# projects

application_id: 7808002
project_number: 5R01ES017217-02
project_title: Mdig gene and histone demethylation in lung cancer
administering_ic: NIEHS
award_notice_date: 2010-02-26
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: ES
serial_number: 017217
program_official: QUINN, ASHLINN KO
project_start_date: 2009-05-01
project_end_date: 2010-10-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 8832153
contact_pi: CHEN, FEI
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): Lung cancer is the most common cancer worldwide accounting for 1.3 million cancer deaths annually. Despite extensive efforts to elucidate mechanisms and develop new therapeutic regimens the worldwide mortality rate of lung cancer remains high. Our long- term goal is to understand how mdig gene contributes to the initiation and progression of the human lung cancer and whether mdig can be served as a biomarker and a therapeutic target for lung cancer resulted from exposure to environmental or occupational hazards. The objective of this application is to investigate the role of Mdig protein played on the lung cell proliferation and carcinogenic transformation induced by environmental and occupational hazards/carcinogens. The central hypothesis is that Mdig promotes cell growth and transformation by functioning as a histone demethylase that antagonizes tri-methyl lysine 9 on histone H3. Down-regulation of tri-methyl lysine 9 of histone H3 will enhance the expression of genes associated with the cell cycle regulation and malignant transformation in lung epithelial cells. The rationale behind this proposal is that expression of mdig gene may be critical for lung cell proliferation and carcinogenic transformation in response to environmental carcinogens. To accomplish the objectives of this application we will pursue three specific aims by using cell lines and nude mice as experimental models: (1) test the potential demethylase activity of mdig protein toward tri-methylated lysine 9 on histone H3; (2) determine whether the expression of the cell cycle-regulated genes such as cyclins Cdc25s and checkpoint proteins is regulated by the methylation regulation of mdig; and (3) study the tumorigenic effect of mdig by both over- expression and down-regulation of mdig in BEAS-2B cells and A549 cells respectively in both cell culture and inoculation of the cells in nude mice. At the completion of these specific aims we expect to have determined how mdig contributes to lung cell growth regulation and carcinogenic transformation in response to factors that cause lung cancer. We additionally expect based on preliminary studies that constitutive expression of mdig will compromise the tri-methylation of lysine 9 on histone H3 leading to attenuation of heterochromatin or the formation of other inhibitory epigenetic markers. As a result the expression of genes associated with the cell cycle transition and cell proliferation will be enhanced. Finally in addition to reveal a previously unknown new mechanism of the human lung cancer it is anticipated that expression of mdig can be potentially served as a new biomarker and therapeutic target of the human lung cancer. PUBLIC HEALTH RELEVANCE:  Lung cancer is the leading cause of malignant-related deaths in the United States (US). It kills more Americans than any other type of malignancy. The main cause of lung cancer is the environmental and occupational exposure to carcinogens including tobacco smoking and occupational dust. This project will investigate the mechanism of mdig gene a newly identified lung cancer associated gene in mediating carcinogen-induced lung cancer by testing the hypothesis that mdig inducing cell growth and transformation through down regulation of the tri-methylation of lysine 9 on histone H3 and the heterochromatin formation. The long-term goals are to understand how mdig gene contributes to the initiation and progression of the human lung cancer induced by environmental and occupational hazards to identify biomarkers for early detection of the lung cancer and to develop intervention and prevention strategies.

project_terms:
A549;Accounting;Acute Promyelocytic Leukemia;Affect;Alveolar Macrophages;American;Area;Biological Assay;Carcinogens;Cell Culture Techniques;Cell Cycle;Cell Cycle Progression;Cell Cycle Regulation;Cell Line;Cell Proliferation;Cells;Cessation of life;Characteristics;Cyclins;Disease;Down-Regulation;Dust;Environmental Carcinogens;Environmental and Occupational Exposure;Epigenetic Process;Epithelial Cells;Experimental Models;Exposure to;G1 Phase;Gene Activation;Gene Expression;Gene Expression Regulation;Genes;Genome;Goals;HL-60 Cells;Heterochromatin;Histones;Human;In Vitro;Intervention;Killings;Knockout Mice;Lung;Lung diseases;Lysine;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mediating;Mediator of activation protein;Methylation;Minerals;Molecular;Mortality Vital Statistics;Names;Nuclear Antigens;Nucleolar Proteins;Nucleosomes;Nude Mice;Occupational;Oncogene Activation;Outcome;Patients;Peptides;Phase Transition;Play;Prevention strategy;Principal Investigator;Proteins;Regimen;Regulation;Role;Screening for Lung Cancer;Signal Transduction;Small Interfering RNA;Stream;Testing;Tobacco smoking;United States;Xenopus laevis;attenuation;base;biomarker;cancer therapy;cancer type;cdc Genes;cell growth;cell growth regulation;cell transformation;demethylation;expectation;improved;insight;loss of function;lung carcinogenesis;mass spectrometer;novel therapeutic intervention;novel therapeutics;occupational hazard;outcome forecast;prognostic;programs;public health relevance;response;small hairpin RNA;therapeutic target;tumorigenesis;tumorigenic

public_health_relevance:
Principal Investigator/Program Director (Last first middle): hn eiLung cancer is the leading cause of malignant-related deaths in the United States (US).It kills more Americans than any other type of malignancy. The main cause of lung canceris the environmental and occupational exposure to carcinogens including tobaccosmoking and occupational dust. This project will investigate the mechanism of mdig genea newly identified lung cancer associated gene in mediating carcinogen-induced lungcancer by testing the hypothesis that mdig inducing cell growth and transformation throughdown regulation of the tri-methylation of lysine 9 on histone H3 and the heterochromatinformation. The long-term goals are to understand how mdig gene contributes to the initiationand progression of the human lung cancer induced by environmental and occupationalhazards to identify biomarkers for early detection of the lung cancer and to developintervention and prevention strategies.Public Health Relevance Statement Page


application_id: 7807532
project_number: 2R01DK071349-06
project_title: Mechanisms Underlying Metabolic Syndrome in Obesity
administering_ic: NIDDK
award_notice_date: 2010-03-22
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: DK
serial_number: 071349
program_official: ABRAHAM, KRISTIN M
project_start_date: 2005-06-01
project_end_date: 2014-03-31
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: KERN, PHILIP 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):  Resident macrophages in adipose tissue account for much of the cytokine expression with obesity. We described the expression of thrombospondin (TSP1) a pleiotropic adipokine in insulin resistant subjects. Through its anti-angiogenic properties and its ability to activate TGF2 TSP1 may be an important part of the adipocyte/macrophage interaction that results in simultaneous impairment of angiogenesis and increased TGF- 2-mediated fibrosis and inflammation. We recently demonstrated that macrophages also infiltrate skeletal muscle with obesity that is strongly correlated with insulin resistance. Furthermore the presence of macrophages in co-culture with muscle cells in the presence of palmitic acid to mimic an obese environment results in a synergistic increase in the expression and secretion of inflammatory cytokines from muscle cells all of which impair insulin action. We hypothesize that macrophages in both muscle and adipose tissues promote the development of metabolic syndrome during obesity. To test this hypothesis adipose (Aim 1) and muscle tissue (Aim 2) from obese insulin resistant compared to normal human subjects will be characterized. Macrophage number the proportion of macrophages that are classically versus alternatively activated and the proportion of macrophages in crown-like structures (in adipose) will be quantified along with markers of the TGF2 pathway fibrosis hypoxia tissue remodeling and vascularity. To specifically determine the role of TSP1 and the TGF2 pathway in insulin resistance adipose and muscle tissue fibrosis hypoxia and macrophage function will be analyzed in high fat fed TSP1 null mice in Aim 3. A peptide that specifically blocks TSP1- mediated TGF2 activation will also be used in wild type high fat fed mice to test the hypothesis that macrophage infiltration and fibrosis in adipose and muscle will be ameliorated in the absence of TSP1 resulting in improved insulin sensitivity. Aim 4 is the intervention aim in which the mechanisms underlying the beneficial effects of aerobic exercise training on insulin sensitivity will be determined. Following 12 weeks of training in obese and lean subjects changes in muscle and adipose macrophage number activation state the TSP1/TGF2 pathway and inflammation in response to a single bout of eccentric exercise will be quantified relative to insulin sensitivity. Finally in Aim 5 the effects of different macrophage populations on adipocytes and muscle cells will be studied in vitro. The expression of genes involved in adipogenesis extracellular matrix and the TGF2 pathway will be monitored in adipocytes following macrophage co-culture. These will also be quantified in muscle cells as well as the response to insulin. We will determine whether mechanical stimulation of myotubes to mimic exercise will alter the muscle cell response to macrophages.  
  
PUBLIC HEALTH RELEVANCE:  The American population is experiencing an explosion in obesity metabolic syndrome and diabetes and this national trend is magnified in Kentucky and the Southeast. The cost of caring for diabetes and its complications is enormous. Impaired glucose tolerance and metabolic syndrome are preludes to the development of type 2 diabetes represent a risk factor for coronary artery disease and are more prevalent than diabetes itself. These studies are intended to examine fundamental mechanisms of insulin resistance and inflammation and involve studies in humans mice and cell culture. New insight into these fundamental mechanisms may form the basis for new treatments.

project_terms:
Accounting;Adipocytes;Adipose tissue;Aerobic Exercise;American;Anti-Inflammatory Agents;Anti-inflammatory;Area;Arkansas;Award;Budgets;Caring;Cell Culture Techniques;Chronic;Clinical;Coculture Techniques;Collaborations;Coronary Arteriosclerosis;Data;Dental crowns;Development;Diabetes Mellitus;Doctor of Philosophy;Environment;Etiology;Exercise;Explosion;Extracellular Matrix;Fatty acid glycerol esters;Fibrosis;Functional disorder;Funding;Funding Mechanisms;Gene Expression;Goals;Grant;Human;Hypoxia;Impairment;In Vitro;Individual;Infiltration;Inflammation;Inflammatory;Insulin;Insulin Resistance;Interleukin-1;Interleukin-6;Intervention;Kentucky;Knockout Mice;Link;Mechanical Stimulation;Mediating;Medical;Metabolic syndrome;Monitor;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscle function;Necrosis;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Palmitic Acids;Pathway interactions;Phenotype;Population;Process;Property;Relative (related person);Research Personnel;Risk Factors;Role;Science;Signal Pathway;Skeletal muscle structure;Stretching;Structure;System;Talents;Testing;Thrombospondin 1;Time;Tissues;Training;United States National Institutes of Health;Universities;Update;Vascularization;Work;adipokines;adiponectin;angiogenesis;base;cost;cytokine;experience;feeding;human subject;impaired glucose tolerance;improved;in vitro Model;innovation;insight;insulin sensitivity;insulin signaling;lipid biosynthesis;lipid metabolism;macrophage;peptide A;programs;public health relevance;repaired;response;skeletal;stem;trend


application_id: 7806563
project_number: 5R01AG026307-05
project_title: Repetitive Thought Stress and Immunity in Older Adults
administering_ic: NIA
award_notice_date: 2010-04-07
opportunity_number: PA-05-027
application_type: 5
activity_code: R01
ic: AG
serial_number: 026307
program_official: NIELSEN, LISBETH
project_start_date: 2006-07-15
project_end_date: 2012-07-31
study_section: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH]
contact_pi_person_id: 1886687
contact_pi: SEGERSTROM, SUZANNE C.
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 effects of stressors on the immune system are particularly relevant for older adults: Potent stressors such as bereavement become more common with age immune reactions to stress grow larger with age and vulnerability to immunological dysregulation and immunologically mediated disease increases with age. Previous studies have linked stressors in old age with increased distress and physiological dysregulation including depression high levels of cortisol poor responses to vaccination and high levels of the proinflammatory cytokine IL-6. The proposed research will address limitations of the extant literature by focusing on the prospective effects of stressors among older adults and by including individual differences in repetitive thought (RT) that is the cognitive interpretation and processing of stressful events. Individual differences in RT can create vulnerability or resilience to stressors: Negative uncontrolled and intrusive thought (e.g. worry) can prolong and amplify negative consequences whereas positive and controlled thought (e.g. reflection) can buffer against negative consequences and promote positive consequences such as growth. In this 5-year longitudinal prospective study married adults aged 60 or older (N = 183) will be interviewed and will collect saliva samples for cortisol every 6 months; they will be vaccinated annually against influenza and serum for antibody and IL-6 will be collected before and after vaccination and at the end of influenza season. The primary aim of the study is to test the following predictions: (1) stressors and RT predict psychological and physiological indices of health or dysregulation; (2) RT moderates the effects of stressors; (3) psychological indices (e.g. depression) mediate the relationship between stressors and RT and physiology. A secondary aim of the study is to relate cortisol autonomic activity and inhibition IL-6 and antibody to each other and to evidence of influenza infection. Another secondary aim is to validate the dimensional structure of RT in older adults and link trait RT (e.g. trait worry) to episodic RT (e.g. thoughts about a specific stressor). Relevance to public health: Stress in older adults can increase their vulnerability to both mental and physical illness. This research will test whether thought styles such as worry put older adults at greater risk. This knowledge could be used to identify and intervene with the most at-risk individuals.

project_terms:
Address;Adult;Affect;Age;Antibodies;Antibody Formation;Bereavement;Buffers;Cognitive;Disease;Distress;Elderly;Environment;Event;Growth;Health;Hydrocortisone;Immune;Immune system;Immunity;Individual;Individual Differences;Influenza;Influenza virus vaccine;Interleukin-6;Interview;Knowledge;Link;Literature;Measures;Mediating;Mental Depression;Neurosecretory Systems;Perception;Personal Satisfaction;Pharmaceutical Preparations;Physiological;Physiology;Process;Prospective Studies;Psyche structure;Psychosocial Stress;Reaction;Regulation;Research;Research Personnel;Risk;Saliva;Sampling;Seasons;Series;Serum;Stress;Stressful Event;Structure;Sympathetic Nervous System;Testing;Thinking function;Vaccinated;Vaccination;Vaccines;Well in self;aged;cytokine;improved;indexing;programs;prospective;psychologic;public health medicine (field);resilience;response;stressor;thought control;trait;young adult


application_id: 7806123
project_number: 1R13HL099227-01
project_title: Diamond Blackfan Anemia International Consensus Conference
administering_ic: NHLBI
award_notice_date: 2010-01-21
opportunity_number: PA-08-149
application_type: 1
activity_code: R13
ic: HL
serial_number: 099227
program_official: QASBA, PANKAJ
project_start_date: 2010-02-01
project_end_date: 2011-01-31
study_section: Special Emphasis Panel[ZHL1 CSR-W (O1)]
contact_pi_person_id: 1922324
contact_pi: ELLIS, STEVEN R
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 Diamond Blackfan Anemia International Consensus Conference (DBA-ICC) is the only annual forum which brings together physicians scientists and other parties interested in all aspects of the congenital bone marrow syndrome Diamond Blackfan Anemia (DBA). DBA is the first human disease linked to a failure of ribosome synthesis. Understanding the pathophysiology of this rare disease has required an interdisciplinary approach bringing together the highly specialized fields composed of hematologists interested in congenital bone marrow failure syndromes and basic scientists interested in ribosome biology. The annual DBA-ICC meetings have fostered an environment that has led to numerous collaborations between these diverse groups providing a rich breeding ground for translational research. Over the past 10 years these conferences have helped create and disseminate advancements in patient care to the wider community of physicians who may only rarely encounter DBA in clinical practice. Similarly research into the underlying molecular basis for DBA has led to a much greater understanding of the role of the ribosome in human disease which has implications for other diseases including cancer. The broadening scope of DBA research has brought new investigators into the DBA field with the result that the DBA-ICC meetings continue to grow in popularity and relevance to physicians and scientists alike. As the annual meeting grows the organizers feel that new sources of funding are needed to maintain the standard of excellence established at past meetings. This proposal therefore represents a request for partial support of the upcoming DBA- ICC meeting from the National Institutes of Health through the R13 award mechanism. PUBLIC HEALTH RELEVANCE: The Diamond Blackfan Anemia International Consensus Conference is the only meeting held each year that brings together physicians scientists and other parties interested in all aspects of Diamond Blackfan anemia. Over the past 10 years this meeting has produced a consensus clinical care document for patient care helped coordinate clinical trials stimulated collaborations promoting translational research and fostered an environment which has led to tremendous advances in understanding the underlying molecular basis for Diamond Blackfan anemia. As Diamond Blackfan anemia is the first human disease caused by a failure of ribosome synthesis an interdisciplinary conference such as this is absolutely essential for bringing together physicians and scientists of diverse disciplines for productive interactions relevant to DBA and broadening applications to other disease states.

project_terms:
Award;Biology;Bone Marrow;Breeding;Clinical Trials;Collaborations;Community Physician;Consensus;Diamond-Blackfan anemia;Discipline;Disease;Environment;Failure (biologic function);Fostering;Functional disorder;Funding Agency;Hematologist;International;Link;Malignant Neoplasms;Molecular;Pancytopenia;Patient Care;Physicians;Rare Diseases;Research;Research Personnel;Ribosomes;Role;Scientist;Syndrome;Translational Research;United States National Institutes of Health;base;clinical care;clinical practice;human disease;interdisciplinary approach;interest;meetings;public health relevance;symposium

public_health_relevance:
The Diamond Blackfan Anemia International Consensus Conference is the only meeting heldeach year that brings together physicians scientists and other parties interested in all aspects ofDiamond Blackfan anemia. Over the past 10 years this meeting has produced a consensusclinical care document for patient care helped coordinate clinical trials stimulatedcollaborations promoting translational research and fostered an environment which has led totremendous advances in understanding the underlying molecular basis for Diamond Blackfananemia. As Diamond Blackfan anemia is the first human disease caused by a failure of ribosomesynthesis an interdisciplinary conference such as this is absolutely essential for bringing togetherphysicians and scientists of diverse disciplines for productive interactions relevant to DBA andbroadening applications to other disease states.


application_id: 7805523
project_number: 5P01AG005119-21
project_title: AB AND NADPH OXIDASE IN MILD COGNITIVE IMPAIRMENT AND ALZHEIMER'S DISEASE
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 005119
study_section: ZAG1
subproject_number: 0012
contact_pi_person_id: 2306174
contact_pi: BRUCE-KELLER, ANNADORA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-15
budget_end_date: 2010-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
4 hydroxynonenal;APP-PS1;Ablation;Affect;Age;Age-Months;Alzheimer's Disease;Amyloid;Amyloid beta-Protein;Amyloid deposition;Attenuated;Automobile Driving;Biochemical;Brain;Brain region;Cell Death;Cerebellum;Cessation of life;Characteristics;Clinical;Data;Dementia;Deposition;Diagnostic;Disease;Dose;Free Radicals;Frontotemporal Dementia;Future;Genetic;Genetic Techniques;Hippocampus (Brain);Histological Techniques;Human;Impairment;In Vitro;Inferior;Inflammation;Inflammatory;Injury;Knock-in Mouse;Link;Lobule;Measures;Mediating;Methods;Microglia;Mitochondria;Modeling;Monitor;Mus;NADPH Oxidase;Nerve Degeneration;Neurofibrillary Tangles;Neuroglia;Neuronal Injury;Neurons;Oxidation-Reduction;Oxidative Stress;Parietal;Pathogenesis;Pathology;Patients;Physiological;Population;Production;Proteins;RNA;Reactive Oxygen Species;Regulation;Respiratory Burst;Role;Senile Plaques;Signal Transduction;Societies;Specimen;Staging;Structure of middle temporal gyrus;Sum;System;Testing;Therapeutic Intervention;Time;Tissue Banking;Tissue Banks;Tissues;Transgenic Mice;acetovanillone;age related;amyloidogenesis;attenuation;base;disorder control;in vivo;indexing;inhibitor/antagonist;innovation;mild cognitive impairment;mind control;mouse model;neuron loss;neuropsychological;neurotoxic;neurotoxicity;nitration;novel;novel strategies;oxidation;pre-clinical;research study;response


application_id: 7805522
project_number: 5P01AG005119-21
project_title: AB AND RAGE INTERACTIONS IN ALZHEIMER'S DIESEASE
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 005119
study_section: ZAG1
subproject_number: 0011
contact_pi_person_id: 7875104
contact_pi: KELLER, JEFFREY NEIL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-15
budget_end_date: 2010-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Advanced Glycosylation End Products;Affinity;Alzheimer's Disease;Amyloid beta-Protein;Biology;Data;Deposition;Goals;Laboratories;Lead;Ligands;Mediating;Mus;Oxidative Stress;Pathogenesis;Pilot Projects;Proteins;Reporting;Testing;Toxic effect;Transgenic Mice;amyloidogenesis;in vivo;mouse model;neurotoxicity;novel therapeutics;receptor;receptor for advanced glycation endproducts


application_id: 7805521
project_number: 5P01AG005119-21
project_title: BRAIN PROTEIN OXIDATION IN AD MCI AND PCAD: ROLES OF AB AND PIN1
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 005119
study_section: ZAG1
subproject_number: 0010
contact_pi_person_id: 8329002
contact_pi: BUTTERFIELD, D. ALLAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-15
budget_end_date: 2010-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Abeta synthesis;Accounting;Affect;Affinity;Age-Months;Alanine;Alzheimer's Disease;Alzheimer's disease model;Amyloid beta-Protein;Amyloid beta-Protein Precursor;Autopsy;Binding (Molecular Function);Binding Sites;Biological Assay;Brain;Brain region;Caenorhabditis elegans;Cerebellum;Cerebral cortex;Cessation of life;Codon Nucleotides;Collaborations;Cysteine;Data;Dementia;Dependovirus;Digestion;Disease;Electrospray Ionization;Ensure;Environment;Event;Free Radicals;Functional disorder;Human;Hydrophobicity;In Vitro;Individual;Institutes;Isomerase;Knock-in Mouse;Laboratories;Lead;Length;Leucine;Lipid Peroxidation;Measures;Mediating;Mediator of activation protein;Methionine;Methodology;Methods;Microtubules;Modeling;Modification;Mus;Mutate;N-terminal;NADPH Oxidase;Nerve Degeneration;Neurofibrillary Tangles;Neurons;Norleucine;Oxidation-Reduction;Oxidative Stress;Pathogenesis;Pathology;Peptides;Peptidylprolyl Isomerase;Persons;Play;Positioning Attribute;Process;Progress Reports;Proline;Property;Protein Binding;Protein Biosynthesis;Protein Dephosphorylation;Proteins;Proteomics;RNA;Recombinants;Research;Research Personnel;Role;Senile Plaques;Series;Serine;Side;Site;Small Interfering RNA;Solubility;Source;Specificity;Staging;Tauopathies;Testing;Therapeutic Intervention;Threonine;Time;Transgenic Mice;Transgenic Organisms;Triose-Phosphate Isomerase;Western Blotting;Wild Type Mouse;abeta deposition;abeta toxicity;aging brain;base;depressed;disorder control;genetic regulatory protein;human DNA;in vivo;in vivo Model;indexing;insight;knock-down;mild cognitive impairment;mind control;mutant;nervous system disorder;neurotoxic;neurotoxicity;novel;numb protein;oxidation;oxidative damage;pre-clinical;protein aminoacid sequence;success;tandem mass spectrometry;tau Proteins;tau phosphorylation;therapeutic target


application_id: 7805283
project_number: 3K01DK078648-02S1
project_title: Role of microRNAs in insulin production and secretion in pancreatic beta-cells
administering_ic: NIDDK
award_notice_date: 2009-04-13
opportunity_number: PAR-05-066
application_type: 3
activity_code: K01
ic: DK
serial_number: 078648
suffix: S1
program_official: HYDE, JAMES F
project_start_date: 2007-09-10
project_end_date: 2010-08-31
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 8781988
contact_pi: TANG, XIAOQING
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  The candidate has been previously studying the mechanisms of insulin-regulated glucose transport in 3T3-L1 adipocytes using RNAi technology and later focused on the mechanisms of RNAi and profiling of microRNAs in cancer cells and mouse tissues. To continue her training in the field of diabetes she has recently joined Dr. Sabire Ozcan's laboratory. Dr. Ozcan's research focuses mainly on glucose-regulated insulin gene transcription in pancreatic beta-cells. The immediate career goal of the candidate is to better acquaint herself with experimental procedures and applications in the regulation of insulin gene expression and glucose regulation of pancreatic beta-cell function. This training will allow her to pursue her long-term goal which is to study the role of miRNAs in regulating beta-cell function and to elucidate the role of miRNAs in the development of type-ll diabetes as an independent investigator.  Recent studies indicate that a novel population of cellular small RNAs termed microRNAs (miRNAs) may play an important role in the development of type 2 diabetes. The expression of these miRNAs may be highly regulated under various environmental and physiological conditions; dysregulation of these small RNAs may lead to the development of type 2 diabetes. For example miR-375 has been discovered to be specifically expressed in pancreatic beta cells and be important in insulin secretion. The functions of most miRNAs in beta cells await to be investigated. The hypothesis of the P.I. is that miRNAs are not functioning alone but rather multiple miRNAs act in cohort to regulate beta cell development and insulin production and secretion in response to glucose. The specific aims of this project are: (1) To profile miRNA expression in pancreatic beta cells in order to identify novel cell-specific and glucose-regulated miRNAs with a recently developed rational miRNA microarray technology; (2) To study the function of the identified glucose-regulated and beta cell-specific miRNAs in MIN6 cells by transfecting with synthetic miRNAs to study overexpression effects and with 2-O-methyl RNA antagomirs to investigate the effects associated with their down-regulation. The results obtained from the proposed activities may lead to the discovery of novel miRNAs or new roles of miRNA network in the development of type 2 diabetes and potential therapeutic approaches to treat or prevent this disease.

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


application_id: 7804472
project_number: 5R01NS060784-02
project_title: Reconstruction of the Nigrostriatal pathway
administering_ic: NINDS
award_notice_date: 2010-03-03
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 060784
program_official: SIEBER, BETH-ANNE
project_start_date: 2009-04-15
project_end_date: 2014-03-31
study_section: Special Emphasis Panel[ZRG1-BDCN-N(93)S]
contact_pi_person_id: 1882501
contact_pi: SMITH, GEORGE M
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 replacement strategies using stem cells or fetal transplants are potential treatments for neurological disorders caused by damage or degeneration of specific neural circuits in the central nervous system (CNS). Parkinson's disease (PD) is one such disorder caused by the degeneration of dopaminergic neurons in the substantia nigra. Many investigators have already explored neural transplantation as therapy for PD both in the lab and in the clinic but in most cases dopaminergic neurons are transplanted directly into their target - the striatum - rather than into their site of origin the substantia nigra (SN). This leads to incomplete recovery of function both in animal models and in human PD patients because the transplanted neurons provide a dopamine source to the striatum but do not reestablish the degenerated neural circuit. This proposal shall examine the hypothesis that a growth-supportive pathway created between the SN and the striatum can guide the growth of axons from dopaminergic neurons transplanted into the SN of the parkinsonian brain resulting in an anatomically and physiologically correct reestablishment of the nigrostriatal pathway and an amelioration of parkinsonian symptoms. Preliminary data is presented showing that a combination of glial cell line-derived neurotrophic factor (GDNF) and its alpha-1co-receptor (GFR-11) or netrin-1 support long distance axon growth from dopaminergic transplants in the SN to the striatum. In this study a series of experiments are proposed to further enhance the growth along the pathway and targeting within the striatum. The specific aims are to: 1) examine these and other potential growth factor candidates either individually and in combination for their ability to support long distance growth of dopaminergic axons within the adult brain; 2) examine the ability BDNF and chondroitinase to enhance axon branching and synaptogenesis within the adult striatum; 3) reconstruct the nigrostriatal pathway using data acquired from Aims 1 and 2 and examine functional recovery; 4) examine the release of dopamine cell type specificity (A9/A10 neurons) and synaptic connectivity of dopaminergic axons re-innervating the striatum. The outcome of these studies will demonstrate the feasibility of targeting the growth of axons using neuronal replacement to ameliorate the symptoms of Parkinson's disease. These studies will also provide a model for developing neuronal replacement strategies for other neurological disorders. PUBLIC HEALTH RELEVANCE Parkinson's disease is a widespread neurodegenerative disease that manifests severe motor dysfunction ultimately leading to death. Present cell replacement therapies and drug treatments have either failed in clinical trials or induce long term side effect and loss of efficacy over time. Neuronal replacement strategies that rebuild the damage circuit have a high probability of reducing or reversing motor deficits associated with Parkinson's disease as well as numerous other neurological disorders.

project_terms:
Address;Adult;Adverse effects;Animal Model;Axon;Behavior;Behavioral;Brain;Brain-Derived Neurotrophic Factor;Cells;Cessation of life;Cholera Toxin;Chondroitin Sulfate Proteoglycan;Chondroitinases;Clinic;Clinical Trials;Contralateral;Corpus Callosum;Corpus striatum structure;Data;Dendritic Spines;Disease;Dopamine;Electron Microscopy;Embryo;Ensure;FGF2 gene;Functional disorder;Growth;Growth Factor;Human;Hyaluronidase;Image;Injection of therapeutic agent;Label;Laboratories;Left;Maps;Measures;Microelectrodes;Modeling;Motor;Neuraxis;Neurodegenerative Disorders;Neurons;Outcome Study;Oxidopamine;Parkinson Disease;Parkinsonian Disorders;Pathway interactions;Patients;Pharmaceutical Preparations;Probability;Rattus;Recombinants;Recovery of Function;Replacement Therapy;Research Personnel;Series;Site;Source;Specificity;Stem cells;Subfamily lentivirinae;Substantia nigra structure;Symptoms;Synapses;Time;Transplantation;axon growth;cell body (neuron);cell type;density;dopaminergic neuron;fetal;functional restoration;glial cell-line derived neurotrophic factor;human NTN1 protein;improved;in vivo;motor deficit;nervous system disorder;netrin-1;neural circuit;neuronal replacement;nigrostriatal pathway;overexpression;public health relevance;receptor;reconstruction;relating to nervous system;research study;restoration;synaptogenesis

public_health_relevance:
Parkinson's disease is a widespread neurodegenerative disease that manifests severemotor dysfunction ultimately leading to death. Present cell replacement therapies anddrug treatments have either failed in clinical trials or induce longterm side effect and lossof efficacy over time. Neuronal replacement strategies that rebuild the damage circuithave a high probability of reducing or reversing motor deficits associated withParkinson's disease as well as numerous other neurological disorders.


application_id: 7804085
project_number: 3R01DE017138-04S1
project_title: Oral Immunity and Adjuvant Receptors
administering_ic: NIDCR
award_notice_date: 2009-04-10
application_type: 3
activity_code: R01
ic: DE
serial_number: 017138
suffix: S1
program_official: LUNSFORD, DWAYNE
project_start_date: 2006-02-01
project_end_date: 2011-01-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6712964
contact_pi: HAJISHENGALLIS, GEORGIOS
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The need to develop new vaccines against mucosal pathogens has compelled a search for adjuvants thatcan effectively stimulate mucosal immunity to vaccine proteins most of which are poor immunogens. Toll-like receptors (TLRs) and gangliosides are considered "adjuvant receptors" because their interaction withcertain classes of noxious microbial molecules generates potent immunomodulatory signals in antigen-presenting cells (APCs) that mobilize adaptive immunity. An ideal adjuvant should thus stimulate adjuvantreceptors without however inducing toxic effects. This proposal will investigate the adjuvant activities of anovel ganglioside-binding TLR2 agonist recently identified by our group. The molecule under investigationis the pentameric B subunit of a unique E. coli enterotoxin designated Type Mb(LT-llb) and quite differentfrom Type I enterotoxins such as cholera toxin. In contrast to the intact toxin the B subunit (designated LT-llb-B) induces TLR2-dependent activation of transcription factor NF-KB which plays a central role in theinduction of immunoregulatory cytokines and costimulatory molecules on APCs such as dendritic cells. Theoverall hypothesis is that LT-llb-B exhibits immunomodulatory activity which requires the cooperation ofGD1a ganglioside and TLR2 promotes antigen-presenting cell function and induces mucosal immunity. Wethus aim to elucidate the immunomodulatory mechanisms of LT-llb-B and demonstrate its mucosaladjuvanticity. Specifically using immunological biophysical and cell imaging techniques we will determinecooperative interactions between gangliosides and TLR2 in response to LT-llb-B and the importance ofthese interactions in upregulating dendritic cell-mediated functional costimulation to CD4+T cells. Moreoverit will be determined if these adjuvant mechanisms of LT-llb-B correlate with induction of mucosal adjuvantactivity in vivo. The proposed studies are supported by a plethora of preliminary findings and are facilitatedby the availability of (a) engineered wild-type and single point substitution mutants of LT-II molecules (b)model cell systems where expression of receptors of interest is manipulated and (c) a well-establishedmouse mucosal immunization model. Using these models and state-of-the-art interdisciplinary techniquesthe generated data will form the basis for our ultimate objective which is to establish LT-llb-B as a safe andeffective adjuvant in vaccine formulations against oral or other mucosal pathogens.

project_terms:
Address;Adjuvant;Adjuvanticity;Agonist;Antibodies;Antigen-Presenting Cells;Antigens;Arts;Bacterial Adhesins;Binding (Molecular Function);Biological Assay;CD4 Positive T Lymphocytes;Catalytic Domain;Cell Line;Cell Proliferation;Cell model;Cell physiology;Cholera Toxin;Co-Immunoprecipitations;Complex;Data;Dendritic Cells;Drug Formulations;Engineering;Enterotoxins;Escherichia coli;Exhibits;Fluorescence Microscopy;Fluorescence Resonance Energy Transfer;GD1a ganglioside;Gangliosides;Genitourinary system;Human;Imaging Techniques;Immune response;Immunity;Immunization;Infection;Invaded;Investigation;Ligands;Lymphoid Cell;Mediating;Membrane Microdomains;Modeling;Molecular;Molecular Structure;Monitor;Mucosal Immune Responses;Mucosal Immunity;Mucous Membrane;Mus;Oral;Play;Point Mutation;Production;Proteins;Reagent;Research Personnel;Role;Route;Scanning;Signal Transduction;Specificity;Stimulus;Stomach;Streptococcus mutans;Structure;Structure-Activity Relationship;Surface;System;TLR2 gene;Techniques;Time;Toll-Like Receptor 2;Toll-like receptors;Toxic effect;Toxin;Up-Regulation (Physiology);Vaccines;base;cellular imaging;cytokine;improved;in vivo;interdisciplinary collaboration;interest;microbial;monocyte;mouse model;mutant;novel;novel vaccines;oral immunity;oral pathogen;pathogen;programs;receptor;receptor expression;respiratory;response;trafficking;transcription factor


application_id: 7802898
project_number: 5K25DK072085-04
project_title: Intelligent Control Approach to Anemia Management
administering_ic: NIDDK
award_notice_date: 2010-04-12
opportunity_number: PA-06-087
application_type: 5
activity_code: K25
ic: DK
serial_number: 072085
program_official: RANKIN, TRACY L
project_start_date: 2007-04-01
project_end_date: 2012-01-31
study_section: Kidney, Urologic and Hematologic Diseases D Study Section[DDK-D]
contact_pi_person_id: 8145755
contact_pi: GAWEDA, ADAM E
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):  
Management of anemia due to end-stage renal disease is a multifactorial decision process involving administration of recombinant human erythropoietin (rHuEPO) and iron as well as assessment of other factors influencing the progress of the disease. This application aims at improving the cost-effectiveness of this process through the use of state-of-the-art numerical tools from control engineering and machine learning. The specific aims are the collection of anemia management data and development of new guidelines for period of measuring hemoglobin levels if necessary development of individualized computer-assisted approach to rHuEPO dosing based on modern control engineering and machine learning approach evaluation of the developed tools through numeric simulation and assessment of the potential improvements in therapy and projected savings in rHuEPO utilization. The final aim is to provide a physical implementation and to perform a clinical evaluation of the developed methodology. The applicant Dr. Adam E. Gaweda is an Instructor of Medicine in the Department of Medicine Division of Nephrology at the University of Louisville. His original training is in the field of electrical engineering (M.Eng.) and computer science (Ph.D.). The applicant plans to develop as an independent and well established researcher in the field of biomedical engineering with focus on translation of state-of-the-art technology to heath care. To achieve this goal the applicant will enroll into the Clinical Research Epidemiology and Statistics Training (CREST) Program at the University of Louisville School of Public Health and Information Sciences

project_terms:
Adverse event;Algorithms;Anemia;Anti-Arrhythmia Agents;Artificial Intelligence;Arts;Biological Models;Biological Neural Networks;Biomedical Engineering;Blood;Blood Vessels;Caring;Chronic;Clinical;Clinical Research;Collection;Comorbidity;Complex;Computer Assisted;Computer Simulation;Computer software;Computing Methodologies;Controlled Clinical Trials;Data;Decision Support Systems;Development;Dialysis procedure;Disease;Doctor of Philosophy;Dose;Drug Prescriptions;Effectiveness;Electrical Engineering;End stage renal failure;Engineering;Enrollment;Epidemiology;Erythropoietin;Evaluation;Feedback;Frequencies (time pattern);Funding;Goals;Guidelines;Hemodialysis;Hemoglobin;Hemoglobin concentration result;Human;Individual;Information Sciences;Insulin;Iron;Machine Learning;Measures;Medicine;Methodology;Methods;Nephrology;Outcome;Patient Monitoring;Patients;Pharmaceutical Preparations;Physiological;Population;Process;Protocols documentation;Public Health Schools;Research;Research Personnel;Safety;Sampling;Savings;Techniques;Technology;Testing;Training;Training Programs;Translations;Universities;Veterans;Waran;Work;base;clinical practice;computer science;cost effectiveness;data management;experience;improved;insight;instructor;mathematical algorithm;novel;patient population;primary outcome;programs;recombinant human erythropoietin;research clinical testing;response;simulation;statistics;theories;tool


application_id: 7800652
project_number: 2R44AR055014-02A1
project_title: Injectable collagen crosslink augmentation for degenerative disc disease
administering_ic: NIAMS
award_notice_date: 2010-01-28
opportunity_number: PA-09-080
application_type: 2
activity_code: R44
ic: AR
serial_number: 055014
suffix: A1
program_official: PANAGIS, JAMES S
project_start_date: 2007-08-15
project_end_date: 2012-01-31
study_section: Special Emphasis Panel[ZRG1 MOSS-L (10)]
contact_pi_person_id: 6575299
contact_pi: HEDMAN, THOMAS P
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 602492451
duns_number: 602492451
fips: US
organization_id: 10009769
organization_name: ORTHOPEUTICS, LP
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405111285
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-02-01
project_abstract:
DESCRIPTION (provided by applicant): With regard to prevalence and cost to society low-back pain has few peers. With a patient population in excess of 15 million/year the societal cost is estimated to be in the realm of $100 billion/year. Current treatment options for this disease have shown limited success including physical therapy medication and surgery. This proposal involves a novel nonsurgical and cost-effective tissue revitalization approach which shows promise for treatment of mechanically and nutritionally challenged tissues like the spinal disc. Previous in vitro and in vivo studies have demonstrated the efficacy of Injectable collagen crosslink augmentation in stabilizing spinal joints decreasing disc bulge under load increasing the strength tear resistance and durability of the tissue while also improving nutritional flow to these largely avascular tissues. Phase I testing was successful in characterizing the crosslinking effects of seven candidate agents in disc annulus fibrosis (AF) tissue using mechanical thermal and protease digestion assays. At least one preferred agent was identified and concentration pH conditioning and buffering were optimized to maximize the efficiency of crosslinking and mechanical effect. Recently in vitro assays have been undertaken to determine agent and buffer biocompatibility. The proposed Phase II testing will provide data necessary for regulatory filings and first-in-man clinical trials. Reagent delivery penetration reaction kinetics permanency (effect duration) and storage requirements (shelf life) will be thoroughly investigated. Acute functional biocompatibility and neurotoxicity studies will be conducted to quantify expected and worst-case treatment effects in an animal model. Further characterization of crosslinking effects will be determined using different subgroups of human AF tissues (variations in age composition degeneration). By bringing this path-breaking treatment to the doorstep of clinical trials SBIR funding will play a vital role in enabling progress towards the ultimate goal of providing a novel cost-effective treatment in the struggle against low back pain and disability.  
  
PUBLIC HEALTH RELEVANCE:  Back pain and disability associated with spinal degeneration and instability remains among the most costly and prevalent health problems in the US today. With a patient population in excess of 15 million/year the societal cost is estimated to be in the realm of $100 billion/year. Due to the limited success of current treatment options it is reasonable to expect that an effective nonsurgical solution could revolutionize clinical care for this pandemic.

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

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


application_id: 7800622
project_number: 1R01HL099014-01
project_title: Role of Glutathione S-Transferase P in Heart Failure
administering_ic: NHLBI
award_notice_date: 2010-01-13
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: HL
serial_number: 099014
program_official: LIANG, ISABELLA Y
project_start_date: 2010-02-01
project_end_date: 2014-01-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 1914941
contact_pi: PRABHU, SUMANTH D
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Although oxidative stress is a hallmark of heart failure (HF) clinical trials with antioxidants targeting first generation reactive oxygen species (ROS) such as O2/ and H2O2 have not yielded compelling benefits. However ROS also generate secondary intermediates derived from lipid peroxidation including peroxides and aldehydes that amplify oxidative injury. Glutathione S-transferases (GSTs) metabolize aldehydes by catalyzing their conjugation with glutathione (GSH). Select GST isoforms also have important non-catalytic functions such as physical interactions with c-Jun N-terminal kinase (JNK) that are modulated by oxidative stress. Although GSTs play a vital role in oxidative stress responses how GSTs impact HF is unknown. Our goal is to define the functional role of GSTP most abundant cardiac GST isoform in HF. Our preliminary studies indicate that GSTP is downregulated in HF and that GSTP deficiency worsens cardiac remodeling augments protein- aldehyde adducts depresses circulating endothelial progenitor cells (EPCs) and impairs neovascularization. Our central hypothesis therefore is that GSTP is a critical cardioprotective protein in post-infarction HF that ameliorates remodeling and promotes cardiac repair. To test this hypothesis we will perform three Specific Aims. In Aim 1 we will define the role of GSTP and the human GSTP variants hGSTP1*A and hGSTP1*C in HF by examining post-infarction LV remodeling in wild-type (WT) GSTP-/- and cardiac-specific hGSTP1*A and hGSTP1*C transgenic (Tg) mice. We will evaluate apoptosis fibrosis and inflammation together with glutathione levels protein-adducted aldehydes and JNK activation in the heart. In Aim 2 we will determine the metabolic contribution of GSTP to the detoxification of lipid peroxidation products in the failing heart. In isolated perfused sham-operated and failing hearts from WT GSTP-/- and hGSTP Tg mice using isotope labeling and mass spectrometry we will characterize the metabolism and detoxification of unsaturated aldehydes. In tissue homogenates we will also determine GSTP-related peroxidase activity and levels of aldehydes and lipid peroxides. In Aim 3 we will delineate the cardiac and bone marrow (BM)-related effects by which GTSP modulates neovascularization in the failing heart. We will first determine EPC and BM progenitor cell function in WT and GSTP -/- mice both with and without concomitant JNK inhibition. Next we will define how GSTP ablation and hGSTP overexpression affect neovascularization and angiogenic gene expression in the sham and failing hearts from Aim 1. Lastly we will evaluate post-infarction remodeling inflammation EPC mobilization and neovascularization in chimeric mice: WT mice with GSTP-/- BM and GSTP-/- mice with WT BM. These studies will establish the role of myocardium-localized versus BM-localized GSTP in the process of remodeling neovascularization and inflammation in the failing heart. Collectively this work will establish a novel paradigm of GSTP as an essential antioxidant anti-inflammatory and pro-angiogenic protein in HF. This model can have important diagnostic and therapeutic implications for HF patients with regard to oxidant injury.  
  
PUBLIC HEALTH RELEVANCE: These studies will establish glutathione S-transferase P (GSTP) as a critical antioxidant and tissue reparative protein in heart failure and identify new determinants of oxidative injury. Hence the results can help design new non-classical antioxidant and regenerative therapies in heart failure. We will also evaluate the cardioprotective potency of human GSTP variants in the failing heart; important differences between GSTP variants can establish a genetic basis for variability of antioxidant responses in the heart and provide a novel biomarker for the progression of heart failure.

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

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


application_id: 7800366
project_number: 5P30ES014443-03
project_title: Community Outreach & Education Core
administering_ic: NIEHS
opportunity_number: RFA-ES-05-008
application_type: 5
activity_code: P30
ic: ES
serial_number: 014443
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 9003
contact_pi_person_id: 9898612
contact_pi: RAMOS, IRMA N
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-01
budget_end_date: 2010-03-31
funding_mechanism: Research Centers
project_abstract:
Goals and Theme of the Community Outreach Educational Core (COEC)The primary goal of the COEC will be to educate residents in the Louisville Metropolitan Area (nine counties inKentucky and four counties in Indiana) on the importance of interactions between genes environment cultureand disease. Our focus during the first four years will be the fast-growing Hispanic community of Shelbyville inShelby County Kentucky. This community consists of 4-8 thousand individuals many of which lack basicsocial and economic infrastructure support and consequently a group deficient in essential tools for promotionof a healthy community. As the Center matures and research programs are established in both the Hispanicand African American communities of Louisville the COEC will extend its educational programs to WestLouisville another disadvantaged community in close proximity to a large industrial chemical complex knownas Rubbertown. These efforts will be complementary to those of the Integrated Health Sciences Facility Core(IHSFC). As detailed in Section 7A the IHSFC will initially work with the more established and environmentallyfocused community-based organizations in West Louisville with plans to increasingly involve Hispanic-focusedorganizations as they acquire a higher level of knowledge about environmental health through the work of theCOEC. This approach will create a synergistic relationship that can significantly advance the Center's goalsand its impact.To achieve our primary goal we seek to empower the community of Shelbyville with sound medical andscientific information on the role of genes in health and disease and how environmental factors and lifestylepractices influence health outcomes. We will begin by working with existing community organizations toidentify community leaders who will be trained by COEC staff and in turn these leaders will train others in theircommunity using a well-established train-the-trainer model (Ramos I. 2003). This approach has been shownto gradually build an environmental health infrastructure that can positively impact the community and itsresidents.The ultimate goal of the COEC is to build a self-sustainable educational program that persists within the targetcommunity after the intervention is completed. Modern theorists have proposed that systems thinking can beused to tackle intractable social issues such as environmental health in depressed communities. Unlikeprevious social theories influenced by a reductionist approach to social problems (reminiscent of theapproaches used in the biomedical sciences) theories developed through systems thinking incorporate theawareness that the entry of new knowledge may lead to conflict between those who are or perceivethemselves to be at risk and those perceived as being responsible for creating or preventing that risk. Thesesocial tensions must be factored into our community outreach efforts with the expectation that application ofintegrative approaches will enhance the quality of its products of the COEC.

project_terms:
African American;Area;Awareness;Biology;Chemicals;Communities;Community Outreach;Complex;Conflict (Psychology);Core Facility;County;Disadvantaged;Disease;Economics;Educational Curriculum;Educational aspects;Effectiveness;Environment;Environmental Health;Environmental Risk Factor;Evaluation;Genes;Genomics;Goals;Health;Health Sciences;Health Status;Hispanics;Human Resources;Indiana;Individual;Institution;Intervention;Kentucky;Knowledge;Lead;Life Style;Medical;Modeling;Outcome;Plant Roots;Research;Research Infrastructure;Resources;Risk;Role;Science;Services;Social Problems;System;Thinking function;Trainers Training;Training;Work;base;community organizations;depressed;design;empowered;expectation;instrument;metropolitan;prevent;programs;social;sound;theories;tool


application_id: 7800364
project_number: 5P30ES014443-03
project_title: Facility Core A: Integrative Health Sciences
administering_ic: NIEHS
opportunity_number: RFA-ES-05-008
application_type: 5
activity_code: P30
ic: ES
serial_number: 014443
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 9001
contact_pi_person_id: 1871961
contact_pi: TOLLERUD, DAVID J
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-01
budget_end_date: 2010-03-31
funding_mechanism: Research Centers
project_abstract:
The central goal of the Integrative Health Sciences Facility Core (IHSFC) is to provide Center investigators withservices and resources that will facilitate the translation of basic research findings into clinical or public healthapplications. The general goals of the Core are to: Provide services instrumentation and technologies that support the bench-to-bedsidetranslation of basic science findings into clinical and public health applications. Support research to improve early detection prevention and/or therapy for disorders related toenvironmental exposures. Foster partnerships between researchers and community-based organizations and healthagencies that will enhance the development and conduct of clinical and public health research. Educate Center investigators on the nature and requirements of clinical and public healthresearch including ethical legal and social implications  and provide technical support formeeting human subjects HIPAA and other human subjects research requirements. Facilitate clinical or public health-oriented pilot projects. Promote synergistic interactions with the Bioinformatics Biostatistics and ComputationalBiology (BBCB) Facility Core.

project_terms:
Basic Science;Bioinformatics;Biology;Biometry;Clinical;Communities;Computational Biology;Core Facility;Development;Disease;Early Diagnosis;Environmental Exposure;Environmental Health;Fostering;Genomics;Goals;Health Insurance Portability and Accountability Act;Health Sciences;Housing;Human;Human Subject Research;Nature;Pilot Projects;Prevention;Public Health Applications Research;Research;Research Personnel;Research Project Grants;Research Support;Resources;Scientist;Services;Technology;Translations;base;bench to bedside;biomarker;ethical legal social implication;health organization;human subject;improved;instrumentation;meetings;member;public health medicine (field);public health research


application_id: 7800362
project_number: 5P30ES014443-03
project_title: Career Development of Environmental Health Investigators
administering_ic: NIEHS
opportunity_number: RFA-ES-05-008
application_type: 5
activity_code: P30
ic: ES
serial_number: 014443
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 0002
contact_pi_person_id: 1886009
contact_pi: PROUGH, RUSSELL ALLEN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-01
budget_end_date: 2010-03-31
funding_mechanism: Research Centers
project_abstract:
CAREER DEVELOPMENTSpecific AimsThe Center's Career Development Program will provide training and mentoring for junior basic and clinicalscientists with interests in environmental health sciences with the aim of assisting them in the development ofproductive independent research careers with an emphasis in the environmental health sciences and bringingthem to full Center membership.

project_terms:
Biology;Clinical;Development;Environmental Health;Genomics;Mentors;Research;Research Personnel;Scientist;Training;career;career development;interest;programs


application_id: 7800161
project_number: 1R01AA018869-01
project_title: Cyclic AMP Cytokine Modulation and Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2009-09-18
opportunity_number: RFA-AA-09-006
application_type: 1
activity_code: R01
ic: AA
serial_number: 018869
program_official: RADAEVA, SVETLANA
project_start_date: 2009-09-20
project_end_date: 2014-08-31
study_section: Special Emphasis Panel[ZAA1 JJ (06)]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alcoholic Liver Disease (ALD) remains a leading cause of liver-related deaths 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 liver function and clinical outcome. Similarly there are depressed levels of the critical anti-inflammatory cytokine IL-10. Studies in animal models support an etiologic role for cytokines in the liver injury of ALD. The major problem to be investigated in this proposal is the mechanism(s) for this dysregulated cytokine metabolism and our overall goal is the development of novel therapeutic interventions. ALD is associated with an increase in oxidative stress with a concomitant decrease in cellular antioxidants such as glutathione (GSH) and importantly S-adenosyl-L-methionine (SAM) due to subnormal synthesis. Clinical studies have suggested that SAM has beneficial effects in many hepatic disorders including ALD and numerous animal studies have clearly demonstrated the protective effects of SAM against a variety of hepatotoxins. Previous studies from our group evaluated the role of SAM in positively modulating endotoxin (LPS)-stimulated TNF and IL-10 production related to ALD. We showed that SAM decreased LPS stimulated TNF production and increased LPS stimulated IL-10 production and that SAM increased cellular levels of cyclic AMP (cAMP) which is known to positively modulate cytokine production. We therefore began an evaluation of the role of cAMP in dysregulated cytokine production in ALD which is the research focus of this current proposal. We present compelling preliminary data that cAMP is decreased in a macrophage cell line chronically cultured in alcohol and in Kupffer cells from mice chronically fed ethanol intragastrically. Our working hypothesis is that altered phosphodiesterase 4B (PDE4B) and cAMP metabolism cause abnormal TNF and IL-10 metabolism which play a critical role in the development and perpetuation of ALD. Specific Objectives for this proposal are to: 1. Document increased PDE4B expression/activity and decreased cAMP in peripheral blood monocytes from patients with alcoholic hepatitis (AH) and alcoholic cirrhosis and evaluate whether in vitro incubation of monocytes with specific phosphodiesterase inhibitors corrects dysregulated cAMP and cytokine metabolism; 2. Determine whether PDE4 (and specifically PDE4B) inhibition blocks the development of alcohol-induced liver injury in a murine intra-gastric ethanol-feeding model of chronic ALD and in a murine model of AH; 3. Evaluate potential molecular and epigenetic mechanisms whereby cAMP metabolism is altered in alcoholic liver disease; and 4. Evaluate the effects of combined consumption of a commercially- available adenyl cyclase agonist (Misoprostol - increases cAMP production) and a phosphodiesterase inhibitor (Pentoxyfilline - decreases cAMP breakdown) in normal volunteers and in patients with stable alcoholic cirrhosis.  
  
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. Abnormal cytokine metabolism is a major feature of ALD. Elevated serum concentration levels 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 liver function and clinical outcome. Similarly there are depressed levels of the critical anti-inflammatory cytokine IL-10. Studies in animal models support an etiologic role for cytokines in the liver injury of ALD. The major problem to be investigated in this proposal is the mechanism(s) for this dysregulated cytokine metabolism and our overall goal is the development of novel therapeutic interventions.

project_terms:
Acute-Phase Reaction;Adenylate Cyclase;Agonist;Alcoholic Hepatitis;Alcoholic Liver Cirrhosis;Alcoholic Liver Diseases;Alcohols;Animal Model;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Attenuated;Biological Models;Cause of Death;Cell Line;Cessation of life;Chronic;Cirrhosis;Clinical;Clinical Research;Consumption;Cyclic AMP;Data;Development;Disease;Disease model;Endotoxins;Epigenetic Process;Ethanol;Evaluation;FDA approved;Glutathione;Goals;Human;IL8 gene;In Vitro;Inflammatory;Injury;Interleukin-10;Interleukin-18;Isoenzymes;Knockout Mice;Kupffer Cells;Lipopolysaccharides;Liver;Liver diseases;Mediating;Metabolism;Methionine;Misoprostol;Modeling;Modification;Molecular;Mus;Outcome;Oxidative Stress;PDE4B;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacotherapy;Phosphodiesterase Inhibitors;Play;Process;Production;Rattus;Reporting;Research;Role;Serum;Stomach;System;Therapeutic Intervention;Tumor Necrosis Factor-alpha;Tumor Necrosis Factors;Whole Blood;Work;alcohol exposure;animal data;base;bench to bedside;chemokine;cytokine;depressed;experience;feeding;hepatotoxin;inhibitor/antagonist;liver function;macrophage;monocyte;novel therapeutic intervention;peripheral blood;phosphoric diester hydrolase;protective effect;public health relevance;research study;volunteer


application_id: 7799817
project_number: 5R01HD023333-18
project_title: Listening Skills in children with and without cochlear implants
administering_ic: NICHD
award_notice_date: 2010-03-31
application_type: 5
activity_code: R01
ic: HD
serial_number: 023333
program_official: KAU, ALICE S
project_start_date: 1989-04-01
project_end_date: 2012-03-31
study_section: Auditory System Study Section[AUD]
contact_pi_person_id: 1963999
contact_pi: WIGHTMAN, FREDERIC L
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
budget_start_date: 2010-04-01
project_abstract:
DESCRIPTION (provided by applicant): The long term goal of this program is a complete understanding of the capabilities and limitations of auditory information processing in children the development of auditory processing skills and how that developmental course may be affected by hearing impairment deafness and the use of a cochlear mplant. The current focus of the project is on the strategies used by children to segregate desired auditory signals from interfering sounds. Results to date suggest that most young children display a remarkable nability to perform this segregation in simple detection tasks and in tasks requiring attention to a target speech message in the presence of other speech distracters. The data also reveal large individual differences in source segregation ability with some teenagers demonstrating child-like performance and some young school-aged children demonstrating adult-like performance. The adult-child differences are argely consistent with what iresults. The new work also addresses the special selective attention problems faced by children and adults with cochlear implants and evaluates strategies by which selective attention can be enhanced. Auditory selective attention is quantified in four kinds of tasks: 1) simple signal detection in which the target signal is masked by random multicomponent tonal complexes; 2) a speech fundamental frequency discrimination task; 3) speech recognition tasks both with and without a visual representation of the speaker; 4) spatial segregation tasks in which the target message and the distracter are spatially separated. The aim of the first task is to quantify auditory selective attention within the constraints of a simple one-parameter model. The second task will produce a scale of talker similarity which will then be used to predict the impact of talker similarity in the selective attention tasks. The third and fourth tasks explore means by which selective attention can be enhanced eithssessed. The overall importance of this project lies in its study of communication situations common in everyday life. Speech communication in noisy environments is an especially important issue for children who are developing speech and language and the results of this project will add important new knowledge about how children and adults are able to address this issue.

project_terms:
3 year old;Acoustics;Address;Adolescence;Adopted;Adult;Affect;Age;Algorithms;Attention;Auditory;Child;Child Development;Cochlear Implants;Communication;Complex;Cues;Data;Deafness;Dependence;Detection;Development;Discrimination (Psychology);Ear structure;Environment;External auditory canal structure;Failure (biologic function);Frequencies (time pattern);Funding;Goals;Hearing;Hearing Impaired Persons;Implant;Individual;Individual Differences;Knowledge;Laboratories;Language;Life;Lipreading;Masks;Measurable;Measurement;Measures;Modeling;Noise;Participant;Performance;Peripheral;Population;Positioning Attribute;Principal Investigator;Process;Publishing;Reading;Rehabilitation therapy;Relative (related person);Research;Research Personnel;Resolution;School-Age Population;Signal Transduction;Simulate;Source;Speech;Stimulus;Techniques;Teenagers;Testing;Training;Uncertainty;Visual;Weight;Work;age effect;age related;base;expectation;hearing impairment;information processing;programs;research study;segregation;selective attention;simulation;skills;sound;speech recognition;stimulus processing;virtual


application_id: 7799297
project_number: 5T35ES014559-05
project_title: Summer Environmental Health Sciences Training Program
administering_ic: NIEHS
award_notice_date: 2010-03-30
application_type: 5
activity_code: T35
ic: ES
serial_number: 014559
program_official: SHREFFLER, CAROL A
project_start_date: 2006-04-01
project_end_date: 2011-03-31
study_section: Environmental Health Sciences Review Committee[EHS(TB)]
contact_pi_person_id: 1886009
contact_pi: PROUGH, RUSSELL ALLEN
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
budget_start_date: 2010-04-01
project_abstract:
This proposal describes a short-term summer training programfor medical students focused on exposing students to career opportunities in basic and clinical research related to environmental health sciences.This application addresses 2 Specific Aims: Aim 1: To provide hands-on training in basic and clinical Environmental Health Sciences-based researchto medical students in a structured mentored environment.Aim 2: To provide an interactive educational experience that introduces medical students the fundamentalskills necessary for basic translational and clinical Environmental Health Sciences-based research. The training program will include didactic instruction as well as a hands-on-research experience under thedirection of a team of experienced basic and clinical researchscientists centered on a core of NIEHS-funded investigators and collaborating faculty. These faculty have long-standing success inmentoring medical and graduate students and post-doctoral fellows. Students who have completed at leastone year of medical school will be eligible to apply for this 10-weektraining program. Trainees will beselected based upon their academic performance letters of recommendation and matching their researchinterests and career goals with suitable mentors. We have been successful in recruiting students fromminority rural and economically disadvantaged backgrounds. The students will participate in anestablished 10-week didactic summer program: "From Bench to Bedside: Introduction to Clinical Research"which included bioethics as well as Environmental Health Sciences-specific seminars and journal clubs inbasic and clinical research. Students will present posters of their research at the end of the program. Thetraining program will begin with six trainees and increase toten trainees as the program.matures. Over thepast 6 years the University of Louisville has increased its commitment to health science research andinfrastructure graduate education and minority recruitment making this short-term training program formedical students particularly timely. . \

project_terms:
Address;Bioethics;Clinical;Clinical Research;Economically Deprived Population;Environment;Environmental Health;Faculty;Funding;Goals;Graduate Education;Hand;Instruction;Journals;Letters;Medical;Medical Students;Mentors;Minority;Performance;Postdoctoral Fellow;Recommendation;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Rural;Structure;Students;Training;Training Programs;Universities;base;bench to bedside;career;experience;graduate student;health science research;interest;medical schools;posters;programs;skills;success


application_id: 7799126
project_number: 5R01CA138623-02
project_title: Role of leukotriene B4 receptors in the interplay of inflammation and infection
administering_ic: NCI
award_notice_date: 2010-01-18
opportunity_number: PA-07-256
application_type: 5
activity_code: R01
ic: CA
serial_number: 138623
program_official: HOWCROFT, THOMAS K
project_start_date: 2009-04-01
project_end_date: 2014-01-31
study_section: Gastrointestinal Mucosal Pathobiology Study Section[GMPB]
contact_pi_person_id: 6074575
contact_pi: BODDULURI, HARIBABU
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): Colon cancer is a leading cause of cancer related deaths in the United States. Exposure to a number of hazardous environmental agents and consumption of the Western diet are known to contribute to the pathogenesis of malignant colon cancer. While chronic inflammation is known to be a major promoter of tumor development the role of gut microflora in contributing to the colon cancer is unknown. Our laboratory has identified leukotriene B4 receptor BLT1 as a major regulator of inflammation and host response to infections. In a mouse model of spontaneous intestinal cancer (ApcMin/+) we have made the observation that absence of BLT1 greatly enhances intestinal tumor development. This has led to the central hypothesis that Absence of BLT1 enhances colon tumor development by defective immune surveillance and/or altered microbial gut homeostasis. This apparently paradoxical result that loss of a proinflammatory mediator increases inflammation and tumor development suggests that the ever changing micro environment of intestine can have a major influence on the development of colorectal cancer. The current proposal will test this hypothesis in three specific aims. In aim 1 we will examine the mechanisms of leukotriene B4 pathway mediated protection of intestinal cancers in ApcMin/+ mice. Aim 2 will establish the immune functions in tumor bearing mice in the context of BLT1+/+ and BLT1-/- mice. Aim 3 will test the novel concept that defective host response and altered gut microbiota are responsible for rapid development of colon tumors in BLT1-/- mice. These studies will provide a comprehensive model system to examine the interplay of inflammation and infections to the development of colon cancer. Since the mouse ApcMin/+ model is highly related to human colon cancers the result will have direct and immediate impact for the treatment of human colon cancer. PUBLIC HEALTH RELEVANCE: Leukotrienes are involved in the pathophysiology of many acute and chronic inflammatory diseases such as systemic anaphylaxis asthma atherosclerosis and arthritis. The novel finding that leukotriene B4-leukotriene B4 receptor1 axis may have a protective function in the development of colon cancer offers a unique opportunity to understand the role of these mediators in tumor development. Understanding the precise function of distinct leukotriene B4 receptors in mice and defining the role of these receptors in host defense and shaping the gut microflora will provide novel approaches to the treatment of colon cancer.

project_terms:
APC gene;Acute;Adoptive Transfer;Affinity;Anaphylaxis;Antibiotics;Arthritis;Asthma;Atherosclerosis;Azoxymethane;Biological Models;Bone Marrow;Cancer Etiology;Cancer Model;Cells;Cessation of life;Chimera organism;Chronic;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Consumption;Defect;Development;Diet;Disease;Environment;Environmental Risk Factor;Event;Exposure to;Functional disorder;Genes;Homeostasis;Host Defense;Human;Immune;Immune System Diseases;Immune response;Immune system;Immunologic Surveillance;Infection;Infiltration;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory disease of the intestine;Integration Host Factors;Intestinal Cancer;Intestinal Neoplasms;Intestines;LTB4R gene;Laboratories;Leukotriene B4;Leukotriene B4 Receptors;Leukotrienes;Link;Malignant - descriptor;Malignant Neoplasms;Mediating;Mediator of activation protein;Messenger RNA;Modeling;Molecular Carcinogenesis;Mus;Mutation;Pathogenesis;Pathway interactions;Phenotype;Play;Process;Proteins;Role;Shapes;Sodium Dextran Sulfate;Testing;Toll-Like Receptor Pathway;Transgenic Mice;Tumor Promoters;United States;Variation (Genetics);airway hyperresponsiveness;base;body system;cell type;environmental agent;gut microbiota;gut microflora;immune function;microbial;microbial colonization;microbicide;microorganism interaction;mouse model;novel;novel strategies;protein expression;public health relevance;receptor;tumor


application_id: 7799076
project_number: 5R44HD050006-04
project_title: Stimulation-Augmented Exercise and Neuromotor Therapy
administering_ic: NICHD
award_notice_date: 2010-05-25
opportunity_number: PA-07-280
application_type: 5
activity_code: R44
ic: HD
serial_number: 050006
program_official: SHINOWARA, NANCY
project_start_date: 2006-05-01
project_end_date: 2013-03-31
study_section: Special Emphasis Panel[ZRG1-MOSS-L(02)B]
contact_pi_person_id: 7771781
contact_pi: HARTMAN, ERIC C
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 129360637
duns_number: 129360637
fips: US
organization_id: 4168101
organization_name: CUSTOMKYNETICS, INC.
organization_city: NICHOLASVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403401290
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-04-01
budget_end_date: 2013-03-31
project_abstract:
DESCRIPTION (provided by applicant):  This Phase II SBIR project proposes to develop an electrical stimulation augmented exercise device for individuals with incomplete spinal cord injury (iSCI).  The device will provide a closed-chain load bearing lower extremity exercise that has the potential to condition muscles and reverse or slow the rate of loss of bone mineral density.  Users will be encouraged to voluntarily perform the exercise.  Client volitional efforts will be augmented by electrical stimulation and a servomotor drive such that the prescribed exercise range of motion is fulfilled with each movement cycle.  The adaptive stimulation controller will continuously adjust the stimulation profile based on movement errors and servomotor activity to provide only the stimulation that is necessary to complete the exercise while encouraging clients to contribute their best volitional effort on each exercise cycle.  A visual feedback infrastructure will be developed that encourages client participation emphasizes clinically relevant therapeutic exercise goals and rewards client achievements.  The visual environment will require clients to generate a series of appropriately timed and executed volitional trigger events (ranging from 'trace levels of applied force' to 'unassisted movements') which will be rewarded with a full range of motion movement cycle and success in a game.  We hypothesize that long-term use of the device in a comprehensive motor rehabilitation program may lead to functional improvements in addition to the localized and systemic benefits of exercise.  Phase I feasibility milestones were achieved including demonstration that: 1) client volitional effort could be synchronized with the stimulation controller; 2) functional stimulation levels could be well tolerated in this population where cutaneous sensation is in-tact (potentially hypersensitive); and 3) the stimulation controller could accommodate client volitional effort and generate only the stimulation that was needed to elicit the desired exercise movement.  We propose to build upon Phase I results through the following Phase II aims: 1) develop a servomotor drive that will improve exercise quality provide a wider range and better control of bodyweight loading allow use by individuals with advanced osteoporosis who are most in need of the exercise and accomplish the goal of coordinating volitional and stimulation-augmented efforts via haptic feedback rather than a real-time visual display; 2) develop intellectually engaging visual display environments that encourage and reward clinically relevant client volitional efforts; and 3) improve reliability and manufacturability.  We will demonstrate efficacy via a two-site clinical trial in which twenty (20) individuals with chronic incomplete spinal cord injury participate in a 12-week exercise paradigm using the device. Outcome measures will include assessment of functional improvements (i.e. FIM gait analysis) and a dynamometer test to assess improvements in volitional control independent of exercise-related improvements in torque generating capability. The target market for the device is clinics who serve individuals with neuromotor disabilities such as incomplete SCI traumatic brain injury or stroke.  The device will be competitively priced within the electrical stimulation-based exercise equipment market.  PUBLIC HEALTH RELEVENCE: The proposed work may benefit public health through development of a clinically viable electrical stimulation based therapeutic exercise device for use in motor rehabilitation following spinal cord injury or stroke. Compared to existing devices and techniques the adaptively controlled electrical stimulation servomotor assist and video game components and tight integration of instrumentation control stimulation visualization and reporting features may improve efficacy and availability of the therapeutic intervention for many affected individuals.

project_terms:
Achievement;Affect;Articular Range of Motion;Bone Density;Cardiovascular Diseases;Chronic;Client;Clinic;Clinical Trials;Craniocerebral Trauma;Cutaneous;Development;Devices;Diabetes Mellitus;Electric Stimulation;Electronics;Environment;Equipment;Esthesia;Event;Exercise;Feedback;Generations;Goals;Imagery;Individual;Lead;Leg;Lower Extremity;Marketing;Mechanics;Motor;Movement;Muscle;Osteoporosis;Outcome Measure;Paralysed;Pattern;Phase;Physical Fitness;Population;Positioning Attribute;Price;Range of motion exercise;Rehabilitation therapy;Reporting;Research Infrastructure;Rewards;Series;Site;Sledding;Small Business Innovation Research Grant;Spinal cord injury;Structure;System;Techniques;Testing;Therapeutic;Therapeutic Intervention;Time;Torque;Traumatic Brain Injury;Video Games;Visual;Weight-Bearing state;Work;base;clinically relevant;design;disability;foot;functional improvement;gait examination;haptics;improved;instrumentation;joint mobilization;motor control;nervous system disorder;phase 2 study;programs;prototype;public health medicine (field);respiratory;sensor;stroke;success;tool;visual feedback


application_id: 7798872
project_number: 1R01AA018844-01
project_title: Adipose Tissue Lipolysis and Alcoholic Fatty Liver
administering_ic: NIAAA
award_notice_date: 2009-09-25
opportunity_number: RFA-AA-09-006
application_type: 1
activity_code: R01
ic: AA
serial_number: 018844
program_official: GAO, PETER
project_start_date: 2009-09-30
project_end_date: 2014-08-31
study_section: Special Emphasis Panel[ZAA1 JJ (06)]
contact_pi_person_id: 6870954
contact_pi: ZHOU, ZHANXIANG
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): Adipose tissue lipolysis and alcoholic fatty liver Project Summary Alcoholic fatty liver is one of the earliest pathological changes in the progression of alcoholic liver disease. Accumulation of lipid in the hepatocyte makes the liver susceptible to inflammatory mediators or other toxic agents leading to further progression to hepatitis and eventually fibrosis. Therefore lipid accumulation is one of the most fundamental cellular disorders in alcoholic liver disease and reduction of liver fat would likely halt or slow the progression of alcoholic liver disease. While alcohol induces fat accumulation in the liver a significant decrease in fat mass (lipoatrophy) has been documented in chronic alcoholism. Our preliminary studies demonstrated a negative correlation between adipose tissue mass and liver fat in mice chronically fed alcohol. We also found that attenuation of alcoholic fatty liver by zinc supplementation is accompanied by partial reversal of lipoatrophy suggesting a link between lipoatrophy and alcoholic fatty liver. Our recent studies further demonstrated that alcohol exposure upregulated hepatic fatty acid transporter 5 (FATP5) and CD36 (also named fatty acid translocase) suggesting an increased fatty acid uptake in the liver. On the other hand chronic alcohol exposure activated both hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) pathways in the adipose tissue indicating an upregulation of lipolysis. Our overall hypothesis is that reverse fatty acid transport due to excess lipolysis of the adipose tissue plays a crucial role in pathogenesis of alcoholic fatty liver. To test this hypothesis four specific aims are proposed. Aim 1 is to determine if increased fatty acid uptake plays a crucial role in the development of alcoholic fatty liver. We will first document alcohol- induced increase in hepatic fatty acid uptake. We will then determine if blocking fatty acid uptake leads to reduction of alcoholic fatty liver. Aim 2 is to determine if excess lipolysis of the adipose tissue is a causal factor in alcohol-increased hepatic fatty acid uptake. We will first determine if alcohol exposure can enhance hepatic deposition of fatty acids mobilized from adipose tissue. We will then determine if blocking adipose tissue fatty acid mobilization can lead to attenuation of alcoholic fatty liver. Aim 3 is to investigate the molecular mechanisms by which alcohol induces excess lipolysis of the adipose tissue. We will first determine how alcohol exposure affects the lipolytic pathways in the adipose tissue. We will then define the role of nicotinic acid deficiency in HSL activation and the role of glucocorticoid in activation of ATGL lipolytic pathway. Aim 4 is to define the role of zinc in the regulation of adipose tissue lipolysis. We will first determine the effects of dietary zinc on lipolytic pathways and nicotinic acid metabolism and glucocorticoid production. We will then determine how zinc affects lipolytic signaling transduction in the adipocytes.  
  
PUBLIC HEALTH RELEVANCE: Alcoholic fatty liver is the earliest pathological change in the progression of alcoholic liver disease but the mechanisms by which alcohol causes hepatic lipid accumulation have not been well defined. Clinical studies have shown a significant decrease in fat mass in patients with alcoholic fatty liver. Our preliminary studies demonstrated a negative correlation between liver fat and adipose tissue mass. We also found that alcohol exposure stimulates adipose tissue lipolysis and hepatic fatty acid uptake. This project will test our hypothesis that reverse fatty acid transport due to excess lipolysis of the adipose tissue plays a crucial role in the pathogenesis of alcoholic fatty liver.

project_terms:
Accounting;Adipocytes;Adipose tissue;Adrenergic Receptor;Affect;Alcohol consumption;Alcoholic Fatty Liver;Alcoholic Liver Diseases;Alcoholism;Alcohols;Attenuated;Body fat;CD36 Antigens;CD36 gene;Chronic;Clinical Research;Coupled;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Data;Deposition;Development;Dietary Zinc;Disease;Fatty Acids;Fatty Liver;Fatty acid glycerol esters;Fatty-acid synthase;Fibrosis;Glucocorticoids;Hand;Hepatic;Hepatic Mass;Hepatitis;Hepatocyte;Homeostasis;Inflammation Mediators;Lead;Link;Lipase;Lipids;Lipoatrophy;Lipolysis;Liver;Mediating;Metabolic syndrome;Metabolism;Molecular;Mus;Names;Nicotinic Acids;Pathogenesis;Pathway interactions;Patients;Play;Principal Investigator;Production;Proteins;Regulation;Research;Role;Signal Transduction;Supplementation;Testing;Triglycerides;Up-Regulation (Physiology);Zinc;Zinc deficiency;alcohol exposure;attenuation;deprivation;fatty acid transport;feeding;problem drinker;programs;public health relevance;receptor;sterol esterase;translocase;uptake

public_health_relevance:
Program Director/Principal Investigator (Last First Middle): Zhou ZhanxiangAdipose tissue lipolysis and alcoholic fatty liverProject NarrativeAlcoholic fatty liver is the earliest pathological change in the progression of alcoholic liver disease but themechanisms by which alcohol causes hepatic lipid accumulation have not been well defined. Clinical studieshave shown a significant decrease in fat mass in patients with alcoholic fatty liver. Our preliminary studiesdemonstrated a negative correlation between liver fat and adipose tissue mass. We also found that alcoholexposure stimulates adipose tissue lipolysis and hepatic fatty acid uptake. This project will test our hypothesisthat reverse fatty acid transport due to excess lipolysis of the adipose tissue plays a crucial role in thepathogenesis of alcoholic fatty liver.PHS 398/2590 (Rev. 11/07) Page Continuation Format Page


application_id: 7798621
project_number: 5R01DA013425-07
project_title: Naltrexone Prodrugs for Transdermal Delivery
administering_ic: NIDA
award_notice_date: 2010-02-17
application_type: 5
activity_code: R01
ic: DA
serial_number: 013425
program_official: PARK, MOO KWANG
project_start_date: 2002-04-01
project_end_date: 2012-03-31
study_section: Medication Development Research Study Section[NIDA-L]
contact_pi_person_id: 1866585
contact_pi: STINCHCOMB, AUDRA L.
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-04-01
project_abstract:
DESCRIPTION (provided by applicant): Alcoholism and opiate addiction lead to major health-related problems and societal costs for people in the United States and the rest of the world as well. Therefore research and development for improved pharmacologic treatments for drug and alcohol abuse are very important. Naltrexone an opioid antagonist is currently used in oral tablet form to help maintain opioid addicts in a drug-free state. Most recently naltrexone has been indicated as an adjunct in the treatment of alcohol dependence as well as reported to reduce alcohol craving in certain alcoholic populations. Transdermal delivery of naltrexone is desirable for opioid addicts and alcoholics in order to help reduce side effects associated with oral therapy and improve compliance. Naltrexone itself does not have the essential physicochemical properties that would allow a therapeutic dose of the drug to cross the human skin barrier. We plan to continue designing and synthesizing prodrugs which are more skin permeable than naltrexone in order to make a therapeutically successful drug delivery system. We hypothesize that prodrugs of naltrexone and prodrugs in combination with microneedle treatment will improve the transdermal delivery rate of naltrexone and that these prodrugs will make excellent research tools for investigating quantitative structure-permeability relationships (QSPR) for transdermal flux and optimization of flux in combination with microneedle enhancement. These prodrugs/microneedles should improve naltrexone delivery rates across the skin because of optimized physicochemical properties for faster diffusion. The specific aims of this project include: (1) to synthesize a series of naltrexone and naltrexol (active metabolite) prodrugs designed to elucidate fundamental QSPRs for transdermal flux optimization with and without microneedle use (2) to characterize the physicochemical parameters of the drugs including molecular weight molecular volume lipophilicity hydrogen-bonding potentials melting points heats of fusion and solubilities in select solvents (3) to measure the drugs' penetration and concurrent bioconversion through human skin in vitro with and without microneedle use and (4) to characterize the pharmacokinetics of the drugs in guinea pigs in vivo with and without 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 prodrugs with and without microneedle use as well as help to identify the most promising prodrug/microneedle system for eventual human use.

project_terms:
6 beta-hydroxynaltrexone;Adverse effects;Alcohol abuse;Alcohol dependence;Alcoholism;Amines;Carbamates;Carbonates;Cavia;Data;Databases;Diffusion;Dosage Forms;Dose;Drug Delivery Systems;Drug Kinetics;Goals;Heating;Human;Hydrogen Bonding;In Vitro;Knowledge;Lead;Measures;Molecular;Molecular Weight;Mono-S;Naltrexone;Narcotic Antagonists;Opiate Addiction;Opioid;Oral;Penetration;Permeability;Pharmaceutical Preparations;Pharmacotherapy;Plasma;Population;Prodrugs;Property;Recovery;Reporting;Research;Research Personnel;Rest;Series;Skin;Solubility;Solvents;Structure;System;Tablets;Therapeutic;United States;alcohol craving;carboxylate;clinical application;cost;craving;design;improved;in vivo;in vivo Model;lipophilicity;melting;problem drinker;research and development;tool


application_id: 7798613
project_number: 5R01AI025098-21
project_title: Plague biofilm formation--regulation and function
administering_ic: NIAID
award_notice_date: 2010-03-25
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AI
serial_number: 025098
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 1993-09-30
project_end_date: 2014-03-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 1864186
contact_pi: PERRY, ROBERT DONALD
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Yersinia pestis is the causative agent of plague which has caused widespread loss of human life during recurrent pandemics. On average approximately 2500 cases of human plague occur world-wide each year. Recently over 98% of the plague cases are found in Africa. In nature the bacterium cycles between mammals (mainly rodents) and fleas. The interaction of plague with fleas is facilitated by the formation of a biofilm. In the oriental rat flea Xenopsylla cheopis formation of the biofilm leads to blockage of the valve between the esophagus and stomach of the flea known as the proventriculus. Blockage of the proventriculus may extend the transmission time. The hemin-storage genes (hms) of Y. pestis are responsible for the production of a biofilm which is essential for flea blockage. The Hms+ phenotype was initially characterized as the ability of cells grown at 26:C but not 37:C to bind exogenous hemin or the dye Congo red and is due to the production of an exopolysaccharide matrix or biofilm. There are at least 5 genes involved in the synthesis of the Hms- dependent biofilm; hmsHFRS hmsT and hmsP. Two of these gene products HmsP and HmsT are responsible for the synthesis and turnover of the signaling molecule cyclic di-guanylic acid. Over-production of HmsT a diguanylate cyclase or the absence of HmsP a phosphodiesterase leads to increased biofilm formation. Polyamines also play a role in the creation of a Y. pestis biofilm. Mutants that are unable to synthesize polyamines can not form a biofilm unless supplied with exogenous putrescine. This proposal will continue studies on the mechanisms that control biofilm development and the protein-protein interactions needed for biofilm formation. The biochemical functions of the Hms proteins as well as the role of the biofilm in fleas and mice will be addressed. In specific aim 1 the interaction between Y. pestis wild-type cells as well as various hms mutants and different flea species will be investigated. The role of c-di-GMP in virulence of plague will also be examined. Specific factors which regulate biofilm development will be studied in specific aim 2. In specific aim 3 the interactions between the Hms proteins as well as their biochemical and enzymatic characteristics will be addressed. The proposed studies will provide new insights into the regulation of plague biofilm formation and its role in the transmission of the disease from fleas to mammals. Systems similar to that responsible for plague biofilm are present in a number of diverse bacteria. Biofilms are often associated with the ability to survive harsh conditions as well as increased resistance to antibiotics. Understanding the mechanisms involved in producing the plague biofilm as well as the factors that regulate its production will likely be relevant for biofilm formation in other pathogens. PUBLIC HEALTH RELEVANCE: pestis the bacterium that causes bubonic and pneumonic plague produces a sticky substance known as a biofilm. Biofilms are made by several different kinds of bacteria and are often associated with their ability to survive harsh environments and in some cases cause disease. Understanding how the plague bacterium makes biofilm may eventually lead to ways to prevent biofilm formation in other bacterial pathogens.

project_terms:
Address;Affect;Africa;Amino Acids;Antibiotic Resistance;Asians;Bacteria;Binding (Molecular Function);Biochemical;Bioterrorism;Blood;Cells;Characteristics;Congo Red;Development;Dinucleoside Phosphates;Disease;Disease Outbreaks;Dyes;Environment;Escherichia coli;Esophagus;Fleas;Genes;Guanosine Monophosphate;Hemin;Human;In Vitro;Individual;Lead;Life;Mammals;Microbial Biofilms;Modeling;Montana;Mus;Mutagenesis;Mutation;Nature;Pathogenesis;Peptide Hydrolases;Phenotype;Plague;Play;Pneumonic Plague;Polyamines;Production;Proteins;Proventriculus;Putrescine;Rattus;Recurrence;Regulation;Rodent;Role;Signaling Molecule;South America;Southeastern Asia;Spermophilus;Squirrel;Stomach;System;Temperature;Testing;Time;Translations;Virulence;Yersinia pestis;bis(3'5')-cyclic diguanylic acid;case finding;cell type;diguanylate cyclase;disease transmission;glycosyltransferase;in vivo;insight;macrophage;mutant;pandemic disease;pathogen;periplasm;phosphoric diester hydrolase;prevent;protein protein interaction;public health relevance;transmission process;vector


application_id: 7798505
project_number: 5R01HD057501-03
project_title: The Mechanism of Cryptorchidism in LH Receptor Knockout Animals
administering_ic: NICHD
award_notice_date: 2010-04-01
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HD
serial_number: 057501
program_official: TAYMANS, SUSAN
project_start_date: 2008-04-01
project_end_date: 2013-03-31
study_section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER]
contact_pi_person_id: 2220008
contact_pi: LEI, ZHENMIN
other_pis: Not Applicable
congressional_district: 03
department: OBSTETRICS & GYNECOLOGY
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):  Cryptorchidism is by far the most common defect of sexual differentiation in humans. Testicular descent can be anatomically divided into two stages i.e. transabdominal and inguinoscrotal phases. It is known that both insulin-like peptide 3 (INSL3) and androgen signaling pathways play critical roles in the control of the transabdominal phase of testis descent. However the mechanism that regulates the inguinoscrotal phase is not completely understood even though the incidence of this defect is much more common clinically. Targeted disruption of luteinizing hormone receptor (LHRKO) in mouse impaired development of adult-type Leydig cells which resulted in a dramatic reduction of INSL3 and testosterone levels. Surprisingly serum estradiol levels were significantly increased. LHRKO males exhibited a bilateral cryptorchid phenotype resulting from a defect in inguinoscrotal testis descent. Histology morphometry cell proliferation and differentiation analyses demonstrated the defect was due to a reduction in mesenchymal cell division and differentiation into cremaster muscle cells during the second stage of testis descent. The expression of several genes in the gubernaculum that are known to be involved in gubernacular development such as Hoxa10 Hoxa11 Wt1 Dll1 and Desrt were not altered in mutant mice while Lgr8 Notch1 and Numb mRNA levels were drastically deceased as compared with age-matched wild type siblings. In contrast the expressions of Esr1 (ER1) and Esr2 (ER2) were significantly elevated. Postnatal testosterone replacement therapy (TRT) completed testicular descent into the scrotum and concomitantly normalized estradiol concentrations in the circulation and Esr1 Esr2 Lgr8 Notch1 and Numb mRNA levels in the gubernaculum. Remedy of the defect by TRT was neither dependent on recovery of adult-type Leydig cells nor the genitofemoral nerve but required androgen receptor activity in the gubernaculum. Using organ culture of the gubernaculum in vitro androgen alone did not significantly stimulate proliferation of gubernacular mesenchymal cells without activation of the leucine-rich repeat-containing G-protein coupled receptor 8 (LGR8) signaling pathway by addition of INSL3 or relaxin. Co-treatment of estrogen with androgen prevented androgen-induced Lgr8 expression. Cotreatment of INSL3 and androgen increased Notch1 but not Numb mRNA levels. Taking these results together we hypothesize that induction of the Lgr8 gene expression by androgen and activation of LGR8 signal impinging on the Notch system to stimulate gubernacular cell proliferation differentiation and myogenesis are the essential molecular pathways in the control of gubernacular development to facilitate inguinoscrotal testis descent. In addition to androgen deficiency unbalanced androgen/estrogen signals also play a role in contributing to the cryptorchid phenotype in LHR null animals. In this grant application we propose four specific aims to verify our hypotheses: (1) to define the underlying mechanism by which androgen modulates the Lgr8 gene expression in the gubernaculum; (2) to assess the role of the LGR8 signaling pathway in androgen-induced inguinoscrotal testis descent in LHR null males; (3) to determine the importance of the Notch signaling pathway in mediating androgen and LGR8 signals to regulate gubernaculum development during inguinoscrotal testis descent and (4) to investigate the effect of estrogen on androgen-induced inguinoscrotal testis descent in LHR null males. Cryptorchidism is by far the most common birth defect in males. Although inguinoscrotal testis descent is known to be androgen dependent the underlying mechanism remains unclear. The current proposal is focusing on determining androgen downstream target genes and subsequent signaling network during the process of inguinoscrotal testis descent which may provide new insight into the causes of testis maldescent.

project_terms:
Adult;Age;Androgen Receptor;Androgens;Animals;Applications Grants;Bilateral;Blood Circulation;Cell Proliferation;Cell division;Cells;Congenital Abnormality;Cryptorchidism;Defect;Development;Estradiol;Estrogens;Exhibits;G-Protein-Coupled Receptors;Gene Expression;Gene Targeting;Genes;Histology;Human;In Vitro;Incidence;Insulin;LH Receptors;Leucine-Rich Repeat;Mediating;Mesenchymal;Messenger RNA;Molecular;Mus;Muscle Cells;Mutant Strains Mice;Nerve;Notch Signaling Pathway;Organ Culture Techniques;Pathway interactions;Peptides;Phase;Phenotype;Play;Process;Recovery;Relaxin;Role;Scrotum;Serum;Siblings;Signal Pathway;Signal Transduction;Staging;System;Testis;Testosterone;cremaster muscle;insight;knockout animal;leydig interstitial cell;male;morphometry;myogenesis;notch protein;postnatal;prevent;testosterone replacement therapy


application_id: 7797693
project_number: 5P01HL078825-05
project_title: CORE--Pathology Core
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 9003
contact_pi_person_id: 1880936
contact_pi: ANVERSA, PIERO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-01
budget_end_date: 2010-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The Pathology Core (Core D) will perform all microscopic analyses needed for the four Projects of this PPG. The Core has state-of-the-art facilities and extensive experiences with virtually all pathologic analyses of cardiac tissues. This Core represents the continuation of the ongoing collaboration between Dr. Anversa's team at the New York Medical College and the Cardiology team at the University of Louisville which have worked together for the past two years. The logistics of this arrangement have been extensively tested and do not pose any problem. Following perfusion fixation tissue samples will be obtained in each of the four Projectsat the University of Louisville and sent to the Pathology Core at New York Medical College for analysis. The Core will perform several functions that can be summarized as follows. 1. Morphometric analysis of infarct size myocyte volume and number and length density of resistance arterioles and capillary network within the myocardium. Myocyte volume will be assessed both in situ and in enzymatically dissociated cells. Myocyte classes and distribution will be analyzed with confocal microscopy both in situ and in isolated myocytes. Thesemeasurements will enable us to calculate the total number of myocytes lost during  post-infarction LV remodeling (Project 2) and to compare the number of lost myocytes with conventional measurements of infarct size by tetrazolium staining at 24 h of reperfusion. 2. Two-photon microscopy to perform simultaneous detection of multiple antigens without the limitations imposed by photobleaching of fluorophores. Two-photon microscopy will also be used to measure pyridine nucleotides in Project 4. 3. Confocal microscopic analysis of tissuesections obtained from perfusion-fixed hearts. The combination of two-photon and confocal microscopy will enable us to quantitate the expression of multiple antigens (e.g. iNOS HO-1 ecSOD nitrotyrosines protein-HNE adducts protein-MDA adducts protein carbonyls) simultaneously in the same tissue section. Two-photon and confocal microscopy will be employed for quantitative analysis of fluorescence intensity of iNOS HO-1 ecSOD protein-HNE adducts protein-MDA adducts nitrotyrosines and 8-hydroxy-deoxyguanosine. Allimmunocytochemistry will be done by using primary antibodies labeled directly with the fluorochromes recognized by our two-photon microscope and confocal microscope which will avoid the complications of nonspecific staining and cross-reactivity between antibodies. 4. Quantitative measurement of apoptotic and necrotic cells with our newly-developed dual-labeling technique (hairpin-1 in situ ligation coupled with immunohistochemistry for active caspase-3 hairpin-2 ligation coupled with immunohistochemistry for active caspase-3) along with TUNEL. The dual hairpin-1/active caspase-3 labeling and hairpin-2/active caspase-3 labeling will afford a very high degree of specificity in assigning a cell to apoptosis vs. necrosis. 5. Routinehistologic examination to assess inflammation fibrosis or any other morphologic changes.

project_terms:
3-nitrotyrosine;Antibodies;Antigens;Apoptosis;Apoptotic;Arts;Blood capillaries;Cardiac;Cardiology;Cells;Collaborations;Confocal Microscopy;Coupled;Deoxyguanosine;Detection;Fibrosis;Fluorescence;Fluorochrome;Heart;Histologic;Immunohistochemistry;In Situ;In Situ Nick-End Labeling;Infarction;Inflammation;Label;Left Ventricular Remodeling;Length;Ligation;Logistics;Measurement;Measures;Microscope;Microscopic;Microscopy;Muscle Cells;Myocardial Ischemia;Myocardium;Necrosis;New York;Pathologic;Pathology;Perfusion;Photobleaching;Proteins;Reperfusion Therapy;Resistance;Specificity;Staining method;Stains;Techniques;Testing;Tetrazolium Salts;Tissue Sample;Tissues;Universities;Work;adduct;arteriole;capillary;caspase-3;cross reactivity;density;experience;fluorophore;immunocytochemistry;medical schools;pyridine nucleotide;sample fixation;two-photon


application_id: 7797692
project_number: 5P01HL078825-05
project_title: CORE--Vector Core
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 9002
contact_pi_person_id: 8307878
contact_pi: LI, QIANHONG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-01
budget_end_date: 2010-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Core C (Vector Core) will provide access to a wide array of gene transfer technology. The Core has assembled a comprehensive inventory of DNA plasmids cell lines and viruses useful for the development of vectors. The Core will provide services in terms of vector creation amplification purification and analysis for Projects 1 2 and 4. This dedicated facility will be run by Dr. Qianhong Li who has extensive experience with recombinant viruses and has studied virus-mediated gene therapy for myocardial ischemia/reperfusion injury for eight years. We have developed an rAAV vector system that is helper adenovirus free thereby eliminating the problem of adenovirus contamination in the final preparation. We have already created and successfully used rAAV/LacZ rAAV/iNOS and rAAV/ecSOD for in vivo cardiac gene transfer in mice. rAAV vectors currently available in the Vector Core include rAAV/LacZ rAAV/hrGFP "empty" rAAV rAAV/ecSOD and rAAV/iNOS. The primary responsibility of the Vector Core will be to design create produce and analyze rAAV vectors for long-term in vivo gene transfer. Specific responsibilities include: (i) cloning the gene of interest into an AAV DNA plasmid containing ITR sequences (ii) cloning the mitochondrial leader sequence into an AAVDNA plasmid containing the ITR and the therapeutic gene (iii) amplifying and maintaining purified stocks of AAV DNA plasmid containing the therapeutic gene (iv) amplifying and maintaining purified stocks of an AAV DNA plasmid containing the rep and cap genes as well as a helper DNA plasmid encoding the Ad5 E2a and E4 gene regions (v) constructing rAAV vectors in 293 cells (vi) purifying titrating and analyzing rAAV vectors (vii) long-term storage of rAAV vectors and (viii) developing mitochondrially-targeted rAAV vectors (mt-rAAV) which will be used in Project 4 to study the effects of targeting iNOS and HO-1 specifically to the mitochondria.

project_terms:
Adenoviruses;Cardiac;Cell Line;Cells;Cloning;Development;Equipment and supply inventories;Gene Transfer;Genes;LacZ Genes;Mediating;Mitochondria;Mus;Myocardial Ischemia;Preparation;Reperfusion Injury;Running;Services;System;Technology;Virus;design;experience;gene cloning;gene therapy;in vivo;interest;plasmid DNA;recombinant virus;therapeutic gene;vector


application_id: 7797691
project_number: 5P01HL078825-05
project_title: CORE--Surgery and Transgenic Mouse Core
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 9001
contact_pi_person_id: 8251726
contact_pi: GUO, YIRU
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-01
budget_end_date: 2010-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The Surgery and Transgenic Mouse Core (Core B) will provide state-of-the-art support to all four Projects with studies involving surgical procedures in murine models and use of transgenic/knockout mice. The Core will consist of two Units the Surgery Unit which will be responsible for all surgical procedures and the Transgenic Mouse Unit which will beresponsible for generating breeding and genotyping the various lines of transgenic and knockout mice. These two Units will be inextricably intertwined as the Transgenic Unit will produce the mice operated on by the Surgery Unit while the Surgery Unit will phenotype the mice generated by the Transgenic Unit. Dr. Yiro Guo an expert surgeon will be Leader of Core B and will be specifically responsible for all operations in the Surgery Unit. Dr. Gregg Rokosh an expert molecular biologist will be Co-Leader of Core B and will be specifically responsible for the functions of the Transgenic Mouse Unit. The complementarity of their backgrounds coupled with their collegial nature provides a strong foundation for productive synergy. The Surgical Unit of Core B will perform coronary artery occlusion/reperfusion studies measurements of infarct size gene transfer procedures administrationof pharmacologicagents perfusion fixation ofcardiac tissue and noninvasive and hemodynamic studies. It will also generate myocardial tissue samples as well as cardiomyocytes to be used for molecular studies. State-of-the-art facilities and equipment are available. All Core personnel have extensive experience with the murine models of myocardialinfarctionand gene therapy to be used in the four Projects. These procedures have been performed in over 9000 mice and are associated with  minimal complications. The postmortem perfusion technique to measure infarct size results in accurate delineation of the infarcted area area at risk and nonischemic area such that measurements of infarct size are highly reproducible. Meticulous attention is paid to maintaining fundamental physiologic parameters (heart rate arterial blood pressure arterial blood pH hematocrit and body temperature) within normal limits throughout the coronary occlusion/reperfusionstudies. The protocol for gene delivery (i.v. infusion of viral vectors with distal aortic clamping under whole-body hypothermia) results in widespread highly efficient transduction (70-90%) of cardiomyocytes throughout the left ventricle. The Core is equipped with fully functional echocardiography and invasive hemodynamic laboratories for accurate assessment of LV function in vivo. The Transgenic Mouse Unit of Core B will provide 14 transgenic or knockout mouse lines to be used by the four Projects. The Unit has already created several transgenic mouse lines with cardiac-specific gene expression including a novelinducible knockout of STAT3 and will create new genetically-engineered models that will allow temporal control of transgenic expression. The Unit will also be responsible for breeding genotyping and handling all of the transgenic and knockout mice to be used in the four Projects. For knockout mice controls will consist of wild-type littermates generated by Het x Het inbreeding; similarly wild-type littermates will be used as controls for transgenic mice. Insummary Core B will provide a strong backbone for this Program Project. The extensive experience of the personnel the superb facilities available and the strong collegiality of the investigators will provide the four Projects with an outstanding experimental resource to undertake physiologically-relevant studies pertaining to the protection of ischemic myocardium.

project_terms:
Area;Arts;Attention;Autopsy;Blood;Blood Pressure;Body Temperature;Breeding;Cardiac;Cardiac Myocytes;Coronary Occlusions;Coronary artery;Coupled;Distal;Echocardiography;Engineering;Equipment;Foundations;Gene Delivery;Gene Expression;Genotype;Heart Rate;Hematocrit procedure;Human Resources;Inbreeding;Infarction;Infusion procedures;Knock-out;Knockout Mice;Laboratories;Left ventricular structure;Measurement;Measures;Modeling;Molecular;Mus;Myocardial Ischemia;Myocardial tissue;Nature;Operative Surgical Procedures;Perfusion;Phenotype;Physiological;Procedures;Protocols documentation;Reperfusion Therapy;Research Personnel;Resources;Risk;STAT3 gene;Surgeon;Techniques;Tissue Sample;Tissues;Transgenic Mice;Transgenic Organisms;Vertebral column;Viral Vector;artery occlusion;experience;gene therapy;hemodynamics;in vivo;natural hypothermia;novel;programs;sample fixation


application_id: 7797690
project_number: 5P01HL078825-05
project_title: Metabolic Basis of Preconditioning
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0004
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-01
budget_end_date: 2010-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The long-term goal of this project is to understand the fundamental molecular mechanisms ofcardioprotection Our central hypothesis is that inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1) protect the heart from ischemia-reperfusion (I-R)injury by partially inhibiting mitochondrial electron transport which decreases the generation of free radicals and prevents mitochondrial permeability transition (MPT). We propose that these changes prevent ischemic cell death and are responsible for the cardioprotective effects of the late phase of preconditioning (PC). We will use electron paramagnetic resonance measurements to quantify the generation of oxygen-derived free radicals and nitric oxide and determine whether free radicals generation and oxidative stress are attenuated in preconditioned hearts subjected to I-R (Aim 1). To test the antioxidant role of iNOS and HO-1 we will measure free radical generation and oxidative stress in hearts transduced with recombinant adeno-associated virus (rAAV) carrying the iNOS or HO-1 gene. Conversely we will determine whether I-R-induced oxidative stress and radical generation are exacerbated in the hearts of iNOS or HO-1 null mice (Aim 2). To examine whether the cardioprotective effects of late PC are derived from inhibition of MPT we will measure permeability transition and the activity of respiratory complexes in mitochondria isolated from naive and preconditioned hearts and test whether PC decreases I-R-induced MPT in isolated perfused hearts (Aim 3). To determine the role of iNOS and HO-1 we will examine whether inhibition or the lack of these proteins abolishes the effects of PC on MPT and conversely whether hearts of mice transduced with rAAV/iNOS or rAAV/HO-1 are resistant to I-R-induced MPT. We will determine whether iNOS and HO-1 prevent mitochondrial injury by associating withthe mitochondria and whether localization of these proteins to the mitochondria (by using mitochondria-specific leader sequence) is sufficient to confer cardioprotection (Aim 4).

project_terms:
Affect;Aldehydes;Antioxidants;Apoptosis;Attenuated;Cell Death;Collaborations;Complex;Development;Electron Spin Resonance Spectroscopy;Electron Transport;Enzyme Inhibition;Enzymes;Free Radicals;Generations;Genes;Genetic Transcription;Goals;Heart;Heme Oxygenase (Decyclizing);Injury;Investigation;Ischemia;Ischemic Preconditioning;Knockout Mice;Late Effects;Lead;Lipid Peroxidation;Measurement;Measures;Mediating;Mediator of activation protein;Metabolic;Metabolism;Mitochondria;Mitochondrial Proteins;Modification;Molecular;Mus;Myocardial;Myocardial Ischemia;Nature;Necrosis;Nitric Oxide;Nitric Oxide Donors;Oxidative Stress;Oxygen;Pathway interactions;Permeability;Phase;Phenotype;Proteins;Recombinant adeno-associated virus (rAAV);Reperfusion Injury;Reperfusion Therapy;Resistance;Respiration;Respiratory Chain;Role;Signal Transduction;Testing;Work;base;clinically relevant;human NOS2A protein;indexing;insight;preconditioning;prevent;protective effect;respiratory


application_id: 7797689
project_number: 5P01HL078825-05
project_title: Delayed Cardioprotection Induced by NO and CO
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0003
contact_pi_person_id: 1964532
contact_pi: XUAN, YU-TING
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-01
budget_end_date: 2010-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Previous work from our laboratory indicates that NO and CO two functionally-coupled molecules confer robust and sustained protection against ischemia/reperfusion injury via mechanisms that are unknown. NO donors are widely used clinically; CO donors have recently been developed by our collaborator Dr. Motterlini and may become a new class of anti-ischemic agents. The overall objective of Project 3 is to illuminate the molecular mechanisms that underlie the long-lasting infarct-sparing and anti-apoptotic effects observed after exposure of the heart to NO and CO. We propose that the NO-CO axis plays a critical role in the cardiac adaptation tostress by virtue of its ability to genetically reprogram the heart. Our fundamenta/hypothesis is that NO and CO act synergistically to induce a sustained cardioprotected phenotype by activating pro-survival signaling pathways via the recruitment of a cluster of stress-responsive transcription factors (STAT1 STAT3 and NF-kappaB) leading to the upregu/ation of anti-apoptotic proteins that inhibit both the death receptor- and the mitochondria-dependentpathways of apoptosis. In Aim 1 we will determine whether the sustained cardioprotective effects of NO and CO are due to inhibition of apoptosis vs. necrosis which will be discerned with state-of-the-art techniques including hairpin-1/caspase-3 and hairpin-2/caspase-3 dual-labeling assays. The influence of NO and CO donors on the extrinsic and intrinsic pathways of apoptosis will be elucidated by examining their effects on the release of cytochrome c and Smac the activation of caspase-3 8 and 9 and the expression of pro-apoptotic proteins (Bax Bak Bid Bad) and anti-apoptotic proteins (Bcl-2 Bcl-XL McI-1 c-FLIPL c-FLIPs ARC XlAP clAP-1 clAP-2). Aims 2 and 3 will establish whether the delayed anti-apoptotic and anti-necrotic actions of NO and CO are mediated by STAT1 and/or STAT3; this will be accomplished by knockout of the STAT1 gene and by genetic inhibition of STAT3 via constitutive cardiac-specific STAT3 knockout or via a novel inducible cardiac-specific STAT3 knockout. Aim 4 will determine whether the cardioprotective effects of the NO-CO axisrequire both Tyr-705 (via JAKs) and Ser-727 (via the PKCepsilon-Raf-1-MEK-1/2-p44/42 MAPK cascade) phosphorylation of STAT3 which will be interrogated by using a Tyr-705 dominant negative mutant of STAT3 and a Ser-727 mutant of STAT3 respectively. The role of PKCepsilon in the activation of the Raf-1-MEK1/2-p44/42 MAPK cascade will be interrogated with targeted deletion of PKCepsilon (PKCepsilon-/- mice). Using I-kappa-B-alpha dominant negativemutant (l-kappa-B-alpha-S32AS36A mice) in Aim 5 we will determine whether (and the mechanism by which) NF-kappaB mediates the sustained cardioprotective effects of NO and CO. These studies will elucidate the specific roles of STAT1 vs. STAT3 and of NF-kappaB in myocardial ischemia/reperfusion injury. The results of this project will provide novelinsights into the mechanism whereby the NO-CO axis genetically reprograms the heart and will also have therapeutic implications for patients with coronary artery disease.

project_terms:
Apoptosis;Apoptotic;Arts;Biological Assay;CASP8 and FADD-like apoptosis regulating protein;Cardiac;Cessation of life;Coronary Arteriosclerosis;Dominant-Negative Mutation;Genetic;Heart;I Kappa B-Alpha;Infarction;Inhibition of Apoptosis;Knock-out;Label;Laboratories;MAP Kinase Gene;MEKs;Mediating;Mitochondria;Molecular;Mus;Myocardial Ischemia;NF-kappa B;Necrosis;Patients;Phenotype;Phosphorylation;Play;Proteins;Reperfusion Injury;Role;STAT1 gene;STAT3 gene;Signal Pathway;Stress;Techniques;Therapeutic;Work;caspase-3;cytochrome c;insight;mutant;novel;pro-apoptotic protein;receptor;transcription factor


application_id: 7797688
project_number: 5P01HL078825-05
project_title: Cardioprotective Genes and Postinfarction Left Ventricular Remodeling
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0002
contact_pi_person_id: 1914941
contact_pi: PRABHU, SUMANTH D
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-01
budget_end_date: 2010-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Heme oxygenase-1 (HO-1) extracellular superoxide dismutase (ecSOD) and inducible nitric oxide synthase (iNOS) are interrelated stress-responsive proteins that are cardioprotective against acute ischemia/reperfusion injury. However their role in chronic heart failure (HF) is not clear. The central objective of this Project is to unravel the pathophysiologic roles of HO-1 ecSOD and iNOS in post-infarction HF using genetically modulated mice and to determine whether these systems can be therapeutically manipulated for long-term benefit. Based on our preliminary studies our central hypothesis is that in HF Iong-term HO-1 and ecSOD induction are important beneficial adaptations that mitigate left ventricular (LV) remodeling. We further hypothesize that the effects of iNOS induction in HF depend on its cellular source i.e. whereas myocyte iNOS is cardioprotective inflammatory cell iNOS is detrimental. To test this hypothesis we will perform four Specific Aims. In Aim 1 we will define the cardiac expression of HO-1 and ecSOD in murine post-infarction HF and its relationship to LV remodeling. We will then determine the effects of HO-1 loss- or gain-of function on LV remodeling via studies in HO-1 null mice and cardiac-specific HO-1 transgenic (TG) mice. Given the antioxidant and anti-apoptotic properties of HO-1 we will evaluate the effects of HO-1 modulation on oxidative stress ecSOD expression and apoptosis. In Aim 2 we will evaluate the role of ecSOD in post-infarction LV remodeling using ecSOD null mice and cardiac-specific ecSOD TG mice. As alterations in ecSOD would primarily impact extracellular free radicals we will carefully examine in addition to oxidative stress the relationship between ecSOD modulation matrix metalloproteinase activation and dysregulation of the cardiac extracellular matrix. In Aim 3 we will determine whether iNOS is beneficial or detrimental in HF and establish the importance of the cellular source of iNOS. We will spatially and temporally define iNOS expression in post-infarction HF and then evaluate the impact of iNOS loss- or gain-of-function on the HF phenotype using iNOS null and cardiac-specific iNOS TG mice. We will then examine mice with iNOS overexpression in the heart but with loss of iNOS in the periphery to determine the role of myocyte versusinflammatory cell iNOS in HF. Finally in Aim 4 we will determine whether the protective effects of HO-1 ecSOD and iNOS in post-infarction HF can be exploited therapeutically by the use of recombinant adeno-associated virus-mediated gene transfer. We will also evaluate whether the benefits of HO-1 gene therapy are lost in ecSOD null mice thereby defining whether ecSOD is necessary for HO-1-mediated cardioprotection. Collectively these studies will provide novelinsights into the pathophysiologic roles of HO-1 ecSOD and iNOS in HF and will establish the mechanistic link between this cardioprotective system and oxidative/nitrative stress apoptosis and chamber remodeling post-infarction.

project_terms:
Ablation;Acute;Address;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Apoptosis;Apoptotic;Biliverdine;Biological;Carbon Monoxide;Cardiac;Cardiomyopathies;Catecholamines;Cells;Cellular Stress Response;Chronic;Classification;Clinical;Collaborations;Coronary;Coupled;Cytoprotection;Dilatation - action;Doctor of Medicine;Enzyme Activation;Enzymes;Extracellular Matrix;Financial compensation;Free Radicals;Functional disorder;Gene Delivery;Gene Transfer;Genes;Genetic;Heart;Heart failure;Heme;Heme Oxygenase (Decyclizing);Homeostasis;Hypertrophy;Infarction;Inflammatory;Injury;Investigation;Iron;Knockout Mice;Left;Left Ventricular Remodeling;Link;Matrix Metalloproteinases;Mediating;Mediator of activation protein;Mus;Muscle Cells;Myocardial;Myocardial Ischemia;Myocardium;Operative Surgical Procedures;Oxidative Stress;Oxygenases;Pathology;Patients;Peripheral;Phase;Phenotype;Play;Process;Property;Protein Isoforms;Proteins;Recombinant adeno-associated virus (rAAV);Relative (related person);Reperfusion Injury;Reperfusion Therapy;Role;Source;Stress;Superoxide Dismutase;System;Testing;Therapeutic;Time;Tissues;Transgenes;Transgenic Mice;Transgenic Organisms;Translations;Up-Regulation (Physiology);Ventricular;Ventricular Remodeling;Wild Type Mouse;base;biological adaptation to stress;cytokine;extracellular;gain of function;gene therapy;genetic manipulation;human NOS2A protein;improved;insight;novel;overexpression;protective effect;research study;transgene expression;vector


application_id: 7797687
project_number: 5P01HL078825-05
project_title: Gene Therapy to Achieve Permanent Cardioprotection
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0001
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-01
budget_end_date: 2010-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The heart has evolved an adaptive response to stress termed late preconditioning (PC) that confers powerful and sustained protection against ischemiaJreperfusion injury. Previous work by us and others has shown that late PC is mediated by the upregulation of a cluster of stress-responsive cardioprotective proteins namely iNOS HO-1 and ecSOD. Our preliminary data indicate that these proteins are organized hierarchically and are inextricably linked forming a functionally inter-related module. Building upon this previous work we will determine the feasibility of transferring these genes to the heart to achieve a permanent preconditioned-likestate. We will also determine the mechanism by which the respective proteins interact. All studies will be performed in a well-established murine model of myocardial infarction using recombinant adeno-associated virus (rAAV) vectors. In Aim 1 we will determine whether rAAV-mediated transfer of the genes that form the iNOS-HO-1-ecSOD module produces chronic cardioprotection and whether this is due to prevention of apoptosis necrosis or both. Mice will undergo iNOS HO-1 or ecSOD gene transfer and then will be subjected to myocardial infarction 1 6 or 12 months later to determine the presence of a protective phenotype. In Aim 2we will decipher the interplay between iNOS and HO-I. Using both a loss-of-function (HO-1-/-) and a gain-of-function (HO-1 TG) approach we will determine whether the infarct-sparing effects of iNOS gene therapy depend on the presence of HO-1 and whether HO-1 modulate iNOS and thus limits oxidative and nitrative stress after iNOS gene therapy. The specific role of CO (one of the by-products of HO-1 ) will be elucidated by using novel CO-releasing agents. In Aim 3 we will use ecSOD-/- mice to test the hypothesis that ecSOD is obligatorily required for iNOS-dependent HO-1-dependent and CO-dependent protection. We will also test thenovel idea that HO-1 augments cardiac NO levels by upregulating ecSOD. Finally in Aim 4 we will use Nrf2 -/- mice to test the hypothesis that Nrf2 a pleiotropic stress-responsive transcription factor mediates iNOS-dependent upregulation of HO-1 and iNOS- and HO-l-dependent upregulation of ecSOD. These studies will test the hypothesis that Nrf2 is a critical "switch" that links iNOS HO-1 and ecSOD. Throughout this Project evidence for or against a functional role of specific proteins will be obtained by using genetic manipulations inintact animals (gene transfer transgenic mice or KO mice). This molecular physiologic strategy will make it possible to arrive at conclusions that are definitive and at the same time physiologically relevant. These studies will be the first to test the novel idea that gene therapy can be used to achieve chronic prophylactic cardioprotection. The results will provide a framework for translating cardioprotective gene therapy to the clinical arena and will have broad pathophysiological implications for numerous biologic processes in which NO and CO are known to serve an important regulatory function.

project_terms:
Acute myocardial infarction;Adenoviruses;Adverse effects;American;Animal Model;Animals;Antioxidants;Apoptosis;Area;Arts;Binding Sites;Cardiac;Cardiac Myocytes;Chloride Ion;Chlorides;Chronic;Clinical;Complement Factor B;Coronary Arteriosclerosis;Coronary Occlusions;Country;Data;Doctor of Medicine;EFRAC;EMSA;Effectiveness;Electrophoretic Mobility Shift Assay;Endoplasmic Reticulum;Enzyme Immunoassay;Experimental Models;Failure (biologic function);Gene Transfer;Genes;Heart;Heme Oxygenase (Decyclizing);I-kappa B Proteins;In Situ Nick-End Labeling;Infarction;Injury;Ischemia;Janus kinase;Label;Laboratories;Left ventricular structure;Link;Measures;Mediating;Modeling;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Mus;Myocardial Infarction;Myocardial Ischemia;Myosin Heavy Chains;N-acetylpenicillamine;NF-kappa B;Nature;Necrosis;Nitric Oxide;Nitric Oxide Donors;Nitric Oxide Synthase;Nuclear;Oxides;PTGS2 gene;Pancreas;Patients;Pharmaceutical Preparations;Phenotype;Phosphotransferases;Physiological;Play;Polymerase Chain Reaction;Prevention;Procedures;Process;Promotor (Genetics);Protein Kinase C;Proteins;Reactive Oxygen Species;Recombinant adeno-associated virus (rAAV);Recombinants;Relative (related person);Reperfusion Injury;Reperfusion Therapy;Research Personnel;Response Elements;Role;S-nitro-N-acetylpenicillamine;Stress;Superoxide Dismutase;TNF gene;TNFRSF5 gene;Techniques;Testing;Therapeutic;Time;Tissues;Transgenic Mice;Transgenic Organisms;Translating;Tumor Necrosis Factor-alpha;Up-Regulation (Physiology);Ventricular Cardiac alpha-Myosin;Work;adeno-associated viral vector;caspase;coronary angioplasty;cyclooxygenase 2;experience;extracellular;gain of function;gene therapy;genetic manipulation;human NOS2A protein;inhibitor/antagonist;limitin;loss of function;myocardial infarct sizing;novel;outcome forecast;palliative;preconditioning;prevent;programs;prophylactic;protective effect;response;thrombolysis;transcription factor;triphenyltetrazolium


application_id: 7797672
project_number: 5R01HL088012-04
project_title: Implications of Endothelial-Myocyte Uncoupling in Cardiac Arrhythmia
administering_ic: NHLBI
award_notice_date: 2010-03-22
application_type: 5
activity_code: R01
ic: HL
serial_number: 088012
program_official: WANG, LAN-HSIANG
project_start_date: 2007-04-18
project_end_date: 2012-03-31
study_section: Special Emphasis Panel[ZRG1-CVS-D(02)M]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-04-01
project_abstract:
DESCRIPTION (provided by applicant):  Elevated levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) are associated with cardiac arrhythmia and sudden cardiac death (SCO). Hey increases the iNOS activates matrix metalloproteinase (MMP) disrupts connexin-43 and increases collagen/elastin ratio. The disruption of connexin-43 and accumulation of collagen (fibrosis) interrupts cardiac conduction and attenuate NO transport from endothelium to myocyte (E-M) causing E-M uncoupling. The novelty of this proposal is that Hcy behaves as an agonist to N-methyl-D-aspartate (NMDA an excitatory neurotransmitter) receptor-1 and blockade of NMDA-R1 reduces SCO. The central hypothesis of this proposal is that Hcy increases iNOS mtNOS activities superoxide levels metalloproteinase activity disrupts connexin-43 exacerbates endothelial-myocyte uncoupling and induces cardiac failure by activating NMDA-R1. Specific Aim #1: To determine whether Hey exacerbates heart failure and endothelial-myocyte uncoupling by increasing iNOS and rendering ineffective eNOS and nNOS by behaving as an agonist to NMDA-R1. CBS heterozygote (-/+) knockout (CBSKO) mice will be crossbred with iNOS homozygote (-/-) knockout (iNOSKO) mice producing wild type (WT) CBSKO iNOSKO and CBS/iNOS (-/+; -/-) double knockout (doubleKO). In these mice chronic volume overload heart failure will be created by aorta-venacava (AV) fistula. NMDA-R1 will be blocked by dizocilpine (MK-801). The endothelial-myocyte coupling will be determined in cardiac rings. LV levels of NMDA-R1 iNOS nNOS and eNOS will be measured. Specific Aim #2: To determine whether Hey increases MMP-2 -9 -13 ADAM-12 decreases TIMP-4 and degrades connexin-43 in heart failure by inducing NMDA-R1. MMP and TIMP activities will be measured by innovative 2-zymography (MMP functional proteomics) and reverse zymography respectively. The degradation of connexin-43 collagen and elastin will be measured by Western analysis. Specific Aim #3: To determine whether Hey decreases LV mitochondrial thioredoxin peroxiredoxin and SOD and increases NADH oxidase and mtNOS activity in heart failure by activating NMDA-R1. In hearts in situ labeling will be performed for thioredoxin peroxiredoxin SOD and NADH oxidase. These studies will delineate the mechanism of Hcy-dependent endothelial-myocyte uncoupling in cardiac arrhythmia and failure and will have therapeutic ramifications for sudden cardiac death.

project_terms:
3-deazaadenosine;Abbreviations;Acetylcholine;Address;Adenosine Diphosphate;Agonist;Alteplase;Aorta;Arginine;Arrhythmia;Attenuated;Basement membrane;Bradykinin;Breeding;Cardiac;Chronic;Collagen;Connexin 43;Coupling;Crossbreeding;Cystathionine;Death Sudden Cardiac;Disintegrins;Dose;EKG QRS Complex;Echocardiography;Eicosatrienoic Acid;Elastin;Electrocardiogram;Endothelial Cells;Endothelin-1;Endothelium;Environment;Extracellular Matrix;Failure (biologic function);Fibrosis;Fistula;Fluorescent Dyes;Gelatinase A;Goals;Heart;Heart Rate;Heart failure;Heterozygote;Homocysteine;Homocystine;Homozygote;Hydrolase;Hydroxyeicosatetraenoic Acids;Hyperhomocysteinemia;Image;In Situ;Knock-out;Label;Left ventricular structure;Lipopolysaccharides;MTHFR gene;Matrix Metalloproteinases;Measures;Mediating;Metalloproteases;Methionine;Methylenetetrahydrofolate reductase (NADPH);Mitochondria;Mus;Muscle Cells;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;NADH oxidase;NADP;Neurons;Neurotransmitter Receptor;Niacinamide;Nitric Oxide;Nitric Oxide Synthase;Nitric Oxide Synthase Type I;Nitroprusside;Norepinephrine;Oxidation-Reduction;Oxides;Pattern;Polymerase Chain Reaction;Preparation;Production;Proteomics;Radio;Reactive Nitrogen Species;Reactive Oxygen Species;Relaxation;Research Personnel;Shunt Device;Superoxide Dismutase;Superoxides;Tail;Telemetry;Therapeutic;Thioredoxin;Time;Tissue Inhibitor of Metalloproteinases;Veins;Ventricular Fibrillation;Ventricular Tachycardia;Western Blotting;analog;dizocilpine;human NOS3 protein;in vivo;innovation;membrane-type matrix metalloproteinase;peroxiredoxin;premature;programs;relating to nervous system;relaxing factor;response;tetrahydrobiopterin;tissue inhibitor of metalloproteinase 4


application_id: 7797495
project_number: 5P01HL080100-05
project_title: Mechanisms of abdominal aortic aneurysm formation
administering_ic: NHLBI
award_notice_date: 2010-03-22
application_type: 5
activity_code: P01
ic: HL
serial_number: 080100
program_official: GOLDBERG, SUZANNE H
project_start_date: 2006-04-08
project_end_date: 2012-03-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
contact_pi_person_id: 8378256
contact_pi: DAUGHERTY, ALAN
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-04-01
project_abstract:
DESCRIPTION (provided by applicant):    
This amended PPG application is designed to provide mechanistic insight into the mechanisms involved in the initiation and propagation of abdominal aortic aneurysms (AAAs). Projects will use a model of AAA in which angiotensin II will be infused into hyperlipidemic mice. This was described originally by faculty who are Project Leaders in this application. This model has now been adopted widely in both academic and pharmaceutical research programs. Many characteristics of the model reproduce features of the human disease including the strong gender specific prevalence in males fragmentation of medial extracellular matrix and presence of inflammatory cells. Studies on the cellular sequence of events in the development of AAAs demonstrate the involvement of inflammatory cells at all stages of development. The unifying hypothesis of this amended program project application is that angiotensin II promotes aneurysm formation by initiating regional-specific matrix degradation in the media of the abdominal aorta leading to recruitment of macrophages medial dissection and subsequent vascular remodeling. Four projects are proposed that mechanistically define the sequence of events outlined in this unifying hypothesis. To facilitate research among Projects 4 core facilities are proposed. This brings together a group of faculty who have interacted for several years. The synergy of their interactions is demonstrated by the multiple joint publications and co-investigator status on grants. 

These projects and cores have been designed to provide mechanistic insight into the development of AAAs in the following areas: Project 1 (Lisa A. Cassis) will study the role of male androgen in promoting regional-specificity of AAA formation through regulation of the angiotensin type 1A receptor. Project 2 (Alan Daugherty) will determine the role of smooth muscle cell specific AT1a receptors in the mechanisms of AAA initiation. Project 3 (Fred C. de Beer) will determine the role of serum amyloid A and its interaction with selected matrix metalloproteinases. Project 4 (Nancy R. Webb) will determine the role of specific isoenzymes of secretory phospholipase A2s in promoting inflammation at the site of macrophage recruitment during the evolving AAA. These projects will be supported by Cores of: A. Administration. B. Human studies. C. Mouse maintenance. D. Quantitative pathology.


application_id: 7797494
project_number: 5P01HL080100-04
project_title: CORE--Mouse
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 080100
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 9002
contact_pi_person_id: 8817787
contact_pi: RATERI, DEBRA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-01
budget_end_date: 2010-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The purpose of this Core is to provide a central location for the supply of mice and services related to mouse
care maintenance genotyping and measurement. Specifically this Core will offer the following services:
1. Managing the mouse colony that includes the oversight of the generation maintenance and supply of
single and compound genetically altered mice.
2. Perform bone marrow transplantation.
3. Measure arterial blood pressure in a standardized manner.
4. Prepare and implant Alzet pumps for the infusion of Angll or saline.
5. Harvest DNA by tail clipping for the purpose of genotyping.
6. In vivo ultrasound. Non-invasively quantify lumen diameter during the evolution of AAAs.
Centralization of these facilities will permit an efficient use of resources for the Program coupled with optimal
quality control and standardization across Projects.

project_terms:
Abdominal Aortic Aneurysm;Blood Pressure;Bone Marrow Transplantation;Caliber;Caring;Clip;Coupled;DNA;Evolution;Generations;Genotype;Harvest;Implant;Infusion Pumps;Location;Maintenance;Measurement;Measures;Mus;Quality Control;Resources;Saline;Services;Standardization;Tail;Ultrasonography;in vivo;programs


application_id: 7796598
project_number: 5R01EY017094-05
project_title: Lipids and the Human Tear Film
administering_ic: NEI
award_notice_date: 2010-03-31
application_type: 5
activity_code: R01
ic: EY
serial_number: 017094
program_official: SHEN, GRACE L
project_start_date: 2006-04-01
project_end_date: 2011-03-31
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 1898534
contact_pi: FOULKS, GARY N
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-04-01
project_abstract:
DESCRIPTION: Dry eye affects six to seven million people in the United States alone. Meibomian gland disease is even more frequent particularly in older patients. Clinically patients may express a combination of two forms of dry eye aqueous deficient and evaporative. Both mechanisms of development of dry eye share the common feature of instability of the tear film with rapid tear break-up time suggesting there may be a shared structural abnormality of the tear film that is responsible for the instability. Disruption of the normal lipid-protein-aqueous structure of the tear film is probably this mechanical event. Understanding the normal lipid-protein-aqueous structure of the tear film is therefore critical to determine the etiology of the tear film instability due to dry eye disease and meibomian gland disease.  Recent advances in spectroscopic technology make it feasible to measure simultaneously and in individuals without pooling or serial collection the pool of meibomian lipid on the lid margins lipids in the meibomian glands and the lacrimal lipids many of which are bound to lipocalin or complexed with other proteins found in tears. We propose to use the latest spectroscopic innovations to determine the relationships among tear lipid structure interactions rate of tear evaporation dry eye symptoms and tear film instability. Advances in clinical diagnosis make it possible to group patients into a number of categories related to production-deficient and evaporative forms of dry eye and monitor their tear film stability. Because of our expertise in spectroscopic techniques knowledge of lipid structure and access to human tear lipid samples in normal subjects and those with dry eye disease coupled with our clinical expertise we are in a uniquely favorable position to identify the nature of the disturbance of the lipid-protein-aqueous interaction of the tear film that could lead to improved therapy.

project_terms:
Accounting;Affect;Age;Anatomy;Binding (Molecular Function);Blinking;Categories;Characteristics;Classification;Clinical;Collection;Complex;Coupled;Data;Development;Disease;Doxycycline;Educational workshop;Essential Fatty Acids;Etiology;Event;Eye diseases;Film;Functional disorder;Gender;Gland;Goblet Cells;Human;In Situ;In Vitro;Individual;Industry;Knowledge;Lacrimal gland structure;Lactoferrin;Lead;Lipids;MUC5AC gene;Measures;Mechanics;Monitor;Mucins;Muramidase;Nature;Pathogenesis;Patients;Positioning Attribute;Production;Proteins;Research Personnel;Sampling;Scheme;Sjogren's Syndrome;Spectrum Analysis;Sphingolipids;Structure;Symptoms;System;Systemic Therapy;Techniques;Technology;Testing;Time;United States;aqueous;clinical Diagnosis;conjunctiva;evaporation;eye dryness;human subject;improved;innovation;lacrimal;lipid structure;meibomian gland;meibomian gland dysfunction;older patient;programs;sex;tear proteins;volunteer


application_id: 7796408
project_number: 7R01NS062306-02
project_title: PPAR Inhibition of Spinal Pain Transmission
administering_ic: NINDS
award_notice_date: 2009-04-03
opportunity_number: PA-07-282
application_type: 7
activity_code: R01
ic: NS
serial_number: 062306
program_official: PORTER, LINDA L
project_start_date: 2008-12-18
project_end_date: 2013-11-30
study_section: Special Emphasis Panel[ZRG1-IFCN-E(02)M]
contact_pi_person_id: 1879170
contact_pi: TAYLOR, BRADLEY K.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Peroxisome proliferator-activated receptor gamma (PPAR 3) is well-characterized as a key target of the thiazolinedione (TZD) class of anti-diabetic drugs. Our preliminary results describe the existence of PPAR 3 mRNA and protein in the dorsal horn. Furthermore we demonstrate that the mechanical and thermal hypersensitivity associated with inflammation or nerve injury was rapidly reduced by intrathecal administration of rosiglitazone (a TZD) and 15d-PGJ2 (an endogenous PPAR 3 ligand) in a dose- and PPAR 3-dependent manner and by systemic administration of pioglitazone a BBB-permeant FDA-approved ligand. The central hypothesis of this proposal is that ligand-dependent activation of PPAR3 in the dorsal horn decreases injury- induced activation of spinal neurons and glia that then dampens behavioral signs of inflammatory and neuropathic pain. The objective of the present application is to identify the mechanisms underlying PPAR- mediated inhibition of inflammatory or neuropathic pain with a focus on pioglitazone. The long-term goal of our research program is to harness the therapeutic potential of PPAR signaling to alleviate chronic pain in humans. AIM 1 will test the hypothesis that PPAR 3 agonists reduce allodynia and hyperalgesia. We will use pharmacological agents and nervous system-specific PPAR 3 deletion mutants to determine the contribution of PPAR 3 signaling in the spinal cord to the induction and maintenance of chronic pain. First we will determine whether single intrathecal or systemic administration of pioglitazone and 15d-PGJ2 reduces behavioral signs of inflammatory and neuropathic pain. We predict that their analgesic actions will be blocked with PPAR 3 antagonists. Second we will determine whether chronic intrathecal or oral administration of PPAR 3 agonists begun before or after tissue or nerve injury reduces behavioral signs of inflammatory and neuropathic pain. Third we predict that anti-allodynic actions will not occur in mice with neuron-specific PPAR 3 knockdown. AIM 2 will test the hypothesis that PPAR 3 ligands reduce injury-induced activation of neurons and microglia in the dorsal horn. Somatosensory stimulation of injured rats induces the expression of the immediate early gene c-fos in the superficial laminae of the dorsal horn. We predict that intrathecal pioglitazone will reduce inflammation- and nerve injury-induced expression of Fos immunoreactive neurons as well as the expression of OX-42 a marker of microglia activation. AIM 3 will test the hypothesis that endogenous PPAR 3 systems tonically inhibit allodynia. First we will determine if PPAR3 expression occurs in neurons and/or glia that are activated during pain. Second in an extension of Aims 1-2 we will determine whether receptor antagonists and genetic deletion increase allodynia and neuronal/glial activation. If affirmative then we will determine whether the PPAR3 signaling elements co- vary with allodynia. At various times after nerve injury or persistent inflammation we will evaluate: behavior and A) PPAR 3 mRNA and protein; B) phosphorylated PPAR 3; and C) 15d-PGJ2 levels with LC/MS/MS. PUBLIC HEALTH RELEVANCE Chronic pain management is a major scientific and health care challenge as current analgesic drugs rarely provide sufficient efficacy in the absence of serious side effects. We propose that ligands for peroxisome proliferator-activated receptor gamma (PPAR 3) such as rosiglitazone and pioglitazone represent a novel class of analgesic / anti-allodynic compounds. These conceptually innovative experiments are important and timely because TZDs are commercially available for diabetes and are in clinical trials for CNS neurodegenerative diseases. Thus confirmation of our hypothesis could lead to rapid translation to the clinical treatment of chronic pain.

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


application_id: 7795949
project_number: 5P42ES007380-13
project_title: Core C: Research Translation Core
administering_ic: NIEHS
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 9004
contact_pi_person_id: 8535916
contact_pi: ORMSBEE, LINDELL E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-01
budget_end_date: 2010-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Academia;Basic Science;Biochemical;Biomedical Research;Biosensor;Cardiovascular Diseases;Chemical Exposure;Chemicals;Clinical;Communication;Communication Tools;Communities;Diabetes Mellitus;Diffusion;Disease;Effectiveness;Ensure;Environment;Environmental Health;Environmental Pollution;Exposure to;General Population;Government;Guidelines;Health;Health Professional;Human;Hypertension;Individual;Industry;Investigation;Kentucky;Knowledge;Letters;Malignant Neoplasms;Nanotechnology;Outcome;Outcomes Research;Plants;Research;Research Institute;Research Project Grants;Role;Services;Superfund;Targeted Research;Techniques;Technology;Toxic effect;Translating;Translational Research;Translations;Universities;Water;college;novel;nutrition;programs;public health medicine (field);remediation;superfund chemical


application_id: 7795948
project_number: 5P42ES007380-13
project_title: Project 7: Chloro-Organic Degradation by Nanosized Metallic Systems and by Chelat
administering_ic: NIEHS
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 0010
contact_pi_person_id: 8534525
contact_pi: BHATTACHARYYA, DIBAKAR
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-01
budget_end_date: 2010-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Advanced Development;Anions;Carbon;Characteristics;Chelating Agents;Chemicals;Chlorine;Development;Educational workshop;Effectiveness;Environment;Enzymes;Equilibrium;Flushing;Foundations;Free Radicals;Future;Generations;Glucose;Health Benefit;Hydrogen;Hydrogen Peroxide;Hydroxyl Radical;Immobilization;In Situ;Iron;Iron Chelating Agents;Kinetics;Lead;Life;Maps;Membrane;Metals;Methods;Modeling;Monitor;Morphology;Nanostructures;Nanotechnology;Nanotubes;Natural regeneration;Operative Surgical Procedures;Parents;Pathway interactions;Phase;Phenols;Pollution;Polychlorinated Biphenyls;Polymers;Production;Property;Reaction;Reagent;Research;Roentgen Rays;Role;Salts;Sampling;Site;Soil;Solvents;Spectrum Analysis;Structure;Superoxides;Surface;System;Techniques;Technology;Testing;Toxic effect;Trichloroethylene;Vascular Endothelial Cell;Vinyl Chloride;Water;Work;base;biodegradable product;catalyst;cost;dechlorination;diphenyl;enzyme immobilization;flexibility;gluconate;glucose oxidase;improved;innovation;membrane assembly;nanoparticle;nanosized;nanostructured;novel strategies;nutrition;organic acid;oxidation;particle;pollutant;reaction rate;remediation;superfund chemical;superfund site;surfactant;technology development


application_id: 7795946
project_number: 5P42ES007380-13
project_title: Project 4: The Impact of Obesity on PCB Toxicity
administering_ic: NIEHS
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 0008
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-01
budget_end_date: 2010-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Abdominal Aortic Aneurysm;Acute-Phase Proteins;Adipocytes;Adipose tissue;Adverse effects;Agonist;Angiotensin II;Apolipoprotein E;Biological;Blood Vessels;Body Weight;Cardiovascular Diseases;Cause of Death;Chronic;Data;Deposition;Diet;Dietary Intervention;Disease;Employee Strikes;Exhibits;Experimental Models;Family;Fatty Acids;Fatty acid glycerol esters;Figs - dietary;Gene Expression;Greater sac of peritoneum;Health Benefit;In Vitro;Incidence;Infiltration;Inflammation;Inflammatory;Laboratories;Ligands;Linoleic Acids;Linolenic Acids;Lipids;Measures;Mortality Vital Statistics;Mus;Obesity;Obesity associated cardiovascular disease;Obesity associated disease;Omega-3 Fatty Acids;Oxidative Stress;Polychlorinated Biphenyls;Polyunsaturated Fatty Acids;Predisposition;Production;Regulation;Research;Role;Sampling;Severities;Signal Pathway;Signal Transduction;Superfund;Toxic effect;Translating;Vascular Diseases;Vascular System;Weight Gain;Work;abdominal aorta;adipocyte differentiation;adipokines;base;cytokine;in vivo;lipophilicity;macrophage;male;nutrition;receptor;remediation;response;superfund chemical


application_id: 7795945
project_number: 5P42ES007380-13
project_title: Project 6: Sensing Superfund Chemicals with Recombinant Systems
administering_ic: NIEHS
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 0004
contact_pi_person_id: 1964876
contact_pi: DAUNERT, SYLVIA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-01
budget_end_date: 2010-03-31
funding_mechanism: Non-SBIR/STTR
project_terms:
Bacteria;Bacterial Transformation;Binding (Molecular Function);Biological;Biosensing Techniques;Biosensor;Cells;Chemicals;Coupled;Detection;Development;Ecology;Elements;Emerging Technologies;Engineering;Environment;Environmental Monitoring;Exhibits;Funding;Genes;Genetic Engineering;Goals;Health;Human;In Situ;Indium;Methods;Microfluidic Analytical Techniques;Microfluidics;Molecular;Molecular Biology;Monitor;Nanotechnology;Nature;Operon;Pathway interactions;Plasmids;Poisons;Polychlorinated Biphenyls;Proteins;Recombinants;Reporter;Reproduction spores;Research Personnel;Sampling;Signal Transduction;System;Technology;Time;Toxic effect;Trademark;Work;analytical method;bacterial resistance;base;cost;design;field study;genetic regulatory protein;improved;miniaturize;nutrition;pollutant;public health relevance;sensor;success;superfund chemical;tool


application_id: 7795850
project_number: 5R44MH078437-04
project_title: Genomic Biomarkers for Neuropsychiatric Illnesses
administering_ic: NIMH
award_notice_date: 2010-03-11
opportunity_number: PA-06-016
application_type: 5
activity_code: R44
ic: MH
serial_number: 078437
program_official: GRABB, MARGARET CHRISTINE
project_start_date: 2006-09-26
project_end_date: 2012-03-31
study_section: Special Emphasis Panel[ZRG1-GGG-J(10)B]
contact_pi_person_id: 8483374
contact_pi: BRENNAN, MARK DAVID
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 609831222
duns_number: 609831222
fips: US
organization_id: 10007145
organization_name: SUREGENE, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402992882
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-04-01
budget_end_date: 2011-03-31
project_abstract:
DESCRIPTION (provided by applicant):  The long-term objective of this project is to develop validated genetic biomarkers to aid in more accurate diagnosis and targeted treatment of schizophrenia and related neuropsychiatric illnesses including bipolar disorder. In Phase I SureGene demonstrated the feasibility of using specific dimensions of mental illness to discover novel genes and genetic variants that influence risk and impact the clinical presentation of these diseases. This project will build on first-generation genetic biomarkers in the form of single nucleotide polymorphisms (SNPs) and chromosomally-related associations of these polymorphisms called haplotypes. The Phase II project will further develop biomarkers for neuropsychiatric illnesses using a set of genes that meet stringent criteria for genetic replication. The project will develop products for research and clinical applications that combine biomarkers in these genes. The aims are 1) Develop a prototype AssureGeneTM array and data set for schizophrenia-spectrum disorders. SureGene will develop a flexible SNP genotyping product incorporating a high density of SNPs in approximately 200 genes and generate a detailed data set relating genotypes to phenotypes based on 2000 NIMH schizophrenia bipolar and control samples. A first-generation array and data set will be made available to the research community by the middle of Grant Year 2. A refined array and data set for prospective clinical applications will be completed by the end of Phase II. 2) Evaluate the utility of the AssureGeneTM test for differential diagnosis and for predicting progression to clinically defined psychosis. SureGene will develop genetic algorithms for the array for use in predicting dichotomous clinical outcomes. This Aim should provide a collective set of predictive models that can be evaluated on the basis of their sensitivity specificity and overall classification accuracy. 3) Develop and implement a flexible medical resequencing platform (ExonReadTM) for high priority genes. SureGene will develop a cost-effective "next generation" medical resequencing platform that can be used by the research community to evaluate the contribution of rare or spontaneous mutations in key genes contributing to psychopathology and clinical outcomes for neuropsychiatric illnesses. A prototype sequencing platform for research use will be completed in Grant Year 2. SureGene will apply ExonReadTM to a sample of African Americans and Caucasians with a family history of schizophrenia or bipolar disorder to establish baseline expectations and limitations of the product. The commercial potential for these products is significant. By targeting common variants the AssureGeneTM array should have broad applicability in research and clinical settings with both diagnostic and pharmacogenetic applications. The ExonReadTM platform will be a valuable cost-effective tool for identifying rare or unique high penetrance mutations expected in familial cases of neuropsychiatric illnesses and will have applications for genetic counseling and for differential diagnosis.   
  
PUBLIC HEALTH RELEVANCE: The long term objective of this project is to develop validated gene-related tests (genetic biomarkers) to aid in more accurate diagnosis and customized treatment of schizophrenia and related "schizophrenia spectrum" disorders including bipolar disorder. SureGene's goals for this research are to refine existing genetic biomarkers and to discover and refine additional novel genetic biomarkers. Products based on these biomarkers should be helpful to individuals suffering from schizophrenia and related disorders their families and health care providers and researchers seeking to improve diagnosis and treatment.

project_terms:
African American;Algorithms;Basic Science;Biological;Bipolar Disorder;Caucasians;Caucasoid Race;Classification;Clinical;Communities;Complex;DNA Resequencing;Data;Data Set;Diagnosis;Diagnostic;Differential Diagnosis;Dimensions;Disease;Exons;Family;Family health status;Family history of;Generations;Genes;Genetic;Genetic Counseling;Genetic Markers;Genetic Models;Genetic Polymorphism;Genetic Programming;Genetic screening method;Genome;Genomics;Genotype;Goals;Grant;Haplotypes;Health;Health Personnel;Individual;Legal patent;Medical;Mental disorders;Mutation;National Institute of Mental Health (U.S.);Outcome;Patients;Penetrance;Pharmacogenetics;Phase;Phenotype;Positioning Attribute;Psychopathology;Psychotic Disorders;Public Domains;Research;Research Personnel;Resources;Risk;Sampling;Schizophrenia;Sensitivity and Specificity;Single Nucleotide Polymorphism;Technology;Testing;Variant;Work;Youth;base;biomarker;case control;clinical application;cohort;cost;density;design;disorder control;disorder risk;disorder subtype;expectation;flexibility;genetic variant;high risk;improved;meetings;neuropsychiatry;next generation;novel;predictive modeling;proband;prospective;prototype;public health relevance;tool

public_health_relevance:
The long term objective of this project is to develop validated gene-related tests (genetic biomarkers) to aid inmore accurate diagnosis and customized treatment of schizophrenia and related "schizophrenia spectrum"disorders including bipolar disorder. SureGene's goals for this research are to refine existing geneticbiomarkers and to discover and refine additional novel genetic biomarkers. Products based on thesebiomarkers should be helpful to individuals suffering from schizophrenia and related disorders their familiesand health care providers and researchers seeking to improve diagnosis and treatment.


application_id: 7795724
project_number: 5R01NS052292-05
project_title: Re-training locomotor circuitry in a rat model of Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2010-02-17
application_type: 5
activity_code: R01
ic: NS
serial_number: 052292
program_official: JAKEMAN, LYN B
project_start_date: 2006-05-15
project_end_date: 2011-09-29
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 1932676
contact_pi: MAGNUSON, DAVID SK
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-04-01
project_abstract:
DESCRIPTION (provided by applicant): One of the most promising therapeutic strategies for spinal cord injury is weight-supported treadmill training. This rehabilitation therapy seeks to re-train the spinal cord circuitry below the level of injury to participate in functional locomotion. The mammalian spinal cord humans included contains complex neuronal circuitry that participates in the generation of the repeating pattern of motor activity (step-cycle) associated with normal over-ground locomotion. Both animal and human studies have demonstrated that moving the hindlimbs to mimic normal walking usually on a treadmill with rehabilitation assistants can lead to improved hindlimb locomotor function. However the treadmill speed that is used is very slow compared to normal walking and much of the body weight of the animal or patient must be supported externally. Consequently relatively few step-cycles are generated during a re-training session certainly far fewer than normal walking. We hypothesized that a re-training strategy that allowed for many more step-cycles to be completed would be more effective and that re-training the locomotor circuitry would be much more successful. Some of the components that are thought to be important for the re-training process include step-cycle number cutaneous feedback from the foot limb position and weight-bearing feedback from the leg. How each of these individual components contribute to successful rehabilitation and the physiological and cellular mechanisms underlying the re-training process are not known. We have devised a strategy to use buoyancy during swimming to provide weight-support which allows for high numbers of step-cycles to be completed during a rehabilitation session. We have also incorporated a simple approach to provide phasic cutaneous feedback during swimming and partial limb-loading (weight- bearing) during walking in shallow water. We hope to uncover what relative contributions step-cycle number and frequency cutaneous feedback and limb-loading make to the overall success of a locomotor rehabilitation strategy. In addition we will begin to look at the mechanisms of rehabilitation associated plasticity using a custom made array to detect changes in mRNA levels in spinal cord tissue following different training protocols.

project_terms:
Animal Model;Animals;Articular Range of Motion;Axon;Body Weight;Complex;Contusions;Custom;Cutaneous;Dorsal;Feedback;Felis catus;Flexor;Frequencies (time pattern);Generations;Golgi Tendon Organs;Hindlimb;Hip region structure;Human;Individual;Injury;Joint Capsule;Lead;Learning;Left;Leg;Length;Limb structure;Link;Locomotion;Locomotor Recovery;Lumbar spinal cord structure;Messenger RNA;Methods;Modeling;Motor;Motor Activity;Motor Neurons;Motor output;Movement;Muscle;Muscle Spindles;Nerve;Nervous system structure;Output;Pathway interactions;Patients;Pattern;Phase;Physiological;Play;Positioning Attribute;Principal Investigator;Process;Protocols documentation;Rattus;Recovery of Function;Rehabilitation therapy;Relative (related person);Research Personnel;Role;Speed (motion);Spinal Cord;Spinal cord injury;Staging;Stress;Surface;Swimming;Testing;Therapeutic;Tissues;Training;Walkers;Walking;Water;Weight;Weight-Bearing state;Work;base;cane includes canes of all materials adjustable or fixed with tip;foot;functional improvement;human subject;improved;injured;neuronal circuitry;programs;receptor;rehabilitation strategy;research study;response;success


application_id: 7795669
project_number: 5R01NS045103-06
project_title: Regulation of Neuronal Survival by the Rit GTPase
administering_ic: NINDS
award_notice_date: 2010-05-11
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 045103
program_official: MAMOUNAS, LAURA
project_start_date: 2003-07-01
project_end_date: 2013-05-31
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 7875195
contact_pi: ANDRES, DOUGLAS ALLEN
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): Signaling pathways that contribute to cell death/survival influence diseases including cancer and many neurodegenerative conditions. Elaborating signal transduction mechanisms that regulate these processes are thus important for understanding basic biology and for therapeutic intervention. Neurotrophins potently stimulate neuronal survival in part by activating the small GTP-binding protein Ras which functions by translating neurotrophin-initiated signals into multiple signaling pathways including PI-3 kinase/Akt and MEK/ERK to promote survival. In the initial funding period it was proposed that a novel and evolutionarily conserved group of Ras-related GTPases including two mammalian proteins (Rit and Rin) and a single Drosophila ortholog (Ric) play critical roles in regulating apoptotic signaling. From this work it is now clear that both Rit and Ric promote neuronal survival in a manner distinct from that of Ras. The original hypothesis is now expanded to address how these anti-apoptotic signaling cascades are regulated. The central hypothesis of this proposal is that the Rit GTPase functions as a molecular switch in neurons responding to both apoptotic stresses and neurotrophin-initiated signals to activate a distinct pro-survival signaling cascade that relies upon p38 MAP kinase signaling. Three specific aims are proposed: Aim 1 will characterize the ability of activated Rit to promote neuronal survival. In particular we will assess the ability of Rit signaling to protect neurons from trophic factor-withdrawal mediated apoptosis. Using primary neurons from two transgenic mouse models either expressing activated Rit specifically in neurons or a homozygous Rit knockout mouse (developed during the previous period) it is now possible to analyze these critical issues. In addition microarray analysis will be used to catalog the neuronal transcriptional program regulated by Rit signaling. Aim 2 will determine the regulatory mechanism that couples NGF-stimulated TrkA to Rit activation and the nature of Rit-dependent regulation of the p38 MAP kinase cascade. Aim 3 will explore the critical signaling pathways utilized for Rit anti-apoptotic signaling. In particular Rit-mediated activation of both the p38- MSK1/2 kinase cascade and CREB transcriptional pathways appear to play central roles and will be tested using a combination of both cell model systems and primary neurons. Importantly data developed since the previous review suggests that a second novel Rit-p38-HSP27-MK2 pathway may stimulate AKT signaling to afford neuronal protection. In summary these studies will establish a role for Rit in neuronal survival. Regulation of this novel Ras-related G-protein may have a pronounced impact on neuronal physiology and would make Rit and its effectors potential targets for the development of new therapeutic strategies. PUBLIC HEALTH RELEVANCE: The death of neurons causes or contributes to various neurodegenerative disorders including stroke epilepsy Parkinson's disease Huntington's disease and Alzheimer's disease. Importantly we have discovered a protein that promotes neuronal survival protecting neurons from potentially lethal stimuli. Understanding the mechanism that foster neuronal survival is of fundamental importance to the development of treatment strategies for these disorders. Thus the goal of this research is to speed progress toward therapeutic exploitation of this protein in neurodegenerative disease.

project_terms:
1-Phosphatidylinositol 3-Kinase;Address;Alzheimer's Disease;Apoptosis;Apoptotic;Biochemical;Biological;Biological Models;Biology;CREB1 gene;Cataloging;Catalogs;Cell Death;Cell Survival;Cell model;Cells;Cellular Stress;Cessation of life;Complex;Couples;Coupling;DNA Microarray Chip;Data;Development;Disease;Dominant-Negative Mutation;Drosophila genus;Epilepsy;Family;Family member;Fostering;Funding;GTP-Binding Proteins;Gene Expression;Genes;Genetic Transcription;Goals;Guanosine Triphosphate Phosphohydrolases;Hippocampus (Brain);Human;Huntington Disease;Injury;Knock-out;Knockout Mice;Ligands;MAP Kinase Modules;MAPK14 gene;MAPK8 gene;MEKs;Malignant Neoplasms;Mediating;Microarray Analysis;Molecular;Nature;Nerve Degeneration;Nervous system structure;Neurodegenerative Disorders;Neuronal Differentiation;Neurons;Orthologous Gene;Parkinson Disease;Pathway interactions;Pheochromocytoma;Phosphotransferases;Physiological;Physiology;Play;Process;Proteins;Proto-Oncogene Proteins c-akt;Reactive Oxygen Species;Recovery;Recruitment Activity;Regulation;Research;Role;Signal Pathway;Signal Transduction;Site;Son of Sevenless Proteins;Speed (motion);Stimulus;Stress;Structure of superior cervical ganglion;Testing;Therapeutic;Therapeutic Intervention;Transducers;Transgenic Mice;Transgenic Organisms;Translating;Withdrawal;Work;biological adaptation to stress;cell growth regulation;extracellular;in vivo;inhibitor/antagonist;insight;mitogen-activated protein kinase p38;mouse model;neuronal survival;neurotrophic factor;novel;novel therapeutics;programs;public health relevance;ras-Related G-Proteins;repaired;response;stroke;treatment strategy

public_health_relevance:
The death of neurons causes or contributes to various neurodegenerative disorders including stroke epilepsyParkinson's disease Huntington's disease and Alzheimer's disease. Importantly we have discovered aprotein that promotes neuronal survival protecting neurons from potentially lethal stimuli. Understanding themechanism that foster neuronal survival is of fundamental importance to the development of treatmentstrategies for these disorders. Thus the goal of this research is to speed progress toward therapeuticexploitation of this protein in neurodegenerative disease.


application_id: 7795381
project_number: 1S10RR027463-01
project_title: Stereology System (Stereologer 2.0)
administering_ic: NCRR
award_notice_date: 2010-07-27
opportunity_number: PAR-09-028
application_type: 1
activity_code: S10
ic: RR
serial_number: 027463
program_official: BIRKEN, STEVEN
project_start_date: 2010-08-01
project_end_date: 2011-07-31
study_section: Special Emphasis Panel[ZRG1 ETTN-K (30)]
contact_pi_person_id: 7875446
contact_pi: YUREK, DAVID M.
other_pis: Not Applicable
congressional_district: 06
department: NEUROSURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Stereology provides an important contribution to the advancement in biomedical research by improving the consistency and dependability of quantitative analytical results produced in the laboratory and reported in scientific publications. Most scientific journals are now requiring authors to only report quantitative data from morphological analyses that are obtained using stereological methods. However the cost of setting up a stereology system in individual laboratories is usually cost-prohibitive. Our broad long-term objective is to provide a shared stereology system that will advance the research goals of four highly productive investigators at the University of Kentucky with a shared interest in examining changes in brain morphology in physiological and pathophysiological processes of the brain and spinal cord. This instrument will be used to detect changes in nerve cells brain structures or spinal cord structures and allow us to quantify these changes using universally accept stereological methods from samples derived from cellular clinical and/or preclinical sources and to do so with unprecedented resolution precision and sensitivity. Other instruments of different configurations potentially available for some of these analyses are heavily used for other purposes. Consequently these investigators are forced to use indirect or inadequate methodologies to accomplish their research goals or to use appropriate instrumentation on a collaborative basis with investigators at other institutions. Acquisition of this instrument would allow this group of investigators to complete their current and future research projects far more efficiently to generate optimal research outcomes.

project_terms:
Biomedical Research;Brain;Clinical;Data;Future;Goals;Individual;Institution;Journals;Kentucky;Laboratories;Methodology;Methods;Neurons;Outcomes Research;Physiological;Process;Publications;Reporting;Research;Research Personnel;Research Project Grants;Resolution;Sampling;Source;Spinal Cord;Structure;System;Universities;base;brain morphology;cost;improved;instrument;instrumentation;interest;pre-clinical


application_id: 7794331
project_number: 1S10RR027400-01
project_title: Olympus BX-DSU Live-Cell Disk Scanning Imaging / Electrophysiology System
administering_ic: NCRR
award_notice_date: 2010-05-13
opportunity_number: PAR-09-028
application_type: 1
activity_code: S10
ic: RR
serial_number: 027400
program_official: LEVY, ABRAHAM
project_start_date: 2010-05-13
project_end_date: 2011-05-12
study_section: Special Emphasis Panel[ZRG1 OBT-A (30)]
contact_pi_person_id: 1879170
contact_pi: TAYLOR, BRADLEY K.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant):  The long-term objectives of our 12 federal grants (R01-type) are to address important and unique problems in neuroscience and cardiac physiology including a better understanding how living cells in the nervous system and heart respond to drugs or other changes in the environment. The current application is in response to a significant need of our 8 Major Users to obtain confocal images and electrophysiological recordings often simultaneously from live neural sensory and cardiac cells or tissue slices. Specific needs include the following major functional capabilities: Confocal imaging of Ca2+ transients and fluorescent markers in live tissue slices; ratiometric Fura-2 imaging of Ca2+ transients; high temporal and spatial resolution of Ca2+ imaging during concomitant patch clamp recordings of ion channel activity; and UV Flash photolysis of caged compounds. All of the Major Users have extensive experience with live cell calcium imaging electrophysiology and/or confocal microscopy. Collectively we have published over a hundred papers using one or more of these techniques including 15 papers that simultaneously used functional confocal imaging and electrophysiological recording in live cells. An inherent problem of laser confocal microscopes is the very intense excitation light leading to substantial dye decomposition (photobleaching) during live-cell imaging. The proposed Olympus BX- DSU Live-Cell Disk Scanning Imaging System overcomes this problem with optimization of signal detection. It uses spinning disk confocal technology with a new generation super-cooled EM-CCD camera to generate images with high temporal and spatial resolution. The broad spectrum light source produces substantially less photobleaching than do lasers. Furthermore this system adds a UV flash illuminator for photolysis of photoactivatable (caged) compounds complete integration of patch-clamp instrumentation for concomitant electrophysiological recordings and an upright stand preferred for tissue slice work. The result is a very cost-effective and flexible solution that responds to all described needs of the Major Users. No other instrument at or near the University of Kentucky can provide this constellation of features. The University will provide appropriate space salary support for experienced technical staff and maintenance for the system. The system will be set up within a large well-established Imaging Facility at the University of Kentucky by experts in scanning disk technology and electrophysiology. This system will allow the Major Users to continue to achieve new discoveries towards the better understanding and treatment of chronic pain obesity auditory disorders olfactory disorders pulmonary disease consequences of brain injury and cardiovascular disease.

project_terms:
Address;Auditory;Brain Injuries;Calcium;Cardiac;Cardiovascular Diseases;Cells;Confocal Microscopy;Detection;Disease;Dyes;Electrophysiology (science);Environment;Fura-2;Generations;Grant;Heart;Image;Ion Channel;Kentucky;Lasers;Life;Light;Lung diseases;Maintenance;Microscope;Nervous system structure;Neurosciences;Obesity;Paper;Pharmaceutical Preparations;Photobleaching;Physiology;Publishing;Resolution;Scanning;Sensory;Signal Transduction;Slice;Solutions;Source;System;Techniques;Technology;Tissues;Universities;Wages;Work;cellular imaging;charge coupled device camera;chronic pain;cost;experience;flash photolysis;flexibility;instrument;instrumentation;olfactory disorder;patch clamp;photolysis;ratiometric;relating to nervous system;response


application_id: 7793550
project_number: 5R01AG029623-05
project_title: Role of TWEAK in Skeletal Muscle Metabolism
administering_ic: NIA
award_notice_date: 2010-02-18
application_type: 5
activity_code: R01
ic: AG
serial_number: 029623
program_official: WILLIAMS, JOHN
project_start_date: 2007-02-01
project_end_date: 2012-01-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
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
budget_start_date: 2010-03-01
project_abstract:
DESCRIPTION (provided by applicant): Skeletal muscle atrophy/wasting is a devastating complication of a number of chronic diseases including aging cancer diabetes sepsis AIDS chronic obstructive pulmonary disease chronic heart failure and cystic fibrosis. Beyond a reduced survival rate muscle atrophy is also related to poor functional status and health-related quality of life in these and many other conditions such as starvation immobilization and disuse. However effective treatments require insight into the etiology of skeletal muscle atrophy. In our search to identify potential regulatory molecules that play an important role in the acquisition and maintenance of skeletal muscle mass we have accumulated several lines of evidence that support a key role for TNF-related weak-inducer of apoptosis (TWEAK) in regulation of skeletal muscle mass. These findings include: 1) Exogenous addition of recombinant TWEAK protein inhibits myoblast differentiation; 2) Inhibition of TWEAK activity using a blocking peptide promotes differentiated functions of myoblasts; 3) TWEAK accelerates degradation of specific muscle proteins in differentiated myoblasts; and 4) Chronic administration of TWEAK in mice reduces body and skeletal muscle weights and induces degradation of muscle proteins suggesting that TWEAK is a powerful muscle wasting molecule. Based on our strong preliminary data we hypothesize that: a) Deletion of TWEAK in mice will cause accretion of skeletal muscle mass and prevent muscle loss in response to aging tumor growth and diabetes; and b) TWEAK effects on myogenic cells are mediated through activation of signaling pathways independent of the Fn14 receptor. In this grant using TWEAK-knockout and transgenic mice we will evaluate the role and mechanisms of action of TWEAK in skeletal muscle. Our specific aims are to investigate: I) The consequence of disruption of TWEAK gene on the acquisition and maintenance of skeletal muscle mass under normal and pathological conditions; II) The key cellular processes that TWEAK affects in skeletal muscles; and III) The molecular pathways through which TWEAK regulates acquisition and maintenance of skeletal muscle mass. The successful completion of the propsoed work should provide the first experimental proof for involvement of TWEAK in the regulation of skeletal muscle mass and could lead to identification of TWEAK as a novel molecular target for future development of therapies to prevent muscle loss.

project_terms:
Ablation;Acquired Immunodeficiency Syndrome;Actins;Adverse effects;Affect;Age;Aging;Anabolism;Apoptosis;Apoptosis Promoter;Area;Attenuated;Bacteria;Binding (Molecular Function);Biological;Body Weight;Cachexia;Catabolism;Cell Culture Techniques;Cell physiology;Cells;Chronic;Chronic Disease;Chronic Obstructive Airway Disease;Complementary DNA;Complication;Cystic Fibrosis;Cytoplasmic Tail;Data;Dexamethasone;Diabetes Mellitus;Differentiation Antigens;Disease;Dominant-Negative Mutation;Endotoxins;Equilibrium;Etiology;Event;Exhibits;Family;Fiber;Fibroblast Growth Factor;Future;Genes;Grant;Growth;HIV;Heart failure;Hypersensitivity;Immobilization;In Vitro;Inflammation;Inflammatory;Interleukin-6;Knock-out;Knockout Mice;Lead;Ligand Binding;Ligand Binding Domain;Maintenance;Malignant Neoplasms;Mediating;Medical;Modeling;Molecular;Molecular Target;Morbidity - disease rate;Mortality Vital Statistics;Mus;Muscle;Muscle Cells;Muscle Development;Muscle Fibers;Muscle Proteins;Muscular Atrophy;Myoblasts;Myogenic Regulatory Factors;Myogenin;Natural Killer Cells;Natural regeneration;Outcome;Pathway interactions;Peptides;Phenotype;Physiological;Play;Prevention;Principal Investigator;Process;Production;Proteins;Publishing;Recombinants;Regulation;Reporting;Research Personnel;Role;Screening procedure;Sepsis;Signal Pathway;Skeletal muscle structure;Small Interfering RNA;Somatomedins;Space Flight;Starvation;Stimulus;Study Section;Survival Rate;Syndrome;Techniques;Testing;Transgenic Mice;Transgenic Organisms;Tropomyosin;Troponin;Tumor Necrosis Factor Receptor;Tumor Necrosis Factor-Beta;Two-Hybrid System Techniques;Weight;Work;Yeasts;angiogenesis;base;cDNA Library;caspase;cell growth;common treatment;cytokine;effective therapy;functional status;gene function;health related quality of life;in vivo;insight;knockout animal;mouse model;muscle form;muscle metabolism;neutralizing antibody;novel;overexpression;prevent;programs;protein degradation;receptor;research study;response;skeletal muscle wasting;success;therapeutic development;therapy development;tumor growth;wasting;yeast two hybrid system


application_id: 7793540
project_number: 5R01AG026711-04
project_title: Role of Neutral Sphingomyelinase-2 in aging
administering_ic: NIA
award_notice_date: 2010-03-11
application_type: 5
activity_code: R01
ic: AG
serial_number: 026711
program_official: FRANKOWSKI, DAVID WITT
project_start_date: 2007-02-15
project_end_date: 2012-01-31
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 6730250
contact_pi: NIKOLOVA-KARAKASHIAN, MARIANA 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
budget_start_date: 2010-03-15
project_abstract:
DESCRIPTION (provided by applicant): Aging is characterized by an altered immune function and stress response. It becomes increasingly clear that at least in part this is due to alterations in ability of the cells to respond to different stress inducers. The hypothesis to be tested in this proposal is that aging-induced up-regulation of neutral sphingomyelianse-2 (NSMase-2) activity underlies the exaggerated response of hepatocytes IL-1beta during aging. We further hypothesized that aging-associated increases in NSMase-2 activity are consequence of the decreases in the cellular glutathione level. Therefore the long-term objective of our study is to understand the relation between aging the altered cellular response to inflammation and the state of oxidative stress. The following specific aims are proposed: Specific aim 1. To test the role of NSMase-2 as a mediator of aging-induced hyperresponsiveness to IL-1b. Studies in this specific aim will decipher the contribution of NSMase-2 to the IL-1b hyperresponsiveness of aged animals. Gene silencing approach will be used in vitro in hepatocytes isolated from old rats and in vivo in aged animals. Specific aim 2. To study the IL-1b hyperresponsiveness in calorie-restricted aged rats. Calorie-restriction (CR) is known to increase the life span of experimental animals and to attenuate the onset of oxidative stress including preventing aging-induced GSH/GSSH decline. Thus we hypothesized that CR attenuates IL-1B hyperresponsiveness of liver. This will be tested in vivo and in vitro. If NSMase-2 mediates IL-1b hyperresponsiveness by acting down-stream of GSH/GSSH changes then NSMase-2 overexpression in aged CR should restore the aging-associated IL-1b hyperresponsiveness. This will be tested by adenoviral-mediated expression of NSMase-2 in isolated hepatocytes and intact liver from aged CR rats. Specific aim 3: To study the role of GSH in aging-associated NSMase-2 activation and IL-1b hyperresponsiveness. These studies will ask whether GSH depletion in aging and NSMase-2 activation are causatively linked and will establish a link between the onset of oxidative stress and the IL-1b hyperesponsivness in aged animals. The proposed studies will provide novel understanding on the cellular mechanisms involved in the onset of aging and may have practical application in the development of new anti-inflammatory drugs for the elderly.

project_terms:
Acute-Phase Proteins;Acute-Phase Reaction;Adenoviruses;Affect;Age;Age of Onset;Aging;Aging-Related Process;Animal Model;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Attenuated;Bypass;CCAAT-Enhancer-Binding Proteins;Caloric Restriction;Cell Aging;Cell Line;Cells;Cellular Stress Response;Ceramides;Characteristics;Cytokine Signaling;Defect;Development;Doctor of Philosophy;Dose;Elderly;Endocrine;Exhibits;Figs - dietary;Gene Silencing;Genes;Glutathione;Glutathione Disulfide;Goals;Hepatocyte;IRAK1 gene;Immune system;In Vitro;Incidence;Inflammation;Inflammatory;Injection of therapeutic agent;Interleukin-10;Interleukins;Link;Liver;Longevity;MAPK8 gene;Measures;Mediating;Mediator of activation protein;Molecular;Mortality Vital Statistics;Neuroglia;Oligonucleotides;Organism;Oxidative Stress;Pattern;Peritoneal Macrophages;Pharmaceutical Preparations;Phenotype;Play;Process;Protein Phosphatase 2A Regulatory Subunit PR53;Rattus;Research Personnel;Role;Signal Pathway;Sphingomyelinase;Stream;Stress;Testing;Ubiquitination;Up-Regulation (Physiology);adenoviral-mediated;aged;biological adaptation to stress;feeding;functional decline;human IRAK1 protein;immune function;in vivo;inhibitor/antagonist;juvenile animal;novel;overexpression;practical application;prevent;programs;receptor;research study;response;scyphostatin


application_id: 7793494
project_number: 5R01DE017680-04
project_title: P. gingivalis: Role of GSK3 in Host Inflammation
administering_ic: NIDCR
award_notice_date: 2010-03-30
application_type: 5
activity_code: R01
ic: DE
serial_number: 017680
program_official: BURGOON, PENNY W
project_start_date: 2007-04-25
project_end_date: 2012-03-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7618997
contact_pi: MARTIN, MICHAEL
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-04-01
project_abstract:
DESCRIPTION (provided by applicant):  The host immune response to periodontal-associated pathogens has been shown to be a key determinant involved in periodontal disease by regulating the production of pro- and anti-inflammatory cytokines that regulate the severity of this disease. An inability to regulate the nature or duration of the host's inflammatory response can often mediate detrimental host effects as observed in chronic inflammatory diseases. Our laboratory has identified the kinase glycogen synthase kinase 3 (GSK3) as a central regulator of the inflammatory process by its ability to differentially regulate the levels of pro- and anti-inflammatory cytokines upon TLR activation. Our specific hypothesis is that the ability of P. gingivalis to interact with TLR2 and TLR4 expressed on immune cells and the subsequent differential regulation of GSK3 activity mediated by these TLRs are major mechanisms responsible for the pathogenesis of this organism by regulating the nature and magnitude of the host's inflammatory response. This hypothesis is based on: 1) stimulation of immune cells from TLR2- or TLR4-deficient mice with P. gingivalis resulted in pronounced differences in the inhibition of GSK3; 2) inhibition of GSK3 in macrophages or dendritic cells stimulated with P. gingivalis resulted in the severe reduction in the levels of pro-inflammatory cytokines i.e. IL-12 while concurrently augmenting the levels of the anti-inflammatory cytokine IL-10; 3) a direct comparison of TLR2- and TLR4- deficient cells stimulated with P. gingivalis demonstrated that the levels of pro-inflammatory cytokines such as IL-12 were largely mediated by TLR4 whereas the levels of the anti-inflammatory cytokine IL-10 were predominantly mediated by TLR2; 4) analysis of the two major isoforms of GSK3 in innate immune cells revealed that dendritic cells contain only detectable levels of GSKS-p whereas macrophages contain both isoforms of GSK3 GSK3-a and GSK3-p; 5) in vivo administration of a GSK3 inhibitor resulted in a potent reduction in the levels of IL-1b IL-6 IL-12 and IFN-y whereas the levels of the anti-inflammatory cytokine IL-10 were potently augmented in response to P. gingivalis; and 6) inhibition of GSK3 in mice resulted in a predominant Th2-assoicated immune response to P. gingivalis. These observations provide a strong rationale and focus concerning the reported differences of TLR2 and TLR4 to mediate pro- and anti- inflammatory cytokine responses and elucidate a critical role for the GSK3 cell-signaling pathway in modulating the host's inflammatory response to P. gingivalis. The specific aims are designed to characterize how host-microbial interactions are involved in the regulation of the host inflammatory response to P. gingivalis. to elucidate and characterize the involvement of GSK3 in regulating these immune responses and to evaluate the efficacy of a therapeutic target (GSK3) that could attenuate the disease process in vivo.

project_terms:
Abscess;Affect;Alveolar Bone Loss;Anti-Inflammatory Agents;Anti-inflammatory;Attenuated;Cell Nucleus;Cell surface;Cells;Chronic;Dendritic Cells;Disease;Event;Figs - dietary;Foundations;Gene Expression;Glycogen Synthase Kinase 3;Host Defense;Immune;Immune response;Immune system;Immunity;Inflammation;Inflammatory;Inflammatory Response;Interleukin-10;Interleukin-12;Interleukin-6;Invaded;Laboratories;Mediating;Microbe;Modeling;Mus;Nature;Organism;Pathogenesis;Pathway interactions;Periodontal Diseases;Phosphotransferases;Play;Porphyromonas gingivalis;Principal Investigator;Process;Production;Property;Protein Isoforms;Receptor Activation;Receptor Signaling;Regulation;Reporting;Role;Severity of illness;Signal Pathway;Signal Transduction;Signaling Molecule;Solid;TLR2 gene;TLR4 gene;Toll-like receptors;base;cytokine;design;in vivo;inhibitor/antagonist;macrophage;microorganism interaction;mouse model;pathogen;programs;response;therapeutic target


application_id: 7793415
project_number: 5P01HL086670-03
project_title: Analytical and Preparative Core
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 086670
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 9001
contact_pi_person_id: 1884301
contact_pi: DE BEER, FREDERICK C.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-01
budget_end_date: 2010-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The purpose of Core B is to facilitate research and stimulate collaboration between the individual projects.
Specifically Core B will offer the following services:
1. Lipoprotein isolation and characterization
2. Plasma lipoprotein analysis
3. Plasma lipid analysis
4. Labeling of proteins/lipoproteins with radioisotopes and fluorescent dyes
5. HDL remnant particle purification and characterization
6. Production of replication-defective adenoviral vectors and helper-dependent adenoviral vectors
7. Purification of total SAA and SAA isoforms
8. Isoelectric focusing
Centralization of these facilities will permit an efficient use of resources for the Program and experienced
technical staff will provide optimal quality control and standardization across Projects.

project_terms:
2-Mercaptoethanol;Acrylamides;Acute;Acute-Phase Reaction;Adenovirus Vector;Adenoviruses;Aliquot;Ampholine;Ampholyte Mixtures;Animals;Antibodies;Apolipoproteins;Apolipoproteins A;Argon;Autoradiography;Binding (Molecular Function);Biological Assay;Blood;Bolus Infusion;Buffers;CETP gene;COS-7 Cell;Canada;Cardiovascular system;Cells;Cellulose;Centrifugation;Chemicals;Cholesterol;Chromatography;Collaborations;Collection;Coupled;Culture Media;Cultured Cells;Cyanogen Bromide;Cytolysis;Density Gradient Centrifugation;Diagnostic;Dialysis procedure;Drug or chemical Tissue Distribution;Dyes;Edetic Acid;Exclusion;Fat emulsion;Fluorescence;Fluorescent Dyes;Fractionation;Freeze Drying;Freezing;Gases;Gel;Gel Chromatography;Generations;Genes;Glass;Hand;Helper Viruses;High Density Lipoproteins;Human;Human Volunteers;Hydrolysis;Imagery;In Vitro;Incubated;Individual;Inflammation;Injection of therapeutic agent;Instruction;Iodination reaction;Iodine;Ion-Exchange Chromatography Procedure;Isoelectric Focusing;Kentucky;Label;Ligands;Lipids;Lipoproteins;London;Low-Density Lipoproteins;Lysophospholipids;Manufacturer Name;Mediating;Metabolism;Methods;Methylene Chloride;Modification;Mus;Natural regeneration;Nitrogen;Nonesterified Fatty Acids;Phase;Phospholipase;Phospholipids;Plant Resins;Plaque Assay;Plasma;Preparation;Procedures;Process;Production;Protein Isoforms;Proteins;Pyroxylin;Quality Control;Radioactivity;Radioisotopes;Radiolabeled;Reaction;Recombinant Proteins;Recombinants;Recovery;Research;Resources;Sampling;Sepharose;Serum;Services;Solid;Speed (motion);Standardization;Sterility;Structure of jugular vein;Superose 12;Tail;Techniques;Temperature;Thick;Time;Triglycerides;Tube;Tyramine;Ultracentrifugation;Universities;Urea;Veins;Very low density lipoprotein;Vial device;Viral;Virion;Virus;Western Blotting;cholesteryl oleyl ether;citrate carrier;defective adenoviral vector;density;evaporation;experience;fast protein liquid chromatography;gel electrophoresis;helper-dependent adenoviral vector;immunoaffinity chromatography;in vivo;interest;iron oxide;mouse model;particle;polyacrylamide gels;pressure;programs;radiotracer;reconstitution;research study;scale up;sodium sulfate;uptake;vector


application_id: 7793179
project_number: 1S10RR024704-01A1
project_title: Zeiss PALM MicroBeam
administering_ic: NCRR
award_notice_date: 2010-04-22
opportunity_number: PAR-09-028
application_type: 1
activity_code: S10
ic: RR
serial_number: 024704
suffix: A1
program_official: LEVY, ABRAHAM
project_start_date: 2010-04-22
project_end_date: 2011-04-21
study_section: Special Emphasis Panel[ZRG1 CB-J (31)]
contact_pi_person_id: 8915754
contact_pi: BLALOCK, ERIC
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This is a proposal to establish laser microdissection instrumentation using Laser Microdissection and Pressure Catapulting (LMPC) technology at the University of Kentucky. Laser microdissection technology has become a standard for cutting-edge biomedical research at many institutions and clearly will revolutionize studies of gene and protein expression. Numerous NIH-supported projects at UK focus on gene and protein expression approaches in many cases with a clear focus on particular cell types tissue lesions genetically modified loci and even subcellular regions. The ability to incorporate computer-automated highly selective specimen collection will vastly accelerate research progress refine interpretation and drive the discovery of novel mechanisms in various physiological and pathological conditions that are the focus of UK's research enterprise. In particular major user projects at UK emphasize detection of subtle changes in tissue cell and subcellular compartments in various cell types cancerous lesions and plaques with aging Alzheimer's disease inflammation traumatic brain injury oxidative stress and infection and heavily integrate translational goals with the concept of personalized medicine. The integrated system proposed here (Zeiss PALM MicroBeam) has the power accuracy and flexibility to address the diverse needs of the Major Users in this application and will allow researchers to focus on homogenous cell collection derived from extant tissue. Coupled with the molecular expertise at UK this system will allow our researchers to investigate the critical interplay among different cell types at the transcriptional and proteomic levels during pathological processes leading to rational development of new drugs and individualized pathological diagnoses. Thus the proposed system will not only specifically enhance progress in multiple NIH-funded projects at UK but will facilitate the development of new methods that may well benefit investigators at many other institutions as well. Relevance: In recent years advances in molecular measurement technology (e.g. proteomics gene expression arrays) have yielded important insights into disease processes. The equipment proposed here will bring sampling technology (i.e. the ability to select an area of tissue for study at the cellular or even subcellular level) up to the same standard. The combination of advanced molecular analysis and cell-level collection specificity will allow us to investigate the roles of different kinds of cells in diseases such as Alzheimer's cancer and heart disease leading to rational development of new drugs and individualized medicine approaches for treatment.

project_terms:
Address;Aging;Alzheimer's Disease;Area;Biomedical Research;Cancerous;Cells;Collection;Computers;Coupled;Detection;Development;Diagnosis;Disease;Equipment;Funding;Gene Expression;Gene Proteins;Goals;Heart Diseases;Infection;Inflammation;Institution;Kentucky;Lasers;Lesion;Malignant Neoplasms;Measurement;Medicine;Methods;Microdissection;Molecular;Molecular Analysis;Oxidative Stress;Pathologic Processes;Pharmaceutical Preparations;Physiological;Plaque (lesion);Process;Proteomics;Research;Research Personnel;Role;Sampling;Specificity;System;Technology;Tissues;Traumatic Brain Injury;Universities;cell type;flexibility;insight;instrumentation;novel;pressure;protein expression;sample collection


application_id: 7792715
project_number: 1R01DE019826-01A1
project_title: Tobacco-induced alterations to P. gingivalis-host interactions
administering_ic: NIDCR
award_notice_date: 2010-05-15
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: DE
serial_number: 019826
suffix: A1
program_official: LUNSFORD, DWAYNE
project_start_date: 2010-05-15
project_end_date: 2015-04-30
study_section: Special Emphasis Panel[ZRG1 MOSS-B (02)]
contact_pi_person_id: 7338645
contact_pi: SCOTT, DAVID A
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
project_abstract:
DESCRIPTION (provided by applicant):  Periodontitis is a destructive infectious disease that has been associated with multiple fatal and debilitating chronic systemic diseases and consumes billions of dollars in health costs annually in the US. Tobacco smokers exhibit increased susceptibility to periodontitis; are more likely to be infected with the key periodontal pathogen Porphyromonas gingivalis; and to harbor higher numbers of this bacterial species relative to non-smokers. Despite this smokers consistently exhibit reduced clinical inflammation. We show that the pro-inflammatory response of purified human monocytes is significantly suppressed when P. gingivalis is exposed to cigarette smoke extracts (CSE) and that the inflammation inducing potential of P. gingivalis is restored when cells are sub-cultured back into fresh medium without CSE. However the influence of tobacco on the regulation of genes encoding P. gingivalis virulence determinants is essentially unknown.  We hypothesize that CSE represents an environmental stress and that P. gingivalis responds by altering gene expression to adapt to this stress. We believe that this adaptive response may involve the induction of stress-related genes virulence determinants and alterations of bacterial surface components. We also hypothesize that such cigarette smoke-induced physiological changes in P. gingivalis will include altered activities of genes encoding key pathogen recognition determinants which will explain the reduced inflammatory response of smoke-exposed P. gingivalis. It is our aim to identify isolate and test CSE-altered gene products in a primary human monocyte model of inflammation.  Preliminary data generated through transcriptome analyses and the structural characterization of several microbial determinants are strongly supportive of our hypotheses. We have identified several genes gene products and bacterial structures that are dysregulated on CSE exposure that may play pivotal roles in the engagement of the innate immune system by P. gingivalis. These include fimbrial proteins LPS major outer membrane antigens and other P. gingivalis components of known inflammatory potential such as dnaJ grpE and ragA.  These studies represent a novel area of investigation and will provide some of the first information illustrating how P. gingivalis responds at the molecular level to cigarette smoke and may provide unique insights into disease pathogenesis in smokers. Thus these studies will break new ground and provide the foundation for future studies that will elucidate mechanisms explaining how tobacco influences pathogen-host response interactions.  
  
PUBLIC HEALTH RELEVANCE:  The Gram negative anaerobic bacterium Porphyromonas gingivalis is a causative agent of chronic periodontitis a destructive tobacco-induced and/or exacerbated disease. Smokers are more likely to be infected by P. gingivalis and to harbor higher numbers of these bacterial cells than non-smokers. However smokers also exhibit reduced clinical inflammation and in keeping with this smoke-exposed P. gingivalis exhibits a reduced capacity to illicit an inflammatory response from immune cells. The mechanisms underlying this reduced inflammatory potential are entirely unknown. Therefore we will identify P. gingivalis genes that are dysregulated by tobacco exposure by microarray analysis of P. gingivalis cultured in cigarette smoke extract (CSE)-conditioned medium. We will also examine the effects of CSE on the characteristics of cellular structures known to play critical roles in the activation of innate immune cells such as LPS and fimbriae. The inflammatory potential of tobacco-altered bacterial structures and the products of CSE-dysregulated genes will be tested in freshly isolated human monocytes. This study will provide some of the first information illustrating how P. gingivalis responds at the molecular level to cigarette smoke and may provide unique insights into disease pathogenesis in smokers.

project_terms:
Anabolism;Antibodies;Antigens;Area;Back;Bacteria;Bacterial Proteins;Cells;Cellular Structures;Characteristics;Chronic;Chronic Obstructive Airway Disease;Clinical;Communicable Diseases;Conditioned Culture Media;Coronary Arteriosclerosis;Cytokine Suppression;Data;Dental;Diabetes Mellitus;Disease;Economic Burden;Exhibits;Exposure to;Foundations;Future;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Genes;Genome;Genomics;Goals;Gram-Negative Anaerobic Bacteria;Health Care Costs;Human;IS Elements;Immune;Immune response;Immune system;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Investigation;Lipid A;Lung diseases;Membrane;Membrane Proteins;Microarray Analysis;Microbial Biofilms;Modeling;Molecular;Non-smoker;Operon;Organism;Pathogenesis;Patients;Periodontitis;Persons;Phenotype;Physiological;Play;Pneumonia;Polysaccharides;Population;Porphyromonas gingivalis;Predisposition;Proteins;Refractory;Relative (related person);Reporter Genes;Risk;Rodent Model;Role;Severities;Smoke;Smoker;Smoking;Specificity;Stress;Structure;Surface;Systemic disease;TNF gene;Testing;Tissues;Tobacco;Tooth structure;Transcript;Transposase;United States;Vascular Diseases;Virulence;capsule (pharmacologic);cigarette smoke;cigarette smoke-induced;fimbria;in vivo;insight;microbial;monocyte;neutrophil;novel;pathogen;public health relevance;response;stroke;tobacco exposure;trait

public_health_relevance:
The Gram negative anaerobic bacterium Porphyromonas gingivalis is a causative agent of chronicperiodontitis a destructive tobacco-induced and/or exacerbated disease. Smokers are more likely to beinfected by P. gingivalis and to harbor higher numbers of these bacterial cells than non-smokers. Howeversmokers also exhibit reduced clinical inflammation and in keeping with this smoke-exposed P. gingivalisexhibits a reduced capacity to illicit an inflammatory response from immune cells. The mechanisms underlyingthis reduced inflammatory potential are entirely unknown. Therefore we will identify P. gingivalis genes thatare dysregulated by tobacco exposure by microarray analysis of P. gingivalis cultured in cigarette smokeextract (CSE)-conditioned medium. We will also examine the effects of CSE on the characteristics of cellularstructures known to play critical roles in the activation of innate immune cells such as LPS and fimbriae. Theinflammatory potential of tobacco-altered bacterial structures and the products of CSE-dysregulated genes willbe tested in freshly isolated human monocytes. This study will provide some of the first information illustratinghow P. gingivalis responds at the molecular level to cigarette smoke and may provide unique insights intodisease pathogenesis in smokers.


application_id: 7792189
project_number: 5R01GM066152-07
project_title: Synthetic Probes of Protein Prenylation
administering_ic: NIGMS
award_notice_date: 2010-05-05
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 066152
program_official: FABIAN, MILES
project_start_date: 2002-05-01
project_end_date: 2012-03-31
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 7875230
contact_pi: SPIELMANN, H PETER
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): Covalent modification by isoprenoid lipids (prenylation) is a critical post-translational event for many proteins involved in cellular signaling and cancer. The primary goal of this research program is to design and test prenyl function inhibitors and to identify and characterize proteins that are farnesylated in vivo. The studies outlined in this proposal will result in the preparation of new tools to probe the specificity of the prenyltransferases protein- farnesyltransferase (FTase) and protein-geranylgeranyltransferase (GGTase-I) enable further development of prenyl function inhibitors and identify new prenylated proteins as potential targets for therapeutic intervention. By varying the chemical structure of the prenyl lipid we are developing reagents to probe the biological function of the posttranslational modification. Taking advantage of the fact that the prenyl group forms a substantial part of the peptide substrate binding site in the prenyltransferases has allowed us to develop peptide selective inhibitors of prenyl function. These unnatural analogues may allow for the selective interference with specific prenylation targets and may provide lead compounds to alleviate the potential toxicity associated with complete inhibition of protein prenylation. In particular the unnatural analogues may be useful to obtain a more complete understanding of the role that alternative prenylation plays in Farnesyl transferase inhibitor (FTI) evasion by oncogenes such as K-Ras. Critical to understanding the clinical effects of existing and future FTIs and geranylgeranyl transferase inhibitors (GGTIs) is the identification of in vivo substrates of FTase and GGTase-I. Our innovative strategy of using unnatural transferable prenyl analogues and analogue specific monoclonal antibodies to identify prenylated cellular proteins will provide valuable information on the cellular targets of inhibitors of prenylation. We expect these studies to result in the identification of previously unknown prenylated proteins. The specific aims of this project are: 1) Synthesis of farnesyl and geranylgeranyl diphosphate analogues to study protein prenylation. 2) Screening these compounds for substrate specificity of FTase and GGTase-I and development of prenyl function inhibitors. 3) Identification of prenylated proteins in cells. The results from these studies may provide leads to new molecules to treat cancer and also identify new molecular targets to develop anti-cancer therapies.  
  
 PUBLIC HEALTH RELEVANCE Substantial evidence points to the central role of proteins normally modified by a prenyl group in cancer progression. We propose to design and test prenyl function inhibitors and to identify and characterize proteins that are modified with prenyl groups. The results from these studies may provide leads to new molecules to treat cancer and also identify new molecular targets to develop future anti-cancer therapies.

project_terms:
Active Sites;Antibodies;Binding Sites;Biochemical;Biological;Biological Assay;Biological Process;Biology;Cells;Chemical Structure;Dependence;Development;Dimethylallyltranstransferase;Discrimination (Psychology);Drug Design;Enzymes;Event;Exhibits;Farnesyl Transferase Inhibitor;Funding;Future;Goals;Growth;Immunoprecipitation;Lead;Lipids;Malignant Neoplasms;Methods;Modification;Molecular Target;Monoclonal Antibodies;Oncogenes;Pathway interactions;Peptides;Play;Post-Translational Protein Processing;Preparation;Process;Protein Isoprenylation;Proteins;Proteomics;Reagent;Research;Role;Screening procedure;Signal Transduction;Site-Directed Mutagenesis;Specificity;Substrate Specificity;Techniques;Testing;Therapeutic Intervention;Toxic effect;Transformed Cell Line;analog;cancer therapy;cellular targeting;chemical synthesis;clinical effect;cytotoxicity;design;enzyme substrate;geranylgeranyl diphosphate;in vivo;inhibitor/antagonist;innovation;isoprenoid;lipophilicity;novel;prenyl;prenylation;programs;protein farnesyltransferase;protein function;protein geranylgeranyltransferase;public health relevance;tool;tumor progression


application_id: 7791087
project_number: 1R01HL095593-01A1
project_title: Atherogenic mechanism of lipid peroxidation-derived aldehydes
administering_ic: NHLBI
award_notice_date: 2010-03-08
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: HL
serial_number: 095593
suffix: A1
program_official: DOMANSKI, MICHAEL
project_start_date: 2010-03-15
project_end_date: 2014-02-28
study_section: Vascular Cell and Molecular Biology Study Section[VCMB]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this project is to understand the role of lipid peroxidation-derived aldehydes in atherosclerosis. Aldehydes such as 4-hydroxynonenal (HNE) and 1-palmitoyl-2-(5-oxovaleroyl)-3- glycero- phosphatidyl choline (POVPC) are the major bioactive products generated from the oxidation of LDL. Based on supportive preliminary studies we propose to test hypothesis that accumulation of lipid-derived aldehydes in macrophages induces endoplasmic reticulum (ER) stress and triggers the unfolded protein response (UPR) leading to cytokine production and foam cell formation. The specific aims of this project are to: (1) delineate the contribution of ER stress and UPR to aldehyde-mediated macrophage activation; (2) elucidate the role of UPR in regulating atherogenesis; and (3) examine the role of aldehyde metabolism in preventing ER stress and UPR in atherosclerotic lesions. To accomplish these aims we will examine whether exposure of murine bone marrow derived macrophages to model lipid-derived aldehydes - HNE or POVPC induces ER stress and UPR. We will determine the extent and the nature of this response and identify which specific UPR-dependent signaling pathways are activated by aldehydes and how they contribute to macrophage activation foam cell formation and apoptosis. To examine the role of ER-stress and UPR during atherosclerotic lesion formation we will determine stage-specific changes in ER stress and UPR in the arterial lesions of apoE-null mice. To probe causality we will examine whether treatment with chemical chaperones which assist protein folding would decrease lesion formation and improve plaque stability. In addition we will test whether genetic ablation of activating factor 3 (ATF3) a UPR-responsive gene which is dramatically induced by lipid aldehydes increases lesion progression and inflammation. To elucidate the role of aldehydes in inducing ER stress in atherosclerotic lesions we will examine how genetic deletion or overexpression of aldose reductase an enzyme which detoxifies both HNE and POVPC affects aldehyde-induced macrophage activation and foam cell formation in culture and ER stress UPR induction in the arterial lesions of apoE-null mice. Successful completion of this project may lead to a better understanding of the mechanisms by which lipid-derived aldehydes affect atherogenesis and how the effects of these aldehydes could be prevented or therapeutically minimized to decrease atherosclerosis.  
  
PUBLIC HEALTH RELEVANCE:  Oxidized lipids have been suggested to play a pivotal role in the formation of atherosclerotic lesions nevertheless the mechanisms by which these lipids or their products induce vascular injury and promote plaque formation or rupture are unknown. Our studies are designed to test the hypothesis that accumulation of lipid-derived aldehydes in macrophages induces endoplasmic reticular (ER) stress and triggers unfolded protein response (UPR). We propose that lipid-derived aldehydes induce the transcription factor 3 (ATF3) which is associated with the alarm phase of UPR and genetic ablation of ATF3 exacerbates and pharmacological inhibition of ER-stress decreases atherogenesis. To examine that aldehydes are indeed causally involved in ER-stress and atherogenesis we will examine whether macrophage specific overexpression or deletion of aldose reductase which converts toxic aldehydes to innocuous alcohols affects their atherogenic effects. Results obtained from this project will help in developing a better understanding and potentially novel therapeutic strategies for decreasing or managing atherosclerosis.

project_terms:
4 hydroxynonenal;Ablation;Affect;Alcohols;Aldehyde Reductase;Aldehydes;Apolipoprotein E;Apoptosis;Arterial Fatty Streak;Asses;Atherosclerosis;Binding (Molecular Function);Blood Vessels;Bone Marrow;Cell Death;Chemicals;Choline;Drug Metabolic Detoxication;Endoplasmic Reticulum;Enzymes;Etiology;Exposure to;Foam Cells;Genes;Genetic;Goals;Inflammation;Inflammatory;Injury;Knockout Mice;Laboratories;Lead;Lecithin;Lesion;Lesion by Stage;Lipid Peroxidation;Lipid-Laden Macrophage;Lipids;Lipoproteins;Low Density Lipoprotein oxidation;Macrophage Activation;Mediating;Metabolism;Mitogen-Activated Protein Kinases;Modeling;Molecular;Molecular Chaperones;Mus;Natural Immunity;Nature;Pathway interactions;Phase;Phospholipids;Play;Production;Proteins;Proteolysis;Relative (related person);Research;Research Design;Role;Rupture;Side;Signal Pathway;Signal Transduction;Staging;Stress;Testing;Toxic effect;activating transcription factor;activating transcription factor 3;adduct;arterial lesion;atherogenesis;base;biological adaptation to stress;cytokine;endoplasmic reticulum stress;improved;in vivo;macrophage;novel therapeutics;overexpression;oxidation;oxidized lipid;prevent;protein degradation;protein folding;public health relevance;response


application_id: 7790695
project_number: 5R01DC009418-02
project_title: Neurotrophin receptor regulation of taste development
administering_ic: NIDCD
award_notice_date: 2010-02-25
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DC
serial_number: 009418
program_official: SULLIVAN, SUSAN L
project_start_date: 2009-04-01
project_end_date: 2013-03-31
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: MINICHIELLO, LILIANA
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Description (provided by applicant): During development sensory innervation to taste buds is tightly regulated by the actions of two neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4). Although both of these factors regulate gustatory innervation their specific functions are different from one another. BDNF is expressed in gustatory epithelium and determines whether gustatory neurons will locate and innervate taste placodes during development while NT4 does not. Both BDNF and NT4 regulate gustatory neuron and taste bud number but they have their influences at different times during development. The long range goal of this research is to understand the cellular and molecular mechanisms that regulate the neural innervation to and the maintenance of taste buds during development. The proposed studies focus on mechanisms by which these two neurotrophins BDNF and NT4 can influence various aspects of neural innervation through the same receptors TrkB and p75. The proposed studies use cell counting tract tracing immunohistochemistry and scanning electron microscopy in gene knockout mice to determine when TrkB and p75 are required for specific aspects of gustatory development including axonal extension into the tongue target selection and geniculate neuron/taste bud survival. Furthermore these studies combine these anatomical approaches with sophisticated genetic tools allowing the function of single phosphorylation sites on the TrkB receptor protein to be blocked in vivo. These experiments will determine which TrkB intracellular signaling pathways are required for axonal extension into the tongue target selection and geniculate neuron/taste bud survival. Together these studies test the hypotheses that TrkB mediates the effects of both BDNF and NT4 but that each function of these neurotrophins requires a different intracellular signaling pathway. While p75's more subtle role is to modulate the regulation of gustatory development by neurotrophins. Because these experiments examine the fundamental mechanisms of how neurotrophins regulate neuronal survival and axon targeting via Trk receptors this project has important implications for the therapeutic use of these signaling mechanisms in controlling neuron survival and axon targeting during regeneration. PUBLIC HEALTH RELEVANCE: The taste system is an ideal and commonly used system for examining axon regeneration following injury. We are examining the signaling mechanisms for two factors (neurotrophins) that influence axon targeting and neuron survival during development. By understanding of how these signaling mechanisms normally function techniques can be developed to manipulate these important signaling factors during nerve regeneration which will improve reinnervation and function following nervous system injury.

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

public_health_relevance:
The taste system is an ideal and commonly used system for examining axonregeneration following injury. We are examining the signaling mechanisms for twofactors (neurotrophins) that influence axon targeting and neuron survival duringdevelopment. By understanding of how these signaling mechanisms normally functiontechniques can be developed to manipulate these important signaling factors duringnerve regeneration which will improve reinnervation and function following nervoussystem injury.


application_id: 7790584
project_number: 1R03AG032099-01A2
project_title: Voxel Based Relaxometry Analysis of ADNI Images
administering_ic: NIA
award_notice_date: 2010-05-31
opportunity_number: PA-06-240
application_type: 1
activity_code: R03
ic: AG
serial_number: 032099
suffix: A2
program_official: HSIAO, JOHN
project_start_date: 2010-06-01
project_end_date: 2012-05-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 6727688
contact_pi: HARDY, PETER A
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Alzheimer's disease is a neurodegenerative disease causing a progressive decline in the memory language and motor abilities of individuals affected leaving them increasingly debilitated and dependent. The high incidence of Alzheimer's Disease is predicted to have a dramatic increase in its prevalence and a commensurate increase in the costs to society. This situation requires the development of improved methods of early detection and identification of subjects likely to progress to full AD so that they might be properly triaged to appropriate therapy. Additionally new techniques for evaluating potential therapies to slow AD progression are urgently needed so that the most promising therapies are moved rapidly through clinical trials into public use. To study a potential non-invasive imaging method for the detection of the pathological changes occurring in the brains of patients who might develop Alzheimer's disease this project will test the hypothesis that individuals with mild cognitive impairment (MCI) and with AD will have a shorter T2 in the GM regions of the brain and higher T2 in WM regions of the brain compared with age and education-matched cognitively normal (CN) individuals. Our broad long-term goal is to develop image acquisition and analysis tools to measure physiological changes occurring in neurodegenerative diseases. Using image and psychometric data obtained on a large group of individuals followed as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI) the project will accomplish three specific aims: (1) To correlate the relaxation time T2 measured from images acquired at 1.5T on a voxel-by-voxel basis across the entire brain with the subject's cognitive status. (2) To correlate the increase in the relaxation rate 1/T2 with magnetic field strength B0 with the subject's cognitive status. (3) To test the power of T2 to predict the probability of conversion from MCI to AD. By comparing the relaxation times and rates of change of subjects who convert to AD with those who remain stable we will build a model relating initial and rates of change of T2 to the probability of conversion to AD. The results of the project will demonstrate that physiological changes in the brain occurring with the progression of Alzheimer's disease can be detected through MRI independently and potentially earlier than brain atrophy is detectable on MR images. Such a non-invasive and sensitive imaging technique will have widespread application in the management and investigation of AD.  
  
PUBLIC HEALTH RELEVANCE: This project makes use of a valuable collection of magnetic resonance images and clinical data on a large (800) group of elderly subjects acquired as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). The ADNI subjects are grouped into three categories cognitively normal mild cognitively impaired or Alzheimer's diseased and are followed for up to three years using MR imaging and clinical testing. ADNI is the most comprehensive effort to date to identify neuroimaging and other biomarkers of the changes associated with Mild Cognitive Impairment and Alzheimer's Disease. This proposed project will analyze the fast spin echo images acquired on the subjects at each of five study points and on two magnet field strengths to generate images sensitive to iron accumulation and axonal loss. The images will be analyzed using Voxel Based Relaxometry to determine brain sites associated with these physiological changes which accompany the progression of Alzheimer's disease. The research will make particular use of the unique information available from images of the same subjects acquired at two field strengths which will increase the likelihood of detecting an association between iron accumulation and the progression of Alzheimer's disease. The work will stimulate further exploration into the development and application of imaging techniques to provide independent information about the likelihood of Alzheimer's disease progression.

project_terms:
Affect;Age;Alzheimer's Disease;American;Area;Basal Ganglia;Brain;Brain region;Categories;Clinical;Clinical Data;Clinical Trials;Cognitive;Collection;Data;Degenerative Disorder;Deposition;Detection;Deterioration;Development;Diagnostic;Disabled Persons;Disease;Disease Progression;Early Diagnosis;Educational aspects;Elderly;Ferritin;Fiber;Future;Goals;Image;Imaging Techniques;Impaired cognition;Incidence;Individual;Intervention;Investigation;Iron;Language;Left;Liquid substance;Magnetic Resonance Imaging;Measurement;Measures;Medial;Memory;Methods;Modeling;Motor;Neocortex;Nerve Degeneration;Neurodegenerative Disorders;Pathologic Processes;Pathology;Patients;Physiological;Population;Prevalence;Probability;Psychometrics;Relaxation;Research;Resolution;Risk;Senile Plaques;Site;Societies;Techniques;Temporal Lobe;Testing;Time;Triage;United States;Work;base;biomarker;cerebral atrophy;cost;effectiveness measure;imaging modality;improved;magnetic field;mild cognitive impairment;neuroimaging;public health relevance;research clinical testing;tool;white matter;white matter change

public_health_relevance:
NarrativeThis project makes use of a valuable collection of magnetic resonance images and clinical data on a large(800) group of elderly subjects acquired as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). TheADNI subjects are grouped into three categories cognitively normal mild cognitively impaired or Alzheimer'sdiseased and are followed for up to three years using MR imaging and clinical testing. ADNI is the mostcomprehensive effort to date to identify neuroimaging and other biomarkers of the changes associated withMild Cognitive Impairment and Alzheimer's Disease. This proposed project will analyze the fast spin echoimages acquired on the subjects at each of five study points and on two magnet field strengths to generateimages sensitive to iron accumulation and axonal loss. The images will be analyzed using Voxel BasedRelaxometry to determine brain sites associated with these physiological changes which accompany theprogression of Alzheimer's disease. The research will make particular use of the unique information availablefrom images of the same subjects acquired at two field strengths which will increase the likelihood of detectingan association between iron accumulation and the progression of Alzheimer's disease. The work will stimulatefurther exploration into the development and application of imaging techniques to provide independentinformation about the likelihood of Alzheimer's disease progression.


application_id: 7788519
project_number: 1R21HD059058-01A2
project_title: Farm to School: A Community-Based Program to Combat Childhood Obesity
administering_ic: NICHD
award_notice_date: 2010-09-01
opportunity_number: PA-06-181
application_type: 1
activity_code: R21
ic: HD
serial_number: 059058
suffix: A2
program_official: ESPOSITO, LAYLA E
project_start_date: 2010-09-01
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZRG1 HDM-G (02)]
contact_pi_person_id: 8931964
contact_pi: SWANSON, MARK
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
project_abstract:
DESCRIPTION (provided by applicant): Located in rural Kentucky the state with the highest adolescent overweight rate in the nation the proposed project examines the feasibility of using a farm to school program as a health intervention. Farm to school projects have the potential to increase student consumption of fruits and vegetables thus decreasing the risk of obesity by linking local farms to school cafeterias and classrooms and combining curriculum on nutrition and food production with experiential education such as farm field trips and school gardens; currently however there are no known empirically-based examinations of this promising ecologically oriented approach to stemming overweight and obesity. A multidisciplinary team including an anthropologist a clinical nutritionist a biostatistician a behavioral epidemiologist and a public health nutritionist will partner with school personnel and farmers in a Community Based Participatory Research program designed to develop implement and assess a farm to school programs as an obesity prevention intervention for preadolescent elementary students. A factorial design will allow us to discern the relative impact of each component of this ecologically- oriented multi-component intervention. The Specific Aims of this project are 1) Utilize formative research to develop a farm to school project to prevent childhood obesity in rural Kentucky; 2) Demonstrate feasibility of implementing and evaluating a farm to school program; 3) Establish financial feasibility and sustainability of farm to school programs as a dietary and health intervention in elementary schools; 4) Identify individual and interacting effects of each component of the intervention on fruit and vegetable consumption; 5) Examine the impact of the intervention on knowledge attitudes and beliefs about food and nutrition; and 6) Identify individual and interacting effects of intervention components on BMI. During Phase I the developmental phase key informant interviews and focus groups will be conducted to gain insights into the most useful components of a farm to school program for school personnel parents children and farmers. During this phase we will work with school administrators and food service personnel teachers area farmers students and parents in program development. Research team members will collaborate closely with community members in curriculum development farmer recruitment selection of produce. During Phase II we will administer the intervention using a group-randomized trial in one rural school. Outcome measures include photographic assessment of cafeteria consumption and BMI measures which are complemented with extensive process evaluation. Upon project completion we will apply and expand the findings of this ecologically oriented CBPR project to create a large scale R01 project capable of reducing childhood obesity in a way enriching and acceptable to the community.  
  
PUBLIC HEALTH RELEVANCE: Project narrative Kentucky has the highest rate in the nation for adolescent obesity. Schools offer an excellent environment to address this epidemic through interventions which address the problem simultaneously in the classroom the cafeteria and the community. The proposed project works with one Kentucky elementary school and its surrounding community to institute and test the impact of a Farm to School program that brings locally grown produce into the cafeteria teaches about nutrition and farming in the classroom and provides experiential education through field trips to farms farmer visits to classrooms and class gardening projects. The success of the intervention is evaluated by stakeholder assessments measuring what students eat in the cafeteria and measuring what effects the program has on student weight.

project_terms:
Address;Administrator;Adolescent;Affect;Area;Attitude;Behavioral;Belief;Child;Child Nutrition;Clinical;Communities;Complement;Consumption;Development;Development Plans;Eating;Educational Curriculum;Educational aspects;Educational process of instructing;Environment;Epidemic;Epidemiologist;Evaluation;Farming environment;Focus Groups;Food;Food Services;Future;Habits;Health;Human Resources;Individual;Institutes;Intervention;Interview;Kentucky;Knowledge;Link;Measures;Nutritional;Nutritionist;Obesity;Outcome;Outcome Measure;Overweight;Parents;Phase;Preventive Intervention;Process;Production;Program Development;Relative (related person);Research;Research Methodology;Research Personnel;Research Project Grants;Rural;School Teachers;Schools;Students;Testing;Underserved Population;Visit;Weight;Work;base;behavioral health;combat;community based participatory research;design;elementary school;farmer;fruits and vegetables;health disparity;improved;informant;insight;intervention effect;member;multidisciplinary;nutrition;obesity in children;obesity prevention;obesity risk;prevent;programs;public health medicine (field);public health relevance;randomized trial;rural area;stem;success;teacher;therapy design

public_health_relevance:
Project narrativeKentucky has the highest rate in the nation for adolescent obesity. Schools offer an excellent environment toaddress this epidemic through interventions which address the problem simultaneously in the classroom thecafeteria and the community. The proposed project works with one Kentucky elementary school and itssurrounding community to institute and test the impact of a Farm to School program that brings locally grownproduce into the cafeteria teaches about nutrition and farming in the classroom and provides experientialeducation through field trips to farms farmer visits to classrooms and class gardening projects. The successof the intervention is evaluated by stakeholder assessments measuring what students eat in the cafeteria andmeasuring what effects the program has on student weight.


application_id: 7788500
project_number: 1K01ES017105-01A1
project_title: Ubiquitous pollutant acrolein inhibits IFN?? antiviral signaling: relevance to HC
administering_ic: NIEHS
award_notice_date: 2009-12-21
opportunity_number: PA-09-040
application_type: 1
activity_code: K01
ic: ES
serial_number: 017105
suffix: A1
program_official: SHREFFLER, CAROL A
project_start_date: 2010-01-01
project_end_date: 2014-12-31
study_section: Special Emphasis Panel[ZES1 LKB-J (K6)]
contact_pi_person_id: 9367807
contact_pi: JOSHI-BARVE, SWATI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Chronic Hepatitis C virus (HCV) infection remains a global health concern with nearly 200 million carriers worldwide. It can be a precursor to cirrhosis hepatocellular carcinoma and end-stage liver disease. In the absence of a vaccine the current FDA approved standard of care for chronic hepatitis C is a combination of pegylated interferon-alpha (IFN1) and ribavirin. Unfortunately this regimen is only effective in about 50% of patients emphasizing the need for studies defining the molecular mechanisms underlying resistance to IFN1. Clinical studies have identified several potential cofactors that may contribute to the failure of anti-HCV therapy including obesity diabetes alcohol abuse oxidative stress cigarette smoking and environmental pollutants. Acrolein is a ubiquitous highly reactive environmental and industrial pollutant and is designated by the U.S. Environmental Protection Agency (EPA) as a high priority air and water pollutant. Notably acrolein is also formed endogenously as a byproduct of lipid peroxidation (LPO) and is itself known to cause oxidative stress. Moreover acrolein is a major component of cigarette smoke and recent studies suggest that smokers with chronic hepatitis C have a lower response rate to IFN1 compared to non-smokers. We have convincing preliminary data showing that non-toxic concentrations of acrolein significantly down-regulate IFN1 signaling and antiviral gene expression in vitro (cultured human hepatic cells) and in vivo (mice).  Published literature and our own compelling data strongly support our hypothesis that acrolein adversely influences IFN1 therapy outcomes by inhibiting or disrupting IFN1 mediated signaling and antiviral gene expression in hepatocytes and that high acrolein exposure (environmental and/or endogenous) will correlate with poor IFN1 response in HCV infected individuals. Our hypotheses will be tested by examining the effects of acrolein on early IFN1-mediated signaling (including components of the Jak/STAT pathway) and antiviral gene expression using well established in vitro and in vivo experimental systems as well as an HCV replicon that directly reports on HCV viral replication. Additionally the investigators will establish a clinical/translational aspect of our hypothesis by conducting a retrospective analysis using banked serum urine and/or liver biopsy samples from healthy uninfected individuals and HCV-infected patients (responders and non-responders). This analysis will explore a possible correlation between acrolein exposure and poor IFN1 response (lack of sustained virologic response SVR).  The investigators expect their studies will elucidate critical mechanisms underlying resistance to IFN1 treatment and will identify potential targets for novel therapeutic intervention.  
  
Public Health Relevance:  Acrolein is one of the major reactive aldehydes ubiquitously present in foods water and in the environment. It is a major constituent of cigarette smoke. Recent data suggest that HCV- infected smokers have worse IFN1 therapeutic outcomes compared with non-smokers. Acrolein is also generated endogenously due to cellular metabolism and this may constitute a significant source of intracellular acrolein in situations of oxidative stress and inflammation. Elevated acrolein adducts have been detected in several disease conditions that are also known to be associated with failure of IFN therapy. Hence based on available literature and the investigators' own compelling preliminary results they have opted to use acrolein as the model compound for this study. The aim of the study is to determine the contribution of acrolein to the mechanisms of IFN1 resistance. The investigators have preliminary evidence to demonstrate that acrolein at nontoxic concentrations significantly down-regulates IFN1 signaling and antiviral/anti-HCV gene expression.

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


application_id: 7788342
project_number: 7R21DA018732-04
project_title: Supraspinal Modulation of Neuropathic Pain
administering_ic: NIDA
award_notice_date: 2009-04-03
opportunity_number: PA-03-152
application_type: 7
activity_code: R21
ic: DA
serial_number: 018732
program_official: THOMAS, DAVID A
project_start_date: 2005-08-01
project_end_date: 2009-07-31
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 1879170
contact_pi: TAYLOR, BRADLEY K
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The brain exerts a powerful influence on the spinal transmission of pain signals. Recent evidence from our laboratory suggests that the locus coeruleus (LC) an important brainstem noradrenergic center facilitates the mechanical and thermal hypersensitivity induced by injury to peripheral nerves. These findings led to the hypothesis that in the setting of peripheral nerve injury descending facilitatory influences from the LC are required for the expression of nerve injury-induced pain (Aim #1) in part by increasing nociceptive processing at the dorsal horn (Aim #2). AIM #1a will test the hypothesis that disruption of synaptic activity in the LC with the microinjection of either a local anesthetic (lidocaine) or a synaptic inhibitor (cobalt) will decrease the tactile and cold hypersensitivity that develops following transection of the tibial and common peroneal branches of the sciatic nerve leaving the sural nerve intact. Aim #1b will test the hypothesis that irreversible destruction of LC neurons with a noradrenergic neurotoxin (DSP-4) before sham or nerve injury will prevent or reduce the development of injury-induced hypersensitivity. Aim #2 will use similar strategies in combination with measurement of stimulus-evoked expression of c-fos in the dorsal horn to test the hypotheses that disruption of LC function will: (a) prevent or (b) reverse nerve injury-induced spinal nociceptive processing. This two-year R21 study seeks to firmly establish whether the LC exerts facilitatory influences that contribute to the expression of neuropathic pain. The results achieved will provide the basis for an R01 application to further investigate the supraspinal network mediating descending facilitation. Increased understanding of the supraspinal noradrenergic mechanisms underlying chronic neuropathic pain may help to identify entirely new classes of analgesic drugs that may work by directly or indirectly blocking descending facilitation.

project_terms:
Acute;Address;Analgesics;Attention;Behavioral;Brain;Brain Stem;Brain region;Class;Cobalt;Data;Development;Disruption;Evaluation;FOS gene;Genes Immediate-Early;Hyperalgesia;Hypersensitivity;Injury;Laboratories;Left;Lesion;Lidocaine;Local Anesthetics;Measurement;Mechanics;Mediating;Microinjections;Modeling;Nerve;Neurons;Neuropathy;Neurotoxins;Nociception;Pain;Pathway interactions;Peripheral Nerves;Peripheral nerve injury;Persistent pain;Prevention;Principal Investigator;Process;Rattus;Research Design;Signal Transduction;Spinal;Stimulus;Structure of locus ceruleus;Structure of sciatic nerve;Structure of sural nerve;Synapses;Tactile;Techniques;Testing;Work;allodynia;base;chronic neuropathic pain;design;dorsal horn;immunoreactivity;inhibitor/antagonist;injured;nerve injury;noradrenergic;painful neuropathy;prevent;programs;research study;transmission process


application_id: 7788131
project_number: 5R01AR055974-02
project_title: Respiratory Muscle Weakness in Chronic Inflammation
administering_ic: NIAMS
award_notice_date: 2010-02-24
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AR
serial_number: 055974
program_official: NUCKOLLS, GLEN H
project_start_date: 2009-04-01
project_end_date: 2014-02-28
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1869134
contact_pi: REID, MICHAEL B
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The long-term goal of this project is to identify therapies that will preserve diaphragm function in chronic inflammatory conditions including heart failure and chronic obstructive pulmonary disease. Our current focus is loss of specific force in diaphragm which promotes exercise intolerance breathlessness and respiratory failure. A promising therapeutic target is tumor necrosis factor (TNF). TNF serum levels are elevated in chronic disease correlate with muscle weakness and are a predictor of morbidity and mortality. TNF depresses contractile function of diaphragm and stimulates oxidant production by diaphragm muscle fibers. The oxidants appear to cause weakness since interventions that limit oxidant activity prevent loss of force. Our central hypothesis is that respiratory muscle function can be preserved in chronic inflammatory disease by inhibiting TNF receptor-mediated effects on diaphragm muscle fibers. This project will define signaling events and redox mechanisms by which TNF depresses force and will evaluate pharmacologic and genetic interventions to preserve diaphragm function. We also will evaluate pathophysiologic relevance defining the role of TNF in a mouse model of disease and testing the capacity of clinical therapeutic agents to preserve diaphragm function. The project addresses three specific aims: Aim 1. To evaluate sphingolipid signaling as an early post-receptor mechanism by which TNF/TNFR1 stimulates oxidant activity and weakness. Cell culture studies will assess sphingomyelinase activation and ceramide-sensitive signaling events downstream of the TNF receptor subtype 1. Aim 2. To assess the source composition and post-translational target of oxidants that mediate TNF-stimulated weakness. Diaphragm fiber bundles and isolated mitochondria will be used to define ROS and NO contributions via redox assays and pharmacologic and genetic tools. Aim 3. To test TNF signaling as a contributor to respiratory muscle weakness in heart failure and a potential target for therapy. An animal model of heart failure will be used to define the diaphragm response to chronic inflammation to test TNF as a systemic mediator and to evaluate potential therapies that are approved for use in humans. PUBLIC HEALTH RELEVANCE: Chronic inflammatory diseases including heart failure and emphysema weaken the muscles used for breathing. This promotes the debilitating sensation of breathlessness decreases exercise tolerance and can lead to respiratory failure. The goal of this project is to identify new therapies that preserve respiratory muscle function in order to lessen illness and prolong life.

project_terms:
Address;Animal Model;Animals;Antioxidants;Arachidonic Acids;Area;Binding (Molecular Function);Biological Assay;Breathing;Calcium;Cardiovascular Diseases;Cell Culture Techniques;Ceramides;Chronic;Chronic Disease;Chronic Obstructive Airway Disease;Clinical;Complement;Data;Depressed mood;Diaphragm (Anatomy);Disease;Dyspnea;Esthesia;Event;Exercise;Exercise Tolerance;Extracellular Signal Regulated Kinases;Fiber;Functional disorder;Genetic;Goals;Heart failure;Hour;Human;Inflammation;Inflammatory;Intervention;Lead;Life;Ligand Binding;Link;Mediating;Mediator of activation protein;Microfilaments;Mitochondria;Mitogen-Activated Protein Kinase 3;Morbidity - disease rate;Mortality Vital Statistics;Muscle;Muscle Fibers;Muscle Weakness;Muscle function;Neurons;Nitric Oxide Synthase;Oxidants;Oxidation-Reduction;Pathway interactions;Patients;Peroxonitrite;Phospholipase;Phospholipase A2;Phosphotransferases;Physiologic intraventricular pressure;Post-Translational Protein Processing;Production;Protein Isoforms;Protein Kinase;Proteins;Publishing;Pulmonary Emphysema;Reactive Oxygen Species;Research;Respiratory Failure;Respiratory Muscles;Role;Serum;Signal Transduction;Source;Sphingolipids;Sphingomyelinase;Symptoms;Testing;Therapeutic Agents;Tumor Necrosis Factor Receptor;Tumor Necrosis Factor-alpha;Tumor Necrosis Factors;Work;drug development;gene therapy;mouse model;muscle strength;novel;premature;pressure;prevent;public health relevance;receptor;research study;response;therapeutic target;tool


application_id: 7787157
project_number: 1R21NS066117-01A1
project_title: PYCNOGENOL AND TRAUMATIC BRAIN INJURY
administering_ic: NINDS
award_notice_date: 2009-09-30
opportunity_number: PA-06-181
application_type: 1
activity_code: R21
ic: NS
serial_number: 066117
suffix: A1
program_official: HICKS, RAMONA R
project_start_date: 2009-09-30
project_end_date: 2011-08-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 1884283
contact_pi: SCHEFF, STEPHEN W
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): Traumatic brain injury (TBI) is a global health problem that is financially crippling for many families because of both specialized care and lost financial income. TBI involves at least two separate injury cascades that lead to neuronal and cognitive dysfunction. The secondary injury cascade may be amenable to pharmacologic intervention but the mechanisms are complicated requiring a multi-faceted approach. Oxidative stress loss of mitochondrial function and neuroinflammation appear to play major roles. Naturally occurring flavonoids are unique in possessing not only tremendous free radical scavenging properties but also the ability to modulate cellular homeostasis leading to a reduction in inflammation and cell toxicity. The proposed studies will investigate the idea that Pycnogenol(r) (PYC) a combination of bioflavonoids can significantly reduce the secondary injury cascade following TBI. This is an extremely novel approach to TBI therapy since it utilizes a family of very closely related biologically active polyphenols derived from tree bark. The first series of studies will explore the best possible dosing of PYC to maximally reduce oxidative stress and neuroinflammation following experimental TBI in rodents. The second set of studies will explore the protective qualities of PYC on mitochondrial bioenergetics and cell survival in the hippocampus following experimental TBI. Successful completion of the studies will pave the way for using PYC in more involved experimental TBI studies and contribute to the development of a rational therapy leading to a more favorable outcome.   
   
PUBLIC HEALTH RELEVANCE: The proposed studies investigate a specialized compound called a bioflavonoid to determine if it can help protect cells in the brain following injury. Using a well characterized animal model of traumatic brain injury subjects are treated with the compound Pycnogenol(r) and tested for a variety of outcome measures. Bioflavonoids are known to manifest multiple different helpful properties such as reducing oxidative stress. If the studies work then more complex and longer term studies can be proposed hopefully leading to a more rational therapy for brain injury.

project_terms:
Age;Animal Model;Animals;Antioxidants;Apoptosis;Bioenergetics;Bioflavonoid;Brain;Brain Injuries;Caring;Cause of Death;Cell Death;Cell Survival;Cells;Cessation of life;Complex;Development;Dose;Early treatment;Elements;Experimental Models;Family;Flavonoids;Free Radical Scavengers;Free Radical Scavenging;Health;Hippocampus (Brain);Homeostasis;Impaired cognition;Income;Individual;Inflammation;Injury;Intervention;Lead;Legal patent;Length;Longitudinal Studies;Membrane;Methods;Mitochondria;Monitor;Neurocognition;Neuronal Dysfunction;Neurons;Outcome;Outcome Measure;Oxidants;Oxidative Stress;Pathogenesis;Pharmaceutical Preparations;Pinus maritima;Play;Population;Property;Proteins;Pycnogenol;Reactive Nitrogen Species;Reactive Oxygen Species;Recovery;Rehabilitation therapy;Research;Rodent;Role;Series;Staining method;Stains;Stress;Synapses;Testing;Therapeutic;Time;Toxic effect;Trauma;Traumatic Brain Injury;Tree Bark;United States;Work;clinical care;cohort;cytokine;disability;fluoro jade;long term hospitalization;macrophage;neurobehavioral;neuroinflammation;novel strategies;polyphenol;public health relevance;research study;response

public_health_relevance:
The proposed studies investigate a specialized compound called a bioflavonoid todetermine if it can help protect cells in the brain following injury. Using a wellcharacterized animal model of traumatic brain injury subjects are treated with thecompound Pycnogenol(R) and tested for a variety of outcome measures. Bioflavonoids areknown to manifest multiple different helpful properties such as reducing oxidative stress. Ifthe studies work then more complex and longer term studies can be proposed hopefullyleading to a more rational therapy for brain injury.


application_id: 7787052
project_number: 5R01HL078976-05
project_title: Saturated Fatty Acid and Cardiovascular Disease
administering_ic: NHLBI
award_notice_date: 2010-02-24
application_type: 5
activity_code: R01
ic: HL
serial_number: 078976
program_official: ERSHOW, ABBY
project_start_date: 2006-03-15
project_end_date: 2011-02-28
study_section: Vascular Cell and Molecular Biology Study Section[VCMB]
contact_pi_person_id: 1896984
contact_pi: SMART, ERIC J
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-03-01
project_abstract:
The central hypothesis to betested in this proposal is that binding of saturated fatty acid to SR-BIactivates AMP kinase which results in the production of eNOS-dependent peroxynitrite andsubsequently an increase in atherosclerotic lesions. Reducing total dietary fat intake has been used as a method for reducing the risk of coronary heartdisease for decades however numerous studies have demonstrated that the type of fat may be moreimportant than the total amount of fat in the diet. Unsaturated fats such as n-3 and n-6 fatty acids arethought to be anti-atherogenic whereas saturated fatty acids with 14-16 carbon atoms (i.e. myristic acid andpalmitic acid) are considered to be pro-atherogenic. Saturated fatty acids are thought to be pro-atherogenicin part by causing an increase in total plasma cholesterol levels. Although plasma cholesterol levels clearlyinfluence the development of atherosclerotic lesions cholesterol is only one factor in the multi-factorialdisease of atherosclerosis. Our preliminary studies demonstrate that saturated fatty acid can cause anincrease in atherosclerosis independent of changes in plasma cholesterol levels. The goal of this proposal isto determine the mechanism whereby saturated fatty acid promotes atherosclerosis without altering plasmacholesterol. The preliminary data suggest that a novel signaling mechanism exists for saturated fatty acidsthat involve SR-BI caveolin AMP kinase and eNOS which subsequently results in the generation of the pro-atherogenic compound peroxynitrite. Three specific aims are proposed.Aim 1: To determine the domains within SR-BI that interact with saturated fatty acids and caveolinand to determine the domain within caveolin that interacts with SR-BI.Aim 2: To elucidate the residue(s) in caveolin that are phosphorylated and the domains withincaveolin and AMP kinase that interact.Aim 3: To determine if an endothelial-specific caveolin null mouse is protected from saturated fattyacid-induced peroxynitrite production andsubsequently atherosclerosis.

project_terms:
5'-AMP-activated protein kinase;Acids;Antiatherogenic;Arterial Fatty Streak;Atherosclerosis;Binding (Molecular Function);Biological Assay;Breeding;Carbon;Cardiovascular Diseases;Cattle;Caveolins;Cell membrane;Cells;Cholesterol;Coronary;Coronary heart disease;Data;Development;Diet;Dietary Fats;Disease;Endothelial Cells;Fatty Acids;Fatty acid glycerol esters;Fibrinogen;Generations;Goals;Intake;Knockout Mice;Ligands;Low Density Lipoprotein Receptor;Methods;Modeling;Mus;Mutate;Myristic Acids;Nitric Oxide;Palmitic Acids;Peroxonitrite;Phosphorylation;Plasma;Production;Reactive Oxygen Species;Recruitment Activity;Research Personnel;Risk;Saturated Fatty Acids;Signal Transduction;System;Unsaturated Fats;adenylate kinase;base;caveolin 1;feeding;novel;programs;receptor


application_id: 7786573
project_number: 7R21AG025721-03
project_title: Effects of Albuterol on Muscle Protein Synthesis
administering_ic: NIA
award_notice_date: 2009-03-19
opportunity_number: PAS-03-122
application_type: 7
activity_code: R21
ic: AG
serial_number: 025721
program_official: NAYFIELD, SUSAN G
project_start_date: 2006-09-15
project_end_date: 2009-08-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 2792727
contact_pi: LAMBERT, CHARLES PAUL
other_pis: Not Applicable
congressional_district: 03
department: OTHER HEALTH PROFESSIONS
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 EDUCATION
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): One of the major goals of PAS-03-122 Frailty in Old Age: Pathophysiology and Interventions is to enhance the development and evaluation of unique interventions that target processes that appear to play an important role in the mechanism(s) of the development and progression of frailty. Frailty has been defined as consisting of low muscle strength slow walking speed weight loss and low physical activity. Clearly sarcopenia or the age related loss of muscle mass and muscle strength contributes substantially to the muscle strength and walking speed decrements of frailty. Beta-two adrenergic agonists (B2A) significantly increase muscle mass in the elderly; however the mechanism(s) for this increase in muscle mass in humans is/are not known. We will examine: 1) the effects of 2.5 and 8.5 days of albuterol administration (16 mg/24h) on skeletal muscle protein synthesis (MPS) and the mRNAs for insulin like growth factor II and Ca2+ dependent proteolysis using Real Time PCR as well as the phosphorylation status of P70 S6 Kinase using the Western Blot technique in elderly (age 60-85) men and women who have body mass indices that correspond to the presence of sarcopenia. Animal data suggest that B2A stimulate MPS for 2-3 days with inhibition of protein degradation occurring at later time points. The 8.5 day measurement will be to determine whether MPS remains elevated later in humans. Elucidating the way in which B2A affect muscle protein metabolism may possibly lead to other therapeutic strategies to target specific components of protein synthetic and/or protein degradative pathways that are activated or deactivated by B2A. Additionally if we determine the primary site of action of B2A we will able to hypothesize whether B2A will likely work in different aging related muscle wasting conditions. Because of the exploratory nature of this study the R21 granting mechanism is appropriate. Muscle mass loss as a result of aging is a major problem. Some strategies for attenuating muscle mass loss such as testosterone replacement may have unwanted side effects. Albuterol an FDA approved drug has been shown to increase muscle mass in the elderly with minimal side effects. Because this is the case it is important to know the mechanism by which albuterol increases muscle mass in humans so that similar strategies may be developed. By finding the precise target(s) of albuterol action alternative strategies can be developed to attenuate the incidence of sarcopenia.

project_terms:
Adrenergic Agonists;Adverse effects;Affect;Age;Aging;Agonist;Albuterol;Animal Model;Animals;Asthma;Attenuated;Blotting Western;Body Weight decreased;Body mass index;Calpain;Condition;Degradation Pathway;Development;Elderly;Evaluation;Exhibits;Family;Fibrinogen;Functional disorder;Goals;Grant;Human;Incidence;Individual;Insulin-Like Growth Factor II;Intervention;Lead;Malignant neoplasm of prostate;Measurement;Measures;Modeling;Muscle;Muscle Proteins;Nature;Numbers;Outcome;Pharmaceutical Preparations;Phenylalanine;Phosphorylation;Physical activity;Placebos;Play;Polycythemia;Polymerase Chain Reaction;Population;Process;Protein Biosynthesis;Protein Degradation Inhibition;Proteins;Proteolysis;RNA Messenger;Rest;Ribosomal Protein S6 Kinases 70-kDa;Role;Safety;Site;Skeletal muscle structure;Skeletal system;Speed (motion);Techniques;Testosterone;Therapeutic;Threonine;Time;United States Food and Drug Administration;Walking;Woman;Work;age related;animal data;calpastatin;day;disability;frailty;indexing;m-calpain;member;men;muscle hypertrophy;muscle strength;prevent;protein degradation;protein metabolism;sarcopenia;synthetic protein;testosterone replacement therapy;wasting


application_id: 7783790
project_number: 5R34MH077507-03
project_title: Enhancing Message Design in Tailored Computerized HIV/STI Interventions
administering_ic: NIMH
award_notice_date: 2010-02-17
opportunity_number: PAR-06-248
application_type: 5
activity_code: R34
ic: MH
serial_number: 077507
program_official: CAMPBELL-ROSEN, HOLLY RENEE
project_start_date: 2008-03-14
project_end_date: 2012-02-28
study_section: ZMH1-ERB-H(03)
contact_pi_person_id: 10905586
contact_pi: CROSBY, RICHARD
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 study will involve the development and pilot testing of an interactive computerized tailored intervention program for HIV/STI prevention among at-risk heterosexually active African-American STI clinic patients aged 18-44. The Attitude-Social-Influence Efficacy model will serve as a conceptual foundation for the intervention and tailored feedback which will assess and give feedback to participants separately for main/steady and other/casual partners. Individual modules will be developed for key theoretical concepts and subsequently tied together into an integrated system. The tailored feedback will additionally be enhanced by crafting intervention messages to be high in message sensation value and by developing interactive intervention activities for skill-building which will be guided by both Social Cognitive Theory and skills training principles. The computerized intervention will be developed and guided using data collected from the target audience to ensure an empirically-based approach to tailoring. The intervention will also be developed with input from the target audience in order to maximize the appropriateness and persuasiveness of the feedback and the program including interactive components. The final year of the project will entail a pilot test of the intervention in order to gather preliminary data on the acceptability and efficacy of such an intervention for increasing safer sexual behaviors among at-risk heterosexually active African- Americans. The specific aims of the study are: 1) to develop tailored feedback on HIV/STI prevention based on the ASE model including condom attitudes social influences self-efficacy including communication / negotiation skills partner and behavioral risk correct condom use and condom stages of change; 2) to enhance the delivery of the tailored messages using sensation- seeking targeting (SENTAR) and skill-building using interactive activities guided by Social Cognitive Theory (SCT) and skills training principles; 3) to tie the individual theoretical modules together and develop a computerized intervention program for HIV/STI prevention which provides tailored risk reduction messages to participants based upon an assessment of participant characteristics; 4) to develop empirically sound cutpoints specific to the target audience to guide the message tailoring; and 5) in a wait-list control group design to pilot test the intervention for acceptability and efficacy in increasing condom use with main and casual partners among at-risk heterosexually active African-Americans relative to a "usual care" comparison condition. The current application is relevant to public health because it focuses on preventing HIV/AIDS in a high-risk group namely African-Americans. The application aims to develop and evaluate a computer-based program to help African-Americans who come to a sexually transmitted disease clinic adopt safer sex practices.

project_terms:
AIDS prevention;AIDS/HIV problem;Adopted;African American;Area;Attitude;Behavioral;Centers for Disease Control and Prevention (U.S.);Characteristics;Clinic;Cognitive;Communication;Computers;Control Groups;Counseling;Data;Development;Educational process of instructing;Effectiveness;Ensure;Esthesia;Feedback;Fostering;Foundations;HIV;Health;Health Promotion;Heterosexuals;Human immunodeficiency virus test;Individual;Infection prevention;Internet;Intervention;Mediation;Meta-Analysis;Modeling;Outcome;Participant;Patients;Persons;Population;Preventive Intervention;Printing;Relative (related person);Research;Resources;Risk;Risk Reduction;Robin bird;Self Efficacy;Sex Behavior;Sexual Partners;Sexually Transmitted Diseases;Staging;Standardization;Surveys;System;Technology;Testing;Waiting Lists;Woman;aged;base;behavior change;computerized;condoms;cost;design;effective intervention;group intervention;high risk;intervention program;prevent;programs;public health medicine (field);safer sex;skills;skills training;social;social cognitive theory;sound;theories;treatment as usual


application_id: 7782689
project_number: 5R01AI044254-10
project_title: Analysis of Borrelia burgdorferi Erp Proteins
administering_ic: NIAID
award_notice_date: 2010-02-25
application_type: 5
activity_code: R01
ic: AI
serial_number: 044254
program_official: BREEN, JOSEPH J
project_start_date: 2000-03-01
project_end_date: 2013-02-28
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-03-01
project_abstract:
Lyme disease is a significant threat to human health throughout many parts of the USA. The causativeagent Borrelia burgdorferi is maintained in nature by infectious cycles involving ticks and many species ofvertebrates with humans being incidental hosts. Understanding the mechanisms by which B. burgdorferiinfects humans and is transmitted from vector ticks will be important in development of improvedmethodologies to prevent and treat this disease. During transmission from tick to mammal 6. burgdorferisignificantly increases expression levels of the Erp family of outer surface proteins. Expression of Erpproteins decreases dramatically during colonization of vector ticks. All natural isolates of B. burgdorferiencode multiple Erp lipoproteins a ubiquity that is highly suggestive of important roles for these proteins inB. burgdorferi biology. Many Erp proteins have been demonstrated to bind the human complement regulatorfactor H in vitro raising the possibility that these proteins may function in vivo to protect the bacteria fromkilling by the host's innate immune system. Based on results of our previous studies we hypothesizethat Erp proteins perform functions that are absolutely critical to B. burgdorferi infectious processesand that these functions necessitate the bacteria regulate Erp expression. To test this hypothesiswewill (1) define the roles of Erp proteins in pathogenesis through analyses of specific B. burgdorferi erpmutants for their abilities to bind factor H resist complement-mediated killing and infect mice and ticks; (2)examine mechanisms by which B. burgdorferi controls Erp expression including innovative analyses oftranscription throughout mammalian and tick infection; and (3) characterize functions of the novelDMAbinding proteins we discovered that specifically bind to erp operator DMA. Results of our studies will provideimportant insight into the mechanisms by which B. burgdorferi infects humans.

project_terms:
Acute;Address;Animals;Area;Arthropods;Bacteria;Binding (Molecular Function);Binding Proteins;Biology;Borrelia burgdorferi;Chronic;Complement;Complement Factor H;Congenic Strain;Controlled Environment;DNA;DNA Sequence;DNA-Binding Proteins;Development;Disease;Family;Gene Expression;Genes;Genetic Transcription;Health;Human;Immune system;Immunocompetent;In Vitro;Infection;Ixodes (genus);Killings;Lipoprotein (a);Lyme Disease;Mammals;Maps;Mediating;Membrane Proteins;Methodology;Morbidity - disease rate;Multigene Family;Mus;Nature;Operon;Order Spirochaetales;Pathogenesis;Plasmids;Process;Production;Protein Binding;Proteins;Regulation;Reporting;Research Design;Resistance;Rest;Role;Series;Signal Transduction;Techniques;Testing;Ticks;Tissues;United States;Variant;Vertebrates;base;genetic manipulation;genetic regulatory protein;improved;in vivo;innovation;insight;member;mutant;prevent;tool;transmission process;vector


application_id: 7781820
project_number: 2R01AR049010-06A1
project_title: Microsomal Prostaglandin E Synthase in Rheumatoid Arthritis
administering_ic: NIAMS
award_notice_date: 2010-01-28
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: AR
serial_number: 049010
suffix: A1
program_official: MAO, SU-YAU
project_start_date: 2004-09-29
project_end_date: 2014-12-31
study_section: Arthritis, Connective Tissue and Skin Study Section[ACTS]
contact_pi_person_id: 1888793
contact_pi: CROFFORD, LESLIE J
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The effectiveness of non-specific and cyclooxygenase (COX)-2-specific non-steroidal anti-inflammatory drugs for treatment of the pain swelling and stiffness of arthritis provides clinical evidence that increased prostaglandin (PG) production is an important contributor to the disease process. PG biosynthesis requires the sequential action of COX-1 or COX-2 and terminal synthases to generate PGs that function as pleiotropic mediators by acting on a variety of cell surface receptors. After stimulation with pro-inflammatory cytokines there is a preferential increase of PGE2 in many different cell types and tissues including the synovium. We demonstrated that increased PGE2 in these tissues requires the inducible PGE synthase microsomal PGE synthase (mPGES)-1. We have also shown that absence of mPGES-1 results in a shift of the PG profile of cells and tissues with the specific profile dependent on the other synthases present. For this reason absence or inhibition of mPGES-1 is a markedly different biology than absence or inhibition of COX. The overall goal of this proposal is to characterize the role of mPGES-1 in immune inflammatory arthritis and how it differs from the role of COX-2. We hypothesize that upregulated mPGES-1 is required for the production of PGE2 and that its specific absence or inhibition results in an altered eicosanoid profile that fundamentally changes the immune inflammatory response. To evaluate this hypothesis we will make use of mice genetically deficient in mPGES-1 (Dba1/LacJ.mPGES-1 -/-) and inhibition of mPGES-1 using a specific inhibitor with activity in humans and mice (AF3485). We will determine the role for mPGES-1-derived PGE2 in comparison with other eicosanoids for initiation and progression of inflammation and immunity. We will determine the specific role of mPGES-1 deficiency for the developing immune response. Having shown profound differences in T- dependent humoral immune responses and in the Th phenotype we will determine the mechanism by which mPGES-1 deficiency leads to these changes. In order to translate these findings we will evaluate the differences between COX inhibition and mPGES-1 inhibition in human immune and inflammatory responses. We will determine effects of different compounds that inhibit PG production on T-helper phenotype and induced T-regulatory cells. These data will provide the scientific basis by which to determine if mPGES-1 is an appropriate target for therapeutic intervention in arthritis.  
  
PUBLIC HEALTH RELEVANCE: The discovery of COX-2 and subsequent development of specific COX-2 inhibitors represented an enormous conceptual advance in eicosanoid biology and opened new possibilities for pharmacologic treatment of inflammation and pain. It is clear however that COX-2-specific NSAIDs have their own toxicities. The finding of a PGE synthase isoform induced during inflammation and required for high level PGE2 production represents a conceptual advance of similar magnitude. In view of the existence of multiple PGES enzymes and other PG subclasses the specific role of mPGES-1-derived PGE2 in inflammation and autoimmunity remains uncertain. Furthermore information on the biology that will inform the development of mPGES-1 as a therapeutic target remains incomplete. It is our expectation that our work will yield new insights into the role of PGs in the functioning of eicosanoids during initiation and resolution of inflammation and the transition from the innate to the acquired immune response.

project_terms:
Acute;Alprostadil;Anabolism;Aneurysm;Anti-Inflammatory Agents;Anti-inflammatory;Antibodies;Antigen Presentation;Arachidonic Acids;Arthritis;Autoimmune Process;Autoimmunity;Back;Biology;Blood Platelets;Blood Vessels;Bone Marrow;CD4 Positive T Lymphocytes;Cardiovascular system;Cell Surface Receptors;Cell physiology;Cell surface;Cells;Chimera organism;Clinical;Clinical Data;Clinical Trials;Collagen;Collagen Arthritis;Collagen Type II;Coxibs;Cytokine Signaling;Data;Dendritic Cells;Development;Dinoprostone;Disease;Effectiveness;Effector Cell;Eicosanoids;Embryo;Enzymes;Epoprostenol;Equilibrium;Event;Exhibits;Failure (biologic function);Fever;Fibroblasts;Generations;Genetic;Goals;Hematopoietic;Homeostasis;Human;Immune;Immune response;Immunity;Inflammation;Inflammatory;Inflammatory Response;K/BxN model;Knockout Mice;Lead;Learning;Leukotriene B4;Lipids;Literature;Lymphocyte;Matrix Metalloproteinases;Mediator of activation protein;Mesenchymal;Modeling;Mus;Pain;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Phenotype;Phospholipase A2;Phospholipids;Play;Process;Production;Property;Prostaglandin D2;Prostaglandin H2;Prostaglandin Production;Prostaglandin-Endoperoxide Synthase;Prostaglandins;Protein Isoforms;Regulatory T-Lymphocyte;Resistance;Resolution;Rheumatoid Arthritis;Risk;Role;Serum;Shunt Device;Small Interfering RNA;Stimulus;Swelling;Synovial Membrane;T-Cell Receptor;T-Lymphocyte;Therapeutic;Therapeutic Intervention;Tissues;Toxic effect;Transgenic Mice;Translating;Up-Regulation (Physiology);Work;analog;base;cell type;cyclooxygenase 1;cyclooxygenase 2;cytokine;expectation;gastrointestinal;hematopoietic tissue;human NOS2A protein;immunoregulation;inhibitor/antagonist;insight;mouse PGE synthase 1;peripheral blood;pre-clinical;progesterone 11-hemisuccinate-(2-iodohistamine);prostaglandin E synthase;public health relevance;research study;response;therapeutic target


application_id: 7781323
project_number: 5R01AA017226-04
project_title: Alcohol and Breast Cancer
administering_ic: NIAAA
award_notice_date: 2010-02-18
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AA
serial_number: 017226
program_official: JUNG, KATHY
project_start_date: 2008-03-05
project_end_date: 2013-02-28
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
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): Alcoholism alcohol abuse and the medical complications of excessive drinking are major world-wide health problems. Alcohol is a tumor promoter. Epidemiological studies indicate that heavy alcohol consumption increases risk of breast cancer and is associated with advanced and invasive breast tumors. However the etiology of alcohol-induced tumor promotion is elusive. Cellular/molecular mechanisms underlying alcohol-promoted tumor development and progression remain unknown. ErbB2 a member of the epidermal growth factor receptor tyrosine kinase family is frequently over-expressed in human breast cancers. We have demonstrated that alcohol dramatically promotes migration/invasion of mammary epithelial cells and breast cancer cells over-expressing ErbB2. We also reveal that the human transmembrane mucin (MUC1) is highly sensitive to alcohol. ?-catenin is a proto-oncogene and plays an important role in tumorigenesis and cancer progression. The E-cadherin/?-catenin complex a critical component of cell-cell adherens maintains the integrity of epithelial cell interactions and regulates cell migration/invasion. We propose a novel role of MUC1 as an adaptor protein that bridges ErbB2 and ?-catenin and facilitate ErbB2/?-catenin interaction and the dissociation of E- cadherin/ ?-catenin complex. Our central hypothesis is that ethanol-induced oxidative stress up- regulates MUC1 as an adaptor protein to promote ErbB2/ ?-catenin interaction which induces dissociation of the ?-catenin/E-cadherin complex leading to cell transformation and cell migration/invasion. Both in vitro and in vivo models will be utilized to test this novel hypothesis. Specific Aim 1 will establish the pivotal role of MUC1 in ethanol-promoted ErbB2/ ?-catenin interaction. Specific Aim 2 will determine whether ethanol-promoted cell transformation and cancer cell migration/invasion is mediated by MUC1-dependent dissociation of the E-cadherin/2-catenin complex. Specific Aim 3 will investigate in vivo effects of ethanol. We will investigate the effect of ethanol on mammary tumorigenesis/metastasis in MMTV-Neu transgenic mice. We will further investigate the effect of ethanol on the interactions among MUC1 ErbB2 ?-catenin and E-cadherin as well as the role of ROS and MUC1 in ethanol- mediated tumorigenesis/metastasis in the transgenic and nude mice. As a cohesive unit the multi-disciplinary approaches using in vitro and in vivo models will systematically explore the mechanisms underlying alcohol-promoted tumorigenesis and malignant progression of breast cancer. The study will elucidate a novel function of ErbB2 and MUC1 in alcohol-induced tumor promotion. The expression/activity of ErbB2 and MUC1 is frequently aberrant in many other human cancers and in a variety of human diseases; their levels are also developmentally regulated. Understanding the interactions among alcohol ErbB2 and MUC1 will also provide an important insight into the pathogenesis of some human diseases related to alcohol abuse as well as alcohol's teratogenic effect during development.

project_terms:
Adaptor Signaling Protein;Alcohol abuse;Alcohol consumption;Alcoholism;Alcohols;Breast Cancer Cell;Cell Communication;Cells;Cellular Structures;Complex;Development;Dissociation;E-Cadherin;ERBB2 gene;Epidemiologic Studies;Epidermal Growth Factor Receptor;Epithelial Cells;Ethanol;Etiology;Family;Health;Heavy Drinking;Human;In Vitro;Malignant - descriptor;Malignant Neoplasms;Mammary Neoplasms;Mammary Tumorigenesis;Mammary gland;Mediating;Molecular;Mucin-1 Staining Method;Mucins;Names;Neoplasm Metastasis;Nude Mice;Oxidative Stress;Pathogenesis;Play;Principal Investigator;Protein Tyrosine Kinase;Proto-Oncogenes;Research;Risk;Role;Testing;Transgenic Mice;Transgenic Organisms;Tumor Promoters;Tumor Promotion;alcohol effect;cancer cell;cell motility;cell transformation;human disease;in vivo;in vivo Model;insight;malignant breast neoplasm;medical complication;member;migration;novel;programs;tumor;tumor progression;tumorigenesis


application_id: 7780367
project_number: 5F31EY017275-04
project_title: Minority Predoctoral Fellowship Program
administering_ic: NEI
award_notice_date: 2010-02-24
opportunity_number: PA-00-069
application_type: 5
activity_code: F31
ic: EY
serial_number: 017275
program_official: SHEN, GRACE L
project_start_date: 2007-03-01
project_end_date: 2010-11-30
study_section: Special Emphasis Panel[ZRG1-GGG-T(29)L]
contact_pi_person_id: 8320211
contact_pi: IMBERT-FERNANDEZ, YOANNIS
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): Dry eye disease is due to tear deficiency or excessive tear evaporation and results in inflammation and damage to the ocular surface. Mucins are highly O-glycosylated proteins that lubricate and protect the ocular surface. Recent findings indicate that the mucin MUC1 has anti-inflammatory properties and also can interact with estrogen receptor-alpha thereby modulating gene transcription. Androgens are key to maintaining homeostasis of the ocular surface. A potential interaction between MUC1 and androgen receptor (AR) could confer additional protection: My long term goal is to elucidate the molecular mechanisms involved in the pathogenesis of dry eye. My hypothesis is that MUC1 and androgen receptor (AR) are key factors that can act together to protect the ocular surface. The hypothesis will be tested by three specific aims: Aim 1- Determine the interaction between MUC1 and AR in human ocular surface epithelial cell lines; Aim 2- Elucidate the anti-inflammatory role of MUC1 and AR in those cells; and Aim 3- We have found that persons expressing the MUC1/A splice variant rather than MUC1/B are less susceptible to dry eye. We will determine if MUC1/A and MUC1/B splice variants differ in their signal transduction capabilities.

project_terms:
Androgen Receptor;Androgens;Anti-Inflammatory Agents;Anti-inflammatory;Breast Cancer Cell;Cell Communication;Cell Line;Cell Survival;Cell physiology;Cells;Chronic;Complex;Country;Defense Mechanisms;Disease;Dry Eye Syndromes;Epithelial;Epithelial Cells;Estrogen Receptor alpha;Estrogen Receptors;Etiology;Excessive tearing;Eye diseases;Fellowship Program;Female;Figs - dietary;Film;Gender;Genetic Transcription;Goals;Growth;Homeostasis;Human;Inflammation;Keratoconjunctivitis Sicca;Laboratories;Lacrimal gland structure;MCF7 cell;Maintenance;Mediating;Minority;Molecular;Mucin-1 Staining Method;Mucins;Pathogenesis;Persons;Play;Population;Postmenopause;Production;Property;Proteins;RNA Splicing;Role;Signal Transduction;Stress;System;Testing;Tissues;Variant;Woman;aqueous;biological adaptation to stress;evaporation;eye dryness;hormone regulation;novel;ocular surface;pre-doctoral;protective effect


application_id: 7780059
project_number: 5R01ES015518-03
project_title: Reactive oxygen species in Ni(II) carcinogenesis
administering_ic: NIEHS
award_notice_date: 2010-02-26
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: ES
serial_number: 015518
program_official: QUINN, ASHLINN KO
project_start_date: 2008-03-01
project_end_date: 2013-02-28
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Nickel-containing compounds are human carcinogens. The mechanisms of their carcinogenic actions remain to be investigated. Recent studies have indicated that reactive oxygen species (ROS) may play an important role. We hypothesize that nickel induces generation of ROS which activate nuclear transcription factors leading to cell transformation and tumorigenesis. Specific Aim 1 will detect and identify ROS generated in human bronchial epithelial cells (BEAS-2B) and mouse embryo fibroblast cells exposed to nickel compounds and investigate the mechanism involved. We hypothesize that nickel (Ni3S2 and NiCl2) can stimulate the cells to activate NADPH oxidase via cdc42 and p47phox to produce superoxide radical which is then converted to hydrogen peroxide and hydroxyl radical. Specific Aim 2 will test the hypothesis that ROS are required for activation of NFAT and NFkappaB in cells and in vivo in response to nickel compounds. The role of ROS in nickel-induced activation of NFAT and NFkappaB in cells will be evaluated by co-transfection of NFkappaB-luciferase or NFAT-luciferase reporter plasmids and specific ROS scavenger enzymes. For in vivo study BALB/c transgenic mice with alternation of antioxidant enzymes or NADPH oxidase (ROS generating enzyme) will be employed. Specific Aim 3 will investigate the role of ROS NFAT and NFkappaB in nickel-induced cell transformation and tumorigenesis. We hypothesize that ROS activate transcription factors and cause cell transformation and tumorigenesis. We will use overexpression of DN-NFAT DN-IkappaBalpha and DN- IKKbeta to investigate the involvement of NFAT and NFkappaB in nickel-cell transformation and induced tumorigenesis. The role of ROS will be investigated using specific antioxidant enzyme expressions and NADPH oxidase alternation. We anticipate that nickel causes activation of NFAT and NFkappaB through ROS reactions leading to cell transformation and tumorigenesis. We attempt to link the cell transformation and tumorigenesis with specific transcription factors and specific reactive oxygen species. The results obtained from this proposal will elucidate the role of ROS and NFAT/NFkappaB signaling in Ni compounds-induced carcinogenesis. The long term goals are to provide a fundamental understanding concerning the mechanism of carcinogenic actions of Ni; to fill a need for the mechanistic information of cancer risk assessment for exposure; to propose methods for early detection; and to develop intervention and prevention strategies. Nickel-containing compounds are human carcinogens. This project will investigate the mechanism of Ni-induced carcinogenesis by testing the hypothesis that nickel induces generation of ROS which activate nuclear transcription factors leading to cell transformation and tumorigenesis. The long term goals are to understand the mechanism of Ni-carcinogenesis; to propose methods for early detection; and to develop intervention and prevention strategies.

project_terms:
Animal Experiments;Animals;Antioxidants;Biological Assay;Breathing;Carcinogenicity Tests;Carcinogens;Cells;Chemicals;Complement Factor B;Confocal Microscopy;Development;Dominant-Negative Mutation;Down-Regulation;Early Diagnosis;Electron Spin Resonance Spectroscopy;Embryo;Enzymes;Epidemiology;Epithelial Cells;Exposure to;Fibroblasts;Gene Expression Regulation;Generations;Goals;Human;Hydrogen Peroxide;Hydroxyl Radical;I Kappa B-Alpha;In Vitro;Inbred BALB C Mice;Intervention;Investigation;Link;Luciferases;Malignant Neoplasms;Manganese Superoxide Dismutase;Measures;Mediating;Mediator of activation protein;Methods;Mitochondria;Molecular;Mus;NADPH Oxidase;Nature;Nickel;Nuclear;Nude Mice;Plasmids;Play;Prevention strategy;Protein Overexpression;Reaction;Reactive Oxygen Species;Reporter;Research;Risk Assessment;Role;Signal Transduction;Signaling Protein;Source;Spin Trapping;Structure of parenchyma of lung;Superoxides;Techniques;Testing;Transfection;Transgenic Mice;Tumor Promotion;activating transcription factor;cancer risk;carcinogenesis;catalase;cell transformation;in vivo;nuclear factors of activated T-cells;overexpression;response;transcription factor;tumorigenesis


application_id: 7780025
project_number: 5R01HL082835-03
project_title: The role of Prostaglandin E2 in Angiotensin II-induced vascular disease
administering_ic: NHLBI
award_notice_date: 2010-02-01
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 082835
program_official: TOLUNAY, ESER
project_start_date: 2008-02-01
project_end_date: 2013-01-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8341067
contact_pi: KING, VICTORIA L
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): Prostanoids including prostaglandin E2 (PGE2) have been implicated in the pathophysiology of a number of cardiovascular diseases. Preliminary data demonstrates that selective pharmacological inhibition of cyclooxygenase-2 (COX-2) markedly attenuates the incidence of abdominal aortic aneurysms (AAA) in mice infused with angiotensin II (AngII) suggesting that prostanoids play a critical role in the development of AAAs. Hallmarks of AAA formation are inflammation and increased expression and activation of matrix metalloproteinases (MMPs) in the vascular wall. During inflammation both COX-2 and microsomal prostaglandin E synthase-1 (m-PGES-1) are rapidly upregulated resulting in increased concentrations of PGE2. PGE2 regulates MMP expression and activation therefore reductions in COX-2 generated PGE2 may result in decreases in MMP expression and activation. Previous studies have associated reductions in PGE2 with decreases in MMPs and aneurysmal expansion. Preliminary data demonstrates that m-PGES1 deficiency attenuates AngII-induced AAA formation. PGE2 concentrations were markedly decreased in the mPGES-1 deficient mice however there was a concomitant increase in prostacyclin (PGI2) concentrations. Blockade of the PGI2 receptor protects against that development of other vascular disease. Therefore the direct role of PGE2 in mediating the development of AAAs has not been elucidated. PGE2 mediates its actions by binding to EP receptors. The EP4 receptor is expressed in aneurysmal tissues and is required for the activation MMPs. The long-term objective of this proposal is to elucidate the role of the PGE2 in AngII-induced AAA formation. We propose to test the hypothesis that mPGES-1 generated PGE2 mediates the initial stage of AngII-induced AAA formation via the EP4 receptor. To test this hypothesis we propose to: 1) define the role of mPGES-1 generated PGE2 in AngII-induced AAAs; 2) define the role of the PGE2-EP4 receptor axis in MMP expression and activation in cells implicated in the development of AAAs and; 3) determine if the EP4 receptor is critical for the development of AngII-induced AAAs. To date there are not therapeutic treatments for AAAs. With the suggestion that an increased risk for cardiovascular events is a class specific effect of COX-2 inhibitors data from these studies will be important in defining which prostanoids generated by COX-2 mediate the initial events in AAA formation and provide us with critical information for targeting specific prostanoid synthases and receptors as therapeutic treatment for this disease.

project_terms:
Abdominal Aortic Aneurysm;Alleles;Angiotensin II;Apolipoprotein E;Atherosclerosis;Attenuated;Binding (Molecular Function);Blood Vessels;Cardiovascular Diseases;Cell Transplants;Cells;Coxibs;Cyclic GMP-Dependent Protein Kinases;Data;Development;Dinoprostone;Disease;EP4 receptor;Epoprostenol;Epoprostenol Receptors;Event;Exhibits;Fetal Liver;Follow-Up Studies;Functional disorder;Gene Expression;Gene Targeting;Genes;Genetic Recombination;Guanylate Cyclase;Hepatocyte;Incidence;Inflammation;Intestines;Knock-in Mouse;Laboratories;Matrix Metalloproteinases;Mediating;Messenger RNA;Modeling;Mortality Vital Statistics;Mus;Myeloid Cells;Neonatal Mortality;Phenotype;Play;Prostaglandins;Prostaglandins I;Regulation;Reporter;Reporting;Role;Smooth Muscle Myocytes;Smooth muscle (tissue);Staging;Staining method;Stains;Suggestion;System;Tamoxifen;Testing;Therapeutic;Tissues;Vascular Diseases;Venous;atherogenesis;cardiovascular risk factor;cyclooxygenase 2;mouse PGE synthase 1;prostaglandin E synthase-1;receptor;receptor expression


application_id: 7780017
project_number: 5R01HL084611-05
project_title: Role of the Nuclear Receptor Nor-1 in Atherosclerosis and Vascular Injury
administering_ic: NHLBI
award_notice_date: 2010-04-06
application_type: 5
activity_code: R01
ic: HL
serial_number: 084611
program_official: HASAN, AHMED A K
project_start_date: 2006-04-01
project_end_date: 2011-03-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8010784
contact_pi: BRUEMMER, DENNIS CHRISTOPHER
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-04-01
project_abstract:
DESCRIPTION (provided by applicant): The evolving understanding of mechanisms contributing to the development of atherosclerosis and neointima formation following vascular injury has identified members of the nuclear hormone receptor superfamily as key transcriptional regulators of gene expression programs controlling inflammation and proliferation. Although much attention has focused on the role of the peroxisome proliferator-activated receptor (PPAR) and liver X receptor (LXR) subfamilies the nuclear receptor superfamily comprises a large number of so-called orphan nuclear receptors whose target genes and physiological functions are unknown and remain to be discovered.   
  
The neuron-derived orphan receptor-1 (Nor-1) is a constitutively-active transcription factor belonging to the nuclear hormone receptor superfamily. Our Preliminary Data identified Nor-1 expression in human atherosclerotic lesions and in the developing neointima following vascular injury. In response to growth factor stimulation vascular smooth muscle cells (SMC) rapidly express Nor-1 characterizing this nuclear receptor as an early response gene. Experiments using SMC isolated from Nor-1 deficient mice further reveal that Nor-1 expression is required for SMC proliferation cell cycle progression and telomerase activity.   
  
Based on these findings the central hypothesis of this proposal is that Nor-1 functions as a transcriptional regulator of SMC proliferation and thereby contributes to the development of atherosclerosis and neointima formation following vascular injury.   
  
To test this hypothesis we propose the following aims: Specific Aim 1: To determine the transcriptional regulation of Nor-1 expression in SMC. Specific Aim 2: To determine the molecular mechanisms by which Nor-1 regulates SMC proliferation. Specific Aim 3: To determine the contribution of Nor-1 to the development of atherosclerosis by cross- breeding Nor-1 deficient mice to atherosclerosis-susceptible apoE-deficient mice. Specific Aim 4: To determine the contribution of Nor-1 to neointima formation using a model of guide-wire induced femoral artery injury in Nor-1 deficient mice.   
  
Ultimately these experiments may characterize a novel transcriptional pathway regulating SMC proliferation in vascular disease and identify suppression of the nuclear receptor Nor-1 as a previously unrecognized target for the treatment of cardiovascular diseases.

project_terms:
Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Attention;Blood Vessels;Breeding;Cardiovascular Diseases;Cell Cycle Progression;Cell Proliferation;Data;Development;ERG gene;Failure (biologic function);Figs - dietary;Functional disorder;Gene Expression;Gene Targeting;Growth Factor;Human;Inflammation;Injury;Ligands;Liver;Modeling;Molecular;Mus;Muscle Cells;Neurons;Nuclear;Nuclear Hormone Receptors;Nuclear Orphan Receptor;Nuclear Receptors;Orphan;Pathogenesis;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Physiological;Play;Process;Regulator Genes;Role;Smooth Muscle Myocytes;Telomerase;Testing;Transcriptional Regulation;Treatment Failure;Vascular Diseases;base;femoral artery;member;neointima formation;novel;prevent;programs;receptor;research study;response;restenosis;transcription factor


application_id: 7779660
project_number: 1R01CA138410-01A1
project_title: Regulation of miRNA in breast cancer
administering_ic: NCI
award_notice_date: 2010-01-01
opportunity_number: PA-07-021
application_type: 1
activity_code: R01
ic: CA
serial_number: 138410
suffix: A1
program_official: FORRY, SUZANNE L
project_start_date: 2010-01-01
project_end_date: 2013-12-31
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The selective estrogen receptor modulator (SERM) tamoxifen (TAM) is the most widely used endocrine therapy for the treatment and prevention of estrogen receptor alpha (ER1) positive breast cancer. However ~ 40% of initially TAM-sensitive tumors become endocrine/TAM-resistant. The mechanism behind such acquired TAM resistance is unknown and biomarkers of TAM-response may be useful to monitor clinical response. MicroRNAs (miRNAs) are a class of naturally-occurring small non-coding RNA molecules that are involved in regulating the translation and processing of mRNAs usually by binding to the 3' untranslated region of target mRNAs and targeting the mRNA transcript to be degraded or by blocking translation. The human genome contains > 700 miRNAs. Aberrant patterns of miRNA expression have been recently implicated in human disease with miRNAs differentially expressed in concordance with other well-established markers of breast cancer stage and patient prognosis including ER1 and progesterone receptor tumor stage number of positive lymph nodes and vascular invasion. Using the NIH-R21 mechanism we obtained preliminary data identifying miRNAs regulated by estradiol (E2) in an ER1-dependent manner in MCF-7 human breast cancer cells and identified downstream target genes that were upregulated via E2 downregulation of miR-21. However to date no one has examined TAM affects the pattern of miRNA expression in human breast cancer and only 2 reports have identified miRNA expression patterns in TAM-resistant derivatives of MCF-7 breast cancer cells. Specific Aim 1 is to identify miRNAs that are differentially regulated by E2 and 4-hydroxyTAM (4-OHT) in antiestrogen- sensitive MCF-7 and T47D breast cancer cells. Specific Aim 2 is to identify miRNAs and their target genes in antiestrogen/ TAM- sensitive versus -resistant breast cancer cell lines and tumor xenografts. This Aim tests the hypothesis that miRNA expression is dysregulated in endocrine/TAM- resistant versus -sensitive breast cancer cells. Specific Aim 3 is to determine if the E2- regulated and 4-OHT- regulated miRNAs identified in breast cancer cell lines show aberrant expression in human breast tumors and correlate with clinical diagnostic measures and patient response to tamoxifen therapy. The overall goal of the proposed research is to determine the identity and gene targets of miRNAs that may provide novel biomarkers and new insights into the mechanisms by which breast tumors gain endocrine/TAM-resistance and become invasive and metastatic.  
  
PUBLIC HEALTH RELEVANCE: Aromatase inhibitor therapy is not useful for all ER1 positive breast cancer patients and the selective estrogen receptor modulator tamoxifen (TAM) remains the most widely used endocrine therapy for the treatment and prevention of estrogen receptor alpha (ER1) positive breast cancer. However ~ 40% of initially TAM-sensitive tumors become endocrine/TAM-resistant. The mechanism behind such acquired TAM/endocrine resistance is unknown. The overall goal of the proposed research is to determine the identity and gene targets of miRNAs that may provide novel biomarkers and new insights into the mechanisms by which breast tumors gain endocrine/TAM-resistance and become invasive and metastatic.

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


application_id: 7778030
project_number: 7R21AG032550-02
project_title: Effect of Antioxidants & Behavioral Enrichment on Gene Expression in Aged Canines
project_terms: Antioxidants;Behavioral;Canis familiaris;Gene Expression;aged
administering_ic: NIA
award_notice_date: 2009-04-14
opportunity_number: PA-06-181
application_type: 7
activity_code: R21
ic: AG
serial_number: 032550
program_official: WAGSTER, MOLLY V
project_start_date: 2008-09-01
project_end_date: 2010-08-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 8662513
contact_pi: HEAD, ELIZABETH
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): During aging there are a number of brain changes that may contribute to neuronal dysfunction and impaired cognition. Higher animal models are essential for understanding the molecular and cellular basis of brain aging. We have been using the aged canine (dog) model to identify key interventions and molecular mechanisms of brain aging. Age-dependent decline in memory and learning along with the progressive accumulation of oxidative damage neuron loss and 2-amyloid (A2) deposition occur in the aging dog brain similar to that in the human. Canine A2 is identical to human A2 accumulates endogenously at levels similar to human and A2 plaque loads are correlated with cognitive function. Thus this model system is useful for exploring links between aging oxidative damage A2 and cognition. We have used a dietary and an environmental enrichment intervention to determine if these can improve cognitive function singly and in combination. We have demonstrated that an antioxidant and mitochondrial co-factor dietary intervention improves learning and maintains cognitive function over a 2.8 year period of time in aged dogs. Along with improved learning we observe decreased A2 in antioxidant treated dogs and decreased oxidative damage using proteomics approaches. We have further shown that behavioral enrichment can also improve cognition but this occurs via a non- A2/plaque mechanism as A2 seems unaffected. Importantly beneficial cognitive effects of the antioxidant diet or behavioral enrichment treatments alone were further enhanced when combined. At present the molecular targets of each treatment and convergence points between the two treatments that lead to additive neuronal function improvements have yet to be established. The primary objective of this application is to take advantage of newly available technologies (Affymetrix Canine Genome Arrays) and utilize brain tissues from these same animals to further establish and map the neurobiological mechanisms underlying the cognitive improving effects of each treatment and the combined treatment. To accomplish these objectives the following aims are proposed: (1) To profile gene expression changes in the temporoparietal cortex as a function of age in dogs and; (2) To profile gene expression changes in aged dogs provided with either or both an antioxidant-enriched diet and behavioral enrichment. Further understanding of the pathways engaged by these two interventions may lead to new research hypotheses treatments and outcome measures that may be directly translated to human clinical trials. PUBLIC HEALTH RELEVANCE: Profiling gene expression changes as a consequence of antioxidant diet and behavioral enrichment interventions in aged canines will allow us to identify and optimize new therapeutics for improving cognition in both normal aging individuals and those with Alzheimer's disease.


application_id: 7777861
project_number: 5R01AG031764-02
project_title: Beta-Amyloid Immunization in a Canine Model of Aging
administering_ic: NIA
award_notice_date: 2010-03-02
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AG
serial_number: 031764
program_official: RYAN, LAURIE M
project_start_date: 2009-03-01
project_end_date: 2014-02-28
study_section: Clinical Neuroimmunology and Brain Tumors Study Section[CNBT]
contact_pi_person_id: 8662513
contact_pi: HEAD, ELIZABETH
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is associated with progressive cognitive decline and the accumulation of senile plaques and neurofibrillary tangles. Senile plaques contain the beta-amyloid peptide (A) which is thought to play a causative role in the disease. Thus a number of therapeutics are being developed that may reduce the production deposition or enhance clearance of A in the brains of patients with AD. In transgenic mouse models of AD deposition of A may be prevented or reduced after immunization with fibrillar A1-42. Further learning and memory is improved by either active or passive immunization with anti-A antibodies. On the basis of work in transgenic mice a clinical trial (AN1792) was initiated in AD patients who were administered fibrillar A42. Cognitive benefits were reported in this study and autopsy studies show a reduction in brain A. We extended immunotherapy studies into the canine model of human brain aging that naturally develop human-type A and cognitive decline. Aged animals were actively immunized for over 2 years (25 injections in total). Our results in immunized aged beagles showed decreased brain A and improved executive function. We hypothesize that we can improve cognition to a greater extent and extend cognitive improvements to include multiple domains by combined treatment with an intervention that may restore neuron health after A removal. Thus we propose to combine immunotherapy with behavioral enrichment in aged dogs and target two molecular pathways that may converge to provide additive benefits. We predict aged dogs will show significant cognitive improvements maintenance of cognition and reduced neuropathology when we combine immunotherapy with behavioral enrichment. Further the combination treatment will provide larger benefits to cognition and neuropathology than either treatment alone. The canine provides a unique model system in which to develop combinatorial treatment approaches involving immunotherapy for reducing AD pathology and improving cognition that may be more directly translated into human clinical trials. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is associated with progressive cognitive decline and the accumulation of brain pathology. We will use a combination treatment approach to improve cognition and reduce neuropathology in the canine model of aging through immunotherapy and behavioral enrichment which is an approach that may be directly translated into human clinical trials.

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

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


application_id: 7777840
project_number: 5R01AI067869-04
project_title: YopM and protective innate defenses against plague
administering_ic: NIAID
award_notice_date: 2010-01-26
opportunity_number: PA-04-119
application_type: 5
activity_code: R01
ic: AI
serial_number: 067869
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2007-03-16
project_end_date: 2012-02-29
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 1864206
contact_pi: STRALEY, SUSAN C
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Yersinia pestis the causative agent of plague delivers a set of 6 Yop toxins that act within host cells to negate and modulate signaling pathways that orchestrate host innate defenses that are crucial for developing an effective immune response. This proposal focuses on the mechanism of YopM. We have found that YopM specifically causes a global loss of natural killer cells and those NK cells remaining do not contain detectable mRNA for IFNg. Concomitantly YopM causes down-regulation in macrophages of net mRNA expression for key proinflammatory cytokines. In this project we will test the hypothesis that YopM acts directly on cells such as macrophages and dendritic cells to prevent expression of cytokines such as IL- 15 and IL-12 that synergize to activate effector cells such as macrophages polymorphonuclear neutrophils natural killer cells and cytolytic T cells for controlling numbers of Y. pestis. In Aim 1 we will determine whether YopM's action is mediated by hypothesized key cells by comparing the infection dynamics for virulent and YopM- Y. pestis (viable numbers dissemination as a function of time) and host response (cell populations and cytokines) in primary pneumonic plague and bubonic plague in mice ablated for the cells genetically or by manipulation. In Aim 2 we will test our hypothesis that the Th1 cytokine and chemokine pathway mediates different host responses to YopM+ and YopM- Y. pestis between d 1 and d 3 to 4 p.i. in bubonic and pneumonic plague by infecting knockout mice or mice ablated for hypothesized key cytokines and analyzing the resulting infection dynamics and host response. In Aim 3 we will map the signaling circuitry of YopM's pathogenic effects by comparing transcriptional profiles (cDNA microarrays) and analyses of intracellular cytokines in purified macrophages from mice with pneumonic or bubonic plague due to virulent and YopM- Y. pestis. The data will reveal the pathogenic mechanism of YopM by identifying cells cytokines and signaling pathways modulated by YopM during plague. The findings will provide a completely new understanding of the biology of plague from both microbial and host perspectives as well as provide a framework for rational enhancement of resistance to plague in people threatened with exposure to plague. The data will reveal immune deviation points during plague and could identify potential therapeutic intervention targets. The findings also will provide a better understanding of mammalian innate defenses and insight into evasive mechanisms of pathogens and will facilitate the defeat of important human pathogens that are not select agents.

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


application_id: 7777755
project_number: 5R01CA129975-02
project_title: Adenovirus E1B55K Functions Related to Oncolytic Replication
administering_ic: NCI
award_notice_date: 2009-12-18
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 129975
program_official: WELCH, ANTHONY R
project_start_date: 2009-03-01
project_end_date: 2012-12-31
study_section: Developmental Therapeutics Study Section[DT]
contact_pi_person_id: 7746559
contact_pi: ZHOU, HESHAN SAM
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Two major "hallmarks" of all cancer cells include dysregulated cell cycle and inhibited apoptosis both of which are also involved in adenovirus (Ad) infection. These two processes are primarily conducted by viral oncoproteins E1A and E1B. Since the function of viral E1 protein is similar to that of cancer cellular factors that promote proliferation and inhibit apoptosis viruses with mutations in oncoprotein E1A and E1B can selectively replicate in cancer cells. One such mutant with deletion of E1B55K known as dl1520 has been used in clinical trials documenting oncolytic effects. However the mechanism of viral oncolytic replication has not been well characterized and the therapeutic efficacy needs improvement. It is generally believed that the major role of E1B55K is to bind to and inhibit p53 activation but many studies have documented that E1B55K-mediated p53 inactivation is not required for virus replication. Our laboratory has shown: (1) that the limited spread of mutant viruses in large tumors is a key factor in decreased therapeutic efficacy; (2) increased Ad E1A expression enhances virus-oncolytic replication; and (3) apoptosis caused by E1B deletion can partially decrease virus replication but does not change the final outcome of virus-mediated cancer killing. Our recent studies have revealed that E1B55K has a novel function in the induction of cyclin E and other cell cycle-related genes. Most importantly we also observed that increased cyclin E expression is correlated with virus replication efficiency. E1B55K-induced cyclin E expression is required for virus replication in normal cells but is not necessary in cancer cells. We hypothesize that E1B55K may target cellular factor(s) to increase cyclin E expression and this factor(s) may already be activated in cancer cells. Thus cyclin E dysregulation in cancer cells may be the molecular basis for oncolytic replication of E1B55K-deleted viruses. Our research team will (1) identify cellular factors targeted by E1B55K for cyclin E induction (2) define the mechanism by which E1B55K activates cyclin E expression and (3) determine the relationship between cyclin E overexpression and oncolytic replication of E1B-deleted viriuses. If we confirm that oncolytic replication relies on cyclin E expression and cell proliferation patients with aggressively growing tumors and dysregulated cyclin E should greatly benefit from this adenoviral therapy. The long-term goal of this work is to increase the efficacy of oncolytic cancer gene therapy. PUBLIC HEALTH RELEVANCE: Adenoviruses lacking an important regulative protein-E1B55K-still can amplify in some cancer cells. Therefore the E1B55K mutant dl1520 has been used in clinical trials. It is important to understand the E1B55K function and the selective replication of E1B55K-deleted dl1520 in cancer cells. Our recently published studies have revealed that E1B55K has a novel function in the induction of cyclin E expression which is crucial for DNA replication. Cancer cells generally express high levels of cyclin E or have a dysregulation of the gene. We reason that viral E1B55K may activate some cellular factors that increase cyclin E expression for viral DNA replication. Cancer cells may already have the factors activated; therefore cancer cells do not require the E1B55K function. The study of this possibility is very important. If we confirm that mutated virus replication relies on cyclin E expression patients with aggressively growing tumors and dysregulated cyclin E should greatly benefit from this adenoviral therapy. The long-term goal of this work is to increase the efficacy of oncolytic cancer gene therapy.

project_terms:
Adenovirus Infections;Adenovirus Protein;Adenoviruses;Affect;Apoptosis;Binding (Molecular Function);Cell Cycle;Cell Proliferation;Clinical Trials;Cyclin E;DNA biosynthesis;E2F Transcription Factor 1;E2F transcription factors;Genes;Goals;Human papillomavirus 16 E1 protein;In Vitro;Killings;Laboratories;Malignant Neoplasms;Mediating;Molecular;Mus;Mutate;Mutation;Normal Cell;Oncogene Proteins;Oncogenes;Oncolytic;Oncolytic viruses;Outcome;Pathway interactions;Patients;Process;Promotor (Genetics);Proteins;Publishing;Regulation;Research;Retinoblastoma Protein;Role;Site;TP53 gene;Testing;Treatment Efficacy;Viral;Viral Physiology;Virus;Virus Replication;Work;Xenograft Model;base;cancer cell;cellular targeting;clinical application;gene therapy;genetic analysis;in vivo;mutant;novel;oncolysis;overexpression;public health relevance;response;tumor;viral DNA

public_health_relevance:
Project NarrativeAdenoviruses lacking an important regulative protein-E1B55K-still can amplify in some cancer cells.Therefore the E1B55K mutant dl1520 has been used in clinical trials. It is important to understand the E1B55Kfunction and the selective replication of E1B55K-deleted dl1520 in cancer cells. Our recently published studieshave revealed that E1B55K has a novel function in the induction of cyclin E expression which is crucial forDNA replication. Cancer cells generally express high levels of cyclin E or have a dysregulation of the gene. Wereason that viral E1B55K may activate some cellular factors that increase cyclin E expression for viral DNAreplication. Cancer cells may already have the factors activated therefore cancer cells do not require theE1B55K function. The study of this possibility is very important. If we confirm that mutated virus replicationrelies on cyclin E expression patients with aggressively growing tumors and dysregulated cyclin E shouldgreatly benefit from this adenoviral therapy. The long-term goal of this work is to increase the efficacy ofoncolytic cancer gene therapy.


application_id: 7777164
project_number: 7R03AI073157-03
project_title: Expression of Decontructed HIV-1 Virus-Like Particles in Bioengineered Plants
administering_ic: NIAID
award_notice_date: 2009-07-13
opportunity_number: PA-06-180
application_type: 7
activity_code: R03
ic: AI
serial_number: 073157
program_official: LI, YEN
project_start_date: 2007-03-15
project_end_date: 2010-02-28
study_section: HIV/AIDS Vaccines Study Section[VACC]
contact_pi_person_id: 8640855
contact_pi: MATOBA, NOBUYUKI
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Extensive AIDS prevention programs and highly active anti-retroviral therapies have been successful in limiting the spread and the onset of the disease in high-income countries. However it is generally agreed that global containment of the HIV/AIDS pandemics depends on our ability to develop prophylactic vaccines minimizing the viral transmission and infection. The long-term goal of this project is to develop an affordable efficacious mucosal vaccine preventing HIV-1 transmission and early stages of infection. To this end our efforts are focused on a novel HIV-1 virus-like particles (VLPs) consisting of the deconstructed HIV-1 Env protein (D-Env) and the Gag protein (D-Env/Gag VLPs). Towards the aim of economical production and mucosal delivery we propose the expression of D-Env/Gag VLPs in plants. D-Env is composed of the external membrane proximal region residue 649-683 (MPR649-683) the transmembrane domain and the cytoplasmic tail of gp41. The specific hypothesis is that mucosally targeted D-Env/Gag VLPs can induce protective humoral and cellular immune responses at the mucosa thereby synergistically blocking HIV-1 transmission and early stages of infection. We base that hypothesis on the findings by us and others that (i) antibodies targeting MPR649-683 were shown to block HIV-1 epithelial transcytosis and potentially neutralize the infection of CD4+ cells and (ii) Gag VLPs were shown to induce Gag-specific cytotoxic T cells in non-human primates.  
  
As an initial step to achieve the long-term goal the specific aim of this proposal is to produce and in vitro characterize D-Env/Gag VLPs which are designed based on the most pandemic HIV-1 subtype C by the coexpression of D-Env and Gag in tobacco cells. In order to obtain high yield the gag gene will be optimized for plant expression and the designed gene will be de novo synthesized. We will employ two expression systems a modified tobacco mosaic virus (TMV)-based transient expression system and a stably transformed tobacco cell (NT1) suspension culture. These systems enable rapid investigations of the VLP assembly in plant cells.  Upon successfully expressing Gag VLPs efforts will be centered on creating the complete D-Env/Gag VLPs. This will be done by co-delivery of the plant optimized d-env gene with the gag gene in the TMV system and super-transformation of the Gag-expressing NT1 cells with D-Env expression vector. To characterize the plant-expressed D-Env/Gag VLPs biochemical analyses by immunoprecipitation and pull-down assay conformational analyses by light scattering and electron microscopy and stability analysis using simulated gastric and intestinal fluids will be performed. The successful outcome of this project will not only provide a novel HIV-1 vaccine candidate that will be evaluated in the follow-up project using animal models but also develop a new technology for its economical production.

project_terms:
AIDS prevention;AIDS/HIV problem;Acquired Immunodeficiency Syndrome;Acute;Africa;Anti-Retroviral Agents;Antibodies;Antigens;Appearance;Biomedical Engineering;CD4 Positive T Lymphocytes;Cells;Chronic;Clinical;Containment;Country;Cytoplasmic Tail;Discrimination (Psychology);Enterocytes;Epidemiologic Studies;Epithelial;Epithelium;Event;Exposure to;Gagging;Gene Products env;Gene Products gag;Genes;Genes env;Genital system;Goals;HIV;HIV Infections;HIV-1;Hand;Heterosexuals;Immune response;Immune system;Immunity Natural;Immunization;Immunization Passive;Income;Infection;Inflammation;Injecting drug user;Intestines;Investigation;Lead;Low income;M cell;Macaca;Membrane;Modeling;Monkeys;Monoclonal Antibodies;Mucous Membrane;Numbers;Onset of illness;Oral;Other Finding;Patients;Peptides;Pharmaceutical Preparations;Phase;Plants;Prevention program;Production;Rate;Rectum;Reporting;Route;Selections Natural;Staging;Strikes Employee;Suspension Culture;System;T-Lymphocytes Cytotoxic;Tobacco;Tobacco Mosaic Virus;Transmembrane Domain;Vaccination;Vaccines;Vaginal delivery procedure;Viral;Viremia;Virus;Virus Replication;Virus-like particle;Woman;Work;base;cost;design;expression vector;intraepithelial;macrophage;men who have sex with men;mucosal vaccine;nonhuman primate;novel;novel vaccines;pandemic disease;prevent;prophylactic;response;simian human immunodeficiency virus;success;transcytosis;transmission process;uptake


application_id: 7776951
project_number: 5R01DE018292-04
project_title: Oral Pathogen Exploitation of Innate Recognition as a Function of Age
administering_ic: NIDCR
award_notice_date: 2010-02-05
opportunity_number: RFA-DE-07-004
application_type: 5
activity_code: R01
ic: DE
serial_number: 018292
program_official: BURGOON, PENNY W
project_start_date: 2007-03-06
project_end_date: 2012-02-28
study_section: ZDE1-YL(20)
contact_pi_person_id: 6712964
contact_pi: HAJISHENGALLIS, GEORGIOS
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Innate immunity is present from birth and represents the inherited resistance to infection. Microbial infection is detected by pattern-recognition receptors (PRRs) through recognition of microbe-associated molecular patterns (MAMPs). Since MAMPs are conserved in a wide range of pathogenic or commensal organisms it is not clear how PRR-MAMP interactions per se lead to differential host responses to pathogens and commensals. This application proposes that pathogens exploit selective pattern recognition pathways in ways that perturb the otherwise homeostatic PRR-MAMP interactions leading to chronic persistence of the pathogen and nonproductive inflammation. This outcome is detrimental especially to the elderly host due to age-related alterations in pattern-recognition mechanisms. In this regard it is proposed that pathway-specific alterations in innate recognition render the aging innate immune system more amenable to exploitation by pathogens than its younger counterpart. Taking advantage of the accessibility and relevance of the oral cavity in host-microbial interactions these concepts will be investigated in the context of periodontitis and the model pathogen Porphyromonas gingivalis. P. gingivalis interacts via its surface fimbriae with the CD14/Toll-like receptor 2 recognition complex and induces phosphatidylinositol-3-kinase signaling for activating the adhesive capacity of CR3 a monocytic beta2 integrin with PRR capabilities. Although this proadhesive pathway promotes the migratory activity of monocytes it has surprisingly been co-opted by P. gingivalis for exploiting CR3. By means of immunological genetic and biophysical techniques as well as a mouse periodontitis model these studies will test the hypothesis that the interaction of P. gingivalis with activated CR3 leads to pathogen internalization suppression of normal defense clearing mechanisms inhibition of apoptosis and promotion of intracellular persistence. Moreover it is hypothesized that the inducibility of this co-opted pathway becomes higher with age leading to enhanced immune evasion by P. gingivalis and potentially increased periodontal disease activity. This study has been designed not only for answering fundamental questions in innate immunity but also for facilitating the development of novel immunomodulatory concepts at a translational level. Indeed only by knowing how the innate response is deregulated by pathogens could effective immunomodulatory strategies be implemented for redirecting the oral mucosal immune defense to the benefit of the elderly host. While the proposed experimental model focuses on a periodontal pathogen the fundamental concept of immune evasion by corruption of PRR function and how this process changes with advancing age may be applicable to infections of less accessible mucosal tracts such as the respiratory gastrointestinal and genitourinary tracts.

project_terms:
1-Phosphatidylinositol 3-Kinase;16p;Adhesives;Age;Aging;Bacteroides thetaiotaomicron;Binding (Molecular Function);Biochemical;Birth;Bone Resorption;CD18 Antigens;Chronic;Clinical;Complex;Data;Development;Dominant-Negative Mutation;Down-Regulation;Elderly;Event;Experimental Models;Genetic;Genitourinary system;Human;Immune;Immune response;Immune system;Infection;Inflammation;Inherited;Inhibition of Apoptosis;Integrins;Interleukin-12;Killings;Lead;Ligand Binding;Literature;Macrophage-1 Antigen;Mediating;Microbe;Modeling;Molecular;Mus;Natural Immunity;Oral cavity;Oral mucous membrane structure;Organism;Outcome;Pathway interactions;Pattern;Pattern Recognition;Pattern recognition receptor;Periodontal Diseases;Periodontitis;Peritonitis;Porphyromonas gingivalis;Predisposition;Process;Receptor Signaling;Research Personnel;Resistance to infection;Role;Severities;Signal Pathway;Signal Transduction;Study models;Surface;Techniques;Testing;Toll-Like Receptor 2;Virulence;Virulence Factors;age related;aged;base;design;fimbria;gastrointestinal;in vivo;inhibitor/antagonist;macrophage;microbial;microorganism interaction;monocyte;mutant;novel;oral pathogen;pathogen;receptor;receptor function;respiratory;response


application_id: 7776867
project_number: 5R37HD029957-18
project_title: Early Development with Williams or Down Syndrome
administering_ic: NICHD
award_notice_date: 2010-07-19
application_type: 5
activity_code: R37
ic: HD
serial_number: 029957
program_official: OSTER-GRANITE, MARY LOU
project_start_date: 1993-03-01
project_end_date: 2014-07-31
study_section: NSS
contact_pi_person_id: 1901361
contact_pi: MERVIS, CAROLYN B.
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
budget_start_date: 2010-08-01
project_abstract:
Program Director/Principal Investigator(Last First Middle): Men/is Carolyn BethPROJECT SUMMARY (Seeinstructions):The overall objective of the proposed research is to delineate and make sense of the process of lexicaldevelopment and its relations to socio-communicative development grammatical development and bothgeneral and specific aspects of nonlinguistic cognitive development. The research will focus on the languageand cognitive development of children with Williams syndrome and children with Down syndrome. Williamssyndrome is associated with relative strengths in language (especially concrete vocabulary and grammar)and verbal short-term memory and severe weakness in visuospatial cognition. In contrast Down syndromeis associated with severe weaknesses in expressive language (especially grammar) and in verbal short-termmemory and relative strength in nonlinguistic aspects of cognition. Because of these differences in thegeneral nature of the relations between language and nonlinguistic cognition inclusion of these two groupsof children in the same studies provides a unique opportunity to distinguish factors that are likely to beuniversal and necessary to language development from those that are specific to particular rates or paths tolanguage development. The proposed research consists of a longitudinal study of early language andcognitive development beginning in late infancy a longitudinal study of cognitive and language developmentof school-age children as measured by standardized assessments and cross-sectional studies of languagedevelopment especially socio-communicative development. Both observational and experimental methodswill be used. There are three specific aims. The first is to delineate the different types of early lexical growthcurves and examinetheir relations to later patterns of language and cognitive development. The second is toexamine socio-communicative development and its role in language and cognitive development. The third isto determine the longitudinal trajectories of language and cognitive abilities of children with Williamssyndrome and factors that influence these trajectories. The researchwill have implications both fortheoretical models of the relations between language and cognitive development and for the design ofcognitive language and reading intervention for children with developmental or intellectual disabilities.RELEVANCE (See instructions):The results of the proposed research will provide a basis for recommendations regarding speech/languageand developmental intervention for children with developmental delay in birth - 3 and preschool programs.The results also will increase the research foundation for the design of language social skills and readingintervention for school age children with developmental or intellectual disabilities.PROJECT/

project_terms:
Birth;Child;Child Development;Cognition;Cognitive;Cross-Sectional Studies;Development;Developmental Delay Disorders;Down Syndrome;Foundations;Growth;Instruction;Intellectual functioning disability;Intervention;Language;Language Development;Longitudinal Studies;Methods;Nature;Nursery Schools;Pattern;Principal Investigator;Reading;Recommendation;Relative (related person);Research;Role;School-Age Population;Short-Term Memory;Speech;Theoretical model;Visuospatial;Vocabulary;Williams Syndrome;base;design;infancy;lexical;lexical processing;programs;social skills;standardize measure


application_id: 7775006
project_number: 5R01NS061933-03
project_title: A specific microRNA (Mir-107) is a potential therapeutic target in Alzheimer's di
administering_ic: NINDS
award_notice_date: 2010-03-02
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 061933
program_official: CORRIVEAU, RODERICK A
project_start_date: 2008-09-30
project_end_date: 2012-02-28
study_section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Abstract MicroRNAs (miRNAs) are recently-discovered small regulatory RNAs that play fundamental roles in neurobiology. Preliminary results indicate that decreased expression of a particular miRNA miR-107 may contribute to Alzheimer's disease (AD) pathogenesis through a metabolic pathway. These are the first published data pertaining to miRNAs in a specific pathway that may contribute to AD. We will test a specific strategy to target this pathway for AD therapy. Hypothesis #1:  MiR-107 expression is decreased very early in AD which increases BACE1 expression and hence increases the amount of neurotoxic Abeta peptides in AD patients' brains. Hypothesis #2:  Bezafibrate treatment decreases AD-type pathology by increasing levels of miR-107. Specific Aim #1:  Characterize fully the regulation of BACE1 by miRNAs. Sub-Aim a. A novel technique will test directly whether BACE1 mRNA is a miRNA target. This biochemical approach involves co- immunoprecipitation using our monoclonal anti-Argonaute antibody. Sub-Aim b. Tissue culture studies will be performed to evaluate exactly which parts of the BACE1 mRNA 3'UTR constitute miRNA targets. Sub-Aim c. `Knock-in' and `knock-down' techniques will be used to alter miR-107 levels specifically in human cultured cells to determine the effects of miR-107 expression changes on the levels of BACE1 protein C99 polypeptide and A2 peptide. Experiments will be performed initially on H4 and SH-SY5Y cells. Specific Aim #2:  Characterize the impact of miR-107 on glucose metabolism and correlate the expression of miR-107 and other miRNAs with AD pathology in situ Sub-Aim a. Tissue culture studies will be performed to assess how pharmacological treatments that alter metabolism affect miR-107 expression and to evaluate how cellular changes in miR-107 influence the levels of specific metabolic intermediaries. Sub-Aim b. Human brain in situ hybridization will be used to understand how miR-107 expression relates to pathological hallmarks of AD and non-AD dementia. Specific Aim #3:  Evaluate bezafibrate for increasing miR-107 levels and decreasing BACE1 protein and A2 peptide(s) formation in vitro and in vivo. Bezafibrate is an orally-administered well-tolerated medication. Sub-Aim a. Preliminary results in cultured cells demonstrated that bezafibrate causes increased miR-107 expression and also induced down-regulation of BACE1 protein. The specific mechanism of bezafibrate action will be characterized using experiments in which the levels of miR-107 are manipulated. Sub-Aim b. Bezafibrate will be administered to mice - APPNLh/NLh x PS1P264L/P264L humanized APP knock-in mutants - that are an excellent model of AD-type amyloidogenesis (1) to demonstrate in vivo the efficacy of bezafibrate in modulating miR-107 BACE1 A2 levels and AD-type neuropathology. PUBLIC HEALTH RELEVANCE:  MicroRNAs are recently-discovered molecules that serve fundamental functions in the human brain. This research demonstrates for the first time that a particular microRNA may play an important role in Alzheimer's disease. A research program is proposed which exploits this new discovery in order to develop and evaluate a novel therapy for patients at risk for Alzheimer's disease.

project_terms:
3' Untranslated Regions;Affect;Alzheimer's Disease;Alzheimer's Disease Pathway;Alzheimer's disease model;Alzheimer's disease risk;Amyloid beta-Protein;Antibodies;Bezafibrate;Biochemical;Biological Assay;Brain;Cells;Clinical Trials;Co-Immunoprecipitations;Cultured Cells;Data;Dementia;Development;Down-Regulation;Glucose;Human;In Situ;In Situ Hybridization;In Vitro;Knock-in Mouse;Lipids;MK-886;Messenger RNA;Metabolic;Metabolic Pathway;Metabolism;MicroRNAs;Mus;Neurobiology;Neuroblastoma;Pathogenesis;Pathologic Processes;Pathology;Pathway interactions;Patients;Peptides;Pharmaceutical Preparations;Pharmacological Treatment;Play;Proteins;Publishing;Regulation;Research;Research Personnel;Role;Stimulus;Techniques;Testing;Time;Translations;abstracting;amyloidogenesis;base;beta-site APP cleaving enzyme 1;brain tissue;glucose metabolism;in vivo;knock-down;mutant;neuropathology;neurotoxic;novel;polypeptide;programs;public health relevance;relating to nervous system;research study;therapeutic target;tissue culture

public_health_relevance:
Project Narrative MicroRNAs are recently-discovered molecules that serve fundamentalfunctions in the human brain. This research demonstrates for the first time that aparticular microRNA may play an important role in Alzheimer's disease. Aresearch program is proposed which exploits this new discovery in order todevelop and evaluate a novel therapy for patients at risk for Alzheimer's disease.


application_id: 7774412
project_number: 5R01AA016166-03
project_title: Developmental Transitions and Risk for Alcohol Use
administering_ic: NIAAA
award_notice_date: 2010-03-02
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AA
serial_number: 016166
program_official: SHIRLEY, MARIELA
project_start_date: 2008-03-10
project_end_date: 2013-02-28
study_section: Risk, Prevention and Intervention for Addictions Study Section[RPIA]
contact_pi_person_id: 2092801
contact_pi: SMITH, GREGORY T.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adolescence;Adolescent;Affect;Alcohol abuse;Alcohol consumption;Behavior;Binge Eating;Child;Development;Developmental Process;Distress;Emotions;Environment;Esthesia;Event;Expectancy;Frequencies (time pattern);Growth;Impulsivity;Individual;Individual Differences;Intercept;Intervention;Investigation;Learning;Left;Light;Longitudinal Studies;Measures;Mental Depression;Modeling;Moods;National Institute on Alcohol Abuse and Alcoholism;Personality;Persons;Play;Process;Psychological reinforcement;Recording of previous events;Research;Risk;Risk Behaviors;Role;Shapes;Smoking;Testing;Time;Variant;alcohol expectancy;base;behavior change;drinking;early onset;experience;girls;middle school;prospective;psychologic;psychosocial;public health relevance;purge;theories;trait;underage drinking


application_id: 7773375
project_number: 1R21HD062833-01
project_title: Parental Problem Drinking and Child Sleep: Family and Physiological Mechanisms of
administering_ic: NICHD
award_notice_date: 2010-06-25
opportunity_number: PA-06-181
application_type: 1
activity_code: R21
ic: HD
serial_number: 062833
program_official: HAVERKOS, LYNNE
project_start_date: 2010-07-01
project_end_date: 2012-06-30
study_section: Special Emphasis Panel[ZRG1 BBBP-C (02)]
contact_pi_person_id: 9623914
contact_pi: KELLER, PEGGY S
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):  Alcohol problems are prevalent in the general population with an estimated 18.8 million Americans currently suffering from alcohol dependence or abuse (www.samhsa.gov) and 1 in 4 American children exposed to problem drinking in their family (Grant 2000). The consequences for children can be serious including emotional and behavioral problems but has been virtually no examination of the impact of parental problem drinking (PPD) on child sleep. Sleep is critical for healthy development and adaptive daytime functioning yet 20% to 40% of children experience clinically significant sleep disruptions. The objectives of the current study are to address these open scientific questions regarding the relation between PPD and child sleep within an exploratory and multidisciplinary framework. Specifically the goals are to (1) examine maternal and paternal PPD as a risk factor for children's shorter sleep duration lower sleep quality and erratic sleep schedule; (2) consider marital conflict and parenting as potential mediators of the association between PPD and child sleep; and (3) test whether vagal functioning (tone and withdrawal) moderates the association between PPD (and associated family dysfunction) and child sleep problems.  The study will include 250 children aged 6 to 11 and their married or cohabiting parents; children will be normally developing and drawn from the broader community. Children's sleep will be assessed over the course of one week using diary reports and actigraphy. PPD marital functioning and parent-child relations will be measured using multiple measures and reporters including collateral reports of drinking and conflict behavior permitting bias-free assessments of key constructs. Well-established procedures will assess vagal tone and withdrawal in response to laboratory procedures. A number of potentially important covariates will also be assessed and included in analyses such as parental depression parental antisocial behavior and child adjustment problems. Differences in relations based on parent and child gender will also be explored.  The proposed study will advance understanding of child outcomes associated with PPD and contribute to the small but growing literature that demonstrates the negative effects of family stress on child sleep (PA-07- 140 Research on Sleep and Sleep Disorders) by providing the first known examination of relations between PPD and child sleep amount quality or schedule. Further the proposed study will examine possible mechanisms of risk at both the interpersonal and physiological levels (PA-07-046 Research on Mind-Body Interactions and Health) providing initial evidence for processes accounting for the associations between PPD and child sleep and identifying those children who may be at greatest risk for sleep problems in the context of PPD. Findings will provide preliminary support for more focused R01 studies and ultimately will shed light on potential targets for intervention or prevention addressing the serious public health concerns of PPD and child sleep problems.  
  
PUBLIC HEALTH RELEVANCE: Alcohol problems are a serious public health concern yet their impact on family and child functioning are understudied. The proposed study is the first known examination between parental problem drinking (PPD) and child sleep parameters. Sleep disturbances in American children are highly prevalent and research increasingly demonstrates their harmful effects on child functioning. However little is known about how family stress may impact child sleep. Further research is needed to identify mechanisms of risk involved in these influences. The proposed study examines relations between maternal and paternal PPD and child sleep quality amount and schedule; it also tests family relationship problems (e.g. marital and parent-child conflict) and physiological stress response (e.g. vagal tone and withdrawal) as mechanisms of risk. Findings of the proposed study will illuminate specific forms of sleep disturbances that are associated with PPD help identify children and families at greatest risk and lay the foundation for a focused program of longitudinal research.

project_terms:
Accounting;Address;Alcohol abuse;Alcohol dependence;American;Attenuated;Behavior;Child;Child Behavior;Communities;Conflict (Psychology);Development;Emotional;Exhibits;Failure (biologic function);Family;Family Relationship;Foundations;Functional disorder;Gender;General Population;Goals;Government;Grant;Health;Individual Differences;Infant;Intervention;Knowledge;Laboratory Procedures;Light;Literature;Measures;Mediating;Mediator of activation protein;Mental Depression;Mental Health;Mind-Body Relationship (Physiology);Nervous System Physiology;Outcome;Parasympathetic Nervous System;Parent-Child Relations;Parenting behavior;Parents;Physiological;Polysomnography;Prevention;Problem behavior;Procedures;Process;Reporter;Reporting;Research;Risk;Risk Factors;Schedule;Sleep;Sleep Disorders;Sleep disturbances;Stress;Surveys;Testing;Withdrawal;actigraphy;aged;anti social;base;biological adaptation to stress;child well being;clinically significant;depressive symptoms;diaries;drinking;experience;multidisciplinary;programs;public health medicine (field);public health relevance;response

public_health_relevance:
Narrative Alcohol problems are a serious public health concern yet their impact on family and child functioning areunderstudied. The proposed study is the first known examination between parental problem drinking (PPD)and child sleep parameters. Sleep disturbances in American children are highly prevalent and researchincreasingly demonstrates their harmful effects on child functioning. However little is known about how familystress may impact child sleep. Further research is needed to identify mechanisms of risk involved in theseinfluences. The proposed study examines relations between maternal and paternal PPD and child sleepquality amount and schedule; it also tests family relationship problems (e.g. marital and parent-child conflict)and physiological stress response (e.g. vagal tone and withdrawal) as mechanisms of risk. Findings of theproposed study will illuminate specific forms of sleep disturbances that are associated with PPD help identifychildren and families at greatest risk and lay the foundation for a focused program of longitudinal research.


application_id: 7772358
project_number: 5R01DK074720-04
project_title: Novel hematopoietic effects of C3 cleavage fragments
administering_ic: NIDDK
award_notice_date: 2010-02-23
application_type: 5
activity_code: R01
ic: DK
serial_number: 074720
program_official: WRIGHT, DANIEL G
project_start_date: 2007-03-01
project_end_date: 2012-02-29
study_section: Hematopoiesis Study Section[HP]
contact_pi_person_id: 2265592
contact_pi: RATAJCZAK, MARIUSZ Z
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-03-01
project_abstract:
DESCRIPTION (provided by applicant): The preliminary data from our laboratory established a novel and previously underappreciated role of the complement (C) system in modulating SDF-1-CXCR4 axis-dependent homing/retention/mobilization of hematopoietic stem/progenitor cells (HSPC) in bone marrow (BM). We found that C proteins are synthesized in BM and C activation provides one of the earliest signals of BM injury e.g. during conditioning for transplant by irradiation/chemotherapy or G-CSF-induced mobilization. We reported that HSPC express functional C3aR and the iC3b-receptor CR3 and while C3a and desArgCSa stimulation of HSPC enhances/sensitizes responsiveness of HSPC to SDF-1 gradients deposition of iC3b on BM stroma tethers early CR3-positive hematopoietic progenitors causing retention in the BM. Four aims are proposed to better elucidate the role of C3 in hematopoiesis during stress situations: 1. The molecular aspects of the C3a-C3aR axis in homing/engraftment of HSPC in bone marrow. Preliminary research points to a crucial role for the C3a-C3aR axis in homing/retention of HSPC in the bone marrow. We will focus on determining the molecular mechanisms of C3aR signaling in HSPC crucial for these processes and test whether priming of HSPC before transplantation with C3 cleavage fragments enhances engraftment of long-term repopulating HSPC in wt mice and human cord blood HSPC engraftment in NOD/SCID mice. 2. Blockade of the C3a-C3aR axis as a new strategy to mobilize stem cells. We reported that the small molecular C3aR antagonist SB2900157 enhances and accelerates G-CSF-induced mobilization. As a continuation of this work we will study the phenotype of mobilized cells and test whether they engraft efficiently after transplantation into syngeneic mice. 3. C3 fragments as modulators of the SDF-1-CXCR4 axis. C3a desArgCSa and iC3b prime chemotaxis of HSPC to SDF-1. This aim will define the molecular mechanism of this phenomenon and explore the hypothesis that C3 cleavage fragments promote a shift of CXCR4 into membrane lipid rafts which increases their responsiveness to SDF-1. 4. C3 and impaired mobilization in immunodeficient mice. We have observed that immunodeficient RAG2-/- and SCID mice show impaired mobilization of HSPC which is restored after infusion of immunoglobulins. We will test the hypothesis that this defect is related to the lack of naturally occurring C cascade-activating IgM antibodies.

project_terms:
Address;Adhesions;Animals;Antibodies;Apoptosis;B-Lymphocytes;Binding (Molecular Function);Biological;Blood;Bone Marrow;Bone Marrow Cells;C3bi;CD34 gene;CSF3 gene;CXCR4 gene;Cell Adhesion Molecules;Cells;Chemotaxis;Cleaved cell;Clinic;Complement;Complement 3 Convertase;Complement 3a;Complement 3b;Complement Activation;Cytostatics;Data;Defect;Deposition;Dose;Engraftment;Exhibits;Exposure to;Generations;Half-Life;Hematopoiesis;Hematopoietic;Hematopoietic stem cells;Homing;Human;Hypoxia;Immunodeficient Mouse;Immunoglobulin M;Immunoglobulins;In Vitro;Inflammation;Infusion procedures;Injury;Laboratories;Lead;Ligands;Link;Liquid substance;Macrophage-1 Antigen;Marrow;Mediating;Membrane Lipids;Membrane Microdomains;Molecular;Mus;NOD/SCID mouse;Organ;Pathway interactions;Patient Care;Patients;Peptides;Phase;Phenotype;Play;Process;Progenitor Cell Engraftment;Proteolysis;Radiation therapy;Radio;Recovery;Reporting;Research;Research Personnel;Role;SCID Mice;Serum;Signal Transduction;Site;Solid;Staging;Stem cells;Stress;Stromal Cell-Derived Factor 1;Stromal Cells;Supplementation;System;Testing;Tissues;Transplantation;Transplantation Conditioning;Umbilical Cord Blood;Work;Zymosan;base;cell motility;chemotherapy;citrate carrier;conditioning;in vivo;in vivo Model;injured;insight;irradiation;mouse model;novel;prevent;progenitor;programs;stem;trafficking


application_id: 7772307
project_number: 5R01AA015407-06
project_title: GSK-3 beta a mediator of ethanol neurotoxicity
administering_ic: NIAAA
award_notice_date: 2009-07-22
application_type: 5
activity_code: R01
ic: AA
serial_number: 015407
program_official: REGUNATHAN, SOUNDAR
project_start_date: 2005-08-01
project_end_date: 2011-03-09
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-08-01
project_abstract:
DESCRIPTION (provided by applicant): Two of the most striking effects of ethanol exposure during development are the disruption of neuronal migration and the deletion of neurons in certain areas of the central nervous system (CMS). The cellular/ molecular mechanisms underlying these damages remain unclear. Glycogen synthase kinase-3/beta (GSK3beta) is predominantly expressed in neurons in the developing CMS and emerges as a critical signaling component regulating diverse events of neuronal development such as neuronal migration and proliferation/survival. It has also been implicated in abnormalities in the adult brain such as neurodegenerative diseases. The activity of GSK3beta is regulated by phoshorylation and subcellular localization. GSK3beta is activated by various cellular stresses including endoplasmic reticulum (ER) stress. We have demonstrated that ethanol exposure induces ER stress and significantly alters the phosphorylation state of a GSK3beta in vitro and in vivo event at modest concentrations (50-100 mg/dl); blocking GSK3beta activation mitigates ethanol-induced neuronal death. Although ethanol alone at relatively low concentrations does not cause neuronal death it greatly potentiates apoptosis caused by various exogenous insults which also activate GSK3beta. In contrast ethanol does not affect cell death induced by pro-apoptotic signals which are independent of GSK3beta. We hypothesize that GSK3beta is a critical mediator of ethanol neurotoxicity. In this proposal we will characterize the effect of ethanol on phosphorylation/activity subcellular localization and expression of GSK3beta in the developing neurons using various model systems (cultured neurons organotypic slice culture of rat cerebellum and the developing cerebellum). Subsequently we will determine the role of GSK3beta in ethanol-induced cell cycle arrest apoptosis inhibition of neurite outgrowth and aberrant migration patterns; we will determine whether blocking GSK3beta activation by selective inhibitors or over- expression of dominant negative GSK3beta (DN-GSK3beta) or GSK3beta binding protein (GBP) provides neuroprotection against ethanol-induced damage. In addition we will investigate the role of Chop (GADD153) another ER stress responsive factor in ethanol-induced neuronal damages. Futhermore we will elucidate the mechanisms underlying GSK3beta activation; we will systematically investigate up-stream signaling of GSK3beta and the contribution of ER stress-responsive components such as protein phosphatase 2A to ethanol-induced GSK3beta activation. Finally we will investigate whether ethanol-induced sensitization or potentiation to apoptosis caused by other insults is dependent on GSK3beta we will determine whether over- expression of DN- GSK3beta and GBP abolishes ethanol-induced potentiation to neuronal death triggered by other pro-apoptotic stimuli. As a unit these experiments will explore a novel mechanism underlying ethanol- induced damage to the CMS using in vitro and in vivo model systems. The systematical study may establish GSK3beta as a potential therapeutic target for the treatment of alcohol neurotoxicity

project_terms:
Adult;Affect;Alcoholism;Apoptosis;Apoptotic;Area;Binding Proteins;Biological Models;Brain;Cause of Death;Cell Cycle Arrest;Cell Cycle Progression;Cell Death;Cell Death Induction;Cell Death Inhibition;Cell Survival;Cell-Free System;Cells;Cellular Stress;Central Nervous System Diseases;Cerebellum;Cessation of life;Chemosensitization;Development;Dominant-Negative Mutation;Employee Strikes;Endoplasmic Reticulum;Ethanol;Event;Exposure to;Fetal development of the mammalian embryo or fetus;Functional disorder;Glycogen Synthase Kinase 3;In Vitro;In-Migration;Induction of Apoptosis;Inhibition of Apoptosis;Mediating;Mediator of activation protein;Molecular;Nerve Degeneration;Neuraxis;Neurites;Neurodegenerative Disorders;Neurons;Neuropathogenesis;Pattern;Phosphorylation;Predisposition;Protein phosphatase;Rattus;Role;Series;Signal Transduction;Slice;Stimulus;Stream;alcohol abuse therapy;alcohol effect;alcohol exposure;biological adaptation to stress;endoplasmic reticulum stress;glycogen synthase kinase 3 beta;in vivo;in vivo Model;inhibitor/antagonist;insight;migration;nervous system disorder;neuron development;neuropathology;neuroprotection;neurotoxicity;novel;prenatal exposure;pup;research study;synaptogenesis;therapeutic target


application_id: 7772254
project_number: 5R01DC009434-02
project_title: Regulation of outer hair cell electromotility and noise-induced hearing loss
administering_ic: NIDCD
award_notice_date: 2010-01-19
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DC
serial_number: 009434
program_official: FREEMAN, NANCY
project_start_date: 2009-02-18
project_end_date: 2014-01-31
study_section: Auditory System Study Section[AUD]
contact_pi_person_id: 8360158
contact_pi: FROLENKOV, GREGORY I
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
4 hydroxynonenal;ATP Receptors;Acoustic Nerve;Acoustics;Action Potentials;Affect;Agonist;Calmodulin;Cell membrane;Cell physiology;Cells;Cochlear structure;Cyclic GMP;Data;Deafness;Evoked Potentials Auditory Brain Stem;Face;GTP-Binding Proteins;Genes;Goals;Gramicidin;Hair Cells;Hearing;Image;In Situ;In Vitro;Intervention;Labyrinth;Lead;Lipid Peroxidation;Mediating;Methods;Molecular Motors;Motor;Motor Activity;Mus;Noise;Noise-Induced Hearing Loss;Organ of Corti structure;Outer Hair Cells;Pathway interactions;Physiological;Predisposition;Preparation;Process;Property;Proteins;Regulation;Research;Resistance;Scientist;Second Messenger Systems;Sensory;Signal Pathway;Signal Transduction Pathway;Spontaneous Otoacoustic Emissions;Stress;TRPA1 Channel;Techniques;Testing;base;cell type;extracellular;flash photolysis;genetic variant;hearing impairment;in vivo;novel;operation;prevent;public health medicine (field);rat Pres protein;response;sound;vibration


application_id: 7771639
project_number: 5K99HL087924-02
project_title: Granule exocytosis and neutrophil activation
administering_ic: NHLBI
award_notice_date: 2010-02-22
opportunity_number: PA-07-297
application_type: 5
activity_code: K99
ic: HL
serial_number: 087924
program_official: MONDORO, TRACI
project_start_date: 2009-03-01
project_end_date: 2011-08-28
study_section: ZHL1-CSR-Z(O1)
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:
DESCRIPTION (provided by applicant):   
  
The postulated role of exocytosis in mediating various functional responses 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 specific objectives of the mentored phase of this proposal are: 1) to determine the ability of TAT-fusion proteins containing the SNARE domains of SNAP-23 syntaxins and VAMPs to inhibit exocytosis of each of the four neutrophil granule subsets. The training goal of this aim is to develop molecular biology and cell biology skills that will allow the applicant to address experimental questions at new levels and apply them in the independent phase of this proposal. 2) To determine the most effective way to administer the TAT-SNARE fusion proteins in vivo and to determine the effect of these fusion proteins on models of acute neutrophil-dependent inflammation in rats. The training goals of this aim are to learn animal models of neutrophil-dependent inflammation and to establish the ability of TAT-fusion proteins to inhibit neutrophil exocytosis in vivo. 3) Define other proteins that interact with SNARE proteins by proteomic analysis. The training goal of this aim is to develop the ability to perform proteomic analysis. The state-of-the-art techniques acquired during the mentored phase will greatly increase the expertise that 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 will receive will 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. (End of Abstract)

project_terms:
Actins;Acute;Address;Adherence (attribute);Air;Alanine;Animal Model;Animals;Antineutrophil Cytoplasmic Antibodies;Area;Arts;Aspartic Acid;Benchmarking;Binding (Molecular Function);Bioinformatics;Biological Assay;Biology;C-terminal;Carrageenan;Cell membrane;Cellular biology;Chemotaxis;Chimeric Proteins;Clathrin;Coiled-Coil Domain;Computer software;Consultations;Cytoplasmic Granules;Cytoskeleton;Data;Data Set;Databases;Development Plans;Disease;Docking;Doctor of Philosophy;Endocytosis;Evaluation;Evaluation Research;Event;Exocytosis;Exocytosis Inhibition;Funding;Future;Gelatinases;Generations;Goals;Human;Hydrogen Peroxide;Immunohistochemistry;Immunology;Immunoprecipitation;In Vitro;Individual;Inflammation;Inflammatory Response;Injection of therapeutic agent;Injury;Institutes;Intracellular Membranes;Journals;Killings;Knowledge;Laboratories;Lead;Learning;Letters;Lung Injury Acute;Manuals;Manuscripts;Mass Spectrum Analysis;Measures;Mediating;Membrane;Membrane Fusion;Membrane Protein Traffic;Mentor's Statement;Mentors;Mentorship;Methodology;Methods;Modeling;Molecular;Molecular Biology;Mutate;N-terminal;Natural Immunity;Nature;Neutrophil Activation;Normal tissue morphology;Online Systems;Paper;Pathway Analysis;Pathway interactions;Peptide Hydrolases;Peptides;Phagocytosis;Phase;Phosphoproteins;Phosphorylation;Phosphorylation Site;Phosphotransferases;Plasmids;Play;Post-Translational Protein Processing;Principal Investigator;Probability;Process;Production;Productivity;Proteins;Proteomics;Publications;Published Comment;Publishing;Rattus;Reactive Oxygen Species;Reading;Regulation;Reporting;Research;Research Personnel;Respiratory Burst;Risk Assessment;Role;Running;S100A9 gene;SNAP receptor;Science;Scientist;Secretory Vesicles;Signal Transduction Pathway;Site;Spleen;Staging;State Interests;Stimulus;Students;Study Section;Superoxides;System;Techniques;Technology;Tertiary Protein Structure;Testing;Text;Therapeutic;Time;Tissues;Training;Vascular Endothelial Cell;Vesicle;Work;abstracting;base;career;career development;design;effusion;experience;extracellular;high risk;improved;in vitro testing;in vivo;member;neutrophil;novel strategies;prevent;programs;receptor;remediation;research study;response;skills;success;syntaxin;uptake


