genes are selectively expressed by Mfs in different physiological and pathologic conditions. Preliminary studies suggest that one such regulator is a histone deacetylase Hdac9. Mfs are located throughout the body and are involved in inflammatory processes tissue repair and innate and adaptive immune responses. Naive Mfs can be activated or polarized to different functional states that have distinct and often opposing regulatory and functional roles in inflammation. They can significantly influence many disease processes including infectious disease autoimmune disease and cancer. Classically activated Mfs M1 are phagocytic secrete pro-inflammatory mediators and promote pathogen destruction and clearance. Alternatively activated Mfs M2 promote tissue repair and secrete cytokines and growth factors that are anti-inflammatory or immunosuppressive. Despite intense interest in Mf polarization and the functions of polarized Mfs there is a large gap in the understanding of the genetic regulatory networks that regulate the activation of naive Mfs into M1and M2 states. Our central hypotheses is that there are genetic regulatory networks controlled by a discrete cascade of transcription factors that promote polarization of naive or 'resting' Mfs to M1 and M2 states and that HDAC9 plays a fundamental role by promoting expression of genes required by M2 Mfs while simultaneously repressing genes expressed in M1 Mfs. This project will use a novel cellular system of Mf polarization as an experimental platform to address this central hypothesis. The specific aims are to: 1) confirm upregulation of HDAC 9 in the M2 phenotype and determine which HDAC9 isoform(s) is(are) expressed in M2 Mfs 2) confirm experimentally that HDAC9 regulates polarization of the M2 macrophage phenotype and 3) identify genes targeted by HDAC9 (M2 genes that are upregulated and M1 genes that are suppressed). Achieving these goals will provide important insights on how Mf polarization is regulated. This information could have a significant impact on therapeutic approaches that would target Mf functions in a wide range of disease processes.     
   
PUBLIC HEALTH RELEVANCE: Macrophages are key cells of the immune system and serve many different functions under differing physiologic and pathologic conditions. This project will identify genetic mechanisms that regulate how macrophages function by characterizing the role of a key regulatory protein HDAC9 that may have a major role in regulating macrophage responses. Understanding the role of this and other factors that regulate macrophage functions should provide new and novel approaches to understanding and targeting macrophage functions in a wide variety of disease processes.

project_terms:
Address;Anatomy;Anti-Inflammatory Agents;Anti-inflammatory;Apoptosis;Autoimmune Diseases;Autoimmunity;Biological Models;Bone Marrow;Cell physiology;Cells;Chronic;Commit;Communicable Diseases;Data;Development;Disease;Environment;Experimental Models;Family;Gene Expression;Gene Targeting;Genes;Genetic;Goals;Growth Factor;Histone Deacetylase;Immune response;Immune system;Immunity;Immunosuppressive Agents;In Vitro;Inflammation;Inflammation Mediators;Inflammatory;Lead;Location;Malignant Neoplasms;Mediator of activation protein;Microarray Analysis;Myeloid Progenitor Cells;NF-kappa B;Natural Immunity;Pathologic;Pathologic Processes;Pathway interactions;Phenotype;Physiological;Plastics;Play;Process;Protein Isoforms;Proteins;Regulation;Regulator Genes;Regulatory T-Lymphocyte;Research;Rest;Role;Signal Transduction;System;T-Lymphocyte;Therapeutic;Tissue-Specific Gene Expression;Tissues;Transcription Repressor/Corepressor;Up-Regulation (Physiology);adaptive immunity;angiogenesis;base;cytokine;genetic regulatory protein;insight;interest;macrophage;member;neuronal survival;novel;novel strategies;novel therapeutics;pathogen;progenitor;response;selective expression;skeletal muscle differentiation;small hairpin RNA;tissue repair;transcription factor

public_health_relevance:
Macrophages are key cells of the immune system and serve many different functions under differing physiologic and pathologic conditions. This project will identify genetic mechanisms that regulate how macrophages function by characterizing the role of a key regulatory protein HDAC9 that may have a major role in regulating macrophage responses. Understanding the role of this and other factors that regulate macrophage functions should provide new and novel approaches to understanding and targeting macrophage functions in a wide variety of disease processes.


application_id: 8301023
project_number: 5R01CA150947-04
project_title: Mechanisms of Immune Modulation Mediated by Yeast-derived Particulate Beta-Glucan
administering_ic: NCI
award_notice_date: 2012-07-23
opportunity_number: RFA-AT-08-003
application_type: 5
activity_code: R01
ic: CA
serial_number: 150947
program_official: KIM, YOUNG S
project_start_date: 2009-09-28
project_end_date: 2015-07-31
study_section: ZAT1-SM(13)
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
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 use of -glucans in complementary and alternative medicine (CAM) has prevailed for centuries in traditional Asian medicine. However their clinical use against malignancies in Western medicine has experienced an oscillating success due to a lack of understanding in their exact mechanisms of action. We have previously demonstrated that soluble yeast -glucan of low molecular weight is capable of binding to the lectin site of complement receptor 3 (CR3 CD11b/CD18) and priming CR3+ effector cells for cytotoxicity of iC3b-opsonized tumor cells. The work presented here shows that particulate yeast -glucan has more unique features than soluble -glucan. The objective of the proposed study is to elucidate the cellular and molecular mechanisms of action for particulate -glucan in tumor immunotherapy.   Preliminary studies demonstrated that particulate -glucan not soluble -glucan stimulated macrophages and dendritic cells (DCs) for activation and proinflammatory cytokine production. Furthermore orally administered particulate -glucan stimulated DCs that captured apoptotic tumor cells for activation and maturation leading to the enhanced anti-tumor CD4 and CD8 T cell responses. Strikingly oral particulate -glucan treatment altered the tumor microenvironment toward Th1 response. Particulate -glucan was also shown to activate the complement system via an alternative pathway leading to C5a deposition on tumors. These preliminary data provide a strong basis for the current study.   Aim 1 will dissect which signaling pathway(s) may be critical for particulate -glucan-mediated DC activation and cytokine release. Toll-like receptor pathway MyD-88- and TRIF-deficient mice CR3-deficient mice and dectin-1 pathway dectin-1- and CARD9-deficient mice will be used to address this issue. In addition T cell differentiation (Th1 Th2 and Th17) in the presence of particulate yeast -glucan stimulated DCs will be examined both in vitro and in vivo. Aim 2 will test the hypothesis that particulate -glucan modulates suppressive cells existing in the tumor microenvironment thereby promoting Th1 response. The function of myeloid-derived suppressive cells (MDSCs) dynamic interaction between regulatory T cells (Treg) and Th17 cells cross-talk between MDSCs and tumor-infiltrating macrophages will be examined. Lewis lung carcinoma transfected with surrogate antigen ovalbumin and tumor-associated antigen MUC1 will be used as the model systems to address those issues. Aim 3 will test the hypothesis that particulate -glucan stimulated complement activation may be partially contributed to the enhanced anti-tumor T cell responses. Furthermore the requirement for C3a and/or C5a and their receptors C3aR and C5aR as modulators of anti-tumor T cell responses will be determined. Further knowledge of the mechanisms involved in these effects of particulate -glucan will be of great value in the design of effective clinical applications.    Public Health Relevance: This study will elucidate the cellular and molecular mechanisms of action of particulate yeast -glucan in tumor immunotherapy. The data generated in this study will allow for the rational design of immunotherapeutic protocols usable in clinical trials.

project_terms:
3-Dimensional;Address;Adjuvant;Affinity;Anti-Infective Agents;Antibodies;Antigens;Apoptotic;Asians;Bacteria;Barley (Food);Binding (Molecular Function);Biological Models;Biological Process;Biological Response Modifiers;Bone Marrow;C3bi;CD4 Positive T Lymphocytes;CD8B1 gene;Cell Maturation;Cells;Clinical;Clinical Trials;Complement;Complement 3a;Complement 5a;Complement Activation;Complementary and alternative medicine;Data;Dendritic Cells;Dendritic cell activation;Deposition;Effector Cell;Frequencies (time pattern);Glucans;Glucose;Helper-Inducer T-Lymphocyte;Host Defense Mechanism;Human;ITGAM gene;ITGB2 gene;Immune response;Immunity;Immunotherapeutic agent;Immunotherapy;In Vitro;Individual;Infection;Integrins;Interleukin-12;Knowledge;Lactosylceramides;Lectin;Lewis Lung Carcinoma;Ligands;Link;Macrophage-1 Antigen;Malignant Neoplasms;Mediating;Medicine;Modeling;Molecular Mechanisms of Action;Molecular Weight;Monoclonal Antibodies;Mucin-1 Staining Method;Mus;Myelogenous;Oral;Ovalbumin;Particulate;Pathway interactions;Production;Protocols documentation;Regulatory T-Lymphocyte;Reporting;Side;Signal Pathway;Site;Solubility;Structure;T cell differentiation;T cell response;T-Lymphocyte;Testing;Toll-Like Receptor Pathway;Treatment Efficacy;Tumor Antigens;Vertebral column;Work;Xenograft procedure;Yeasts;activation product;base;beta-Glucans;clinical application;complement system;cytokine;cytotoxic;cytotoxicity;dectin 1;design;experience;fungus;immunoregulation;in vivo;interest;macrophage;microbial;neoplastic cell;public health relevance;receptor;response;scavenger receptor;success;tool;tumor

public_health_relevance:
Project NarrativeThis study will elucidate the cellular and molecular mechanisms of action of particulate yeast -glucan in tumor immunotherapy. The data generated in this study will allow for the rationaldesign of immunotherapeutic protocols usable in clinical trials.


application_id: 8300468
project_number: 1K01DA031764-01A1
project_title: Community Intervention Research on Prescription Drug Safety in Older Rural Adults
administering_ic: NIDA
award_notice_date: 2012-04-09
opportunity_number: PA-11-190
application_type: 1
activity_code: K01
ic: DA
serial_number: 031764
suffix: A1
program_official: KAHANA, SHOSHANA Y
project_start_date: 2012-04-15
project_end_date: 2017-03-31
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 8705215
contact_pi: ZANJANI, FAIKA
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 PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  My training objectives for this K01 Career Development Award are to enhance my knowledge and experience in a) prescription drug and alcohol interactions among older adults; b) alcohol and substance abuse; and c) developing implementing and examining a community-based health intervention program. These training goals will support me in reaching my long-term career objective to become an expert in interventions for health behavior change among older adults to reduce inadvertent prescription drug use adversities. This will be accomplished through randomized community-based behavioral trials and designing and implementing awareness and motivational interventions. The ultimate goal of this K01 Career Development Award project is to support my development as an independent scientist capable of conducting community-based behavioral health intervention that will reduce alcohol-prescription drug interactions in rural older patients who regularly take prescription medications. The impetus behind this K01 Career Development Award application is the need for effective interventions to address the devastating health effects of prescription drug and alcohol interactions. Prescription overdoses that require medical attention in older adults are commonly associated with alcohol. In combination alcohol and prescription drug misuse can seriously undermine the medical condition that is being treated by the prescription drug medication lead to potential alcohol drug interactions increase the risk fo alcohol and illicit drug use and ultimately increase health costs. In the training component of th proposed program I will gain a more thorough understanding of principles surrounding prescription drug safety (PDS) alcohol interactions and community-based health interventions. Specifically my efforts will focus on understanding PDS by targeting the reduction of prescription drug and alcohol interactions in rural pharmacy settings. The proposed project will focus on older adults in rural settings because they are at high risk for prescription misuse in addition to having limited resources for managing PDS issues. The proposed research will involve the development implementation and evaluation of an intervention in a community setting designed to improve PDS through a) raising awareness about alcohol use and prescription drug interactions and b) using motivational interviewing to reduce alcohol consumption among at-risk alcohol consumers (consuming above recommended age-defined limits (>1 alcoholic drink a day in combination with prescription drugs). Prescription drug safety is characterized by consuming correct quantities and avoiding prescriptions in combination with adverse substances (e.g. alcohol) to prevent negative health outcomes. This K award will be a platform for the development of expertise but also a novel promising and wide reaching approach to prevent prescription drug interactions through community-based prevention methods targeting modifiable behaviors in community pharmacies. Promoting moderate alcohol use patterns to encourage safer use of prescription drugs is significant since approximately 50% of older adults consume alcohol of whom 25% consume more than the recommended age-defined limits. Additionally older adults use prescription drugs more than any other age group. Risky alcohol consumption (the age-defined definition involves consuming more than 1 drink/day on average) can have negative interactions with many medications commonly used by older adults and consequently can have detrimental impacts on health. These health effects include medication and disease-management non-adherence and increased likelihood of falls cognitive impairment medical adversities and fatality. The proposed study will involve the implementation of an intervention in community settings with the aid of local pharmacists and will include an awareness and motivational interviewing component to promote PDS. Specific Aims of the research proposal are to 1) Obtain community insights about PDS to examine rural resources/barriers which will inform the development of the PDS intervention program; 2) Create PDS intervention material for the awareness and motivational interviewing components 3) Implement and evaluate intervention components (Awareness and Motivational Interviewing) to promote PDS in rural regions and 4) Disseminate findings and develop an R01 NIH grant to examine the proposed intervention on a larger scale. Achieving the proposed aims will lead to an innovative approach to promote PDS within other rural communities. Establishing an effective PDS intervention will reduce adversities related to prescription drug and alcohol interactions for older adults and consequently improve their quality of life.       
   
PUBLIC HEALTH RELEVANCE:  This research will aid in reducing the rates and consequences of prescription drug and alcohol interactions among older adults residing in rural US areas. Reducing prescription drug and alcohol interactions can ultimately reduce individual and societal health burden and improve life quality through improved cognition and mental and physical capabilities.

project_terms:
Accidental Injury;Address;Adult;Age;Aging;Alcohol abuse;Alcohol consumption;Alcohols;Area;Awareness;Behavior;Behavioral;Cessation of life;Clinical Trials Design;Cognition;Communities;Community Pharmacy;Community based prevention;County;Data;Development;Disease;Disease Management;Drug Interactions;Drug Prescriptions;Drug usage;Drug user;Educational aspects;Effectiveness;Elderly;Evaluation;Focus Groups;Future Generations;Goals;Grant;Guidelines;Health;Health Care Costs;Health behavior change;Illicit Drugs;Impaired cognition;Individual;Intervention;Intervention Studies;K-Series Research Career Programs;Knowledge;Lead;Manuals;Manuscripts;Medical;Medication Errors;Methods;Morbidity - disease rate;Mortality Vital Statistics;Myocardial Infarction;Outcome;Overdose;Pamphlets;Pattern;Pharmaceutical Preparations;Pharmacists;Pharmacy facility;Physiology;Psyche structure;Quality of life;Randomized;Randomized Controlled Trials;Research;Research Proposals;Resources;Risk;Risk Factors;Rural;Rural Community;Safety;Scientist;Substance abuse problem;Telephone;Testing;Training;United States National Institutes of Health;age group;alcohol risk;base;behavioral health;career;community setting;design;drinking;drug metabolism;effective intervention;experience;falls;follow-up;high risk;high risk drinking;improved;innovation;insight;intervention program;medical attention;meetings;misuse of prescription only drugs;motivational enhancement therapy;motivational intervention;novel;older patient;prevent;problem drinker;programs;public health medicine (field);research study;rural area

public_health_relevance:
This research will aid in reducing the rates and consequences of prescription drug and alcohol interactions among older adults residing in rural US areas. Reducing prescription drug and alcohol interactions can ultimately reduce individual and societal health burden and improve life quality through improved cognition and mental and physical capabilities.


application_id: 8300175
project_number: 5R01CA139844-05
project_title: The role of MRP1 in Protection of Cardiac Injury
administering_ic: NCI
award_notice_date: 2012-07-24
application_type: 5
activity_code: R01
ic: CA
serial_number: 139844
program_official: FORRY, SUZANNE L
project_start_date: 2008-09-25
project_end_date: 2014-07-31
study_section: 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: 2012-08-01
project_abstract:
SPACE PROVIDED. ' The goal of the present application is to characterize the role of multidrug resistance protein 1 (Mrp1) inprotecting the heart from oxidative stress. We postulate that cancer treatment with Adriamycin (ADR)leadsto oxidative stress which in turn leads to production of tumor necrosis factor-a (TNF) that amplifies oxidativestress and causes normal tissue injury. Mrp1 is an ATP-binding cassette (ABC) transporter that mediates theATP-dependent efflux of glutathione (GSH) and its conjugates including the GSH conjugate of the cytotoxicproduct of oxidative stress 4-hydroxynonenal (HNE; GS-HNE). We will test the hypotheses that 1) Cardiacexpression of Mrp1 protects the heart from oxidative stress and injury induced by ADR by mediating efflux ofGS-HNE; 2) Mrp1 expression increases and is localized in plasma membrane and mitochondria in responseto oxidative stress and/or TNF and 3) excessive production of HNE and GS-HNE inactivates Mrp1overwhelming its protective role and exacerbating oxidative injury. Four Specific Aims will test thesehypotheses; Aim 1will utilize Mrp1 null mice to assess its role in protecting the heart from ADR-inducedoxidative stress and injury the ability of MnSODto compensate for loss of Mrp1 and the function of TNF inregulating Mrp1 expression. Aim 2 will characterize the subcellular localization and function of Mrp1 followingADR and TNF treatment. Aim 3 will assessthe role of oxidative stress in the regulation of Mrp1 expressionand localization. Finally Aim 4 will characterize the ability of HNEand GS-HNE to inactivate Mrp1 byalkylation of key cysteine histidine or lysine residues. We will utilize mice of various genotypes (Mrp1 nullmice MnSOD transgenic and heterozygous (+/-) mice) to assessthe roles of these genes in protectionagainst cardiac injury confocal immunofluorescent immunohistochemistry and quantitative immunogoldanalysis for localization of Mrp1 expression in the cardiomyocyte and HEK293 cells for expression of Mrp1to characterize its function; proteomic analyses will be used to identify potential structural isoforms of Mrp1and the sites of HNE alkylation of Mrp1. Understanding the roles of Mrp1 TNF and GSH in protecting theheart from ADR-induced tissue injury will lead to the development of ancillary therapeutic modalities toprotect against such injury and thus permit utilization of higher doses of this highly effectivechemotherapeutic agent.

project_terms:
4 hydroxynonenal;ABCC1 gene;ATP-Binding Cassette Transporters;Adriamycin PFS;Alkylation;Antibodies;Biochemical;Biological Assay;Cardiac;Cardiac Myocytes;Cardiotoxicity;Cell Line;Cell membrane;Cells;Collaborations;Coupled;Cysteine;Development;Dose;Esters;Fractionation;Genes;Genotype;Glutathione;Glutathione Disulfide;Goals;Heart;Histidine;Human;Immunohistochemistry;In Vitro;Injury;Knockout Mice;Lead;Lysine;Measures;Mediating;Messenger RNA;Mitochondria;Modality;Morphology;Mus;Normal tissue morphology;Oxidation-Reduction;Oxidative Stress;P-Glycoprotein;P-Glycoproteins;Production;Protein Isoforms;Proteins;Proteomics;Quantitative Microscopy;Regulation;Role;Sarcolemma;Schiff Bases;Site;Testing;Therapeutic;Time;Tissues;Toxic effect;Transgenic Mice;Transgenic Organisms;Tumor Necrosis Factor-alpha;Vesicle;Wild Type Mouse;adduct;base;buthionine;cancer therapy;chemotherapeutic agent;cytotoxic;functional group;in vivo;novel;overexpression;oxidant stress;oxidative damage;response;treatment effect;uptake


application_id: 8300013
project_number: 5R01HD056002-05
project_title: Sensory-driven motor recovery in poorly recovered subacute stroke patients
administering_ic: NICHD
award_notice_date: 2012-06-04
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HD
serial_number: 056002
program_official: MICHEL, MARY E
project_start_date: 2008-09-01
project_end_date: 2014-06-30
study_section: Musculoskeletal Rehabilitation Sciences Study Section[MRS]
contact_pi_person_id: 7375465
contact_pi: SAWAKI-ADAMS, 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):  Project Summary Stroke is the leading cause of long-term disability in the United States. Approximately 70-88% of persons with stroke have some degree of motor impairment. A major goal of research in stroke rehabilitation is to harness the ability of the brain to reorganize after neurologic 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 (PNS) can be successfully combined to motor training especially in poorly recovered subacute stroke patients. The proposed study will evaluate the effectiveness of sustained PNS coupled with motor training to improve hand motor function in subacute stroke patients with severe motor deficit. Our preliminary data in chronic stroke patients with severe motor deficit demonstrate that motor function can be substantially enhanced when PNS is paired with motor training. In addition a separate study in patients with mild motor deficit receiving motor training alone suggests that the optimal therapeutic time window to deliver motor training is within the first year after stroke. The improvement of behavioral motor function was associated with corticomotor reorganization. Therefore we now propose to evaluate the effectiveness of sustained PNS paired with motor training to promote functional motor recovery in subacute stroke patients with severe motor deficit. The central hypothesis is that subacute stroke patients with severe motor deficit receiving PNS and intensive task-oriented therapy will have improved motor function compared to patients receiving sham-PNS and task-oriented therapy and also when compared to patients receiving PNS-only. Further the degree of this behaviorally-measured effect will correlate with the neurophysiological effect measured by transcranial magnetic stimulation. We plan to accept or reject the central hypothesis by accomplishing two Specific Aims: 1) test the effect of PNS preceding task-oriented therapy on hand motor function and 2) test the effect of PNS preceding task-oriented therapy on motor map measured by transcranial magnetic stimulation. The long-range goals are: a) to maximize the restoration of hand motor function after stroke b) to determine the impact of this intervention in activities of daily living. PUBLIC HEALTH RELEVANCE This research project addresses a scientifically important question that cannot be answered by other means. The use of peripheral nerve stimulation has the potential to enhance recovery in subacute stroke patients with poor functional recovery. The primary objective of this proposal is to demonstrate that peripheral nerve stimulation combined with intensive motor training has the ability to further improve hand motor function when compared to intensive training alone or nerve stimulation alone. The results from this study have the potential to develop new strategies in neurorehabilitation. The risk involved to subjects in this study is very low.

project_terms:
Activities of Daily Living;Acute;Address;Adult;Affect;Animals;Area;Behavioral;Brain;Brain Injuries;Chronic;Complex;Control Groups;Coupled;Data;Disease;Effectiveness;Future;Goals;Hand;Health;Human;Intervention;Lead;Learning;Maps;Measures;Metacarpophalangeal joint structure;Modeling;Motor;Motor Cortex;Motor Skills;Motor output;Muscle;Nerve;Neurologic;Neurorehabilitation;Patients;Peripheral Nerve Stimulation;Persons;Phase;Plastics;Play;Quality of life;Recovery;Recovery of Function;Rehabilitation therapy;Research;Research Project Grants;Risk;Role;Sensory;Solid;Testing;Therapeutic;Therapeutic Intervention;Time;Tissues;Training;Transcranial magnetic stimulation;United States;Upper Extremity;Wolves;Work;Wrist;acute stroke;animal data;chronic stroke;constraint induced therapy;disability;experience;extensor digitorum;improved;memory process;motor deficit;motor impairment;neurophysiology;post stroke;randomized trial;restoration;sensory cortex;skill acquisition;stroke;stroke rehabilitation


application_id: 8299184
project_number: 5R01DE014605-11
project_title: Intra- and interspecies communication in oral bacteria
administering_ic: NIDCR
award_notice_date: 2012-07-19
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DE
serial_number: 014605
program_official: LUNSFORD, DWAYNE
project_start_date: 2003-02-01
project_end_date: 2014-07-31
study_section: Special Emphasis Panel[ZRG1-MOSS-E(02)S]
contact_pi_person_id: 1859425
contact_pi: DEMUTH, DONALD R
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Periodontal disease is caused by bacterial pathogens that thrive in a complex multi-species community that forms in the gingival pocket. The initiation and growth of this biofilm requires sophisticated molecular communication among the species in this community. We have shown that the periodontal pathogens A. actinomycetemcomitans and P.gingivalis produce the quorum sensing signal autoinducer2 (AI-2) which may be involved in intra- and interspecies communication among these organisms. AI-2 regulates genes involved in virulence iron acquisition and biofilm formation and is likely an important mechanism that allows these organisms to sense and respond to their local environment. Our general hypothesis that A. actinomycetemcomitans and P. gingivalis respond differentially to AI-2 and the outcomes of these signaling systems are tailored to the specific survival strategies that are employed by these organisms in the oral biofilm. The long term goal of this proposal is to determine if AI-2 quorum sensing can be exploited to control oral biofilm development. The specific aims are to characterize the AI-2 receptors and early events that initiate the cellular response to AI-2 of A. actinomycetemcomitans and P. gingivalis since these are ideal targets for therapeutic intervention. We will determine if importation and intracellular processing of AI-2 is required to initiate the cellular response. The QseBC and GppX two component signaling systems of A. actinomycetemcomitans and P. gingivalis respectively will be studied to determine if they couple the detection of AI-2 to downstream gene regulatory events. Finally we will determine if the function of high and low affinity AI-2 receptors in A. actinomycetemcomitans facilitate colonization of both early and mature biofilms by this organism. These studies will define at the molecular level how oral pathogens detect and interact with AI-2 and how these processes lead to alteration in gene expression that facilitates their growth in microbial communities. This information may facilitate the rational design of new therapeutics that may control the growth and development of oral microbial biofilms by interfering with their communication pathways. PUBLIC HEALTH RELEVANCE: Periodontitis is a common oral disease that is present in up to 40% of the adult population in the United States and annual expenditures for treatment and prevention of periodontitis are over $14 billion. Periodontitis caused by a community of bacteria that live in the gingival pocket but it is also associated with systemic illnesses such as heart disease. Preventing periodontal disease requires eliminating or controlling the microbial community. Our studies examine a unique microbial communication pathway that facilitates the development of the bacterial community. We seek to develop new potential drugs that prevent the formation of microbial communities by interfering with this communication system in order to control or prevent periodontitis.

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

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


application_id: 8299070
project_number: 8P20GM103482-10
project_title: Molecular Targets COBRE
administering_ic: NIGMS
award_notice_date: 2012-07-02
opportunity_number: RFA-RR-07-001
application_type: 8
activity_code: P20
ic: GM
serial_number: 103482
program_official: CANTO, MARIA TERESA
project_start_date: 2003-09-01
project_end_date: 2013-06-30
contact_pi_person_id: 1898718
contact_pi: MILLER, DONALD M.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-07-01
project_abstract:
The University of Louisville Molecular Targets Center of Biomedical Research Excellence (MT-COBRE) is focused on identification of novel molecular targets for cancer therapy emphasizing structural biologic approaches for development of novel therapeutics. The overall objective of the MT-COBRE is to recruit and ensure the success of junior investigators who are members of the Molecular Targets Program at the UofL's Brown Cancer Center. We have made considerable progress towards accomplishment of the goals of the original application during the first five year funding period. Four of the original five COBRE scientists have received NIH R01 funding the fifth was encouraged to pursue other directions. Five outstanding new scientists have taken their places three of whom have NIH R01 applications under review or being revised for resubmission. We have been quite fortunate during the initial funding period to have retained all of the MT-COBRE faculty. We have leveraged the MT-COBRE support to create a set of effective Core Facilities which have significantly enhanced the productivity of the MT-COBRE investigators and other Brown Cancer Center scientists. The renewal application has added a new Core the Biophysics Core Facility and deleted a Core which was underutilized the Proteomics Core Facility. The specific aims of the proposal are to:  1. develop successful independent research careers for each of the principal investigators that will lead to independent R01 grants. 2. develop core facilities that will enhance the research capability of the principal investigators and the other members of the MT program. 3. continue to develop the Molecular Targets Program as a cohesive research program which will enhance collaborative research projects and funding opportunities. 4. develop a nationally and internationally recognized program which will attract the very best graduate students postdoctoral fellows and additional faculty. 5. make discoveries leading to new and more effective treatments for patients with cancer.  During the next funding period the MT-COBRE will utilize focused recruitment to enhance the scope of the program. Funding of this renewal application is critically important to allow the program to achieve its potential. Based on its current faculty and projected growth during the next funding period this program is poised to become one of the nation's premiere cancer drug development programs.

project_terms:
Antineoplastic Agents;Biophysics;Cancer Center;Centers of Research Excellence;Core Facility;Development;Ensure;Faculty;Funding;Funding Opportunities;Goals;Grant;Growth;Lead;Malignant Neoplasms;Molecular Target;Patients;Postdoctoral Fellow;Principal Investigator;Productivity;Proteomics;Recruitment Activity;Research;Research Personnel;Research Project Grants;Scientist;United States National Institutes of Health;Universities;base;cancer therapy;career;drug development;effective therapy;graduate student;member;novel;novel therapeutics;programs;success


application_id: 8298618
project_number: 5R01CA139843-05
project_title: MbSOD in chemotherapeutic-Induced Cardiac Injury
administering_ic: NCI
award_notice_date: 2012-08-01
application_type: 5
activity_code: R01
ic: CA
serial_number: 139843
program_official: ALLEY, MICHAEL C
project_start_date: 2008-09-25
project_end_date: 2015-07-31
study_section: 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: 2012-08-01
project_abstract:
SPACE PROVIDED. Heart disease is a major dose limiting factor of cancer therapy that uses anthracycline as a componentof the protocol. Generation of reactive oxygen species (ROS) has been implicated in the toxicity of a largenumber of therapeutic agents including those containing the redox cycling groups. The goal of this study isto identify novel mechanisms that lead to cardioprotection during cancer treatment. Our studies of animaland isolated cardiomyocytes indicate that overexpression of the mitochondrial antioxidant enzymemanganese containing superoxide dismutase (MnSOD) protects the heart against adriamycin (ADR)-inducedcardiac injury. Interestingly ADR treatment leads to an increase in circulating levels of tumor necrosis factoralpha (TNF)t a pleiotropic cytokine that has also been shown to produce ROS. We also found that ADR-induced cardiac injury is associated with translocation of p53 to the mitochondria and interaction of p53 withMnSOD. Based on these novel findings we hypothesize that ADR toxicity is the result of a cascade thatinvolves ADR producing direct oxidative stress that sequentially leads to TNF production and amplification ofoxidative stress in mitochondria. To test this hypothesis cardiac tissue and cardiomyocytes isolated fromMnSOD deficient wild type and mice overexpressing MnSOD as well as p53 deficient p53 deficient withMnSOD deficient and p53 deficient overexpressing MnSOD mice of the same inbred background will beused as models. Aims 1 and 2 will test the hypothesis that ADR toxicity is the result of a cascade thatinvolves ADR and its metabolites producing direct oxidative stress that sequentially leads to TNF productionand amplification of oxidative stress in heart tissues and in cardiomyocytes. Aim 3 will test the hypothesisthat oxidative stress initiated in mitochondria serves as a death signal which regulates p53 translocation andits mitochondrial-mediated transcription dependent and independent pathways . Aim 4 will test thehypothesis that selective modulation of cellular antioxidant status or TNF levels alters ADR-induced cardiacnjury in experimental therapeutic settings. The results from these studies will provide important insights formechanistic-based pharmacological interventions to reduce cancer therapy-associated cardiac injury.Because the extensive use of ADR translation of these findings will not only improve the quality of life butwill also enhance the probability of cancer free survival for a large number of cancer patients.

project_terms:
ABCC1 gene;Acute;Adriamycin PFS;Animals;Anthracyclines;Antibodies;Antioxidants;Apoptosis;Biochemical;Biological Assay;Brain;Cancer Patient;Cardiac;Cardiac Myocytes;Cell Death;Cell Fractionation;Cessation of life;Chimeric Proteins;Chronic;Confocal Microscopy;Coupled;Data;Dose-Limiting;Drug Kinetics;Echocardiography;Enzymes;Gene Targeting;Generations;Genes;Genetic Transcription;Goals;Heart;Heart Diseases;Immunoprecipitation;Inbreeding;Injury;Intervention;Kinetics;Knock-out;Knockout Mice;Lead;Link;Malignant Neoplasms;Manganese;Mediating;Messenger RNA;Methods;Mitochondria;Modeling;Morphology;Mus;Nuclear;Oxidation-Reduction;Oxidative Stress;P-Glycoproteins;Pathway interactions;Plasma;Probability;Production;Proteins;Proteomics;Protocols documentation;Quality of life;Reactive Oxygen Species;Role;Signal Transduction;Source;Superoxide Dismutase;Superoxides;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;Toxic effect;Translations;Treatment Efficacy;Treatment Protocols;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;overexpression;treatment effect;tumor


application_id: 8297382
project_number: 2R01AG027297-06A1
project_title: Calcineurin and inflammatory signaling processes in aging and Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2012-03-12
opportunity_number: PA-10-067
application_type: 2
activity_code: R01
ic: AG
serial_number: 027297
suffix: A1
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 2006-09-01
project_end_date: 2017-03-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
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
project_abstract:
DESCRIPTION (provided by applicant): The experiments in this project use innovative gene delivery techniques and a multipronged approach to assess the fundamental role of astrocyte activation in neurologic function in an intact mouse model of Alzheimer's disease (AD). Studies use adeno-associated virus vectors (AAV) bearing the astrocyte-specific promoter Gfa2 to target the protein phosphatase calcineurin (CN) and NFAT transcription factors in astrocytes of wild-type and APP/PS1 mice. AAV-Gfa2 vectors are bilaterally delivered to the hippocampus at different ages/disease stages and mice are assessed on different AD biomarkers. In Aim 1 cognitive status is assessed using the active avoidance task while synaptic function is evaluated using hippocampal slice electrophysiology and Western blot measures of synaptic proteins. In Aim 2 hippocampal glutamate regulation is investigated using ceramic enzyme-based microelectrode arrays and measures of glutamate transporter levels. In Aim 3 levels of glial activation and neuroinflammation are determined with immunohistochemical (IHC) analyses and assessment of cytokine levels using Multiplex ELISAs. In Aim 4 IHC is used to determine the extent of A? deposition while ELISAs are used to quantify levels of A?40 and A?42 in soluble and insoluble hippocampal tissue fractions and Westerns used to assess BACE protein expression. AAV-Gfa2 vectors encode either potent inhibitors or activators of CN/NFAT signaling and therefore will determine the necessity and sufficiency of this astrocytic pathway in driving and/or maintaining neurologic dysfunction in AD mice. These studies provide a highly novel approach to the study of activated astrocytes and could have a major impact on the development of treatment strategies for AD and other neurodegenerative conditions.   
   
PUBLIC HEALTH RELEVANCE: Increasing evidence implicates activated astrocytes in a variety of neurodegenerative conditions including Alzheimer's disease (AD). However these cells are difficult to target selectively with therapeutics. In this project we use cutting-edge adeno associated virus vectors to selectively prevent astrocyte activation and improve neurologic function in intact AD model mice. This approach could emerge as a new treatment strategy for AD and other neurodegenerative disorders.

project_terms:
APP-PS1;Age;Aging;Alzheimer's Disease;Alzheimer's disease model;Animals;Astrocytes;Automobile Driving;Avoidance Learning;Behavior;Behavioral;Biochemical Process;Biological Assay;Brain;Brain Diseases;Calcineurin;Cells;Ceramics;Cognitive;Data;Dependence;Dependovirus;Deposition;Development;Disease;Electrodes;Electrophysiology (science);Enzyme-Linked Immunosorbent Assay;Enzymes;Funding;Gene Delivery;Glial Fibrillary Acidic Protein;Glutamate Receptor;Glutamate Transporter;Glutamates;Hippocampus (Brain);Human;Hypertrophy;Impaired cognition;Implant;In Vitro;Inflammatory;Ipsilateral;Label;Measurement;Measures;Methods;Microelectrodes;Microglia;Mus;NFAT Pathway;Nerve Degeneration;Nervous System Physiology;Neurodegenerative Disorders;Neurologic Dysfunctions;Outcome Measure;Pathologic;Pathology;Pathway interactions;Phenotype;Process;Production;Promotor (Genetics);Protein phosphatase;Proteins;Reaction;Regulation;Resolution;Rodent Model;Role;Signal Transduction;Slice;Staging;Synapses;Synaptic plasticity;Techniques;Testing;Therapeutic;Time;Tissues;Transgenic Mice;Transgenic Organisms;Western Blotting;Wild Type Mouse;adeno-associated viral vector;aging brain;amyloid pathology;astrogliosis;base;beta-site APP cleaving enzyme 1;biomarker;computerized data processing;cytokine;functional outcomes;improved;in vivo;inhibitor/antagonist;innovation;interest;mouse model;neuroinflammation;neuropathology;neuroprotection;novel strategies;prevent;protein expression;relating to nervous system;research study;response;synaptic function;transcription factor;treatment strategy;vector


application_id: 8296610
project_number: 5R13AI091316-03
project_title: Autumn Immunology Conference
administering_ic: NIAID
award_notice_date: 2012-05-07
opportunity_number: PA-08-149
application_type: 5
activity_code: R13
ic: AI
serial_number: 091316
program_official: COULTER, NANCY A
project_start_date: 2010-07-01
project_end_date: 2013-06-30
study_section: ZAI1-MMT-M(M1)
contact_pi_person_id: 1863468
contact_pi: WOODWARD, JEROLD G
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This proposal requests funds to support the annual Autumn Immunology Conference (AIC). The AIC was established in 1972 to promote Immunology research in the upper Midwest region of the United States. The conference provides a forum for the exchange of scientific data and ideas fosters collaborations between scientists at different institutions and provides career development and education opportunities to a diverse group of individuals with an interest in Immunology.  The scientific focus of the meeting is intentionally broad; it includes basic Immunology and related biomedical fields such as cancer biology pathogenesis vaccine development inflammation and autoimmunity. Special emphasis is given to providing pre- and post-doctoral trainees with an opportunity to share their data participate in scientific and career discussions and to meet and exchange ideas with established investigators. We also seek to attract involve and promote the careers of women and racial/ethnic minorities that are underrepresented in science.  These objectives are met by inviting a group of outstanding Immunology researchers (12-13 each year) from around the world to speak at the meeting. All presenters present both an oral and poster presentation and are designed to provide the greatest opportunity for feedback to the trainees. Finally scholarship programs career development workshops and mentoring luncheons promote the inclusion of minority scientists and seek to recruit undergraduates into the discipline of Immunology.

project_terms:
Allergic Disease;Applied Research;Autoimmunity;Basic Science;Cancer Biology;Collaborations;Communicable Diseases;Communities;Country;Data;Discipline;Educational aspects;Educational workshop;Faculty;Feedback;Fees;Fostering;Funding;Immune System Diseases;Immunologist;Immunology;Individual;Inflammation;Institution;Mentors;Minority;Minority Groups;Mission;National Institute of Allergy and Infectious Disease;Oral;Pathogenesis;Postdoctoral Fellow;Recruitment Activity;Request for Applications;Request for Proposals;Research;Research Personnel;Scholarship;Science;Scientist;Students;United States;United States National Institutes of Health;Woman;career;career development;cost;design;interest;meetings;posters;pre-doctoral;prevent;programs;public health medicine (field);symposium;vaccine development

public_health_relevance:
Project Narrative High quality scientific conferences are vital to the public health mission of the NIH. This application requests funding for an annual scientific conference called the Autumn Immunology Conference. The purpose of this meeting is to exchange and disseminate information and to explore contemporary problems in the field of Immunology. Thus it is consistent with the fiscal and programmatic priorities of the National Institutes of Allergy and Infectious Diseases (NIAID) which is to conduct and support basic and applied research to better understand treat and ultimately prevent infectious immunologic and allergic diseases.


application_id: 8296174
project_number: 5R01HL078663-07
project_title: Lysolipid Signaling in Cardiovascular Disease
administering_ic: NHLBI
award_notice_date: 2012-06-08
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 078663
program_official: HASAN, AHMED A K
project_start_date: 2004-09-24
project_end_date: 2014-06-30
study_section: Special Emphasis Panel[ZRG1-VH-E(02)M]
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are essential bioactive lysolipid mediators that regulate a range of developmental and physiological processes and are emerging as targets for a new class of molecular therapeutics. In the cardiovascular system LPA is poised to serve as a mediator of atherothrombotic disease: it is abundant in atherosclerotic plaque present in the blood produced by activated platelets triggers phenotypic responses in smooth muscle cells and potentiates platelet activation. Exposure of LPA during atherosclerotic plaque rupture/erosion has been proposed as a key modulator of platelet thrombosis. We report a novel pathway for regulation of platelet LPA responses that involves recruitment of the lysophospholipase D enzyme autotaxin responsible for LPA production to activated platelets. We have also found that LPA inhibits mouse platelet function and that approximately 20% of human volunteers also lack a stimulatory response to LPA. We have evidence that this inhibitory LPA-signaling pathway confers vascular protection from thrombosis in mice and potentially from atherosclerotic disease in humans. We suggest that a therapeutic strategy directed at blocking stimulatory platelet LPA responses while promoting inhibitory ones could result in beneficial anti-thrombotic effects. Implementation of this strategy requires the molecular characterization of platelet LPA responses and proof of a role for circulating or locally produced LPA in regulating hemostasis and thrombosis. The broad goal of this proposal is to provide mechanistic insight essential for establishing LPA signaling as a viable anti-thrombotic target. We will take advantage of the differences in murine and human platelet LPA responses to identify the receptor(s) responsible for LPA signaling in mice and humans and then generate a transgenic mouse with platelet-specific expression of a stimulatory LPA receptor that phenocopies the human LPA response so that processes of relevance to human disease can be studied in a small animal mode. We are uniquely well-prepared to achieve these goals based on our expertise in bioactive lipid signaling and the tools we have amassed to study LPA in the vasculature. Completion of these studies promises to provide valuable insight into regulation of platelet function and may have exciting implications for the development of novel anti-thrombotic strategies that target LPA signaling.    PUBLIC HEALTH RELEVANCE: Atherothrombotic vascular disease is a leading cause of death in the United States. Blood platelets are essential for acute thrombotic events such as heart attacks and strokes and also contribute to local and systemic inflammation. This research project seeks to understand how the production of a class of pro-inflammatory lipid molecules is influenced by platelets and how the lipids affect platelet function. Completion of the work will provide new insights into pathways that could be targeted to prevent and treat arterial thrombosis.

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

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


application_id: 8295967
project_number: 5K01CA133138-05
project_title: Promoting Mammography in African American Women Visiting the Emergency Department
administering_ic: NCI
award_notice_date: 2012-05-24
opportunity_number: PAR-06-220
application_type: 5
activity_code: K01
ic: CA
serial_number: 133138
program_official: SOYOMBO-SHOOLA, ABIGAIL ADEBISI
project_start_date: 2008-06-12
project_end_date: 2013-08-31
study_section: Education Study Section (G)[NCI-G]
contact_pi_person_id: 8003903
contact_pi: HATCHER, JENNIFER
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): Breast cancer is a pressing public health concern. It is the most common cancer and the second leading cause of cancer death among African American women. Screening mammography is the single most effective method of early detection of breast cancer; however African American women are screened at suboptimal rates with only 53% of African American women aged 40 and older having had a mammogram within the past year. Low income women women without health insurance and those without a usual source of health care have even lower screening rates of 44% 34% and 28% respectively. Many of these women use the Emergency Department as the only source of medical care. Through a training plan of mentoring by a team of interdisciplinary cancer control and nursing scientists formal class work and seminars this K01 Award will provide the applicant with the opportunity to develop and conduct a study that pilot tests a culturally tailored stage matched intervention delivered by peer educators to increase mammography use among African American women visiting the Emergency Department. The specific aims of the study are: (1) to examine the barriers and benefits that influence the use of screening mammography among African American women and develop a peer educator delivered intervention and tailored educational materials; (2) to develop and evaluate culturally tailored stage appropriate mammography educational materials for African American women to determine cultural acceptability readability and applicability for women visiting the Emergency Department; and (3) to compare in a randomized controlled trial with a sample of African American women the effect of two different interventions (a culturally tailored stage-matched peer educator breast cancer intervention versus tailored educational materials only) on receipt of a screening mammogram and knowledge of and intent to follow screening guidelines. The proposed study's conceptual framework integrates concepts from both the Health Belief Model and the Transtheoretical Model. These specific aims correspond to three phases: a qualitative phase a developmental phase and an intervention phase. The combination of this progressive research project and the structured training plan will prepare the applicant to meet the long-term goal of becoming an independent investigator by allowing her to develop skills in mixed methodology refine skills in advanced quantitative research methods incorporate communication in cancer control theory and principles and demonstrate the ability to integrate knowledge and experience related to health disparities and cancer control into the design and implementation of a randomized controlled clinical trial. In addition the results from the proposed project will form the foundation for further research to promote the use of screening mammography among this vulnerable group of women.

project_terms:
Accident and Emergency department;Address;African American;Breast Cancer Early Detection;Cancer Control;Cancer Etiology;Cancer Intervention;Caring;Cessation of life;Communication;Development;Discipline of Nursing;Educational Materials;Evaluation;Foundations;Goals;Guidelines;Health Insurance;Healthcare;Intervention;Knowledge;Low income;Mammography;Medical;Mentored Research Scientist Development Award;Mentors;Methodology;Methods;Modeling;Movement;Phase;Pilot Projects;Qualitative Research;Randomized Controlled Clinical Trials;Randomized Controlled Trials;Readability;Research;Research Methodology;Research Personnel;Research Project Grants;Sampling;Schedule;Scientist;Screening procedure;Second Primary Cancers;Services;Source;Staging;Structure;Testing;Training;Visit;Vulnerable Populations;Woman;Work;aged;cancer prevention;design;experience;health belief;health disparity;malignant breast neoplasm;meetings;peer;public health medicine (field);research study;skills;theories


application_id: 8295796
project_number: 2R01CA109136-06A1
project_title: Novel Mechanisms of Carcinoma Cell Migration
administering_ic: NCI
award_notice_date: 2012-08-08
opportunity_number: PA-10-067
application_type: 2
activity_code: R01
ic: CA
serial_number: 109136
suffix: A1
program_official: WOODHOUSE, ELIZABETH
project_start_date: 2006-03-09
project_end_date: 2017-03-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1947523
contact_pi: O'CONNOR, KATHLEEN L.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Tumor invasion and metastasis still claim the majority of cancer patients' lives. Although great strides have been made in cancer detection and prevention the need for a more effective treatment for cancer metastasis remains a central problem. Notably molecules that control spatial signaling for cell polarization and directed migration contribute to the lethality of cancer through their ability to improve the efficiency of he first steps of metastasis. RhoA contributes to cell polarization during directed cell motility yet
how RhoA is spatially controlled remains unclear. We propose that integrin signaling through cAMP/PKA is instrumental for spatial signaling of RhoA and cell polarization. Importantly our previous work has shown that ?1 integrins control the generation of PKA activity gradients at the leading edge of migrating carcinoma cells where it controls RhoA function. We provide compelling evidence that these PKA activity gradients exist in breast carcinoma patient samples and in three-dimensional breast carcinoma cultures which attest to the significance of these gradients in human breast cancer. Integrin??6?4 is upregulated in advanced breast cancers where it is most closely associated with basal-like breast cancers. Importantly integrin ??6?4 promotes the activation of RhoA by a mechanism that we propose reverses the effect of PKA. Therefore we suggest that the counter-opposing modes of regulation these integrins have on RhoA permit efficient compartmentalization of RhoA that facilitates breast carcinoma motility invasion and metastasis. Accordingly the central hypothesis of this application is that cooperative signaling between ?1 integrins and integrin ?6?4 facilitates the spatial distribution of RhoA activity to promote lamellae formation and directed migration. The long-term goal of our group is to determine how integrins contribute to tumor invasion so that they may be eventually targeted appropriately for therapeutic intervention with special emphasis on integrin ?6?4. We will test our central hypothesis and achieve our long- term goal through the completion of the following aims: 1) Define the macromolecular complex that couples ?1 integrins to PKA activation thereby limiting RhoA activity at the leading edge 2) Determine how integrin ?6?4 leads to the activation of RhoA and 3) Elucidate how RhoA function is altered to promote lamellae formation. We are uniquely suited to perform these studies due to our strong collaborations; our well-characterized models of ?6?4 integrin- and RhoA-dependent invasion and migration; our expertise in integrin biology and Rho signaling and our solid preliminary data supporting this project. The results obtained from this study will be important as they will go int mechanistic depth regarding how integrins coordinate spatial signaling to achieve polarization lamellae formation directed cell migration and finally invasion. Ultimately our study will be significant as it will generate a firmer understanding of signaling pathways that govern leading edge dynamics that will produce successful methods to therapeutically target the early steps in metastasis.   
   
PUBLIC HEALTH RELEVANCE:  Understanding how integrins signal continues to have a sustained impact on our understanding of cancer biology. Notably integrins contribute to the most deadly aspects of cancer progression including tumor invasion and metastasis; yet how they contribute to these processes remains poorly understood. Here we will go into mechanistic depth regarding how integrins coordinate spatial signaling to achieve polarization lamellae formation directed cell migration and ultimately invasion. By understanding leading edge dynamics of invading cells better methods of therapeutically targeting the early steps in metastasis will be achievable.


application_id: 8295636
project_number: 2R01HL056652-14A1
project_title: Molecular Mechanism of Platelet Exocytosis
administering_ic: NHLBI
award_notice_date: 2012-02-29
opportunity_number: PA-10-067
application_type: 2
activity_code: R01
ic: HL
serial_number: 056652
suffix: A1
program_official: SARKAR, RITA
project_start_date: 1996-07-01
project_end_date: 2016-03-31
study_section: Hemostasis and Thrombosis Study Section. Committee was terminated on 11/30/2020. [HT]
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Platelets are central to hemostasis because they respond to vascular damage and secrete a variety of granule cargo molecules which are critical to thrombosis and its normal as well as pathogenic sequellae. This property makes platelets a target for modulation of hemostasis but it also raises questions about how these anucleated cell fragments function. Are platelets an active participant specifically releasing context-appropriate material or are they random delivery devises? The overall goal of this proposal is to understand the process of platelet secretion at the cellular and molecular level. The first Aim addresses one of the most important questions facing the field. Is platelet secretion thematically responsive? The experiments in Aim 1 will characterize the heterogeneity in cargo release from activated platelets. The goal is to determine if platelet secretion is thematic stochastic or controlled kinetically. Micro-ELISA assays will be used to measure the secretion of several released molecules and detailed mathematical analysis of the release kinetics will be used to identify patterns. The second Aim seeks to dissect a novel signaling cascade that directly controls platelet secretion. The goal is to identify the signaling pathways that activate IkB Kinase to phosphorylate SNAP-23 and to determine how the modification affects platelet secretion. This Aim focuses on the role that IkB Kinase (IKK) plays in regulating platelet secretion by probing both how the kinase is activated and how SNAP-23 phosphorylation affects platelet secretion. Additional studies will determine if IKK inhibitors can be used as anti-thrombotic agents. The final Aim focuses on the mechanism of a limiting element of the platelet secretory machinery Munc13-4. The goal will be to define the mechanism by which Munc13-4 mediates platelet secretion. The experiments in this Aim will characterize the molecular mechanisms of Munc13-4 by probing its interactions and their roles in secretion. Since Munc13-4 is a limiting factor in platelets and is required for normal hemostasis it is an attractive target for therapeutic intervention. The experiments in the final Aim will yield the detailed molecular characterization required for such targeting. In sum the data gained for the proposed experiments will illuminate the process of platelet secretion and thus set the constraints for future models of platelet function in the vasculature. The experiments will also identify aspects of the secretory machinery that can be exploited for therapeutic intervention to modulate thrombosis. Cardiovascular disease is the #1 cause of death in the US and is estimated to cost $500 billion in medical expenses and lost productivity in 2010 (AHA Fact Sheet). These staggering statistics underline the need for new therapeutic agents designed to ameliorate the pathologies associated with platelet dysfunction. The insights gained from the proposed experiments and their potential for identifying novel targets will clearly benefit the search for such agents.     
   
PUBLIC HEALTH RELEVANCE:  Strokes and heart attacks are major killers in the United States and both are caused by a loss of blood flow usually because a blood clot has formed in the wrong place. This application focuses on how platelets release molecules that cause clot formation. This work is critical because it will direct the development of future drugs needed to decrease the risk of spurious clot formation.

project_terms:
Address;Adhesions;Affect;Agonist;Atherosclerosis;Attenuated;Basic Science;Biochemical;Biochemistry;Biological Assay;Blood Clot;Blood Platelets;Blood Vessels;Blood coagulation;Blood flow;Cardiovascular Diseases;Cause of Death;Cell membrane;Cells;Cellular biology;Cessation of life;Clinical;Coagulation Process;Complex;Cytoplasmic Granules;Data;Defect;Development;Disease;Docking;Elements;Enzyme-Linked Immunosorbent Assay;Event;Exocytosis;Functional disorder;Future;Goals;Hemorrhage;Hemostatic function;Heterogeneity;In Vitro;Inflammation;Integral Membrane Protein;Kinetics;Knockout Mice;Knowledge;Lead;Learning;Measures;Mediating;Medical;Membrane Fusion;Modeling;Modification;Molecular;Monitor;Mus;Myocardial Infarction;Participant;Pathology;Pathway interactions;Pattern;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Physicians;Platelet Activation;Play;Process;Productivity;Property;Publishing;Reaction;Risk;Role;S-nitro-N-acetylpenicillamine;SNAP receptor;Signal Pathway;Signal Transduction;Site;Sum;System;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Thrombosis;Time;United States;Work;Wound Healing;angiogenesis;base;cohort;cost;design;disability;enhancing factor;in vivo;insight;kinase inhibitor;neurotransmitter release;novel;novel therapeutics;outcome forecast;protein protein interaction;research study;response;statistics;stroke;target SNARE proteins;therapeutic target;wound


application_id: 8295633
project_number: 1R01HL107326-01A1
project_title: Sex Differences in Angiotensin-Induced Vascular Diseases
administering_ic: NHLBI
award_notice_date: 2012-03-21
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: HL
serial_number: 107326
suffix: A1
program_official: VARAGIC, JASMINA
project_start_date: 2012-03-21
project_end_date: 2016-02-29
study_section: Special Emphasis Panel[ZRG1 VH-D (90)]
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Abdominal aortic aneurysms (AAAs) are a common life-threatening disorder with no therapeutic strategies that effectively blunt growth and progression of the disease. Male sex is a strong risk factor for AAAs. Similarly AAAs induced by infusion of angiotensin II (AngII) exhibit marked sexual dimorphism with a 4-fold higher prevalence in male compared to female mice. Previous results demonstrated that testosterone exhibits region-specific regulation of angiotensin type 1a receptor (AT1aR) expression in abdominal aortas to promote AngII-induced AAAs. We also demonstrated that exposures of neonatal females to testosterone induced permanent increases in adult susceptibility to AAAs. This model of female androgenization which mimics surges in testosterone shortly after birth in males resulted in increased AT1aR expression in abdominal aortas and markedly enhanced AAA susceptibility of adult females. Since males require continued testosterone exposures to exhibit high AAA susceptibility our results demonstrate that males and females respond differently to testosterone during development. We propose that sex hormones as well as sex chromosomes mediate sexual dimorphism of AngII-induced AAAs. The central hypothesis of this proposal is that testosterone effects (developmental and/or adult) at pivotal cell types in addition to sex chromosome effects promote region- specific increases in aortic AT1aR expression and AngII-induced AAAs. Aim 1 will define the cell-specific role of androgen receptors in developmental and/or adult effects of testosterone on abdominal aortic AT1aR expression and AngII-induced AAAs. Aim 2 will define the relative contribution of sex hormones versus sex chromosomes in developmental and/or adult effects of testosterone on abdominal aortic AT1aR expression and AngII-induced AAAs. In both aims approaches will include studies designed to quantify effects on AAA formation versus progression. In addition to identifying mechanisms for sexual dimorphism of AngII-induced AAAs results from these studies may identify targets amenable to therapy that either protect (females) or augment (males) AAA susceptibility.   
   
PUBLIC HEALTH RELEVANCE: The proposed research will define mechanisms for sex differences in susceptibility to abdominal aortic aneurysms (AAAs). A unique and relevant aspect of these studies is a focus on effects of male sex hormone exposures during development as a mediator of greater susceptibility to AAAs in adult males. This shift in focus to development may identify novel interventions early in life that can prevent or decrease vascular disease in aging males and females. In addition these are the first studies to define the role of sex chromosomes as mediators of the pronounced sexual dimorphism in AAA formation and/or progression.

project_terms:
Abdomen;Abdominal Aortic Aneurysm;Adult;Affect;Aging;Androgen Receptor;Androgenization;Angiotensin II;Angiotensin Type 1a Receptor;Angiotensins;Aorta;Aortic Aneurysm;Apolipoprotein E;Atherosclerosis;Birth;Blood Pressure;Blood Vessels;Cardiovascular system;Cells;Cessation of life;Chromosomes;Development;Disease;Disease Progression;Dose;Early treatment;Embryo;Employee Strikes;Exhibits;Exposure to;Female;Genes;Genotype;Goals;Gonadal Steroid Hormones;Growth;High Prevalence;Infusion procedures;Life;Low-Density Lipoproteins;Medial;Mediating;Mediator of activation protein;Mesoderm;Mesoderm Cell;Messenger RNA;Modeling;Mus;Neonatal;Operative Surgical Procedures;Pathology;Predisposition;Prevalence;Regulation;Relative (related person);Research;Research Design;Risk Factors;Role;Rupture;Sex Characteristics;Sex Chromosomes;Site;Smooth Muscle Myocytes;Smooth muscle (tissue);Testing;Testosterone;Therapeutic;Thoracic aorta;Vascular Diseases;abdominal aorta;aged;base;blastomere structure;cell type;effective therapy;human disease;interest;male;mouse model;neonatal exposure;novel;prevent;receptor expression;response;sex;sexual dimorphism


application_id: 8294972
project_number: 5R01AI078756-06
project_title: IFN-gamma production by microglia for prevention of toxoplasmic encephalitis
administering_ic: NIAID
award_notice_date: 2012-05-21
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: 2015-06-30
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_abstract:
DESCRIPTION (provided by applicant): Reactivation of chronic Toxoplasma gondii infection in the brains of immunocompromised individuals results in the development of life-threatening toxoplasmic encephalitis (TE). To improve prevention and management of TE it is important to understand the immunopathogenesis of the disease. The murine models of TE that we developed provide an excellent opportunity to critically analyze the mechanisms of host defense in the brain. It is well documented that T cells recruited into the brain are an essential source of IFN-3 for prevention of TE. However it is not known how the host defense functions during the early stage of reactivation of infection before large numbers of T cells enter the brain. This early defense system could be crucial for limiting tachyzoite growth and initiating T cell immunity to prevent TE. We recently found that microglia which are resident macrophages in the brain parenchyma produce IFN-3 during the early stage of reactivation. Our studies also suggest that production of IFN-3 by brain-specific cells in addition to T cells is required for prevention of TE. Therefore IFN-3 production by microglia appears to be a novel early defense mechanism essential for prevention of the disease. The specific aims in this proposal are designed to define the role of IFN-3 produced by microglia in inhibition of tachyzoites growth induction of T cell immunity and prevention of TE. In the first aim we will examine the inhibitory effects of IFN-3 produced by microglia on tachyzoite proliferation in the brain after reactivation of infection using mice that have IFN-3 production only by microglia. The second aim is to determine if IFN-3 production by microglia induces expression of mediators that recruit T cells into the brain. We will examine whether IFN-3 production by microglia induces expression of chemokines in brain cells and adhesion molecules on cerebrovascular endothelial cells. We will then use in vivo T cell migration assays to determine whether IFN-3 production by microglia facilitates infiltration of immune T cells into the brain. The third aim is to determine if IFN-3 production by microglia induces expression of MHC molecules for activation of T cells in the brain. In the fourth aim we will determine the requirement of IFN-3 production by microglia and T cells for prevention of TE. For this purpose we will purify immune T cells from infected wild-type or IFN-3-deficient mice and transfer these T cells into infected mice that express IFN-3 only by microglia or lack expression of this cytokine. Host mice will be followed for development of TE. We will also examine the role of IFN-3-dependent mediators of T cell recruitment determined in Specific Aim 2 for prevention of TE. The studies in these four specific aims will provide novel and crucial information that allows us to understand how IFN-3-production by microglia enables the host defense system in the brain to prevent TE. PUBLIC HEALTH RELEVANCE Reactivation of chronic Toxoplasma gondii infection in the brains of immunocompromised individuals results in the development of life-threatening toxoplasmic encephalitis (TE). The proposed studies are to analyze how brain cells (microglia) inhibit parasite growth and induce the immune responses to prevent TE. This information will contribute to better understanding of the immunopathogenesis of TE and to improved prevention and management of the disease.

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;Health;Host Defense;Host Defense Mechanism;Immune;Immune response;Immunity;Immunocompromised Host;Individual;Infection;Infiltration;Interferon Type II;Interferons;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 response;T-Cell Activation;T-Lymphocyte;Toxoplasma gondii;Toxoplasmosis;brain cell;cerebrovascular;chemokine;cytokine;design;disorder prevention;immune activation;improved;in vivo;macrophage;novel;prevent;response


application_id: 8294586
project_number: 5R03DA033175-02
project_title: Identification of substances that change alternative pre-mRNA splicing of the ser
administering_ic: NIDA
award_notice_date: 2012-06-14
opportunity_number: PAR-09-129
application_type: 5
activity_code: R03
ic: DA
serial_number: 033175
program_official: PUROHIT, VISHNUDUTT
project_start_date: 2011-07-01
project_end_date: 2013-06-30
study_section: Special Emphasis Panel[ZRG1-BST-F(50)]
contact_pi_person_id: 8899488
contact_pi: STAMM, STEFAN
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): Identification of substances that change alternative pre-mRNA splicing of the serotonin 2C receptor the serotonin receptor 2C (5-HT2CR) protein is a validated anti-obesity drug target that binds to the anorectic substances fen-phen (fenfluramine and phentermin). Due to their cross-reactivity with other receptors these drugs are no longer in use.  The activity of the 5-HT2CR protein is regulated by alternative processing pathways of its pre- mRNA. Only when the alternative exon Vb is included in the mRNA a functional receptor can be formed. This inclusion can be achieved by two mechanisms: (i) RNA editing which generates less active receptors and (ii) promotion by specific small nuclear RNAs which generates the most active receptors. Patients with Prader-Willi syndrome do not express the small nuclear RNAs which most likely contributes to their obesity.  We propose to identify compounds that promote inclusion of the alternative exon Vb without a change on RNA editing. This change in pre-mRNA processing will generate the most active 5-HT2CR protein that is likely to exert an anti-appetite effect.  We generated cell lines containing a fluorescent-based splicing reporter construct. These cell lines were successfully validated in a pilot screen using a library of 1692 compounds. The screen was robust (Z factor 6.1) and resulted in one compound pyrvinium pamoate that showed an IC50 of 65M in established secondary and tertiary PCR-based screens.  Our preliminary analysis of pyrvinium pamoate and small nuclear RNAs acting on serotonin pre-mRNA processing suggests that exon Vb functions similar to a bacterial riboswitch. A conformational change triggered by low molecular weight compounds causes a change in its structure that allows its splice site to be recognized leading to its inclusion.  To gain insight into structure activity relationships we therefore further propose to test the influence of pyrvinium pamoate and other validated hits on serotonin receptor 2C pre-mRNA structure. In addition to conventional structure probing experiments we will use RNA oligonucleotides with modified bases that reflect an alteration in structure by a change in fluorescence the selective modification of the processing pathways of a structured pre-mRNA has not been attempted yet and is the major innovation of the proposal. The identification of compounds that promote the activity of the serotonin receptor 2C by changing its pre-mRNA processing would be highly significant as they are expected to have anti-appetite properties. Identifying a compound that combats obesity would have a major therapeutic impact and the possible identification of the first mammalian riboswitch will have a strong scientific impact.

project_terms:
Adult;Adverse effects;Affect;Agonist;Alternative Splicing;American;Amino Acids;Anti-Obesity Agents;Appetite Depressants;Binding (Molecular Function);Biological Assay;Cell Line;Chemicals;Data;Desire for food;Drug Binding Site;Drug Delivery Systems;Drug Receptors;Eating;Epidemic;Exons;Fenfluramine;Fluorescence;Gene Expression Profile;Health;Hormonal;Human;Hunger;Inhibitory Concentration 50;Intervention;Libraries;Marketing;Messenger RNA;Modeling;Modification;Molecular Bank;Molecular Weight;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oligonucleotides;Outcome;Pathway interactions;Patients;Pharmaceutical Preparations;Population;Prader-Willi Syndrome;Prevalence;Process;Production;Property;Protein Isoforms;Proteins;Public Sector;Pyrvinium pamoate;RNA;RNA Editing;RNA Splicing;Receptor Serotonin 5-HT2C;Regulation;Reporter;Research Personnel;Role;Screening procedure;Serotonin;Site;Small Nuclear RNA;Small Nucleolar RNA;Structure;Structure of nucleus infundibularis hypothalami;Structure-Activity Relationship;Testing;Therapeutic;United States National Institutes of Health;Work;base;combat;cost;cross reactivity;fighting;gene function;high throughput screening;innovation;insight;mRNA Precursor;mouse model;receptor;research study;response;serotonin 5 receptor;serotonin receptor;small molecule

public_health_relevance:
Obesity is a major health problem affecting more than 26% of adult Americans. This project will identify compounds that change the way the body makes the serotonin receptor protein. Since this protein is a major control point of hunger the compounds are expected to decrease appetite which could help fighting the obesity epidemic.


application_id: 8293693
project_number: 2P30AG028383-06
project_title: Neuropathology Core
administering_ic: NIA
opportunity_number: RFA-AG-11-005
application_type: 2
activity_code: P30
ic: AG
serial_number: 028383
project_start_date: 2006-07-15
study_section: Special Emphasis Panel[ZAG1 ZIJ-5 (M2)]
subproject_number: 6077
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-08-01
budget_end_date: 2012-06-30
project_terms:
Address;Aged 80 and over;Aging;Alzheimer's Disease;Autopsy;Biochemical;Biometry;Biostatistics Core;Brain;Brain Diseases;Brain region;Caring;Centenarian;Cerebrospinal Fluid;Cerebrum;Clinical;Clinical Data;Cognition Disorders;Collaborations;Complement;Consensus;Correlation Studies;Correlative Study;Country;Data;Databases;Degenerative Disorder;Dementia;Deposition;Diagnosis;Diagnostic;Disease;Down Syndrome;Elderly;Enrollment;Ensure;Freezing;Frontotemporal Dementia;Genomics;Goals;Hippocampus (Brain);Individual;Institutes;Instruction;Investigation;Kentucky;Lesion;Lewy Body Disease;Life;Measures;Methodology;Methods;Metric;MicroRNAs;Mission;National Institute on Aging;Neurodegenerative Disorders;Neurofibrillary Tangles;Oxidative Stress;Parkinson Disease;Pathology;Patients;Plasma;Preparation;Preventive;Process;Protocols documentation;Relative (related person);Religion and Spirituality;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Sampling;Sclerosis;Senile Plaques;Services;Specimen;Staging;Synapses;Synaptosomes;Syndrome;Therapeutic;Tissue Banking;Tissue Banks;Tissue Sample;Universities;age related;aged;aging brain;amyloid precursor protein processing;brain tissue;cohort;data management;experience;genome wide association study;innovation;meetings;mild cognitive impairment;neuroinflammation;neuropathology;normal aging;pre-clinical;symposium;tau Proteins;tool


application_id: 8293393
project_number: 5R01DK081324-05
project_title: An Intergenerational CBPR Intervention to Reduce Appalachian Health Disparities
administering_ic: NIDDK
award_notice_date: 2012-06-29
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: 2014-06-30
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_abstract:
DESCRIPTION (provided by applicant): Appalachian communities are disproportionately affected by the leading causes of morbidity and mortality. Specifically cancer and diabetes mortality rates are 17 percent and 33 percent above national rates. The Appalachian region also has the nation's highest cardiovascular death rates with 328.9 to 405.9 deaths per 100000 population. A leading risk factor implicated in all of these health disparities is problematic energy balance; BRFSS data indicate that only 22 percent of Appalachian Kentuckians receive the RDI for fruit and vegetable intake between 62-76 percent are overweight or obese and between 45-62 percent report sedentary lives. Nationally Kentucky ranks third in not meeting fruit and vegetable intake #3 in overweight #9 in obesity and #3 for sedentary behavior. Of particularly elevated concern the obesity rate has doubled since 1990 and Kentucky youth rank #1 in overweight and significantly lower than their national counterparts in fruit/vegetable intake and physical activity. Despite the pervasiveness of these risk factors and disease burdens Appalachian culture contains many characteristics and structures that offer locally based solutions including strong intergenerational ties faith-based activism and healthy traditional activities. Drawing on epidemiologic evidence and informed by our current successful faith-based trained lay health advisor tailored intervention (R01CA108696) we propose to administer and evaluate an intergenerational culturally appropriate CBPR energy balance intervention that has the potential of greatly preventing and reducing cancer CVD and diabetes morbidity and mortality by increasing fruit and vegetable intake lowering BMI and increasing physical activity. Working in partnership with 70 faith-based institutions in Appalachian Kentucky the proposed project has three phases: Phase I (Developmental phase) will use ethnographic methods (socio-ecological inventories key informant interviews participant observation) to assess the barriers to and facilitators of healthy diet weight and physical activity; develop culturally appropriate instruments; and modify existing interventions (Healthy Body/ Healthy Spirit and We Can!) to be responsive to local culture. During Phase II we will administer the group randomized staggered CBPR intervention based on Healthy Body/ Healthy Spirit and NHLBI's We Can! Theoretically informed by the SCT TTM and socio-ecological determinants of health the intervention will include culturally appropriate workshops (with locally relevant activities like square dance community gardening story telling and cooking classes) tailored lay health adviser visits and motivational interviewing. Throughout the project the RE-AIM model will inform our evaluation. During Phase III we will undertake qualitative process evaluation interviews and evaluate consistency with CBPR principles. PUBLIC HEALTH RELEVANCE: Rural Appalachian communities suffer some of the highest rates of the most common causes of death; cancer heart disease and diabetes. These conditions are strongly associated with being overweight and having a substandard diet and inadequate physical activity risk factors that are pervasive in Appalachia. The proposed project works in partnership with 70 faith-based institutions in Appalachian Kentucky to develop administer and evaluate an intergenerational intervention that uses culturally appropriate activities and workshops to reduce overweight and increase physical activity and fruit and vegetable intake.

project_terms:
Affect;Appalachian Region;Applied Research;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;Epidemiology;Equipment and supply inventories;Evaluation;Exercise;Goals;Health;Health care facility;Heart Diseases;Institution;Intake;Intervention;Interview;Kentucky;Linguistics;Malignant Neoplasms;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Nutritionist;Obesity;Overweight;Participant;Phase;Physical activity;Population;Process;Protocols documentation;Psychologist;Questionnaires;Randomized;Regimen;Reporting;Research;Research Personnel;Research Project Grants;Risk Factors;Rural;Solutions;Structure;Testing;Training;Translational Research;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;sedentary


application_id: 8292166
project_number: 5F31CA142317-04
project_title: Functional conversion of tumor associated macrophages via cytokine therapy
administering_ic: NCI
award_notice_date: 2012-07-18
opportunity_number: PA-07-106
application_type: 5
activity_code: F31
ic: CA
serial_number: 142317
program_official: MCNEIL FORD, NICOLE
project_start_date: 2009-07-10
project_end_date: 2014-07-09
study_section: Special Emphasis Panel[ZRG1-SBIB-V(29)L]
contact_pi_person_id: 9679618
contact_pi: MITCHELL, COURTNEY JETUN
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Breast cancer is the leading cancer diagnosis in women and second most common cause of women cancer deaths. Although mortality has decreased and incidence has remained steady persons diagnosed with late Stage disease have dismal survival rates. Hence the need for therapies with the ability to prevent cancer altogether. The objective of this project is to determine if IL-12 induced functional conversion of tumor associated macrophages from anti-inflammatory and tumor supportive to pro-immunogenic and anti- tumorigenic can be extended for therapeutic exploitation. The mice 4T1 mammary carcinoma with lung metastases model will be employed to accomplish the objective and achieve the specific aims of this project. Specific aim 1 will examine the immune cells and cytokines that contribute to the maintenance of the IL-12 induced pro-immunogenic functional conversion of the macrophages. Two approaches will be used in this aim. First the IL-12 response of scid mice which are T and B cell deficient will be compared with NK depleted scid mice. Secondly the role of IL-18 and IFN-y in the maintenance of the IL-12 induced conversion will be assessed by neutralizing these cytokines with anti-IFN-y or anti-IL-18. In specific aim 2 the ability of IL-15 and IL-18 to extend the pro-immunogenic status of tumor associated macrophages will be examined by injecting mice bearing 4T1 tumors with the encapsulated IL-12 alone and then injecting the mice subcutaneously with encapsulated IL-15 or IL-18 one to four days later. Specific aim 3 will determine if the extension of the IL-12 induced pro-immunogenic window enhances the efficacy of a tumor-dendritic cell vaccine via immunization of 4T1 bearing mice with a 4T1-dendritic cell fusion vaccine in combination with encapsulated buffer or encapsulated IL-12 alone or in combination with other cytokines as determined by specific aim 2. Analysis for each of our aims will include q-rt-PCR for various anti-inflammatory and tumor supportive as well as pro-immunogenic and anti-tumorigenc factors ELISA for serum IFN-gamma measurement of cytoplasmic levels of IFN-gamma perforin and granzyme B perfusion assisted weight and volume measurements for the primary tumor perfusion assisted quantification of lung metastases and anti- IFN-gamma and CD71 labeling for measurement of number of infiltrating leukocytes. By exploring the effects of IL-12 on tumor associated macrophages we may gain a better understanding of how cytokines and macrophages interact for tumor maintenance and progression.   PUBLIC HEALTH RELEVANCE: This project will benefit public health by providing new information regarding potential cancer immunotherapy including including preventative vaccines for breast cancer.

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


application_id: 8292161
project_number: 5R01HL094419-04
project_title: O-GlcNAc Signaling in Heart Failure
administering_ic: NHLBI
award_notice_date: 2012-06-21
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 094419
program_official: WONG, RENEE P
project_start_date: 2009-08-01
project_end_date: 2013-06-30
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cardiac hypertrophy arises from multiple often idiopathic origins. Pressure overload induces cardiomyocyte hypertrophy and eventually can lead to heart failure. The induction of pathologic hypertrophy involves the transcriptional reprogramming of metabolic machinery. Thus hypertrophy involves a metabolic disturbance leading to cardiac dysfunction. Glucose represents the quintessential substrate for metabolism albeit to a limited extent in the heart. Less than 5% of intracellular glucose is shunted to accessory pathways such as Hexosamine Biosynthetic Pathway which forms the monosaccharide donor for the post-translational modification known as O-linked-2-N- acetylglucosamine (O-GlcNAc). Many of the signaling pathways involved with the development of cardiac hypertrophy particularly during the transition to failure have been elegantly elucidated by other laboratories. The present proposal will unravel the contribution of O-GlcNAc signaling to the development of hypertrophy in addition to understanding a potential role in pressure overload-induced heart failure. PGC-11 is recognized as a regulator of metabolism and its loss can aggravate pressure overload- induced heart failure. Nothing is currently known about the relationship between O-GlcNAc signaling and PGC-11 during the development of hypertrophy and heart failure. One goal of the present study is to investigate the mechanisms through which O-GlcNAc signaling participates in myocyte response to hypertrophy by focusing on the transcriptional activity of PGC-11. This proposal will identify the role O-GlcNAc signaling in the development of cardiomyocyte hypertrophy and heart failure by: 1) Determining what changes occur in O-GlcNAc signaling in the myocardium during hypertrophy. 2) Ascertaining whether O-GlcNAc signaling is essential during hypertrophy. 3) Identifying the influence of O-GlcNAc signaling on PGC-11 during hypertrophy. 4) Elucidating the impact of altered O-GlcNAc signaling at the mitochondrial level during hypertrophy. The PI's hypothesis is that O-GlcNAc signaling is augmented during the development of hypertrophy and such augmentation of is maladaptive. Furthermore the PI posits that O-GlcNAc signaling suppresses PGC-11 and such changes are instrumental in the development of the hypertrophied and failing phenotypes. Findings from such mechanistic studies will provide novel insights into the pathophysiologic mechanisms operative during the development of hypertrophy and in the failing myocardium. PUBLIC HEALTH RELEVANCE: One limiting factor in identifying more efficacious treatments for heart failure is our lack of understanding of the initiation and progression of the disease particularly as it relates to metabolic signaling. The present series of studies will provide keen insights into mechanisms of cardiac growth metabolism and the development of pressure overload induced hypertrophy which will lay the groundwork for the creation of new therapeutics.

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

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


application_id: 8292037
project_number: 5R03AR061561-02
project_title: Sensory-Targeted Ankle Rehabilitation Strategies (STARS)
administering_ic: NIAMS
award_notice_date: 2012-04-09
opportunity_number: PAR-09-031
application_type: 5
activity_code: R03
ic: AR
serial_number: 061561
program_official: PANAGIS, JAMES S
project_start_date: 2011-07-01
project_end_date: 2013-06-30
study_section: ZAR1-EHB(M1)
contact_pi_person_id: 9341091
contact_pi: MCKEON, PATRICK OWEN
other_pis: WIKSTROM, ERIK A
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): Injury associated with sport and recreation is a leading reason for physical activity cessation which is linked with significant long-term negative sequelae. Ankle sprains are the most common injuries associated with physical activity and at least 1 out of every 3 individuals who sprain their ankle will go on to develop chronic ankle instability (CAI) defined by life-long residual symptoms including decreased physical activity. Traditional rehabilitation strategies for CAI have focus on motor impairments but the high incidence of disability post- traumatic ankle osteoarthritis and consequent healthcare burdens clearly indicate that this treatment model is ineffective. Thus a pressing need exists for a paradigm shift in the development of effective evidenced-based interventions to treat CAI. To date little attention has been paid to the potential to improve function by intervening through sensory pathways. Research has shown that the sensorimotor system shifts reliance on various sensory inputs depending on the demands placed on the system. Those with CAI place a greater emphasis on cutaneous and musculotendinous receptors due to damage of the lateral ankle joint receptors. However by using sensory-targeted ankle rehabilitation strategies such as ankle joint mobilizations plantar massage and triceps surae stretching we hypothesize that we can enhance the information available to the sensorimotor system in order to tune effective movement solutions. Indeed our evidence suggests that sensory-targeted strategies may be essential to most effectively treating those with CAI. Therefore the purpose of this proposal is to determine the effectiveness of sensory-targeted ankle rehabilitation strategies at causing immediate and prolonged improvements in subjective and objective outcome measures of clinical disablement and sensorimotor dysfunction in those with CAI. This preliminary investigation will be a randomized controlled trial in which 80 subjects with CAI will be randomly assigned to receive one of three experimental interventions (mobilization massage stretch) or a control treatment. To evaluate the effects of the experimental treatments the following baseline measures will be taken: 1) self-assessed disability 2) ankle dorsiflexion range of motion and 3) sensorimotor function via measures of postural control and gait initiation. Subjects will then be randomly assigned to receive ankle mobilization (n=20) plantar massage (n=20) triceps surae stretching (n=20) or a control treatment (n=20). Follow up measures will be taken immediately after the first and final treatment of a two-week intervention as well as 1-month after receiving the treatment intervention. For this investigation separate MANOVAs will assess the effects of treatment (mobilization massage stretch control) and time (baseline post 1st treatment post final treatment 1-month follow-up) on subjective and objective measures of clinical disablement and sensorimotor function in those with CAI. The results of this randomized controlled study will elucidate the effectiveness of sensory-targeted ankle rehabilitation strategies at improving sensorimotor function and disability in those with CAI.

project_terms:
Activities of Daily Living;Aftercare;Ankle;Articular Range of Motion;Attention;Chronic;Clinical;Cutaneous;Data;Degenerative polyarthritis;Development;Effectiveness;Equilibrium;Evaluation;Evidence based intervention;Foundations;Functional disorder;Gait;Goals;Health;Healthcare;Impairment;Incidence;Individual;Injury;Intervention;Investigation;Lateral;Life;Link;Lower Extremity;Massage;Measures;Modeling;Motor Pathways;Motor output;Movement;Musculoskeletal Equilibrium;Outcome;Outcome Measure;Pathway interactions;Patient Self-Report;Patients;Physical activity;Quality of life;Randomized;Randomized Controlled Trials;Recreation;Recurrence;Regulation;Reliance;Research;Research Proposals;Residual state;Sensorimotor functions;Sensory;Solutions;Source;Sports;Sprain;Stretching;Symptoms;System;Testing;Time;Triceps brachii muscle structure;Weight-Bearing state;ankle joint;base;coping;cost;disability;effective therapy;experience;follow-up;foot;improved;improved functioning;innovation;joint mobilization;motor impairment;novel strategies;pressure;public health medicine (field);receptor;rehabilitation strategy;sensorimotor system;treatment effect

public_health_relevance:
: Ankle sprains are the most common injury experienced by those who are physically active and recurrent disability associated with these injuries is extremely common. In this study we aim to determine the benefits of sensory-targeted ankle rehabilitation strategies on subjective and objective outcomes of clinical disablement and sensorimotor function in those with chronic ankle instability. By developing new sensory-targeted strategies for this pervasive condition we hope to optimize treatment efficiency and quality for patients with chronic ankle instability and subsequently reduce their associated long-term negative sequelae and disability.


application_id: 8291893
project_number: 5R01CA116812-06
project_title: Lung extracellular matrix and tumor progression
administering_ic: NCI
award_notice_date: 2012-05-22
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 116812
program_official: JHAPPAN, CHAMELLI
project_start_date: 2008-07-02
project_end_date: 2014-05-31
study_section: Special Emphasis Panel[ZRG1-RES-B(02)M]
contact_pi_person_id: 1876531
contact_pi: ROMAN, JESSE
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This project will investigate the signaling mechanisms that control non-small cell lung carcinoma (NSCLC) cell growth and resistance to therapy and will explore the anti- cancer effects of novel strategies designed to modulate these signals. It addresses this area by focusing on the growth promoting signaling mechanisms triggered in NSCLC by aberrant extracellular matrices deposited in the lung. It is generally well-accepted that tumor cells interact with their surrounding matrix and that this and related host factors contribute to carcinoma development and progression. Unfortunately this idea has not translated into clinically useful strategies for the management of lung cancer. This project will test the hypothesis that host cell- and tumor cell-derived fibronectin a matrix molecule highly expressed in tobacco-related lung disease is an important factor that stimulates NSCLC cell growth and survival through signals related to the mTOR pathway that are elicited by activation of the integrin a51. This hypothesis is supported by our own work showing that exposure to tobacco-related products stimulates fibronectin expression in lung fibroblasts both in vitro and in vivo and that fibronectin stimulates the growth of NSCLC by triggering a51 integrin receptor-mediated signals that appear mediated via mTOR. Fibronectin also inhibits NSCLC apoptosis induced by chemotherapeutic agents. Interestingly the relative expression of fibronectin isoforms seems to play a role in tumor proliferation. Finally we have generated data in vivo showing that strategies able to affect fibronectin expression or recognition and mTOR signaling inhibit tumor progression. These data suggest that an "altered" lung matrix characterized by a relative increase in fibronectin content stimulates NSCLC proliferation. This hypothesis will be tested in specific aims designed to: 1) determine the role of Akt/mTOR/S6K1 related pathways in fibronectin-induced proliferation/survival and chemotherapy-induced apoptosis of NSCLC and 2) examine the role of fibronectin 1521 and the Akt/TOR/S6K1 pathway in NSCLC using the K-ras and Lewis Lung Carcinoma models of lung cancer. Project Narrative: This project will investigate how alterations in the connective tissue matrix of the lung promotes lung cancer progression and how agents that affect the lung matrix may inhibit this process.

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


application_id: 8290842
project_number: 1R15ES020053-01A1
project_title: Genetic Susceptibility to PCB-induced Motor Dysfunction
administering_ic: NIEHS
award_notice_date: 2012-05-25
opportunity_number: PA-10-070
application_type: 1
activity_code: R15
ic: ES
serial_number: 020053
suffix: A1
program_official: HOLLANDER, JONATHAN
project_start_date: 2012-06-01
project_end_date: 2017-05-31
study_section: Special Emphasis Panel[ZRG1 MDCN-E (96)]
contact_pi_person_id: 8110072
contact_pi: CURRAN, CHRISTINE PERDAN
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
project_abstract:
DESCRIPTION (provided by applicant): Polychlorinated biphenyls (PCBs) are persistent organic pollutants that bio-accumulate in the food supply and resist environmental degradation. Studies of human populations near the most polluted sites have found learning memory and motor impairments in children exposed during pregnancy and breast-feeding. Animal studies show that PCBs significantly alter dopamine concentrations in the brain and that toxicity may be mediated through the ryanodine receptor. Recent evidence suggests PCB exposures may increase the risk of Parkinson's Disease; [however PCBs also have significant effects on cerebellar development and function.] Not all exposed individuals experience the same level of adverse health effects indicating that genetic differences affect risk. Our previous studies in mice identified two genes that affect susceptibility to PCB-induced developmental neurotoxicity: the aryl hydrocarbon receptor (AHR) and cytochrome P450 1A2 (CYP1A2). AhrbCyp1a2(-/-) mice with a high-affinity AHR and lacking CYP1A2 showed deficits in spatial and non-spatial learning and memory following developmental PCB exposure while AhrbCyp1a2(+/+) mice were resistant. Our [published and new] preliminary data show motor deficits and [learning and memory deficits that vary by sex and genotype using a mixture of congeners with little to no activity toward the ryanodine receptor. Therefore we hypothesize that [additional pathways contribute to PCB developmental neurotoxicity in addition to toxicity mediated by the ryanodine receptor. To test this hypothesis we will use these three lines of mice to: 1.) Compare motor function in PCB-exposed offspring and corn oil-treated controls 2.) Assess gene expression changes and crosstalk in pathways associated with motor function. 3.) Quantify protein levels in brain regions essential to normal motor function.]   
   
PUBLIC HEALTH RELEVANCE: Significance: Polychlorinated biphenyls are persistent organic pollutants that are neurotoxic to the developing brain. Genetic differences can affect an individual's risk of adverse health effects from environmental toxicants. The proposed research is designed to identify neural pathways affected by PCB exposure and humans at highest risk of PCB developmental neurotoxicity using a mouse model that mirrors known genetic variations in humans.

project_terms:
Adult;Affect;Affinity;Age;Animals;Aromatic Polycyclic Hydrocarbons;Aryl Hydrocarbon Receptor;Binding (Molecular Function);Brain;Brain region;Breast Feeding;Child;Corn Oil;Corpus striatum structure;Cytochrome P-450 CYP1A2;Data;Development;Dioxins;Dopamine;Enzymes;Female;Food Supply;Functional disorder;Gene Expression;Generations;Genes;Genetic;Genetic Predisposition to Disease;Genetic Transcription;Genotype;Goals;Health;Human;Individual;Intervention;Knowledge;Lead;Learning;Ligand Binding;Ligands;Link;Mediating;Memory;Memory impairment;Motor;Mus;Neural Pathways;Neuraxis;Parkinson Disease;Pathway interactions;Play;Polychlorinated Biphenyls;Predisposition;Pregnancy;Production;Promotor (Genetics);Proteins;Publishing;Receptor Activation;Research;Resistance;Risk;Rodent;Role;Ryanodine Receptor Calcium Release Channel;Site;Testing;Tetrachlorodibenzodioxin;Toxic Environmental Substances;Toxic effect;Tyrosine 3-Monooxygenase;Variant;Variation (Genetics);Work;activating transcription factor;aryl hydrocarbon receptor ligand;cell motility;design;developmental neurotoxicity;direct application;experience;exposed human population;granule cell;high risk;human population study;motor deficit;motor impairment;motor learning;mouse model;nervous system development;neurotoxic;neurotoxicity;nigrostriatal pathway;novel;offspring;pollutant;public health medicine (field);response;sex

public_health_relevance:
Significance: Polychlorinated biphenyls are persistent organic pollutants that are neurotoxic to the developing brain. Genetic differences can affect an individual's risk of adverse health effects from environmental toxicants. The proposed research is designed to identify neural pathways affected by PCB exposure and humans at highest risk of PCB developmental neurotoxicity using a mouse model that mirrors known genetic variations in humans.


application_id: 8290765
project_number: 1R15GM101604-01
project_title: Transition metal catalyzed construction of ring systems
administering_ic: NIGMS
award_notice_date: 2012-05-28
opportunity_number: PA-10-070
application_type: 1
activity_code: R15
ic: GM
serial_number: 101604
program_official: LEES, ROBERT G
project_start_date: 2012-06-01
project_end_date: 2016-11-30
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 1979376
contact_pi: HAMMOND, GERALD B
other_pis: Not Applicable
congressional_district: 03
department: CHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Quick and efficient access to diverse classes of biologically active lead compounds is an essential part of drug discovery. Heterocycles of different ring sizes and with different substitution patterns constitute extremely important structure classes (e.g. alkaloids) in the search for bioactivity. A contemporary challenge in organic synthesis is the mapping of new chemical spaces through tandem or cascade reactions in an atom economical fashion. Our strategy to access these biologically important heterocycles relies on a cyclization-triggered tandem addition to alkynes catalyzed by readily available alkynophilic coinage metals like copper through an electrophilic activation of the enamine intermediate. Our tandem chemistry will enable us to generate biologically important N-heterocycles like cyclic aminoacids with a facility unmatched by previous methods. During our preliminary work we synthesized various nitrogen heterocycles through an amination/alkynylation sequence and a tandem amination/cyanation in near quantitative yields all in one pot. Our research plan will expand the scope of this strategy substantially. The major part of this proposal focuses on exploring the chemical space of these versatile tandem transformations by changing the components of the transformation and applying them to the synthesis of biologically important heterocycles. We plan to 1) explore nucleophiles in tandem sequences; 2) develop an asymmetrical version; 3) seek alternative roles for transient cyclic enamines. The proposed work is significant for the following reasons: first having a functionalized group on the N-heterocycle will enable further transformations resulting in more complex ring systems (Scheme 1). Second one of the tenets of this proposal--transforming an enamine into a good electrophile--will shed light on the relatively obscure role of enamines as electrophiles. Third beyond bringing about efficient ways to generate N-heterocycles of various ring sizes (5-7) and diverse carbon connectivities (fused bridged spiro) this work will produce scores of new compounds that will be screened by Eli Lilly in their drug discovery program for Alzheimer's disease cancer and diabetes.     
   
PUBLIC HEALTH RELEVANCE: Nitrogen ring system of different ring sizes and with various substitution patterns constitute extremely important structure leads in the search for drug candidates. In this regard alkaloids are representative examples. We have discovered a powerful strategy to access many important N-heterocycles through a cyclization triggered tandem protocol that relies on a transition metal-catalyzed electrophilic activation of the enamine intermediate. The proposed work will furnish single- fused- bridged- or spiro-heterocyclic systems including biologically important unnatural cyclic aminoacids and fluorinated ring systems.

project_terms:
3-hydroxybutanal;Alkaloids;Alkylation;Alkynes;Alzheimer's Disease;Amination;Amines;Amino Acids;Carbon;Chemicals;Chemistry;Complex;Copper;Cyclic Amino Acids;Cyclization;Diabetes Mellitus;Gold;Lead;Ligands;Light;Malignant Neoplasms;Maps;Metals;Methods;Nitrogen;Organic Synthesis;Pattern;Pharmaceutical Chemistry;Process;Protocols documentation;Reaction;Reagent;Research;Role;Scheme;Structure;System;Transition Elements;Work;carbonyl group;catalyst;drug candidate;drug discovery;oxidation;pi bond;programs;stereochemistry

public_health_relevance:
Nitrogen ring system of different ring sizes and with various substitution patterns constitute extremely important structure leads in the search for drug candidates. In this regard alkaloids are representative examples. We have discovered a powerful strategy to access many important N-heterocycles through a cyclization triggered tandem protocol that relies on a transition metal-catalyzed electrophilic activation of the enamine intermediate. The proposed work will furnish single- fused- bridged- or spiro-heterocyclic systems including biologically important unnatural cyclic aminoacids and fluorinated ring systems.


application_id: 8289659
project_number: 5P50DA005312-21
project_title: CORE
administering_ic: NIDA
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
project_end_date: 2012-07-14
study_section: ZDA1
subproject_number: 9001
contact_pi_person_id: 1884463
contact_pi: BARDO, MICHAEL T
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
budget_end_date: 2012-07-14
funding_mechanism: Research Centers
project_abstract:
The current renewal application for the Center for Drug Abuse Research Translation (CDART) consists of acore and four projects that are linked around the central theme that individual differences in personality areimportant predictors of drug abuse vulnerability during adolescence and young adulthood. Previous work inour center and other laboratories has identified sensation seeking as a critical personality constructassociated strongly with drug use especially use of illicit drugs. In the current proposal sensationseekingwill be divided into two separate constructs namely reward seeking and inhibition both of which are thoughtto be associatedwith drug use. In Project 1 (Bardo PI) a laboratory rat model will be used to determine ifindividual differences in reward seeking and inhibition are associated with stimulant drug self-administrationand mesocorticolimbic cellular processes. In Project 2 (Kelly PI) human volunteers will be used to assess ifindividual differences in reward seeking and inhibition are associated with differences in drug self-administration and neural function as measured by fMRI and EEC. In Project 3 (Lynam PI) a cohort ofstudents transitioning from high school to college will be used to determine if individual differences in rewardseeking and inhibition are associated with the initiation escalation and/or cessation of drug use in alongitudinal design. In Project 4 (Zimmerman PI) students will be used in experimental reserch designed toevaluate if individuals who vary in reward seeking and inhibition show a differential response to televisedanti-drug public service announcements. There are three specific aims in the Core: one scientific one organizational and one that involvescontinuing and expanding leadership in translating the prevention science and drug abuse researchcommunities. In relation to the four projects some key functions of the Core are to: (1) provide thematicscientific integration of the different projects around the constructs of reward seeking and inhibition; (2)create synergy across the four proposed projects and other ongoing projects on campus; (3) facilitateinterdisciplinary collaboration among basic and prevention sciences using both neurobehavioral andpsychosocial levels of analysis; and (4) oversee the long-range goal of translating our basic research intopractice by designing more effective anti-drug public service announements that target at-risk young adults.

project_terms:
Adolescence;Advocate;Basic Science;Cell physiology;Commit;Communities;Drug abuse;Drug usage;Educational workshop;Electroencephalography;Environment;Esthesia;Faculty;Functional Magnetic Resonance Imaging;Funding;Goals;Human Resources;Human Volunteers;Illicit Drugs;Individual;Individual Differences;Institution;International;Laboratories;Laboratory Rat;Leadership;Link;Measures;Modeling;National Institute of Drug Abuse;Neurophysiology - biologic function;Personality;Pharmaceutical Preparations;Positioning Attribute;Prevention;Preventive Intervention;Process;Professional Organizations;Publications;Publishing;Research;Research Personnel;Resources;Rewards;Risk;Role;Science;Scientist;Self Administration;Series;Services;Structure;Students;Testing;Training;Translating;Translational Research;Translations;Work;base;cohort;college;design;drug abuse prevention;drug reward;evidence base;high school;implementation science;interdisciplinary collaboration;longitudinal design;neurobehavioral;next generation;outreach;programs;psychologic;psychosocial;relating to nervous system;research study;research to practice;response;social;symposium;trait;young adult


application_id: 8289658
project_number: 5P50DA005312-21
project_title: IMPROVING EFFECTIVE DESIGN AND TARGETING OF SUBSTANCE AUBSE PREVENT MESSAGES
administering_ic: NIDA
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
project_start_date: 2011-07-01
project_end_date: 2012-07-14
study_section: ZDA1
subproject_number: 0014
contact_pi_person_id: 1963601
contact_pi: ZIMMERMAN, RICK S.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
budget_end_date: 2012-07-14
project_abstract:
Interventions to prevent or reduce substance use or abuse among young adults are few and generallynot effective. This is unfortunate as young adults are among the most frequent users of a varietyofsubstances including marijuana alcohol and various illicit substances. Most substance abuse preventiveinterventions have largely ignored biologically-basedpredispositions that lead individuals both to engage inrisky behaviors including substance use and to attend and respond to certain kinds of interventionmessages. This project builds on our previous work using sensation seeking to target and tailor messagesaimed at reducing substance use and risky sexual behavior Specifically building on emerging research fromthe Center wedecompose sensation seeking into its component parts of reward-seeking and inhibition.Drawing on recent advances in message targeting and tailoring we move beyond our previous work onmessage sensation value to include consideration of the influence of message framing and fear on messageeffectiveness. The present proposal offers and tests a general model of message effectivenessthatconsiders the interaction between individual differences (i.e. reward seeking and inhibition) and messagecharacteristics (i.e. message sensation value framing and fear). The model is tested in three studies usingpublic service announcements (PSA) an intervention mode with which our team has extensive experience. There are four specific aims: 1) To examine the persuasive effects of high vs. low sensation value (HSVvs. LSV) substance abuse prevention messages on young adults varying in reward seeking and inhibition;2) To examine the persuasive effects of two emotion-based dimensions of substance abuse messages:message framing (gain vs. loss-framed [GF vs. LF]) and fear (high vs. low threat [HT vs. LT]) on youngadults varying in their levels of reward seeking and inhibition.; 3) To assess the extent to which thedifferential persuasive effects of HSV vs. LSV GF vs. LF and LT vs. HT substance abuse preventionmessages generalize to another high-risk behavior risky sex; and 4) Develop and pilot-test the effectivenessof substance abuse prevention public service announcements (PSAs) with young adults who are either highin reward seeking low in inhibition or both. We propose to accomplish these aims through three studies.The first examines the impact of message sensation value framing and fear on message effectiveness forPSAs aimed at reducing marijuana use as a function of reward seeking and inhibition; the second tests theboundaries of our model using PSAs aimed at reducing risky sexual behavior; the third begins the process ofdesigning optimally effective PSAs based on previous results. Outcomes from the experiments andqualitative studies proposed in this project may be immediately applied to an established body of workboth ours and others in the development of PSAs that are targeted at the reduction of marijuana use.

project_terms:
Accounting;Address;Affective;Alcohol or Other Drugs use;Alcohols;Anxiety;Attention;Attitude;Behavior;Characteristics;Complex;Data;Development;Dimensions;Drug abuse;Effectiveness;Elements;Emotions;Esthesia;Failure (biologic function);Fright;Impulsivity;Individual;Individual Differences;Intervention;Knowledge;Lead;Literature;Marihuana;Marijuana Smoking;Modeling;Outcome;Personality;Predisposition;Prevention;Prevention program;Preventive Intervention;Probability;Process;Reaction;Reading;Recording of previous events;Research;Research Personnel;Review Literature;Rewards;Risk;Risk Behaviors;Risk-Taking;Schools;Services;Simplexvirus;Specific qualifier value;Substance abuse problem;Teenagers;Testing;Translational Research;Work;base;design;drug abuse prevention;experience;high risk behavior;high risk sexual behavior;improved;member;novel;prevent;programs;reduce marijuana use;research study;sex;substance abuse prevention;success;trait;willingness;young adult


application_id: 8289657
project_number: 5P50DA005312-21
project_title: MEDIATING PROCESSES IN THE PERSONALITY SUBSTANCE USE RELATION
administering_ic: NIDA
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
project_start_date: 2011-07-01
project_end_date: 2012-07-14
study_section: ZDA1
subproject_number: 0013
contact_pi_person_id: 3122080
contact_pi: LYNAM, DONALD 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: 2011-07-01
budget_end_date: 2012-07-14
project_abstract:
To optimally design targeted interventions aimed at reducing substance use one must know whichcharacteristics or traits are involved in substance use and how these characteristics lead to substanceuse;these relations are likely to be complex and to involve bi-directional influences. The present project focuseson two separable traits related to substance use: reward seeking defined as a tendency to enjoy and pursueexciting activities and new experiences and low inhibition defined as the tendency to act without thinking orreflection. The research primarily examines basic elemental processes (e.g. risk tolerance inhibitorycontrol delay discounting Behavioral Inhibition or Activation System functioning) that may mediate therelations between these traits and substance use. The elemental processes are hypothesized to reflect theactivity of two biological systems: an approach/reward seeking system and an inhibitory system. The rewardsystem is theorized to be responsive to reward and is responsible for activating approach behavior. Theinhibition system is theorized to be sensitive to punishment and is responsible for inhibiting ongoing behaviorand initiating active information processing. Several potential social variables are also examined as potentialmediators (i.e. substance use expectancies and peers). The research also allows for the possibility thatsubstance use itself changes the traits and the underlying elemental processes. Finally the project examinesthe interrelations among the elemental processes themselves. All of these issues are examined in thecontext of a three-year two cohort longitudinal study. There are four specific aims:1. To identify the mechanisms underlying the relations leading from reward seeking and inhibition tosubstance use. Inhibition and reward seeking are distinct traits with distinct outcomes including substanceuse and abuse. Little is known however about the processes that link these traits to their outcomes.2. To examine the effect of substance use on the processes associated with reward seeking and inhibition.Research has shown acute effects of drug exposure on the processes under study. For examplealcoholhas been shown to have acute effects on inhibitory control. Additionally a number of studies havedemonstrated process deficits in substance abusers. Thus it is possible that drug use influences theprocesses underlying reward seeking and inhibition although this has not been demonstrated longitudinally.3. To examine the relations among the underlying processes themselves. The processes examined in thepresent research come from a variety of levels and modes of assessment ranging from elementary inhibitorycontrol through Behavioral Inhibition System functioning assessed via psychophysiology. Although each taskand measure is related to substance use and has been designed to assess one of the two hypotheticalsystems these tasks have not been examined together previously.

project_terms:
Acute;Alcohol consumption;Alcohol or Other Drugs use;Alcohols;Behavior;Behavioral inhibition;Cardiac;Characteristics;Complex;Cues;Drug Exposure;Drug abuse;Drug usage;Elements;Esthesia;Expectancy;Failure (biologic function);Galvanic Skin Response;Incentives;Intervention;Lead;Left;Link;Longitudinal Studies;Measures;Mediating;Mediator of activation protein;Motivation;Names;Outcome;Personality;Pharmaceutical Preparations;Process;Psychophysiology;Punishment;Reaction Time;Research;Research Personnel;Rewards;Risk;Risk Factors;Short-Term Memory;Signal Transduction;Substance abuse problem;System;Thinking function;Time;Translational Research;Withdrawal;analog;approach behavior;biological systems;cognitive system;cohort;design;discounting;experience;information processing;longitudinal design;peer;programs;response;social;substance abuser;trait


application_id: 8289656
project_number: 5P50DA005312-21
project_title: INDIVIDUAL DIFFERENCES IN DRUG ABUSE LIABILITY
administering_ic: NIDA
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
project_start_date: 2011-07-01
project_end_date: 2012-07-14
study_section: ZDA1
subproject_number: 0012
contact_pi_person_id: 1901822
contact_pi: KELLY, THOMAS H.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
budget_end_date: 2012-07-14
project_abstract:
Prevention investigators in our Center and elsewhere have demonstrated that drug abuse preventionefficacy can be significantly enhanced by targeting individuals who are most vulnerable to developingproblems and tailoring message content and format based on the characteristics of these individuals. Furtherdevelopment of laboratory models to identify individuals who are vulnerable to developing regular andproblematic patterns of drug use and identifying the characteristics of these individuals that predispose themto vulnerability and/or influence the efficacy of communication/education programs is of critical importancefor informing and advancing the field of drug abuse prevention. This application proposes five years of research to continue laboratory investigations of individualdifferences associated with drug abuse vulnerability. Prior epidemiological research has established a linkbetween the biologically-based personality trait of sensation-seeking (or novelty-seeking) and drug abuse inhumans. Research with rat models suggests that novelty-seeking behavior is predictive of individualdifferences in dopamine function and in the reinforcing and other behavioral effects of drugs of abuse. Ourrecent clinical laboratory studies demonstrate an association between sensation seeking and individualdifferences in both brain function and in the reinforcing and other behavioral effects of drugs of abuse.Sensation seeking consists of dissociable biologically-based dimensions of reward seeking and inhibition;each of these dimensions has been postulated to play an important role in determining drug abusevulnerability via distinct and separable biobehavioral mechanisms. A multidisciplimary approach combininglaboratory abuse liability assessment and brain imaging methodologies will be used to examine the separateand combined effects of reward seeking and inhibition traits on 1) drug abuse vulnerability 2) brainresponses associatedwith reward and inhibition processing 3) brain responses associated with drug effectson reward and inhibition processing and 4) brain responses to emotional and novel stimulus materials.These studies will support the development of more efficacious prevention interventions by definingindividual characteristics and associated brain processes that are linked to drug abuse vulnerability that canbe used to improve the precision of targeted and tailored programs.

project_terms:
Accounting;Address;Alcohols;Behavior;Behavioral;Brain;Brain imaging;Brain region;Characteristics;Clinical;Communication;Complex;Data;Detection;Development;Dextroamphetamine;Diazepam;Dimensions;Dopamine;Dopamine Agonists;Drug abuse;Drug usage;Educational aspects;Emotional;Epidemiology;Esthesia;Event-Related Potentials;Exhibits;Functional Magnetic Resonance Imaging;Funding;Human;Image;Individual;Individual Differences;Investigation;Laboratories;Laboratory Study;Link;Measures;Methodology;Methylphenidate;Modeling;Neurobiology;Nicotine;Novelty-Seeking Behaviors;Pattern;Personality;Personality Traits;Pharmaceutical Preparations;Play;Prevention;Preventive Intervention;Probability;Process;Rattus;Research;Research Personnel;Rewards;Risk-Taking;Role;Stimulus;Substance abuse problem;Translational Research;base;biobehavior;drug abuse prevention;drug of abuse;drug sensitivity;emotional stimulus;experience;improved;neurobehavioral;novel;programs;psychostimulant;response;trait;willingness


application_id: 8289655
project_number: 5P50DA005312-21
project_title: INDIVIDUAL DIFFERENCES IN RESPONSE TO AMPHETAMINE
administering_ic: NIDA
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
project_end_date: 2012-07-14
study_section: ZDA1
subproject_number: 0011
contact_pi_person_id: 1884463
contact_pi: BARDO, MICHAEL T
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
budget_end_date: 2012-07-14
funding_mechanism: Research Centers
project_abstract:
Recent theories describe drug abuse as a disorder involving not only positive incentive motivation but as adisorder also charactered by a loss of inhibitory control. In this project we will use a laboratory animalmodel to determine the critical neural mechanisms that underlie the association between risk-related traitsand drug abuse questions that cannot be addressed fully using human subjects. Our working hypothesis isthat individual differences in the risk-related traits reward seeking and inhibition play a role in drug abusevulnerability and that individual differences in these two behavioral constructs are mediated by dissociableneural systems. While reward seeking and inhibition undoubtedly involve complex and overlapping neuralcircuits our current knowledge suggests that reward seeking is subserved by ascending mesocorticolimbicdopamine (DA) systems whereas inhibition is subserved by frontal cortical regions involving both DA andserotonin (5-HT). Anatomical studies have also revealed that the medial prefrontal cortex (mPFC) isimplicated in both reward seeking and inhibition whereas the orbitofrontal cortex (OFC) is implicated ininhibition. These neural systems will be examined to determine their role in the association of rewardseeking and inhibition with drug reward. Rats will be assessedfor individual differences in reward seekingand inhibition using a variety of behavioral tests and then will assessed for amphetamine reward DA and 5-HT transporter function and neural activity assessed by in vivo voltammetry and electrophysiologicalstudies. We predict that rats that are high in reward seeking and low in inhibition will be most vulnerable tothe rewarding effect of amphetamine and related drugs. Also we predict that rats that are high in rewardseeking and low in inhibition will be most sensitive to nondrug alternative reinforcers that compete with drugreward which may have important translational implications for the design of effective drug abuse preventionintervention strategies in humans. Finally we predict that individual differences in reward seeking andinhibition will be associatedwith differences in DA and 5-HT systems within the nucleus accumbens mPFCand/or OFC. These results combined with the human behavioral pharmacology and neuroimaging results inProject 2 will provide a more comprehensive understanding the neural systems involved in risk-related traitsrelevant to the design of tailored anti-drug prevention intervention messages.

project_terms:
Address;Adolescent;Affect;Amphetamines;Animal Model;Behavioral;Clinical;Complex;Corpus striatum structure;Disease;Dopamine;Drug Formulations;Drug abuse;Drug usage;Esthesia;Exposure to;Human;Incentives;Individual Differences;Intervention;Investigation;Knowledge;Laboratory Animal Models;Medial;Mediating;Motivation;Neurophysiology - biologic function;Nucleus Accumbens;Pharmaceutical Preparations;Play;Population;Prefrontal Cortex;Preventive Intervention;Rattus;Rewards;Risk;Role;Serotonin;Signal Transduction;System;Translational Research;Work;behavior test;behavioral pharmacology;design;dopamine system;drug abuse prevention;drug reward;human subject;in vivo;monoamine;neural circuit;neuroimaging;neuromechanism;neuronal patterning;non-drug;pre-clinical;reinforcer;relating to nervous system;response;theories;trait;young adult


application_id: 8288932
project_number: 1UM1HL113530-01
project_title: University of Louisville Regional Clinical Center for the CCTRN
administering_ic: NHLBI
award_notice_date: 2012-03-22
opportunity_number: RFA-HL-12-026
application_type: 1
activity_code: UM1
ic: HL
serial_number: 113530
program_official: SKARLATOS, SONIA
project_start_date: 2012-03-22
project_end_date: 2019-02-28
study_section: Special Emphasis Panel[ZHL1 CSR-O (F2)]
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
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 University of Louisville/Jewish Hospital has a remarkably vibrant basic and clinical research program in cardiovascular medicine particularly in the area of stem cells and patients with heart failure (HF) left ventricular assist devices (LVADs) and ischemic cardiomyopathy. A highly cohesive and collegial team of investigators from the Divisions of Cardiovascular Medicine and Thoracic and Cardiovascular Surgery has worked productively for many years in several multicenter trials with outstanding performance. This existing clinical infrastructure coupled with the strong preclinical research work conducted on cell-based therapies for several years provides a superb platform for participation in the CCTRN as a Regional Clinical Center. The ability of our Center to carry out Phase l/ll studies of stem cells is exemplified by our success i performing the first in-human study of c-kit+ cardiac stem cells in patients with HF (SCIPIO). The same investigators and the infrastructure that made SCIPIO possible will be leveraged for the CCTRN studies. Here we propose SENECA (StEm cell treatmeNt for End stage CArdiac failure) in which we will test the feasibility and safety (Aim 1) and efficacy (Aim 2) of intracoronary delivery of CD34+ cells or very small embryonic-like cells (VSELs) to patients with end-stage ischemic cardiomyopathy (ICM) following implantation of an LVAD. Our hypothesis is that cell therapy will promote repair and regeneration of the injured myocardium resulting in improved cardiac function functional capacity and overall quality of life and recovery of myocardial function to a degree that permits consideration of LVAD explantation. In Aim 3 we will identify patient characteristics and in vitro parameters of stem cell function that are associated with effectiveness (or lack thereof) of CD34+ cells and VSELs in improving LV function in vivo. SENECA will be the first study of VSELs in humans and the first controlled trial to test the effects of CD34+ cells in end-stage ischemic HF. Therefore the results will be entirely novel and may provide a new option for patients who currently have a dismal prognosis. Thus the potential impact of SENECA is considerable. No cell therapy study has ever been reported before in patients with LVADs and ICM although these are the very patients who need it the most. Therefore SENECA will address a major therapeutic gap in the management of cardiac patients. This trial has the potential to provide a novel clinical breakthrough in the treatment of end-stage ischemic heart disease.

project_terms:
Activities of Daily Living;Address;Affect;Area;Basic Science;CD34 gene;Cardiac;Cardiac Surgery procedures;Cardiomyopathies;Cardiovascular Surgical Procedures;Cardiovascular system;Cell Therapy;Cell physiology;Cells;Cellular biology;Characteristics;Clinical;Clinical Research;Collaborations;Commit;Coupled;Effectiveness;Embryo;Enrollment;Environment;Event;Faculty;Goals;Heart failure;Hospitals;Human;Human Resources;Implant;In Vitro;Infarction;Institution;Left;Letters;Life;Medicine;Motivation;Multicenter Trials;Myocardial;Myocardial Ischemia;Myocardium;Names;Natural regeneration;Patients;Performance;Personnel Staffing;Phase;Population;Positioning Attribute;Postdoctoral Fellow;Proto-Oncogene Protein c-kit;Quality of life;Recovery;Reporting;Research;Research Infrastructure;Research Personnel;Resources;Safety;Staging;Stem cells;Testing;Therapeutic;Thoracic Surgical Procedures;Time;Universities;Work;base;clinical infrastructure;control trial;follower of religion Jewish;human study;implantation;improved;in vivo;injured;insight;member;novel;outcome forecast;phase 1 study;phase 2 study;phase 3 study;pre-clinical research;preclinical study;programs;repaired;stem cell population;stem cell therapy;success;ventricular assist device


application_id: 8288761
project_number: 5R01HL073085-09
project_title: Angiotensin: A Link Between Obesity and Hypertension
administering_ic: NHLBI
award_notice_date: 2012-06-05
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 073085
program_official: OH, YOUNGSUK
project_start_date: 2003-06-03
project_end_date: 2014-04-30
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryObesity is one of the most serious health problems in the United States and the most common cause ofhypertension. Our laboratory demonstrated that adipocytes express components of the renin-angiotensinsystem (RAS) and that mice with diet-induced obesity and hypertension exhibit adipose-specific dysregulationof these components favoring an increase in blood pressure. Angiotensinogen (AGT) angiotensin type 1areceptors (AT1aR) and ACE2 are three components of the RAS that were regulated specifically in adiposetissue from mice with hypertension from diet-induced obesity. Preliminary data suggest that fatty acidsenriched in the western high fat (HF) diet regulate specific RAS components in adipocytes serving as amechanism for adipose-specific regulation of the RAS. We hypothesize that the RAS of adipocytescontributes to the development of obesity-induced hypertension. In aim 1 we hypothesize that adiposetissue is a predominant source for increased local and systemic angiotensin II (AngII) in obesity-hypertension.To test this hypothesis we will feed low fat (LF) or HF diets to mice with adipocyte-specific AGT deletion anddetermine the impact on the development of obesity-hypertension. In vitro studies will use adipose tissue fromadipocyte AGT deficient mice to test the hypothesis that fatty acids regulate oxidative stress andproinflammatory adipokines through an AngII-dependent mechanism. In Aim 2 we hypothesize that adipocyteAT1aR mediate effects of local and/or systemic AngII to increase proinflammatory adipokine expression andpromote obesity-hypertension. To test this hypothesis we will feed LF or HF diets to mice with adipocyte-specific AT1aR deficiency and determine the impact on the development of obesity-hypertension. In vitrostudies will test the hypothesis that adipocyte AT1aR mediate effects of AngII to promote oxidative stress andadipokine expression. In Aim 3 we hypothesize that specific fatty acids regulate ACE2 expression andshedding to increase the development of obesity-hypertension. In vitro studies will define effects of specificfatty acids on ACE2 gene transcription and/or shedding in adipocytes and in vivo approaches will use ACE2deficient mice to define their susceptibility to the development of obesity-hypertension. Results from thesestudies will identify dietary or pharmacologic sites for targeted reductions in the adipocyte RAS in the treatmentof obesity-hypertension.

project_terms:
Acids;Adipocytes;Adipose tissue;Adult;Angiotensin II;Angiotensin Type 1a Receptor;Angiotensinogen;Angiotensins;Blood Pressure;CCL2 gene;Cardiovascular Diseases;Cause of Death;Coupled;Data;Development;Diet;Epidemic;Exhibits;Fatty Acids;Fatty acid glycerol esters;Framingham Heart Study;Genetic Transcription;Health;Hypertension;In Vitro;Laboratories;Leptin;Link;Liver;Measures;Mediating;Mus;Obese Mice;Obesity;Overweight;Oxidative Stress;Patients;Predisposition;Prevalence;Production;Regulation;Relative (related person);Renin-Angiotensin System;Reporting;Site;Source;Testing;Therapeutic;Tissues;United States;Woman;Work;adipokines;clinically significant;feeding;in vivo;mRNA Expression;men;novel;obesity treatment;public health medicine (field);receptor coupling;resistin;response

public_health_relevance:
Project NarrativeThe relevance of this project to public health is the definition of mechanisms contributing to the development ofhypertension in obese subjects. Given the epidemic of obesity in the US results from these studies will definewhether an adipocyte renin-angiotensin system is a primary mechanism linking the epidemic of obesity to agrowing prevalence of hypertension. Since the principal cause of death in obese patients is cardiovasculardisease results from these studies are clinically significant.


application_id: 8288260
project_number: 5T32DA007304-15
project_title: Research Training in Drug Abuse Behavior
project_terms: Behavior;Drug abuse;Research Training
administering_ic: NIDA
award_notice_date: 2012-05-30
opportunity_number: PA-06-468
application_type: 5
activity_code: T32
ic: DA
serial_number: 007304
program_official: MANDLER, RAUL N
project_start_date: 1998-08-01
project_end_date: 2013-06-30
study_section: ZDA1-EXL-T(04)
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
This training program co-directed by Thomas Garrity and Carl Leukefeld proposes to support three preand three postdoctoraltrainees with a training faculty of 24 drawn from six different academic and researchunits of the University. The environment is rich with opportunities for biobehavioral research in facilities suchas the Center on Drug and Alcohol Research the Center for Drug and Alschool Research and Transaltionand the Residential Research Facility. Trainees will be housed in offices and laboratories of their researchsupervisor with 24 hour/day access to laboratories and computer facilities. This program is designed to prepare trainees to assume research responsibilities in academic and otherscientific organizations concerned with drug abuse and the behavioral aspects of health and medical care.Postdoctoral fellows will either have a doctorate in a behavioral science discipline and will be preparing for aresearch role in the drug abuse field or they will be health professionals who are seeking a behavioralscience research orientation in drug abuse. Predoctoral trainees will concentrate in behavioral aspects ofdrug abuse as part of their program for a doctorate in a behavioral science discipline. Basic elements of theprogram include: (1) research training designed to provide experience in utilizing the basic building blocks ofresearch (interviewing case study experimental design development and pretesting of instruments dataanalysis) and independent research competence; (2) an interdisciplinary orientation which takes studentsbeyond their basic discipline and provides exposure to key theoretical concepts and methodological issuesof the related behavioral sciences along with a biobehavioral'conceptualization; (3) a program ofenculturation and orientation to drug abuse health and mental health settings; (4) opportunities to exploredrug abuse topics from a medical behavioral perspective through courses offered by training faculty; and (5)opportunities for research around relevant questions in drug abuse behavior that can constitute significantlearning experiencesfor postdoctoral fellows and a dissertation project for predoctoral trainees. Theprogram for postdoctoral fellows will be individually geared to the objectives of the fellows and will build ontheir previous knowledge and experience.


application_id: 8288114
project_number: 5R01HL062053-13
project_title: Host Response to P. carinii in Neonatal Mice
administering_ic: NHLBI
award_notice_date: 2012-06-27
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 062053
program_official: PEAVY, HANNAH H
project_start_date: 1998-09-30
project_end_date: 2014-06-30
study_section: AIDS-associated Opportunistic Infections and Cancer Study Section[AOIC]
contact_pi_person_id: 1945284
contact_pi: GARVY, BETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Pneumocystis pneumonia PCP) causes significant morbidity and mortality among HIV-infected individuals who are newly diagnosed failed retroviral therapy or do not have access to care. Infants are particularly susceptible to pulmonary infections and it has been recently appreciated that not only are individuals exposed to Pneumocystis early in life but infants appear to carry the infection as evidenced by the high incidence found in autopsy specimens from babies that died of SIDS. HIV-infected infants tend to have a more fulminant course of PCP likely because of the immature immune system along with depletion of CD4+ cells. In the previous funding period we found that in contrast to our hypothesis the delay in clearance of Pneumocystis we observed in neonatal mice was not solely due to elevated anti-inflammatory cytokines in the lungs through the first 3 weeks of life. Instead we found that alveolar macrophages from neonatal mice are intrinsically unresponsive to Pneumocystis. The goal for this funding period is to differentiate the contribution of environmental factors and intrinsic factors to neonatal alveolar macrophage function in response to Pneumocystis. Specifically we will test the hypothesis that: neonatal alveolar macrophages fail to respond to Pneumocystis due to a defect in signaling through pattern recognition receptors along with delayed second signals from proinflammatory cytokines or costimulatory molecules on T cells. To address this hypothesis we have proposed two aims. 1. We will determine whether alveolar macrophages from neonatal mice are intrinsically unresponsive to Pneumocystis. In vitro and in vivo experimental strategies will be used to determine whether neonatal alveolar macrophages can respond to stimuli through the dectin-1 ?-glucan receptor mannose receptor or TLR2. 2. We will determine whether secondary signals from T cells are required to stimulate neonatal alveolar macrophages. We will use adoptive transfer of cells and treatment with exogenous stimulatory molecules in an attempt to stimulate alveolar macrophages to respond to Pneumocystis. These studies are a logical extension of our previous funding period and will address the mechanisms responsible for neonatal unresponsiveness Pneumocystis. PUBLIC HEALTH RELEVANCE: Pneumocystis pneumonia (PCP) is an AIDs defining illness that is still prevalent in newly diagnosed HIV-infected individuals and those who fail therapy are non-compliant or do not have access to antiretroviral therapy. PCP often has a worse course in children due to the immaturity of the immune system. The goal of this project is to understand the function of alveolar macrophages and CD4 T cells and their interactions in infants with PCP.

project_terms:
Address;Adoptive Cell Transfers;Adult;Age;Agonist;Alveolar Macrophages;Anti-Inflammatory Agents;Anti-inflammatory;Antibodies;Autopsy;Binding (Molecular Function);CD 200;CD4 Positive T Lymphocytes;Cell physiology;Child;Cyst;Cytokine Activation;Data;Defect;Environment;Environmental Risk Factor;Epithelial Cells;Funding;Glucans;Goals;HIV;Health;Health Services Accessibility;Immune response;Immune system;In Vitro;In-Migration;Incidence;Individual;Infant;Infection;Intrinsic factor;Life;Ligation;Lung;Macrophage-1 Antigen;Mannans;Morbidity - disease rate;Mortality Vital Statistics;Mus;Neonatal;Newly Diagnosed;Pattern recognition receptor;Phagocytosis Induction;Phenotype;Pneumocystis;Pneumocystis carinii;Pneumocystis carinii Pneumonia;Production;Regulatory T-Lymphocyte;Signal Pathway;Signal Transduction;Site;Specificity;Specimen;Stimulus;Sudden infant death syndrome;T-Lymphocyte;TLR2 gene;TNFSF5 gene;Testing;Toll-Like Receptor 2;Transgenic Mice;Up-Regulation (Physiology);antiretroviral therapy;cytokine;dectin 1;in vivo;macrophage;mannose receptor;neonate;non-compliance;pup;receptor;response

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


application_id: 8288084
project_number: 5R01GM094155-03
project_title: Mechanism of Neuropilin Dependent Angiogenesis
administering_ic: NIGMS
award_notice_date: 2012-06-29
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 094155
program_official: DUNSMORE, SARAH
project_start_date: 2010-09-06
project_end_date: 2015-06-30
study_section: Macromolecular Structure and Function C Study Section[MSFC]
contact_pi_person_id: 9627039
contact_pi: VANDER KOOI, CRAIG
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Angiogenesis the production of new blood vessels from existing vasculature is required for normal development wound repair and vascular homeostasis. Neuropilin is an essential mammalian cell surface receptor for one of the most potent pro-angiogenic molecules vascular endothelial growth factor (VEGF) and functions in synchrony with VEGFR receptor tyrosine kinases. Neuropilin is of particular medical importance because it is critical to the pathology of VEGF dependent hyper-vascularization in tumor angiogenesis.  We propose a series of parallel and complementary structural and functional studies to understand the physical interactions and receptor coupling at the heart of the VEGF signaling complex. Unlike many other kinase systems VEGF binding to VEGFR in the absence of neuropilin is insufficient to induce angiogenesis. We seek to first understand the molecular mechanism(s) underlying neuropilin's unique role in VEGF dependant angiogenesis. In Aim 1 we will determine the basis for competitive binding of ligands to neuropilin and the role that this competition plays in regulating angiogenesis. In Aim 2 we will explore the structural and conformational changes that neuropilin undergoes in its transition from inactive monomer to activated dimer. More globally we seek to define the physical basis for the coordinated action of VEGF neuropilin and VEGFR. Aim 3 is focused on utilizing multiple structural and biochemical tools coupled with endothelial cell signaling assays to determine the physical interactions and conformational changes necessary to couple extracellular ligand binding to receptor activation. Taken together these studies will provide a molecular understanding of the physical mechanisms underlying the critical first step connecting VEGF ligand binding to receptor activation.    PUBLIC HEALTH RELEVANCE: Neuropilin is an essential receptor needed for the formation of new blood vessels. New blood vessels are critical during normal development and wound repair but also provide a tumor with critical nutrients for its growth. Understanding how neuropilin works in the formation of new blood vessels will help us understand how this pathway normally functions and how we can block its activity in tumors and related diseases.

project_terms:
Angiogenesis Inhibitors;Arginine;Binding (Molecular Function);Biochemical;Biological Assay;Blood Vessels;Breast;C-terminal;Cardiovascular system;Cell Surface Receptors;Colon;Competitive Binding;Complex;Coupled;Coupling;Development;Dimerization;Disease;Electron Microscopy;Endothelial Cells;Extracellular Structure;Family;Goals;Growth;Growth Factor;Growth Factor Interaction;Heparin;Homeostasis;Ligand Binding;Ligands;Mammalian Cell;Mediating;Medical;Membrane;Molecular;Nature;Neuropilins;Nutrient;Pathology;Pathway interactions;Peptide Hydrolases;Phosphotransferases;Pituitary Gland;Play;Production;Prostate;Proteolytic Processing;Publishing;Receptor Activation;Receptor Protein-Tyrosine Kinases;Resolution;Role;Semaphorins;Series;Signal Pathway;Signal Transduction;Solid Neoplasm;Structure;System;Techniques;Tumor Angiogenesis;Vascular Endothelial Growth Factor Receptor;Vascular Endothelial Growth Factors;Vascularization;Work;Wound Healing;angiogenesis;antiangiogenesis therapy;axon guidance;base;cytokine;dimer;extracellular;glucosaminoglycans;member;monomer;novel;public health relevance;receptor;receptor coupling;tool;tumor

public_health_relevance:
Neuropilin is an essential receptor needed for the formation of new blood vessels. New blood vessels arecritical during normal development and wound repair but also provide a tumor with critical nutrients for itsgrowth. Understanding how neuropilin works in the formation of new blood vessels will help us understandhow this pathway normally functions and how we can block its activity in tumors and related diseases.


application_id: 8287995
project_number: 5P20NR010679-05
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: 2011-07-01
budget_end_date: 2012-06-30
funding_mechanism: Research Centers
project_abstract:
Chronic cardiovascular and pulmonary diseases adversely affect the quality of life of millions of
Americans. 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 and
pulmonary diseases and to support investigators in the development of extramural research proposals
junior as well as established investigators need training and mentoring with research program development
(e.g. establishing a research trajectory developing researchable problems conceptualizing theoretical
foundations for hypothesis formation proposal development) data analysis (e.g. selection of appropriate
statistical methods interpretation of statistical output presentation of statistical findings) and dissemination
of results via scientific presentations and publications in appropriate venues. The Research Program
Development Data Analysis and Dissemination Core will build on existing support services available in
the College of Nursing and extend services to support Center investigators in other ways.
The purposes of the Research Program Development Data Analysis and Dissemination Core
are to: (1) provide support services to assist faculty in developing a focused ongoing funded program of
research related to evidence-based interventions to promote self-management in patients with
cardiovascular and pulmonary diseases; (2) offer faculty development opportunities and mentoring in
research proposal development psychosocial instrumentation and surveys research design and sampling
data management and analysis and data-based presentation and manuscript preparation; and (3) through
collaboration with the Administrative Core the Self-management Pilot/Feasibility and Biobehavioral
Outcomes Core the Executive Committee and the Advisory Committee provide the infrastructure and
resources necessary for development of ongoing programs of research focused on improving selfmanagement
of patients with cardiovascular and pulmonary diseases.

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


application_id: 8287993
project_number: 5P20NR010679-05
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: 2011-07-01
budget_end_date: 2012-06-30
funding_mechanism: Research Centers
project_abstract:
Development of evidence-based strategies to improve self-management of cardiovascular and pulmonary diseases requires that investigators develop scientifically sound rigorous research studies. Measuring biobehavioral outcomes of self-management of cardiovascular and pulmonary diseases presents challenges to investigators entering this field of study. The University of Kentucky College of Nursing is doubling the size of the undergraduate program. Funding to hire eight additional faculty members who will have 50% release time for research has been approved by the Board of Regents. These new members who will be investigators early in their research careers will be hired over three years. Three of these members will start in the Fall of 2007. In addition we have junior faculty (Darlene Welsh and Misook Chung) and established investigators (Ann Peden and 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 develop programs 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 project investigators in the development and conduct of pilot/feasibility studies aimed at improving self-management of cardiovascular and pulmonary diseases that include measurement of biobehavioral outcomes. Advice training and mentorship will be provided in research design as well as measurement and interpretation of three types of outcomes: 1) biobehavioral variables that demonstrate effectiveness of interventions (e.g. knowledge psychological status physiological status) 2) biobehavioral variables that demonstrate improvement in self-management behaviors (e.g. adherence nutritional status physiological status) and 3) biobehavioral
variables that demonstrate improvement in clinical outcomes (e.g. physiological status mortality morbidity and quality of life).

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


application_id: 8287184
project_number: 5R01EB003730-09
project_title: Assembly of phi29 pRNA nanoparticles for siRNA delivery to prostate cancer cells
administering_ic: NIBIB
award_notice_date: 2012-05-22
opportunity_number: PA-08-052
application_type: 5
activity_code: R01
ic: EB
serial_number: 003730
program_official: TUCKER, JESSICA
project_start_date: 2004-09-01
project_end_date: 2015-05-31
study_section: Nanotechnology Study Section[NANO]
contact_pi_person_id: 1878565
contact_pi: GUO, PEIXUAN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary Nanotechniques involve the creation characterization and modification of organized nanomaterials toserve as building blocks for the construction of submicro or nanoscale devices and systems with applications intechnology and medicine. Living systems contain a wide variety of ordered macromolecular structures andpowerful bionanomachines. The ingenious novel design of the bacteriophage phi29 DNA packaging motor andits constituents has inspired the artificial synthesis and assembly of phi29 biomimetic motor and itscomponents. The 30-nm nanomotor was geared by six copies of ATP-binding packaging RNAs (pRNAs). Thestructural versatility of pRNA coupled with its ability to form dimers trimers hexamers and patternedsuperstructures via interlocking loop interactions make it a promising tool for nanomachine fabricationpathogen detection and drug/gene delivery. The low-resolution global structures of the pRNA and its dimertrimer and hexamer have been probed by photoaffinity cross linking chemical modification interferencecompensatory modification Cryo-AFM and 3D computer modeling. The long-term objective is to introduce exogenous components nano-materials modules moietiesdrugs and other therapeutic reagents into the motor and develop it for various applications in nanotechnologyand medicine. During the first four years of this grant we have demonstrated that pRNA can be used as abuilding block for bottom-up assembly of polyvalent nanoparticles to deliver siRNA ribozymes and othertherapeutics to specific cells. A single molecule fluorescence dual-view imaging system was designed andconstructed to count the number of pRNA copies within the constructed pRNA nanoparticles. The short-termobjective of this proposal is to utilize prostate cancer as a model system to determine the feasibility of usingthe phi29 pRNA motor for targeted delivery of siRNA or other therapeutic molecules and treatment ofcancerous diseases. Specifically the novel RNA nanotechnology approach previously developed for thebottom-up assembly of multimeric pRNA nanoparticles will be exploited to construct polyvalent pRNA vehiclescarrying an RNA aptamer to specifically bind to prostate surface antigens and a therapeutic siRNA targeting ananti-apoptosis factor for the prostate cancer treatment. Methods for large scale production of pRNAnanoparticles and construction of stable pRNA therapeutic nanoparticles resistant to RNase digestion in vivowill be developed. Approaches designed to combine therapy with the simultaneous detection of the therapeuticeffect will be developed by exploiting the polyvalent nature of the pRNA nanoparticles. The efficacy in prostatecancer therapy the biodistribution pharmacokinetics toxicity off-target effects as well as the double strandedRNA induced interference will be evaluated in both prostate cancer cells and mice models.

project_terms:
Androgen Receptor;Animal Model;Antineoplastic Agents;Antisense RNA;Apoptosis;Bacteriophages;Binding (Molecular Function);Biodistribution;Biological Models;Biomimetics;Cancerous;Catalytic RNA;Cell Culture Techniques;Cells;Chemicals;Column Chromatography;Computer Simulation;Coupled;DNA Packaging;Detection;Devices;Digestion;Disease;Double-Stranded RNA;Drug Kinetics;Drug or Chemical;Endosomes;Engineering;Ensure;Environment;Evaluation;Fermentation;Fluorescence;Folate;Gene Delivery;Glutamate Carboxypeptidase II;Goals;Grant;Image;Immunity;Individual;Industry;Label;Left;Ligands;Malignant neoplasm of prostate;Medicine;Metallothionein IIA;Methods;Modification;Molecular Structure;Motor;Nanotechnology;Nature;Organism;Pathogen detection;Pattern;Pharmaceutical Preparations;Production;Prostate;Prostate Cancer therapy;Quality Control;RNA;Reagent;Reporting;Reproducibility;Resistance;Resolution;Ribonucleases;Small Interfering RNA;Structure;Surface Antigens;System;Techniques;Technology;Therapeutic;Therapeutic Agents;Therapeutic Effect;Toxic effect;Xenograft Model;aptamer;base;cancer cell;cancer therapy;clinical application;crosslink;design;design and construction;dimer;in vivo;large scale production;milligram;monomer;mouse model;nanodevice;nanomachine;nanomaterials;nanoparticle;nanoscale;novel;receptor mediated endocytosis;sephadex;single molecule;survivin;targeted delivery;three dimensional structure;tool

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


application_id: 8286390
project_number: 5T32DA016176-09
project_title: Training in Drug Abuse Related Research
project_terms: Drug abuse;Research;Training
administering_ic: NIDA
award_notice_date: 2012-06-06
opportunity_number: PA-06-468
application_type: 5
activity_code: T32
ic: DA
serial_number: 016176
program_official: BABECKI, BETH
project_start_date: 2004-07-01
project_end_date: 2014-06-30
study_section: Career Development Education and Training Study Section[NIDA-K]
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
project_abstract:
DESCRIPTION ( provided by applicant):  This application is for renewal of a training program directed by Louis Hersh and co-directed by Linda Dwoskin and Sharon Walsh. We request continued support for four predoctoral and two postdoctoral trainees utilizing a training faculty of 15 housed in three colleges and 5 different departments within the University of Kentucky. All of the training faculty have been funded through NIDA or collaborate with NIDA funding training faculty with their research broadly focused on the molecular aspects of drug abuse. The University of Kentucky has a long history of involvement in drug abuse research and includes the Center on Drug and Alcohol Research and the Center for Drug and Alcohol Research and Translation. The goal of this training program continues to be the preparation of promising graduate students and postdoctoral fellows for careers in drug abuse research. The program provides broad-based training in modern aspects of drug abuse research with a particular emphasis on studying the cellular and molecular aspects of receptors involved in the response to drugs and the development of ligands which interact with these receptors as potential pharmacotherapy's for drug abuse. The training faculty share a common interest in understanding basic mechanisms related to drug abuse at the molecular level. The emphasis of the training faculty focus on the structure of opiate receptor ligands the effects of opiate receptor ligands on physiological processes and the structure and function of the proteins and ligands involved in opiate receptors. Trainees learn from a strong faculty who utilize state-of-the-art methodological approaches to drug abuse research. A unique aspect of this program is the interaction of trainees with other faculty and trainees involved in the behavioral aspects of drug abuse giving them a broad based understanding of drug abuse research. This unique training opportunity is hoped to fill the need for new investigators in drug abuse research who have a broad understanding of the field.   PUBLIC HEALTH RELEVANCE: This program is designed to train graduate students and postdocs for a career in drug abuse research providing them with the tools to conduct research on the molecular aspects of drug abuse while at the same time endowing them with an understanding of the behavioral aspects of drug abuse.


application_id: 8286381
project_number: 5R01DA025100-05
project_title: High-activity mutants of cocaine esterase for treatment of drug addiction
administering_ic: NIDA
award_notice_date: 2012-05-31
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DA
serial_number: 025100
program_official: SHIH, MING L
project_start_date: 2008-08-15
project_end_date: 2016-06-30
study_section: Medication Development Research Study Section[NIDA-L]
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
other_pis: LANDRY, DONALD W;WOODS, JAMES H
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Enhancing cocaine metabolism by administration of cocaine esterases has been recognized as a promising treatment strategy for cocaine overdose and addiction. The esterase CocE is the most efficient native enzyme for metabolizing naturally occurring (-)-cocaine yet identified. Through catalysis of (-)-cocaine hydrolysis CocE can both prevent and reverse extreme (-)- cocaine toxicity in rodent models and it has the potential to be developed into a chemically useful antagonist of the toxic and behavioral effects of (-)-cocaine. In order to optimize the efficacy of this potential anti-cocaine medication and minimize its possible side effects (particularly immunogenicity) we propose to improve the catalytic efficiency of CocE against (-)- cocaine. The higher the catalytic efficiency of the enzyme against (-)-cocaine the lower the dose required to achieve therapeutic effectiveness and the decrease in dose can reduce the overall immunological response. Hence we will focus on the rational design discovery and preclinical testing of CocE mutants with an improved catalytic efficiency against (-)-cocaine. The rational design of high-activity mutants of CocE against (-)-cocaine requires a detailed understanding of the mechanism for CocE-catalyzed hydrolysis of cocaine. This mechanism can be understood by performing computational studies using the state-of-the-art computational techniques of molecular modeling simulation and calculation. The specific aims include: (1) Elucidation of the detailed mechanism and reaction coordinate and the corresponding free energy profiles for CocE-catalyzed hydrolysis of cocaine by performing quantum mechanical (QM) calculations hybrid quantum mechanical/molecular mechanical (QM/MM) calculations and molecular dynamics (MD) simulations etc. (2) Design discovery and testing of CocE mutants with an improved catalytic efficiency against (-)-cocaine by using a recently developed novel computational design approach based on the transition state modeling and simulation to computationally evaluate a large number of hypothetical CocE mutants followed by wet experimental tests including site-directed mutagenesis protein expression and purification and in vitro and in vivo activity tests. The long-term objective of this investigation will be to eventually develop an efficient anti-cocaine medication using a high-activity mutant of CocE. PUBLIC HEALTH RELEVANCE: Enhancing cocaine metabolism by administration of cocaine esterase (CocE) has been recognized as a promising treatment strategy for cocaine overdose and addiction. The high-activity mutants of CocE to be designed and discovered in this project will eventually lead to an efficient anti-cocaine medication.

project_terms:
Adverse effects;Behavioral;Catalysis;Cocaine;Cocaine Dependences;Computational Technique;Coupled;Dose;Drug Addiction;Enzymes;Evaluation;Free Energy;Health;Hybrids;Hydrolysis;In Vitro;Investigation;Lead;Mechanics;Metabolism;Modeling;Molecular;Molecular Models;Performance;Pharmaceutical Preparations;Preclinical Testing;Process;Protocols documentation;Reaction;Rodent Model;Roentgen Rays;Site-Directed Mutagenesis;Structure;Testing;Toxic effect;base;cocaine esterase;cocaine overdose;cocaine use;computer studies;design;esterase;immunogenicity;improved;in vivo;models and simulation;molecular dynamics;molecular modeling;mutant;novel;preclinical study;prevent;protein expression;protein purification;quantum;response;therapeutic effectiveness;three dimensional structure;treatment strategy


application_id: 8286331
project_number: 5R01NS062993-04
project_title: Cyclophilin D as a Therapeutic Target following Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2012-06-27
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 062993
program_official: HICKS, RAMONA R
project_start_date: 2009-07-15
project_end_date: 2014-06-30
study_section: Special Emphasis Panel[ZRG1-BDCN-T(03)M]
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W.
other_pis: SULLIVAN, PATRICK G
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The goal of this research is to minimize the secondary cell death and resultant morbidity following traumatic brain injury (TBI). Clinical interventions to improve outcome following TBI are extremely limited. Mitochondrial dysfunction is a pivotal link in the neuropathological sequalae of traumatic brain injury (TBI). TBI-induced increases in mitochondrial Ca2+ cycling/overload ultimately lead to opening of the mitochondrial permeability transition pore (mPTP). This pore located on the inner mitochondrial membrane opens in response to elevated Ca2+ and oxidative stress and is gated by the mitochondrial protein cyclophilin D (CypD). When prolonged mPTP opening is catastrophic as a result of the loss of mitochondrial membrane potential and the release of calcium and death-related proteins from mitochondria. The goal of this research is to minimize the secondary cell death and resultant morbidity following TBI by limiting mPTP opening. The immunosuppressant Cyclosporin A (CsA) inhibits mPTP opening by binding to CypD. We and others previously demonstrated that CsA reduces the extent of tissue damage when administered following experimental TBI. Unfortunately CsA is toxic at high concentrations resulting from its inhibition of calcineurin. Recently we have demonstrated that CypD levels in primary neurons are approximately double the levels found in astrocytes and that CypD levels are also significantly higher in synaptic mitochondria (neuronal origin) compared to non-synaptic mitochondria (predominately non-neuronal origin). As a result of their high CypD content we hypothesize that neuronal mitochondria are more vulnerable to mPTP opening and also require greater CsA levels to inhibit mPTP opening. To test this hypothesis we propose to use genetic and newer pharmacologic approaches to inhibit CypD following neuronal injury. Specifically we will use CypD knockout mice and a CsA derivative NIM811 which does not bind to or inhibit calcineurin. The specific aims are: 1: To evaluate the hypothesis that the high CypD content of neuronal mitochondria enhances vulnerability to mPTP opening following insults that result in elevated intracellular Ca2+ and oxidative stress. 2: To evaluate the hypothesis that the levels of the CypD inhibitor NIM811 required to protect neurons from excitotoxic insult is proportional to their CypD content. 3: To examine the hypothesis that mitochondrial CypD levels modulate the neuropathologic and functional outcome following TBI in mice. 4: To examine the hypothesis that CypD inhibitor NIM811 reduces tissue damage and improves functional outcome following TBI. Based on the results of these studies we anticipate that NIM811 will exhibit strong potential as novel therapy for TBI. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a devastating healthcare problem in the United States with no pharmacological treatments currently approved for clinical intervention following injury. Improved TBI treatment options are urgently needed. This proposal examines the potential of NIM811 a derivative of CsA to limit the brain damage and dysfunction resulting from TBI.

project_terms:
Abbreviations;Adenine Nucleotide Translocase;Adenine Nucleotides;Affinity;Amino Acids;Animal Model;Astrocytes;Attenuated;Binding (Molecular Function);Binding Proteins;Blood - brain barrier anatomy;Brain Injuries;Calcineurin;Calcium;Calpain;Cell Death;Cessation of life;Chemical Structure;Cleaved cell;Clinical;Clinical Trials;Cyclophilin A;Cyclophilins;Cyclosporine;Cyclosporins;Cytosol;Dose;Endoplasmic Reticulum;Event;Exhibits;Functional disorder;Generic Drugs;Genes;Genetic;Goals;Health;Healthcare;Heterozygote;Hydrogen Peroxide;Immunosuppressive Agents;In Vitro;Injury;Inner mitochondrial membrane;Intervention;Isoleucine;Knockout Mice;Lead;Link;Liver Mitochondria;Membrane Potentials;Mitochondria;Mitochondrial Matrix;Mitochondrial Proteins;Mitochondrial Swelling;Modeling;Morbidity - disease rate;Mus;N-Methylaspartate;Names;Neuroglia;Neuronal Injury;Neurons;Nomenclature;Outcome;Oxidative Stress;Peptidylprolyl Isomerase;Performance;Permeability;Pharmaceutical Preparations;Pharmacological Treatment;Proteins;Rattus;Reactive Oxygen Species;Research;Specificity;Staging;Synapses;Synaptosomes;Testing;Tissues;Toxic effect;Traumatic Brain Injury;United States;Wallerian Degeneration;analog;apoptosis inducing factor;base;calcium green;caspase;cis-trans-Isomerases;controlled cortical impact;cyclophilin D;endonuclease G;functional outcomes;improved;in vivo;inhibitor/antagonist;leucine methyl ester;mitochondrial dysfunction;mitochondrial membrane;mitochondrial permeability transition pore;neuron loss;novel;response;solute;therapeutic target

public_health_relevance:
Traumatic brain injury (TBI) is a devastating healthcare problem in the United States with no pharmacologicaltreatments currently approved for clinical intervention following injury. Improved TBI treatment options areurgently needed. This proposal examines the potential of NIM811 a derivative of CsA to limit the braindamage and dysfunction resulting from TBI.


application_id: 8286239
project_number: 5R01GM079684-05
project_title: The Regulation of Smoothened in Hedgehog Signaling
administering_ic: NIGMS
award_notice_date: 2012-06-27
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 079684
program_official: HOODBHOY, TANYA
project_start_date: 2008-07-01
project_end_date: 2014-06-30
study_section: Development - 1 Study Section[DEV1]
contact_pi_person_id: 8575677
contact_pi: JIA, JIANHANG
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):     The hedgehog (hh) family members control many aspects of development in both vertebrates and invertebrates. Hh signaling is associated with important biological phenomena such as patterning cell growth and morphogenesis. Abnormal activation of this pathway has been observed in several types of human cancers. The seven-pass transmembrane protein Smoothened (Smo) is required in both insects and mammals for transduction of the Hh signal. Our strategy is to use Drosophila as a simple and genetically tractable model system to explore the mechanisms of Hh signal transduction. The long-term goal of our research is to elucidate how Hh signals are sensed and transmitted to control downstream biological events that ultimately govern cell growth and patterning. We showed that Smo transduces the Hh signals by directly recruiting a Costal2-Fused (Cos2-Fu) complex. We also showed that Smo activation requires phosphorylation by protein kinase A (PKA) and casein kinase I (CKI) and that phosphorylation leads to increased Smo cell-surface levels and signaling activity. We recently uncovered a feedback mechanism by which Fu promotes Smo hyperphosphorylation and cell-surface accumulation by antagonizing Cos2. These findings provide new tools and hypotheses to investigate the mechanisms of Hh signaling at the cell membrane. In this project our central hypothesis is that Smo cell-surface accumulation and signaling activity are regulated by multiple kinases while phosphatase(s) act as inhibitory components to attenuate Smo activation. To test our hypothesis we will use a combination of genetic and biochemical approaches in three Specific Aims: 1) To further determine if differential Smo phosphorylation transduces gradient Hh activity; 2) to investigate the molecular mechanisms by which G protein-coupled receptor kinase 2 (GRK2) is involved in Hh signaling; and 3) to determine the role of phosphatase in Smo dephosphorylation and inactivation. HEALTH RELEVANCE Abnormal Smoothened (Smo) activation results cancers such as basal cell carcinoma (BCC) and medulloblastoma. Investigation of the Smo signaling mechanisms will provide both insights into fundamental developmental problems and new avenues for developing diagnostic tools and therapeutical treatments of cancers. PHS 398/2590 (Rev. 09/04 Reissued 4/2006) Page Project Narrative

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


application_id: 8286234
project_number: 5R01AR059810-02
project_title: TAK1/TRAF6 Signaling in Skeletal Muscle
administering_ic: NIAMS
award_notice_date: 2012-06-29
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AR
serial_number: 059810
program_official: BOYCE, AMANDA T
project_start_date: 2011-07-01
project_end_date: 2016-06-30
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1917770
contact_pi: KUMAR, ASHOK
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adult;Affect;Aging;Apoptosis;Area;Atrophic;Biochemical;Biology;Calcineurin;Cell Culture Techniques;Cell Cycle Arrest;Cell Line;Cell Surface Proteins;Cells;Child;Chronic;Chronic Disease;Chronic Obstructive Airway Disease;Complex;Complication;Cytoplasmic Tail;Data;Denervation;Development;Disease;Drug Delivery Systems;Elements;Embryonic Development;Endocrine;Event;Family;Fiber;Genetic;Growth;Health;Heart failure;Human;Impairment;Inflammation;Knockout Mice;Laboratories;Lead;Link;Lysine;MAP Kinase Gene;MAP3K7 gene;MAPK14 gene;Maintenance;Malignant Neoplasms;Mediating;Methods;Molecular Target;Muscle;Muscle Development;Muscle Fibers;Muscular Atrophy;Myoblasts;Myopathy;Natural regeneration;Neonatal;Nude Mice;Pathway interactions;Perinatal;Phenotype;Phosphotransferases;Physiological;Play;Polyubiquitin;Process;Protein Biosynthesis;Proteins;Regulation;Rhabdomyosarcoma;Role;Sepsis;Signal Transduction;Signal Transduction Pathway;Skeletal muscle structure;Staging;Stem cells;Stimulus;Stress;System;TRAF6 gene;Testing;Transforming Growth Factors;Travel;Tumor Necrosis Factor Receptor;Ubiquitination;autocrine;base;human morbidity;human mortality;improved;in vivo;injured;insight;mouse model;muscle form;muscle regeneration;myogenesis;novel;paracrine;postnatal;prevent;protein degradation;repaired;response to injury;sarcopenia;satellite cell;skeletal muscle growth;skeletal muscle wasting;transcription factor NF-AT c3;ubiquitin-protein ligase;wasting


application_id: 8284297
project_number: 5R25GM083835-05
project_title: Appalachian Kentucky Bridges to Success
administering_ic: NIGMS
award_notice_date: 2012-07-31
opportunity_number: PAR-07-039
application_type: 5
activity_code: R25
ic: GM
serial_number: 083835
program_official: HAMLET, MICHELLE R
project_start_date: 2008-07-11
project_end_date: 2014-03-30
study_section: Special Emphasis Panel[ZRG1-IMM-A(50)R]
contact_pi_person_id: 8581205
contact_pi: KNOX, TAMARA L.
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Kentucky has set a goal of increasing the educational attainment level of the Commonwealth to the national average by 2020 and to do this Kentucky needs to double the number of baccalaureate degree holders over the next 14 years from roughly 400000 in 2000 to nearly 800000 by 2020. This goal is especially daunting for educational institutions serving the eastern (Appalachian) region of Kentucky. Recent research has shown that students entering the Kentucky Community and Technical College System (KCTCS) and 4-year universities that serve the regions with the greatest need (largely comprised of eastern Kentucky) were the least prepared for college study of all students in the state. To address this problem a collaboration between the Hazard Community and Technical College University of Kentucky Center for Excellence in Rural Health and University of Kentucky has been developed to propose a program to engage promising rural Appalachian community college students in academic research psychosocial and financial support networks to enable them to successfully complete their baccalaureate degree in the biomedical or behavioral sciences. This application proposes to: (a) recruit program participants from HCTC; (b) carefully assess participants' learning- related skills and deficits; (c) provide a program that includes mentoring instruction in skills necessary to be successful in 4-year institutions of higher learning structured experiences to expose participants to career options and group support; (d) facilitate participants' efforts to transfer from community college to 4-year institutions; (e) carefully evaluate each component of the program; and (f) track participants to document and assess participant experience at 4-year institutions. Program evaluation milestones will include the successful recruitment retention transfer and graduation of promising students in the biomedical and behavioral sciences; increased communication between faculty at community colleges and baccalaureate institutions; faculty participation in transfer initiatives and program development that promotes the seamless transition of students between participating institutions; development of programs that advance and improve science teaching and mentoring; and development of program resources.    This project proposes to develop a comprehensive program for community college students in southeastern Kentucky a region with very low educational levels. The program will include instruction and experiences to increase participants' awareness of career options mentoring and support in applying to transfer from community college to 4-year educational institutions. The program will be evaluated rigorously and will include documentation of all activities assessment of participant progress and follow-up after transfer from the community college.

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


application_id: 8282944
project_number: 5R01DE009761-20
project_title: BACTERIAL PROTEINASES IN PERIODONTAL DISEASE
administering_ic: NIDCR
award_notice_date: 2012-06-11
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DE
serial_number: 009761
program_official: LUNSFORD, DWAYNE
project_start_date: 1991-08-01
project_end_date: 2014-06-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6947603
contact_pi: POTEMPA, JAN S
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): Periodontitis is classified as a microbiota shift disease whereby a very rich and diverse commensal flora characteristic for good oral health becomes dominated by several Gram-negative anaerobic bacterial species among which Porphyromonas gingivalis Tannerella forsythia and Treponema denticola constitute the so called "red complex" of microorganisms frequently associated with the development and progression of the disease. The common consequence of these three bacteria and a secondary periodontopathogen Prevotella intermedia is their production of proteolytic enzymes. Proteases of P. gingivalis and T. denticola are known to dysregulate tissue homeostasis and/or to frustrate defensive inflammatory responses thus significantly contributing to pathological changes in the infected periodontium. In contrast virtually nothing is known about proteases of T. forsythia and P. intermedia although it has been well documented that proteases from the former organism are produced in vivo and their activity correlates with periodontal destruction. Here we postulate that novel proteases produced by T. forsythia (forsypsin) and P. intermedia (interpains) promote periodontal tissue damage by deregulation of tightly controlled host proteolytic systems. Furthermore we suggest that the combined proteolytic activity produced locally by periodontopathogens may be a primary mechanism for synergistic periodontal tissue damage and contributes to mutual survival of the red complex bacteria. Most interestingly we have found that forsypsin and interpains as well as many other acknowledged virulence factors of P. gingivalis and T. forsythia share with gingipains a conserved C-terminal domain. We have shown that this domain together with a unique periplasmic protein and a unique outer membrane translocon protein conserved in these species is essential for gingipain secretion. This implies that a novel bacterial protein export system is employed by periodontopathogens to secrete a number of confirmed and putative virulence factors. For these reasons the specific aims of this project are as follows: 1) to use an array of biochemical and molecular biological methods to investigate the mechanism of gingipain translocation through the outer membrane of P. gingivalis and confirm the presence of this unique secretion pathway in both T. forsythia and P. intermedia; 2) to characterize novel proteases from T. forsythia and P. intermedia especially with regard to their ability to complement and/or synergize with the gingipain activity and 3) to determine the complementary or synergistic role of proteases from P. gingivalis T. forsythia and P. intermedia for in vivo proliferation and dissemination of bacteria in monomicrobial and mixed microbial infections using a murine chamber model.     PUBLIC HEALTH RELEVANCE: The results of these proposed studies should not only illuminate the synergistic role of bacterial proteases in mixed infections but also shed light on a novel pathway for the secretion of virulence factors unique to P. gingivalis T. forsythia and P. intermedia. This insight may enable the design of antibodies or chemical compounds to block the export of multiple virulence factors from major periodontopathogens which in the long term may revolutionize treatment and prophylaxis of periodontal disease.

project_terms:
Affect;Albumins;Anti-Bacterial Agents;Antibodies;Bacteria;Bacterial Proteins;Bacteroidetes;Biochemical;Biological;Blood Circulation;C-terminal;Cell Surface Receptors;Cell surface;Characteristics;Chemicals;Coagulation Process;Complement;Complex;Cysteine Protease;Data;Development;Disease;Disease Progression;Elements;Enzymes;Extracellular Protein;Fibrinolysis;Forsythia;Foundations;Future;Goals;Gram-Negative Bacteria;Heavy-Chain Immunoglobulins;Homeostasis;Homologous Gene;Host Defense;Host Defense Mechanism;Human;Infection;Inflammatory Response;Injury;Kinins;Light;Link;Mediating;Membrane;Membrane Proteins;Methods;Modeling;Modus;Molecular;Mono-S;Mus;Nutrient;Oral health;Organism;Outcome;Pathway interactions;Peptide Hydrolases;Periodontal Diseases;Periodontal Infection;Periodontitis;Periodontium;Periplasmic Proteins;Plasma;Play;Porphyromonas gingivalis;Prevention;Preventive Intervention;Prevotella intermedia;Production;Progress Reports;Properdin;Property;Prophylactic treatment;Protein Export Pathway;Protein Secretion;Protein translocation;Proteins;Research;Role;Secretory Component;Seminal;Signal Transduction;Site;Solid;Structure;System;Testing;Therapeutic;Therapeutic Intervention;Tissues;Treponema denticola;Trypsin;Virulence;Virulence Factors;antibody inhibitor;arginyllysine;base;design;drug development;gingipain;human MADHIP protein;in vivo;inhibitor/antagonist;insight;microbial;microbial community;microorganism;mutant;neutrophil;novel;pathogen;periodontopathogen;proteinase In;public health relevance;streptopain


application_id: 8282631
project_number: 5R01AI091953-02
project_title: Viral and Cellular Determinants of HCV Assembly
administering_ic: NIAID
award_notice_date: 2012-05-02
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AI
serial_number: 091953
program_official: KOSHY, RAJEN
project_start_date: 2011-06-15
project_end_date: 2012-09-30
study_section: Virology - A Study Section[VIRA]
contact_pi_person_id: 6801917
contact_pi: LUO, GUANGXIANG GEORGE
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): Hepatitis C virus (HCV) infection continues to be a major burden on public health affecting approximately 170 million people worldwide and 3-4 million Americans. HCV-associated end-stage liver disease is the leading indicator of liver transplantation. Current standard therapy with pegylated interferon-? in combination with ribavirin only achieves limited (<50%) antiviral response and causes severe side effects. The HCV protease- and polymerase-specific inhibitors currently in clinical trials are promising but are undermined by rapid emergence of drug-resistant HCV mutants. Future antiviral therapy for hepatitis C likely requires a combination of several drugs targeting different steps of the HCV life cycle. The lack of knowledge about the molecular details of the HCV life cycle has significantly impeded the discovery and development of antiviral drugs against HCV infection. A more complete understanding of the roles of viral and cellular proteins in the HCV life cycle will provide additional novel targets for anti-HCV drug discovery. Our recent studies have demonstrated that human apolipoprotein E (apoE) is an important determinant for the outcomes of HCV infection and assembly. ApoE was also found to interact with the HCV NS5A in our preliminary studies. In Specific Aim 1 we will dissect apoE domains and amino acid residues important for its dual functions in HCV infection and assembly. We will also determine the importance and the underlying molecular mechanisms of apoE and its interaction with NS5A in HCV infection and assembly respectively. In preliminary studies we have demonstrated that adaptive mutations in the HCV non-structural (NS) proteins greatly enhanced HCV production and cytopathogenicity in cell culture. We have also found that HCV NS proteins interact with viral structural proteins as demonstrated by experiments with the mammalian two-hybrid system and co-immunoprecipitation assay. Consistent with our findings recent genetic studies done by others suggest that HCV NS proteins play important roles in HCV assembly and/or production. However the underlying molecular mechanisms of the HCV NS proteins in the HCV life cycle have not been defined. In Specific Aim 2 we will decipher the roles and mechanisms of action of cell culture adaptive mutations in HCV assembly and induction of cytopathogenicity. In Specific Aim 3 we will determine the importance of viral NS proteins and their interactions with structural proteins in HCV assembly. We will accomplish these specific aims using a robust HCV reverse genetics system recently developed in our lab in conjunction with mutagenesis studies and the use of biochemical immunological and cell biological approaches. New knowledge derived from these studies will lead to a paradigm shift in virology with respect to the roles of viral NS proteins in HCV assembly. Our studies will also provide novel targets for discovery of antiviral drugs to effectively treat hepatitis C.

project_terms:
Address;Adverse effects;Affect;American;Amino Acids;Antiviral Agents;Antiviral Response;Antiviral Therapy;Apolipoprotein E;Binding (Molecular Function);Biochemical;Biological;Biological Assay;Cell Culture System;Cell Culture Techniques;Cells;Cessation of life;Cirrhosis;Clinical Trials;Co-Immunoprecipitations;Combined Modality Therapy;Development;Drug Delivery Systems;Drug resistance;Ectopic Expression;Future;Genetic;Genome;Genotype;Goals;HCV Vaccine;Hepatitis;Hepatitis C;Hepatitis C Therapy;Hepatitis C virus;Human;Infectious hepatitides;Interferons;Knowledge;Lead;Life Cycle Stages;Liver diseases;Molecular;Mutagenesis;Mutation;Outcome;Peptide Hydrolases;Play;Polymerase;Primary carcinoma of the liver cells;Production;Protein Isoforms;Proteins;RNA Sequences;RNA replication;Research;Research Design;Ribavirin;Role;Sequence Analysis;Staging;Structural Protein;Structure;System;United States;Variant;Viral;Viral Nonstructural Proteins;Viral Proteins;Viral Structural Proteins;Virion;Virus;Virus Assembly;anti-hepatitis C;base;drug development;drug discovery;inhibitor/antagonist;liver transplantation;mutant;novel;positional cloning;public health medicine (field);research study;viral RNA;virology;yeast two hybrid system

public_health_relevance:
Hepatitis C virus (HCV) infection continues to be a major burden on public heath affecting approximately 170 million people worldwide and 4 million Americans. Our overall objective is to determine the roles and mechanisms of action of viral and cellular proteins that determine the outcomes of HCV infection and production. Our proposed studies will provide new knowledge and novel targets for discovery and development of antiviral drugs for treatment of HCV infection.


application_id: 8281508
project_number: 5R01HL072936-07
project_title: Regulation of Calcium Channel Function by the Rem GTPase
administering_ic: NHLBI
award_notice_date: 2012-04-30
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 072936
program_official: LATHROP, DAVID A
project_start_date: 2003-04-15
project_end_date: 2014-04-30
study_section: Electrical Signaling, Ion Transport, and Arrhythmias Study Section[ESTA]
contact_pi_person_id: 7875195
contact_pi: ANDRES, DOUGLAS ALLEN
other_pis: SATIN, JONATHAN
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): Voltage-activated Ca channels serve two critical functions: the regulation of cellular excitability and the regulation of Ca entry. Alterations in the density or function of L-type Ca channels are implicated in a variety of cardiovascular diseases. Thus elaborating the basic mechanisms that regulate Ca channels is important for understanding both fundamental channel physiology and for therapeutic intervention. During the past funding period we have identified the Rem GTPase as a novel modulator of I(Ca). It was originally thought that Rem association with CaVbeta- subunits chronically regulated I(Ca) by inhibiting channel trafficking. Our studies have disproved this hypothesis demonstrating Rem-mediated Ca channel regulation without changes in surface density. Instead Rem seems to modulate Ca channel activity through interactions with both CaVbeta and the proximal CaV1.2 C-terminus near the CB/IQ domain. Two of the most physiologically relevant controls of I(Ca) are PKA-modulation and calmodulin (CaM)-modulation. Our most recent studies suggest that Rem modulates I(Ca) responses to each of these signaling pathways. Thus Rem appears to contribute to both beta-adrenergic and Ca-CaM control of I(Ca). The specific hypothesis to be tested is that Rem GTPase regulates Ca channel activity in cardiac muscle through interactions with both CaVb-subunits and the CaV1.2 C- terminus. Three hypothesis driven aims focus our studies and advance knowledge of this novel regulatory mechanism. Aim 1 will explore the nature of Rem-mediated channel regulation by examining the effect of Rem loss on Ca channel regulation. Initial characterization of Rem knockout mice indicates that i) Rem functions in vivo to regulate I(Ca); ii) contributes to the cardiac response to pressure-overload; and iii) contributes to cardiac myocyte growth/maturation homeostasis. Aim 2 will determine whether interaction of Rem with CaVbeta or CB/IQ is critical for modulation of I(Ca). Aim 3 will investigate how Ca- calmodulin modulates Rem-mediated channel blockade and determine whether PKA phosphorylation alters Rem membrane trafficking or the interaction between Rem and its binding partners. RGK G-proteins function as modulators of Ca channel activity contributing to regulation of I(Ca) excitation- contraction coupling and the cardiac response to pressure-overload. The goal of this research is to generate a deeper understanding of the physiological ramifications and molecular mechanism of RGK/Ca channel modulation to speed progress toward the therapeutic exploitation of RGKs in cardiovascular disease.    PUBLIC HEALTH RELEVANCE: Voltage-activated calcium channels serve two critical functions:  the regulation of calcium entry and the control of heart contraction.  Changes in the number or function of L-type calcium channels are implicated in a variety of cardiovascular disease including atrial fibrillation heart failure and ischemic heart disease.  Thus understanding the basic mechanisms that regulate calcium cannels is important in understanding both fundamental heart muscle performance and for therapeutic intervention.  We have identified a family of proteins that regulate calcium channels and the goal of this research is to speed progress toward the day when these proteins can be used to treat heart disease.

project_terms:
Adrenergic Agents;Animal Model;Atrial Fibrillation;Attenuated;Binding (Molecular Function);Biochemical;Calcium;Calcium Channel;Calmodulin;Cardiac;Cardiac Myocytes;Cardiovascular Diseases;Cell membrane;Chronic;Complex;Coupling;Critiques;Cyclic AMP-Dependent Protein Kinases;Echocardiography;Family;Funding;GTP-Binding Proteins;Goals;Grant;Growth;Guanosine Triphosphate Phosphohydrolases;Health;Heart;Heart Diseases;Heart Hypertrophy;Heart failure;Histology;Homeostasis;Knock-out;Knockout Mice;Knowledge;L-Type Calcium Channels;Measurement;Mediating;Membrane Protein Traffic;Molecular;Monomeric GTP-Binding Proteins;Myocardial Contraction;Myocardial Ischemia;Myocardium;Nature;Performance;Phosphorylation;Physiological;Physiology;Process;Protein Family;Proteins;Regulation;Regulatory Pathway;Research;Role;Signal Pathway;Signal Transduction;Site-Directed Mutagenesis;Speed (motion);Surface;Testing;Therapeutic;Therapeutic Intervention;Transcriptional Regulation;Transgenic Organisms;adrenergic;cell growth regulation;density;heart function;in vivo;insight;member;mutant;novel;overexpression;pressure;protein function;response;stoichiometry;trafficking;voltage

public_health_relevance:
Project Narrative:Voltage-activated calciwn channels serve two critical functions: the regulation of calciwn entry and the control of heart contraction. Changes in the nwnber or function of L-type calcium channels are implicated in a vartety of cardiovascular diseases including atrial fibrillation heart failure and ischemic heart disease. Thus understanding the basic mechanisms that regulate calcium channels is important for understanding both fundamental heart muscle performance and for therapeutic intervention. We have identified a family of proteins that regulate calcium channels and the goal of this research is to speed progress toward the day when these proteins can be used to treat heart disease.


application_id: 8281461
project_number: 5R01GM086888-05
project_title: Geometry of gene cophylogenies as relates to genome evolution and speciation
administering_ic: NIGMS
award_notice_date: 2012-06-15
opportunity_number: RFA-GM-08-607
application_type: 5
activity_code: R01
ic: GM
serial_number: 086888
program_official: ECKSTRAND, IRENE A
project_start_date: 2008-08-01
project_end_date: 2014-06-30
study_section: ZGM1-CBCB-5(BM)
contact_pi_person_id: 9408221
contact_pi: YOSHIDA, RURIKO
other_pis: Not Applicable
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  A fundamental understanding of microbial genome and species evolution as well as human genome evolution is important for public health and medical science. This proposal addresses the concept of codivergence i.e. the divergence of one gene or species lineage concomitantly with the divergence of another. In this process two or more lineages stay closely associated with one another:  In this process two or more lineages stay closely associated with one another: genes with species and hosts with pathogens parasites or symbionts. Deviations from codivergence that are increasingly recognized in pathogen and human genomes include gene duplications lateral gene transfers between species retention of ancestral polymorphisms by balancing selection and accelerated evolution by neofunctionalization. This project will bring together complementary expertise and cross-train students in algebraic geometry and mathematical biology molecular biology and evolution of symbiotic systems and computer science and bioinformatics. The investigators propose to: (1) develop a new statistical model and corresponding methods and algorithms for simultaneous derivation of pairs of gene trees to allow rigorous tests of their codivergence or deviation from codivergence; (2) design and develop software that efficiently implements these new methods; and (3) apply such methods to the large number of genes available from genome sequences in order to better assess the history of speciation and genome evolution. Unlike existing methods based on independently constructed phylogenetic trees a novel statistical model is proposed based on polyhedral and algebraic geometry to determine whether sets of gene sequences exhibit codivergence. The method will develop two or more trees jointly to better reflect the properties of codivergent lineages. This approach will be implemented together with phylogenomic tools to characterize ancestral genomes or species modeling most-recent common ancestor species as "clouds" of associated gene lineages with related but nonidentical gene tree topologies. Because exact algorithms for these techniques will be computationally impractical for genome-scale data sets heuristics and approximations will also be developed and tested. The proposed methods will be applicable to a broad array of biological problems such as identifying codivergent and noncodivergent gene sets in whole genomes evaluating possible host-parasite codivergence and coevolution and testing codivergence of modules in multi-modular enzymes. In this project teams of students both graduate and undergraduate from all of the represented disciplines will conduct joint projects. They will learn how to gather sequence data design and use bioinformatic tools and analyze biological data with mathematics and statistics to infer gene and species relationships. Additionally a new phylogenetics course building on an existing interdisciplinary Informatics Certificate curriculum will be offered to graduate students.

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


application_id: 8281092
project_number: 1K99DA033373-01
project_title: Tonic and Phasic Glutamate Release in Incentive Salience and Cocaine Reinforcemen
administering_ic: NIDA
award_notice_date: 2012-04-09
opportunity_number: PA-11-197
application_type: 1
activity_code: K99
ic: DA
serial_number: 033373
program_official: AVILA, ALBERT
project_start_date: 2012-05-01
project_end_date: 2014-04-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 9713925
contact_pi: BECKMANN, JOSHUA
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The proposed career development plan is designed to provide the PI with a unique skill set and experience to meet the short-term goal of becoming a productive independent researcher and long-term goal of becoming a significant contributor to the understanding and treatment of substance abuse disorders. The plan will be carried out at the University of Kentucky an institution with a rich history of interdisciplinary substance abuse
research. The PI will be mentored by Dr. Michael Bardo and co-mentored by Dr. Greg Gerhardt established experts in neuropsychopharmacology and neurochemistry respectively. The plan proposes to use enzyme based microelectrode arrays to uncover the role of sub-second tonic/physic mesocorticolimbic glutamate release in individual differences in incentive salience/value attribution to reward-related cues and cocaine reinforcement in a preclinical rat model. When a stimulus reliably predicts reward some animals attribute incentive value to the stimulus and thus will approach and contact it (sign-trackers); other animals use the stimulus as a simple signal of forthcoming reward and thus will approach the receptacle into which reward will be delivered (goal-trackers). Recently it has been demonstrated that differences in sign and goal tracking are related to novelty seeking impulsivity initial vulnerability to cocaine reinforcement and relapse vulnerability. In addition to mesocorticolimbic dopamine stimulus-reward learning and drugs of abuse are known to alter mesocorticolimbic glutamate signaling. The overall proposed hypothesis is that differences in incentive value attribution are mediated by differential mesocorticolimbic glutamate release upon cue exposure; this differential release is then exacerbated by repeated cocaine self-administration giving rise to differential substance abuse vulnerability and relapse. Specific Aim 1 will determine if second-by-second tonic/physic glutamate signaling is differentially affected by food-associated cues in sign- vs. goal-tracking animals. Specific Aim 2 will determine the role of dopaminergic receptor function on the expression of sign-/goal tracking and underlying tonic/physic glutamate signaling. Specific Aim 3 will determine if second-by-second tonic and physic glutamatergic signaling in sign- and goal-tracking animals changes differentially with repeated cocaine self-administration. Specific Aim 4 will then determine the role of dopaminergic receptor function on cocaine self-administration and tonic/physic glutamate signaling in sign- and goal-trackers. Collectively these results will provide insight into the role of tonic/physic glutamate signaling in stimulus reward learning incentive value attribution to reward-associated stimuli and cocaine reinforcement while providing the PI with unique training in neuropsychopharmacology and neurochemistry by experts in both fields.     
   
PUBLIC HEALTH RELEVANCE: The proposed studies will provide insight into the underlying mechanisms that accompany individual differences in substance abuse disorders that may aid in the development of novel therapies for abuse disorders involving stimulants.  Although many people may experiment with drugs of abuse few come to develop a substance use disorder. These individual differences suggest that some people may be more or less prone to develop such disorders. These individual differences may be related to differential attribution of incentiv value to reward-related stimuli; the broad goal of this research is to identify the underlying neurochemical basis for individual differences in substance abuse vulnerability and will be beneficial in identifying novel pharmacological targets for the development of substance abuse pharmacotherapies.

project_terms:
Abstinence;Addictive Behavior;Affect;Animals;Behavior;Cell Nucleus;Chronic;Cocaine;Control Animal;Cues;Development;Development Plans;Disease;Dopamine;Dopamine Antagonists;Dopamine Receptor;Enzymes;Exhibits;Food;Glutamates;Goals;Impulsivity;Incentives;Individual;Individual Differences;Institution;Kentucky;Learning;Maintenance;Mediating;Mentors;Microdialysis;Microelectrodes;Modeling;Neurons;Pharmaceutical Preparations;Pharmacotherapy;Phase;Physics;Play;Psychological reinforcement;Rattus;Receptor Inhibition;Recording of previous events;Relapse;Relative (related person);Research;Research Personnel;Resolution;Rewards;Role;Schedule;Self Administration;Self-Administered;Signal Transduction;Stimulus;Substance Use Disorder;Substance abuse problem;Technology;Time;Training;Universities;awake;base;career development;classical conditioning;cocaine exposure;design;drug of abuse;experience;insight;meetings;neurochemistry;novel;pre-clinical;prevent;receptor function;research study;response;skills;substance abuse treatment

public_health_relevance:
The proposed studies will provide insight into the underlying mechanisms that accompany individual differences in substance abuse disorders that may aid in the development of novel therapies for abuse disorders involving stimulants.  Although many people may experiment with drugs of abuse few come to develop a substance use disorder. These individual differences suggest that some people may be more or less prone to develop such disorders. These individual differences may be related to differential attribution of incentiv value to reward-related stimuli; the broad goal of this research is to identify the underlying neurochemical basis for individual differences in substance abuse vulnerability and will be beneficial in identifying novel pharmacological targets for the development of substance abuse pharmacotherapies.


application_id: 8280393
project_number: 5R01DK048498-18
project_title: Surgical Studies of Functional Gene Expression
administering_ic: NIDDK
award_notice_date: 2012-06-05
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 048498
program_official: SERRANO, JOSE
project_start_date: 1996-03-15
project_end_date: 2014-05-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
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 mammalian intestinal mucosa is in a constant state of renewal that is characterized by active proliferation of stem cells localized in the crypts progression of these cells up the crypt villus axis with cessation of proliferation and subsequent differentiation. A delicate and precise balance of proliferation -> differentiation -> apoptosis must exist in the gut mucosa to maintain this normal intestinal homeostasis. Surgical resection of the small intestine results in an adaptive hyperplasia whereas the inability to provide enteral nutrients as occurs in certain post-operative or trauma patients results in atrophy. The major focus of our group has been the analysis of mechanisms regulating intestinal proliferation differentiation adaptation and apoptosis. With the support of this grant we have made great strides in our better understanding of the molecular mechanisms regulating intestinal homeostasis. We have shown that stimulation of PI3K/Akt increases normal intestinal proliferation. Our most recent findings have identified novel and differential roles for the mammalian target of rapamycin (mTOR) protein complex a major downstream effector of PI3K in intestinal proliferation and differentiation and intestinal cell survival. In preliminary findings we have shown that inhibition of mTORC2 but not mTORC1 enhances intestinal cell differentiation suggesting differential effects for these proteins in the gut. Also we have recently described the molecular mechanisms contributing to glutamine-mediated intestinal cell survival and proliferation; the PI3K/mTOR pathway plays an important protective role to limit apoptosis associated with cellular stress. Finally we have demonstrated a novel role for the mTOR pathway in intestinal cell autophagy following glutamine deprivation. Based on our recent published and preliminary findings we have refined our central hypothesis to state that intestinal cell proliferation and differentiation are regulated by signaling mechanisms involving the PI3K/mTOR pathway acting on critical downstream effector proteins; novel and differential effects of mTOR and Akt components exist that further add to the complex but highly regimented regulation of intestinal homeostasis. To examine this hypothesis we have planned experiments with the following Specific Aims: 1) to determine the differential effects of mTOR complexes on intestinal cell homeostasis 2) to delineate the signaling proteins that mediate the effects of mTOR in the intestine and 3) to define the role of mTOR/mTOR complexes in intestinal cell growth in vivo. The studies in the current proposal represent direct extensions of our previous findings and are designed to define in a systematic fashion the molecular mechanisms and signaling events regulating the processes of intestinal proliferation differentiation and adaptation. To achieve our goals we have assembled a multidisciplinary diverse and highly collaborative team of investigators who each bring unique expertise and background to the project.    PUBLIC HEALTH RELEVANCE: The intestinal mucosa is in a constant state of growth and renewal; the molecular pathways contributing to this critical function are poorly understood. Our recent findings have identified novel roles for components of the PI3K/Akt/mTOR signaling pathway in intestinal homeostasis. Delineating the cellular factors and signaling pathways regulating these processes is crucial to our understanding of not only normal gut development and maturation but also the effects of surgical resection and stress on intestinal adaptation and survival.

project_terms:
1-Phosphatidylinositol 3-Kinase;Alkaline Phosphatase;Apoptosis;Atrophic;Autophagocytosis;Brush Border;Cell Differentiation process;Cell Proliferation;Cell Survival;Cell physiology;Cells;Cellular Stress;Characteristics;Chemicals;Complex;Cyclin-Dependent Kinase Inhibitor;Development;Differentiated Gene;Enteral;Enterocytes;Enteroendocrine Cell;Enzymes;Epithelial Cells;Equilibrium;Event;Excision;Gene Expression;Glutamine;Glycogen Synthase Kinase 3;Goals;Goblet Cells;Grant;Growth;Homeostasis;Hyperplasia;Intestinal Mucosa;Intestinal Volvulus;Intestines;Ischemia;MAPK3 gene;MAPK8 gene;Mediating;Molecular;Mucous Membrane;Nutrient;Oligo-16-Glucosidase;Operative Surgical Procedures;PTEN gene;Paneth Cells;Pathway interactions;Patients;Pattern;Play;Postoperative Period;Process;Proliferating;Proteins;Publishing;Regulation;Research Personnel;Role;Signal Pathway;Signal Transduction;Signaling Protein;Small Intestines;Stem cells;Stress;Sucrase;Trauma;Tumor Suppressor Proteins;Villus;base;cell growth;cell type;deprivation;design;in vivo;inhibitor/antagonist;mTOR protein;multidisciplinary;novel;overexpression;protein complex;public health relevance;research study

public_health_relevance:
The intestinal mucosa is in a constant state of growth and renewal; the molecular pathways contributing to thiscritical function are poorly understood. Our recent findings have identified novel roles for components of thePI3K/Akt/mTOR signaling pathway in intestinal homeostasis. Delineating the cellular factors and signalingpathways regulating these processes is crucial to our understanding of not only normal gut development andmaturation but also the effects of surgical resection and stress on intestinal adaptation and survival.


application_id: 8280324
project_number: 5K02DA031766-02
project_title: Medications Development for Cannabis-Use Disorders: Clinical Studies
administering_ic: NIDA
award_notice_date: 2012-07-05
opportunity_number: PA-10-057
application_type: 5
activity_code: K02
ic: DA
serial_number: 031766
program_official: HAMPSON, AIDAN
project_start_date: 2011-07-01
project_end_date: 2016-06-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Abstinence;Address;Admission activity;Adopted;Adverse effects;Agonist;Area;Attenuated;Baclofen;Behavioral Sciences;Biological Assay;Brain;Cannabinoids;Cannabis;Cannabis Smoking;Clinical;Clinical Data;Clinical Research;Clinical Treatment;Clinical Trials;Commit;Communities;Controlled Clinical Trials;Data;Dependence;Development;Development Plans;Diagnostic;Disease;Dose;Drug Combinations;Drug usage;Ecology;Environment;Foundations;Funding;Future;Goals;Gold;Grant;Hybrids;Illicit Drugs;Independent Scientist Award;Individual;Inpatients;Institution;Kentucky;Knowledge;Laboratories;Laboratory Procedures;Laboratory Research;Link;Maintenance;Measures;Mediating;Mentors;Methods;Monitor;Nabilone;Neurons;Neuropharmacology;Outpatients;Persons;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacotherapy;Phase;Population;Procedures;Process;Productivity;Publications;Receptor Cannabinoid CB1;Relapse;Reporting;Research;Research Training;Resistance;Resources;Risk;Safety;Sampling;Screening procedure;Self Administration;Series;Solid;Stimulus;System;Testing;Therapeutic;Time;Toxicology;Training;Treatment Efficacy;Treatment outcome;United States;Universities;Urine;Withdrawal;absorption;base;career;career development;clinical efficacy;clinical practice;cost effective;drug discrimination;drug of abuse;efficacy evaluation;efficacy testing;endogenous cannabinoid system;evidence base;experience;gabapentin;gamma-Aminobutyric Acid;improved;innovation;interest;meetings;next generation;post-doctoral training;post-market research;programs;public health medicine (field);responsible research conduct;safety testing;skills;tiagabine


application_id: 8279944
project_number: 1K23NR013480-01
project_title: Cognitive Therapy for Depressive Symptoms in Hospitalized Patients with Heart Fai
administering_ic: NINR
award_notice_date: 2012-03-27
opportunity_number: PA-11-194
application_type: 1
activity_code: K23
ic: NR
serial_number: 013480
program_official: HUSS, KAREN
project_start_date: 2012-04-01
project_end_date: 2015-03-31
study_section: Special Emphasis Panel[ZNR1 REV-W (09)]
contact_pi_person_id: 8622756
contact_pi: DEKKER, REBECCA
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): This Mentored Patient-Oriented Research Career Development Award will enhance my ability to achieve my long-term career goal of becoming an independent cardiovascular nurse researcher with expertise in testing psychological interventions to improve biobehavioral outcomes of patients with heart failure (HF). One third of hospitalized patients with HF experience major depressive disorder and up to half of patients experience depressive symptoms. Patients with HF and depressive symptoms have worse health-related quality of life and are twice as likely to be rehospitalized or die; thus there is a
critical need to test interventions for the treatment of depressive symptoms in this population. In
this project I will receive formal training and mentorship in cognitive therapy and the conduct of
clinical trials. I will use the skills and competencies I gain to complete the proposed randomized
controlled pilot study which will test the feasibility and efficacy of nurse delivered cognitive therapy for depressive symptoms in patients who are hospitalized with HF. The intervention is an innovative streamlined approach to cognitive therapy consisting of one brief 30-minute session initiated in-person during hospitalization and four 30-minute sessions delivered via phone after discharge. A total of 36 patients with HF who are hospitalized and experiencing moderate to severe depressive symptoms will be randomized to receive either the cognitive therapy intervention or usual care. Data demonstrating feasibility and efficacy of this interventio will be used to develop an R01 application to conduct a larger randomized controlled trial. This study will fill an important gap in the evidence base for depression treatment in patients with HF by demonstrating the feasibility and efficacy of a nurse-delivered cognitive therapy intervention for hospitalized patients with HF. This contribution is significant because interventions designed to treat depressive symptoms may decrease the risk of hospital readmission and improve health-related quality of life among patients with HF who have depressive symptoms.   
   
PUBLIC HEALTH RELEVANCE: People with heart failure often experience depressive symptoms which lead to poor quality of life and an increased risk of death and hospitalization. The intervention for depressive symptoms proposed in this project is designed to be delivered by nurses to a large number of patients. The knowledge gained from this project will help fulfill the need for new treatment strategies for depressive symptoms in people with heart failure that subsequently improve quality of life lower risk of rehospitalization and decrease health care costs.

project_terms:
Address;Adherence (attribute);Antidepressive Agents;Care given by nurses;Cessation of life;Cognitive;Cognitive Therapy;Conduct Clinical Trials;Data;Discipline of Nursing;Dyspnea;Fatigue;Goals;Health;Health Care Costs;Heart;Heart failure;Hospital Readmission;Hospitalization;Hospitals;Human;Intervention;Knowledge;Lead;Length;Long-Term Effects;Major Depressive Disorder;Mental Depression;Mental Health;Mentored Patient-Oriented Research Career Development Award;Mentorship;Mission;Morbidity - disease rate;Mortality Vital Statistics;Nurses;Outcome;Participant;Patients;Persons;Pilot Projects;Population;Psychological Tests;Quality of life;Randomized;Randomized Controlled Trials;Recruitment Activity;Research;Research Personnel;Research Project Grants;Risk;Symptoms;Techniques;Telephone;Testing;Time;Training;Vulnerable Populations;biobehavior;cardiovascular nursing;career;cost effective;depressive symptoms;design;evidence base;experience;group intervention;health related quality of life;high risk;improved;innovation;nursing intervention;post intervention;programs;psychologic;public health medicine (field);skills;symptom management;therapy design;treatment as usual;treatment strategy

public_health_relevance:
People with heart failure often experience depressive symptoms which lead to poor quality of life and an increased risk of death and hospitalization. The intervention for depressive symptoms proposed in this project is designed to be delivered by nurses to a large number of patients. The knowledge gained from this project will help fulfill the need for new treatment strategies for depressive symptoms in people with heart failure that subsequently improve quality of life lower risk of rehospitalization and decrease health care costs.


application_id: 8279153
project_number: 5R21AI096323-02
project_title: Mechanism of inhibition of +RNA virus replication by cyclophilins
administering_ic: NIAID
award_notice_date: 2012-05-02
opportunity_number: PA-10-069
application_type: 5
activity_code: R21
ic: AI
serial_number: 096323
program_official: PARK, EUN-CHUNG
project_start_date: 2011-06-15
project_end_date: 2014-05-31
study_section: Virology - B Study Section[VIRB]
contact_pi_person_id: 7353039
contact_pi: NAGY, PETER
other_pis: Not Applicable
congressional_district: 06
department: OTHER BASIC SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Host factors are key determinants of RNA virus pathology host - virus interactions and evolution of viruses. Recent genome-wide screens with several viruses have identified several host proteins which directly inhibit +RNA virus accumulation. These host proteins might be novel components of the host innate systems against viruses. Among the identified inhibitory host proteins are the family of cyclophilins which are effective against several viruses. Cyclophilins are a large family of ubiquitous highly conserved proteins that have peptidyl-prolyl isomerase and protein chaperone activities. Cyclophilins are involved in several diseases such as human cancers neurodegenerative diseases and viral infections. Determining the mechanism of inhibition by host factors like cyclophilins is a major frontier in current virology research. The identified inhibitory host factors could be used in antiviral approaches with several advantages over traditional antivirals including broader antiviral effects against many related viruses and more durable antiviral effects since viruses may have a more difficult challenge to evolve mutants that evade these host factors.  Progress in our understanding of the mechanisms of the inhibitory activity of host factors is slow due to functional redundancy in the host cells or lack of knowledge about their functions. However easily tractable virus - host systems such as Tomato bushy stunt virus (TBSV) and yeast as a model host can greatly contribute to our understanding of the functions of these host proteins. This project will likely advance our understanding of the role of cyclophilins in virus-host interactions. This advance could immensely help other scientists working with less tractable but devastating viral pathogens for which similar studies are currently not yet feasible.  The gained knowledge will not only be useful for TBSV but to other significant human pathogens such as West Nile virus Dengue virus and other flaviviruses and pestiviruses due to the similarity of their replicase proteins. Collectively the major advances with TBSV will stimulate development of new approaches for studying RNA replication and host - pathogen interactions for important human pathogens.  The following are the major strengths of the proposal: (i) Viral RNA replication is clearly of immense importance for viruses to infect living organisms. (ii) Cyclophilins are major proteins affecting viral and other human diseases yet their functional roles are currently poorly defined. (iii) The combination of yeast and authentic cell-free assay developed by the investigator is currently the most potent for studying the mechanism of host factors involvement in viral RNA replication and viral pathogenesis. (iv) The research holds promise of benefiting society by leading to groundbreaking results in the area of virus replication host-virus interactions and the adaptation of viruses to their hosts.

project_terms:
Affect;Animals;Antiviral Agents;Area;Biochemical;Biological Assay;Cataloging;Catalogs;Cells;Complex;Cyclophilins;Dengue Virus;Development;Disease;Evolution;Family;Flavivirus;Genes;Human;Integration Host Factors;Knowledge;Lead;Life;Malignant Neoplasms;Modeling;Molecular;Molecular Chaperones;Neurodegenerative Disorders;Organism;Pathology;Peptidylprolyl Isomerase;Pestivirus;Plants;Play;Protein Family;Proteins;Proteomics;RNA Viruses;RNA replication;Research;Research Personnel;Role;Scientist;Societies;System;Tombusvirus;Viral;Viral Pathogenesis;Virus;Virus Diseases;Virus Replication;West Nile virus;Work;Yeast Model System;Yeasts;base;frontier;genome wide association study;human disease;insight;mutant;novel;novel strategies;pathogen;replicase;tomato bushy stunt virus;viral RNA;virology;virus host interaction;yeast genetics

public_health_relevance:
The host cells express antiviral proteins that restrict RNA viruses which are important pathogens of humans animals and plants. Cyclophilins which are involved in human cancers neurodegenerative diseases and viral infections are a large family of ubiquitous conserved proteins that have peptidyl-prolyl isomerase and protein chaperone activities. The investigator will use the powerful Tomato bushy stunt virus (TBSV)-yeast model system to determine the molecular mechanism of antiviral activity of several cyclophilins thus contributing to our understanding of host-virus interactions.


application_id: 8277910
project_number: 5R01GM089684-03
project_title: DNA repair mechanisms in trinucleotide repeat instability
administering_ic: NIGMS
award_notice_date: 2012-05-14
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 089684
program_official: KRASNEWICH, DONNA M
project_start_date: 2010-06-01
project_end_date: 2014-05-31
study_section: Molecular Genetics A Study Section[MGA]
contact_pi_person_id: 7875365
contact_pi: LI, GUO-MIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of the project is to understand the mechanisms by which cells maintain trinucleotide repeat (TNR) stability. Expansions of TNR sequences e.g. (CAG)n and (CTG)n are tightly associated with progression of certain human neurological and neurodegenerative diseases including Huntington's disease (HD) and myotonic dystrophy. However the mechanisms and factors that promote/prevent TNR expansions are unknown. Because CAG and CTG repeats form thermo- stable hairpins with multiple A-A and T-T mispairs in the hairpin stem respectively DNA mismatch repair (MMR) and TNR hairpin repair have been proposed to play major roles in TNR maintenance. Surprisingly previous studies in transgenic mice suggest that mismatch recognition protein MSH2- MSH3 heterodimer (also called MutS2) promotes (CAG)n expansions by binding to (CAG)n-formed hairpins and inhibiting their repair. Our recent studies have shown that human cells catalyze error-free repair of (CAG)25 and (CTG)25 hairpins in a nick-directed PCNA-dependent manner. The repair targets the nicked strand for incisions at the repeat sequences followed by repair DNA synthesis using the continuous strand as a template thereby ensuring TNR stability. However MutS2 does not inhibit stimulates (CAG)25 or (CTG)25 hairpin repair. Interestingly our preliminary studies have shown that cell lines derived from HD patients are defective in (CAG)n hairpin repair hinting possible pathogenesis for HD. In this application Specific Aim 1 is to evaluate the model that the MMR system promotes (CAG)n expansion. Human and animal cell lines with or without MutS2 overexpression will be examined for their ability to repair (CAG)n hairpins in vitro and to replicate CAG repeats in vivo. Determination of TNR hairpin repair activity and (CAG)n stability in these cells will clarify if the MMR system is responsible for (CAG)n expansions in human cells. Specific Aim 2 is to further test the hypothesis that hairpin repair defects are associated with TNR diseases by screening hairpin repair proficiency in cell lines derived from HD patients. Specific Aim 3 is to purify and characterize a protein required for (CAG)n hairpin repair but defective in an HD cell line. A successful completion of the proposed work will provide significant insight into the mechanisms of TNR expansions and the etiology of TNR expansion-associated diseases.    PUBLIC HEALTH RELEVANCE: Expansion of simple nucleotide repeats in DNA is the genetic basis for more than 40 human familial neurological neurodegenerative and neuromuscular disorders including Huntington's disease myotonic dystrophy Friedreich ataxia and fragile X syndrome. The repeat expansion can occur in any part of a gene and leads to a defective gene product. However how the repeat units expand and what cellular mechanism(s) prevent such an expansion in normal population are not fully understood. This application is to identify protein components that promote or prevent repeat expansions. A successful completion of the proposed work will provide significant insight into the pathogenesis underlying diseases associated with repeat expansions and approaches to develop effective treatments for the diseases.

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

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


