# projects

application_id: 9042337
project_number: 4R01DE012505-19
project_title: Molecular Aspects of Oral Plaque Formation
administering_ic: NIDCR
award_notice_date: 2016-04-12
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: DE
serial_number: 012505
program_official: LUNSFORD, DWAYNE
project_start_date: 1998-09-01
project_end_date: 2018-04-30
study_section: Special Emphasis Panel[ZRG1-MOSS-B(02)M]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: DEMUTH, DONALD R
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Periodontal disease one of the most common infections of humans has a polymicrobial etiology whereby groups of microorganisms exhibit synergistic pathogenicity. As a model system for the study of polymicrobial synergy we are investigating P. gingivalis-S. gordonii interactions. S. gordonii an early colonizer of the plaquebiofilm provides an attachment substratum for the more pathogenic later colonizer P. gingivalis. Contact dependent signaling and metabolite perception initiate further accumulation of P. gingivalis and the development of a dual species community. Interspecies coadhesion is mediated by the short fimbriae (comprised of the Mfa1 structural subunit) of P. gingivalis that engage the Ssp surface proteins of S. gordonii. Within SspB several amino acid motifs within a region spanning residues 1167-1193 (designated BAR) dictate binding activity and specificity. Development and later constraint of community development depends on the balance of tyrosine phosphorylation (through the kinase Ptk1) and dephosphorylation (through the phosphatase Ltp1) within P. gingivalis which controls expression of community effectors such as Mfa1 and LuxS. This tyrosine (de)phosphorylation dependent signal transduction pathway also converges on the expression genes encoding proteases and a dual species community of P. gingivalis and S. gordonii is more pathogenic compared to either species alone in a murine alveolar bone loss model. The objectives of this study are to: i) characterize the structural and functional motifs of Mfa1 that interact with the BAR domain of SspB; ii) define the role of the P. gingivalis tyrosine kinase Ptk1 in regulatory networks that control heterotypic community development with S. gordonii; and iii) determine the responses of P. gingivalis to the streptococcal metabolite 4-aminobenzoate (pABA) that regulate community development and pathogenic potential. Successful completion of these objectives will provide novel structure and function information on the P. gingivalis Mfa1 fimbrial adhesin. In addition we will unravel the interplay between tyrosine kinase (Ptk1) and phosphatase (Ltp1) activities in the signal transduction events that regulate community development. We will also generate novel information regarding metabolite sensing and its role in both community development and pathogenic potential. Our broad long-term goal is to translate this fundamental mechanistic information into the identification of novel targets for therapeutic intervention directed toward pathogenic community inhibition. As single target intervention can have limited utility and has yet to yield any significant advances in periodontal therapeutic options interference with multiple components of pathogenic community development including adhesive and maturation events may have a greater likelihood of success.

project_terms:
Adherence;Adhesives;Affect;Alveolar Bone Loss;Amino Acid Motifs;Bacteria;Bacterial Infections;Bacteroides;Binding;Biochemical;Biological Models;Catalytic Domain;Cell Communication;Cells;Communication;Communities;Community Developments;Complex;Coupled;Development;Disease;Disease Progression;Equilibrium;Etiology;Event;Exhibits;Fimbrial Adhesins;Gene Expression;Gene Expression Regulation;Genes;Goals;Health;Human;Infection;Intercept;Intervention;Maps;Mediating;Membrane Proteins;Metabolic;Microbial Biofilms;Modeling;Molecular;Molecular Models;Mono-S;Mus;Oral;Oral cavity;Organism;Pathogenesis;Pathogenicity;Peptide Hydrolases;Perception;Periodontal Diseases;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Porphyromonas gingivalis;Process;Production;Protein Dephosphorylation;Protein S;Protein Tyrosine Kinase;Protein Tyrosine Phosphatase;Proteins;Regulation;Role;Severities;Signal Transduction;Signal Transduction Pathway;Specificity;Streptococcus gordonii;Structure;Surface;System;Testing;Therapeutic;Therapeutic Intervention;Tooth structure;Toothpaste;Translating;Tyrosine;Tyrosine Phosphorylation;Virulence;base;bone loss;fimbria;microbial;microbial community;microorganism;microorganism culture;molecular modeling;mutant;novel;oral plaque;pathogen;prevent;protein metabolite;response;success;yeast two hybrid system

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Information that will be obtained from this study has the potential to be translated into the development of toothpastes or mouthrinses that can prevent disease causing organisms from accumulating on the teeth. These would reduce the ability of disease causing bacteria to persist in the mouth and consequently prevent or reduce the severity of gum disease.


application_id: 9041665
project_number: 4R01HL113494-04
project_title: Treatment of Skeletal Muscle Dysfunction in ICU Patients
administering_ic: NHLBI
award_notice_date: 2016-04-18
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: HL
serial_number: 113494
program_official: ZHOU, GUOFEI
project_start_date: 2013-08-01
project_end_date: 2018-04-30
study_section: Special Emphasis Panel[ZRG1-MOSS-A(02)S]
contact_pi_person_id: 1879110
contact_pi: SUPINSKI, GERALD S.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Recent studies indicate that mechanically ventilated MICU patients develop severe respiratory and limb muscle weakness and that weakness is associated with poor clinical outcomes in these patients. As a result administration of drugs thatimprove skeletal muscle strength should theoretically reduce the need for mechanical ventilation shorten hospital stay improve mortality and increase exercise tolerance in this patient population. The purpose of the present proposal is to address this issue and evaluate the impact of anabolic agents on strength and outcomes in a large diagnostically broad based MICU patient population. Two experiments are planned:  Aim 1 will test the hypothesis that limb and respiratory skeletal muscle weakness in critically ill patients can be attenuated by administration of hydroxymethylbutyrate (HMB) and/or eicosapentaenoic acid (EPA). We will first measure indices of muscle strength (magnetically stimulated diaphragm and quadriceps strength) muscle size (diaphragm and quadriceps thickness) and quadriceps muscle biopsy characteristics (force-pCa relationships biomarker levels). We will next randomize mechanically ventilated MICU patients to receive either placebo HMB EPA or both HMB+EPA for 10 days. We will then repeat parameter testing (muscle strength size and biopsy characteristics) on days 11 and 21. Data will be analyzed to determine if anabolic treatments improve muscle strength increase muscle size alter muscle biomarker levels and reduce the duration of mechanical ventilation.  Aim 2 will test the hypothesis that muscle training will augment the response to muscle strength enhancers (HMB+EPA) in mechanically ventilated MICU patients. We will measure muscle strength size and biomarker levels. We will then randomize patients to either placebo muscle strength enhancers (HMB+EPA) alone targeted muscle training alone (loaded breathing leg cycling exercise) or the combination of strength enhancers plus muscle training for 10 days. Parameter assessment will be repeated at days 11 and 21. We will determine if these treatments improve muscle strength muscle size alter biomarkers and reduce the duration of mechanical ventilation.  Our pilot study data suggest that both EPA and HMB can induce increases in both limb and respiratory muscle strength shortening the duration of mechanical ventilation in critically ill patients. These data support our hypotheses and suggest that the proposed studies are likely to define a new treatment that will have an important impact on the care of critically ill patients.

project_terms:
Activities of Daily Living;Address;Anabolic Agents;Attenuated;Biological Markers;Biopsy;Breathing;Caring;Characteristics;Clinical;Critical Illness;Data;Disease;Eicosapentaenoic Acid;Enhancers;Exercise;Exercise Tolerance;Financial cost;Functional disorder;Health;Hospitals;Hyperglycemia;Intensive Care Units;Leg;Length of Stay;Limb structure;Measurement;Measures;Mechanical ventilation;Medical;Morbidity - disease rate;Muscle;Muscle Weakness;Muscle function;Outcome;Patient Care;Patients;Performance;Pharmaceutical Preparations;Pharmacotherapy;Physicians;Pilot Projects;Placebos;Pneumonia;Randomized;Reporting;Respiratory Diaphragm;Respiratory Failure;Respiratory Muscles;Skeletal Muscle;Testing;Thick;Training;Ventilator;Work;base;cytokine;design;exercise intolerance;improved;improved outcome;indexing;mortality;muscle strength;patient population;pressure;prevent;quadriceps muscle;research study;respiratory;response;theories;treatment effect

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Skeletal muscle weakness is a major contributor to morbidity and mortality in critically ill MICU patients but currently there is no drug therapy available for his problem. The studies in this proposal are designed to identify a practical safe and potent therapy to prevent/reverse skeletal muscle weakness in these patients. We believe this work will define a new treatment that will have a major impact on the care of critically ill patients.


application_id: 9041660
project_number: 5R01HL120507-02
project_title: Lipid phosphate phosphatase 3 as a novel atherosclerosis suppressor
administering_ic: NHLBI
award_notice_date: 2016-03-24
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 120507
program_official: HASAN, AHMED A K
project_start_date: 2015-04-01
project_end_date: 2019-03-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S.
other_pis: MORRIS, ANDREW J
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Lysophosphatidic acid (LPA) is an essential bioactive phospholipid mediator that regulates a range of developmental and physiological processes which are emerging as targets for a new class of molecular therapeutics. In the cardiovascular system LPA is poised to serve as a mediator of atherothrombotic disease: it is abundant in atherosclerotic plaque increases during acute myocardial infarction triggers phenotypic responses in smooth muscle cells and disrupts endothelial integrity. We and others have demonstrated that LPA promotes both the development of intimal hyperplasia following injury and atherosclerosis in experimental models. Lipid phosphate phosphatase 3 (LPP3) encoded by the PPAP2B gene is an integral membrane enzyme that regulates the bioavailability of LPA. We have recently demonstrated that LPP3 is an intrinsic negative regulator of vascular inflammation suppresses smooth muscle cell proliferation and promotes endothelial barrier function likely by limiting LPA signaling. Analysis of data from a series of genome-wide association studies of coronary artery disease (CAD) identified a striking association between the PPAP2B locus and myocardial infarction. We provide evidence that CAD-risk associated PPAP2B variant disrupts an intronic enhancer that increases transcription of the gene and LPP3 expression in ox-LDL stimulated macrophages. These findings suggest the testable hypothesis that LPP3 functions as an atherosclerosis suppressor and that reduced PPAP2B gene expression aggravates cellular events underlying atherosclerosis and increases the likelihood of myocardial infarction. In this proposal we will define the role of LPP3 in the development of atherosclerosis provide insight into the molecular mechanism(s) involved and validate the predicted risk allele associated with CAD in humans. We are uniquely well-prepared to achieve these goals based on our expertise in bioactive lipid signaling and the tools we have amassed to study LPP3. Completion of these studies promises to provide valuable insight into the mechanism(s) by which extracellular bioactive lipid mediators influence the development of atherosclerosis and provide novel and innovative targets to predict prevent and treat CAD.

project_terms:
Acute myocardial infarction;Alleles;Arterial Fatty Streak;Atherosclerosis;Attenuated;Binding;Biological Availability;Blood Cells;Blood Vessels;CCAAT-Enhancer-Binding Proteins;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Cell Proliferation;Cell Survival;Cell surface;Cells;Clinical;Complement;Coronary Arteriosclerosis;Coronary artery;Cultured Cells;Data Analyses;Deposition;Development;Developmental Process;Diagnosis;Disease;Drosophila genus;Employee Strikes;Enhancers;Enzymes;Event;Experimental Models;Family;Gene Expression;Genes;Genetic;Genetic Polymorphism;Genetic Transcription;Goals;Health;Homologous Gene;Human;Human Genetics;Hyperplasia;Inflammatory;Injury;Introns;Investigation;Knowledge;Lipids;Lysophospholipids;Mass Spectrum Analysis;Mediating;Mediator of activation protein;Membrane;Molecular;Mus;Myocardial Infarction;Myocardial Ischemia;Phospholipids;Phosphoric Monoester Hydrolases;Physiological Processes;Positioning Attribute;Predisposition;Publishing;Reagent;Recording of previous events;Research;Research Project Grants;Resolution;Risk;Risk Factors;Role;Series;Signal Transduction;Single Nucleotide Polymorphism;Site;Site-Directed Mutagenesis;Smooth Muscle Myocytes;Stable Isotope Labeling;Stimulus;Testing;Therapeutic;Tissues;United States;Up-Regulation;Variant;Variation (Genetics);Work;base;cardiovascular disorder risk;cell motility;disorder risk;extracellular;genetic variant;genome wide association study;improved;inducible gene expression;innovation;inorganic phosphate;insight;lipid mediator;lipid metabolism;lipid phosphate phosphatase;lysophosphatidic acid;macrophage;monocyte;mortality;mouse model;novel;novel therapeutic intervention;oxidized low density lipoprotein;prevent;response;risk variant;tool;vascular inflammation

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Ischemic heart disease is a leading cause of death in the United States. Genetic variation in the gene encoding lipid phosphate phosphatase 3 (LPP3) an enzyme that regulates the bioavailability of lysophospholipids was recently identified to predict the development of coronary artery disease and acute myocardial infarction. We propose that LPP3 functions as an atherosclerosis suppressor. Completion of our work will define mechanism(s) involved and may implicate bioactive lipid mediators in the development of ischemic heart disease which will ultimately provide novel and innovative targets to predict prevent and treat coronary artery disease.


application_id: 9041011
project_number: 5R00HL111215-04
project_title: Regulation of Airway Protective Behaviors
administering_ic: NHLBI
award_notice_date: 2016-04-26
opportunity_number: PA-11-197
application_type: 5
activity_code: R00
ic: HL
serial_number: 111215
program_official: TIGNO, XENIA
project_start_date: 2013-02-23
project_end_date: 2018-03-31
study_section: NSS
contact_pi_person_id: 10816268
contact_pi: PITTS, TERESA G
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The long-term goal of this project is to determine the role of tracheal and pharyngeal sensory feedback inthe regulation of cough and swallow. Our central hypothesis is that an aspiration event produces a series ofcoughs and swallows which are expressed in various behavioral interaction patterns and that there aredecipherable rules that regulate the various patterns of expression. Cough and swallow are airwayprotective behaviors. The pharyngeal phase of swallow prevents aspiration of oral material (saliva food andliquid) by epiglottal movement laryngeal adduction and clearing the mouth and pharynx. Cough is anaspiration-response behavior that clears material from the airway. Coordination of these behaviors is vital toprotect the airway from further aspiration-promoting events such as a swallow occurring during theinspiratory phase of cough. The peripheral inputs operational characteristics and primary strategies thatcoordinate cough and swallow are unknown. This lack of information impedes understanding of the deficitsin airway protection with co-occurrence of dystussia and dysphagia which occurs with diseases such asParkinson's disease and Alzheimer's disease. The Specific Aims of the project are: 1) Develop a predictivecomputational distributed network model of the central influence of tracheal sensory pathways on theexpression of cough and swallow; and 2) Identify the role of neurons in the reticular formation in processingtracheal and pharyngeal afferent feedback on cough and swallow. Our preliminary data demonstrates amodulatory effect of sensory feedback of the production of cough and swallow. Stimulation of trachealafferents by an aspiration stimulus increases the magnitude of swallows providing evidence of airwayfeedback-induced increased pharyngeal clearance. In aim 2 we will: 1) record from neurons in the reticularformation using a multi-electrode array to obtain multiple-spike train data during: a) the selective stimulationof the trachea or pharynx to elicit cough or swallow; 2) test an acute model of dystussia and dysphagiainduced by microinjection of the endogenous excitatory amino acid antagonist kynurenic acid into themedial reticular formation.

project_terms:
Acute;Alzheimer's Disease;Behavior;Behavioral;Characteristics;Coughing;Data;Deglutition;Deglutition Disorders;Disease;Disease model;Event;Excitatory Amino Acid Antagonists;Feedback;Food;Goals;Kynurenic Acid;Larynx;Liquid substance;Medial;Microinjections;Modeling;Movement;Neurons;Oral;Oral cavity;Parkinson Disease;Pathway interactions;Pattern;Peripheral;Pharyngeal structure;Phase;Process;Production;Regulation;Reticular Formation;Role;Saliva;Sensory;Series;Specificity;Stimulus;Testing;Trachea;Training;behavioral response;multi-electrode arrays;network models;prevent;protective behavior;sensory feedback;therapeutic target

public_health_relevance:
This information will allow the testing of disease models with greater specificity and highlight therapeutictargets. This project will provide new fundamental information advancing the understanding of airwayprotection and the coordination of cough and swallow.


application_id: 9040963
project_number: 5R21EY025408-02
project_title: Exsomes derived from retinal astrocytes in the regulation of retinal vasculature
administering_ic: NEI
award_notice_date: 2016-03-22
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: EY
serial_number: 025408
program_official: SHEN, GRACE L
project_start_date: 2015-04-01
project_end_date: 2018-03-31
study_section: Diseases and Pathophysiology of the Visual System Study Section[DPVS]
contact_pi_person_id: 6193432
contact_pi: SHAO, HUI
other_pis: KAPLAN, HENRY JERROLD
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The normal retinal vasculature perfuses the macula of the neurosensory retina while avoiding interference with image resolution. The abnormal growth of blood vessels and associated bleeding and/or vascular leakage in retinopathy of prematurity (ROP) diabetics retinopathy (DR) exudative aged-related macular degeneration (AMD) and vascular occlusions are major causes of vision loss. Multiple cellular and soluble factors are involved in the formation stabilization and regression of new retinal vessels. Among the cellular components retinal astrocytes (RACs) play an important role in endothelial seeding of the primary retinal vasculature. However the mechanism of astrocyte- endothelial cell interaction is incompletely understood. This proposal investigates a novel mechanism in which exosomes released by RACs target endothelial cells and result in normal retinal vasculature development. To test our hypothesis that molecules in RAC exosomes are important in the development of normal retinal vasculature as well as the inhibition of aberrant retinal angiogenesis we will 1) test the effect of exosomes from murine postnatal day 2 (P2) RACs (developing RAC exosomes) on proliferation migration and tubule formation using retinal endothelial cells; 2) determine whether developing RAC exosomes can rescue aberrant angiogenesis induced by hypoxemia [i.e. oxygen-induced retinopathy (OIR)]; and 3) determine whether the angiogenic profiles of these exosomes reflect their function. Information derived from these results will further our understanding of the role of RAC exosomes in the development and maintenance of normal retinal vasculature. These observations may result in novel therapy to control aberrant retinal angiogenesis.

project_terms:
Adult;Affect;Age related macular degeneration;Angiogenic Proteins;Astrocytes;Blindness;Blood Vessels;Caliber;Cell Communication;Cell membrane;Cells;Choroidal Neovascularization;Development;Diabetic Retinopathy;Disease;Endostatins;Endothelial Cells;Extravasation;Exudative age-related macular degeneration;Goals;Growth;Health;Hemorrhage;Hypoxemia;Image;Lasers;Lead;Life;Lipids;Maintenance;Mediating;Messenger RNA;MicroRNAs;Microglia;Modeling;Multivesicular Body;Mus;Neonatal;Neurophysiology - biologic function;Oxygen;Parents;Pathology;Phase;Phenotype;Physiological;Physiology;Plasma Cells;Play;Proteins;Proteomics;Regulation;Resolution;Retina;Retinal;Retinal Diseases;Retinopathy of Prematurity;Role;Staging;Testing;Tissue Inhibitor of Metalloproteinase-1;Vascularization;Vesicle;Visual;Western Blotting;angiogenesis;base;exosome;macula;migration;nanoscale;neovascular;neurosensory;novel;novel therapeutics;pigment epithelium-derived factor;postnatal;proliferative diabetic retinopathy;retina blood vessel structure;retinal angiogenesis;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Normal retinal vasculature is critical for visual integrity. Any abnormality affecting vessel formation and regression during development or at later stages of life will lead to severe pathologies resulting in blindness such as retinopathy of prematurity (ROP) proliferative diabetic retinopathy (PDR) and wet age-related macular degeneration (AMD). The goal of this application is to investigate a novel mechanism whereby exosomes released from retinal astrocytes (RACs) are involved in the development and maintenance of normal retinal vasculature and to explore a novel therapy to control abnormal retinal vasculature related diseases.


application_id: 9040215
project_number: 5P30GM110787-03
project_title: Pilot Grant Program
administering_ic: NIGMS
award_notice_date: 2016-04-19
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
study_section: ZGM1-TWD-C
subproject_number: 6094
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
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: 2016-05-01
budget_end_date: 2017-04-30
project_abstract:
The long-term goal of the Pilot Grant Program is to provide resources to COBRE investigators so that they can generate new preliminary data for extramural grant applications and thus expand their research programs. The Pilot Grant Program was begun in Phase I continued in Phase II and its success will be built upon in Phase III. During Phase I and II the Program was extremely successful. Awardees produced -200 publications and the success rate for gaining independent extramural funding was -80%. Many of the initial awardees have now been granted tenure. This successful program will continue in Phase III. The Pilot Grant Program will feature three grant categories all designed to further the goals of the COBRE Center for Molecular Medicine and to promote innovation by allowing meritorious investigators to explore novel ideas and develop new technologies. Category 1 grants are for newly-independent non-tenured tenure-track research faculty with no prior NIH ROI or equivalent external grant support as a principal investigator. A strong mentoring component is associated with this class of grant. Category 2 grants are for more established faculty who wish to pursue a new research area for which they do not currently have an NiH R01 or equivalent. These grants are meant to promote innovation and allow investigators to expand their research programs into new areas. Category 3 grants are available to groups of investigators planning to submit a multi-PI or Program Project grant application working collaboratively on a specific research problem and can be comprised of both junior and more established investigators. These grants are meant to promote synergistic collaborations. The grants are designed for 2 years of funding ($50000 per year) with the second year contingent on demonstrated progress. Evaluation of the grant applications and funding decisions will be made by the External Advisory Board in consultation with the Program Coordinator. All applicants regardless of funding decisions will receive a review of their proposals with a full evaluation of NIH's five criteria so that their future proposals can be improved. This Pilot Grant program has had a highly successful past and its philosophy of operation will be carried into Phase III.

project_terms:
Animal Model;Applications Grants;Area;Award;Basic Science;Categories;Cellular biology;Centers of Research Excellence;Clinical;Collaborations;Consultations;DNA;Data;Development;Diagnostic;Discipline;Evaluation;Evolution;Extramural Activities;Faculty;Feasibility Studies;Fostering;Foundations;Funding;Future;Generations;Goals;Grant;Growth;Kentucky;Knowledge;Mentors;Molecular;Molecular Medicine;Neurodegenerative Disorders;Participant;Patients;Phase;Philosophy;Pilot Projects;Positioning Attribute;Principal Investigator;Program Research Project Grants;Publications;RNA;Research;Research Personnel;Research Project Grants;Resources;Science;Signal Pathway;Sum;Technology;Therapeutic;Translational Research;United States National Institutes of Health;Universities;Work;base;career;design;experience;faculty research;human disease;improved;innovation;interest;new technology;novel;operation;programs;success;tenure track;tool;trafficking;translational study

public_health_relevance:
The Pilot Grant Program promotes innovation by supporting COBRE investigators in the exploration of novel ideas and in the development of new technologies. This new knowledge will be the foundation for developing the future diagnostics tools and clinical therapeutics needed in the treatment of human disease.


application_id: 9040214
project_number: 5P30GM110787-03
project_title: Genetic Technologies Core
administering_ic: NIGMS
award_notice_date: 2016-04-19
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
study_section: ZGM1-TWD-C
subproject_number: 6093
contact_pi_person_id: 1893692
contact_pi: MENDENHALL, MICHAEL D.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-05-01
budget_end_date: 2017-04-30
project_abstract:
The Genetic Technologies Core evolved from the Viral Core that began with funding from an ARRA supplement grant in 2009 and was incorporated into the COBRE in 2011. It was initially conceived as a central service facility for the preparation purification and titering of recombinant lentlviruses adenoviruses and adeno-associated viruses for the use of investigators associated with the Center for Molecuair Medicine and for other investigators interested in the use of recombinant viruses as a delivery tool for nucleic acids. Over the past four years the Core has steadily grown in the number of individual viral preparations that it produced and the number of investigators it served. There has evolved an interest from users for services in addition to those associated with viral production and the Core has adapted by increasing the scope of services provided necessitating the change to its new designation as the Genetic Technologies Core. At present the Genetic Technologies Core provides a broad range of services related to the manipulation and analysis of recombinant DNAs especially for those laboratories with clinical/translational interests that are not equipped for recombinant DNA work. Evolution of the Core continues as it adds capacity in genomic manipulation through the development and use of "recombineering" TALEN and piggybac technologies. These technologies will be especially valuable for the creation of cellular and animal models of human diseases that can be exploited by members of the Center for Molecular Medicine. In addition to its scientific development the Core is also expanding its outreach programs by interfacing with the expanding Masters of Medical Science program (currently over 30 students) to provide hands-on and didactic instruction in recombinant DNA technologies including viral production and assay mammalian genomic manipulation tissue culture techniques and federal regulatory and safety requirements for up to three students each semester. A parallel didactic-only class is being developed for PhD graduate students. These courses will serve as additional revenue sources to sustain this core beyond COBRE funding.

project_terms:
Adenoviruses;American;Animal Model;Biological Assay;Cell model;Cells;Centers of Research Excellence;Clinical;Complex;Consultations;DNA;DNA Sequence Alteration;DNA laboratory;Dependovirus;Development;Disease model;Doctor of Philosophy;Evolution;Exposure to;Fee-for-Service Plans;Fees;Funding;Genetic Engineering;Genome;Genomics;Grant;Individual;Institution;Instruction;Investments;Kentucky;Laboratories;Leadership;Master of Science;Medical;Medicine;Modeling;Molecular;Molecular Medicine;Nucleic Acids;Phase;Plasmids;Positioning Attribute;Preparation;Production;Reagent;Recombinant DNA;Recombinants;Recovery;Research;Research Personnel;Resources;Safety;Science;Services;Source;Speed;Students;System;Techniques;Technology;Time;Tissue Culture Techniques;Training;Training Activity;Training Programs;United States National Institutes of Health;Universities;Viral;Work;base;cost;design and construction;genetic technology;graduate student;human disease;interest;mammalian genome;meetings;member;operation;outreach program;programs;recombinant virus;tool;transcription activator-like effector nucleases

public_health_relevance:
The Genetic Technologies Core provides a wide range of services relating to the manipulation of recombinant DNAs and mammalian genomes for investigators associated with the Center for Molecular Medicine. Of particular importance are the production of recombinant viruses for the delivery of nucleic acids for experimental use and the manipulation of mammalian genomes for creation of cell-based and animalbased human disease models.


application_id: 9040213
project_number: 5P30GM110787-03
project_title: Organic Synthesis Core
administering_ic: NIGMS
award_notice_date: 2016-04-19
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
study_section: ZGM1-TWD-C
subproject_number: 6092
contact_pi_person_id: 1964895
contact_pi: WATT, DAVID STEWART
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: 2016-05-01
budget_end_date: 2017-04-30
project_abstract:
The Organic Synthesis Core prepares novel specialized organic compounds that are not readily obtainable from commercial sources for faculty in the Center for Molecular Medicine as well as other investigators at the University of Kentucky other Kentucky universities. The core has all of the appropriate equipment needed to prepare small organic compounds (< 2 kDa) along with access to appropriate analytical techniques including NMR and mass spectrometry for confirming structural assignments to characterize the final product(s) an essential element of any synthesis project. The core has synthesized and characterized novel probes for more than twenty-five investigators including photoactive drug analogs fluorescent compounds used as molecular probes modified natural products unnatural peptides and compounds used for the affinity purification of proteins. The core has developed small molecule libraries that have been effectively used for ligand and drug screening leading to the identification of novel targets and the development of therapeutics. In Phase III this core will continue to provide novel small-molecule probes for disease-relevant studies further develop and expand its libraries of small-molecules for biological screening and promote and facilitate the use of small-molecule approaches in our translational research efforts. In addition the core will provide training opportunities for students and researchers who seek to learn synthetic organic chemical techniques and apply them to their research projects. An important but potentially overlooked aspect of the Organic Synthesis Core is that it does not compete with pharmaceutical companies rather the services provided by the core complement what private enterprises do. Generally a potentially valuable new compound developed by the core in collaboration with an investigator will be patented and then licensed to a pharmaceutical company for development and testing leading ultimately to clinical trials.

project_terms:
Affinity Chromatography;Biological;Businesses;Centers of Research Excellence;Clinical Trials;Collaborations;Complement;Consult;Consultations;Detection;Deuterium;Development;Disease;Drug Industry;Elements;Equipment;Extramural Activities;Faculty;Fees;Funding;Grant;Health;Human;Institution;Investigation;Investigational Drugs;Investments;Kentucky;Label;Learning;Legal patent;Licensing;Ligands;Link;Lipids;Malignant Neoplasms;Mass Spectrum Analysis;Medicine;Molecular;Molecular Medicine;Molecular Probes;Monitor;NMR Spectroscopy;National Center for Research Resources;National Institute of General Medical Sciences;Natural Products;Nature;Neurodegenerative Disorders;Organic Chemicals;Organic Synthesis;Outcome;Peptide Nucleic Acids;Peptides;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacy facility;Phase;Polymers;Positioning Attribute;Postdoctoral Fellow;Preclinical Drug Evaluation;Private Enterprises;Proteins;Publications;Radiolabeled;Research;Research Personnel;Research Project Grants;Research Support;Resources;Services;Source;Structure;Students;Techniques;Testing;Time;Training;Translating;Translational Research;Universities;X-Ray Crystallography;analog;base;college;design;drug candidate;functional group;graduate student;human disease;improved;industry partner;instrumentation;molecular mass;novel;novel therapeutics;operation;outreach;programs;radiotracer;screening;small molecule;small molecule libraries;therapeutic development;training opportunity;undergraduate student

public_health_relevance:
This Organic Synthesis core synthesizes small organic molecule use by investigators for their research projects related to understanding the molecular basis of human disease.


application_id: 9040212
project_number: 5P30GM110787-03
project_title: Protein Core
administering_ic: NIGMS
award_notice_date: 2016-04-19
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
study_section: ZGM1-TWD-C
subproject_number: 6091
contact_pi_person_id: 7875214
contact_pi: RODGERS, DAVID W
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-05-01
budget_end_date: 2017-04-30
project_abstract:
The Protein Core in the University of Kentucky Center for Molecular Medicine works with biomedical investigators to facilitate the expression purification and characterization of recombinant proteins and other macromolecules. It makes available equipment instrumentation and expertise not normally be found within individual research laboratories. The Core has fermentors bioreactors and tissue culture facilities for expressing recombinant protein in bacteria yeast insect or mammalian cells as required. It also maintains cell cracking equipment and an extensive facility for the purification of recombinant proteins. In addition a range of analytical instruments for biophysical characterization are available in the Core including dynamic light scattering spectropolarimetry fluorescence isothermal titration calorimetry high performance liquid chromatography analytical ultracentrifugation and X-ray crystallography. Crystallography facilities include instruments for automated crystallization trials in house data collection equipment and membership in a group (SER-CAT) operating a state-of-the-art data collection facility at the Advanced Photon Source located within Argonne National Laboratory. A Core staff member maintains the equipment provides training and works with researchers on their individual projects. Experienced users have direct access to Core facilities while new users are first trained by Core personnel and assisted in initial experiments. Users with more difficult projects receive additional assistance from the Core personnel. Service projects are undertaken selectively for users who lack the expertise or personnel to carry out the work on their own. The Core is used by investigators representing 50-70 research groups each year with over 4200 individual uses of instruments or facilities documented for the first four years of Phase II COBRE funding. Outreach activities include the Core web site talks given by Core associated faculty individual and group training sessions a monthly research talk series and participation in graduate courses and an NSF REU summer program. The Core is active in obtaining new instrumentation and introducing new techniques. Transition to a selfsustaining regional facility is planned over the course of Phase III COBRE funding.

project_terms:
Area;Bacteria;Behavior;Biological;Biomedical Research;Bioreactors;Calorimetry;Cells;Centers of Research Excellence;Chromatography;Collaborations;Communities;Consult;Core Facility;Core Protein;Crystallization;Crystallography;Data Collection;Equipment;Fees;Fluorescence;Fostering;Funding;Goals;Grant;Growth;High Pressure Liquid Chromatography;Housing;Human Resources;Individual;Insecta;Institution;Kentucky;Laboratories;Laboratory Research;Mammalian Cell;Mission;Molecular Medicine;Phase;Photons;Production;Protein Chemistry;Proteins;Recombinant Proteins;Research;Research Personnel;Resources;Schedule;Series;Services;Source;Structural Biologist;Structure;Techniques;Time;Titrations;Training;Universities;Work;X-Ray Crystallography;Yeasts;analytical ultracentrifugation;base;biophysical properties;cell type;design;equipment acquisition;experience;instrument;instrumentation;light scattering;macromolecule;member;mid-career faculty;operation;outreach;outreach program;research study;structural biology;summer program;tissue culture;web site

public_health_relevance:
This Protein Core in the Center for Molecular Medicine provides a variety of services aimed at the production and characterization of proteins for investigator inflated biomedical research. The Core makes available well maintained instruments and facilities not generally found in individual research labs and provides both training in their use and expert guidence. In addition service projects carried out by Core personnel are undertaken.


application_id: 9040211
project_number: 5P30GM110787-03
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2016-04-19
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
study_section: ZGM1-TWD-C
subproject_number: 6090
contact_pi_person_id: 7875201
contact_pi: LOUIS HERSH, LOUIS HERSH LOUIS HERSH
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: 2016-05-01
budget_end_date: 2017-04-30
project_abstract:
The Administrative Core will provide the administrative oversight for the Center for Molecular Medicine and the COBRE resources designed to build and strengthen the Center. The Administrative Core under the direction of Lou Hersh the COBRE PI and Sidney Whiteheart Program Coordinator will provide leadership oversight and coordination of the various activities associated with the Ceriter and it COBRE resources. The Administrative Core will facilitate and implement the goals and objectives of this COBRE and facilitate the transition of the Center for Molecular Medicine and its associated Cores to a sustainable independent status. The Administrative Core will provide oversight of the various activities associated with the COBRE grant including its voucher program its pilot grant program its mentoring activities and its scientific cores. The Administrative Core will work with the Intemal and External Advisory Committees and the Core directors and to meet our goals and objectives. The Administrative Core will oversee the budgets associated with the COBRE coordinate the various mentoring and Advisory Board meetings track core usage prepare reports etc. The specific objectives of the Administrative Core include enhancing and sustaining the infrastructure of the Center for Molecular Medicine including its research core facilities increasing the critical mass of investigators whose research focuses on the molecular basis of human disease fostering new collaborative and novel research in the Center providing a foundation for investigators to obtain extramural research support and to expand and develop educational activities through the scientific cores. The Administrative Core will use a number of approaches to facilitate faculty mentoring especially for junior untenured faculty to enhance educational initiatives associated with the Center and its cores to optimally use the pilot grant program to enhance competitive research to facilitate programmatic grant development and to develop collaborations with other IDeA centers and institutions in the region.

project_terms:
Achievement;Advisory Committees;Basic Science;Biochemistry;Budgets;Centers of Research Excellence;Collaborations;Core Facility;Data;Department chair;Development;Educational Activities;Equipment;Extramural Activities;Faculty;Fostering;Foundations;Goals;Grant;Head;Housing;Institution;Kentucky;Leadership;Medicine;Mentors;Mission;Molecular;Molecular Medicine;Performance;Phase;Recruitment Activity;Reporting;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Running;Services;Solid;Techniques;Technology;Universities;Work;base;college;design;faculty mentor;human disease;meetings;new technology;novel;programs;tool;voucher

public_health_relevance:
This Administrative Core will oversee all of the activities of this COBRE including the scientific cores the voucher program and the pilot grant program.


application_id: 9040210
project_number: 5P30GM110787-03
project_title: COBRE for the Center for Molecular Medicine
administering_ic: NIGMS
award_notice_date: 2016-04-19
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
program_official: ZLOTNIK, HINDA
project_start_date: 2014-07-01
project_end_date: 2019-04-30
study_section: ZGM1-TWD-C(3C)
contact_pi_person_id: 7875201
contact_pi: LOUIS HERSH, LOUIS HERSH LOUIS HERSH
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): This COBRE Phase III proposal aims to further develop the Center for Molecular Medicine at the University of Kentucky. This Center focuses on research aimed at understanding the molecular mechanisms associated with human disease with emphases on cancer neurodegenerative diseases diabetes and cardiovascular diseases. We propose to transition to independence the research infrastructure developed during previous COBRE funding. Our COBRE funded Center for Molecular Medicine has had a number of successes. During the previous funding period 30 junior faculty from 12 different departments and centers were funded as COBRE project or pilot grant PIs. These mentored faculty received 27 NIH ROI grants 11 other NIH grants and 41 other peer-reviewed extramural grants. The COBRE-supported junior faculty published more than 400 research papers. These and other successes can in large part be attributed to a strong mentoring program excellent institutional support and the availability of the scientific cores associated with the Center. For this application we propose to transition the Center for Molecular Medicine and its three scientific cores to independence of NIH/NIGMS support and to enhance and upgrade core technologies. It is worth noting that two of our original cores have or soon will transition to independence; the
Proteomics core developed by this COBRE is now a University fee-for-service core and the COBRE supported Imaging core is soon to become a department supported core. During the proposed five-year transition period we will increase the critical mass of faculty associated with the Center and continue to enhace its Cores. The use of vouchers will promote core usage and pilot grants will develop research collaborations and competitive grant submissions. The Administrative Core will serve as the focal point of the grant and in conjunction with the Program Coordinator and Internal Advisory Committee will serve as the operational arm of the Center. An External Advisory Committee consisting of world-renown scientists will provide ongoing assessment and evaluation of the Center. Continuing Institutional commitments will ensure programmatic growth and long-term sustainability.

project_terms:
Advisory Committees;Cardiovascular Diseases;Centers of Research Excellence;Collaborations;Diabetes Mellitus;Ensure;Evaluation;Extramural Activities;Faculty;Fee-for-Service Plans;Funding;Grant;Growth;Image;Kentucky;Malignant Neoplasms;Mentors;Molecular;Molecular Medicine;National Institute of General Medical Sciences;Neurodegenerative Disorders;Paper;Peer Review;Phase;Proteomics;Publishing;Research;Research Infrastructure;Scientist;Technology;Translational Research;United States National Institutes of Health;Universities;arm;base;faculty mentor;human disease;mid-career faculty;programs;success;voucher

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This COBRE funded Center for Molecular Medicine has as a focus the molecular basis of human disease. The COBRE scientific cores have supported and will continue to support and enhance translational research at the University of Kentucky and other regional institutions.


application_id: 9039350
project_number: 7R01CA177679-02
project_title: The role of adipocyte/macrophage fatty acid binding protein in breast cancer deve
administering_ic: NCI
award_notice_date: 2015-07-09
opportunity_number: PA-13-302
application_type: 7
activity_code: R01
ic: CA
serial_number: 177679
program_official: WOODHOUSE, ELIZABETH
project_start_date: 2015-07-09
project_end_date: 2019-05-31
study_section: Tumor Microenvironment Study Section[TME]
contact_pi_person_id: 9620088
contact_pi: LI, BING
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):  Despite recent improvements in survival rates breast cancer still kills nearly half-a-million women worldwide annually. As the two most predominant populations in breast cancer stroma macrophages and adipocytes play central roles in breast tumorigenesis and progression. Thereby modifications in these cells can greatly influence tumor behavior. The objectives of this proposal are to determine the role of adipocyte/macrophage fatty acid binding protein (A-FABP) in promoting breast cancer development through simultaneously targeting both macrophages and adipocytes and to develop inhibitors to modulate A-FABP activity for breast cancer therapy. A-FABP abundantly expressed in macrophages and adipocytes has been identified as a central regulator of metabolic and inflammatory pathways in these cells. Our preliminary studies demonstrate that A- FABP is significantly upregulated in human and murine breast/mammary cancers. In response to tumor stimulation cytoplasmic A-FABP expression is markedly elevated in tumor associated macrophages (TAMs) whereas circulating A-FABP is mainly released by adipocytes. More importantly A-FABP deficiency alters macrophage phenotype and protects mice against mammary tumor growth and metastasis. While obesity is associated with poor prognosis and increased mortality in patients with breast cancer the mechanistic basis for this association remains unclear. We found that obesity increases A-FABP in both cytosol and the circulation and promotes breast cancer progression. It is likely that A-FABP links obesity and breast cancer via regulating macrophage and adipocyte functions. Thus we hypothesize that A-FABP as an unidentified link underlying the obesity-breast cancer association promotes the development of breast cancer through enhancing pro-tumor functions of macrophages and adipocytes. Therefore modulating A-FABP activity will represent a novel strategy for breast cancer therapy. Specific Aim 1 will answer how cytoplasmic A-FABP regulates macrophage functions for breast cancer progression. We hypothesize that upregulation of cytoplasmic A-FABP in TAMs reprograms the macrophages to promote a pro-tumor environment. Specific Aim 2 will delineate how circulating A-FABP released by adipocytes contributes to breast cancer invasion. Experiments will designed to test the hypothesis that circulating A-FABP released by adipocytes favors breast cancer progression by increasing tumor cell aggressiveness. Specific Aim 3 will address whether obesity promotes breast cancer through increasing A-FABP expression. We propose that A-FABP represents an unidentified factor in obesity to promote breast cancer risk and inhibition of A-FABP with inhibitors may suppress breast cancer development and progression. In conclusion the data collected will help us unravel the critical role of A-FABP in breast cancer development and identify specific A-FABP inhibitors for potential breast cancer therapy.

project_terms:
Address;Adipocytes;Basic Science;Behavior;Blood Circulation;Breast;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Treatment;Breast Cancer therapy;Cell Cycle Regulation;Cells;Clinical;Cytosol;Data;Development;Environment;Health;Human;Infiltration;Inflammatory;Killings;Link;Mammary Neoplasms;Mediating;Metabolic;Mitotic Cell Cycle;Modification;Mortality Vital Statistics;Mus;Neoplasm Metastasis;Obesity;Pathway interactions;Patients;Phenotype;Play;Population;Prevention;Protein Deficiency;Role;Survival Rate;Testing;Therapeutic;Up-Regulation (Physiology);Woman;Women's Health;base;breast tumorigenesis;cancer risk;design;fatty acid-binding proteins;in vivo;inhibitor/antagonist;macrophage;malignant breast neoplasm;mouse model;neoplastic cell;novel strategies;outcome forecast;protein expression;research study;response;tumor;tumor growth;tumor progression;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Breast cancer poses a major threaten to women's health. Uncovering new mechanisms of breast cancer development represents a critically important focus for prevention and/or treatment of breast cancer. This proposal will establish A-FABP as a new player in breast cancer development. The data obtained will not only have basic science ramifications for understanding mechanisms of how A-FABP promotes breast tumorigenesis and progression but will also have clinical impact for the treatment of breast cancer.


application_id: 9039129
project_number: 4UM1HL113530-05
project_title: University of Louisville Regional Clinical Center for the CCTRN
administering_ic: NHLBI
award_notice_date: 2016-02-22
opportunity_number: RFA-HL-12-026
application_type: 4
activity_code: UM1
ic: HL
serial_number: 113530
program_official: EBERT, RAY F
project_start_date: 2012-03-22
project_end_date: 2019-02-28
study_section: ZHL1-CSR-O(F2)
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    The University of Louisville/Jewish Hospital has a remarkably vibrant basic and clinical research program in cardiovascular medicine particularly in the area of stem cells and patients with heart failure (HF) left ventricular assist devices (LVADs) and ischemic cardiomyopathy. A highly cohesive and collegial team of investigators from the Divisions of Cardiovascular Medicine and Thoracic and Cardiovascular Surgery has worked productively for many years in several multicenter trials with outstanding performance. This existing clinical infrastructure coupled with the strong preclinical research work conducted on cell-based therapies for several years provides a superb platform for participation in the CCTRN as a Regional Clinical Center. The ability of our Center to carry out Phase l/ll studies of stem cells is exemplified by our success i performing the first in-human study of c-kit+ cardiac stem cells in patients with HF (SCIPIO). The same investigators and the infrastructure that made SCIPIO possible will be leveraged for the CCTRN studies. Here we propose SENECA (StEm cell treatmeNt for End stage CArdiac failure) in which we will test the feasibility and safety (Aim 1) and efficacy (Aim 2) of intracoronary delivery of CD34+ cells or very small embryonic-like cells (VSELs) to patients with end-stage ischemic cardiomyopathy (ICM) following implantation of an LVAD. Our hypothesis is that cell therapy will promote repair and regeneration of the injured myocardium resulting in improved cardiac function functional capacity and overall quality of life and recovery of myocardial function to a degree that permits consideration of LVAD explantation. In Aim 3 we will identify patient characteristics and in vitro parameters of stem cell function that are associated with effectiveness (or lack thereof) of CD34+ cells and VSELs in improving LV function in vivo. SENECA will be the first study of VSELs in humans and the first controlled trial to test the effects of CD34+ cells in end-stage ischemic HF. Therefore the results will be entirely novel and may provide a new option for patients who currently have a dismal prognosis. Thus the potential impact of SENECA is considerable. No cell therapy study has ever been reported before in patients with LVADs and ICM although these are the very patients who need it the most. Therefore SENECA will address a major therapeutic gap in the management of cardiac patients. This trial has the potential to provide a novel clinical breakthrough in the treatment of end-stage ischemic heart disease.

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

public_health_relevance:
We have conducted preclinical studies of stem cells for several years. In 2009 we started SCIPIO the first in-human study of c-kit+ cardiac stem cells and one that demonstrates the ability of our Center to carry out Phase l/ll studies of cell therapy in humans effectively and successfully. This application builds on SCIPIO and on the superb program in advanced heart failure at Jewish Hospital. The results may pave the way for the use of novel cell-based therapies (CD34+cells and/or VSELs) in patients with ischemic cardiomyopathy.


application_id: 9039015
project_number: 5R21CA188792-02
project_title: Oxidized redox state a new potential biomarker for prostate cancer progression
administering_ic: NCI
award_notice_date: 2016-03-14
opportunity_number: PAR-12-096
application_type: 5
activity_code: R21
ic: CA
serial_number: 188792
program_official: SCHWARTZ, ELENA IVAN
project_start_date: 2015-04-01
project_end_date: 2018-12-31
study_section: Special Emphasis Panel[ZRG1-OBT-J(55)R]
contact_pi_person_id: 11588541
contact_pi: CHAISWING, LUKSANA
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: UNIVERSITY-WIDE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Prostate cancer (PCa) is an increasingly common malignancy worldwide; progression to advanced cancer is highly unpredictable resulting in a need for new clinically relevant biomarkers or diagnosis tools. A better understanding of PCa pathologic progression would allow development of more sensitive and specific biomarkers. Based on preliminary results from analyses of human PCa tissues oxidized redox state and posttranslational modification of thioredoxin 1 (Trx1) protein levels were significantly increased in primary PCa with high Gleason scores and metastatic PCa in comparison to adjacent benign tissues. We hypothesize that increased oxidized redox state is contributed to redox imbalance in PCa leading to increased production of reactive oxygen species/reactive nitrogen species oxidative DNA damage mutation of tumor suppressor genes epigenetic changes and subsequent PCa progression. To fully understand the relationship of oxidized redox state and PCa progression a first step involves determining the correlation of oxidized redox state with PCa progression in patient samples. In Specific Aim 1 human PCa-tumor microarrays with different pathological stages will be constructed stained with oxidative damage products and analyzed using Vectra/Nuance system. Additionally thiol redox couples will be measured in human prostate frozen tissues with different pathological stages compared to adjacent benign epithelial prostate tissues. Defining the redox state of PCa and its correlation with disease stageis a necessary first step to determine 1) if oxidized redox state may potentially be used as biomarker for PCa diagnosis and 2) whether oxidized redox state is the cause or consequence of PCa progression. Biochemical analyses of redox state in Aim 1 are time-and labor-intensive and require a large amount of tissues. To overcome these problems Specific Aim 2 will evaluate if TEMPOL-enhanced MRI could potentially be used in the diagnosis of intracellular redox state of prostate cancer in vivo. TEMPOL can undergo oxidation to the corresponding oxoammonium cation by variant oxidants and its paramagnetism property can be captured by MRI. Oxidizing tissues will exhibit longer-lived MRI signal than reducing tissues. We will scan nude mice with orthotopic xenograft transplant LNCaP-luc-M6 or PC3M-luc-C6 cells to evaluate the possibility and validity of TEMPOL-enhanced MRI. To our knowledge the present proposal will be the first to 1) attempting correlate tissue redox status with the aggressiveness of PCa in patient samples and 2) use cutting edge technique TEMPOL enhanced MRI to visualize redox state and diagnosis of PCa. Upon completion of these studies a better understanding of PCa pathologic/metabolic progression may allow development of more sensitive more relevant and more specific biomarkers for early prediction or prognosis of those patients destined for clinical cancer progression.

project_terms:
4 hydroxynonenal;Acceleration;Advanced Malignant Neoplasm;Affect;Antibodies;Antioxidants;Benign;Biochemical;Biological;Biological Markers;Cancer Etiology;Cations;Cells;Cessation of life;Characteristics;Clinical;Couples;Cysteine;Cystine;DNA Sequence Alteration;Deoxyguanosine;Detection;Development;Diagnosis;Disease;Disseminated Malignant Neoplasm;Environment;Epigenetic Process;Epithelial;Epithelium;Equilibrium;Exhibits;Freezing;Future;Gleason Grade for Prostate Cancer;Glutathione;Glutathione Disulfide;Health;High Pressure Liquid Chromatography;Human;Image;Image Analysis;Imaging technology;Immunohistochemistry;LNCaP;Lead;Life;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Metabolic;Metastatic Neoplasm to the Bone;Metastatic Prostate Cancer;Methods;Molecular;Monitor;Mus;Mutation;Neoplasm Metastasis;Nuclear;Nude Mice;Oxidants;Oxidation-Reduction;Oxidative Stress;PC3 cell line;Pathologic;Pathologic Processes;Pathological Staging;Patients;Post-Translational Protein Processing;Production;Property;Prostate;Proteins;Public Health;Reactive Nitrogen Species;Reactive Oxygen Species;Resolution;Role;Sampling;Scanning;Sensitivity and Specificity;Signal Transduction;Site;Staging;Staining method;Stains;Sulfhydryl Compounds;System;TXN gene;Techniques;Time;Tissue Microarray;Tissues;Transplantation;Tumor Suppressor Genes;Variant;Western Blotting;Xenograft procedure;base;cancer diagnosis;clinically relevant;comparative;extracellular;imaging modality;improved;in vivo;interest;liquid crystal polymer;male;men;mortality;outcome forecast;overexpression;oxidation;oxidative DNA damage;oxidative damage;potential biomarker;prognostic;protein expression;response;sensor;specific biomarkers;standard of care;targeted treatment;tempol;therapeutic target;tool;tumor;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This project is relevant to public health because prostate cancer (PCa) primarily affects men and is the second leading cause of cancer deaths in males in the US. Since most PCa mortality results from metastases to the bone more effective diagnosis tool and treatment of metastases is crucial. Defining intracellular redox state (reduction/oxidation) would aid in understanding the pathological process of PCa and may lead to potentially new biomarkers that possibly be used to differentiate benign prostate tissue from less aggressive or from highly aggressive prostate cancer. Thus developing non-invasive method for accuracy determination of intracellular redox state in prostate cancer in vivo herein TEMPOL-enhanced MRI is an important step toward developing redox state as a new biomarker for aggressiveness/metastatic prostate cancer and target-therapies for clinical utility.


application_id: 9038740
project_number: 7R01CA180986-02
project_title: Prevention of Breast Cancer Development by Epidermal Fatty Acid Binding Protein (
administering_ic: NCI
award_notice_date: 2015-06-24
opportunity_number: PA-13-302
application_type: 7
activity_code: R01
ic: CA
serial_number: 180986
program_official: EMENAKER, NANCY J
project_start_date: 2015-08-01
project_end_date: 2019-07-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 9620088
contact_pi: LI, BING
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): The increasing incidence of breast cancer poses a major threat to women's health in the USA and worldwide. How to prevent breast tumorigenesis and to identify new protective factors for the control of breast cancer represents a great challenge in this field. The objectives of this proposal are to unravel a protective role of epidermal fatty acid binding protein (E-FABP) in preventing breast cancer development and to determine the molecular mechanisms by which E-FABP regulates IFNb production and signaling in a specific subset of tumor associated macrophages for antitumor responses. E-FABP abundantly expressed in macrophages has been recognized as an important regulator to coordinate cell metabolic and inflammatory pathways. Our preliminary studies demonstrate that E-FABP deficient mice exhibit significant increases in mammary tumor growth and lung metastasis compared to wild type mice suggesting a protective role of host expression of E-FABP in mammary tumor prevention. Further analysis of E-FABP expression profile indicates that E-FABP is specifically expressed in the subset of F4/80+CD11b+MHCII+CD11c+ cells. Microarray and qPCR experiments show that tumor-induced IFN production and signaling in macrophages are significantly impaired by E-FABP deficiency. Interestingly IFNb stimulation specifically induces E-FABP upregulation in the process of M1 polarization. Moreover o-3 fatty acids can greatly enhance E-FABP expression in macrophages. Thus we hypothesize that E-FABP may regulate macrophage function by promoting IFNb production signaling and M1-like phenotype switch through enhancing cell lipid metabolism. E-FABP as a new cancer protective factor can prevent breast carcinogenesis through promoting macrophage anti-tumor responses. Therefore modulating E-FABP activity will represent a novel strategy for breast cancer prevention. Specific Aim 1 will determine how E-FABP regulates IFNb production in macrophages. We hypothesize that E-FABP is an unidentified host-derived factor to regulate tumor-induced IFNb production through impacting lipid-mediated signals in specific subsets of macrophages. Specific Aim 2 will determine how E-FABP regulates IFNb signaling to promote anti-tumor responses. We will test the hypothesis that E-FABP-regulated IFNb signaling promotes tumor specific T lymphocyte infiltration and IFNb production which further upregulates E-FABP expression to facilitate macrophage M1 polarization for antitumor immunity. Specific Aim 3 will address whether host-derived E-FABP protects against breast cancer development in clinically relevant animal models and in humans. We will verify E-FABP as a host-derived protective factor in breast cancer prevention and establish an effective strategy for the control o breast cancer via dietary upregulation of E-FABP. In conclusion successful completion of this project will reveal E-FABP as a new protective factor in control of breast cancer development and help us develop an effective strategy to prevent breast cancer via targeting E- FABP.

project_terms:
Address;Animal Model;Antitumor Response;Basic Science;Breast Cancer Model;Breast Cancer Prevention;Breast Carcinogenesis;Cells;Clinical;Data;Development;Diet;Diet Modification;Exhibits;Fatty Acids;Hematopoietic;Human;ITGAM gene;ITGAX gene;Immunity;Incidence;Infiltration;Inflammatory;Interferon-beta;Interferons;Killings;Lipids;Lung;Malignant Neoplasms;Mammary Neoplasms;Mammary Tumorigenesis;Mediating;Metabolic;Molecular;Molecular Profiling;Mouse Mammary Tumor Virus;Mus;Neoplasm Metastasis;Pathway interactions;Phenotype;Population;Prevention;Preventive;Process;Production;Protein Deficiency;Role;Signal Transduction;T-Lymphocyte;Testing;Tissues;Up-Regulation (Physiology);Wild Type Mouse;Women's Health;breast tumorigenesis;clinically relevant;design;human FABP5 protein;in vivo;lipid metabolism;macrophage;malignant breast neoplasm;novel strategies;prevent;protein expression;public health relevance;research study;response;tumor;tumor growth

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Breast cancer poses a major threat to women's health. Identifying new protective factors and uncovering the molecular mechanisms of their action represent critically important foci for the control of breast cancer. This proposal will establish -FABP as a new protective factor for breast cancer prevention. The data obtained will not only have basic science ramifications for understanding mechanisms of how E-FABP prevents breast tumorigenesis and progression but will also have clinical impact for the prevention of breast carcinogenesis.


application_id: 9038438
project_number: 5U01HL127518-02
project_title: The ExCITE Program: Expediting Commercialization Innovation Translation & Entrepreneurship
administering_ic: NHLBI
award_notice_date: 2016-03-10
opportunity_number: RFA-OD-14-005
application_type: 5
activity_code: U01
ic: HL
serial_number: 127518
program_official: ROUSCHE, KATHLEEN T
project_start_date: 2015-03-20
project_end_date: 2018-02-28
study_section: ZHL1-CSR-O(F1)
contact_pi_person_id: 6663799
contact_pi: BATES, PAULA J.
other_pis: KRENTSEL, EUGENE ;MILLER, DONALD M.
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 overarching goal of this project is to increase the success rate and speed with which the results of basic biomedical research are translated into products that have a positive impact on human health. To do this we propose to create a commercialization program at the University of Louisville (UofL) with a structure that is designed to overcome the many obstacles that currently impede translation. Though UofL is a relatively small institution in an IDeA state it has invested in talent and infrastructure for translational research in order to create a pro-entrepreneurial culture. This has already paid dividends and UofL has been awarded numerous major grants including three current COBRE awards a Coulter Translational Partnership the NIH Cardioprotection Consortium the NIH-UofL RBL (a BSL-3 facility) and multiple P-/U- series grants. Moreover UofL discoveries have led to interventions that have already benefited patients such as a first-in- class anticancer drug a method to prevent transplant rejection and a protocol that has allowed paraplegic patients to stand again. Many more UofL innovations are now on their way to clinical trials including new vaccines and minimally invasive devices to detect cancer. The proposed UofL REACH program will be known as "the ExCITE Hub" to reflect its function as a central resource for Expediting Commercialization Innovation Translation and Entrepreneurship. The hub is designed to fulfill the goals of the FOA (RFA-OD- 14-005) but is tailored to match UofL's specific strengths and needs. In short the university will supply a robust pipeline of diverse technologies and the infrastructure/expertise required for translational research whereas the Hub will deliver the necessary funding education and access to business expertise to bridge the gap between a great idea and the marketplace. The ExCITE Hub has three major aims: (1) identify the most promising technologies and provide funding for product definition studies (2) promote commercialization of selected products and transition to a self-sustaining ExCITE program and (3) expand educational experiential and networking opportunities for stakeholders. Our approach includes innovative features: (1) a geographically focused program to expedite operations and maximize impact on the local eco-system (2) an innovative governance structure to integrate the three main goals and avoid silos (3) a proactive rather than passive approach to education (4) a mentored technology development grant program that requires early interactions between scientists tech transfer staff and industry consultants and (5) an emphasis on improving academia-industry relationships by increasing mutual understanding ensuring robust technologies and being responsive to industry needs. Institutional and regional commitment to the ExCITE Hub is evident from the >$3.1M in matching funds and 40 letters of support. Success in this project will have a major economic impact on the region and will speed the delivery of innovative new products to the patients that need them.

project_terms:
Academia;Antineoplastic Agents;Award;Back;Basic Science;Biomedical Research;Businesses;Centers of Research Excellence;Clinical Trials;Complement;Development;Development Plans;Devices;Economic Development;Education;Educational process of instructing;Ensure;Entrepreneurship;Environment;Evaluation;Faculty;Federal Government;Funding;Goals;Graft Rejection;Grant;Health;Human;Income;Incubators;Industry;Institution;Intellectual Property;Intervention;Investments;Kentucky;Knowledge;Leadership;Letters;Malignant Neoplasms;Marketing;Mentors;Mentorship;Methods;Mission;Monitor;Nature;Paraplegia;Patients;Positioning Attribute;Private Sector;Problem Solving;Protocols documentation;Research;Research Infrastructure;Research Personnel;Resources;Scientist;Series;Source;Speed;Structure;System;Talents;Technology;Technology Transfer;Testing;Time;Translating;Translational Research;Translations;United States National Institutes of Health;Universities;Work;base;bench to bedside;biosafety level 3 facility;clinically relevant;commercialization;design;economic impact;education access;experience;human disease;improved;innovation;member;minimally invasive;novel vaccines;operation;prevent;programs;public-private partnership;success;technology development

public_health_relevance:
The federal government invests billions of dollars per year in basic research which has led to great advances inunderstanding human diseases but it is difficult to translate these discoveries into new treatments or tests thathelp patients. This is mainly because university scientists generally do not know how to convert their greatideas into useful products plus there is relatively little funding for product-driven research. This project willattempt to solve this problem by providing grants for technology development and teaching researchers aboutbusiness.


application_id: 9038210
project_number: 5R01AG045775-03
project_title: Translating CD33 genetic mechanism into a novel Alzheimers therapeutic
administering_ic: NIA
award_notice_date: 2016-03-31
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AG
serial_number: 045775
program_official: REFOLO, LORENZO
project_start_date: 2014-04-15
project_end_date: 2018-03-31
study_section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND]
contact_pi_person_id: 1859637
contact_pi: ESTUS, STEVEN
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 overarching theme of this proposal is that polymorphisms identified by recent Alzheimer's disease (AD) genome wide association studies biologically define rate-limiting steps in AD pathways. Hence elucidating their mechanism of action will identify robust pharmacologic targets. Notably a SNP with modest molecular actions may reduce AD risk by 10% but a drug that acts strongly at the same target may have a large effect on AD risk. This proposal will elucidate the mechanism of action of rs3865444 (rs444) an AD-associated SNP in CD33 and translate this mechanism into a proof of concept AD treatment. In our highly compelling preliminary results we associate the AD-protective minor allele of rs444 with (i) a robust increase in the proportion of CD33 lacking exon 2 (D2-CD33) which appears critical to CD33 function. Large pharma have developed humanized monoclonal antibodies against CD33 for acute myeloid leukemia (AML); these antibodies and their derivatives have potential AD relevance as CD33 antagonists. This leads to our global hypothesis: Reduced CD33 function decreases AD risk whether CD33 inhibition is due to genetics or pharmacologic agents. To test our hypothesis we will (i) Elucidate the mechanism underlying the CD33 AD SNP (ii) Compare CD33 and D2- CD33 function especially relative to AD pathogenic mechanisms and (iii) Translate CD33 genetics into a novel AD therapeutic mimic. Overall this focused proposal will develop our compelling mechanistic genetic results elucidate the differences in D2-CD33 and CD33 function and begin to translate these changes into an AD-preventive agent. In work beyond the scope of this focused proposal we anticipate that these therapeutic agents will be tested in "AD" murine models that are transgenic for human CD33 and eventually humans.

project_terms:
Acute Myelocytic Leukemia;Alleles;Alzheimer disease prevention;Alzheimer's Disease;Alzheimer's Disease Pathway;Alzheimer's disease risk;Antibodies;Apolipoprotein E;Apoptotic;Asses;Binding;Brain;Critical Pathways;Exons;Fab Immunoglobulins;Family member;Foundations;Future;Genes;Genetic;Genetic Polymorphism;Genotype;Goals;Half-Life;Health;Human;Immunoglobulins;In Vitro;Individual;Lectin;Length;Ligands;Mediator of activation protein;Messenger RNA;Microglia;Minor;Molecular;Mutate;NR0B2 gene;Neurons;Odds Ratio;PTPN11 gene;Phagocytosis;Pharmaceutical Preparations;Preventive;Process;Production;Protein Isoforms;Proteins;Public Health;RNA Splicing;Reporting;Sialic Acids;Signal Transduction;Single Nucleotide Polymorphism;Staging;Testing;Therapeutic;Therapeutic Agents;Transgenic Organisms;Translating;Work;cohort;cytokine;genome wide association study;humanized monoclonal antibodies;in vivo;inhibitor/antagonist;mouse model;novel;novel therapeutics;pre-clinical;receptor;sulfated glycoprotein 2;targeted agent;transcription activator-like effector nucleases;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The significance of this proposal to public health is that we will identify the mechanism whereby a genetic factor modulates the risk of Alzheimer's disease. We will then perform studies to identify agents that target this mechanism as proof-of-concept pre- clinical Alzheimer's disease prevention studies.


application_id: 9037780
project_number: 7R44GM099206-03
project_title: Novel method to create knockout rats using endonucleases and spermatogonial stem
administering_ic: NIGMS
award_notice_date: 2015-04-06
opportunity_number: PA-13-234
application_type: 7
activity_code: R44
ic: GM
serial_number: 099206
program_official: MAAS, STEFAN
project_start_date: 2011-09-05
project_end_date: 2017-08-31
study_section: Special Emphasis Panel[ZRG1-IMST-J(15)B]
contact_pi_person_id: 12627415
contact_pi: JAMLING, TSETEN YESHI
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 079703270
primary_uei: JK2VCZCBR8R4
duns_number: 079703270
uei: JK2VCZCBR8R4
fips: US
organization_id: 10038664
organization_name: HERA TESTING LABORATORIES, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405059002
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The laboratory rat is the preferred rodent model in pre-clinical drug studies and encompasses the bulk ofaccumulated knowledge in drug development. Their larger size facilitates procedures otherwise difficult inmice including studies using instrumentation blood sampling and surgeries. Although rats are moresuitable than mice for pharmacological toxicological physiological and many other biological assays theease of genetic engineering technologies has made the mouse the preeminent rodent model. Howeverthe recent emergence of new and more precise gene targeting techniques for the rat has resulted insignificant growth in the production of genetically-modified rats. In Phase I we demonstrated the feasibilityof combining custom site-specific Xanthomonas TAL Nuclease (XTNTM) [a.k.a. TALEN] technology withspermatogonial stem cells (SSCs) for rapid cost-effective and precise genome engineering in the rat.Indeed the Phase I studies enabled Transposagen to launch custom XTNTM and knockout rat productionservices in 2012. The proposed studies will address the unmet need for rat models for drug discoveryapplications. Creating knockout models for enzymes involved in drug metabolism which are often arrangedas closely linked members of multi-gene families presents a new production challenge. In this proposalwe will develop strategies for creating large-scale deletions of multi-gene families combined withhumanizing transgenic engineering to create novel and more predictive models for drug discovery.We will develop protocols to use XTNTMs to generate large-scale chromosomal deletions in SSCs that willeliminate whole gene families from the genome. To optimize the experimental approach we will outlinestudies to delete the 2-gene MATE complex which is located within a 70-kb segment of Chromosome 10and the 5-gene Cyp2d cluster located within a 60-kb segment of Chromosome 7. SSCs that harbor a 45-kb deletion that knocks out the entire Cyp2d complex will be transplanted into recipient males to create aCyp2d null rat for CYP2D6 humanization studies. To create humanized rats we will clone the wild typeCYP2D6 gene (including its promoter) as well as four other common CYP2D6* variant genes into individualpiggyBacTM (PB) vectors. The five PB-CYP2D6 constructs will be used to create five SSC lines that carryan average of one copy of the transgenic vector per cell and founder animals will be generated from eachSSC line. Each PB-CYP2D6 transgenic allele will be crossed into the Cyp2d cluster mutant background forphenotypic analysis. In the future humanized animal models in which various combinations of CYP2D6*alleles would be of great value for testing the effect of drug candidates. The proposed Phase II studies willdevelop multiple protocols for genome engineering in the rat so that the most appropriate strategy can beexecuted to engineer the desired mutation. The success of this project will promote cost-effectivetechnologies that can be used to create humanized models of choice in the appropriate null background fordrug testing.

public_health_relevance:
Project NarrativeThe laboratory rat has been a valuable animal model for biomedical research due to its similarity to humanphysiology. Pharmaceutical companies currently rely primarily on animal or transformed cell models for pre-clinical metabolism and toxicity testing during drug discovery. Thus there is a compelling need for animalmodels that are more predictive for ADME properties in humans. However the ease and lower costsassociated with generating mutations in mice has lead to a greater reliance on genetically engineered mousemodels despite the inability of many of these models to mimic human pathways. We outline a strategy thatintegrates our expertise in spermatogonial stem cells (SSCs) with a site-specific enzyme technology to createknockout and humanized rat models for drug discovery applications. Thus this project would benefit manygoals of public health by making the production of mutations in the rat that better model human physiologyreadily accessible to the research community.


application_id: 9036544
project_number: 7R03NS089433-02
project_title: microRNA-124 restores nerurogenesis in HIV-1 associated neurocognitve disorders
administering_ic: NINDS
award_notice_date: 2015-05-05
opportunity_number: PA-13-304
application_type: 7
activity_code: R03
ic: NS
serial_number: 089433
program_official: WONG, MAY
project_start_date: 2014-07-01
project_end_date: 2016-06-30
study_section: NeuroAIDS and other End-Organ Diseases Study Section[NAED]
contact_pi_person_id: 9742546
contact_pi: PENG, HUI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION: Neurological disorders associated with HIV-1 affect 40-70% of infected individuals and is characterized as HIV- 1-associated neurocognitive disorders (HAND). While antiretroviral therapy (ART) has diminished disease severity milder forms of cognitive impairment remain commonplace. It is critical to discover new therapeutic strategies to fully prevent the neurocognitive impairment. Active neurogenesis occurs throughout life and relies upon the proliferation migration and proper differentiation of neural stem/progenitor cells (NPCs). Under pathological conditions of the central nervous system (CNS) associated with neuroinflammation such as HAND monocytes/macrophages infiltrating the CNS in concert with activated resident microglia play a major role in the neurodegenerative process of HAND. Activated macrophage/microglia produce inflammatory mediators such as cytokines and chemokines affect the capacity of brain stem cells and alter neurogenesis. Various types of macrophage/microglia activation depending on the conditions can either enhance or suppress neurogenesis. Inflammation-associated M1 macrophages/microglia can inhibit neurogenesis; whereas IL-4-activated M2 macrophages/microglia can induce both neurogenesis and oligodendrogenesis. In HAND HIV-1 infection in the brain inhibits neurogenesis with generation of fewer adult NPCs in the dentate gyrus of the hippocampus. Moreover NPCs preferably differentiate into astrocytes rather than neurons. Our previous studies demonstrated HIV-1-infected and LPS-activated (M1) Macrophages inhibit neurogenesis while enhancing gliogenesis through secretion of inflammatory cytokines such as IL-1? and TNF-?. microRNA- 124 (miR-124) has recently been shown to deactivate M1 macrophages and skew their polarization from an M1 toward an M2 phenotype. miR-124 may serve as a useful tool to transfer detrimental pro-inflammatory M1 macrophages/microglia to beneficial M2 macrophages/microglia. Therefore we propose the following specific aims: Aim 1: To investigate how miR-124 deactivates HIV-1-infected M1 macrophages/microglia or polarizes them to an M2 phenotype and promotes neurogenesis in vitro. Aim 2: To investigate the therapeutic potential of miR-124 for ameliorating HIV-1-infection-mediated inhibition of neurogenesis in HIV-1 encephalitis (HIVE) and humanized mouse models. We will test our hypothesis using primary human NPC macrophage/microglia culture systems and HIVE and humanized mouse models. This novel system mimics the HIV-1-infection and immune-activation of brain macrophage/microglia as they occur within the CNS during HAND. We will validate the effect of miR-124 on modulating macrophage/microglia activation and its subsequent effect on neurogenesis in vitro and in vivo. The data generated from this study will help to identify a highl innovative strategy for HAND therapy. Furthermore these findings will provide insight into a range of other neurodegenerative and neuroinflammatory diseases in which macrophage/microglia activation plays an important role.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: HIV infection of the central nervous system can result in HIV-1-associated neurocognitive disorders (HAND) while neural stem cell dysfunction may contribute to disease pathogenesis. This proposal is aimed at understanding the molecular mechanisms that regulate neurogenesis in HAND and testing the therapeutic potential of microRNA-124 for ameliorating disrupted neurogenesis.


application_id: 9036506
project_number: 1R01AT008617-01A1
project_title: Plant exosomes non-coding RNA-mediated anti-inflammatory mechanisms
administering_ic: NCCIH
award_notice_date: 2015-11-20
opportunity_number: PAR-13-375
application_type: 1
activity_code: R01
ic: AT
serial_number: 008617
suffix: A1
program_official: HOPP, CRAIG
project_start_date: 2015-12-01
project_end_date: 2020-11-30
study_section: Special Emphasis Panel[ZRG1 EMNR-V (55)]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Anti-Inflammatory Agents;Anti-inflammatory;Antigens;Bacteria;Binding;Biological;Cells;Chronic;Colitis;Communication;Complementary Medicine;Complex;Crohn's disease;Data;Dendritic Cells;Diet;Disease;Edible Plants;Encapsulated;Escherichia;Escherichia coli;Exposure to;Food;Foundations;Genes;Ginger;Goals;Grapefruit;Health;Heating;Homeostasis;Immune;Immune Tolerance;Immune response;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Inflammatory disease of the intestine;Interleukin-1;Interleukin-1 beta;Interleukin-10;Interleukin-6;Intestines;Investigation;Killings;Lamina Propria;Lipids;Literature;Macrophage Activation;Mediating;MicroRNAs;Modeling;Molecular;Mononuclear;Mucous Membrane;Mus;Myeloid Cell Activation;Natural Products;Oral Administration;Pathway interactions;Patients;Phagocytes;Plant Extracts;Plants;Play;Prevention;Production;Property;Proteins;Publishing;RNA Binding;Role;Sampling;Signal Transduction;Small RNA;Sodium Dextran Sulfate;Sorting - Cell Movement;TNF gene;Testing;Untranslated RNA;Untranslated Regions;base;bioactive natural products;cytokine;exosome;feeding;fruits and vegetables;in vitro testing;in vivo;lymph nodes;macrophage;mouse model;nanoparticle;prevent;public health relevance;research study;transcription factor;uptake


application_id: 9036128
project_number: 1R01CE002690-01
project_title: Randomized Trial Integrating Substance Abuse with Bystander-Based Violence Prevention
administering_ic: NCIPC
award_notice_date: 2015-08-27
opportunity_number: RFA-CE-15-001
application_type: 1
activity_code: R01
ic: CE
serial_number: 002690
program_official: WRIGHT, MARCIENNE
project_start_date: 2015-09-01
project_end_date: 2018-08-31
study_section: Special Emphasis Panel[ZCE1 EEO (01)]
contact_pi_person_id: 9247640
contact_pi: BUSH, HEATHER M
other_pis: COKER, ANN L
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Rates of sexual violence (SV) or dating violence (DV) remain high among college students (22% in the past year for female undergraduates). Binge drinking commonly occurs (25% of undergraduates report binge drinking in the past month) and is a strong predictor of sexual risk taking and violent victimization and perpetration. Given connections between SV/DV risk and alcohol use and abuse many advocate prevention programming to jointly address SV/DV and alcohol abuse. Bystander interventions recognized as promising violence prevention strategies are unique in their engagement of all community members to 1) recognize situations that may become violent and 2) learn to safely and effectively intervene to reduce violence risk. Based on their promise the Campus Sexual Violence Elimination Act (SaVE) now requires all publicly-funded colleges to provide a bystander intervention aimed at reducing SV/DV. No randomized intervention trial to date has compared bystander interventions focused exclusively on SV/DV prevention with those that also address alcohol abuse prevention within the bystander context. We propose such an experimental trial at the University of Kentucky (UK) a nationally recognized leader in addressing SV through bystander intervention programming. This randomized intervention trial is designed to evaluate the relative efficacy of three bystander training conditions. Per UK policy all incoming undergraduates participate in mandatory online SV training and students recruited for this study will be randomized to a condition with one of the following additional elements: 1) Green Dot Intensive Bystander Training combined with Substance Abuse Prevention Training (SubINT); 2) Green Dot Intensive Bystander Training (INT) or 3) No add-on online bystander training alone (Online). Aim 1: Evaluate methods to capture bystander behaviors and diffusion of training through social media communications (e.g. Facebook Twitter and Instagram). Aim 2: Determine the relative efficacy of the three bystander training conditions to a) increase bystander efficacy and behaviors by domain (alcohol abuse and violence prevention) b) reduce acceptance of SV/DV alcohol's role in sexual behavior and alcohol use / abuse and c) reduce risk taking behaviors by domains of sexual behavior and alcohol use / abuse. Aim 3: Determine the relative cost of implementing bystander approaches and their cost effectiveness. Design: Incoming UK undergraduates will be recruited and randomized to one of the three conditions and followed for one academic year (9 months) (n=6000 total over 3 academic year cohorts). A mixed-method approach will measure intervention fidelity and costs over time and by condition. Value-Added: UK Analytics and Technology will serve as a trusted broker to link and aggregate by randomized condition available external data from mandatory Campus Attitudes Toward Safety (CATS) and other assessments and academic records. Using the most rigorous design available we seek to generate a new understanding of how novel bystander intervention approaches work to reduce not only SV/DV risk taking behaviors but also reduce alcohol abuse.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: While publicly-funded colleges are now required to implement bystander interventions focused on sexual violence (SV) prevention few intervention programs have been rigorous evaluated to determine efficacy and cost effectiveness to reduce sexual violence. This large randomized intervention trial of 6000 undergraduates will provide such an evaluation. These results will assist colleges in selecting interventions most likely to reduce the
epidemic of SV (1 in 5 women undergraduates report unwanted sex in the year).


application_id: 9035960
project_number: 1R21AG050133-01A1
project_title: Can low blood glucose extend health
administering_ic: NIA
award_notice_date: 2016-04-21
opportunity_number: PA-13-156
application_type: 1
activity_code: R21
ic: AG
serial_number: 050133
suffix: A1
program_official: FRIDELL, YIH-WOEI
project_start_date: 2016-05-01
project_end_date: 2018-04-30
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 1927079
contact_pi: EPSTEIN, PAUL N
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Aging of the world population has made prolongation of health a more important priority than ever.Several models of extended health and delayed aging such as caloric restriction and mouse models ofdwarfism demonstrate low blood glucose. However these models have complex physiology and it isnot known whether low blood glucose is important to their prolonged health and extended lifespan. Ofpotential value to understanding the relationship between blood glucose and aging is a transgenicmouse line designated Inshex with a healthy phenotype but permanently low blood glucose 25-50%lower than normal mice. The mouse was originally developed mice to study pancreatic -cells anddiabetes. The Inshex transgene produced a left shift in the pancreatic -cell insulin secretion responseto glucose but the final phenotype is hypoglycemia with almost normal serum insulin levels. Thisproposal will use Inshex mice to test if blood glucose influences aging. Inshex mice are healthy ofnormal size and fertile. Blood glucose is reduced at 500 days of age. The first goals of this project areto confirm that blood glucose stays low permanently and that reduced blood glucose extends longevity.Lifespan will be determined in cohorts of 30 male Inshex and 30 non-transgenic littermates that will befollowed undisturbed to determine the age when mice become moribund and require euthanasia. Aveterinary pathologist will assess the cause of morbidity. Over the course of their lives mice will beobserved daily and weighed monthly. In separate cohorts of Inshex and control mice blood and urinesamples will be obtained at 3 month intervals to measure blood glucose HbA1c plasma free fatty acidsand urine albumin to creatinine ratio. Groups of mice will be sacrificed at 5 10 and 20 months of age.The day before sacrifice mice will be placed in metabolic chambers to determine respiratory quotient byindirect calorimetry and simultaneously measure ambulatory activity. Unlike other mouse models withlow glucose initial results indicate that Inshex mice have a normal respiratory quotient. After themetabolic chamber animals will be anesthetized for DEXA scan measurement of body composition andfor obtaining a large blood sample to measure metabolic hormones implicated in modulation of aging(insulin IGF1 or growth hormone). Aging is the leading cause for loss of renal function in people. Apreliminary analysis indicated less glomerular scarring in 400-500 day Inshex kidneys. The beneficialeffect of Inshex low glucose on kidney structure and function will be confirmed by examining renalhistology of control and Inshex mice sacrificed at 5 10 and 20 months and by comparing ageassociated leakage of albumin into the urine. These studies will demonstrate whether low bloodglucose extends function of the kidney and lifespan of the mouse.

project_terms:
Age;Age-Months;Aging;Albumins;Animals;Backcrossings;Biological Assay;Blood;Blood Glucose;Blood specimen;Body Composition;Caloric Restriction;Cause of Death;Cicatrix;Comorbidity;Complex;Creatinine;Development;Diabetes Mellitus;Diabetic Nephropathy;Dual-Energy X-Ray Absorptiometry;Dwarfism;Euthanasia;Extravasation;FVB Mouse;Figs - dietary;Founder Generation;Glucose;Glycosylated hemoglobin A;Goals;Health;Histology;Hormonal;Hormones;Hypoglycemia;IGF1 gene;Indirect Calorimetry;Insulin;Kidney;Kidney Diseases;Laboratories;Left;Life;Longevity;Measurement;Measures;Metabolic;Metabolic Control;Metabolism;Modeling;Morbidity - disease rate;Mus;Nonesterified Fatty Acids;Organ;Paper;Pathologist;Pathology;Phenotype;Physiology;Plasma;Population;Proteins;RNA;Renal function;Reporting;Research;Sampling;Scanning;Serum;Somatotropin;Spottings;Staining method;Stains;Structure;Structure of beta Cell of islet;Testing;Time;Transgenes;Transgenic Mice;Urine;blood glucose regulation;cohort;functional decline;insulin secretion;male;mouse model;novel;respiratory;response

public_health_relevance:
Lowbloodglucoseiscommontoseveralcomplexmodelsofextendedhealthandlifebutitisnotknowniflowglucoseisimportanttoprolongedhealthoranonessentialbyproduct.Thisprojectwilltestanovelmousemodelwhichhaslowbloodglucoseastheprimarydifferencefromnormalmicetotestiflowbloodglucoseissufficienttoextendlongevity.


application_id: 9035924
project_number: 1U01CE002668-01
project_title: BYSTANDER PROGRAM ADOPTION & EFFICACY TO REDUCE SV-IPV IN COLLEGE COMMUNITY
administering_ic: NCIPC
award_notice_date: 2015-09-07
opportunity_number: RFA-CE-15-003
application_type: 1
activity_code: U01
ic: CE
serial_number: 002668
program_official: WRIGHT, MARCIENNE
project_start_date: 2015-09-30
project_end_date: 2019-09-29
study_section: Special Emphasis Panel[ZCE1 GXC (01)]
contact_pi_person_id: 9247640
contact_pi: BUSH, HEATHER M
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Rates of physically forced sex to dating violence remain high in college communities (22% of 10000 female undergraduates disclosed these forms of violence against women (VAW) in the past 12 months (2010-2013).  Bystander interventions recognized as promising violence prevention strategies are unique in their engagement of all community members to 1) recognize situations that may become violent and 2) learn to safely and effectively intervene to reduce violence risk.  Based on their promise the Campus Sexual Violence Elimination Act (SaVE) now requires all publicly-funded college to provide bystander intervention.  With SaVE's policy intervention requiring bystander intervention a "natural experiment" has arisen to determine the relative efficacy of students' bystander training across multiple colleges.  We propose a quasi-experimental design with fractional factorials to evaluate the relative efficacy of bystander interventions components to reduce violence in college communities.  Green Dot will be one of the bystander intervention components evaluated because our group has considerable experience rigorously evaluating Green Dot and we have recently found that this bystander intervention is associated with a 20-40% reduction in VAW in college and high school settings.  Aim 1.  Compare the relative efficacy of bystander interventions to 1) increase bystander efficacy and behaviors 2) reduce violence acceptance 3) reduce violence victimization and perpetration and 4) increase program cost effectiveness.  The three primary bystander groups compared will be:  a) exclusively online training Green Dot (speeches and intensive bystander training) and other skills-based by stander training.  Program efficacy data will be obtained from student surveys campus crime statistics and surveys with college staff and administrators responsible for selecting and implementing bystander interventions.  We will collect data at each college for the full 4 years of
the project (~50000 students annually.  Infrastructure provided by the Kentucky Center for Clinical and Translational Science at the University of Kentucky and West Virginia University will support a VAW Research Coordinating Center for all electronic data collection and analyses from 24 recruited colleges comparing the different bystander interventions.  VAW researchers draw from multiple disciplines yet few training programs support this diverse field of highly relevant applied research.  Thus we seek to grow communities of VAW prevention researchers.  Researcher communities will form through researcher' engagement with college recruitment survey design data collection and analyses.  Aim 2.  Determine the efficacy of this program to increase VAW prevention research productivity defined as 1) increasing research skills and 2) increasing research communities measured as manuscript submissions presentations and publications.  This natural experiment will generate new understanding of how and what bystander components work to prevent violence.  It will also provide the VAW research community an opportunity to increase our skill-sets and share our experiences with and help grow the next generation of VAW prevention researchers.

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Campus SaVE (2013) now requires publicly-funded colleges to provide training in bystander interventions.  We seek to seize this "natural experiment" opportunity and will evaluate the efficacy of implemented training components to reduce sexual and dating violence in 24 large colleges over 4 years.  Through this evaluation we will also develop a collaboration to grow the next generation of violence prevention researchers.


application_id: 9034411
project_number: 7R43ES023718-02
project_title: Novel reporter cell lines for neurotoxicant assays
administering_ic: NIEHS
award_notice_date: 2015-03-25
opportunity_number: PA-14-071
application_type: 7
activity_code: R43
ic: ES
serial_number: 023718
program_official: SHAUGHNESSY, DANIEL
project_start_date: 2014-09-18
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZRG1-ETTN-M(11)B]
contact_pi_person_id: 3075176
contact_pi: OSTERTAG, ERIC M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 079703270
primary_uei: JK2VCZCBR8R4
duns_number: 079703270
uei: JK2VCZCBR8R4
fips: US
organization_id: 10038664
organization_name: HERA TESTING LABORATORIES, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405059002
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): While it has been demonstrated that gene mutations are associated with an increasing number of neurodegenerative syndromes environmental neurotoxicants remain a key factor in the etiology of many such diseases. For example exposure to pesticides such as maneb and paraquat increase the risk of developing Parkinson's disease. Unfortunately there is no optimal in vitro model system to assess the neurotoxic potential of compounds. As result exposure to poorly characterized compounds represents a significant contributor to the development of environmentally-induced diseases. There is a compelling unmet need for in vitro models and endpoint assays that are cost-effective accurate predictive and sensitive that would also be amenable to high throughput screening. In particular there is a need to develop homogeneous in vitro screens that can be used in quantitative high-throughput screening to query large libraries of chemical compounds such as the 'Tox21 10K' chemical library. We will take advantage of our core strengths in site-specific nuclease genome engineering and Footprint-Free" Gene Editing to produce reporter cell lines in which we will insert reporter genes into the endogenous toxicant-responsive genes SERPINE1 and DDIT3 by homologous recombination (i.e. create knockin mutations) in order to create a cost- effective rapid system for neurotoxicity testing. Briefly we engineer a SERPINE1 exon 2-specific site-specific nuclease in-house to drive the targeted insertion of firefly luciferase T2A-renilla luciferase (lux) reporter immediately downstream of the SERPINE1 initiator ATG so that the lux gene will be placed under the control of SERPINE1 promoter within the native genomic context; similarly we will knock in a TEM1-beta lactamase reporter behind the ATG of DDIT3. The targeting vectors will contain a piggyBac selection module containing the puromycin resistance and thymidine kinase genes to allow selection for candidate targeted clones via puromycin resistance and to select for complete removal of the expression module upon transient expression of excision-only piggyBac transposase via ganciclovir resistance. As a result the endogenous SERPINE1 and DDIT3 loci will contain their respective reporters without any other foreign DNA sequences will be created. To validate the function of the reporter cells we will compare the induction properties of the targeted lux and BLA reporters with that of their corresponding untargeted (wild type) alleles using reporter (luciferase or beta-lactamase) and qRT-PCR assays respectively. Success will be achieved if the magnitude of induction for the reporters falls within 20% of the induction observed for each reporter's corresponding endogenous gene for each test compound assayed. Validation of the cell lines will provide an initial tool for screening high-throughput screening for neurotoxicants and will represent the development of a powerful platform technology for the creation of cell lines for neurotoxicology screening. In the long term Phase II studies would be aimed at creating a bank of reporter cell lines that sample the responses of multiple loci in a variety of lines that we will be able to markt as catalog items; we would also be able to market custom creation of knock-in toxicant-responsive reporter lines and the use of either catalog or custom cell lines in fee-for-service toxicity testing as a service to academic and industry investigators and open new opportunities for examining the impact of agents on specific pathways in a wide variety of cellular contexts.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The in vitro tools currently used for testing the toxicity of potential neurotoxicants are not optimal and frequently result in incorrect information about a compound or screen. Given that neurotoxicity can lead to Parkinson-like degenerative diseases new strategies that are cost-effective accurate predictive and sensitive would be a great value for preventing disease caused by man-made or natural compound exposure.


application_id: 9034312
project_number: 1K08DK102542-01A1
project_title: Nephritogenic autoantibodies in systemic lupus
administering_ic: NIDDK
award_notice_date: 2016-02-25
opportunity_number: PA-14-046
application_type: 1
activity_code: K08
ic: DK
serial_number: 102542
suffix: A1
program_official: RANKIN, TRACY L
project_start_date: 2016-02-25
project_end_date: 2021-02-24
study_section: Kidney, Urologic and Hematologic Diseases D Study Section[DDK-D]
contact_pi_person_id: 11177796
contact_pi: CASTER, DAWN
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): Up to 60% of SLE patients develop clinical evidence of kidney injury termed lupus nephritis (LN). LN is thought to be caused by glomerular immune complex deposition activating an inflammatory cascade that injures glomerular cells leading to proteinuria and loss of filtration capacity. LN is classified based on renal histopathology into si classes of which proliferative LN (ISN/RPS class III or IV) is most likely to cause renal failure.
Most studies examining the causes of proliferative LN have focused on the nephritogenic potential of anti-nuclear antibodies diverting attention from a potential role for tissue/cell-specific autoantibodies. There is increasing evidence that autoantibodies to tissue specific target antigens contribute to the pathogenesis of many glomerular diseases including LN. Our preliminary data show that sera from patients with proliferative LN contain autoantibodies to human glomerular proteins including annexin A2 and moesin. These findings support our central hypothesis that autoantibodies targeting glomerular proteins including annexin A2 and moesin result in immune complex deposition that causes proliferative LN. This mentored career development proposal will focus on further characterization of autoantibodies to annexin A2 and moesin in proliferative LN validation of those autoantibodies as biomarkers for disease examination of the functional changes in podocytes and mesangial cells exposed to those autoantibodies and evaluation of the nephritogenic potential of those antibodies in animal models. As evidenced by the advances in understanding primary membranous nephropathy after the identification of target antigens this will lead to improved understanding of the pathogenic mechanisms of disease and provide new diagnostic and prognostic biomarkers. This mentored career development award also will provide protected time for the applicant to develop the skills required to become an independent physician-scientist investigating clinical and basic aspects of lupus nephritis through an individualized career development plan which has been developed by the mentorship team.

project_terms:
Accounting;Actins;Address;Affect;American;Animal Model;Annexins;Antibodies;Antigen Targeting;Antigen-Antibody Complex;Attention;Autoantibodies;Autoimmune Diseases;Award;Biological Markers;Cell physiology;Cells;Clinical;Cytoskeleton;Data;Deposition;Development;Development Plans;Dialysis procedure;Discipline;Disease;End stage renal failure;Evaluation;Filtration;Functional disorder;Goals;Histopathology;Human;Immunoglobulin G;Inflammatory;Inflammatory Response;Injection of therapeutic agent;Injury;K-Series Research Career Programs;Kidney;Kidney Failure;Knowledge;Lead;Life;Lupus;Lupus Nephritis;Membranous Glomerulonephritis;Mentors;Mentorship;Nuclear;Nucleosomes;Pathogenesis;Patients;Physicians;Prognostic Marker;Proteins;Proteinuria;Publications;Renal glomerular disease;Research;Role;Scientist;Serum;Systemic Lupus Erythematosus;Testing;Therapeutic immunosuppression;Time;Tissues;Training;Treatment Protocols;Validation;base;career;career development;diagnostic biomarker;disease diagnosis;ds-DNA;experience;improved;improved outcome;injured;lupus prone mice;mesangial cell;moesin;mouse model;novel diagnostics;podocyte;programs;public health relevance;research study;skills;treatment response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The objective of this mentored Career Development proposal is to characterize cell/tissue specific nephritogenic autoantibodies that cause proliferative LN (class III/IV). This research is expected to establish the pathophysiologic basis for proliferative
LN as well as identify biomarkers for the diagnosis of this disease providing the technologic and intellectual framework necessary for the applicant to develop an independent research program in this discipline.


application_id: 9033942
project_number: 4R25HL084695-10
project_title: Summer Undergraduate Experiences in Biomedical Research
administering_ic: NHLBI
award_notice_date: 2016-04-04
opportunity_number: RFA-HL-12-031
application_type: 4
activity_code: R25
ic: HL
serial_number: 084695
program_official: WANG, WAYNE C
project_start_date: 2006-04-07
project_end_date: 2018-03-31
study_section: ZHL1-CSR-F(M1)
contact_pi_person_id: 1917399
contact_pi: JOSHUA, IRVING G
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The primary goal of this program is to provide minority and disadvantaged undergraduate students with an initial exposure to basic and clinical science researchers and their areas of cardiovascular interest at the University of Louisville Health Sciences Center. This program is designed to support 8 undergraduate students each summer. It is anticipated that a significant number of the undergraduate students will elect to enter into graduate research programs at either this university or others around the country as a result of the experiences in our program. Emphasis will be placed on exposing students to literature-based hypothesis generation experimental design and appropriate data analysis procedures. The students will be exposed to a biomedical research environment that emphasizes collaboration between basic and clinical science researchers and that clearly demonstrates the clinical relevance of cardiovascular research that is being conducted at this university. Based on results from our first 5 years of the program we expect that at least 25% of the graduating participants will enter into a biomedically related research program. We also expect a number of minority and disadvantaged students interested in a medical or medically related career to participate in this program. We therefore project that at least 50% of our student participants will either enter a graduate research program or medical school when they complete their undergraduate program.  (End of Abstract)

project_terms:
Animal Experimentation;Animals;Area;Basic Science;Biomedical Research;Cardiovascular system;Clinical Sciences;Collaborations;Country;Data Analyses;Degree program;Development;Disadvantaged;Doctor of Philosophy;Environment;Ethics;Experimental Designs;Exposure to;Generations;Goals;Health Sciences;Investigation;Literature;Medical;Medicine;Methods;Minority;Participant;Perception;Procedures;Research;Research Personnel;Residencies;Students;Training Programs;Universities;abstracting;base;career;clinically relevant;design;disadvantaged student;experience;interest;medical schools;minority student;programs;research study;summer program;undergraduate student

public_health_relevance:
This summer program provides minority and disadvantaged undergraduate students with an initialexposure to basic and clinical science researchers and their areas of cardiovascular interest at theUniversity of Louisville Health Sciences Center. It is anticipated that significant number of theundergraduate students will elect to enter into graduate research programs at either this university orothers around the country as a results of the experiences in our program.


application_id: 9033662
project_number: 5F31CA196219-02
project_title: Erbin-mediated regulation of colon cancer progression
administering_ic: NCI
award_notice_date: 2016-01-29
opportunity_number: PA-14-147
application_type: 5
activity_code: F31
ic: CA
serial_number: 196219
program_official: SCHMIDT, MICHAEL K
project_start_date: 2015-03-03
project_end_date: 2018-03-02
study_section: Special Emphasis Panel[ZRG1-F09B-B(20)L]
contact_pi_person_id: 12351385
contact_pi: STEVENS, PAYTON D
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): Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Approximately 136000 new cases and 50310 deaths are predicted for the year 2014; this mortality is predominantly due to metastasis to other organs. If advances are to be made in the survival of colorectal cancer patients a better understanding of the molecular mechanisms involved in CRC metastasis is required. In this proposed study I plan to investigate the role of Erbin a basolateral-localized scaffolding protei in inhibiting CRC invasion and metastasis. This proposal centers on a novel discovery that Erbin plays an important role in suppressing epithelial-mesenchymal transition (EMT) of CRC cells by controlling cell polarity. The proper establishment of epithelial polarity allows cells to sense an respond to signals that arise from the microenvironment in a spatiotemporally controlled manner. Increasing evidence has suggested that disruption of this cellular polarity promotes the malignant progression of cancer cells. However the molecular mechanism underlying polarity regulation in the initiation and progression of CRC remains largely unknown. In my preliminary experiments I have found that knockdown of Erbin induces an EMT-like phenotype and promotes migration in CRC cells. In addition silencing Erbin resulted in the disruption of cell polarity in 3D cultures mislocalization of EGF receptors (EGFRs) and an increase in the activation of EGFR signaling. To begin to elucidate the underlying molecular mechanism we identified PHLPP a novel tumor suppressor in CRC as an interacting protein of Erbin. Interestingly loss of Erbin expression resulted in an increase in both Akt and ERK activation similar to that observed in PHLPP knockdown cells. I hypothesize that Erbin serves as a scaffolding protein bringing PHLPP in close proximity with its substrates. This interaction between PHLPP and Erbin could provide the spatial-temporal control necessary to suppress oncogenic Akt and RAS/RAF signaling. Furthermore the analysis of Erbin mRNA expression in two large sets of CRC patient samples revealed that Erbin is significantly down regulated in cancer specimens compared to normal controls thus supporting the role of Erbin as a tumor suppressor in CRC. In light of our preliminary findings the central hypothesis driving this proposal is that Erbin plays a critical role in inhibiting CRC metastasis and it functions by maintaining cell polarity to inhibit Akt- and RAS/RAF-mediated oncogenic signaling. The following specific aims are proposed: 1) to define the functional effects of Erbin in inhibiting CR invasion and metastasis. We will elucidate the molecular mechanism by which loss of Erbin promotes CRC invasion and metastasis both in vitro and in vivo; 2) to determine the role of Erbin in regulating PHLPP-dependent inhibition of Akt and RAS/RAF pathways. Defining the role of Erbin in tumor metastasis will have sustained impact on improving CRC patient care. Working on this project I will not only gain more research experience but also master the problem solving and communication skills needed to fulfill my career goals.

project_terms:
Automobile Driving;Binding Proteins;Cancer Center;Cancer Etiology;Cell Polarity;Cell Proliferation;Cells;Cessation of life;Characteristics;Colon Carcinoma;Colorectal Cancer;Communication;Complex;Data;ERBB2 gene;Epidermal Growth Factor Receptor;Epithelial;Epithelial Cells;Event;Goals;Growth;Homeostasis;Human;In Vitro;In-Migration;Knowledge;Leucine-Rich Repeat;Light;Maintenance;Malignant - descriptor;Malignant Neoplasms;Mediating;Mentors;Mesenchymal;Molecular;Neoplasm Metastasis;Oncogenic;Organ;Outcome;Pathway interactions;Patient Care;Phenotype;Play;Problem Solving;Prognostic Marker;Protein Family;Protein phosphatase;Proteins;Proteus;Publishing;RAF1 gene;Receptor Signaling;Regulation;Research;Role;Sampling;Scaffolding Protein;Signal Pathway;Signal Transduction;Specimen;Structure-Activity Relationship;Substrate Interaction;Testing;Tissues;Training;Tumor Suppressor Proteins;United States;Work;base;cancer cell;career;cell motility;collaborative environment;colon cancer patients;epithelial to mesenchymal transition;experience;improved;in vivo;insight;knock-down;mRNA Expression;member;mortality;mouse model;novel;outcome forecast;prevent;public health relevance;research study;scaffold;skills;spatiotemporal;three dimensional cell culture;tumor;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Approximately 142000 new cases and 51000 deaths are predicted for the year 2014; this mortality is predominantly due to metastasis to systemic organs. A better understanding of the molecular events leading to cancer metastasis is needed in order to improve the treatment and prognosis of CRC patients. Our studies we will focus on elucidating the functional importance of a novel tumor suppressor Erbin in preventing metastasis in CRC.


application_id: 9032474
project_number: 5R01CA186661-03
project_title: Small molecule targeting of MIF as a novel melanoma therapeutic
administering_ic: NCI
award_notice_date: 2016-03-26
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 186661
program_official: ALLEY, MICHAEL C
project_start_date: 2014-04-03
project_end_date: 2019-03-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 7360475
contact_pi: MITCHELL, ROBERT A
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are critically important determinants of solid tumor immunosuppression neovascularization and metastatic dissemination. Despite intensive efforts aimed at identifying TAM/MDSC regulatory effectors very few have been identified that can orchestrate this process and be effectively targeted.  Macrophage migration inhibitory factor (MIF) is one the oldest cytokine activities described and is a centrally important mediator of monocyte/macrophage immune responses. TAMs and MDSCs from melanoma bearing MIF-deficient mice exhibit a unique reversion in their "polarization" state resulting in a switch from n immunosuppressive angiogenic phenotype (MIF+/+ TAM/MDSC) into an immunostimulatory non-angiogenic phenotype (MIF-/- TAM/MDSC) which results in significant reductions in primary and metastatic melanoma disease progression. Intriguingly our previously discovered MIF small molecule antagonist - 4-iodo-6- phenylpyrimidine (4-IPP) - fully recapitulates MIF-deficiency both in vitro and in vivo and serves to attenuate TAM and MDSC alternative activation immunosuppression neoangiogenesis and melanoma disease progression [1601]. We very recently discovered that 4-IPP functionally inhibits MIF by dramatically reducing intracellular MIF protein levels in a proteasome-dependent manner. However relatively high 4-IPP IC50 values and a lack of information on its mechanism of action bioavailability and chronic toxicity dictate that much more study is needed to fully identify optimize and characterize lead MIF-degradation inducing compounds before moving forward with small molecule MIF targeting in a clinical setting. To fulfill the stated objectives of this application the following aims areproposed: Aim 1: Delineate the mechanisms of action of 4-IPP and MIF-dependent TAM/MDSC polarization Aim 2: Characterize TAM/MDSC modulatory in vivo bioavailability toxicity and anti-tumor activities of existing and newly identified MIF inhibitor scaffolds and Aim 3: Evaluatethe therapeutic potential of lead MIF small molecule antagonists as individual and combinatorial modalities against established melanoma.

project_terms:
5'-AMP-activated protein kinase;American;Antibody Therapy;Attenuated;Binding;Biological Availability;Cancer Center;Cancer Patient;Cells;Chemotherapy-Oncologic Procedure;Chimeric Proteins;Chronic;Clinical;Clinical Trials;Cytotoxic T-Lymphocyte-Associated Protein 4;Denileukin Diftitox;Diagnosis;Disease Progression;Drug Targeting;Effector Cell;Exhibits;Future;Gene Expression;Goals;Growth;Health;IL2 gene;IL2RA gene;Immune;Immune response;Immunosuppressive Agents;Immunotherapeutic agent;Immunotherapy;In Vitro;In complete remission;In-Migration;Individual;Invaded;Lead;Lesion;Lifetime Risk;Ligands;Malignant Neoplasms;Mediator of activation protein;Metastatic Melanoma;Migration Inhibitory Factor;Modality;Molecular Profiling;Mus;Myelogenous;Natural immunosuppression;Neoplasm Metastasis;Outcome;Pathway interactions;Patients;Phenotype;Population;Process;Proteins;Quantitative Structure-Activity Relationship;Regulatory T-Lymphocyte;Resistance;Role;Signal Pathway;Skin Cancer;Solid;Solid Neoplasm;Specificity;Staging;Suppressor-Effector T-Lymphocytes;Survival Rate;Testing;Therapeutic;Toxic effect;Tumor-Derived;United States;analog;angiogenesis;base;cancer cell;cell motility;clinical efficacy;combinatorial;cytokine;design;improved;in vivo;inhibitor/antagonist;insight;lung metastatic;macrophage;melanoma;monocyte;mouse model;multicatalytic endopeptidase complex;neovascularization;novel;novel therapeutics;partial response;phenylpyruvate tautomerase;prevent;receptor;scaffold;small molecule;small molecule inhibitor;subcutaneous;therapeutic target;therapy resistant;tumor;tumor microenvironment;tumorigenic

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Malignant melanoma is the most deadly form of skin cancer due in large part to its aggressive ability to locally invade and distally metastasize. One in 50Americans has a lifetime risk of developing melanoma and nearly 69000 people in the United States were diagnosed with it last year. The five year survival rate for those diagnosed with stage IV metastatic melanoma remains unacceptably low at only 5 - 10%. Despite the advent of new immunotherapies designed to enhance the patient's immune response to attack melanocytic cancer cells no appreciable improvements have been observed in overall patient survival percentages. Our recent studies now demonstrate that small molecule targeting of macrophage migration inhibitory factor (MIF) induces substantial resistance to implantable subcutaneous and lung metastatic melanoma. Studies described in this proposal seek to fully delineate the mechanism(s) by which small molecule MIF antagonists induce intracellular degradation of MIF thereby reverting immunosuppressive pro-angiogenic TAM/MDSC cell populations into immunostimulatory non-angiogenic innate immune effector cells. These studies will rigorously characterize and refine the clinical efficacy of small molecule MIF targeting as both an individual and combinatorial therapeutic modality targeting malignant melanoma.


application_id: 9032344
project_number: 4R01CA109136-10
project_title: Novel Mechanisms of Carcinoma Cell Migration
administering_ic: NCI
award_notice_date: 2016-03-15
opportunity_number: PA-10-067
application_type: 4
activity_code: R01
ic: CA
serial_number: 109136
program_official: AULT, GRACE S
project_start_date: 2006-03-09
project_end_date: 2017-07-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1947523
contact_pi: O'CONNOR, KATHLEEN L.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Tumor invasion and metastasis still claim the majority of cancer patients' lives. Although great strides have been made in cancer detection and prevention the need for a more effective treatment for cancer metastasis remains a central problem. Notably molecules that control spatial signaling for cell polarization and directed migration contribute to the lethality of cancer through their ability to improve the efficiency of he first steps of metastasis. RhoA contributes to cell polarization during directed cell motility yet how RhoA is spatially controlled remains unclear. We propose that integrin signaling through cAMP/PKA is instrumental for spatial signaling of RhoA and cell polarization. Importantly our previous work has shown that 1 integrins control the generation of PKA activity gradients at the leading edge of migrating carcinoma cells where it controls RhoA function. We provide compelling evidence that these PKA activity gradients exist in breast carcinoma patient samples and in three-dimensional breast carcinoma cultures which attest to the significance of these gradients in human breast cancer. Integrin 64 is upregulated in advanced breast cancers where it is most closely associated with basal-like breast cancers. Importantly integrin 64 promotes the activation of RhoA by a mechanism that we propose reverses the effect of PKA. Therefore we suggest that the counter-opposing modes of regulation these integrins have on RhoA permit efficient compartmentalization of RhoA that facilitates breast carcinoma motility invasion and metastasis. Accordingly the central hypothesis of this application is that cooperative signaling between 1 integrins and integrin 64 facilitates the spatial distribution of RhoA activity to promote lamellae formation and directed migration. The long-term goal of our group is to determine how integrins contribute to tumor invasion so that they may be eventually targeted appropriately for therapeutic intervention with special emphasis on integrin 64. We will test our central hypothesis and achieve our long- term goal through the completion of the following aims: 1) Define the macromolecular complex that couples 1 integrins to PKA activation thereby limiting RhoA activity at the leading edge 2) Determine how integrin 64 leads to the activation of RhoA and 3) Elucidate how RhoA function is altered to promote lamellae formation. We are uniquely suited to perform these studies due to our strong collaborations; our well-characterized models of 64 integrin- and RhoA-dependent invasion and migration; our expertise in integrin biology and Rho signaling and our solid preliminary data supporting this project. The results obtained from this study will be important as they will go int mechanistic depth regarding how integrins coordinate spatial signaling to achieve polarization lamellae formation directed cell migration and finally invasion. Ultimately our study will be significant as it will generate a firmer understanding of signaling pathways that govern leading edge dynamics that will produce successful methods to therapeutically target the early steps in metastasis.

project_terms:
A kinase anchoring protein;Adenylate Cyclase;Adhesions;Binding;Biochemical;Biology;Breast Carcinoma;Cancer Biology;Cancer Detection;Cancer Patient;Carcinoma;Cells;Collaborations;Complex;Consensus;Couples;Coupling;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Data;Equilibrium;Generations;Goals;Growth;Growth Factor Receptors;Guanine;Guanine Nucleotide Exchange Factors;Human;Imaging Techniques;Integrin alpha6beta4;Integrins;Invaded;Joints;Macromolecular Complexes;Malignant Epithelial Cell;Malignant Neoplasms;Mediating;Methods;Modeling;Molecular;Monomeric GTP-Binding Proteins;Morphology;Neoplasm Metastasis;Operative Surgical Procedures;Output;Pathology;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphorylation Site;Positioning Attribute;Process;Production;Protein Serine/Threonine Phosphatase;Regulation;Research;Sampling;Signal Pathway;Signal Transduction;Solid;Spatial Distribution;Stress Fibers;Study models;Testing;Therapeutic Intervention;Tumor Cell Invasion;Validation;Work;cancer prevention;cell motility;cellular imaging;effective therapy;improved;in vivo;inorganic phosphate;insight;malignant breast neoplasm;migration;novel;rho;rhotekin;three dimensional cell culture;tissue-factor-pathway inhibitor 2;tumor;tumor progression

public_health_relevance:
Understanding how integrins signal continues to have a sustained impact on our understanding of cancer biology. Notably integrins contribute to the most deadly aspects of cancer progression including tumor invasion and metastasis; yet how they contribute to these processes remains poorly understood. Here we will go into mechanistic depth regarding how integrins coordinate spatial signaling to achieve polarization lamellae formation directed cell migration and ultimately invasion. By understanding leading edge dynamics of invading cells better methods of therapeutically targeting the early steps in metastasis will be achievable.


application_id: 9032066
project_number: 1R01NS091329-01A1
project_title: PERK as a central mediator of neurotoxicity in tauopathies
administering_ic: NINDS
award_notice_date: 2015-09-18
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: NS
serial_number: 091329
suffix: A1
program_official: CORRIVEAU, RODERICK A
project_start_date: 2015-09-30
project_end_date: 2020-06-30
study_section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND]
contact_pi_person_id: 10569691
contact_pi: ABISAMBRA, JOSE FRANCISCO
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): Tauopathies are a group of nineteen known debilitating neurodegenerative disorders that affect nearly eight million people in the United States. Currently there is no cure for tauopathies and there are temporary and limited benefits to current therapeutic strategies. The endoplasmic reticulum (ER) stress sensor PERK (protein kinase R-like ER kinase) has been identified as a participant in the pathogenesis and progression of tauopathies. However the mechanism by which the PERK pathway causes neuronal dysfunction is still unknown. The long-term goal is to better understand the mechanism(s) that induce(s) neuronal dysfunction in tauopathies and the overall objective is to determine the mechanism by which tau and PERK synergize to induce neuronal dysfunction. The central hypothesis is that tau and PERK engage in a pathological cycle whereby aberrant accumulation of tau chronically activates PERK and active PERK activates enzymes that contribute to the production of pathogenic tau. The overall consequence of this cycle is potentiation of tau pathogenic pathways as well as chronic inhibition of protein synthesis. Characterizing the role of the PERK pathway in neuronal dysfunction will identify novel urgently needed therapeutic targets for tauopathies. The hypothesis will be tested in three specific aims. Aim 1 is designed to determine the extent to which the PERK pathway causes neuronal dysfunction in tauopathies. Aim 2 is designed to determine the mechanism by which PERK activity modulates tau pathology. Finally Aim 3 will determine the extent of PERK pathway activation in a newly described tauopathy called Primary Age-Related Tauopathy (PART). In Aim 1 we will use pharmacologic and genetic approaches to inhibit PERK in in vivo in situ and in vitro models of tauopathy; neuronal function will be measured by cognitive tests a novel and non-invasive imaging approach called manganese-enhanced MRI and electrophysiological measurements. Secondly we will use biochemical immunohistochemical and gene expression assays to determine the extent of PERK activity. In Aim 2 we will use pharmacologic and genetic approaches to activate and inhibit PERK in in vivo and in vitro models of tauopathy; we will measure changes to pathological tau and the PERK pathway. Finally in Aim 3 we will measure changes in the levels of PERK pathway markers and pathological tau in PART CSF and brain parenchyma. This will be the first extensive biochemical approach to PART which could unveil novel biomarkers of the disease. The identification of a pathogenic PERK-tau cycle is innovative because it departs from the status quo by identifying an effector of disease (PERK) that can cause neuronal dysfunction (downstream) while also potentiating tau aberrancies (upstream). Therefore the PERK pathway offers a unique repertoire of novel therapeutic targets that can modulate disease in multiple aspects. This approach is significant because of the central role the pathway plays in disease and therefore the potential to offer therapeutic solutions to tauopathies.

project_terms:
Acute;Affect;Alzheimer's Disease;Attenuated;Biochemical;Biological Markers;Brain;Cerebrospinal Fluid;Chemosensitization;Chronic;Cleaved cell;Code;Cognition;Data;Defect;Dementia;Development;Disease;Disease Progression;Endoplasmic Reticulum;Enzymes;Gene Expression Profiling;Genes;Goals;Homeostasis;Human;Impaired cognition;In Situ;Individual;Lead;Link;Magnetic Resonance Imaging;Manganese;Measurement;Measures;Mediating;Mediator of activation protein;Modeling;Morphology;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neurofibrillary Tangles;Neurologic;Neuronal Dysfunction;Neurons;Outcome;Participant;Pathogenesis;Pathology;Pathway interactions;Patients;Phosphotransferases;Play;Prion Diseases;Production;Progressive Supranuclear Palsy;Protein Synthesis Inhibition;Proteins;RNA;Reporting;Research;Risk;Role;Slice;Solutions;Synapses;Tauopathies;Testing;Therapeutic;Time;Transgenic Mice;Translations;United States;Work;age related;aging population;attenuation;base;caspase;caspase-3;cerebral atrophy;cognitive testing;design;effective therapy;endoplasmic reticulum stress;genetic approach;immortalized cell;improved;in vitro Model;in vivo;innovation;mouse model;neurotoxicity;new therapeutic target;non-invasive imaging;novel;novel therapeutics;protein kinase R;public health medicine (field);public health relevance;sensor;tau Proteins;tau aggregation;tau mutation;tau-protein kinase;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it aims to identify a pathway known as PERK as a contributor of damage to neurons in nineteen related neurodegenerative disorders called tauopathies the most common of which is Alzheimer's disease. These diseases present irreversible and severe brain atrophy and cognitive impairment and impact millions of people. Discovery of the mechanisms by which PERK damages neurons in the brain will establish a specific target that may lead to development of novel therapeutics.


application_id: 9031790
project_number: 5R01HL074185-12
project_title: Reversing diabetic muscle myopathy by exercise and exosomes
administering_ic: NHLBI
award_notice_date: 2016-01-29
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 074185
program_official: SCHWARTZ, LISA
project_start_date: 2003-09-05
project_end_date: 2019-01-31
study_section: Special Emphasis Panel[ZRG1-MOSS-C(02)S]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Although exercise mitigates diabetic complications and myopathy the mechanism is unclear. The long-term goal of this project is to understand the mechanism of diabetic myopathy. Studies from previous funding period revealed causative role of endothelial-myocyte (E-M) uncoupling in cardiomyopathy. The connexin -37 and -43 are associated with endothelial and myocyte coupling; and mitochondria contains connexin-43. Matrix metalloproteinase-9 (MMP-9) disrupts connexins and is activated in diabetes unequivocally. Interestingly the exercise decreases MMP-9 activity. Exosomes 50-100 nm nanovesicles contain mir-RNAs and are released from myocytes. In this renewal application we will determine the role of exercise-mediated release in exosome containing mir-RNAs that mitigates the endothelium-myocyte myocyte-myocyte and mitochondrial-myocyte uncoupling by down regulating the MMP-9. The central hypothesis of this proposal is that MMP-9 degrades connexins and causes endothelial-myocyte myocyte-myocyte and mitochondria-myocyte uncoupling in diabetes. Exercise releases exosomes containing mir-RNAs that decreases MMP-9 and mitigates uncoupling. We will test the central hypothesis by following three specific aims. Specific aim #1: To determine whether the exercise releases exosomes that contain mir-29b mir-323 mir-455 and mir-466 which negatively regulate MMP-9 and mitigate fibrosis and uncoupling. Specific aim #2: To determine whether endothelial-myocyte uncoupling is caused by perivascular/pericapillary fibrosis and myocyte-myocyte uncoupling is caused by interstitial fibrosis in diabetes and exercise mitigates these conditions. Specific aim #3: To determine whether the dys-synchronization of mitochondrial fusion-fission causes mitochondria-myocyte uncoupling (mitochondrial remodeling) in diabetes and exercise alleviate. To evaluate the release of exosomes and their effect on MMP-9 and consequently Cx-37 and Cx-43 adult male db/db and controls db/+ wild type (WT-C57 and FVB) mice MMP-9 KO db/db/MMP-9 DKO Cx-37-Tg db/db/Cx-37-Tg; Cx-43-Tg and db/db/Cx-43-Tg mice with and without exercise will be used. Plasma and cardiac tissue exosomes will be isolated by ultracentrifugation/exoquick and characterized by electron microscopy/FACS/MACS. The levels of mir466 mir455 mir29b mir323 will be determined by RT-PCR and in situ hybridization. These studies will determine the mechanism of muscular structural functional and mitochondrial remodeling and exosomal therapeutic ramifications for diabetic myopathy.

project_terms:
3' Untranslated Regions;Acetylcholine;Adult;Adverse effects;Binding;Blood capillaries;Cardiac;Cardiomyopathies;Chimeric Proteins;Clinical Trials;Collagen;Complications of Diabetes Mellitus;Connexin 43;Connexins;Consumption;Coupling;Cytochromes;Cytosol;Diabetes Mellitus;Electron Microscopy;Endothelium;Exercise;Extravasation;FVB Mouse;Fibrosis;Funding;Gelatinase B;Goals;Health;In Situ Hybridization;Label;Laboratories;Matrix Metalloproteinases;Measures;Mediating;MicroRNAs;Mitochondria;Mitochondrial Matrix;Mus;Muscle;Muscle Cells;Myocardial Infarction;Myopathy;Nitroprusside;PECAM1 gene;Perivascular Fibrosis;Plasma;Preparation;Proteins;Reverse Transcriptase Polymerase Chain Reaction;Role;Swelling;Techniques;Testing;Therapeutic;Tissues;Ultracentrifugation;Untranslated Regions;capillary;connexin 37;diabetic;exosome;inhibitor/antagonist;innovation;interstitial;male;nanovesicle;response;treatment strategy

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Because cardiac matrix is unique general matrix metalloproteinase-9 (MMP-9) inhibitors may not mitigate the cardiac remodeling (Clinical trial- PREMIER-Pevention of Myocardial Infarction Early Remodeling using the MMP-9 inhibitor PG-116800). Exosomes that carry microRNAs can provide alternate treatment strategy to inhibit MMP-9 since exosomes are non-immunogenic and have no side effects. Myocyte releases exosomes and exosomes contains miRNA. The miRNA inhibits MMP- 9 by binding to the 3'UTR region. These studies will determine the mechanism of muscular structural functional and mitochondrial remodeling and exosomal therapeutic ramifications for diabetic myopathy.


application_id: 9031755
project_number: 5R34DA038869-02
project_title: A Feasibility Trial for Inhibitory-Control Training to Reduce Cocaine Use
administering_ic: NIDA
award_notice_date: 2016-02-08
opportunity_number: PA-13-078
application_type: 5
activity_code: R34
ic: DA
serial_number: 038869
program_official: AKLIN, WILL
project_start_date: 2015-03-15
project_end_date: 2018-01-31
study_section: Special Emphasis Panel[ZRG1-RPIA-N(09)F]
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cocaine abuse is an unrelenting public-health concern. Behavioral therapies are considered the "standard of care" for reducing cocaine use and preventing relapse. However even with intense behavioral interventions rates of relapse to cocaine use are discouragingly high (i.e. 60-95% of patients return to drug use). Novel strategies are urgently needed to improve treatment outcomes for cocaine-use disorders. The overarching goal of this project is to assess the feasibility acceptability and initial efficacy o an innovative cocaine-based inhibitory-control training procedure. This goal will be accomplished through the conduct of a Stage I pilot trial. Cocaine-dependent participants will be enrolled and randomized to receive inhibitory-control training to cocaine or neutral images (N=20/condition). This proposed intervention cocaine- based inhibitory-control training will be delivered using an innovative computer program which teaches cocaine abusers to inhibit a pre-potent response to cocaine or neutral cues. The primary hypothesis is the proposed procedures are feasible and acceptable to the participants. Feasibility will be assessed by determining time needed to enroll the target sample; adaptive randomization outcomes; maintenance of blind for blinded study personnel; participant attendance completion and adherence to study procedures. Acceptability will be determined using a Treatment Acceptability Questionnaire. The secondary hypothesis is that participants receiving cocaine-based inhibitory-control training will reduce their drug use toa greater extent than their counterparts in the neutral-image condition. Reduced cocaine use will be demonstrated by fewer positive-urine samples using qualitative urinalysis and a reduction in levels of benzoylecgonine as determined by quantitative urinalysis (i.e. ELISA). The third hypothesis is that participants receiving cocaine-based inhibitory-control training will show improved inhibitory control and neurocognitive functioning relative to their counterparts in the neutral-image condition. Improved inhibitory control impulsivity and cognitive functioning will bedemonstrated using a battery of clinical instruments and laboratory tasks. The proposed research is highly innovative in that it will provide critical information regarding the feasibilit acceptability initial efficacy of cocaine-based inhibitory-control training to reduce drug use andimprove inhibitory control and neurocognitive functioning in cocaine-dependent participants. Cocaine-based inhibitory- control training is also easy to administer (i.e. 15 minutes) inexpensive need not be administered by a clinician and could easily be incorporated into current behavioral or community-based treatment approaches to enhance sustained abstinence thereby quickly impacting clinical research and practice. The cocaine-based inhibitory-control training program could also be converted to a smart-phone for administration outside the clinic. Administering training outside of the clinic would allow patients to receive more frequent booster sessions further improving sustained abstinence by allowing them to be exposed to therapy as needed.

project_terms:
Abstinence;Address;Adherence;Alcoholic beverage heavy drinker;Alcohols;Behavior Therapy;Behavioral;Blinded;Cellular Phone;Clinic;Clinical;Clinical Research;Cocaine;Cocaine Abuse;Cocaine Dependences;Cues;Development;Disease;Double-Blind Method;Drug usage;Ecology;Educational process of instructing;Employee Strikes;Enrollment;Enzyme-Linked Immunosorbent Assay;Future;Gambling;Goals;Health;Human Resources;Image;Impulsivity;Intervention;Intervention Studies;Iowa;Laboratories;Maintenance;Modification;NIH Program Announcements;Neurocognitive;Outcome;Participant;Patients;Procedures;Public Health;Questionnaires;Randomized;Relapse;Research;Risk;Sampling;Signal Transduction;Staging;Testing;Time;Training;Training Programs;Treatment outcome;Urinalysis;Urine;attentional bias;base;benzoylecgonine;blind;clinical practice;cocaine use;cognitive function;community based treatment;computer program;discounting;drinking;efficacy trial;improved;improved outcome;innovation;instrument;novel strategies;pilot trial;prevent;programs;response;standard of care;therapy development;trial design

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The research proposed in this application will demonstrate the feasibility acceptability and initial efficacy of an innovative cocaine-based inhibitory-contol training procedure for cocaine-use disorders. A Stage I double blind pilot trial will be conducted. The proposed research is innovative because cocaine-based inhibitory- control training is easy to administer (i.e. requires about 15 minutes) inexpensive need not be administered by a clinician and could easily be incorporated into current behavioral or community-based treatment approaches to enhance sustained abstinence.


application_id: 9031125
project_number: 4R01HL107640-05
project_title: Mechanisms of Mitochondrial Dysfunction in Brain Vasculature
administering_ic: NHLBI
award_notice_date: 2016-02-23
opportunity_number: PA-10-067
application_type: 4
activity_code: R01
ic: HL
serial_number: 107640
program_official: REID, DIANE M
project_start_date: 2012-03-01
project_end_date: 2018-02-28
study_section: Special Emphasis Panel[ZRG1-VH-J(02)]
contact_pi_person_id: 9959914
contact_pi: TYAGI, NEETU
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Clinical data suggest an association between elevated levels of Hcy also known as hyperhomocysteine-mia (HHcy) and stroke. HHcy is generated due to increase in de-methylation of methionine by S-adenosine- homocysteine hydrolase (SAHH) and a decrease in methyltetrahydrofolate reductase (MTHFR) and cystathionine-y-lyase (CSE an enzyme responsible for Hcy metabolism to H2S a most potent vasodilator antioxidant and anti-hypertensive agent) contribute to mitochondria dysfunction (mitophagy) and ischemic stroke. Cytochrome-C transports electrons and facilitates mitochondrial bioenergetics. Interestingly during HHcy cytochrome-C becomes homocysteinylated (N-Hcy-cyt-c). However it's consequence to mitophagy and stroke is unclear. The long-term goal of this project is to understand the mechanism of mitophagy mitochondrial repair and permeability in brain vasculature during I/R injury. Our preliminary studies suggest that during I/R total Hcy levels increases causes N-Hcy-cyt-C  increases mitochondrial matrix metalloproteinase-9 (mtMMP-9) in-part degradation of mt-matrix (connexin and tight junction protein TJP) which led to mitophagy and permeability in brain vasculature. Interestingly THC decreases Hcy level and mitigates brain damage. Tetra hydro-curcumin (THC) a major herbal antioxidant and anti-inflammatory agent has shown to protect brain against I/R injury. The central hypothesis of this proposal is that HHcy contributes to mitophagy mediated brain damage through N-Hcy-cyt-C in part by increasing oxidative stress mtMMP-9 degrades connexin-43 and TJP (Figure 1). The treatment with THC CSE gene and SAHH shRNA gene transfer attenuates mitophagy and permeability. We will test this hypothesis by following three specific aims: Specific Aim #1: To determine whether the Hcy contributes to mitophagy in part by inducing oxidative stress exacerbating homocysteinylation of cytochrome-c in ischemia reperfusion and if THC CSE and SAHH shRNA gene therapy mitigates these changes. Specific Aim #2: To determine whether the homocysteinylation of cytochrome-c activates mt-MMP-9 disruption of collagen/elastin ratio mtCxn43 and mt-tight junction proteins in ischemia reperfusion and if THC CSE and SAHH shRNA gene therapy ameliorate. Specific Aim #3: To determine whether Hcy alters mitochondrial (mt) bioenergetics and cerebro-vascular remodeling in ischemia reperfusion and if THC CSE and SAHH shRNA gene therapy alleviate. These studies will demonstrate the novel mechanism of cerebrovascular remodeling and have therapeutic ramifications for mitochondrial repair in cerebral ischemic stroke.

project_terms:
ATP Synthesis Pathway;Adenosine;Albumins;Angiography;Anti-Inflammatory Agents;Antihypertensive Agents;Antioxidants;Attenuated;Bioenergetics;Blood Vessels;Blood flow;Brain;Brain Injuries;Brain Stem;Caliber;Cerebrovascular system;Cerebrum;Clinical Data;Co-Immunoprecipitations;Cognitive;Collagen;Collagen Type IV;Connexin 43;Connexins;Curcumin;Cystathionine;Cytochromes;DNA;DNA Methylation;Diet;Dyes;Elastin;Electron Transport;Enzymes;Event;Extravasation;Functional disorder;Gel;Gelatin;Gelatinase B;Gene Transfer;Genes;Goals;Histocytochemistry;Homocysteine;Homocystine;Hydrolase;In Situ;Injection of therapeutic agent;Injury;Ischemia;Ischemic Stroke;Label;Lyase;Matrix Metalloproteinases;Measures;Mediating;Membrane Potentials;Messenger RNA;Metabolism;Methionine;Methylation;Mitochondria;Mitochondrial DNA;Mitochondrial Matrix;Mus;Operative Surgical Procedures;Oxidants;Oxidation-Reduction;Oxidative Stress;Oxidoreductase;Oxygen Consumption;Pathway interactions;Permeability;Plasmids;Production;Proteins;Proteolysis;Proteome;Reperfusion Injury;Reperfusion Therapy;Respiration;Reverse Transcriptase Polymerase Chain Reaction;Stress;Testing;Therapeutic;Tight Junctions;Time;Vascular remodeling;Vasodilator Agents;Western Blotting;calcein AM;cerebrovascular;cytochrome c;gene therapy;knock-down;middle cerebral artery;mitochondrial dysfunction;mitochondrial membrane;novel;prevent;repaired;response;sham surgery;small hairpin RNA;stroke;tetrahydrocurcumin

public_health_relevance:
These studies will delineate the mechanisms of mitophagy and cerebrovascular remodeling in brain vasculature. The treatment with dietary herbal antioxidant tetrahydrocurcumin naked CSE DNA and SAHH shRNA gene therapy mediated stabilization of mitochondrial membrane potential by inhibition of mitochondrial DNA methylation; oxidant and proteolysis stress via novel mechanistic pathways will be powerful therapeutic strategy for preventing ischemic stroke.


application_id: 9029178
project_number: 1R01DC014468-01A1
project_title: In vivo patterns of receptor activation by odorants
administering_ic: NIDCD
award_notice_date: 2015-11-13
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: DC
serial_number: 014468
suffix: A1
program_official: SULLIVAN, SUSAN L
project_start_date: 2015-12-01
project_end_date: 2020-11-30
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Alcohols;Biological Assay;Breathing;Carboxylic Acids;Characteristics;Chemicals;Code;Color;Complex;Complex Mixtures;Data;Detection;Development;Discrimination;Environment;Esthesia;Face;Flavoring;Hearing;Human;Individual;Ketones;Knowledge;Lead;Learning;Life;Ligands;Mammals;Mus;Nature;Odorant Receptors;Odors;Pattern;Perception;Pest Control;Pharmacology;Prevalence;Problem Solving;Receptor Activation;Receptor Cell;Smell Perception;Testing;Time;Vision;coping;improved;in vitro Assay;in vivo;novel strategies;public health relevance;receptor;research study;sensor;stem


application_id: 9028712
project_number: 1R01NS091582-01A1
project_title: The role of macrophage phenotype and age in spinal cord injury
administering_ic: NINDS
award_notice_date: 2015-09-17
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: NS
serial_number: 091582
suffix: A1
program_official: JAKEMAN, LYN B
project_start_date: 2015-09-30
project_end_date: 2020-07-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 8201969
contact_pi: GENSEL, JOHN C
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Spinal cord injury (SCI) triggers a heterogeneous neuroinflammatory response consisting of macrophages with the potential to both aggravate tissue damage and promote wound healing and repair. These macrophages have been identified as pro-inflammatory pathological "M1" macrophages or anti-inflammatory alternatively activated pro-reparative "M2" macrophages. There is published evidence that driving M2 macrophage activation improves SCI recovery. The mechanisms underlying the reparative effects of M2 macrophages however are not well understood. As a result the development of clinically viable pharmacological interventions that harness the reparative potential of activated macrophages remains a critical challenge that is compounded by a changing SCI demographic. The incidence of SCI among older individuals has increased in recent years with a more equal balance of SCI across sexes. The purpose of this proposal is to investigate the mechanisms of M2 macrophage-mediated SCI repair and determine the effects of age and sex on SCI macrophage activation. Aim 1 will determine the role of arginase in M2 macrophage-mediated SCI repair processes through the use of genetically engineered mice with macrophages that lack arginase-1 (Arg1) and a newly identified treatment that increases M2-mediated arginase production. Parallel in vivo and in vitro SCI models of neurotoxicity axon growth/dieback and remyelination will test the hypothesis that the effects of M2 macrophages are dependent upon Arg1 production. In Aim 2 mice of different ages and sex will be used to determine the effect of these physiological factors on the acute SCI macrophage response. The macrophage response over time will be evaluated using newly developed focused gene profiling and flow cytometry techniques. The hypothesis to be tested is that aged males will have impaired M2 macrophage activation. In Aim 3 the effect of age and sex on M2 macrophage-mediated SCI repair and recovery will be evaluated using a clinically relevant mouse SCI model and a newly developed immunomodulatory SCI treatment. Forms of M2 macrophage activation occur in most CNS pathologies; therefore the current work is significant because it is expected to have broad translational impact on a wide range of neuroinflammatory conditions. This project is both conceptually and technically innovative. It will employ creative use of Arg1 knockout mice and a novel immunomodulatory agent. The investigation of the effects of age and sex on the macrophage response to SCI using a comprehensive focused gene array approach is novel. Collectively the completion of the proposed research will improve scientific knowledge regarding macrophage biology as it specifically relates to age and sex. This knowledge will improve clinical practice by leading to sophistication of treatment strategies that include sex and
age as potential influences in the context of SCI treatment and recovery.

project_terms:
Acute;Affect;Age;Age Factors;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Automobile Driving;Azithromycin;Biology;Cell Proliferation;Cells;Chronic;Clinical;Clinical Data;Contusions;Data;Development;Dose;Effectiveness;Equilibrium;Estradiol;Female;Flow Cytometry;Genes;Genetically Engineered Mouse;Goals;Gonadal Steroid Hormones;Healed;Health Care Costs;Human;In Vitro;Incidence;Individual;Inflammatory;Inflammatory Response;Intervention;Investigation;Knockout Mice;Knowledge;Macrolide Antibiotics;Macrophage Activation;Mediating;Modeling;Mus;Outcome Measure;Paralysed;Pathology;Patients;Phenotype;Physiological;Process;Production;Progesterone;Publishing;Recovery;Recovery of Function;Research;Rodent;Role;Spinal cord injury;Techniques;Testing;Time;Tissues;United States;Work;Wound Healing;age effect;aged;arginase;axon growth;axon regeneration;base;clinical practice;clinically relevant;functional disability;gain of function;healing;improved;in vivo;injury and repair;innovation;loss of function;macrophage;male;middle age;mouse model;neuroinflammation;neuropathology;neuroprotection;neurotoxic;neurotoxicity;novel;pre-clinical;public health relevance;remyelination;repaired;response;sex;treatment strategy


application_id: 9028572
project_number: 2R01GM070559-10
project_title: Epigenetic and post-translational modifier regulation of juvenile hormone action
administering_ic: NIGMS
award_notice_date: 2015-12-21
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: GM
serial_number: 070559
program_official: CHIN, JEAN
project_start_date: 2005-02-01
project_end_date: 2020-01-31
study_section: Vector Biology Study Section[VB]
contact_pi_person_id: 7355989
contact_pi: PALLI, SUBBA R
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acetylation;Adult;Agonist;Biological;Biological Assay;Biological Metamorphosis;Biological Models;CHD1 gene;Cell Culture Techniques;Cells;Chromatin;Culicidae;Cyclic AMP-Responsive DNA-Binding Protein;DNA;Development;Disease;Disease Vectors;Ecdysone;Ecdysteroids;Ensure;Epigenetic Process;Event;Food;Gene Expression Regulation;Genes;Helix-Turn-Helix Motifs;Histone Acetylation;Histone Deacetylase;Histone Deacetylase Inhibitor;Histone H3;Histones;Homologous Gene;Hormone Receptor;Hormones;Human;Insect Control;Insect Vectors;Insecta;Insecticides;Juvenile Hormones;Knowledge;Laboratories;Lead;Livestock;Lysine;Mass Spectrum Analysis;Mediating;Medicine;Methods;Methoprene;Molecular;Molting;Nuclear Proteins;Outcome Study;Physiological;Play;Post-Translational Protein Processing;Post-Translational Regulation;Proteins;RNA Interference;Regulation;Reporter;Reproduction;Research;Role;Steroid Receptors;Testing;Tissues;Transferase;Tribolium;Trichostatin A;Vertebrates;base;brahma;genome sequencing;hormone regulation;human disease;method development;novel;promoter;public health relevance;receptor;research study;response;success;transcription factor;vector control;whole genome;yeast two hybrid system


application_id: 9028438
project_number: 3R01AG026307-09S1
project_title: Self-Regulation Immunological Aging and Health in Older Adults
administering_ic: NIA
award_notice_date: 2016-04-14
opportunity_number: PA-13-302
application_type: 3
activity_code: R01
ic: AG
serial_number: 026307
suffix: S1
program_official: NIELSEN, LISBETH
project_start_date: 2006-07-15
project_end_date: 2016-04-30
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
project_abstract:
DESCRIPTION (provided by applicant): The parent grant for which this competing revision is being requested (AG026307-R01) evaluates longitudinal relationships between measures of self-regulation and self-control and measures of physical health in older adults including peripheral markers of cardiovascular and immunological health. Critically however older adults high in self-regulation (e.g. conscientiousness) also demonstrate positive health outcomes that implicate improved central nervous system/brain health such as reduced risk for Alzheimer's disease slower cognitive decline and increased longevity. Despite this apparent link to successful brain aging relationships between individual differences in trait self-regulation and brain structure and function have not been studied to date. The parent study longitudinally and repeatedly assesses self-regulation and health in older adults (current N=135). Here we seek to broaden this well-established study with multi-modal magnetic resonance imaging (MRI) measures of brain structure and function. The proposed project stands to bridge the knowledge gap between personality and behavioral variants associated with superior health outcomes in older adults and the determinants of successful brain aging. The proposed project will: 1) Examine whether better self-regulation correlates with less evidence of brain structural decline. We and others have shown that healthy behaviors such as exercise promote the integrity of white matter tracts and protect against atrophy in the brain. Here volumetric and diffusion tensor imaging will be used to assess relationships between brain structure self-regulation and potential behavioral mediators (including physical activity and other healthy behaviors). 2) Examine whether better self-regulation is associated with more youthful brain function. A more youthful pattern of brain activation in older age is one important marker of successful cognitive aging. In our previous work we have shown that high performing older adults exhibit more youthful patterns and levels of functional activation during cognitive control tasks. Moreover we have shown that older adults protected by advantageous cognitive traits (e.g. lifelong bilingualism) as a group exhibit more youthful activation and superior cognitive control task performance compared to age-matched peers. 3) Examine whether better self-regulation correlates with successful compensatory patterns of brain activity. Successful cognitive task performance in older adults is often accompanied by reorganized patterns of brain activation and functional connectivity. Such changes are thought to reflect the functional plasticity of the aging brain and likely reflect a shift in the cognitive strategies used to perform cognitive tasks.
Since not all older adults express such compensatory changes it is important to understand the role that psychological resources e.g. self-regulation play in promoting successful adaptation to brain aging.

project_terms:
Accounting;Adult;Age;Aging;Alzheimer's Disease;Alzheimer's disease risk;Anatomy;Atrophic;Behavior;Behavioral;Brain;Cardiovascular system;Cerebrovascular Circulation;Cognitive;Cognitive aging;Development;Diffusion Magnetic Resonance Imaging;Elderly;Exercise;Exhibits;Financial compensation;Functional Magnetic Resonance Imaging;Health;Health Benefit;Image;Impaired cognition;Individual Differences;Informal Social Control;Knowledge;Link;Longevity;Longitudinal Studies;Magnetic Resonance Imaging;Maintenance;Measures;Mediator of activation protein;Motivation;Neuraxis;Outcome;Parents;Pathway interactions;Pattern;Performance;Perfusion;Peripheral;Personality;Physical activity;Play;Regulation;Resources;Risk;Role;Self-control as a personality trait;Spin Labels;Structure;Task Performances;Testing;Variant;Work;age related;aging brain;bilingualism;brain health;cognitive control;cognitive reserve;cognitive task;diet and exercise;emotion regulation;executive function;frontal lobe;functional plasticity;gray matter;heart rate variability;improved;nervous system disorder;parent grant;peer;physical conditioning;psychologic;public health relevance;relating to nervous system;scaffold;trait;white matter

public_health_relevance:
PUBLIC HEALTH RELEVANCE: People who are high in self-control enjoy a number of health benefits including reduced risk of neurological disease such as Alzheimer's disease but the underlying effects of self-control on brain structure and function are unknown. This project will expand on an existing longitudinal study measuring self-control and health in older adults by adding measures of brain health. We expect that older adults who are typically more self-controlled will show less evidence of age-related decline in brain structure and function.


application_id: 9028131
project_number: 1R01HL124015-01A1
project_title: Latexin function in the maintenance and regeneration of the hematopoietic system
administering_ic: NHLBI
award_notice_date: 2015-12-19
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: HL
serial_number: 124015
suffix: A1
program_official: BAI, C BRIAN
project_start_date: 2016-01-01
project_end_date: 2020-12-31
study_section: Molecular and Cellular Hematology Study Section[MCH]
contact_pi_person_id: 9839693
contact_pi: LIANG, YING
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_terms:
Ablation;Acute;Apoptosis;Attenuated;Binding;Binding Proteins;Biological Models;Biological Preservation;Blood;Bone Marrow;Bone Marrow Cells;Bone Marrow Transplantation;CD34 gene;Cancer Patient;Cell Count;Cell Death;Cell Survival;Cell physiology;Cells;Complex;DNA Damage;Development;Exposure to;Genes;Genetic;Genetic Transcription;Genomics;Goals;Hematologic Neoplasms;Hematopoiesis;Hematopoietic;Hematopoietic Stem Cell Transplantation;Hematopoietic System;Hematopoietic stem cells;Human;In Vitro;Injury;Knockout Mice;Late Effects;Lead;Liquid substance;Maintenance;Mediating;Modeling;Molecular;Mouse Strains;Mus;Myelosuppression;NF-kappa B;Natural regeneration;Nuclear Translocation;PC3.1 antigen;Pathway interactions;Patients;Population Sizes;Process;Protein Subunits;Publishing;Quality of life;Radiation;Radiation Dosage;Radiation Injuries;Radiation Tolerance;Radiation Toxicity;Radiation therapy;Radioprotection;Reactive Oxygen Species;Regulation;Regulator Genes;Reporting;Research;Ribosomal Proteins;Role;Second Primary Cancers;Signal Transduction;Solid;Stem cells;Stress;Techniques;Therapeutic;Toxic effect;Variant;Variation (Genetics);Work;Xenograft procedure;base;cancer therapy;cell injury;chemotherapy;effective therapy;functional decline;genome integrity;in vivo;knock-down;mortality;mouse model;novel;overexpression;p65;preconditioning;prevent;promoter;radiation response;radiation-induced injury;response;self-renewal;senescence;small hairpin RNA;stem cell population;tumor


application_id: 9027919
project_number: 3R34MH104208-01S1
project_title: Improving Transition Outcomes in ASD using COMPASS
administering_ic: NIMH
award_notice_date: 2015-04-02
opportunity_number: RFA-MH-14-101
application_type: 3
activity_code: R34
ic: MH
serial_number: 104208
suffix: S1
program_official: JULIANO-BULT, DENISE M
project_start_date: 2015-04-01
project_end_date: 2017-07-31
study_section: ZMH1-ERB-K(05)
contact_pi_person_id: 1960113
contact_pi: RUBLE, LISA A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF EDUCATION
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This application responds to the identified need for developing and testing a model for transition to adult supports and services for individuals with autism spectrum disorders (ASD) that prevents lapses in services and enhances functional life outcomes. The proposal also addresses concerns raised by the Interagency Autism Coordinating Committee of a "critical lack of tested interventions for adolescents and young adults." Although federal education law mandates that public schools provide transition services as part of the Individualized Education Program (IEP) the promise and potential for a well-coordinated and planned transition is not being met. The proposed study builds on two randomized controlled trials of a parent-teacher consultation intervention called the Collaborative Model for Promoting Competence and Success (COMPASS) for young children with ASD data on efficacy for both traditional face-to-face and videoconferencing technology delivery methods and a book-length treatment manual. COMPASS is an implementation strategy that assists in transferring evidence based approaches into classrooms and assists public school special educators and parents in ecological assessment research-informed goal development and person-centered decision-making for individualizing evidence-based interventions for children with ASD. The COMPASS intervention consists of an initial parent-teacher session (3 hours) occurring near the start of the school year followed by four 1-hour teacher coaching. The first aim is to conduct focus groups with stakeholders including policy makers parents teachers service providers and persons with ASD to get feedback on (i) strengths and weaknesses of state policies and services and resources that exist or are needed to support effective implementation of best practices for transition age youth with ASD; (ii) otherconcerns impacting adult services such as housing social security health insurance transportation; and (iii) specific aspects of COMPASS that would need to be adapted/revised to meet the needs of transition age youth. Based on these results we will identify measures that would need to be adapted/developed and obtain feedback from a subsample of focus group members on the measures. Our second aim is to conduct a two wave pilot randomized controlled trial of the adapted COMPASS for transition planning using the new procedures and measures (n = 32 participant triads-consultant teacher student with ASD) using a mixed methods approach. We will obtain qualitative feedback on the intervention (acceptability feasibility outcomes) and use data to revise/adapt second wave implementation as well as to help inform further applications in adult settings. Lastly we will conduct qualitative case studie based on individuals with ASD who have low and high performing outcomes to understand factors that might explain differential response to the intervention and use to revise/adapt second wave implementation.

project_terms:
Accounting;Address;Adolescent and Young Adult;Adult;Age;Autistic Disorder;Books;Case-Control Studies;Characteristics;Child;Competence;Consultations;Control Groups;Data;Decision Making;Development;Educational aspects;Employment;Environmental Risk Factor;Evidence based intervention;Feedback;Focus Groups;Funding;Future;Goals;Health;Health Insurance;Hour;Housing;Individual;Intervention;Laws;Length;Life;Manuals;Measures;Methods;Modeling;National Institute of Mental Health (U.S.);Occupations;Outcome;Parents;Participant;Persons;Placebo Control;Policies;Policy Maker;Procedures;Process;Provider;Randomized Controlled Trials;Reporting;Research;Resources;Sampling;School Teachers;Schools;Services;Social Security;Students;Technology;Testing;Transportation;Triad Acrylic Resin;United States National Institutes of Health;Videoconferences;Videoconferencing;Youth;autism spectrum disorder;base;evidence base;implementation research;improved;meetings;member;person centered;prevent;programs;research study;response;skills;success;teacher

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This application responds to the need for developing and testing a model for transition to adult supports and services for individuals with autism spectrum disorders (ASD) that prevents lapses in services and enhances functional life outcomes. The parent-teacher consultation intervention called the Collaborative Model for Promoting Competence and Success (COMPASS) for young children with ASD will be adapted based on stakeholder input and tested in a randomized controlled study of 32 participants. Variables to help understand factors that explain optimal and poor outcomes will also be obtained.


application_id: 9027836
project_number: 4R01DK093496-05
project_title: MIF: a pro-inflammatory cytokine as a novel target to reduce bladder inflammation
administering_ic: NIDDK
award_notice_date: 2016-03-09
opportunity_number: PA-10-067
application_type: 4
activity_code: R01
ic: DK
serial_number: 093496
program_official: KIRKALI, ZIYA
project_start_date: 2012-04-01
project_end_date: 2018-12-31
study_section: Urologic and Kidney Development and Genitourinary Diseases Study Section[UKGD]
contact_pi_person_id: 8093598
contact_pi: VERA, PEDRO L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078344581
primary_uei: JCSKALYM8HU6
duns_number: 078344581
uei: JCSKALYM8HU6
fips: US
organization_id: 10030991
organization_name: LEXINGTON BIOMEDICAL RESEARCH INSTITUTE
organization_city: LEXINGTON
organization_state: KY
organization_type: Research Institutes
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Experimental evidence supports the pro-inflammatory effect of Macrophage Migration Inhibitory Factor (MIF) in bladder inflammation but how MIF mediates bladder inflammation is poorly understood. The long-term goal is to understand the mechanisms of MIF-mediated bladder inflammation with the aim of altering these processes to reduce or abolish bladder inflammation in patients with chronic painful conditions of the lower urinary tract. The overall objective of this proposal is to determine the contribution of specific urothelial receptors to MIF release and to MIF-mediated signaling and bladder inflammation. The central hypothesis is that there are two components to inflammation involving MIF: 1) increased release of MIF; and 2) upregulation of MIF receptors and subsequent increased signaling via MIF/receptor interactions that enhances and/or maintains inflammation. This hypothesis has been formulated based on preliminary data generated in the applicants' laboratory. The rationale for propos- ing these studies is that by increasing our understanding of signaling events both upstream and downstream of MIF in the bladder will identify potential therapeutic targets.  The hypothesis will be tested by the following specific aims: 1) Determine the contribution of urothelial Protease Activated Receptors (PAR) to a novel mechanism of urothelial MIF release: Agonists with specificity for different PAR receptors will be used to induce MIF release from urothelial cells (both human in vitro and in vivo using mice) to determine which receptors are involved in MIF release. To determine the contribution of MIF to PAR-mediated bladder inflammation in vivo bladder inflammation will be induced in mice by instilling specific PAR agonists while simultaneously antagonizing MIF. Physiological histological and molecular changes in the bladder will be measured. 2) Identify the contribution of urothelial MIF receptors (CD74; CXCR4) to MIF signaling and cystitis: MIF receptor blockade will be used to examine changes in MIF-mediated signaling during a well-established model of cystitis (cyclophosphamide) in mice. These experiments will also determine the effect of MIF receptor blockade on mediating cystitis by measuring physiological histological and molecular changes in the bladder. 3) Determine MIF and MIF receptor levels in clinical conditions with bladder inflammation: Urinary MIF levels will be determined in UTI radiation cystitis and PBS/IC (Hunner ulcer vs non-Hunner ulcer) patients. MIF CD74 and CXCR4 urothelial immunostaining will be examined in PBS/IC (Hunner ulcer vs non-Hunner ulcer) and MIF-mediated cytokine production in human detrusor smooth muscle cells from PBS/IC patients will be examined.  This proposal is innovative because it focuses on MIF a novel mediator of bladder inflammation. The pro- posed research is significant because a greater understanding of the mechanisms of MIF release during bladder inflammation and of the signaling pathways activated by MIF binding to urothelial MIF receptors is expected to result in the identification of novel therapeutic targets for inflammatory conditions of the lower urinary tract.

project_terms:
Acute;Agonist;Binding;Biology;Bladder;Bladder Tissue;CXCR4 gene;Chronic;Clinical;Complex;Cyclophosphamide;Cystitis;Data;Development;Disease;Etiology;Event;F2R gene;Goals;Human;In Vitro;In-Migration;Inflammation;Inflammation Mediators;Inflammatory;Interstitial Cystitis;Knock-out;Laboratories;Lesion;Link;Lower urinary tract;Maintenance;Measures;Mediating;Mediator of activation protein;Migration Inhibitory Factor;Modeling;Molecular;Mus;Outcome;PAWR gene;Pain;Patients;Phosphotransferases;Physiological;Play;Process;Production;Proteinase-Activated Receptors;Quality of life;Radiation;Recurrence;Regulation;Research;Role;Signal Pathway;Signal Transduction;Smooth Muscle Myocytes;Specificity;Spinal cord injury;System;Testing;Tetracyclines;Therapeutic;Therapeutic Intervention;Thrombin;Transgenic Mice;Ulcer;Up-Regulation;Urinary tract infection;Urination;Urine;Urothelial Cell;Urothelium;Work;base;chronic pain;cytokine;in vivo;innovation;insight;new therapeutic target;novel;novel strategies;phenylpyruvate tautomerase;prevent;receptor;research study;therapeutic development;therapeutic target;urinary

public_health_relevance:
Inflammation of the lower urinary tract occurs in several diseases including urinary tract infections radiation cystitis and chronic painful conditions such as Painful Bladder Syndrome/Interstitial Cystitis. This proposal will examine Macrophage Migration Inhibitory Factor a novel regulator of bladder inflammation and will describe new potential targets to decrease or abolish bladder inflammation. Research into the mechanisms of bladder inflammation will provide new information that may benefit a large group of patients suffering from this condition and may suggest potential targets for ameliorating this disease.


application_id: 9026853
project_number: 1R01AG049806-01A1
project_title: The effects of exercise on satellite cell dynamics during aging
administering_ic: NIA
award_notice_date: 2015-12-21
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: AG
serial_number: 049806
suffix: A1
program_official: WILLIAMS, JOHN
project_start_date: 2016-01-01
project_end_date: 2020-11-30
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: MCCARTHY, JOHN JOSEPH
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Ablation;Address;Adult;Affect;Age;Age-Months;Aging;Biological Assay;Breeding;CD34 gene;Cell Nucleus;Cell physiology;Cells;Coculture Techniques;Collagen;Data;Development;Disease;Elderly;Environment;Etiology;Exercise;Fiber;Fibroblasts;Fibrosis;Functional disorder;Gastrocnemius Muscle;Gene Targeting;Genetic;Goals;Growth;Homeostasis;Human;Hypertrophy;Immunohistochemistry;Individual;Integrins;Intervention;Knock-out;Knowledge;Label;Life;Longevity;MAPK14 gene;Maintenance;Measures;Mediating;Methods;MicroRNAs;Modeling;Molecular Profiling;Mouse Strains;Mus;Muscle;Muscle Fibers;Nucleosomes;Outcome;Phase;Phenotype;Physical activity;Production;Proteins;Publishing;Quality of life;Regulation;Reporter;Reporting;Research;Rodent;Role;Running;Skeletal Muscle;Skeletal Muscle Satellite Cells;Stem cells;Stimulus;Testing;Therapeutic;Time;Untranslated Regions;Work;abstracting;base;exosome;extracellular;falls;frailty;improved;loss of function;muscle aging;muscle form;muscle hypertrophy;muscle strength;normal aging;novel;progenitor;regenerative;research study;response;sarcopenia;satellite cell;sedentary;senescence;skeletal;skeletal muscle growth;tool


application_id: 9026277
project_number: 2R01CA131075-06A1
project_title: Defining the contribution of ATR to MC1R-enhanced DNA repair in melanocytes
administering_ic: NCI
award_notice_date: 2016-04-15
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: CA
serial_number: 131075
suffix: A1
program_official: PELROY, RICHARD
project_start_date: 2010-07-01
project_end_date: 2021-03-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 8508402
contact_pi: D'ORAZIO, JOHN A
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
A kinase anchoring protein;ATR gene;Accounting;Address;Adenylate Cyclase;Affect;American;Ataxia;Binding;Biological Assay;Cancer Etiology;Cells;Cessation of life;Co-Immunoprecipitations;Complex;Coupled;Coupling;Cutaneous;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;DNA;DNA Binding;DNA Damage;DNA Repair;Defect;Development;Diagnosis;ERCC1 gene;Event;Funding;Generations;Genetic Polymorphism;Genome;Goals;Gravin;Incidence;Individual;Inherited;Laboratories;Left;Ligation;Link;Maintenance;Malignant Neoplasms;Measures;Mediating;Melanins;Melanocortin 1 Receptor;Melanocyte stimulating hormone;Melanoma Cell;Membrane;Modeling;Molecular;Mus;Mutagenesis;Mutagens;Mutation;Nuclear;Nucleotide Excision Repair;Oligonucleotides;Pathway interactions;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Pigmentation physiologic function;Population;Positioning Attribute;Post-Translational Protein Processing;Prevention strategy;Preventive therapy;Production;Protein Kinase;Protein Phosphatase 2A Regulatory Subunit PR53;Proteomics;Public Health;Radiation therapy;Receptor Signaling;Regulation;Repair Complex;Reporting;Resistance;Retrieval;Risk;Risk Factors;Role;Seminal;Signal Transduction;Skin;Skin Cancer;Surface;Surgical incisions;Tissues;UV Radiation Exposure;UV response;Ultraviolet Rays;United States;Woman;Xeroderma Pigmentosum;base;cell type;chemotherapy;defined contribution;design;high risk;loss of function;melanocyte;melanoma;men;mortality;prevent;receptor;repaired;research study;response;therapy development;ultraviolet;ultraviolet damage


application_id: 9025649
project_number: 5P40OD019794-02
project_title: Ambystoma Genetic Stock Center
administering_ic: OD
award_notice_date: 2016-01-30
opportunity_number: PAR-14-005
application_type: 5
activity_code: P40
ic: OD
serial_number: 019794
program_official: CONTRERAS, MIGUEL A
project_start_date: 2015-03-01
project_end_date: 2020-02-29
study_section: Special Emphasis Panel[ZRG1-BBBP-Y(45)R]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adolescent;Adult;Advisory Committees;Ambystoma;Ambystoma mexicanum;Applied Research;Area;Behavior;Biological;Biomedical Research;Body part;Brain;Breeding;Cells;Cellular biology;Collection;Communities;Community Services;Computers;Custom;Data;Development;Embryo;Embryonic Development;Ensure;Equipment;Evolution;Funding;Genes;Genetic;Genome;Genomics;Health;Heart;Hour;Housing;Human;IACUC;Informatics;Injection of therapeutic agent;Institution;Jaw;Kentucky;Knock-in;Life;Limb structure;Methods;Microinjections;Mission;Modeling;Monitor;Natural regeneration;Neurobiology;Organism;Physiology;Population;Preparation;Procedures;Production;Protocols documentation;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Retina;Services;Site;Site-Directed Mutagenesis;Speed;Spinal Cord;System;Tail;Time;Tissues;Transgenic Organisms;Translating;United States National Institutes of Health;Universities;Vertebrates;Visit;Work;animal resource;base;experience;gene function;innovation;knowledge base;learning strategy;meetings;operation;organ regeneration;tissue repair;transcription activator-like effector nucleases;web site


application_id: 9025468
project_number: 5P01CA163223-04
project_title: Stable Isotope Resolved Metabolomics Analytical Shared Core
administering_ic: NCI
award_notice_date: 2016-03-01
opportunity_number: PAR-12-005
application_type: 5
activity_code: P01
ic: CA
serial_number: 163223
study_section: ZCA1-RPRB-0
subproject_number: 7605
contact_pi_person_id: 8656419
contact_pi: HIGASHI, RICHARD M
other_pis: FAN, TERESA WHEI-MEI;YAN, JUN
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: 2016-03-01
budget_end_date: 2017-02-28
project_abstract:
PROJECT SUMMARY (See instructions): The Stable Isotope Resolved (SIRM) Analytical Shared Core will provide high information throughput (HIT) bioanalytical support for the groups with special emphasis on stable isotope-based metabolic pathway tracing. The basis for this Core already exists in the form of the NSF-initiated UofL Center for Regulatory and Environmental Analytical Metabolomics (CREAM) established expressly for SIRM metabolomic bioanalytical services and collaborations on sample preparation and handling high field NMR mass spectrometry and biochemoinformatics since 2002. CREAM houses state of the art instrumentation that has profoundly influenced experimental design for several research groups. Therefore many Core interactions are by their nature long-standing collaborative efforts. The main goals of the SIRM Shared Core are to provide a set of shared resources for all three Research Projects and seamlessly integrate experimental design data collection and data analysis spanning tissue culture mouse models and human subjects. The Core will provide a combination of experimental methods to determine metabolic phenotypes of cancerous and non-cancerous lung cells and tissue using our state of the art analytical platforms in both NMR and mass spectrometry. In consultation with individual project leaders specific experimental design for stable isotope analysis will be tailored to individual project needs but with consistency across projects to facilitate integrated analyses. We have 3 specific aims to achieve our goals: Specific Aim 1. Provide infrastructure and expert sample handling that ensures consistent handling processing and archiving of samples across all three Research Projects; Specific Aim 2. Provide access and expertise across a wide range of NMR and MS technologies to the three Research Projects: A) Provide access to instrumentation and expertise for robust and consistent SIRM-based analytical experimental design and B) Provide expert data collection and analysis across a wide range of NMR and MS technologies. Specific Aim 3. Provide data analytical support to the Research Projects including data metabolic pathway and biochemical mechanism analyses that include: A) Implement a web-based platform for data reduction quality control and data analytical support; B) Provide methodologies for identifying and quantifying metabolites; C) Provide a bridge between the Projects data acquisition and biochemical analysis in Gore A. Core B provides extensive interoperability handling and advising all aspects of sample preparation data collection data analysis & quality control ensuring consistency of data across all 3 research projects.

project_terms:
Animal Model;Archives;Biochemical;Biochemistry;Biological;Biometry;Cancerous;Cells;Cessation of life;Collaborations;Collection;Computers and Advanced Instrumentation;Consultations;Data;Data Analyses;Data Collection;Data Quality;Early Diagnosis;Ensure;Experimental Designs;Goals;Housing;Human;Individual;Informatics;Instruction;Knowledge;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Metabolic Marker;Metabolic Pathway;Methodology;Methods;Modeling;Nature;Non-Small-Cell Lung Carcinoma;North America;Online Systems;Paper;Pathway interactions;Persons;Preparation;Process;Publishing;Quality Control;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resource Sharing;Sampling;Services;Software Tools;Statistical Data Interpretation;Structure of parenchyma of lung;Support Groups;System;Technology;Time;Tissues;Validation;Water;base;cancer cell;cancer subtypes;data acquisition;data reduction;human subject;improved;instrumentation;interoperability;metabolic phenotype;metabolomics;mouse model;novel strategies;operation;outcome forecast;stable isotope;stem;tissue culture


application_id: 9025467
project_number: 5P01CA163223-04
project_title: Administration Bioinformatics and Biostatistics Core
administering_ic: NCI
award_notice_date: 2016-03-01
opportunity_number: PAR-12-005
application_type: 5
activity_code: P01
ic: CA
serial_number: 163223
study_section: ZCA1-RPRB-0
subproject_number: 7604
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
other_pis: FAN, TERESA WHEI-MEI;YAN, JUN
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: 2016-03-01
budget_end_date: 2017-02-28
project_abstract:
In this Program Project "Systems Biochemistry in Lung Cancer: toward a mechanistic understanding of NSCLC" we aim to achieve a better understanding of the basic biochemistry of lung cancers as a prerequisite to mechanism-based reliable early detection of the disease and to improved approaches to treatment. The role of the Administrative Bioinformatics and Biostatistics Core is to provide overall administration and oversight to the project directors and core leaders (T. W-M. Fan Ph.D. Project 1; J. Yan M.D. Ph.D. Project 2; A. N. Lane Ph.D. Project 3; R. M Higashi Ph.D. Core B Analytical) on this Program Project. In addition Biostatistics and Informatics support (leaders S. N. Rai Ph.D. and H. N. B Moseley Ph.D.) for the Projects will be provided through this Core. To ensure smooth interoperability of the program the administrative core will be responsible for maintaining the budgets and cost reporting of the projects and cores as well as coordinating annual reports regular meetings among the project personnel and the internal and external advisory committees. The primary objective of the Bioinformatics / Biostatistics portion of this core is to provide support for investigators performing translational research and Informatics for biochemical pathway reconstruction and flux modeling. The core services are matched to the needs of each project and cover a full range of services from collaboration and routine service; protocol preparation and review; development of informatics approaches to ensure interoperability; and biochemical network analysis.

project_terms:
Advisory Committees;Annual Reports;Biochemical;Biochemical Pathway;Biochemistry;Bioinformatics;Biometry;Biostatistics Core;Budgets;Cessation of life;Collaborations;Data;Data Analyses;Data Quality;Data Set;Development;Disease;Doctor of Medicine;Doctor of Philosophy;Early Diagnosis;Ensure;Experimental Designs;Human Resources;Ice;Informatics;Instruction;Knowledge;Laboratories;Malignant Neoplasms;Malignant neoplasm of lung;Modeling;Non-Small-Cell Lung Carcinoma;North America;Pathway Analysis;Preparation;Protocols documentation;Quality Control;Reporting;Research Personnel;Role;Services;System;Translational Research;Universities;Validation;base;cancer subtypes;cost;data management;data visualization;improved;interoperability;meetings;model building;novel strategies;operation;outcome forecast;programs;reconstruction


application_id: 9025466
project_number: 5P01CA163223-04
project_title: Determining Molecular Mechanisms of NSCLC and Response to beta-glucan
administering_ic: NCI
award_notice_date: 2016-03-01
opportunity_number: PAR-12-005
application_type: 5
activity_code: P01
ic: CA
serial_number: 163223
study_section: ZCA1-RPRB-0
subproject_number: 7603
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
other_pis: FAN, TERESA WHEI-MEI;YAN, JUN
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: 2016-03-01
budget_end_date: 2017-02-28
project_abstract:
The gold standard for understanding the connection between tumor metabolism tumor progression and ultimately therapeutic efficacy is the human subject but more detailed information is needed from appropriate better controlled models. We have begun a Stable Isotope Resolved Metabolomics (SIRM) study of non-small cell lung cancer (NSCLC) from patients who underwent surgical resection. In our pilot study we capitalized on the inherent power of the matched pairs of malignant and benign lung tissue and the use of "C-labeled glucose administered iv prior to surgery to map in situ intracellular metabolic pathways for the first time. This led to the discovery that mitochondrial pyruvate carboxylase (PCB) is activated to replenish Krebs cycle intermediates required for biosynthesis (i.e. anaplerosis) in tumors. This was further corroborated by increased mRNA and protein expression of PCB in the tumors compared with the paired benign lung tissue as well as growth inhibition of NSCLC cells by PCB knockdown. Critical to the interpretation of these studies was the additional detailed information that we obtained on cell culture and mouse models which provided metabolic signatures to look for in the tumor tissue.). Our preliminary findings also indicate that there are many more metabolic distinctions in lung tumors; the underlying pathways and regulation have yet to be defined. We now seek to extend the approach to a larger cohort of NSCLC and added a new ex vivo "Warburg" tissue slice approach to better define in large-scale the metabolic reprogrammings in NSCLC with prevailing driver gene defects. These direct human studies will be conducted in parallel with model cell (Project 1) and animal studies (Project 2) to facilitate interpretation. We will also apply this integrated approach to explore the metabolic mechanism underlying the tumor-regressive effect of a pre-operative treatment with beta-glucans. We hypothesize that this effect may be in part mediated by beta-glucan's activation of glucose and Gin metabolism in resident macrophages a key immune modulator in the tumor microenvironment based on our most recent data and the literature (cf. Project 2). We will further explore the linkage of lung tumor tissue to blood plasma metabolism via the lipidic microvesicles (MV) known to be released by lung cancer cells with metastasis-promoting capacity. We have new evidence that the lipid profile of plasma MV is distinct among early stages of lung and breast cancer patients and healthy subjects. We will test if beta-glucan treatment can alter MV metabolic signatures for future application as clinical indicators. These goals will be achieved via the three specific aims.

project_terms:
Adenocarcinoma;Age;Anabolism;Animals;Benign;Biochemical;Biochemistry;Breast Cancer Patient;Cancer Patient;Cell Culture Techniques;Cell model;Cells;Cessation of life;Characteristics;Citric Acid Cycle;Clinical;Coupled;Data;Defect;Diagnostic Neoplasm Staging;Early Diagnosis;Excision;Future;Gene Expression Profile;Genes;Glucose;Glutamine;Goals;Gold;Growth;Human;Immune;Immune response;In Situ;Infusion procedures;Instruction;Knowledge;Label;Learning;Link;Lipids;Literature;Lung Neoplasms;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Modeling;Molecular;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;North America;Oncogenes;Oncogenic;Operative Surgical Procedures;Outcome;Pathological Staging;Pathway interactions;Patients;Pilot Projects;Plasma;Pyruvate Carboxylase;Recruitment Activity;Regulation;Resected;Sample Size;Sampling;Slice;Squamous cell carcinoma;Staging;Structure of parenchyma of lung;System;Testing;Therapeutic;Time;Tissues;Tracer;Treatment Efficacy;Tumor Subtype;Tumor Tissue;Tumor stage;base;beta-Glucans;cancer cell;cancer subtypes;cohort;design;diagnostic biomarker;human subject;improved;knock-down;mRNA Expression;macrophage;metabolomics;microvesicles;mouse model;novel diagnostics;novel strategies;outcome forecast;protein expression;response;stable isotope;tumor;tumor metabolism;tumor microenvironment;tumor progression


application_id: 9025465
project_number: 5P01CA163223-04
project_title: Determining Tumor Metabolism and Biochemical Mechanism of beta-glucan Action in
administering_ic: NCI
award_notice_date: 2016-03-01
opportunity_number: PAR-12-005
application_type: 5
activity_code: P01
ic: CA
serial_number: 163223
study_section: ZCA1-RPRB-0
subproject_number: 7602
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: FAN, TERESA WHEI-MEI;YAN, JUN
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: 2016-03-01
budget_end_date: 2017-02-28
project_abstract:
Deaths from lung cancer are the highest of all cancers in the US. The complexity of lung cancer (LC) development suggests that a combination of approaches is needed to understand the mechanism of LC biology and tumor cell interactions with other cells such as immune cells within the tumor microenvironment. The concept of "cancer immunoediting" recognizes the complex and dynamic interactions between the tumor and host during tumor development progression and metastasis. Although how the immune system plays a role in development and progression of human non-small cell lung carcinoma (NSCLC) is still elusive innate macrophages are abundant in the NSCLC tumors. These macrophages are of immune suppressive M2 phenotype promote tumor angiogenesis and metastasis and limit efficacy of chemotherapy for NSCLC. beta-Glucans polysaccharides derived from various sources can stimulate both innate and adaptive immune responses. Our preliminary data further demonstrate that beta-glucan treatment in vitro converts immune suppressive M2 macrophages into tumoricidal M1 phenotype and significantly decreases tumor-associated macrophage (TAM)-mediated immune suppression on CD4 and CDS T cells. Using the stable isotope resolved metabolomics (SIRM) approach we show that glutamine (Gin) uptake and subsequent metabolism to glucose glutathiones and lactate are enhanced when immune suppressive M2 macrophages are converted into an Ml phenotype. The central hvpothesis of this proposal is that differential human NSCLC subtypes may have distinct metabolic profiles and p-glucan treatment modulates TAM activity and metabolism leading to the alterations of metabolic networks in NSCLC. We will use stable isotopic (13C 15N) nutrient tracers in combination with the SIRM approach and metabolomics-edited transcriptomic analysis (META) to define key metabolic components of human NSCLC in vivo and investigate how beta-glucan treatment influences TAM phenotype function metabolism and subsequently tumor microenvironmental metabolic events. Three Specific Aims are proposed to determine the: 1 specific metabolic patterns of human NSCLC cells in xenografted tumors in severe combined immunodeficient (SCID) mice; 2) biochemical mechanisms of beta-glucan action in murine lung carcinoma models; 3) biochemical and phenotypic characteristics of human primary tumors implanted in N0D/SCID/IL-2gcNULL mice in response to beta-glucan administration. These investigations will advance our understanding of the biochemical underpinnings of tumor microenvironment nutrient utilization by NSCLC and how these processes are related to tumor immune evasion and immunomodulation.

project_terms:
Affect;Antigen Presentation;Arginine;Biochemical;Biochemical Pathway;Biochemistry;Cancer Biology;Cell Communication;Cell Line;Cells;Cessation of life;Clinical;Complex;Data;Development;Early Diagnosis;Event;Genes;Glucans;Glucose;Glutamine;Glutathione;Goals;Human;Human Characteristics;Immune;Immune system;Immunomodulators;Immunophenotyping;Implant;In Situ;In Vitro;In Vivo NMR Spectroscopy;Instruction;Investigation;Knowledge;Label;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Measurement;Mediating;Mediator of activation protein;Metabolic;Metabolism;Modeling;Mus;Natural immunosuppression;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;North America;Nutrient;Outcome;Particulate;Pathway interactions;Patients;Pattern;Phenotype;Play;Polysaccharides;Primary Neoplasm;Process;Protein Analysis;Role;SCID Mice;Slice;Source;System;T-Lymphocyte;Tissues;Tracer;Tumor Angiogenesis;Yeasts;adaptive immunity;angiogenesis;beta-Glucans;cancer cell;cancer subtypes;chemotherapy;immunoregulation;improved;in vivo;lung Carcinoma;macrophage;metabolic profile;metabolomics;neoplastic cell;novel strategies;outcome forecast;response;stable isotope;subcutaneous;transcriptomics;tumor;tumor growth;tumor metabolism;tumor microenvironment;tumor xenograft;uptake


application_id: 9025464
project_number: 5P01CA163223-04
administering_ic: NCI
award_notice_date: 2016-03-01
opportunity_number: PAR-12-005
application_type: 5
activity_code: P01
ic: CA
serial_number: 163223
study_section: ZCA1-RPRB-0
subproject_number: 7601
contact_pi_person_id: 7213583
contact_pi: FAN, TERESA WHEI-MEI
other_pis: FAN, TERESA WHEI-MEI;YAN, JUN
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: 2016-03-01
budget_end_date: 2017-02-28
funding_mechanism: Non-SBIR/STTR
project_title:
Microenvironmental Nutrient Availability and Immunomodulation in Lung Cancer Cells: A systems biochemical approach

project_abstract:
PROJECT SUMMARY (See instructions); We propose a systems biochemical study of lung cancer (LC) cell nutrient metabolism of importance to LC development survival and progression in the tumor microenvironment (TME). The primary approach is to utilize stable isotopic (13C and 15N) nutrient tracers in conjunction with stable isotope-resolved metabolomics (SIRM) and metabolomics-edited transcriptomic analysis (META) to discern key metabolic events in LC cells that govern their behavior and vulnerability in response to major TME factors such as hypoxia and nutrient deficiency. A central focus of this cell-based project is to understand the interaction of nutrient availability and hypoxia in modulating LC cell metabolism and how this may affect its ability to grow survive and progress. This focus is in part motivated by our recent finding from the gene array data of paired cancerous and benign lung tissues resected from human patients regarding the dysregulations of key enzymes (e.g. arginase glutaminase hyaluronan synthase 2) involved in metabolism of glutamine and glucose. It is also driven by our recent discovery of arginase suppression in lung tumor xenograft and activation of Gin metabolism in murine macrophages by a natural immune activator B-glucan. We will accomplish this with the following specific aims: SAI: SIRM profiling of lung cells for reconstructing biochemical pathways involved in utilization of glucose and glutamine. Biochemical pathways of these nutrients relevant to energy anabolism immunomodulatory sensors and cell migration-related extracellular matrix factors will be mapped in LC cells harboring major driver gene anomalies normal epithelial cells and relevant stromal cells for comparison. SA2: Probe interactions of nutrient availability in combination with hypoxia. We will focus on 2 key questions: 1) How does Gin alleviate glucose demand by LC cells?; 2) Is Gin metabolism crucial to hypoxic LC cells?. SAS: Examine Arg metabolism in human tumor-associated macrophages as a function of Gin and Arg availability. Gin and Arg utilization pathways of relevance to immunomodulation in tumor-associated human macrophages will be probed in response to immune activator (B-glucans) and M2 to Ml polarization. The knowledge gained from this project will be used to help interpret data obtained from Projects 2 and 3.

project_terms:
Affect;American;Anabolism;Apoptosis;Behavior;Benign;Biochemical;Biochemical Pathway;Biochemistry;Cancer cell line;Cancerous;Cell Line;Cells;Cessation of life;Citric Acid Cycle;Clinical;Colon Carcinoma;Data;Development;Early Diagnosis;Enzymes;Epidermal Growth Factor Receptor;Epithelial Cells;Event;Extracellular Matrix;Fibroblasts;Food Interactions;Gene Expression;Gene Proteins;Genes;Glucans;Gluconeogenesis;Glucose;Glutaminase;Glutamine;Glutathione Metabolism Pathway;Glycolysis;Goals;Growth;HAS2 gene;Hexosamines;Human;Hyaluronan;Hypoxia;Immune;Instruction;KRAS2 gene;Killings;Knowledge;Label;Link;Lung;Lung Neoplasms;Macrophage Activation;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Maps;Mediating;Medicine;Metabolic;Metabolic Pathway;Metabolism;Methods;Modification;Mus;Nitric Oxide Pathway;Non-Small-Cell Lung Carcinoma;North America;Nutrient;PIK3CA gene;Pathway interactions;Patients;Pattern;Pentosephosphate Pathway;Polyamines;Proteins;Regulation;Research;Resected;Stable Isotope Labeling;Stromal Cells;Structure of parenchyma of lung;Surface;System;TP53 gene;Testing;Therapeutic;Tissues;Tracer;Tumor Tissue;Tumor-Derived;Yeasts;arginase;base;cancer cell;cancer subtypes;cell growth;cell motility;cell stroma;cytokine;immune function;immunoregulation;improved;in vivo;interest;lipid metabolism;macrophage;malignant breast neoplasm;metabolomics;mortality;novel;novel strategies;nucleotide metabolism;nutrient metabolism;outcome forecast;response;sensor;stable isotope;transcriptomics;tumor;tumor metabolism;tumor microenvironment;tumor xenograft;tumorigenesis;urea cycle


application_id: 9025455
project_number: 5P01CA163223-04
project_title: Systems Biochemistry in Lung Cancer: Toward a Mechanistic Understanding of NSCLC
administering_ic: NCI
award_notice_date: 2016-03-01
opportunity_number: PAR-12-005
application_type: 5
activity_code: P01
ic: CA
serial_number: 163223
program_official: SPALHOLZ, BARBARA A
project_start_date: 2014-08-19
project_end_date: 2018-02-28
study_section: ZCA1-RPRB-0(O1)
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
other_pis: FAN, TERESA WHEI-MEI;YAN, JUN
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Deaths from lung cancer are the highest of all cancers in North America and elsewhere and because of the long incubation time are likely to remain so for the foreseeable future. Furthermore although the 5-year survival rate of stage I lung cancer is 60-70% later stage disease has a very poor prognosis. Accurate detection of asymptomatic early stage lung cancer in individuals at risk is currently unreliable. A better understanding of the basic biochemistry of lung cancers is a prerequisite to mechanism-based reliable early detection of the disease and to improved approaches to treatment. The very complexity of the transformed cells and the variable host-tumor interactions makes the problem refractory to any single approach. A systems biochemistry approach in which lung cancers are studied at the mechanistic level in the laboratory in mouse models and in human subjects offers the opportunity to address the complexity of cancer development and progression. The use of stable isotope resolved metabolomics provides the necessary direct biochemical information about lung cancer with minimal processing that is not otherwise available. This program will address the problem in a 3-pronged approach based on the following integrated projects: Project 1: Cellular Systems Biochemistry. Microenvironmental nutrient availability and immune modulation in lung cancer cells. Project 2; Preclinical Systems Biochemistry. Using SIRM in Human NSCLC xenograft mouse to determine biochemical mechanisms of immunomodulator -glucan.    
Project 3: Translational Systems Biochemistry. Molecular mechanisms of NSCLC and response to -glucan by SIRM. The three projects will use a common mechanistic approach to understanding cancer biochemistry namely stable isotope resolved metabolomics (SIRM) that we have been developing over the last eight years. The analytical requirements will be met in the SIRM Analytical Core which also supplies the necessary sample handling and bioinformatics support for the three projects. Core A provides overall administrative support.

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

public_health_relevance:
RELEVANCE: Deaths from lung cancer are the highest among all cancers in North America and cure rates remain low. We seek to gain a deeper understanding of lung cancer biochemistry using a novel approach we developed. Improved knowledge will have direct impact on early diagnosis and prognosis. The biochemical differences between lung cancer subtypes can be related to appropriate treatments.


application_id: 9024538
project_number: 4R01EY012716-17
project_title: Functional State of Developing Retinogeniculate Synapse
administering_ic: NEI
award_notice_date: 2016-02-23
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: EY
serial_number: 012716
program_official: GREENWELL, THOMAS
project_start_date: 2001-05-01
project_end_date: 2018-02-28
study_section: Special Emphasis Panel[ZRG1-IFCN-Q(02)M]
contact_pi_person_id: 1864719
contact_pi: GUIDO, WILLIAM
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): We have developed a powerful mouse model to study visual circuit development in the dorsal lateral geniculate nucleus (dLGN) the thalamic relay of retinal information to the visual cortex. To date studies have focused largely on the retinogeniculate pathway and the refinement of connections between retinal ganglion cells and dLGN neurons. While many of the changes in retinogeniculate axon patterning and connectivity have been delineated information about two fundamental aspects of organization is still lacking. One relates to the cell- class specificity of connections between RGCs and dLGN cells and the other pertains to the source of connections to dLGN cells namely the wealth of input that arises from nonretinal projections. Both aspects are critical for a contemporary understanding of thalamic function which is to provide a faithful relay of retinal signals but at the same time to modulate the gain of transmission based on changes in behavioral state. The goals of this proposal are to assess how retinogeniculate refinement relates to class specific connections whether retinogeniculate refinement proceeds in a way that establishes separable parallel visual channels to determine when nonretinal projections develop in dLGN and to assess how such input coordinates with the innervation and refinement of the retinogeniculate pathway. To address these issues we will conduct anatomical electrophysiological and optogenetic experiments in transgenic mice that allow for the visualization and experimental isolation of specific cell types arising from the retina or from such nonretinal sources as layer VI of visual cortex the thalamic reticular nucleus and cholinergic nuclei of the brainstem. These studies willprovide valuable information about how the developing brain forms precise patterns of connections and offer further insight into the study and treatment of developmental and neurological disorders that result from the formation of abnormal patterns of connectivity.

project_terms:
3-Dimensional;Address;Adopted;Age;Architecture;Axon;Behavioral;Biological Models;Brain;Brain Stem;Cell Nucleus;Cells;Cholera Toxin Protomer B;Deafferentation procedure;Development;Disease;Dorsal;Electrophysiology (science);Event;Exhibits;Eye;Felis catus;Genetic;Goals;Health;Imagery;In Vitro;Injection of therapeutic agent;Injury;Interneurons;Knowledge;Label;Lateral Geniculate Body;Life;Light;Mus;Neurons;Optic Nerve;Pathway interactions;Pattern;Preparation;Retina;Retinal;Retinal Ganglion Cells;Rhodopsin;Signal Transduction;Slice;Source;Specificity;Synapses;Testing;Thalamic structure;Time;Transgenic Mice;Transgenic Organisms;Trees;Variant;Viral;Visual;Visual Cortex;base;biocytin;cell type;cholinergic;developmental disease/disorder;field study;insight;loss of function;monocular;mouse model;mutant;nerve supply;nervous system disorder;optogenetics;postnatal;preference;reconstruction;research study;response;retinal axon;retinal progenitor cell;retinogeniculate;synaptogenesis;transcription factor;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE: These studies will provide valuable information about how the developing brain forms precise patterns of connections and offer further insight into the study and treatment of developmental and neurological disorders that result from the formation of abnormal patterns of connectivity. Knowledge gained from these studies will also have important implications for understanding and predicting how thalamic circuits involving retinal and nonretinal projections respond to disease or injury.


application_id: 9024502
project_number: 5K23DC014074-02
project_title: Promoting Early Diagnosis of Congenital Hearing Loss through Patient Navigation
administering_ic: NIDCD
award_notice_date: 2016-02-25
opportunity_number: PA-14-049
application_type: 5
activity_code: K23
ic: DC
serial_number: 014074
program_official: RIVERA-RENTAS, ALBERTO L
project_start_date: 2015-03-01
project_end_date: 2018-02-28
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 11512687
contact_pi: BUSH, MATTHEW LEE
other_pis: Not Applicable
congressional_district: 06
department: OTOLARYNGOLOGY
primary_duns: 939017877
primary_uei: 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): With the incidence of approximately 1.5 per 1000 births pediatric hearing loss is the most common neonatal sensory disorder in the United States. During the early years of life the sense of hearing is vital for the optimal development o speech language and cognition. Deafness in early childhood can result in lifelong learning delay and disability leading to adulthood challenges in education employment and social life. The economic costs of hearing loss and impaired language development are substantial. Early identification and intervention can prevent these adverse economic educational and social consequences. National standards dictate that infants who are deaf or hard of hearing should be diagnosed by 3 months of age and subsequent intervention services should be initiated no later than 6 months of age. Unfortunately 24% of infants have no diagnostic testing after abnormal infant screening and 29% of children with hearing loss are not enrolled in intervention services.1 Children from rural Appalachia and economically depressed regions have poor adherence to follow-up testing and are often delayed in diagnosis and treatment of pediatric hearing loss.2 The process of obtaining timely hearing health care for infants is complex and many factors such as communication breakdowns lack of decisional support and poor care coordination contribute to the disparity. Early infant hearing detection and intervention (EHDI) i coordinated on a state level and in spite of multiple initiatives to decrease EHDI non-adherence there is no established method to address this problem. In fact there is no evidence-based research that addresses the effectiveness of initiatives designed to decrease non-adherence for diagnosis or intervention.3 The research proposed in this application seeks to rectify this health disparity by addressing non-adherence and delays in the EHDI process during the first year of life through a novel intervention involving a patient navigator program (PNP). Navigators are trained healthcare workers who educate patients on health conditions and healthcare systems and expeditiously facilitate adherence to complex healthcare. PNPs have successfully decreased non- adherence to clinical testing and treatment in other health areas (e.g. cancer) but have not been utilized in the EHDI field. The hypothesis of this study is that a PNP will significantly decrease non-adherence to and timing of diagnostic audiological testing and intervention for infant hearing loss. The specific aims are to 1) examine the efficacy of a PNP to decrease non-adherence to and timing of recommended infant audiological testing within 3 months after birth in Appalachian and non-Appalachian participants 2) assess the efficacy of a PNP to decrease non-adherence to and timing of hearing aid fitting in infants diagnosed with hearing loss and 3) determine the maternal socioeconomic educational demographic and infant factors involved in non- adherence and delays to testing and treatment. We will accomplish Aim 1 by enrolling mother-child dyads in which the child fails newborn hearing screening into a randomized prospective study. The participants will be stratified into Appalachian and non-Appalachian based on county of residence and then within each stratum the subjects will be randomized into either the patient navigator group or the standard of care group. The navigator group will have weekly phone contact with a patient navigator after birth while the control group will receive the standard of care only and will have no contact with a navigator. Non-adherence to obtain audiological outpatient diagnostic testing before 3 months after birth (Aim 1) will be the primary outcome measure. Infants identified with hearing loss at our institution will be enrolled in Aim 2 and randomized into a patient navigator group or standard of care group similar to Aim 1. Non-adherence with fitting of hearing aids before 6 months of age will be the primary outcome for Aim 2. Secondary outcomes will include timing of diagnostic testing after birth (Aim 1) and the timing of hearing aid fitting after diagnosis (Aim 2. Aim 3 will characterize maternal and infant factors in non-adherence. The candidate is a clinician scientist at the University of Kentucky in the Department of Otolaryngology who has demonstrated commitment to a career in clinical and translational research. The mentors in this application Nancy Schoenberg Ph.D. Karl White Ph.D. Richard Kryscio Ph.D. will provide balanced training and guidance in the areas of health disparity infant hearing loss and intervention initiatives and clinical research design and implementation. The overall goal of thisK23 award is to provide the candidate with research and training activities that are focused on expediting diagnosis and treatment of infant hearing loss in the setting of health disparity. The training will expand the candidate's knowledge and experience with pediatric hearing health disparities research EHDI research and patient navigator integration and clinical trial design and analysis. The candidate is uniquely poised to investigate methods to expedite rural congenital hearing loss diagnosis and intervention. This application is intended to result in a research portfolio including subsequent R01 funding devoted to expediting hearing loss intervention in children who face barriers to care. The overall career goal of the candidate is to become an independently funded surgeon scientist focused on transforming the delivery of effective multidisciplinary hearing interventions. These goals are in line with NIH and NIDCD priority areas of improving diagnosis and treatment of hearing loss and developing evidence-based approaches that increase awareness access and affordability for those experiencing health disparities.

project_terms:
Address;Adherence;Adult;Affect;Age-Months;Appalachian Region;Area;Auditory;Awareness;Balance training;Behavioral;Birth;Caring;Child;Childhood;Clinical Research;Clinical Treatment;Clinical Trials Design;Cognition;Communication;Complex;Congenital Disorders;Control Groups;County;Data;Deafness;Decision Making;Depressed mood;Detection;Development;Diagnosis;Diagnostic;Diagnostic tests;Doctor of Philosophy;Early Diagnosis;Early Intervention;Early identification;Economics;Education;Effectiveness;Employment;Enrollment;Face;Family;Funding;Goals;Health;Health Personnel;Health Services Accessibility;Healthcare;Healthcare Systems;Hearing;Hearing Aids;Hearing Impaired Persons;Hearing Tests;Incidence;Infant;Infant Care;Institution;Intervention;Intervention Studies;Joints;Kentucky;Knowledge;Language;Language Development;Learning;Life;Literature;Malignant Neoplasms;Medical;Mentored Patient-Oriented Research Career Development Award;Mentors;Methods;Mothers;National Institute on Deafness and Other Communication Disorders;Nature;Neonatal;Newborn Infant;Otolaryngology;Outcome;Outcome Measure;Outpatients;Parents;Participant;Patients;Plant Roots;Process;Prospective Studies;Randomized;Recruitment Activity;Research;Research Activity;Research Design;Rural;Rural Health;Scientist;Sensory;Sensory Disorders;Services;Speech;Surgeon;Testing;Therapeutic Intervention;Time;Training;Training Activity;Translational Research;Trust;United States;United States National Institutes of Health;Universities;base;career;design;disability;early childhood;economic cost;effective therapy;evidence base;experience;follow-up;health care disparity;health disparity;hearing impairment;hearing screening;improved;multidisciplinary;navigator intervention;novel;prevent;primary outcome;programs;research clinical testing;residence;screening;secondary outcome;service intervention;social;socioeconomics;sound;standard care;standard of care;success;theories;therapy development

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Hearing loss is the most common sensory congenital disorder and this condition is diagnosable and treatable. Children who are born with hearing loss must undergo several hearing tests to diagnose the condition and many families are delayed in receiving this testing or never obtain the necessary testing and treatment. This research evaluates a new method for helping children with hearing loss obtain timely care by using a patient navigator which is a trusted layperson who provides educational support for parents of these children by making a personal connection.


application_id: 9024491
project_number: 5R03CA187839-02
project_title: The role of Sin1 in colorectal cancer progression
administering_ic: NCI
award_notice_date: 2016-03-07
opportunity_number: PAR-14-007
application_type: 5
activity_code: R03
ic: CA
serial_number: 187839
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2015-04-01
project_end_date: 2017-09-30
study_section: ZCA1-SRB-C(J1)
contact_pi_person_id: 8737920
contact_pi: YANG, HSIN-SHENG
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Colon cancer is the third most fatal cancer in both men and women in the United States. For more than 90% of patients who develop hepatic metastases the disease is fatal within 5 years: often within 1-2 years. Inactivation of tumor suppressor genes is one type of somatic genetic changes that occur in colon cancer. Understanding the function and action mechanism of tumor suppressors in colon cancer metastasis will benefit the design of new therapeutic drugs to reduce the mortality rate of metastatic colon cancer. Programmed cell death 4 (Pdcd4) a novel tumor suppressor is frequently down-regulated in cancerous colon tissues compared to adjacent normal tissues. Indeed knockdown of Pdcd4 expression in colon tumor cells promotes invasion in cultured cells and metastasis in nude mice. Conversely over-expression of Pdcd4 inhibits colon tumor cell invasion and intravasation. Promotion of tumor invasion by Pdcd4 knockdown is believed to elevate Snail expression and thereby down-regulate E-cadherin and activate -catenin and AP-1 dependent transcription. In addition Pdcd4 has been demonstrated to inhibit protein translation through its ability to bind with translation initiation factor 4A (eIF4A). Pdcd4 has alo been shown to inhibit activation of Akt (also known as protein kinase B) a kinase frequently activated in human colon cancer. Preliminary studies showed that knockdown of Akt suppresses colon tumor cell invasion caused by Pdcd4 knockdown suggesting that Pdcd4 controls colon tumor invasion/metastasis via regulation of Akt activation. A key finding was that over-expression of Pdcd4 inhibits the level of Sin1 (stress-activated-protein kinase-interacting protein1) whereas knockdown of Pdcd4 elevates Sin1. In addition knockdown of Pdcd4 increased Sin1 translation. Since Sin1 is a critical component of mammalian target of rapamycin complex 2 (mTORC2) which controls Akt activation these promising findings suggest a mechanism by which Pdcd4 regulates Akt activation through the control of Sin1 translation. However the clinical importance of Sin1 expression in colon cancer progression and the role of Sin1 in colon tumor cell invasion/metastasis are unknown. Since Pdcd4 suppresses colon tumor invasion/metastasis and inhibits Sin1 expression the hypothesis is that Pdcd4 suppresses colon tumor cell invasion/metastasis through inhibition of Sin1 translation. To test this hypothesis two specific aims are proposed. Aim 1: determine whether Sin1 expression correlates with colon cancer progression. Aim 2: determine whether suppression of Sin1 translation by Pdcd4 leads to inhibition of Akt activation thereby impeding invasion/metastasis. Accomplishment of the proposed study will establish the clinical significance of Sin1 expression in colon cancer progression and the promoter role of Sin1 in colon tumor invasion/metastasis. The proposed work is highly innovative and of significant impact given the translational value in providing a solid rationale for development of agents to target Sin1 as a unique strategy for colon cancer therapeutics.

project_terms:
Antineoplastic Agents;Apoptosis;Binding;Cancerous;Cause of Death;Cell physiology;Clinical;Colon;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Complex;Cultured Cells;Data;Development;Diagnosis;Disease;Down-Regulation;E-Cadherin;FRAP1 gene;Future;Genetic Transcription;Half-Life;Health;Human;Lead;Liver;Malignant Neoplasms;Messenger RNA;Metastatic Neoplasm to the Liver;Mutation;Neoplasm Metastasis;Normal tissue morphology;Nude Mice;Patients;Peptide Initiation Factors;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Play;Proteins;Proto-Oncogene Proteins c-akt;Recurrence;Regulation;Role;Signal Pathway;Snails;Solid;Survival Rate;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;Transcription Factor AP-1;Translations;Tumor Cell Invasion;Tumor Cell Migration;Tumor Suppressor Proteins;Tumor-Suppressor Gene Inactivation;United States;Up-Regulation;Woman;Work;cancer diagnosis;cell motility;clinically relevant;clinically significant;colon cancer patients;design;helicase;implantation;inhibitor/antagonist;innovation;insight;knock-down;lymph nodes;men;mortality;mouse model;neoplastic cell;novel;novel therapeutics;overexpression;promoter;stress activated protein kinase;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Colon cancer is the third most commonly diagnosed cancer and the third leading cause of death in both men and women in the United Sates largely due to the spread of cancer to the liver and lymph nodes. In this proposal we intend to understand the clinical relevance of an important protein Sin1 in colon cancer tissues and the role of Sin1 in the spread of the colon tumor. This work will provide an understanding of how Pdcd4 a novel tumor suppressor modulates Sin1 expression resulting in control of the spread of colon cancer and may lead to a new target for treatment of colon cancer.


application_id: 9024396
project_number: 4K02AG033629-05
project_title: Self-Regulation and Aging: Substrates and Health Consequences
administering_ic: NIA
award_notice_date: 2016-02-29
opportunity_number: PA-10-057
application_type: 4
activity_code: K02
ic: AG
serial_number: 033629
program_official: NIELSEN, LISBETH
project_start_date: 2012-03-15
project_end_date: 2018-02-28
study_section: Behavior and Social Science of Aging Study Section[NIA-S]
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): Suzanne C. Segerstrom is an independent investigator (PhD 1997) who has established a productive research program in personality self-regulation and physiology. The application proposes to protect a high level of research effort (80%) by releasing her from teaching service and administrative responsibilities. This support will facilitate an expansion of her research program in the interactions among self-regulation physiology well-being and health in older adults. The application has three foci: (i) executive cognitive function and heart rate variability are predicted to covary with self-regulatory success (ii) self-regulatory success across domains (e.g. control of repetitive thought acquisition of social or status resources) is predicted to correlate with mental and physical health and (iii) social resources will have disproportionate effects on health with increasing age as predicted by socioemotional selectivity theory. Career development activities under the award will include didactic and experiential training in aging longitudinal design and analysis and the responsible conduct of research; collaborations with dedicated aging researchers in cognition neuropsychology immunology neurology and methodology; and spearheading special projects and meetings. Research activities will include analysis of the relationship between executive function and self- regulation in her existing R01-funded longitudinal research with community-dwelling older adults (N = 150) and studies of self-regulation and health in the R01 sample a cross-sectional study of younger and older women focusing on immunosenescence (N=76) a longitudinal follow-up in a study of middle-aged adults (N = 96) that began in 1994 and a longitudinal study of amyotrophic lateral sclerosis patients and caregivers (N = 266). Proposed studies illustrating future directions examine the role of goal selection and optimization in promoting psychological and physiological well-being in older women with pain and the role of self-regulation in socioemotional selectivity and the contributions of executive cognitive function and heart rate variability to this relationship in older adults. The University of Kentucky and the Department of Psychology provide a rich environment for the development of this work. It is expected that K02 support would allow Dr. Segerstrom to acquire additional expertise in cognition physiology and aging; produce and disseminate cutting-edge research in self-regulation aging and health; expand her grant portfolio to continue this line of research; and train PhD students in the conduct of this research.

project_terms:
Adult;Age;Aging;Amyotrophic Lateral Sclerosis;Attention;Award;Behavior;Caregivers;Cognition;Collaborations;Communities;Cross-Sectional Studies;Data Collection;Databases;Development;Disease Progression;Doctor of Philosophy;Educational process of instructing;Elderly;Emotional;Emotions;Environment;Failure;Funding;Future;Goals;Grant;Health;Health Resources;Hydrocortisone;Immune response;Immunology;Individual;Individual Differences;Inflammation;Informal Social Control;Interleukin-6;Kentucky;Lead;Longevity;Longitudinal Studies;Medical;Memory;Mental Depression;Mental Health;Methodology;Neurology;Neuropsychology;Pain;Patients;Peripheral;Personal Satisfaction;Personality;Physiological;Physiology;Process;Psychology;Public Health;Regimen;Regulation;Research;Research Activity;Research Personnel;Resources;Rest;Risk;Role;Sampling;Science;Self-control as a personality trait;Series;Services;Social Interaction;Social status;Students;Testing;Thinking;Time;Training;United States National Institutes of Health;Universities;Vaccination;Work;behavior change;beta-2 Microglobulin;career development;cognitive function;executive function;falls;follow-up;heart rate variability;immune activation;immunosenescence;longitudinal analysis;longitudinal design;meetings;middle age;older women;physical conditioning;programs;psychologic;psychosocial;research study;response;responsible research conduct;satisfaction;social;success;theories;thought control;vaccine trial;young woman

public_health_relevance:
NARRATIVE Older adults' ability to control thoughts emotions and behaviors - that is to self-regulate - is important for acquiring and maintaining resources such as social relationships as well as meeting other demands such as compliance with medical regimens. Understanding the underlying resources for self-regulation such as cognitive function as well as the psychological social and physical consequences of self-regulatory ability and success is important for optimizing older adults' health and well-being.


application_id: 9024353
project_number: 5R01DE024509-03
project_title: Filifactor alocis interactions with neutrophils
administering_ic: NIDCR
award_notice_date: 2016-02-26
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DE
serial_number: 024509
program_official: LUNSFORD, DWAYNE
project_start_date: 2014-07-01
project_end_date: 2019-03-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
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_terms:
Adult;Affect;Animal Model;Bacteria;Bacterial Infections;Biology;Cells;Chronic;Communicable Diseases;Cytoplasmic Granules;Data;Development;Diagnostic;Disease;Enzymes;Etiology;Exocytosis;Functional disorder;Future;Gingiva;Goals;Health;Health Status;High-Throughput Nucleotide Sequencing;Human;Immune;Immune response;Immune system;In Vitro;Infection;Inflammation;Inflammatory;Integration Host Factors;Intention;Killings;Knockout Mice;Knowledge;Lesion;Leukocytes;Maintenance;Matrix Metalloproteinases;Modeling;Mus;Neutrophil Activation;Neutrophil Infiltration;Oral;Oral health;Organism;Outcome;Oxygen;Particulate;Pathogenesis;Pathogenicity;Periodontal Diseases;Periodontitis;Phagosomes;Population;Porphyromonas gingivalis;Process;Research;Research Personnel;Respiratory Burst;Role;Site;Staging;Stimulus;TLR2 gene;Technology;Testing;Tissues;Tooth structure;United States;abstracting;antimicrobial;combat;in vivo;innovation;microbial;microbial host;microbiota;neutrophil;novel therapeutic intervention;novel therapeutics;oral bacteria;oral pathogen;pathogen;pathogenic bacteria;response;retinal rods;subcutaneous;trafficking


application_id: 9023832
project_number: 1R21CA191663-01A1
project_title: Common hTERT Promoter Mutations Represent a Novel Therapeutic Target
administering_ic: NCI
award_notice_date: 2016-02-15
opportunity_number: PAR-13-146
application_type: 1
activity_code: R21
ic: CA
serial_number: 191663
suffix: A1
program_official: FU, YALI
project_start_date: 2016-02-15
project_end_date: 2018-01-31
study_section: Special Emphasis Panel[ZCA1 SRB-X (O1)]
contact_pi_person_id: 1898718
contact_pi: MILLER, DONALD M.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Telomerase reverse transcriptase (hTERT) is a catalytic subunit of the enzyme telomerase which is frequently overexpressed in human tumors. It has recently been shown that the hTERT promoter is commonly mutated in a malignant melanoma and glioblastoma (>75% of tumors). These mutations occur at four specific sites in a G-rich region which has been shown to form quadruplex DNA and to downregulate hTERT expression. We have shown that these mutations destabilize quadruplex-formation resulting in increased hTERT expression and cellular proliferation. Stabilization of the quadruplex structure with TMPYP4 reverses these changes. Treatment of cells in which the hTERT promoter is mutated with "strand-invading" oligonucleotides downregulates hTERT expression and dramatically inhibits the growth of transformed cells. This application will test the hypothesis tht stabilization of the mutated hTERT promoter quadruplex structure by sequence specific oligonucleotides will result in downregulation of hTERT and inhibition of growth by cells with the mutated sequence(s). The Specific Aims of this application are: 1. To characterize the gene and sequence specificity of oligonucleotides targeted to the mutated or wild type hTERT promoter sequences. 2. To characterize the potential synergy of strand invading hTERT promoter targeted  oligonucleotides with targeted agents and standard chemotherapy drugs. 3. To characterize the therapeutic potential of hTERT strand invading oligonucleotides in animal models alone and in conjunction with targeted therapies. The results of the proposed studies will have important clinical implications as inhibition of hTERT gene expression is relevant to a wide variety of tumor types. In addition the proposed experiments will provide important new information about the role of quadruplex-formation in the regulation of hTERT gene expression.

project_terms:
Animal Model;Binding;Catalytic Domain;Cell Proliferation;Cells;Chromosomal translocation;Clinical;Clinical Trials;Down-Regulation;Enzymes;Functional disorder;Gene Expression;Gene Silencing;Genes;Glioblastoma;Goals;Growth;Human;Invaded;Malignant - descriptor;Mutate;Mutation;Oligonucleotides;Patients;Pharmaceutical Preparations;Physiological;Play;RNA-Directed DNA Polymerase;Regulation;Role;Site;Specificity;Structure;Telomerase;Testing;Therapeutic;Transcriptional Regulation;Tumor Cell Line;analytical ultracentrifugation;cancer cell;cancer therapy;cell growth;cell transformation;chemotherapy;design;experience;interest;malignant phenotype;melanoma;mutant;new therapeutic target;novel;overexpression;promoter;public health relevance;quadruplex DNA;research study;targeted agent;targeted treatment;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE   
Telomerase is overexpressed in over 90% of human tumors. It represents a very attractive target for anticancer therapy. The recent discovery of "common mutations" in the hTERT promoter has suggested that quadruplex formation may play an important physiologic role in hTERT silencing. We have shown that the mutations destabilize quadruplex and that these changes can be reversed by sequence-specific strand-invading oligonucleotides. This approach allows the stabilization of mutated hTERT promoter sequences and the reversal of hTERT dysregulation. We believe that these observations suggest that inhibition of hTERT expression is a reasonable goal with considerable clinical potential.


application_id: 9023536
project_number: 4K01DK096042-04
project_title: Enhancement of NAFLD risk by vinyl chloride: interaction of gut-liver-adipose axi
administering_ic: NIDDK
award_notice_date: 2016-03-25
opportunity_number: PAR-12-020
application_type: 4
activity_code: K01
ic: DK
serial_number: 096042
program_official: SASLOWSKY, DAVID E
project_start_date: 2013-04-01
project_end_date: 2018-03-31
study_section: Digestive Diseases and Nutrition C Study Section[DDK-C]
contact_pi_person_id: 10438358
contact_pi: BEIER, JULIANE I
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): Obesity and its metabolic complications are major health problems in the United States and worldwide. A major disease associated with obesity is non-alcoholic fatty liver disease (NAFLD). Indeed obesity may influence individual susceptibility to other environmental exposures such as vinyl chloride (VC). Specifically we hypothesize that experimental NAFLD sensitizes the liver to VC as a 2nd hit. Recent studies indicate that intestinal barrier function and GI tract flora play a key role in the development of NAFLD. Supplementation with probiotics has been shown to decrease induced gut permeability and liver injury. We therefore propose that VC via altering intracellular signaling cascades impairs barrier function integrity in NAFLD and that probiotic supplementation [Lactobacillus rhamnosus Gorbach-Goldin (LGG)] will attenuate these effects. Aim 1. To test the hypothesis that VC exposure exacerbates liver injury caused by HFD. It is well-known that liver injury is increased by high fat (HFD) diet. It has been shown that VC is hepatotoxic. We propose here that VC exposure will exacerbate liver injury caused by experimental NAFLD (HFD) in mice. Subaims will determine: a) the minimal low dose VC exposure conditions that exacerbate fatty liver due to HFD; b) potential mechanisms by which VC exposure enhances liver damage caused HFD. Aim 2. To determine mechanisms by which VC accentuates fatty liver disease caused by HFD. It is known that there is a critical crosstalk between the GI tract the adipose tissue and the liver tha plays an important role in the development of NAFLD (i.e. the 'gut-liver-adipose axis'). The purpose of this Aim is to determine the effect of VC metabolites on responses in in vitro paradigms of the gut-liver-adipose axis. Subaims will characterize the response of: a) hepatocytes to cytotoxic stimuli b) response of macrophages to inflammatory stimuli and c) stimulus of adipocytes to produce adipogenic mediators. Aim 3. To test the hypothesis that VC exposure exacerbates intestinal permeability caused by HFD. It is known that intestinal permeability is increased after HFD feeding. The barrier function of the intestinal epithelium is also dependent on the gut microbiota profile. Probiotic microorganisms have been shown to improve barrier integrity of the intestinal epithelium. We propose here that VC exposure will exacerbate gut permeability due to HFD in mice and that gut microbiota play an important role in gut permeability and VC-induced toxicity in HF-fed mice. We will further determine if probiotics [e.g. lactobacillus rhamnosus GG (LGG)] will decrease VC-induced toxicity in HF-fed mice via improvement of gut permeability and TJ integrity. Subaims will determine: a) the combined effect of VC and HFD on intestinal integrity in vivo (mice) and in vitro (Caco-2 cells); b) the effct of VC and dietary fatty acids on mRNA and surface expression of key tight junction proteins and the role of SAPK signaling in this process in Caco-2 cells; c) if HFD and VC synergistically impair TJ barrier functions in vivo; and d) the protective effect of probiotic LGG on HFD and VC-induced gut permeability.

project_terms:
Accounting;Adipocytes;Adipose tissue;Attenuated;Caco-2 Cells;Chemicals;Data;Development;Diet;Dietary Fatty Acid;Disease;Dose;Endotoxemia;Environmental Exposure;Environmental Pollutants;Fatty Liver;Fatty acid glycerol esters;Gastrointestinal tract structure;Health;Hepatocyte;Human;In Vitro;Individual;Inflammatory;Inflammatory Response;Intestines;Lactobacillus casei rhamnosus;Liver;Liver diseases;Mediating;Mediator of activation protein;Messenger RNA;Metabolic;Modeling;Mus;Nutrient;Obesity;Permeability;Play;Population;Predisposition;Probiotics;Process;Production;Proteins;Relative Risks;Risk;Risk Factors;Role;SAPK;Safety;Signal Transduction;Stimulus;Surface;Testing;Tight Junctions;Toxic effect;Toxin;Treatment Protocols;United States;Vinyl Chloride;Work;cytokine;cytotoxic;disorder risk;feeding;gut microbiota;improved;in vivo;in vivo Model;intestinal epithelium;liver injury;macrophage;microbiota;microorganism;non-alcoholic fatty liver;nonalcoholic steatohepatitis;novel;probiotic supplementation;protective effect;response;toxicant

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  We propose that vinyl chloride exposure even below levels that are overtly hepatotoxic may increase the stimulated inflammatory response in the liver potentially adding another risk factor to the development of liver disease associated with obesity (i.e. non-alcoholic fatty liver disease). The project will focus on the individual and combined effects of vinyl chloride and diet on gut-liver-adipose axis in experimental NAFLD.


application_id: 9022667
project_number: 1R15CA203605-01
project_title: Integrated framework to predict chemotherapy response post lung tumor resection
administering_ic: NCI
award_notice_date: 2016-05-26
opportunity_number: PA-13-313
application_type: 1
activity_code: R15
ic: CA
serial_number: 203605
program_official: COUCH, JENNIFER A
project_start_date: 2016-06-01
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZRG1 BST-C (80)]
contact_pi_person_id: 10797120
contact_pi: FRIEBOES, HERMANN
other_pis: Not Applicable
congressional_district: 03
department: ENGINEERING (ALL TYPES)
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: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The standard of care for intermediate stage (Stage II and III) non-small cell lung (NSCLC) cancer is treatment via resection of the affected portion of the lung followed by chemotherapy with taxane/platinum derivatives to prevent relapse. Unfortunately despite these treatments the cancer recurs in a large percentage of these patients presumably due to resistance to chemotherapy. In order to avoid the toxic exposure associated with needless treatment it would be beneficial to know a priori which patients are expected to benefit from chemotherapy post treatment. In addition this knowledge would allow non-responding patients to be treated at the outset with second-line therapies thus gaining valuable time to pursue a cure. It is non-trivial however to make this determination for the tumor as a system as the factors involved include a variety of characteristics (e.g. cell proliferation angiogenic and metabolic activity) that span a wide range of physical (nm to cm) and temporal (second to month) scales. We propose to distill tumor characteristics that are measurable from patients into parameter values of a mathematical model that provides a quantitative perspective needed for system analysis. We apply our experience in metabolomics analysis from live tissue and biopsies imaging evaluation of tissue hypoxia and glucose uptake in vitro techniques for 3D cell culture and advanced mathematical modeling integrated with experimental data to predict the patient response to chemotherapy. Our hypothesis is that the combination of patient tumor analysis and mathematical modeling provides a system framework to predict response to chemotherapy post lung tumor resection. A computational model of tumor growth will be applied to describe cell proliferation apoptosis and necrosis of lung lesions and
to include glucose oxygen growth factor and drug transport and uptake. We plan to extract cells with biopsy-proven NSCLC obtained from surgical lobectomies as part of standard oncologic treatment protocols into a 3D cell culture system. FDG-PET analysis before surgery will help establish a baseline for glucose uptake specific to these cells. This measurement along with tissue metabolomic information in vivo will be correlated to the metabolic activity and drug response observed in the cell culture. Samples will be subjected to physiologically- relevant dosages of cisplatin and paclitaxel chemotherapy or to molecular targeted therapy via erlotinib in case of epidermal growth factor receptor (EGFR) over-expression. These data will be combined with the mathematical model to project tumor response to chemotherapy and the projections will be compared to actual patient outcomes. This project will thus establish a first step towards an integrated patient data/computational framework to predict response to chemotherapy post lung tumor resection.

project_terms:
Affect;Aftercare;Apoptosis;Biological Assay;Biological Markers;Biopsy;Cell Culture System;Cell Culture Techniques;Cell Extracts;Cell Proliferation;Cells;Characteristics;Cisplatin;Combination Drug Therapy;Computational Technique;Computer Simulation;Data;Deoxyglucose;Development;Drug Transport;Epidermal Growth Factor Receptor;Erlotinib;Evaluation;Excision;Gene Expression;Genomics;Glucose;Growth;Heterogeneity;Hypoxia;Image Analysis;In Vitro;Knowledge;Lesion;Life;Lobectomy;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Measurable;Measurement;Medicine;Metabolic;Modeling;Necrosis;Non-Small-Cell Lung Carcinoma;Oncologist;Operative Surgical Procedures;Output;Oxygen;Paclitaxel;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Platinum;Positron-Emission Tomography;Relapse;Resistance;Sampling;Staging;Structure;System;Systems Analysis;Techniques;Testing;Thoracic Surgeon;Time;Tissues;Toxicant exposure;Treatment Protocols;Tumor Burden;angiogenesis;base;cancer therapy;chemotherapy;clinical practice;computer framework;dosage;experience;glucose uptake;in vivo;mathematical model;metabolomics;molecular targeted therapies;novel;overexpression;predicting response;prevent;public health relevance;response;screening;simulation;standard of care;success;taxane;three dimensional cell culture;treatment response;tumor;tumor growth;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Patients with intermediate stage non-small cell lung (NSCLC) cancer are treated by removing the affected portion of the lung followed by chemotherapy. Unfortunately the cancer recurs for many of these patients presumably due to resistance to chemotherapy; it would be beneficial to know beforehand which patients would benefit from chemotherapy and which would not so that everybody is treated faster and with the most suitable medicines. We propose to combine detailed analysis of patient tumors with advanced mathematical modeling to predict the response to chemotherapy - the combination of experimental data and computational simulation will provide a system for more efficient patient evaluation.


application_id: 9022476
project_number: 4R01ES021375-05
project_title: PCBs worsen obesity/metabolic syndrome through 'toxic metabolic endotoxemia'
administering_ic: NIEHS
award_notice_date: 2016-02-22
opportunity_number: PAR-11-170
application_type: 4
activity_code: R01
ic: ES
serial_number: 021375
program_official: SCHUG, THADDEUS
project_start_date: 2012-05-08
project_end_date: 2018-02-28
study_section: Special Emphasis Panel[ZRG1-EMNR-D(55)R]
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
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): 68% of US adults are either overweight or obese and more than 100 million Americans have diabetes or pre- diabetes. These conditions may lead to cardiovascular disease and cancer. Recent research indicates a potential role for polychlorinated biphenyls (PCBs) which are persistent organic pollutants in obesity and diabetes. PCBs were previously used in electrical transformers. Although they were banned over 30 years ago PCBs are still present in the US food supply and in all adult Americans. Preliminary research performed by our group and others suggests that PCBs cause a "leaky gut" to disrupt the gut:liver:adipose axis. Subsequently intestinal-derived bacterial products enter the bloodstream causing inflammation liver disease and contribute to obesity and diabetes. We call this problem "toxic-metabolic endotoxemia". We hypothesize that PCBs interact with high fat or high carbohydrate diets through toxic metabolic endotoxemia to worsen obesity and diabetes; and studying this hypothesis is the overall objective of this grant. The specific aims of this novel nutrient:toxin interaction translational project are to:1) Determine in mice mechanisms by which PCBs disrupt the gut:liver:adipose axis to increase metabolic endotoxemia and worsen diet-induced obesity/insulin resistance. 2) Determine the potential role of cellular receptors in PCBs-associated toxic-metabolic endotoxemia in mice and cell culture models. 3) Study mechanisms of toxic metabolic endotoxemia in stored blood samples from a large group of highly PCB-exposed humans. We expect to find that PCBs activate receptors perturb the gut:liver:adipose axis and worsen obesity/diabetes via toxic metabolic endotoxemia in mice and in humans. This innovative project is the first to study PCB- related endotoxemia in obesity/diabetes and is expected to lead to a new understanding of these conditions. The proposal is relevant to all overweight/obese people exposed to environmental pollution.

project_terms:
Adipose tissue;Adult;Alabama;American;Animal Model;Antioxidants;Archives;Attenuated;Binding;Biological Assay;Biological Markers;Blood Circulation;Blood specimen;Body fat;C57BL/6 Mouse;Carbohydrates;Cardiovascular Diseases;Cell Culture Techniques;Cells;Chemicals;Cytokeratin 18;Data;Diabetes Mellitus;Diet;Dose;Endotoxemia;Endotoxins;Environmental Pollution;Epidemiologic Studies;Exposure to;Fatty Liver;Fatty acid glycerol esters;Food Supply;Fructose;General Population;Genetic;Glutathione;Grant;Hepatocarcinogenesis;High Fat Diet;Hormones;Human;Inflammation;Inflammatory;Insulin Resistance;Intestines;Lead;Ligands;Liver;Liver diseases;Malignant Neoplasms;Measures;Metabolic;Metabolic syndrome;Modeling;Mus;Nutrient;Obesity;Occupational Exposure;Organ;Overweight;Oxidative Stress;Pathogenesis;Permeability;Plants;Polychlorinated Biphenyls;Prediabetes syndrome;Production;Proteins;Research;Role;Sampling;Serum;Site;Steatohepatitis;TLR4 gene;Tight Junctions;Toll-like receptors;Toxin;Wild Type Mouse;base;clinically relevant;cohort;cost;cytokine;driving force;feeding;gut microbiota;innovation;macrophage;member;mutant;non-alcoholic fatty liver;nonalcoholic steatohepatitis;novel;persistent organic pollutants;receptor;receptor expression;research study;toxicant

public_health_relevance:
We expect to find that PCBs worsen obesity/diabetes via toxic metabolic endotoxemia in mice and in humans. This innovative project is the first to study PCB-related endotoxemia in obesity/diabetes and is expected to lead to a new understanding of these conditions. The proposal is relevant to all overweight/obese people exposed to environmental pollution.


application_id: 9021688
project_number: 5R34MH106661-02
project_title: Systematically Adapted Delivery of the Family Check-Up in Underserved Communities
administering_ic: NIMH
award_notice_date: 2016-02-09
opportunity_number: RFA-MH-15-330
application_type: 5
activity_code: R34
ic: MH
serial_number: 106661
program_official: PINTELLO, DENISE
project_start_date: 2015-03-01
project_end_date: 2018-02-28
study_section: ZMH1-ERB-I(01)
contact_pi_person_id: 8804342
contact_pi: STUDTS, CHRISTINA RUTH
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): When disruptive behavior problems manifest in very young children the risk of later antisocial behaviors- including substance abuse school failure and criminality-escalates significantly. Evidence-based behavioral parent training (BPT) interventions have demonstrated efficacy and effectiveness in a range of settings in preventing the negative outcomes and costs associated with disruptive behavior problems. However the public health impact of these interventions has yet to be realized in part due to reliance on delivery by trained mental health professionals in clinic or community settings. Although implementation studies of BPT have been reported these results lack generalizability because of their methodological idiosyncrasies in implementation. To maximize the public health benefits of BPT systematic implementation studies are needed particularly in underserved community settings. In Appalachia a region recognized for its dramatic health disparities at least one in five children exhibits sub-clinical to clinical levels of disruptive behavior problems. Risk factor for child disruptive behavior problems are pervasive; Appalachian residents suffer high poverty rates low education levels disproportionately high rates of substance abuse and mental health disorders and persistent disparities in a wide range of health problems. A challenging combination of cultural barriers and poor access to mental health services hinders the usual delivery model for BPT in Appalachia (i.e. by trained mental health professionals). The vast majority of Appalachian counties are designated as mental health provider shortage areas and cultural considerations (e.g. distrust of outsiders the primacy of kinship networks history of authoritarian parenting styles strong self-reliance) may limit uptake of the few services available. The goal of this mixed-methods pilot study is to prepare for a future large-scale hybrideffectiveness-implementation trial of an evidence-based BPT intervention across rural Appalachian communities. Our preliminary data revealed community preferences for brief BPT delivery by local community health workers. Thus to increase the accessibility and acceptability of BPT in this region we will use the ADAPT-ITT framework to systematically adapt the delivery model for the Family Check-Up a brief BPT intervention previously shown to be effective in reducing behavior problems and preventing negative outcomes when delivered by trained mental health professionals in clinic and community settings. Following the systematic adaptation of the Family Check-Up delivery model we will pilot-test its implementation by community health workers in four high-need under- resourced Appalachian communities to assess feasibility acceptability and costs. Our primary questions are whether we can effectively train community health workers in these communities to deliver the Family Check- Up with fidelity; whether we can enroll parents/caregivers and children to initiate and complete the intervention; and whether the battery of assessments and measures planned for the subsequent R01 effectiveness- implementation trial are feasible and appropriate for these community settings.

project_terms:
Address;Aggressive behavior;Appalachian Region;Area;Authoritarianism;Behavioral;Behavioral Model;Caregivers;Caring;Child;Child Behavior;Child Mental Health;Child Rearing;Child Welfare;Church;Clinic;Clinical;Communities;Community Health;County;Data;Development;Disruptive Behavior Disorder;Educational Background;Educational Intervention;Effectiveness;Enrollment;Ensure;Evidence based intervention;Exhibits;Failure;Family;Feedback;Foundations;Future;Gap Junctions;Goals;Health;Health Benefit;Health Personnel;Health Professional;Health Services Research;Healthcare;Home environment;Hybrids;Individual;Intervention;Kinship Networks;Lead;Location;Longevity;Measures;Mental Health;Mental Health Services;Mental disorders;Methods;Modality;Modeling;National Institute of Mental Health;Nursery Schools;Outcome;Parents;Pilot Projects;Poverty;Prevalence;Problem behavior;Protocols documentation;Public Health;Recording of previous events;Reporting;Research Project Grants;Research Support;Resistance;Risk;Risk Factors;Rural;Schools;Services;Societies;Substance abuse problem;Testing;Training;Training Programs;Underserved Population;Work;aged;antisocial behavior;behavioral study;checkup examination;community setting;cost;early childhood;evidence base;experience;health disparity;implementation research;implementation science;implementation trial;innovation;medical specialties;preference;prevent;self reliance;social stigma;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Early childhood disruptive behavior problems lead to significant costs to families and society but can be reduced with behavioral parent training interventions. To increase the public health impact of these interventions their feasibility accessibility and acceptability in high-need underserved communities must be ensured. This pilot project will systematically adapt and pilot-test the delivery model of an existing effective parent training intervention for implementation in rural Appalachia a region with many documented health disparities high levels of poverty and shortages of mental health providers.


application_id: 9021423
project_number: 1R21AI122078-01
project_title: Blocking RNA virus replication through the antiviral functions of cellular helicases
administering_ic: NIAID
award_notice_date: 2015-12-17
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: AI
serial_number: 122078
program_official: NATARAJAN, RAMYA
project_start_date: 2015-12-17
project_end_date: 2017-11-30
study_section: Virology - A Study Section[VIRA]
contact_pi_person_id: 7353039
contact_pi: NAGY, PETER
other_pis: Not Applicable
congressional_district: 06
department: OTHER BASIC SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Blocking RNA virus replication through the antiviral functions of cellular helicases. A recently emerging concept in innate immunity is the significant roles of cell-intrinsic restriction factors (CIRFs) against several viruses which are expressed by
the host cells. CIRFs greatly reduce virus replication and facilitate combating viruses and making the induced and passive innate immune responses more potent. The PI has identified cellular DEAD-box helicases as strong CIRFs against an RNA virus. RNA helicases are involved in all aspects of cellular metabolism and perform RNA duplex unwinding and remodeling of RNA-protein complexes in cells. Dissecting the mechanism of antiviral function of cellular helicases promises a new avenue to develop effective antiviral strategies against plant and possibly animal viruses Progress in our understanding of the mechanisms of host factors is greatly accelerated by the use of easily tractable virus - host systems such as Tomato bushy stunt virus (TBSV) and yeast model. The PI will identify and characterize the most potent cellular helicases to block plant and insect virus replication. The proposal will focus on two cellular helicases that showed the most potent antiviral effect thus justifying the potential of tis novel approach. The following are the major strengths of the proposal: (i) Viral RNA replication is clearly of immense importance for viruses to infect living organisms. (ii) The combination of yeast and authentic cell-free assay developed by the PI is currently the most potent for studying the mechanism of host factors involvement in viral RNA replication and viral pathogenesis. (iii) Cellular helicases are emerging as major cell-intrinsic restriction factors against several viruses (iv) This work has the potential to obtain a novel effective antiviral approach that has several advantages over traditional viral targets. The advantages include broader antiviral effects against many related and possibly even unrelated viruses and more durable antiviral effects. Developing an efficient antiviral strategy based on blocking viral replication via cellular helicass could rapidly be done in this elegant tombusvirus-yeast system. Based on the possible broad antiviral effect of these cellular helicases which are highly conserved from plants to animals research can then adapt the gained knowledge and methods for other animal human and plant viruses. The research holds promise of benefiting society by leading to groundbreaking results in the area of virus replication host-virus interactions and the adaptation of viruses to their hosts.

project_terms:
Animal Experimentation;Animals;Antiviral Agents;Area;Biological Assay;Boxing;Cell physiology;Cells;Complex;Human;Immune response;Infection;Insect Viruses;Integration Host Factors;Knowledge;Life;Metabolism;Methods;Modeling;Natural Immunity;Organism;Plant Viruses;Plants;Protein Family;RNA;RNA Helicase;RNA Viruses;RNA replication;Research;Role;Societies;System;Tombusvirus;Viral;Viral Pathogenesis;Virus;Virus Replication;Work;Yeast Model System;Yeasts;base;combat;fighting;frontier;genome-wide analysis;helicase;novel;novel strategies;pathogen;protein complex;public health relevance;replicase;tomato bushy stunt virus;tool;viral RNA;virology;virus host interaction

public_health_relevance:
PUBLIC HEALTH RELEVANCE: A recently emerging concept in innate immunity is the significant roles of cell-intrinsic restriction factors against several viruses which are expresse by host cells. The PI has identified cellular DEAD-box helicases as antiviral factors against an RNA virus. The proposed work will unravel the antiviral functions of two cellular helicases.


application_id: 9021081
project_number: 1R21LM012274-01
administering_ic: NLM
award_notice_date: 2016-05-14
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: LM
serial_number: 012274
program_official: VANBIERVLIET, ALAN
project_start_date: 2016-06-01
project_end_date: 2018-05-31
study_section: Biomedical Informatics, Library and Data Sciences Review Committee[BLR]
contact_pi_person_id: 11081240
contact_pi: KAVULURU, VENKATA NAGA RAMAKANTH
other_pis: Not Applicable
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-06-01
project_title:
From Syntactic Relations to Semantic Predications: Porting Open Information Extraction to Biomedicine

project_abstract:
DESCRIPTION (provided by applicant):ABSTRACT Owing to exponential growth in scientic literature it has become increasingly difcult for researchers to keep up with the latest developments in their elds of study. Hence computational approaches that automatically mine large amounts of free text to extract essential information have gained popularity. This information is typically represented in the form of binary relations between different biomedical concepts. In this context automatic extraction of meaningful relations from natural language narratives a task often termed biomedical relation extraction (BRE) has garnered attention from informaticians. The relations extracted are used in high level applications including information retrieval (IR) literature based discovery (LBD) question answering and text summarization. Most current BRE efforts tend to focus on a specic subdomain in biomedicine. For example researchers built models that extract gene-protein or gene-gene interactions; in the clinical domain recent results are focused on drug-drug and drug-disease interactions mentioned in clinical narratives. The only effort that extracts a broad set of relations adhering t a large standardized vocabulary is the rule based SemRep program being developed by researchers at the National Library of Medicine (NLM). SemRep extracts binary relations called semantic predications between biomedical entities from the UMLS Metathesaurus with predicates coming from an extension of the UMLS Semantic Network. Although SemRep achieves reasonable precision its recall is very low on a gold standard dataset created for its evaluation. Given many applications in LBD and IR already use the predication database SemMedDB (obtained by running SemRep on all biomedical citations made available through PubMed) a predication extraction framework with a higher recall and a low acceptable loss in precision is more desirable especially if it can complement SemRep's extractions. We propose to build and evaluate a supervised BRE framework that converts syntactic relations obtained using the paradigm of open information extraction (OIE) to semantic predications by leveraging the existing database of predications in SemMedDB and relations from the UMLS Metathesaurus through distant supervision. We will conduct domain independent evaluation based on a gold standard dataset built by researchers at the NLM for evaluating SemRep. We will also conduct application oriented evaluations by simulating predication graph based document and passage retrieval using the Text REtrieval Conference (TREC) Genomics and OHSUMED datasets for IR experiments. We will also evaluate the quality of subgraphs resulting from LBD experiments to rediscover nine well known biomedical discoveries. We hypothesize that the predications extracted through our methods will complement those in SemMedDB and the combined predication dataset will result in improved overall performance compared with using SemMedDB alone.

project_terms:
Area;Attention;Automated Abstracting;Clinical;Complement;Computer software;Data Set;Databases;Development;Discipline;Disease;Distant;Drug Interactions;Evaluation;Event;Explosion;Gene Proteins;Generic Drugs;Genes;Genomics;Gold;Graph;Growth;Information Retrieval;Literature;Measures;Methodology;Methods;Mining;Modeling;Output;Peer Review;Performance;Pharmaceutical Preparations;Process;PubMed;Reporting;Research;Research Personnel;Resources;Retrieval;Running;Semantics;Supervision;System;Testing;Text;Training;UMLS Metathesaurus;Unified Medical Language System;United States National Library of Medicine;Update;Vent;Vocabulary;Work;abstracting;base;gene interaction;improved;indexing;metathesaurus;model building;natural language;open source;programs;protein function;research study;search engine;symposium;syntax;web services

public_health_relevance:
NARRATIVESemantic predications are binary relations extracted from biomedical text by the SemRep program and connectbiomedical entities with a xed set of relation types. Although SemRep extractions have reasonable precisiontheir recall is very low. We propose to build a supervised predication extraction framework whose results willcomplement SemRep's extractions in terms of improved performance in both direct gold standard evaluation andapplication oriented evaluation in the context of information retrieval and literature based discovery.


application_id: 9020761
project_number: 4R01CA175105-04
project_title: Targeting Translation Dependence in Colorectal Cancer Progression
administering_ic: NCI
award_notice_date: 2016-04-07
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: CA
serial_number: 175105
program_official: AULT, GRACE S
project_start_date: 2013-04-01
project_end_date: 2018-03-31
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 10534129
contact_pi: SHE, QING-BAI
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):  Mutational activation of the RAS/RAF/MEK/ERK and PI3K/AKT pathways is associated with colorectal cancer (CRC) progression and metastasis. Several small molecularly-targeted PI3K AKT RAF and MEK inhibitors have been tested in the clinic for the treatment of CRC but have shown only limited activity as a single agent. We have recently discovered that inhibition of both the ERK and AKT pathways exhibits potent synergistic anti-CRC effects both in vitro and in vivo by effectively inhibiting eIF4E-initiated cap-dependent translation. Our overarching hypothesis is that the activation of cap-dependent translation by cooperative ERK and AKT signaling can selectively upregulate key oncoproteins that confer CRC progression and metastasis. By characterizing the molecular details of the activation of cap-dependent translation by cooperative ERK and AKT signaling we aim to understand the molecular mechanisms underlying translational activation for CRC metastatic progression and to explore the therapeutic applications of targeting translational regulation for CRC treatment. Our Specific Aims are: Aim 1. Determine the biologic and therapeutic consequences of translational activation by cooperative ERK and AKT signaling in CRC. We will determine 1) the extent to which the mTOR kinase integrates the function of ERK and AKT signaling in translational regulation of CRC cell growth and motility; 2) how mTOR inhibition-induced feedback activation of ERK and AKT deregulates cap-dependent translation and causes mTOR-independence; and 3) the molecular basis of metastatic progression-modulated translational activity using our well-established orthotopic metastastic model of CRC. Aim 2. Characterize the molecular mechanism of translational activation by cooperative ERK and AKT signaling for CRC progression and metastasis. We demonstrate that survivin is a key translational target of the ERK and AKT pathways. We will explore the possible mechanism by which the translationally-regulated survivin acts as an important growth/metastasis-promoting effector of these pathways. We will use combined polysome profiling and proteomic approaches to systematically identify other mRNAs that are selectively recruited to polysomes and translated by cooperative ERK and AKT signaling and characterize in detail the functional importance of these genes in CRC progression and metastasis. Aim 3. Evaluate the in vivo utility of combined inhibition of the MEK/ERK and AKT/mTOR pathways and targeting the convergence of their signals on translation initiation for enhancing CRC therapy. We will use both the mouse orthotopic model of CRC and the patient tumor-derived xenograft model to determine the effectiveness of MEK AKT and mTOR inhibitors alone and in combination and to characterize the ability of the translation initiation inhibitor 4EGI-1 to prevent tumor progressio and metastasis. The expression and modulation of eIF4E 4E-BP1 and survivin and their correlation with the mutational activation status of ERK and AKT pathways will also be characterized in response to the targeted therapies and in clinical specimens.

project_terms:
Address;Animal Model;Biochemical;Biology;Biometry;Cancer Cell Growth;Clinic;Clinical;Colonic Neoplasms;Colorectal Cancer;Data;Dependence;EIF4EBP1 gene;Effectiveness;Exhibits;FRAP1 gene;Feedback;Genes;Goals;Growth;Health;Human;In Vitro;Knowledge;MEK inhibition;MEKs;Messenger RNA;Modeling;Molecular;Mus;Mutation;Neoplasm Metastasis;Oncogenes;Operative Surgical Procedures;PI3K/AKT;PTEN gene;Pathogenesis;Pathology;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Play;Polyribosomes;Proteomics;Proto-Oncogene Proteins c-akt;Recruitment Activity;Research Infrastructure;Resistance;Role;Signal Pathway;Signal Transduction;Solid;Specimen;Techniques;Testing;Therapeutic;Translating;Translation Initiation;Translational Activation;Translational Regulation;Translational Repression;Translations;Tumor-Derived;Tyrosine Kinase Receptor Inhibition;Xenograft Model;base;cancer therapy;cell motility;clinically relevant;colon cancer cell line;colon cancer patients;in vivo;inhibitor/antagonist;insight;interdisciplinary collaboration;mTOR Inhibitor;mTOR inhibition;metastatic colorectal;new therapeutic target;novel;novel marker;novel therapeutics;pre-clinical;prevent;response;survivin;targeted treatment;tumor;tumor growth;tumor progression;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The great majority of patients with metastatic colorectal cancer (CRC) is unresponsive to currently known therapy. This proposal aims to lay the groundwork for understanding the molecular mechanisms involved in the translational control of metastatic progression and treatment of CRC and is therefore of clinical relevance in itself since new therapy for metastatic CRC is urgently needed. The overarching high impact of this proposal lies in the proof-of-concept that will be established for discovery of novel biomarkers and therapeutic targets for CRC.


application_id: 9017642
project_number: 1R03DK107912-01
project_title: Vinyl chloride-NAFLD interaction
administering_ic: NIDDK
award_notice_date: 2016-01-08
opportunity_number: PAR-12-285
application_type: 1
activity_code: R03
ic: DK
serial_number: 107912
program_official: SASLOWSKY, DAVID E
project_start_date: 2016-01-15
project_end_date: 2017-12-31
study_section: Digestive Diseases and Nutrition C Study Section[DDK-C]
contact_pi_person_id: 10438358
contact_pi: BEIER, JULIANE I
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): Obesity and its metabolic complications are highly prevalent and are major health problems in the United States and worldwide. Indeed obesity may influence individual susceptibility to other environmental exposures such as vinyl chloride (VC). Specifically we hypothesize that experimental NAFLD and the consumption of certain types of dietary fat such as poly-unsaturated fatty acids (PUFA) sensitize the liver to VC as a 2nd hit. We therefore propose that that LA metabolites sensitize the liver to VC hepatotoxicity via molecular organelle and cellular VC effects (NAFLD mechanisms). Aim 1. Evaluate the role of OXLAMs in VC-enhanced hepatocyte death in an animal model of NAFLD. Specifically we will: a) determine the dose response for NAFLD/NAFLD mechanisms following sub-acute VC exposures and the impact of co-exposures with HF/LA diets b) determine whether the ablation of OXLAMs via 12/15-LO genetic deficiency attenuates VC-induced liver inflammation and injury and the mechanisms involved. This work will be performed in vivo comparing wild-type (WT) to 12/15-LO knockout mice with complementary in vitro models that target 12/15-LO pharmacologically or genetically (e.g. primary cells derived from 12/15-LO KO mice). Mechanistic endpoints based on preliminary data will include mitochondrial dysfunction hepatocyte death (necrosis vs. apoptosis) ER stress and metabolism/ bioenergetics impacting steatosis/cell survival. The aims of this R03 build on my K01 research and extend that project. However here we are building on that foundation to leverage new questions in investigating the role of a specific fat type (and its oxidized metabolites) that is prevalent in the US. This focus s distinct and unique from my K01 research but will complement it very aptly. This proposal is consistent with the goals of NIDDK to investigate the causes/consequences of obesity.

project_terms:
Ablation;Acids;Acute;Air;Animal Model;Apoptosis;Arachidonate 15-Lipoxygenase;Attenuated;Bioenergetics;Camping;Carbohydrates;Cell Survival;Cells;Cessation of life;Chemicals;Complement;Consumption;Data;Development;Diet;Dietary Fats;Disease;Dose;Environmental Exposure;Environmental Pollutants;Environmental Pollution;Enzymes;Exposure to;Fatty Liver;Fatty acid glycerol esters;Foundations;Genetic;Goals;Health;Hepatic;Hepatocyte;Hepatotoxicity;Human;Individual;Industry;Inflammation;Inflammatory Response;Injury;Knockout Mice;Linoleic Acids;Liver;Liver diseases;Metabolic;Metabolism;Molecular;National Institute of Diabetes and Digestive and Kidney Diseases;Necrosis;Nutrient;Obesity;Occupational;Occupational Exposure;Organelles;Pilot Projects;Play;Predisposition;Production;Research;Risk;Risk Factors;Role;Solvents;Steatohepatitis;Stress;Tetrachloroethylene;Toxin;Trichloroethylene;United States;Unsaturated Fatty Acids;Up-Regulation;Vinyl Chloride;Water Supply;Work;base;contaminated drinking water;cytokine;drinking water;hepatotoxin;in vitro Model;in vivo;landfill;lipid metabolism;liver inflammation;liver injury;mitochondrial dysfunction;non-alcoholic fatty liver;octadecadienoic acid;oxidation;public health relevance;response;superfund site;toxicant

public_health_relevance:
PUBLIC HEALTH RELEVANCE   
We propose that vinyl chloride exposure even below levels that are overtly hepatotoxic may increase the stimulated inflammatory response in the liver potentially adding another risk factor to the development of liver disease associated with diet induced obesity (i.e. non-alcoholic fatty
liver disease). The project will focus on the interaction of vinyl chloride and specific dietary faty acids in experimental NAFLD.


application_id: 9015431
project_number: 5R01DK056132-13
project_title: Neural Circuitry in the Dorsal Vagal Complex
administering_ic: NIDDK
award_notice_date: 2016-01-26
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 056132
program_official: HYDE, JAMES F
project_start_date: 2001-06-01
project_end_date: 2020-01-31
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 1911523
contact_pi: SMITH, BRET N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Abdomen;Address;Affect;Animal Model;Area;Autonomic Dysfunction;Blindness;Blood Glucose;Brain;Brain Diseases;Brain Stem;Cell Nucleus;Chronic;Complex;Data;Dependence;Development;Diabetes Mellitus;Diabetic mouse;Disease;Dorsal;Electrophysiology (science);Functional disorder;Future;GABA Receptor;Gastrointestinal tract structure;Genetic Transcription;Glucose;Goals;Health;Heart Diseases;Hepatic;Homeostasis;Human;Hyperglycemia;Hyperinsulinism;Hypertension;Insulin;Insulin-Dependent Diabetes Mellitus;Knowledge;Liver;Maintenance;Mediating;Metabolic Control;Modeling;Modification;Molecular;Motor Neurons;Motor output;Mus;Nervous System Trauma;Neurons;Neurophysiology - biologic function;Non-Insulin-Dependent Diabetes Mellitus;Nucleus solitarius;Organ;Output;Pancreas;Pathology;Patients;Peripheral;Physiological;Play;Regulation;Role;Slice;Staging;Stomach;Streptozocin;Symptoms;Synapses;System;Testing;United States;Vagus nerve structure;Viscera;Visceral;Whole Blood;base;blood glucose regulation;cell motility;diabetes mellitus therapy;diabetic;dorsal motor nucleus;gamma-Aminobutyric Acid;gastrointestinal;glucose metabolism;glucose production;mouse model;neural circuit;receptor;research study;response;stroke;symptom treatment;trafficking;type I and type II diabetes;type I diabetic


application_id: 9015230
project_number: 1R21NS094891-01
project_title: Characterization of the Fidelity to PD of a Unique Rat Model
administering_ic: NINDS
award_notice_date: 2015-08-19
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: NS
serial_number: 094891
program_official: SIEBER, BETH-ANNE
project_start_date: 2015-09-01
project_end_date: 2017-08-31
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 8329002
contact_pi: BUTTERFIELD, D. ALLAN
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Parkinson disease (PD) the second most prevalent neurodegenerative disorder of the elderly is associated with movement and cognitive symptoms and current pharmacological treatments result in transient symptomatic relief but are not disease-modifying. PD results from degeneration of dopaminergic neurons in the substantia nigra (SNPC) and loss of striatal dopaminergic function is undoubtedly the cause of the symptoms of PD. Current treatments for PD have been focused on augmenting dopamine levels and include levodopa dopamine agonists and MAO-B inhibitors. Arguably the first biochemical deficits in PD which arise before symptoms appear are loss of parenchymal glutathione (GSH) the brain's major small molecule antioxidant and elevation of its oxidized form (GSSG) (Chinta et al. 2006). This has led researchers to show that PD is associated with oxidative stress though the cause of PD remains unknown. Familial PD cases have been linked to altered genes among which is PTEN-induced putative kinase-1 (Pink-1).  Genetic models of PD mostly mice bearing mutations in PD-relevant genes for unknown reasons do not have pathology or dopaminergic neuronal loss in the SNPC unlike PD patients. An ideal animal model of PD would display progressive loss of dopaminergic neurons and formation of Lewy bodies exhibit motor deficits and also mimic non-dopaminergic characteristics of PD i.e. loss of cognition and sense of smell (anosmia). It is thought that no mouse model of PD fulfills these criteria.  Sage Labs (Horizon) has produced a Pink-1 knockout rat [PINK-1 KO] that exhibits progressive dopaminergic loss in the SNPC moderate to severe motor deficits and non-motor characteristics of PD i.e. anosmia. At 8 months of age abundant pathology in the SNPC and PD-relevant symptomology are present. This may be the only rodent model of PD that has PD-relevant pathology in the SNPC. It would be helpful to utilize this exciting novel biological tool or environmental studies relevant to environmental-gene interaction in the neurodegeneration associated with PD. However this laudable goal is presently premature since this rat has not been fully characterized for goodness of fit to PD. Hence to fill this critical need this R21 proposal will achieve the goal of characterizing this unique rat model of PD to test the overall hypothesis that this unique rat has high fidelity to PD in terms of pathology biochemistry and behavior. If this hypothesis is sustained by these studies future investigations will employ this rat to probe gene-environmental interactions of relevance to PD.

project_terms:
ATP phosphohydrolase;Age;Age-Months;Animal Model;Anosmia;Antioxidants;Autophagocytosis;Behavior;Biochemical;Biochemistry;Biological;Bradykinesia;Brain;Brain region;Caenorhabditis elegans;Characteristics;Cognition;Complex;Corpus striatum structure;Dependence;Disease;Dopamine;Dopamine Agonists;Elderly;Environmental Risk Factor;Etiology;Exhibits;Future;Genes;Genetic;Genetic Models;Glutathione;Glutathione Disulfide;Goals;Heat shock proteins;Heavy Metals;Herbicides;Histopathology;Human;Image;Impaired cognition;Investigation;Knock-out;Knowledge;Lead;Levodopa;Lewy Bodies;Link;Lipid Peroxidation;Metabolic;Mitochondria;Modeling;Molecular;Monoamine Oxidase B;Movement;Mus;Mutation;Nature;Nerve Degeneration;Neurobehavioral Manifestations;Neurodegenerative Disorders;Oxidation-Reduction;Oxidative Stress;PINK1 gene;PTEN-induced putative kinase;Parkinson Disease;Pathogenesis;Pathology;Pathway interactions;Patients;Pharmacological Treatment;Physiology;Process;Proteins;Proteomics;Publishing;Rattus;Relative (related person);Research;Research Personnel;Rest Tremor;Rodent Model;Role;Signs and Symptoms;Smell Perception;Solvents;Substantia nigra structure;Susceptibility Gene;Symptoms;Techniques;Testing;age related;alpha synuclein;base;brain size;dopaminergic neuron;drug discovery;environmental stressor;gene interaction;inhibitor/antagonist;innovation;insight;learned behavior;leucine-rich repeat kinase 2;mitochondrial dysfunction;motor deficit;mouse model;neurochemistry;neuron loss;novel;oxidation;parkin gene/protein;pre-clinical research;premature;public health relevance;response;small molecule;stress protein;success;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Parkinson disease (PD) is associated with key susceptibility genes one of which is pink1 and PINK-1 knockout (KO) rats provide arguably the only rodent model of PD that shows pathology in a brain region similar to that of PD patients. This R21 proposal seeks to characterize the fidelity of pathology biochemistry and signs and symptoms to PD in this PINK-1 KO rat. Success will permit future investigations of interactions of environmental stressors and this susceptibility gene thought to be important in PD etiology and pathogenesis.


application_id: 9014473
project_number: 5R03AG047452-02
project_title: Increasing PKG activity protects aging kidney from ischemic-reperfusion induced injury
administering_ic: NIA
award_notice_date: 2016-02-02
opportunity_number: PA-13-142
application_type: 5
activity_code: R03
ic: AG
serial_number: 047452
program_official: WILLIAMS, JOHN
project_start_date: 2015-03-01
project_end_date: 2018-02-28
study_section: Pathobiology of Kidney Disease Study Section[PBKD]
contact_pi_person_id: 7837422
contact_pi: WANG, SHUXIA
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Aging is associated with increased incidence of acute kidney injury (AKI). This age-dependent increase in susceptibility to AKI is linked to a decreased renal functional recovery and even progression to advanced chronic kidney disease a severe health problem worldwide. Despite advances in our understanding of the cellular and molecular aspects of AKI in recent years the relationship between aging and AKI remains poorly understood and requires further mechanistic studies. Preliminary studies demonstrated that nitric oxide (NO) and its downstream signaling pathway cGMP and cGMP-dependent protein kinase (PKG) was down-regulated in aging kidney which was associated with aging-related renal functional changes. Moreover preliminary data identified a novel inhibitory effect of PKG on tubular cell necrosis and apoptosis following renal ischemia reperfusion (IR) induced AKI in young mice and an inhibitory effect of PKG on macrophage migration suggesting a therapeutic potential of PKG for renal IR injury. In this proposal we will test the hypothesis that down-regulation of NO/cGMP/PKG signaling in the kidney contributes to increased susceptibility to ischemia reperfusion-mediated AKI in older individuals. We will determine whether genetically or pharmacologically increased PKG activity reduces the susceptibility of old animals to ischemia mediated AKI in Aim 1. The mechanisms of reduced NO/cGMP/PKG signaling in aging kidney will be determined in Aim 2. These studies will establish the significance of PKG in acute kidney injury in aging population. Importantly we will test a novel potential application of sildenafil fr AKI in older population. Sildenafil is an inhibitor of cGMP specific phosphodiesterase 5 (PDE5) and a FDA approved drug for treatment of pulmonary hypertension and erectile dysfunction. Hopefully these proposed studies will lead to new therapeutic strategy for acute kidney injury in aging population.

project_terms:
Acute Renal Failure with Renal Papillary Necrosis;Aging;Animals;Antibodies;Apoptosis;Binding Proteins;CD47 gene;Cell Proliferation Regulation;Cell physiology;Cells;Chronic Kidney Failure;Cyclic GMP;Cyclic GMP-Dependent Protein Kinases;Data;Development;Dilator;Down-Regulation;Elderly;Erectile dysfunction;FDA approved;Genetic;Genotype;Glomerular Filtration Rate;Guanylate Cyclase;Health;Healthcare Systems;Incidence;Individual;Inflammation;Injury;Ischemia;Kidney;Knockout Mice;Lead;Link;Mediating;Mediator of activation protein;Molecular;Mus;Necrosis;Nitric Oxide;Older Population;Pathway interactions;Pharmacotherapy;Play;Predisposition;Production;Pulmonary Hypertension;Recovery;Recovery of Function;Regulation;Renal Blood Flow;Renal function;Reperfusion Injury;Reperfusion Therapy;Role;Signal Pathway;Signal Transduction;Signaling Molecule;System;Testing;Therapeutic;Transgenic Mice;Tubular formation;Up-Regulation;age related;aging population;base;genetic approach;improved outcome;inhibitor/antagonist;juvenile animal;macrophage;male;migration;normal aging;novel;novel therapeutic intervention;novel therapeutics;phosphodiesterase V;receptor;renal ischemia;sildenafil

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Aging is associated with increased incidence of acute kidney injury. The proposed studies will provide novel information on the mechanisms of aging mediated down-regulation of renal nitric oxide/cGMP/PKG signaling and its contribution to increased susceptibility of old animals to acute kidney injury. These studies may lead to new therapeutic strategy for acute kidney injury in aging population.


application_id: 9013245
project_number: 1K22CA201036-01
project_title: Defining epigenetic vulnerabilities of subtype-specific lung cancers
administering_ic: NCI
award_notice_date: 2016-09-02
opportunity_number: PAR-15-056
application_type: 1
activity_code: K22
ic: CA
serial_number: 201036
program_official: JAKOWLEW, SONIA B
project_start_date: 2016-09-30
project_end_date: 2019-08-31
study_section: Transition to Independence Study Section (I)[NCI-I]
contact_pi_person_id: 10317047
contact_pi: BRAINSON, CHRISTINE FILLMORE
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): Future Research Questions: As an independent investigator I will focus on answering two important questions: 1) What are the cells-of-origin orepigenetic programs that produce the two major types of lung tumors? and 2) How can epigenetic therapies be incorporated into useful cancer therapeutics? Background Lung cancer remains the leading cause of cancer related deaths world-wide. Precision medicine options for lung cancer patients may help to decrease the mortality of the disease by targeting the most vulnerable pathways in each specific cancer. However these efforts are complicated by both the genetic and epigenetic complexity of lung tumors. How epigenetic programs influence critical aspects of lung tumorigenesis and normal lung biology remains an uncharted area. Furthermore the lineage relationship and epigenetic differences between the two major subtypes of non-small cell lung cancer namely lung adenocarcinoma and lung squamous cell carcinoma are unclear. My main goal is to find methods to incorporate epigenetic drugs into effective cancer therapies. I will initially focus on lung stem cell biology as my platform to elucidate the cellular origins and epigenetic therapeutic vulnerabilities in lung cancer. Methodology The research proposed herein will allow for direct comparison of the transformation capacity of several lung stem/progenitor cell pools through FACS isolation lentiviral genetic modulation and 3D organotypic culture. The transformation potential and subtype acquisition of the cell pools will be tested by injection into the lungs of immunocompromised mice. This novel system will allow for careful dissection of what lung cells can serve as tumor cells-of-origin and in what contexts (i.e. genetic mutations and epigenetic modulation). These results can be linked back to the most permissible epigenetic states for transformation and allow understanding of how epigenetic programs are co-opted by tumor cells during malignant transformation. In parallel I will study the effects of different epigeneti therapeutics namely inhibition of BRD4 EZH2 or G9A on genetically defined murine lung tumors. I will again use the 3D organotypic culture assay which I have optimized for primary tumor cell growth. This approach will allow cost-effective but biologically relevant assessment of the effects of epigenetic therapies on varied subtypes and genotypes of lung cancer. Both of these approaches will be translated to human biology by using human cells in the 3D cultures. Career Potential I have had a very successful post-doctoral career in the laboratory of Carla Kim at Boston Children's Hospital and I have established a strong relationship with my collaborators for this award Drs. Leonard Zon and Kwok- Kin Wong. I have an outstanding environment and a comprehensive plan that will allow me to transition to an independent research role. My ultimate goal is to lead a research group exploring the relationships between stem cells and cancer with a specific focus on novel cancer therapeutics. I know that the K22 award would greatly aid me in realizing these goals.

project_terms:
AGTR2 gene;ATAC-seq;Adenocarcinoma;Area;Award;Back;Basal Cell;Biological Assay;Biology;Boston;Cancer Etiology;Cancer Patient;Cancer stem cell;Cells;Cessation of life;ChIP-seq;Complex;DNA Sequence Alteration;Disease;Dissection;Drug Combinations;EZH2 gene;Environment;Epidermal Growth Factor Receptor;Epigenetic Process;Genes;Genetic;Genomics;Genotype;Goals;Growth;Health;Histology;Human;Human Biology;Immunocompromised Host;Infection;Injection of therapeutic agent;K22 Award;Knowledge;Laboratories;Lead;Link;Lung;Lung Adenocarcinoma;Lung Neoplasms;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Methodology;Methods;Mus;Non-Small-Cell Lung Carcinoma;Organoids;Pathway interactions;Patients;Pediatric Hospitals;Pharmaceutical Preparations;Phenotype;Postdoctoral Fellow;Primary Neoplasm;Reader;Research;Research Personnel;Role;Running;Sampling;Squamous Cell Lung Carcinoma;Squamous cell carcinoma;Stem cells;Structure of parenchyma of lung;System;TP53 gene;Techniques;Testing;Therapeutic;Translating;Transplantation;Tumor Subtype;Vision;Xenograft procedure;cancer therapy;career;cell growth;cell transformation;cost effective;disorder subtype;epigenetic drug;fitness test;in vivo;inhibitor/antagonist;lung tumorigenesis;mortality;mouse model;neoplastic cell;novel;pre-clinical;precision medicine;programs;research study;response;stem;stem cell biology;three dimensional cell culture;transcriptome sequencing;tumor;tumor initiation

public_health_relevance:
PUBLIC HEALTH RELEVANCE   Lung cancer is the leading cause of cancer-related deaths worldwide and is a highly complex disease with many possible cells-of-origin and genetic drivers. These studies will allow for a better understanding of which cells can serve as cells-of-origin of lung tumors and how differences in epigenetic programs can influence tumor initiation and subtype acquisition. In addition these experiments will help to determine the contexts in which epigenetic therapies which are widely believed to be game-changing in the field of cancer therapeutics will be viable strategies to treat lineage-specific lung cancers.


application_id: 9012797
project_number: 5R01DC014658-02
project_title: Repair of mechano-electrical transduction in mammalian auditory hair cells
administering_ic: NIDCD
award_notice_date: 2016-01-12
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DC
serial_number: 014658
program_official: FREEMAN, NANCY
project_start_date: 2015-02-15
project_end_date: 2020-01-31
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:
Actins;Affect;Auditory;CDH23 gene;Cells;Data;Deafness;Exposure to;Freezing;Genes;Hair;Hair Cells;Health;Hearing;Human;Immunogold Technics;Individual;Inner Hair Cells;Knock-in Mouse;Labyrinth;Link;Mechanical Stimulation;Mechanics;Modeling;Molecular;Mus;Mutation;Myosin ATPase;Natural regeneration;Noise;Noise-Induced Hearing Loss;PCDH15 gene;Point Mutation;Predisposition;Probability;Process;Public Health;Recovery;Regulation;Research;Rest;Role;Sampling;Scanning Electron Microscopy;Sensory;Stereocilium;Techniques;Time;Transmission Electron Microscopy;extracellular;gamma Actin;hearing impairment;mouse model;nanoscale;novel;overexpression;postnatal;repaired;research study;response


application_id: 9012116
project_number: 5R01NS070899-07
project_title: Regulation signaling and dynamics of glucan phosphatases
administering_ic: NINDS
award_notice_date: 2016-05-17
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 070899
program_official: STEWART, RANDALL R
project_start_date: 2010-07-01
project_end_date: 2020-04-30
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Affect;Aminoglycosides;Binding;Biochemical;Biochemistry;Biological Assay;Biology;Carbohydrates;Cell Culture Techniques;Cells;Cellular Metabolic Process;Clinical;Complex;Comprehension;Diagnosis;Disease;Disease Progression;Energy Metabolism;Enzymes;Epilepsy;Event;Family;Fibroblasts;Genes;Glucans;Glycogen;Glycogen Phosphorylase;Glycogen Storage Disease;Goals;Health;Inherited;Knockout Mice;Lafora Disease;Lead;Life;Link;Liver;Metabolism;Methods;Missense Mutation;Modeling;Molecular;Muscle;Mutagenesis;Mutation;Mutation Spectra;Nature;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Physiological;Play;Point Mutation;Process;Progressive Myoclonic Epilepsies;Proteins;Proteome;Protocols documentation;Reading;Regulation;Reporting;Role;Signal Transduction;Starch;Structure;Symptoms;Terminator Codon;Testing;Therapeutic;Tissues;Translating;Ubiquitin;Ubiquitination;Water;Work;X-Ray Crystallography;biochemical tools;cell type;design;disease-causing mutation;gene product;glycogen metabolism;in vivo;insight;loss of function mutation;member;mouse model;neuron apoptosis;neurotoxicity;novel;novel therapeutics;particle;potency testing;premature;screening;tool;ubiquitin-protein ligase


application_id: 9010096
project_number: 1R01NS094741-01
project_title: Mechanisms controlling distinct modes of adult axon growth
administering_ic: NINDS
award_notice_date: 2015-08-19
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: NS
serial_number: 094741
program_official: JAKEMAN, LYN B
project_start_date: 2015-09-01
project_end_date: 2020-07-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 9011081
contact_pi: PETRUSKA, JEFFREY C
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adult;Affect;Animals;Area;Autonomic Dysreflexia;Axon;Behavioral;Bioinformatics;Biomedical Research;Characteristics;Cutaneous;Data;Death Sudden Cardiac;Disease;Epilepsy;Equilibrium;Foundations;Future;Gene Deletion;Gene Expression;Genes;Genetic;Genetic Programming;Goals;Growth;Growth Factor;Health;Health Services Research;Histology;Individual;Injury;Knock-out;Knockout Mice;Literature;Maintenance;Modeling;Molecular;Molecular Genetics;Molecular Profiling;Mus;Natural regeneration;Nerve;Nerve Crush;Nervous System Trauma;Nervous system structure;Neuronal Plasticity;Neurons;Outcome;Pathology;Peripheral;Peripheral Nervous System;Population;Process;Productivity;Quality of life;Recovery;Recovery of Function;Reflex action;Regulation;Research Proposals;Role;Skin;Spinal Ganglia;Spinal cord injury;Structure;System;Testing;Therapeutic;Time;United States National Institutes of Health;Work;activating transcription factor 3;axon growth;axon regeneration;base;cell type;chronic pain;conditioning;design;functional restoration;improved;injured;nerve supply;neurological pathology;novel;prevent;programs;public health relevance;relating to nervous system;research study;screening;transcription factor;transcriptomics


application_id: 9008875
project_number: 1R01EY026180-01
project_title: Tear Film Lipid Compositional Structural Functional Relationships and Dry Eye
administering_ic: NEI
award_notice_date: 2015-11-26
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: EY
serial_number: 026180
program_official: MCKIE, GEORGE ANN
project_start_date: 2015-12-01
project_end_date: 2020-11-30
study_section: Diseases and Pathophysiology of the Visual System Study Section[DPVS]
contact_pi_person_id: 1962526
contact_pi: BORCHMAN, DOUGLAS
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affect;Age;Anti-Bacterial Agents;Area;Asians;Azithromycin;Back;Blinking;Caucasians;Cells;Cholesterol Esters;Chronic;Clinical;Development;Diet;Disease;Elasticity;Environment;Film;Genetic;Goals;Hydrocarbons;In Vitro;Incidence;Knowledge;Lateral;Lead;Lipids;Measures;Microscopy;Modification;Molecular Conformation;Nuclear Magnetic Resonance;Osmolar Concentration;Patients;Production;Property;Protein Conformation;Proteins;Raman Spectrum Analysis;Rheology;Sampling;Sampling Studies;Signs and Symptoms;Sjogren's Syndrome;Structural defect;Structure;Surface;Symptoms;Techniques;Technology;Terpenes;Testing;Time;United States;Variant;Visual;aqueous;evaporation;experience;eye dryness;in vivo;meibomian gland;meibomian gland dysfunction;pressure;public health relevance;spectroscopic survey;therapy development


application_id: 9008664
project_number: 1R01DK107646-01
project_title: Cold Induced Changed in Human Subcutaneous White Adipose
administering_ic: NIDDK
award_notice_date: 2015-09-21
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: DK
serial_number: 107646
program_official: HAFT, CAROL R
project_start_date: 2015-09-21
project_end_date: 2018-07-31
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The recent rediscovery of human brown adipose tissue through PET-CT has initiated more research on thermogenesis and defense defense against obesity. Many studies have demonstrated that white adipose tissue (WAT) in mice has the ability to upregulate its thermogenic capacity and become "beige". No studies have demonstrated browning of typical human WAT depots except for our recent studies. We have recently examined the subcutaneous (SC) WAT of humans and found a considerable ability to upregulate UCP1 and other mitochondrial genes in response to cold and to seasons and we have demonstrated this phenomenon with human adipocytes in culture. The seasonal changes in WAT are of particular interest since this indicates a physiologic response to colder weather without provocative and unphysiologic experimental conditions. In addition we found that obese humans with a high SC WAT macrophage burden do not upregulate SC WAT UCP1 as well suggesting that adipose inflammation inhibits the increased thermogenic capacity of WAT. A number of immune-mediate functions are involved in this process. Based on these data we propose the following hypotheses. Hypothesis 1. Repeated exposure to cold temperatures will amplify changes in human subcutaneous WAT beiging. These beiging effects are seen acutely in response to seasons and involve an activation of immune mediators. Hypothesis 2. The beiging of SC WAT involves an acute increase in adipose tissue immune mediators which may be a source of catecholamines that activate protein kinase A (PKA). This process is inhibited by -blockers in vivo. Hypothesis 3. Obese insulin resistant subjects are resistant to cold induced changes in WAT due to the proinflammatory milieu which inhibits local mediators of beiging. Hypothesis 4. Cold- and season-induced changes in SC WAT will lead to functional changes in the tissue characterized by increased mitochondrial uncoupling increased TG turnover (lipolysis) and increased resting metabolic rate.   
   
PUBLIC HEALTH: Obesity is closely linked with insulin resistance diabetes and heart disease. Recent studies have focused on brown adipose tissue in humans which may increase energy expenditure and help prevent obesity. This proposal examines the extent to which subcutaneous white adipose can become brown-like or beige. We will determine whether this process is inhibited by the inflammatory state of obesity/metabolic syndrome and we will characterize the effects of cold on adipose triglyceride turnover.

project_terms:
Abbreviations;Acute;Address;Adipocytes;Adipose tissue;Adrenergic Agents;Adrenergic Receptor;Adult;Area;Basal metabolic rate;Biological Response Modifiers;Brown Fat;Catecholamines;Cyclic AMP-Dependent Protein Kinases;Data;Development;Diabetes Mellitus;Energy Metabolism;Exposure to;Genes;Health;Heart Diseases;Human;Image;Immune;Immune system;Inflammation;Inflammatory;Insulin;Insulin Resistance;Iodothyronine Deiodinase;Lead;Link;Lipids;Lipolysis;Mammals;Mediating;Mediator of activation protein;Metabolic syndrome;Mitochondria;Mus;Neck;OGTT;Obesity;Phenotype;Physiological;Positron-Emission Tomography;Process;Property;Proteins;Regulation;Research;Resistance;Rodent;Role;Seasons;Societies;Source;Stem cells;Sympathetic Nervous System;Temperature;Thermogenesis;Tissues;Triglycerides;Vertebral column;Weather;adrenergic;base;cold temperature;glucose uptake;improved;in vivo;interest;macrophage;prevent;receptor;response;subcutaneous

public_health_relevance:
Obesity is closely linked with insulin resistance diabetes and heart disease. Recent studieshave focused on brown adipose tissue in humans which may increase energy expenditure andhelp prevent obesity. This proposal examines the extent to which subcutaneous white adiposecan become brown-like or beige. We will determine whether this process is inhibited by theinflammatory state of obesity/metabolic syndrome and we will characterize the effects of coldon adipose triglyceride turnover.


application_id: 9005566
project_number: 1R01DA040637-01
project_title: NK-1 Receptor Antagonism: A Role in Opioid Use Disorders
administering_ic: NIDA
award_notice_date: 2015-09-14
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: DA
serial_number: 040637
program_official: ANDERSON, ANN
project_start_date: 2015-09-15
project_end_date: 2019-07-31
study_section: Risk, Prevention and Intervention for Addictions Study Section[RPIA]
contact_pi_person_id: 1877426
contact_pi: WALSH, SHARON L.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Accounting;Acute;Admission activity;Agonist;Anxiety;Attenuated;Behavior;Brain;Buprenorphine;CD94 Antigen;Clinical;Clinical Trials;Cocaine;Crossover Design;Data;Dependence;Disease;Dose;Double-Blind Method;Drug Formulations;Enrollment;Equilibrium;Genetic;Heroin;Heroin Abuse;Human;Individual;Inpatients;Intravenous;Laboratories;Laboratory Study;Maintenance;Measures;Mediating;Mediation;Methadone;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Naltrexone;Narcotic Antagonists;Nociception;Opiate Addiction;Opioid;Opioid Receptor;Oral;Outcome;Oxycodone;Pain;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Pharmacotherapy;Phase;Physical Dependence;Physiological;Placebo Control;Placebos;Procedures;Randomized;Receptors Opioid mu;Research;Rewards;Role;Safety;Self Administration;Signs and Symptoms;Specific qualifier value;Stress;Substance P;Substance P Receptor;System;Testing;United States;base;behavioral outcome;design;effective therapy;experience;healthy volunteer;improved;meetings;novel;opioid withdrawal;overdose death;prescription opioid;research study;response;volunteer


application_id: 9005174
project_number: 1R01DA040694-01
administering_ic: NIDA
award_notice_date: 2015-09-15
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: DA
serial_number: 040694
program_official: WALTON, KEVIN
project_start_date: 2015-09-15
project_end_date: 2019-07-31
study_section: Pregnancy and Neonatology Study Section[PN]
contact_pi_person_id: 9641889
contact_pi: ASHFORD, KRISTIN H.
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-09-15
project_terms:
1-Butanol;Adult;Adverse effects;Air;Analysis of Covariance;Appalachian Region;Behavior;Biological;Biological Markers;Birth;Birth Weight;Bone Density;Butanones;Carbon Monoxide;Cigarette;Cotinine;Data;Data Analyses;Electronic cigarette;Exhibits;Female of child bearing age;Fetal development of the mammalian embryo or fetus;Fetus;Gestational Age;Goals;Harm Reduction;Health;Heart Diseases;Immune;Immune Sera;Immune response;Immunologic Markers;Infant;Interleukin-1 beta;Interleukin-10;Interleukin-6;Interleukin-8;Interleukins;Kentucky;Liquid substance;Literature;Malignant neoplasm of lung;Marketing;Measures;Methods;National Institute of Drug Abuse;Nature;Neutrophil Collagenase;Nicotine;Nitrosamines;Outcome;Participant;Perception;Perinatal;Pharmaceutical Preparations;Postpartum Period;Postpartum Women;Pregnancy;Pregnancy Outcome;Pregnant Women;Premature Birth;Recruitment Activity;Relapse;Research;Risk;Safety;Series;Serum;Smoke;Smoking;Smoking Behavior;Smoking Status;Spontaneous abortion;Surveys;Time;Tobacco;Tobacco use;Tumor Necrosis Factor-alpha;United States;United States Food and Drug Administration;Urine;Vulnerable Populations;Woman;Work;authority;burden of illness;cigarette smoking;cytokine;design;experience;fetal tobacco exposure;maternal tobacco use;meetings;modifiable risk;novel;premature;prenatal;prenatal smoking;prospective;public health relevance;smoking cessation;urinary


application_id: 9004587
project_number: 271201100017C-4-0-1
project_title: OTHER FUNCTIONS: Development and Manufacture of Pharmaceutical Products for Addic
administering_ic: NIDA
project_start_date: 2011-09-18
project_end_date: 2015-09-17
contact_pi_person_id: 12576703
contact_pi: MURTY, RAM
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 943117366
primary_uei: DNJBTJ3XBQM6
duns_number: 943117366
uei: DNJBTJ3XBQM6
fips: US
organization_id: 3514301
organization_name: MURTY PHARMACEUTICALS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405091016
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
The purpose of this contract is to carry out the development and manufacture of pharmaceutical preparations to be used in the medications development program of the National Institute on Drug Abuse (NIDA) for addiction treatment.

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


application_id: 9003795
project_number: 4R01DE017680-09
project_title: Role of GSK3 in host inflammation
administering_ic: NIDCR
award_notice_date: 2016-02-22
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: DE
serial_number: 017680
program_official: CHANDER, PREETHI
project_start_date: 2007-04-25
project_end_date: 2018-02-28
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7338645
contact_pi: SCOTT, DAVID A
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 DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The overall goal of this project is to elucidate interacting endogenous anti-inflammatory pathways that can be harnessed to suppress an over-exuberant host response to periodontal bacteria and other pathogens. Bacteria are initially recognized by Toll-like receptors (TLRs) and other pathogen recognition receptors expressed on innate cells. TLR interaction with microbe-specific molecular patterns induces the innate production of pro- inflammatory cytokines which direct the intensity and direction of the immune response leads to recruitment of leukocytes to the site of infection and the production of an arsenal of anti-bacterial molecules many of which have the potential to cause the collateral tissue damage that defines destructive inflammatory diseases. There are at least three endogenous anti-inflammatory pathways. The first life cycle of DE017680 focused on the in vitro elucidation of the PI3K/ AKT anti-inflammatory pathway the key role of GSK3b in this signaling cascade and the mechanisms by which this pathway regulates the expression of IFNb IL-1Ra IL-10 in innate cells in addition to controlling T cell development and proliferation. In addition o the PI3K/ AKT cascade this renewal will also consider the a7 nicotinic acetylcholine receptor-dependent cholinergic and the Wnt3a anti- inflammatory pathways. Crosstalk between these three pathways will be elucidated with particular attention paid to the pivotal role of the centra inflammatory mediator GSK3b in pathway convergence. While each pathway is efficacious in its own right therapeutic interventions that maximize the anti-inflammatory potential of convergent signaling events are likely to be particularly potent. To this end anti-inflammatory signaling events will be exploited using murine models of inflammation (sub-cutaneous chamber) and periodontitis (alveolar bone loss). Therefore this project will lay the groundwork for the development of novel approaches to the treatment of periodontitis and other inflammatory diseases and identify therapeutic targets that should be readily translatable.

project_terms:
Alveolar Bone Loss;Amplifiers;Anti-Bacterial Agents;Anti-Inflammatory Agents;Anti-inflammatory;Attention;Bacteria;Bacterial Infections;Cardiovascular system;Cells;Cessation of life;Chronic;Communicable Diseases;Complex;Cutaneous;Data;Dental Plaque;Development;Disease;Disease Progression;Event;Glycogen Synthase Kinases;Goals;Health Care Costs;Host Defense;Human;Immune;Immune response;Immune system;In Vitro;Infection;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Interferon-beta;Interleukin-10;Invaded;Lead;Leukocytes;Life Cycle Stages;Lung diseases;Matrix Metalloproteinases;Mediating;Microbe;Modeling;Molecular;Mus;Natural Immunity;Nature;Nicotinic Receptors;PI3K/AKT;Pathology;Pathway interactions;Pattern;Pattern recognition receptor;Periodontal Diseases;Periodontitis;Pharmacologic Substance;Play;Porphyromonas gingivalis;Production;Regulation;Role;Seminal;Signal Pathway;Signal Transduction;Site;T-Cell Development;TLR2 gene;TLR4 gene;Testing;Therapeutic;Therapeutic Intervention;Tissues;Toll-like receptors;adaptive immunity;anakinra;cholinergic;controlled release;cytokine;driving force;in vivo;microbial;mouse model;novel;novel strategies;oral pathogen;pathogen;pathogenic bacteria;public health relevance;receptor;response;therapeutic target;tool

public_health_relevance:
It is the host response to dental plaque that leads to the development of periodontitis one of the most common infectious diseases in humans that consumes   >$14 billion dollars in health costs in the U.S. per annum. We will identify overlapping events between several endogenous mechanisms of inflammatory suppression (the PI3K/AKT/GSK3b; cholinergic; and Wnt3a anti-inflammatory pathways); elucidate specific mechanisms that suppress pro-inflammatory cytokine production in response to bacterial infection; determine anti-inflammatory events that control the release of tissue degrading matrix metalloproteinases; and establish if we can exploit these anti-inflammatory pathways to reduce inflammation and periodontal disease progression in murine models. These data will identify novel potential therapeutic approaches to the control of destructive inflammation.


application_id: 9003208
project_number: 3R01AG042419-02S1
project_title: Modulation of microRNA pathways by gemfibrozil in predementia Alzheimer disease
administering_ic: NIA
award_notice_date: 2015-03-31
opportunity_number: PAR-11-100
application_type: 3
activity_code: R01
ic: AG
serial_number: 042419
suffix: S1
program_official: RYAN, LAURIE M
project_start_date: 2013-07-15
project_end_date: 2016-06-30
study_section: Special Emphasis Panel[ZRG1-BBBP-V(55)R]
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY A
other_pis: NELSON, PETER T.
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Our preliminary data indicate that miR-107 plays an important role in AD pathogenesis. Fibrates (PPAR agonists) increase miR-107 expression and down-regulated BACE1 protein an essential enzyme contributing to AD in cultured H4 cells. We plan to test our hypotheses and evaluate a potential therapy for Alzheimer's disease (AD) based on this novel microRNA (miRNA) pathway. Preclinical work in this area using animal models of AD has been thwarted by the species-specific hepatotoxicity not seen in humans. Thus human clinical trials are necessary to test this important hypothesis on the disease modifying properties of fibrates in AD. Specifically we propose an evaluation of the safety and efficacy of gemfibrozil administration on micro-RNA modulation of AD mechanisms in a parallel-design double- blind placebo-controlled study. We will evaluate both safety and target engagement of miR- 107 by gemfibrozil as well as alterations in relevant AD biomarkers. Gemfibrozil is a safe orally- administered FDA-approved drug for treatment of hyperlipidemia in aged individuals. The FDA has indicated IND exemption status for these studies. This study is designed to provide the foundation for future large-scale Phase II & III studies of fibrates in AD and AD prevention trials and represents the first attempt we are aware of designed to modulate disease progression in AD through influences on novel micro-RNA pathways. As such the proposed study represents a cutting-edge data-driven exploration of a novel disease relevant pathway that may hold promise for our global efforts targeting this major health priority among developing and developed nations.

project_terms:
5 year old;Adult;Adverse event;Age;Agonist;Alzheimer disease prevention;Alzheimer's Disease;Amyloid;Animal Model;Area;Attenuated;Biological Markers;Cells;Clinical;Clinical Trials;Clinical Trials Design;Cognition;Cognitive;Cohort Studies;Data;Dementia;Developed Countries;Developing Countries;Development;Disease;Disease Progression;Double-Blind Method;Elderly;Enzymes;Epidemic;Evaluation;FDA approved;Fibrates;Foundations;Frequencies (time pattern);Future;Gemfibrozil;Glucose;Health;Health Priorities;Hepatotoxicity;Human;Hyperlipidemia;Impaired cognition;Individual;Intervention;Lipids;Measurement;Measures;Metabolic;Metabolism;MicroRNAs;Monitor;Mus;Outcome Measure;Pathogenesis;Pathology;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Pharmacotherapy;Phase;Placebo Control;Placebos;Plasma;Play;Population;Prevention trial;Primary Prevention;Production;Property;Proteins;Publishing;Randomized;Regulation;Research;Role;Safety;Secondary Prevention;Staging;Target Populations;Testing;Visit;Work;aged;base;beta-site APP cleaving enzyme 1;cognitive testing;cost;design;drug discovery;human subject;mild cognitive impairment;novel;peptide A;placebo controlled study;pre-clinical;primary outcome;secondary outcome;tau Proteins;trial design

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Widespread recognition of the current and projected impact of the AD epidemic has spurred research into novel drug discovery efforts. This proposal seeks to further progress in this area investigating the novel actions of PPAR agonists as a disease modifying therapy in AD through their modulation of novel miRNA pathways that influence A production repurposing an existing drug therapy. As such the proposed study represents a cutting-edge data-driven low-cost exploration of a novel disease relevant pathway that may hold promise for our global efforts targeting this major health priority among developing and developed nations.


application_id: 9002787
project_number: 4R13CA168316-05
project_title: Advancing Health Communication Research through the KCHC-DCHC Conference Series
administering_ic: NCI
award_notice_date: 2016-01-28
opportunity_number: PA-10-071
application_type: 4
activity_code: R13
ic: CA
serial_number: 168316
program_official: BLAKE, KELLY D
project_start_date: 2012-04-19
project_end_date: 2018-03-31
study_section: ZCA1-PCRB-G(F2)
contact_pi_person_id: 1974135
contact_pi: HARRINGTON, NANCY GRANT
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): This R13 application requests support for the Kentucky Conference on Health Communication (KCHC)- District of Columbia Health Communication (DCHC) conference series which currently is planning its 13th meeting to be held April 19-21 2012. The overall goal of the annual KCHC-DCHC conference series is to promote health communication research and practice in order to advance our understanding of behavioral and communication science; such advanced understanding will through translational research subsequently enhance the effectiveness of interventions designed to promote health and prevent illness. The specific aims of this R13 are to increase the impact of KCHC-DCHC through 1) expanding dissemination; 2) increasing participation by early career researchers and graduate students; 3) increasing participation from underrepresented groups; and 4) continuing emphasis on scholarly excellence. Across all four aims our goal is to positively influence the field of health communication and increase its impact by enhancing dissemination of leading research and promoting the career development of early career scientists particularly those from underrepresented groups. Our emphasis on health message design and dissemination is relevant to the mission of the National Institutes of Health (NIH) given our goal to apply our knowledge "to enhance health lengthen life and reduce the burdens of illness and disability" [1]. This scientific focus is consistent with the aims of the U.S. government which has recognized the importance of communication in promoting the health and well-being of our nation in its Healthy People publications. The timeliness of our conference series is especially reflected by the theme the of 2012 conference Health Literacy Research and Practice a theme that addresses the number one Healthy People 2020 [2] health communication objective: health literacy. Our three- day international interdisciplinary conference encompasses several disciplines representing communication social behavioral and health sciences. Topics addressed at the conference include interventions designed for health risk behavior reduction in areas such as cancer diabetes substance abuse and HIV/AIDS; community media and technology-related issues; and methodological issues in behavioral/social science research. Such health communication-focused inquiry is now recognized as instrumental in promoting public health [3]. Past conference attendance has averaged approximately 200 participants. The audience primarily includes graduate postdoctoral and academic faculty researchers; we emphasize participation by graduate students and early career scientists. This audience composition allows the conference series to support one of NIH's goals: "to develop maintain and renew scientific human...resources that will ensure the Nation's capability to prevent disease" [1].

project_terms:
AIDS/HIV problem;Address;Area;Behavioral;Behavioral Genetics;Behavioral Sciences;Communication;Communication Research;Communities;Diabetes Mellitus;Discipline;Discipline of Nursing;Disease;District of Columbia;Effectiveness of Interventions;Ensure;Event;Faculty;Goals;Government;Growth;Health;Health Communication;Health Personnel;Health Promotion;Health Sciences;Healthy People 2020;Human Resources;Interdisciplinary Study;International;Internet;Kentucky;Knowledge;Life;Malignant Neoplasms;Medical Informatics;Medicine;Mission;Participant;Personal Satisfaction;Persuasive Communication;Process;Psychology;Public Health;Publications;Publishing;Request for Applications;Research;Research Personnel;Risk;Risk Reduction Behavior;Scholarship;Science;Scientist;Series;Sister;Social Sciences;Sociology;Students;Substance abuse problem;Technology;Translational Research;Travel;Underrepresented Groups;United States National Institutes of Health;Work;behavioral/social science;burden of illness;career;career development;design;disability;disorder prevention;drug abuse prevention;graduate student;health information technology;health literacy;interest;meetings;member;prevent;public health relevance;skills;social media;social science research;substance abuse prevention;symposium;therapy design

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The Kentucky Conference on Health Communication (KCHC)-District of Columbia Health Communication (DCHC) conference series will advance health communication research and practice in order to reduce the burden of pressing public health problems such as cancer diabetes substance abuse and HIV/AIDS. The conference will promote career development in the social and behavioral sciences through support of early career researchers and graduate students increasing the number of professionals with expertise in health communication.


application_id: 9000082
project_number: 5R01AA021978-03
project_title: Role of ECM and inflammatory remodeling in alcohol-induced liver and lung damage
administering_ic: NIAAA
award_notice_date: 2016-02-01
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AA
serial_number: 021978
program_official: RADAEVA, SVETLANA
project_start_date: 2014-02-01
project_end_date: 2019-01-31
study_section: Special Emphasis Panel[ZRG1-DKUS-D(03)M]
contact_pi_person_id: 2047731
contact_pi: ARTEEL, GAVIN E
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_terms:
Accounting;Acute;Acute Lung Injury;Address;Alcohol abuse;Alcohol consumption;Alcohol-Induced Disorders;Alcoholic Liver Diseases;Alcohols;Animals;Cells;Chronic;Clinical;Data;Deposition;Disease;Endotoxemia;Epithelial Cells;Ethanol;Event;Extracellular Matrix;Fibrin;Fibrinolysis;Functional disorder;Gastrointestinal tract structure;Genetic Engineering;Goals;Health;Hepatic;Hepatotoxicity;Hypoxemia;In Situ;In Vitro;Incidence;Individual;Inflammation;Inflammatory;Inflammatory Response;Injury;Intervention;Intestines;Investigation;Kupffer Cells;Laboratories;Lead;Life;Link;Liver;Lung;Lung Inflammation;Mediating;Mediator of activation protein;Modeling;Morbidity - disease rate;Mus;Nicotinic Receptors;Organ;Peptide Hydrolases;Plasminogen Activator Inhibitor 1;Predisposition;Preparation;Pulmonary Edema;Risk;Role;Series;Structure of parenchyma of lung;Testing;Tissues;Translating;Up-Regulation;Work;alcohol effect;alcohol exposure;alcohol response;base;in vivo;liver inflammation;liver injury;lung injury;mortality;new therapeutic target;novel;novel therapeutic intervention;nutrition;problem drinker;response


application_id: 9000016
project_number: 5R01ES016893-09
project_title: Particulate Cr(VI) Toxicology in Human Lung Epithelial Cells and Fibroblasts
administering_ic: NIEHS
award_notice_date: 2015-12-23
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: ES
serial_number: 016893
program_official: TYSON, FREDERICK L
project_start_date: 2009-07-06
project_end_date: 2018-12-31
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)S]
contact_pi_person_id: 6094413
contact_pi: WISE, JOHN PIERCE
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_terms:
Acetylation;Affect;Anchorage-Independent Growth;Binding;Biological Assay;Cancer Etiology;Carcinogen exposure;Carcinogens;Cells;Chromates;Chromium Compounds;Chromosomal Instability;Chronic;Cytogenetic Analysis;Cytoplasm;DNA Double Strand Break;DNA Repair;Data;Deacetylation;Defect;Double Strand Break Repair;E2F1 gene;Environmental and Occupational Exposure;Epigenetic Process;Epithelial Cells;Event;Exposure to;Fibroblasts;Frequencies;Gene Expression;Genomic Instability;Goals;Health;Histone Deacetylase;Human;Immunoblotting;Immunofluorescence Immunologic;In Vitro;Ions;Lead;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Mediating;Metals;Modeling;Molecular;Mutation;Neoplastic Cell Transformation;Nonhomologous DNA End Joining;Nuclear;Particulate;Peptide Mapping;Phenotype;Proteins;Public Health;Publishing;Reporting;Research;Risk;Salts;Solubility;Spectral Karyotyping;System;Techniques;Testing;Toxicology;Zinc;carcinogenesis;chromium hexavalent ion;homologous recombination;interest;prevent;recombinational repair;repaired;response;tandem mass spectrometry;tumor;zinc chromate


application_id: 8999025
project_number: 5R21NS088608-02
project_title: Optogenetic Mapping of Adult Newborn Neuron Projections
administering_ic: NINDS
award_notice_date: 2016-01-25
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: NS
serial_number: 088608
program_official: WHITTEMORE, VICKY R
project_start_date: 2015-02-01
project_end_date: 2017-07-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 1911523
contact_pi: SMITH, BRET N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Over 2 million people in the United States have experienced unprovoked seizures or been diagnosed with epilepsy. In approximately 25% of cases seizures are refractory to medical therapies. Inability to effectively treat epilepsy reflecs a lack of understanding of the basic mechanisms of this disorder. Up to 50% of traumatic brain injury survivors develop epilepsy. Posttraumatic epilepsy (PTE) is associated with alterations in hippocampal circuits including cell loss and reactive plasticity. In the mammalian brain there is continual generation of new neurons in a few key brain regions throughout adulthood. This process referred to as adult neurogenesis represents a form of experience-dependent plasticity that is believed to support normal brain function. Brain insults including traumatic bran injury seizures and stroke are associated with increases in hippocampal adult neurogenesis and abnormal integration of adult-born neurons within hippocampal circuitry may provide a substrate for hyperexcitable circuits that contribute to seizures. Epilepsy is associated with the emergence of adult-born dentate granule cells (DGCs) that display abnormal dendritic fields and axons that may project to unexpected targets. Adult-born DGCs are associated with spontaneous seizures in experimental epilepsy and blockade of adult neurogenesis reduces spontaneous seizure expression in an animal model of PTE. Despite these reports inherent limitations of the techniques used have prevented the characterization of functional cellular connections formed by adult-born neurons with their synaptic targets. This proposal aims to develop a new technique to selectively label and stimulate newly-born neurons in the adult brain and then use this technique to assess functional outputs of hippocampal adult-born neurons in a mouse model of PTE. Work here aims to: 1) Selectively target expression of channelrhodopsin (ChR2) in adult-born progenitor cells based on their tamoxifen-inducible expression of nestin using Nestin-Cre mice. Nestin-Cre mice will be administered with a Cre-inducible adeno-associated virus (DIO-AAV) with double- floxed reverse cassettes containing channelrhodopsin (ChR2) and the fluorescent report mCherry (abbreviation: ChR2-mCherry; construct: pAAV-Ef1a-DIO-hChR2(H134R)-mCherry-WPRE-pA); and 2) Use blue-light stimulation parameters to activate adult-born neurons and drive signaling to their postsynaptic targets. Whole-cell patch-clamp recordings will be performed on DGCs in hippocampal slices from Nestin-Cre mice that have received injections of the ChR2-mCherry construct to describe the functional projections formed by adult-born neurons after brain injury. Improved understanding of how adult-born neurons incorporate into neural networks and signal during normal and PTE states will help define their relevance as therapeutic targets and will also provide new context for evaluation of clinically available drugs that have documented effects on adult-born cells.

project_terms:
Abbreviations;Adult;Animal Model;Axon;Behavior assessment;Biological Neural Networks;Brain;Brain Injuries;Brain region;Cells;Dependovirus;Development;Diagnosis;Disease;Electrophysiology (science);Employee Strikes;Epilepsy;Epileptogenesis;Evaluation;Experimental Models;Frequencies;Generations;Health;Hilar;Hippocampus (Brain);Injection of therapeutic agent;Injury;Intermediate Filament Proteins;Label;Laboratories;Light;LoxP-flanked allele;Maps;Measures;Medical;Methodology;Methods;Mus;Neuronal Plasticity;Neurons;Newborn Infant;Outcome Measure;Output;Pharmaceutical Preparations;Population;Process;Property;Refractory;Reporting;Role;Seizures;Services;Severities;Signal Transduction;Slice;Stem cells;Stimulus;Survivors;Synapses;Tamoxifen;Techniques;Temporal Lobe Epilepsy;Testing;Transgenic Organisms;Traumatic Brain Injury;United States;Work;adult neurogenesis;base;calretinin;cell preparation;controlled cortical impact;experience;fundamental research;gene therapy;granule cell;improved;in vivo;inducible gene expression;injured;mossy fiber;mouse model;nerve stem cell;nestin protein;neural circuit;neurogenesis;neurotransmission;newborn neuron;optogenetics;patch clamp;postsynaptic;prevent;recombinase;response;selective expression;stroke;therapeutic target;vector;voltage

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The continual generation of new neurons in select regions of the adult brain a process referred to as adult neurogenesis is a form of experience-dependent neural plasticity that may critically contribute to posttraumatic epilepsy but remains poorly understood. This proposal aims to develop a new methodology to study functional projections of adult-born neurons by inducing their selective expression of channelrhodopsin (ChR2) allowing their activation and synaptic effects on downstream targets in order to determine how they contribute to neural circuitry. Comparisons of how adult-born neurons incorporate into local neural networks in normal states and after brain injury that leads to epilepsy will provide information that will help define the role of adult neurogenesis in brain plasticity during epileptogenesis and the relevance of modulating neurogenesis as a therapeutic target.


application_id: 8998976
project_number: 4R01HL112085-04
project_title: Effects of Sleep Deprivation on Infection Induced Organ Failure
administering_ic: NHLBI
award_notice_date: 2016-01-28
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: HL
serial_number: 112085
program_official: LAPOSKY, AARON D
project_start_date: 2013-02-15
project_end_date: 2019-01-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 6210708
contact_pi: CALLAHAN, LEIGH A
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): Recent studies indicate that critically ill patients experience poor sleep frequent disruptions loss of circadian rhythm and a marked reduction of the percentage of sleep time spent in restorative stages. Importantly sleep deprivation in these patients may have adverse consequences. In keeping with this concept two recent animal studies found that sleep deprivation markedly increases death in sepsis but the mechanisms responsible for this phenomenon are completely unknown. We will test the specific hypotheses that sleep deprivation interacts with infection to activate endoplasmic reticulum (ER) stress pathways and that ER stress pathway activation in turn causes failure of multiple organs. Aim 1 will determine if infection and sleep deprivation synergistically induce ER stress in multiple tissues and if ER stress pathway activation produces organ failure. Studies will be performed using animal models of sepsis (cecal ligation and puncture CLP) and sleep deprivation (SD). Experiment 1.1 will test the hypothesis that sepsis and sleep deprivation interact to induce ER stress with ER stress pathways activated in parallel with development of organ failure. Experiment 1.2 will test the hypothesis that chemical activation of ER stress triggers pathological alterations (e.g. activation of downstream proteolytic pathways) that produce organ dysfunction. Aim 2 will elucidate the upstream mechanisms by which sepsis and sleep deprivation activate ER stress pathways. Experiment 2.1 will test the hypothesis that cytokine-induced production of reactive oxygen species (ROS) is the key upstream trigger that activates ER stress in sepsis. Experiment 2.2 will test the hypothesis that upstream alterations in peripheral tissue clock gene function activate ER stress pathways in response to sleep deprivation. Experiment 2.3 will test the hypothesis that disruption of peripheral tissue clock function increases ROS generation and activates ER stress pathways. Aim 3 will determine if administration of pharmacological inhibitors of ER stress pathways improves organ function in sepsis and sleep deprivation. Experiments 3.1 3.2 and 3.3 will test the hypothesis that either z-ATAD-fmk (a caspase 12 inhibitor) salubrinal (a selective inhibitor of eIF2 dephosphorylation) or melatonin (an endogenous hormone that inhibits the IRE1 pathway) will block ER stress pathway dependent cell damage and improve organ function in CLP+SD. Experiment 3.4 will test the hypothesis that delayed administration of the pharmacologic agent to found to produce the best therapeutic effect will block ER stress pathway dependent cell damage and improve organ function in CLP+SD.

project_terms:
Animal Model;Animals;Area;Cause of Death;Cells;Cessation of life;Chemicals;Circadian Rhythms;Cognitive;Complex;Critical Illness;Data;Development;Diagnostic tests;Disease;Functional disorder;Generations;Genes;Goals;Heart Diseases;Hormones;Hospitalization;Infection;Ligation;Light;Malignant Neoplasms;Melatonin;Modeling;Multiple Organ Failure;Noise;Organ;Organ failure;Pathway interactions;Patients;Peripheral;Pharmaceutical Preparations;Physiological;Population;Production;Protein Dephosphorylation;Puncture procedure;Reactive Oxygen Species;Recovery;Risk;Sepsis;Sleep;Sleep Deprivation;Staging;Survivors;Testing;Therapeutic Effect;Time;Tissues;United States;adverse outcome;caspase 12;cell injury;cytokine;endoplasmic reticulum stress;experience;gene function;improved;inhibitor/antagonist;mortality;novel therapeutics;nursing intervention;psychologic;public health relevance;research study;response;septic

public_health_relevance:
PUBLIC HEALTH RELEVANCE: During hospitalization patients' sleep is constantly disrupted due to diagnostic tests frequent nursing interventions noise from alarms and changes in light levels. Recent studies show that sleep deprivation increases death when combined with infection but how this occurs is not known. We have discovered that sleep disruption during infection activates pathways that cause several of the body's organs to fail so the purpose of our proposal is to determine the cellular mechanisms responsible for the interaction of sleep deprivation and infection and to define new treatments which may improve survival and recovery in hospitalized patients.


application_id: 8998802
project_number: 4K23AR060275-05
project_title: Clinical and Biochemical Predictors of Outcome after Knee Injury in Young Patient
administering_ic: NIAMS
award_notice_date: 2016-04-13
opportunity_number: PA-10-060
application_type: 4
activity_code: K23
ic: AR
serial_number: 060275
program_official: WASHABAUGH, CHARLES H
project_start_date: 2012-03-05
project_end_date: 2018-02-28
study_section: Arthritis and Musculoskeletal and Skin Diseases Special Grants Study Section[AMS]
contact_pi_person_id: 9042382
contact_pi: LATTERMANN, CHRISTIAN
other_pis: Not Applicable
congressional_district: 06
department: ORTHOPEDICS
primary_duns: 939017877
primary_uei: 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): Posttraumatic osteoarthritis is an acknowledged outcome of contact-related sports injuries but is an underestimated and understudied problem occurring after non-contact rupture of the anterior cruciate ligament (ACL).  It is estimated that approximately 40-50% of young athletes are at significant risk for developing progressive osteoarthritis (OA) 10-20 years after ACL injury suffered during high school sports participation. Unfortunately reliable predictors of which athletes are at highest risk for developing OA after ACL injury do not exist.   We propose to establish for the first time baseline serum measures of specific biomarkers in 350 injury- free adolescent high school athletes before during and after their competitive season (Aim 1). We will follow this cohort of subjects prospectively for 4 years. Simultaneously we will study a second age- matched cohort of young high school athletes with documented ACL tears. Biomarkers will be measured in these subjects post-injury until biomarker values normalize.  These subjects will be followed for two years post-operatively using patient reported outcome (PRO) instruments. We hypothesize that biomarker levels will increase after ACL injury relative to a normative population. In addition we hypothesize that biomarkers will be highest in subjects with more severe bone bruising after ACL injury (Aim 2).  Finally we will determine outcomes of subjects with severe bone bruises following ACL injury (Aim 3). The presence of bone bruise is not known to be a predictor of posttraumatic OA and lower clinical outcomes scores however bone bruises have been implicated in the progression of osteoarthritis after ACL injury. We will examine if any correlation exists between the magnitude distribution or severity of bone bruise lower patient reported outcomes and evidence of posttraumatic OA initiation at 2 year follow-up. We will also re-examine pre-operative MRI scans pre and post-operative standardized  x-ray and patient reported outcomes followed over 2 years (with a follow-up rate of 85%) in a  prospective longitudinal cohort of 112 isolated ACL injured patients with no additional comorbidities.   Typically 90-100% of these patients may be expected to have a bone bruise after ACL injury.   The impact of these studies is expected to be significant. The identification and validation of biomarkers with and without supporting correlating data from the extent of bone bruise associated with ACL rupture  will provide clinicians with the means to identify adolescents at high risk for the development of  disabling and crippling posttraumatic osteoarthritis and tailor treatment and rehabilitation protocols  that may prevent or delay early onset osteoarthritis in this vulnerable population.

project_terms:
Adolescent;Age;Anterior Cruciate Ligament;Arthritis;Athletic Injuries;Biochemical;Biological Markers;Bone Injury;Cartilage;Cartilage injury;Characteristics;Clinical;Comorbidity;Contusions;Data;Degenerative polyarthritis;Development;Elderly;Employee Strikes;Enrollment;Film;Goals;Image Analysis;Individual;Injury;Knee;Knee Injuries;Lead;Lesion;Location;Lower Extremity;MRI Scans;Magnetic Resonance Imaging;Measures;Operative Surgical Procedures;Outcome;Patient Outcomes Assessments;Patients;Pattern;Physiologic pulse;Population;Postoperative Period;Protocols documentation;Recommendation;Regimen;Rehabilitation therapy;Reporting;Risk;Seasons;Serum;Severities;Sports;Testing;Time;Universities;Validation;Visual;Vulnerable Populations;Work;anterior cruciate ligament rupture;articular cartilage;bone;cohort;design;disability;early onset;follow-up;high risk;high school;individualized medicine;injured;instrument;ligament injury;mammalian COMP;outcome prediction;potential biomarker;prevent;prospective;specific biomarkers;young adult

public_health_relevance:
Non-contact injuries to the knee in the young are becoming prevalent at an alarming rate as participation in high school sports increases. Anterior cruciate ligament (ACL) injuries with bone bruises may hasten cartilage loss predisposing some individuals to early onset osteoarthritis. This study investigates the ability of a serum biomarkerand magnetic resonance imaging to predict (separately or in combination) progressive unremitting cartilage loss in high school athletes at the time of ACL injury. The result of this study may significantly impact the design and implementation of new better treatment and rehabilitation protocols in these young athletes.


application_id: 8998279
project_number: 3P42ES007380-17A1S1
project_title: Nutrition and Superfund Chemical Toxicity
administering_ic: NIEHS
award_notice_date: 2015-01-26
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: A1S1
program_official: HENRY, HEATHER F
project_start_date: 1997-04-07
project_end_date: 2015-03-31
study_section: ZES1-LKB-K(S)
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Adipose tissue;Affinity;Atherosclerosis;Binding (Molecular Function);Biological;Biological Markers;Biology;Biomedical Research;Biomimetics;Blood Vessels;Chemicals;Collaborations;Communities;Coupled;Detection;Diabetes Mellitus;Diet;Diffusion;Disease;Drug Metabolic Detoxication;Ecology;Educational aspects;Environment;Environmental Health;Exercise;Exposure to;Health;Human;In Vitro;Inflammation;Inflammatory;Insulin Resistance;Iron;Kentucky;Lead;Learning;Life Style;Longevity;Mass Spectrum Analysis;Mediator of activation protein;Membrane;Mentorship;Methods;Modeling;Monitor;Nanostructures;National Institute of Environmental Health Sciences;Nutritional;Nutritional Toxin;Obesity;Outcome;Oxidation-Reduction;Oxidative Stress;Pigments;Plants;Policies;Policy Developments;Polychlorinated Biphenyls;Polymers;Population;Populations at Risk;Prevention strategy;Primary Prevention;Process;Production;Recommendation;Relative (related person);Research;Research Design;Research Project Grants;Research Support;Research Training;Risk;Risk Assessment;Risk Management;Role;Rotation;Scientist;Site;Solutions;Statutes and Laws;Students;Superfund;System;Techniques;Technology;Technology Transfer;Tissues;Toxic effect;Training;Translational Research;Translations;Trichloroethylene;United States Environmental Protection Agency;Universities;Work;base;biomedical scientist;chemical stability;computer infrastructure;cytokine;data management;dechlorination;development policy;evidence base;experience;fetal;global environment;improved;in vivo Model;innovative technologies;insight;lifestyle intervention;manufacturing process;nanomaterials;nanostructured;novel;nutrition;organic contaminant;particle;pollutant;programs;public health medicine (field);public health relevance;remediation;science education;sensor;superfund chemical;superfund site;technology development;tool;toxicant;translational engagement


application_id: 8998113
project_number: 7R01DK084045-04
project_title: The Insulin/IGF-I Axis in Diabetic Osteopathy
administering_ic: NIDDK
award_notice_date: 2015-03-23
opportunity_number: PA-14-078
application_type: 7
activity_code: R01
ic: DK
serial_number: 084045
program_official: MALOZOWSKI, SAUL N
project_start_date: 2012-05-23
project_end_date: 2018-03-31
study_section: Special Emphasis Panel[ZRG1-MOSS-B(02)S]
contact_pi_person_id: 6741266
contact_pi: FOWLKES, JOHN L
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
project_abstract:
DESCRIPTION (provided by applicant): Type 1 diabetes mellitus (T1D) is associated with several disorders of skeletal health including decreased bone mineral density (BMD) and an increased risk for osteoporosis and fragility fracture. Moreover clinical evidence suggests that skeletal abnormalities in T1D result from the detrimental effects of T1D on bone formation. While BMD is typically not diminished in Type 2 diabetes mellitus (T2D) bone quality is impaired and fracture risk is increased. The shared as well as distinct features underlying diabetic osteopathy in T1D and T2D are not well understood at this time; however studies have suggested that impaired insulin production insulin action insulin-like growth factor-I (IGF-I) action as well as indirect effects of insulin to promote insulin-like growth factor-I (IGF-I) production may be central events in promoting diabetic bone disease. Recent data from our laboratory examining animal models of diabetes have demonstrated that: 1) severe deficits in bone formation occur in the context of insulin-deficiency in mouse models of T1D; 2) normalization of systemic insulin levels stimulates new bone formation through RUNX2 and RUNX2 target genes in diabetic animals; and 3) insulin and IGF-I may signal via similar down-stream pathways to promote osteoblastogenesis. To clarify mechanisms by which insulin and/or IGF-I modulate osteogenesis and how deficiencies or impaired signaling of each may contribute to diabetic osteopathy we will examine through which signaling pathway(s) insulin regulates RUNX2 and RUNX2 target genes. We also will study mice generated in our laboratory with conditional knock-out of the insulin receptor (IR) in osteoblasts (OIRKO mice) in regards to in utero skeletal development postnatal affects on skeletal growth and development and de novo bone formation. Furthermore we will dissect the specific roles of insulin and IGF-I and their cognate receptors in the osteoblastogenic process by comparing control osteoblasts to osteoblasts lacking the IR the IGF-1 receptor (IGFR) or both the IR and IGFR in regards to insulin IGF-I or insulin and IGF-I stimulated proliferation differentiation and osteogenic gene expression. To specify the roles that insulin and IGF-I may play in the pathogenesis and treatment of diabetic osteopathy we will investigate the effects of diabetes on bone homeostasis and integrity in the osteoblast-specific insulin receptor knock-out (OIRKO) mouse the IGFR knock-out (OIGFRKO) mouse or the IR/IGFR double-knock out (DKO) mouse. We then will evaluate the impact of insulin or IGF-I therapy to affect bone integrity in the diabetic OIRKO OIGFRKO and DKO mouse. Finally we will determine if FoxO transcription factors major down-stream targets of insulin and IGF-I signaling are integral to the diabetic bone phenotype. We will study the effects of osteoblast-specific deficiencies in FoxO1 FoxO3 and FoxO4 in STZ- induced diabetes as a way to preserve skeletal integrity in T1D. Together these studies will provide critical mechanistic and pre-clinical information needed to better understand how corrections in insulin and/or IGF-I in diabetes may be beneficial in preventing and treating diabetic osteopathy.

project_terms:
Affect;Animal Model;Animals;Biology;Bone Density;Bone Diseases;Clinical;Data;Development;Diabetes Mellitus;Event;Financial compensation;Fracture;Fracture Healing;Gene Expression;Gene Targeting;Growth and Development function;Health;Homeostasis;Homologous Gene;Human;Impairment;Insulin;Insulin Receptor;Insulin Signaling Pathway;Insulin-Dependent Diabetes Mellitus;Insulin-Like Growth Factor I;Knock-out;Knockout Mice;Laboratories;Ligands;Molecular;Mus;Non-Insulin-Dependent Diabetes Mellitus;Osteoblasts;Osteogenesis;Osteopathic Medicine;Osteoporosis;Pathogenesis;Pathway interactions;Personal Satisfaction;Phenotype;Play;Process;Production;Receptor Signaling;Relative (related person);Risk;Role;Signal Transduction;Skeletal Development;Stream;Streptozocin;Therapeutic;Time;To specify;blood glucose regulation;bone;bone quality;diabetic;improved;in utero;mouse model;osteogenic;postnatal;pre-clinical;prevent;receptor;skeletal;skeletal abnormality;skeletal disorder;therapy development;transcription factor

public_health_relevance:
Humans with Type 1 diabetes (T1D) and Type 2 diabetes (T2D) are susceptible to diabetic bone disease and are at increased risk for fracture. Despite the well- recognized increased risk of osteoporosis fracture and poor fracture healing that occurs with diabetes how insulin or its homolog insulin-like growth factor 1 (IGF-I) directly affects skeletal well-being in diabetes is poorly understood. This proposal is intended to better define the relative contributions of insulin and IGF-I to the molecular and cellular events involve in development of diabetic bone disease as well as explore their therapeutic potential in preventing diabetic bone disease.


application_id: 8997402
project_number: 4R01CA165469-04
project_title: Role of Tcl1 and Par-4 in regulation of chronic lymphocytic leukemia
administering_ic: NCI
award_notice_date: 2016-01-12
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: CA
serial_number: 165469
program_official: JHAPPAN, CHAMELLI
project_start_date: 2013-02-07
project_end_date: 2018-01-31
study_section: Developmental Therapeutics Study Section[DT]
contact_pi_person_id: 7739669
contact_pi: BONDADA, SUBBARAO
other_pis: RANGNEKAR, VIVEK M
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):  Chronic lymphocytic leukemia (CLL) also known as small cell lymphoma constitutes almost 30% of all cases of non-Hodgkin's lymphoma. It is the most common adult leukemia. Despite advances in chemotherapy treatment options for CLL patients are limited with only a modest efficacy especially for patients with unmutated types of B cell receptors (BCR) del (17p13.1) and p53 mutations. Tcl-1 an oncogene initially found to be translocated in T-cell leukemias has been found to be expressed at higher levels in CLL phenotypes that are classified as aggressive. A mouse model for CLL has been generated by expressing the Tcl-1 oncogene in B cells using immunoglobulin promoter and the E enhancer. These mice reproducibly develop CLL in 13-18 months and have been shown to be excellent models for human CLL. Par-4 is a pro-apoptotic tumor suppressor discovered by us that induces apoptosis in cancer but not normal cells using both the Fas pathway and by inhibiting NF-B. We made four novel observations. First the B-cell receptor signaling pathway is active both in the human CLL cells and in the E-Tcl-1 mouse model of CLL as reflected by constitutive activation of Src family protein tyrosine kinases (SFK). Second we discovered that expression of Tcl1 is down regulated upon inhibition of SFK suggesting a role for BCR signaling in Tcl1 expression. Third we found that expression of Par-4 is down-regulated in E-Tcl1 CLL cells compared to normal mice while its expression has been found to be variable in human CLL cells. Fourth we discovered that E-Tcl1 cells are killed by soluble Par-4 and SAC a specific domain of Par-4 that is cytotoxic only to tumor cells. Based on these observations we hypothesize that a balance between Tcl1 and Par-4 regulated by BCR signaling decides the fate of CLL cells between survival and death. We have three specific aims. Aim 1 will determine the importance of BCR signaling and the role of specific SFKs in the regulation of Tcl-1 and Par-4 expression using the E-Tcl-1 mouse model of CLL. Aim 2 will investigate the importance of Par-4 overexpression for CLL development using a newly generated inducible Par-4 transgenic mice mouse model and the E-Tcl-1 mice. Aim 2 will involve preclinical studies to test the efficacy of extracellular Par-4 and SAC to inhibit CLL growth in the E-Tcl-1 mouse model. The relative importance of Tcl-1 and Par-4 will be studied in Aim 3 with primary CLL cells from patients thus translating the basic research findings in Aims 1 and 2 to clinical samples. The collaboration between UK and OSU provides us an opportunity to integrate the basic science and pre-clinical findings from the first two Aims with studies in Aim 3 using patient derived CLL cells. The exciting aspect of these studies is the possibility that soluble Par-4 or SAC can be developed into a treatment strategy for CLL cells either in isolation or in combination with SFK inhibitors or other targets that are currently being investigated in our laboratories.

project_terms:
17p13.1;Affect;Animal Model;Apoptosis;Apoptotic;B lymphoid malignancy;B-Cell Lymphomas;B-Lymphocytes;Basic Science;Biology;Bone Marrow;Cell Aging;Cell Survival;Cells;Cessation of life;Chromosomal translocation;Chronic Lymphocytic Leukemia;Clinical;Clinical Data;Clinical Investigator;Clinical Trials;Collaborations;Development;Disease;Down-Regulation;Elderly;Enhancers;Equilibrium;Family;Family member;GRP gene;GRP78 gene;Genes;Goals;Grant;Growth;Health;Human;Immunoglobulins;In Vitro;Induction of Apoptosis;Killings;Laboratories;Leukemic Cell;Lymphoid;Malignant Neoplasms;Mediating;Modality;Modeling;Mus;Mutation;Nature;Non-Hodgkin's Lymphoma;Normal Cell;Oncogenes;Organ;PAWR gene;Pathway interactions;Patients;Peptides;Phenotype;Play;Predisposition;Protein Tyrosine Kinase;Proteins;Receptor Signaling;Receptors Antigen B-Cell;Regulation;Resistance;Role;Sampling;Signal Pathway;Signaling Molecule;Small Interfering RNA;Small-Cell Lymphoma;Surface;T-Cell Leukemia;T-Cell Receptor;T-Lymphocyte;TP53 gene;Testing;Therapeutic;Therapeutic Effect;Transcription Factor AP-1;Transgenic Mice;Transgenic Organisms;Translating;Tumor Suppressor Proteins;Western World;Whole Blood;adult leukemia;base;cancer cell;cell age;cell killing;chemotherapy;clinically relevant;cytotoxic;efficacy testing;extracellular;genetic approach;in vivo;inhibitor/antagonist;member;molecular marker;mouse model;neoplastic cell;novel;novel therapeutics;outcome forecast;overexpression;peripheral blood;pre-clinical;preclinical study;pro-apoptotic protein;promoter;receptor;response;therapy development;transcription factor;treatment strategy;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  The efficacy of existing therapeutic modalities for Chronic lymphocytic leukemias which affect mainly older adults is not high and new therapies for this disease are not yet available. The proposed studies will focus on two novel molecules Tcl-1 and Par-4 that have antagonistic roles in survival of CLL cells and may provide new avenues that can be developed into therapeutic strategies.


application_id: 8997085
project_number: 4R01EY012354-16
project_title: Isolation of Congenital Stationary Night Blindness Genes
administering_ic: NEI
award_notice_date: 2015-12-22
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: EY
serial_number: 012354
program_official: GREENWELL, THOMAS
project_start_date: 1999-02-01
project_end_date: 2017-12-31
study_section: Neurotransporters, Receptors, and Calcium Signaling Study Section[NTRC]
contact_pi_person_id: 1885008
contact_pi: GREGG, RONALD G
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): Vision begins when light is converted to an electrical signal in the photoreceptors. Increases in light decrease release of the neurotransmitter glutamate from cone and rod photoreceptor terminals and decreases in light increase its release. These changes in synaptic glutamate concentration are detected by two classes of bipolar cells that then transmit the signal vertically through the retinal circuit to the ganglion cells. The neurotransmitter changes also are detected by horizontal cells that provide lateral transmission in the form of feedback and feedforward inhibition.  There are two classes of bipolar cells hyperpolarizing (HBCs) and depolarizing (DBCs). HBCs utilize ionotropic glutamate receptors and hyperpolarize in response to a light flash. DBCs utilize a metabotropic glutamate receptor mGluR6 that signals to TRPM1 depolarizing in response to a light flash. Defects in transmission in DBCs results in complete congenital stationary night blindness (cCSNB). Mutations in GRM6 NYX TRPM1 and GPR179 cause cCSNB. The mechanism by which mGluR6 signals TRPM1 is largely unknown. The long term goal of this project is study the molecular interactions between two recently discovered retinal components GPR179 and Cav1.1 and the other DBC signal transduction components. The specific aims are: 1) Determine the role of GPR179 in DBC signalplex assembly/function 2) determine the role of Cav1.1 in DBC signalplex assembly and function and 3) Determine functional and trafficking interdependence of DBC signalplex components.  At the completion of this project we will have characterized the function of newly discovered proteins (GPR179 and Cav1.1) critical to signal transmission in DBCs. Further we will have identified new candidate genes for congenital stationary night blindness.

project_terms:
Address;Alleles;Binding;Brain;Candidate Disease Gene;Cations;Cells;Coin;Complex;Data;Defect;Disease;Dissection;Elements;Feedback;Functional disorder;Future;G-Protein-Coupled Receptors;GRM6 gene;Genes;Glutamate Receptor;Glutamates;Goals;Grant;Health;Human;Knock-out;Knockout Mice;Knowledge;L-Type Calcium Channels;Lateral;Lead;Left;Light;Literature;Mediating;Metabotropic Glutamate Receptors;Mus;Mutant Strains Mice;Mutate;Mutation;Nature;Neurons;Neurotransmitters;Night Blindness;Pathway interactions;Photoreceptors;Point Mutation;Positioning Attribute;Property;Protein Isoforms;Proteins;Publishing;Retinal;Retinal Cone;Retinal Ganglion Cells;Role;Signal Transduction;Skeletal Muscle;Staging;Synapses;Synaptic Transmission;TRPM1 gene;Therapeutic;Transmembrane Domain;Vision;Visual system structure;ganglion cell;horizontal cell;human disease;luminance;member;mutant;neurotransmitter release;novel;research study;response;retinal rods;trafficking;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Vision requires a light signal to be converted to an electrical signal which is then transmitted to the brain via a neuronal network. The group of diseases being studied is referred to as complete congenital stationary night blindness. They have defects in signal transmission between photoreceptors and the second order neurons in the pathway. The studies in this proposal will characterize the nature of the defects and determine new proteins critical to function. Such knowledge is essential to future efforts to restore normal vision.   PUBLIC HEALTH RELEVANCE: Vision requires a light signal be converted to an electrical signal which is then transmitted to the brain via a neuronal network. The diseases being studied are referred to as congenital stationary night blindness. The studies in this proposal will characterize the nature of the defects and determine the function of newly identified proteins critical for normal vision which will set the stage of therapeutic approaches in the future.


application_id: 8997069
project_number: 5K01DA031961-03
project_title: Glutamate Receptor Modulation of Calcium Signaling in Neuropathic Pain
administering_ic: NIDA
award_notice_date: 2016-02-01
opportunity_number: PA-11-190
application_type: 5
activity_code: K01
ic: DA
serial_number: 031961
program_official: RAPAKA, RAO
project_start_date: 2014-02-01
project_end_date: 2019-01-31
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 10670168
contact_pi: DOOLEN, SUZANNE
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 K01 career award is to understand the mechanisms that lead to injury-induced central sensitization and to establish ameliorative therapeutic targets for chronic pain. My preliminary data suggests that AMPA receptors drive glutamate-evoked Ca2+ transients in spinal cord neurons and that glutamate-evoked Ca2+ transients are potentiated following nerve injury. The central hypothesis is that nerve injury potentiates neuronal activity and Ca2+ mobilization (Aim 1) via increased GluR2 AMPA receptor phosphorylation and trafficking in the dorsal horn (Aim 2) and that this mechanism of neuropathic pain is tonically inhibited by endogenous opioids (Aim 3). This hypothesis will be tested using innovative simultaneous Ca2+ imaging and whole-cell electrophysiology to evaluate dorsal root stimulated (DRS) Ca2+ transients and neuronal activity in dorsal horn of adult spinal cord slices. Aim 1. Experiment 1a will evaluate the effect f sham or spared nerve injury (SNI) on isolated AMPA receptor Ca2+ signals and membrane currents. Experiment 1b will evaluate Ca2+ mobilization and membrane currents DRS at A A and c-fiber activation strength. Aim 2 While AMPA GluR2 phosphorylation and trafficking have been implicated in inflammatory pain the mechanisms that mediate nerve injury-induced potentiation of Ca2+ levels are not known. To address this question Experiment 2a will determine levels and subcellular localization of total and phosphorylated GluR2 in dorsal horn. Based on studies indicating inflammation-induced GluR2 internalization is NMDA receptor-dependent Experiment 2b will test the hypothesis that intrathecal administration of NMDA receptor antagonists will reduce nerve-injury induced phosphorylation and internalization of GluR2. Aim 3. My new data suggest that opioids tonically inhibit glutamate receptor function after inflammation and thus mask neuropathic pain. Aim 3 seeks to extend this discovery to our model of peripheral neuropathic pain. Experiment 3a will attempt to correlate Ca2+ mobilization with pain-like behavior following traditional SNI and a modified nerve injury model that resolves over 4 weeks. Establishing a decrease in Ca2+ mobilization in association with behavioral resolution will allow us to test our hypothesis in Experiment 3b. Experiment 3b will evaluate the effects of opioid receptor antagonists on: DRS-stimulated Ca2+ transients and neuronal activity and GluR2 phosphorylation and subcellular localization. We expect that opioid receptor antagonists will increase Ca2+ mobilization neuronal activity GluR2 phosphorylation and shift Ca2+-impermeable GluR2 expression away from the cell surface.

project_terms:
AMPA Receptors;Address;Adult;Adverse effects;Analgesics;Award;Behavior;Behavioral;CTOP;Calcium;Calcium Signaling;Cell Fractionation;Cell surface;Cells;Chemosensitization;Data;Electrophysiology (science);Endogenous Opiates;Fiber;Glutamate Receptor;Glutamates;Goals;Health;Healthcare;Hyperalgesia;Image;Inflammation;Inflammatory;Injury;Lead;Masks;Mediating;Membrane;Mentors;Mission;Modeling;Mus;N-Methyl-D-Aspartate Receptors;NMDA receptor antagonist;Naltrexone;Neurons;Opioid;Opioid Receptor;Pain;Pain management;Peripheral;Permeability;Phosphorylation;Receptor Activation;Receptor Signaling;Receptors Opioid mu;Research;Research Technics;Resolution;Signal Transduction;Slice;Spinal Cord;Techniques;Testing;Western Blotting;base;career;central sensitization;chronic pain;clinically relevant;dorsal horn;inflammatory pain;innovation;nerve injury;neuronal excitability;painful neuropathy;postsynaptic;receptor function;research study;response;sensory input;spared nerve;spinal nerve posterior root;therapeutic target;trafficking

public_health_relevance:
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. This project is relevant to NIDA's mission because it will 1) determine mechanisms that lead to injury-induced central sensitization and 2) establish clinically relevant therapeutic targets for alleviating chronic pain and 3) target mechanisms of endogenous opioids on long-lasting pain vulnerability following injury. This Research Plan employs highly innovative wide-field calcium imaging from numerous cells in a single spinal cord slice from adult mice.


