# projects

application_id: 8716845
project_number: 1F32AR065337-01A1
project_title: Regulation of skeletal muscle extracellular matrix remodeling by satellite cells
administering_ic: NIAMS
award_notice_date: 2014-03-31
opportunity_number: PA-11-113
application_type: 1
activity_code: F32
ic: AR
serial_number: 065337
suffix: A1
program_official: BOYCE, AMANDA T
project_start_date: 2014-04-01
project_end_date: 2014-07-01
study_section: Special Emphasis Panel[ZRG1 F10B-B (20)]
contact_pi_person_id: 11267737
contact_pi: FRY, CHRISTOPHER
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
project_abstract:
DESCRIPTION (provided by applicant): The maintenance of skeletal muscle mass and the ability to increase mass in response to load are crucial for whole body function and quality of life. The role of satellite cells or muscle stem cells in muscle mass regulation is equivocal. Effective muscle hypertrophy can occur independently of satellite cells; however long- term muscle adaptation in the absence of satellite cells has not been explored. Preliminary data suggest that in the absence of satellite cells muscle becomes fibrotic and hypertrophy plateaus. This raises the possibility that activated satellite cells play a paracrine role in regulating the muscle fiber niche. Excess extracellular matrix (ECM) production and muscle fibrosis observed in muscular dystrophies and in aging negatively impact muscle plasticity and function. Activated satellite cells may mediate skeletal muscle ECM production through modulation of transforming growth factor  (TGF-) signaling. TGF- promotes increased production of ECM in muscle fibroblasts and satellite cells may prevent TGF- downstream signaling thereby influencing fibroblast activity and ECM production. It is hypothesized that in the absence of activated satellite cells production of ECM by muscle fibroblasts increases via activation of TGF- signaling resulting in muscle fibrosis and attenuated muscle growth and function. Further we propose to test the novel hypothesis that muscle fibrosis rather than a myonuclear domain ceiling limits muscle hypertrophy in satellite cell-depleted muscle. Functional overload of plantaris muscle in two novel mouse strains will determine the role of activated satellite cells in
modulating the extracellular environment to enable hypertrophy. The Pax7-DTA strain enables specific depletion of satellite cells and the Pax7-N-WASp strain enables satellite cell activation
and proliferation but not fusion. Aim 1 will assess TGF- signaling activity fibroblast proliferation expression of ECM components functional consequences of fibrosis and the hypertrophic response in skeletal muscle following satellite cell depletion in the Pax7-DTA mouse in response to overload. Immunohistochemistry fluorescent activated cell sorting qRT-PCR western blotting biochemical assays and whole muscle function assessment will be performed. Increased fibroblast proliferation expression of ECM components and depressed force production associated with reduced growth in satellite cell-depleted muscle will demonstrate a regulatory role for activated satellite cells in controlling the fiber extracellular environment. Aim 2 will utilize the Pax7-N-WASp mouse to determine the role of activated satellite cells in the hypertrophic response irrespective of their ability to contribute new nucleito growing fibers. Activated satellite cell regulation of fibroblast proliferation and ECM production will be assessed during muscle overload as in Aim 1. Restoration of hypertrophy in Pax7-N-WASp mice will demonstrate a novel role for activated satellite cells in adult skeletal muscle adaptability that may prove equally as important as their well-characterized role in muscle fiber regeneration.

project_terms:
Ablation;Activation Analysis;Adult;Affect;Aging;Aging-Related Process;Angiotensin II Type 1 Receptor Blockers;Area;Attenuated;Biochemical;Biological Assay;Breeding;Bromodeoxyuridine;Cell Nucleus;Cell Separation;Cells;Chronic Disease;Clinical;Data;Depressed mood;Environment;Excision;Extracellular Matrix;Fiber;Fibroblasts;Fibrosis;Gastrocnemius muscle structure;Growth;Health;Hypertrophy;Immunohistochemistry;In Vitro;Label;Lead;Losartan;Maintenance;Measures;Mechanics;Mediating;Molecular;Mouse Strains;Mus;Muscle;Muscle Contraction;Muscle Fibers;Muscle function;Muscle satellite cell;Muscular Dystrophies;Natural regeneration;Operative Surgical Procedures;Plantaris muscle;Play;Population;Prevention;Production;Proliferating;Quality of life;Regulation;Role;Signal Pathway;Signal Transduction;Skeletal muscle structure;Soleus muscle structure;Tamoxifen;Techniques;Testing;Transforming Growth Factors;Weight;Western Blotting;extracellular;improved;in vivo;muscle form;muscle hypertrophy;novel;paracrine;prevent;public health relevance;response;restoration;satellite cell

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Numerous chronic diseases such as muscular dystrophy as well as the aging process are characterized by an increase in skeletal muscle fibrosis which negatively impacts muscle contraction and can result in a loss of independence and a reduced quality of life. This project explores the role of muscle stem cells known as satellite cells in he maintenance of the muscle environment and in the prevention of muscle fibrosis. The ability of satellite cells to prevent fibrosis of skeletal muscle during adaptation and growth highlights thes cells as a target for therapies to improve muscle quality in clinical populations where muscle fibrosis occurs.


application_id: 8716031
project_number: 2P20GM103436-14
project_title: EKU Lead Faculty Award
administering_ic: NIGMS
award_notice_date: 2014-08-01
opportunity_number: PAR-12-205
application_type: 2
activity_code: P20
ic: GM
serial_number: 103436
study_section: Special Emphasis Panel[ZGM1 TWD-7 (IN)]
subproject_number: 7046
contact_pi_person_id: 10574352
contact_pi: CALIE, PATRICK JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-08-01
budget_end_date: 2015-04-30
project_terms:
Adopted;Animal Model;Applications Grants;Award;Basic Science;Bioinformatics;Biomedical Research;Biometry;Biotechnology;Cell Culture Techniques;Centers of Research Excellence;Clinical;Computer software;Core Facility;DNA;Data Analyses;Data Collection;Defect;Development;Educational workshop;Ensure;Event;Experimental Designs;Faculty;Funding;Gene Expression;Gene Expression Profile;Gene Mutation;Genetic Transcription;Genomic DNA;Genomics;Genotype;Goals;Grant;Health Sciences;Human;Human Resources;Hybridization Array;Individual;Information Sciences;Institution;Internet;Kentucky;Lead;Libraries;Longevity;Manuscripts;MicroRNAs;Microarray Analysis;Molecular;Molecular Profiling;Molecular Target;Mus;National Institute of Environmental Health Sciences;National Institute of General Medical Sciences;Nursing Faculty;Oligonucleotide Microarrays;Pattern;Preparation;Procedures;Process;Provider;RNA;RNA Splicing;RNA amplification;Research Personnel;Resources;Sample Size;Sampling;Scanning;Schools;Services;Single Nucleotide Polymorphism;Specimen;Technology;Training;Training Programs;Variant;base;data mining;deep sequencing;density;experience;medical schools;next generation sequencing;operation;outreach;rapid growth;tool


application_id: 8716029
project_number: 2P20GM103436-14
project_title: Genomics Core
administering_ic: NIGMS
award_notice_date: 2014-08-01
opportunity_number: PAR-12-205
application_type: 2
activity_code: P20
ic: GM
serial_number: 103436
study_section: Special Emphasis Panel[ZGM1 TWD-7 (IN)]
subproject_number: 7045
contact_pi_person_id: 1969307
contact_pi: ZACHARIAS, WOLFGANG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-08-01
budget_end_date: 2015-04-30
project_terms:
Anatomy;Biochemistry;Bioinformatics;Biological Sciences;Biology;Biomedical Research;Biometry;Chemistry;Clinical Research;Clinical and Translational Science Awards;Collaborations;Commit;Computer software;Computers;Core Facility;Data Analyses;Development;Educational Curriculum;Educational aspects;Engineering;Exercise;Faculty;Flowers;Funding;Genomics;Head;Health;Health Sciences;Information Sciences;Institution;Mathematics;Mediation;Mission;Modeling;Molecular Biology;Movement;Neurobiology;Output;Provider;Psychology;Research;Research Infrastructure;Research Personnel;Research Training;Resources;Science;Services;Training;Training and Education;Translational Research;Translations;Universities;Videoconferences;Videoconferencing;Visit;biomedical informatics;computer science;experience;functional genomics;interest;medical schools;member;outreach;programs;undergraduate student


application_id: 8716014
project_number: 1P30GM110787-01
project_title: COBRE for the Center for Molecular Medicine
administering_ic: NIGMS
award_notice_date: 2014-06-27
opportunity_number: PAR-13-238
application_type: 1
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: Special Emphasis Panel[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_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;Institution;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;human disease;programs;public health relevance;success;voucher


application_id: 8715739
project_number: 5R01CA172379-02
project_title: Novel resveratrol analogs and colorectal cancer treatment
administering_ic: NCI
award_notice_date: 2014-05-07
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 172379
program_official: EMENAKER, NANCY J
project_start_date: 2013-08-06
project_end_date: 2018-05-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 7013090
contact_pi: LIU, CHUNMING
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:
APC gene;Accounting;Adenomatous Polyposis Coli;Adverse effects;Affect;Anabolism;Animal Model;Antineoplastic Agents;Binding (Molecular Function);Biological;Biological Assay;Biological Factors;Biological Process;CTNNB1 gene;Cancer Cell Growth;Cancer Etiology;Cell Proliferation;Cell model;Cells;Cessation of life;Chemoprevention;Chemopreventive Agent;Colorectal Cancer;Development;Disclosure;Drug Targeting;Epigenetic Process;Event;Family;Funding;Future;Generations;Genes;Genetic Transcription;Genetically Engineered Mouse;Goals;Grant;Grapes;Growth;Half-Life;Histones;Human;Hypermethylation;In Vitro;Lead;Legal patent;Malignant Neoplasms;Malignant neoplasm of liver;Mediating;Metabolism;Methionine;Methylation;Modeling;Molecular;Molecular Target;Mortality Vital Statistics;Mus;Mutation;Neoplasms;Nude Mice;Organoids;Pathway interactions;Patients;Polyamines;Promotor (Genetics);Publications;Reporting;Resveratrol;Role;S-Adenosylmethionine;Signal Pathway;Signal Transduction;Skin;Testing;Therapeutic;Therapeutic Agents;Toxic effect;United States;Xenograft procedure;analog;base;cancer cell;cancer prevention;cancer therapy;colon carcinogenesis;colorectal cancer prevention;design;drug candidate;efficacy testing;in vivo;inhibitor/antagonist;methionine adenosyltransferase;mouse model;novel;public health relevance;research study;trans-resveratrol;tumor metabolism;tumor progression


application_id: 8714415
project_number: 4R00CA158009-03
project_title: The role of the first mammalian N-term. methyltransferase NRMT in tumorigenesis
administering_ic: NCI
award_notice_date: 2013-09-06
opportunity_number: PA-10-063
application_type: 4
activity_code: R00
ic: CA
serial_number: 158009
program_official: OKANO, PAUL
project_start_date: 2011-09-05
project_end_date: 2015-08-31
study_section: NSS
contact_pi_person_id: 8476980
contact_pi: SCHANER-TOOLEY, CHRISTINE E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The list of genes involved in tumorigenesis is quite extensive however many of their biological functions remain unknown. One such gene Mettl11a (now renamed NRMT) has been shown to be under-expressed in breast cancers but has only recently been identified as the first mammalian N-terminal methyltransferase. Reduction of NRMT also results in a multi-spindle phenotype and the associated aneuploidy is often considered to contribute to cancer progression. As NRMT is a newly discovered protein the goals of this proposal are to understand the role of N-terminal methylation on protein and cellular function in order to study how its misregulation leads to tumorigenesis. The first two aims determining whether N-terminal methylation is constitutive and determining whether N-terminal methylation universally alters the DNA binding of its substrates are designed to better understand the basic biology of N-terminal methylation. These aims will involve mass spectrometry fluorescent-activating cell sorting FRET analysis and construction of a knockout mouse. The objective of the third aim is to determine the role of NRMT in development and tumorigenesis. A mouse mammary transplant model will be established for assaying if the multi-spindle NRMT knockdown phenotype leads to developmental defects and/or tumorigenesis. The key element of the career development aspect of this proposal will be learning the mouse system needed for successful completion of the third aim. The experiments of aims one and two have been designed for the downtime between surgeries and gland or tumor harvesting. Environment The University of Virginia is well equipped for completion of all three aims of this proposal. The on-campus mass spectrometry facility of advisory committee member Dr. Don Hunt has a Fourier transform mass spectrometer necessary for distinguishing N-terminal methylation from acetylation. The UVA Flow Cytometry Core will provide the training necessary for all fluorescent-activating cell sorting experiments. The UVA Gene Targeting and Transgenic Facility will create the NRMT knockout mouse. The Research Histology Core will paraffin embed and make slides of all normal mouse tissue and tumors. My advisory committee member Dr. Amy Bouton will aid in interpretation of the histology. The expertise and reagents of advisory committee member Dr. Todd Stukenberg will aid in characterization of the NRMT multi-spindle phenotype. The UVA W.M. Keck Center for Cellular Imaging supplies state-of-the art imaging facilities for immunofluorescent imaging of mouse tissue samples and training in FRET analysis. The Macara lab currently has three expert mouse biologists available for training in mouse handling and surgical techniques. In addition UVA offers numerous courses aimed at career development/training including the UVA transgenic methods and applications workshop the Flow Cytometry Training Workshop the Workshop on FRET Microscopy and a monthly career development seminar series offered by the Office of Postdoctoral Professional Development.

project_terms:
A Mouse;Acetylation;Advisory Committees;Affect;Aneuploidy;Antibodies;Apoptotic;Binding (Molecular Function);Biological;Biological Assay;Biological Process;Biology;Cell Cycle;Cell Line;Cell Proliferation;Cell Separation;Cell physiology;Chromatin;Committee Members;Consensus Sequence;Cytoplasm;DNA;DNA Binding;DNA repair protein;DNA-Binding Proteins;Data;Defect;Development;Educational workshop;Elements;Embryo;Environment;Epithelial Cells;Exhibits;Fatty acid glycerol esters;Fibroblasts;Flow Cytometry;Fluorescence Resonance Energy Transfer;Fourier Transform;Future;Gene Combinations;Gene Targeting;Genes;Genetic;Gland;Glioblastoma;Goals;Growth;Harvest;Histology;Image;Immunoprecipitation;In Vitro;Knockout Mice;Learning;Mammary gland;Mass Spectrum Analysis;Measures;Mentors;Methods;Methylation;Methyltransferase;Microarray Analysis;Microscopy;Mitotic;Modeling;Modification;Monitor;Mono-S;Mus;Mutation;N-terminal;Neoplasm Metastasis;Nuclear;Oncogene Proteins;Operative Surgical Procedures;Paraffin Embedding;Patients;Pattern;Pharmaceutical Preparations;Phase;Phenotype;Post-Translational Protein Processing;Process;Proteins;Reagent;Research;Retinoblastoma Protein;Role;Running;Series;Site;Slide;System;Techniques;Testing;Therapeutic Agents;Tissue Sample;Training;Transgenic Organisms;Transplantation;Tumor Suppressor Genes;Tumor Suppressor Proteins;Tumor Tissue;Universities;Virginia;career development;cellular imaging;chromatin immunoprecipitation;design;in vitro Assay;in vivo;interest;leukemia;malignant breast neoplasm;mass spectrometer;mouse model;mutant;myosin light chain 2;protein function;research study;skills;stoichiometry;tool;tumor;tumor progression;tumorigenesis

public_health_relevance:
The biological roles of many genes involved in tumorigenesis remain unknown. We need to study their functions in order to achieve a complete understanding of cancer progression and obtain an inclusive list of potential druggable targets. One such protein NRMT the newly identified mammalian N-terminal methyltransferase is under-expressed in breast cancers and its knockdown results in mitotic defects often considered to contribute to cancer progression. The goal of this proposal is to understand how NRMT is regulated and how its misregulation contributes to tumorigenesis.


application_id: 8714025
project_number: 5U24HL094373-05
project_title: Preclinical Consortium to Facilitate Translation of Cardioprotective Therapies
administering_ic: NHLBI
award_notice_date: 2014-08-01
application_type: 5
activity_code: U24
ic: HL
serial_number: 094373
program_official: EVANS, FRANK
project_start_date: 2010-08-01
project_end_date: 2016-07-31
study_section: ZHL1-CSR-H(O1)
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
budget_start_date: 2014-08-01
project_abstract:
DESCRIPTION (provided by applicant):     Ischemic heart disease causes -600000 deaths/year (-20% of all deaths). An estimated 1.3 million Americans have a myocardial infarction every year; because their prognosis is determined by the size of the infarct reducing infarct size is of paramount importance to alleviate morbidity and mortality. For more than 30 years the NHLBI has invested enormous resources (at least several hundred million dollars) in preclinical studies aimed at developing infarct-sparing therapies and several hundred (if not thousands) therapies have been claimed to limit infarct size in preclinical models. Unfortunately due to methodological problems this enormous investment has not produced any notable clinical application and no cardioprotective therapy is currently available for clinical use. After >30 years of futile efforts a new approach is needed to overcome the problems that have impeded the translation of cardioprotective therapies. The time has come to apply to preclinical research the same standards of scientific rigor that are applied to clinical trials. Using the clinical trials networks established by the NHLBI as a model for developing a collaborative infrastructure for research sharing we propose a preclinical consortium that will operate in a manner analogous to a clinical network. Six Institutions will work together to conduct blinded randomized and adequately powered studies using a rigorous design full dose-response analyses optimal statistical methods independent data analysis and statistical Cores histology plasma biomarkers and relevant animal models (including conscious animals and models of comorbidities) in three species (mouse rabbit pig). To ensure reproducibilitv. each study will be performed in two Centers using identical protocols. This unique infrastructure will enable rigorous preclinical evaluation of promising cardioprotective therapies and will serve the entire scientific community (both in academia and in biomedical industry) thereby constituting a public resource. Proposals for studying therapies will be solicited from the entire scientific community and reviewed by an independent Protocol Review Committee which will select those that will be implemented. At least 3 therapies/year will be tested. The consortium structure will ensure that it will be a true public resource available to all interested investigators and that all proposed studies will be evaluated in an equitable fashion. The need for this infrastructure is attested to by 30 letters (Appendix). This will be a paradigm shift in cardioprotection. By screening promising therapies and identifying those that are reproduciblv effective in relevant experimental models and thus most likely to be effective in patients the consortium will dramatically advance our ability to rationally translate basic findings into clinical use.     This proposal addresses an issue that has major importance for the NHLBI mission and for public health at large namely the failure to translate experimental studies of cardioprotection into clinical therapies. Ischemic heart disease is the number one cause of death and disability in America. Since ~1.3 million Americans have a myocardial infarction each year and their prognosis is determined by the size of the infarct reducing infarct size will have a major impact on their morbidity and mortality and thus enormous implications for public health. (End of Abstract)

project_terms:
Academia;Acute myocardial infarction;Address;American;Americas;Animal Model;Basic Science;Biological Markers;Blast Cell;Blinded;Carbon Monoxide;Cause of Death;Cessation of life;Clinical;Clinical Trials;Clinical Trials Network;Communities;Comorbidity;Conscious;Doctor of Medicine;Dose;Educational workshop;Electronic Mail;Ensure;Evaluation;Experimental Models;Failure (biologic function);Family suidae;Funding;Future;Goals;Healthcare;Histology;Individual;Industry;Infarction;Institution;Intervention;Investments;Ischemic Preconditioning;Journals;Laboratories;Letters;Logistics;Mind;Mission;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mus;Myocardial Infarction;Myocardial Ischemia;Myocardial tissue;National Heart Lung and Blood Institute;Oryctolagus cuniculus;Participant;Patients;Phase;Plasma;Pre-Clinical Model;Probability;Protocols documentation;Publishing;Randomized;Recommendation;Reperfusion Therapy;Reporting;Reproducibility;Research;Research Infrastructure;Research Personnel;Resource Sharing;Resources;Review Committee;Role;Sodium Nitrite;Statistical Data Interpretation;Statistical Methods;Structure;System;Testing;Therapeutic Intervention;Time;Translating;Translational Research;Translations;United States National Institutes of Health;Work;abstracting;clinical application;design;disability;interest;meetings;member;myocardial infarct sizing;novel strategies;operation;outcome forecast;pre-clinical;pre-clinical research;preclinical evaluation;preclinical study;programs;public health medicine (field);research study;response;screening;sildenafil;success;web site;working group


application_id: 8713887
project_number: 5R01AA021722-02
project_title: Behavioral Dysregulation and Alcohol Sensitivity in Risky Drivers
administering_ic: NIAAA
award_notice_date: 2014-08-01
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AA
serial_number: 021722
program_official: BLOSS, GREGORY
project_start_date: 2013-08-05
project_end_date: 2017-07-31
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 6368360
contact_pi: FILLMORE, MARK T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alcohol-related traffic fatality and injury continue to be a major public health problem prompting the need for research aimed at identifying characteristics of DUI drivers in efforts to improve treatment and prevention. Although DUI offenders report traits of impulsivity suggesting poor inhibitory control and heightened reward sensitivity the specific cognitive characteristics underlying such behavioral dysregulation have not been systematically studied in the laboratory. The over-arching hypothesis of this application is that deficient inhibitory control and increased sensitivity to the disinhibiting effects of alcool contribute to the risk of DUI and possibly to its recidivism. The proposed project views DUI offenders from a cognitive dysfunction perspective that targets deficits in specific mechanisms of behavioral regulation. The research will directly evaluate driving performance and mechanisms of self-regulation (e.g. inhibitory control reward-seeking) in recidivist DUI offenders and will test hypotheses that these high-risk drivers respond differently to alcohol wit increased disinhibition and risk-taking and that these factors contribute to their decisions to drive after drinking. The application represents an innovative application of state-of-the-art assessments and techniques to identify the specific neurocognitive characteristics that underlie risky driving behavior and which could be candidate mechanisms for treatment and prevention. The project aims fit well with the recent NIH Funding Opportunity Announcement (PA-10-255) Behavioral Regulation Mechanisms of Alcohol Dependence and Related Phenotypes aimed at promoting research on the effects of alcohol on neurocognitive mechanisms implicated in impulse control.

project_terms:
Acute;Address;Alcohol dependence;Alcohols;Attention deficit hyperactivity disorder;Automobile Driving;Awareness;Behavior;Behavioral;Behavioral Mechanisms;Blood;Blood alcohol level measurement;Characteristics;Cognitive;Cognitive deficits;Counseling;Data;Disinhibition;Dose;Environment;Environmental Risk Factor;Funding Opportunities;Impaired cognition;Impairment;Impulsivity;Incentives;Incidence;Informal Social Control;Injury;Intervention;Laboratories;Legal;Licensing;Link;Neurocognitive;Patient Self-Report;Performance;Personality inventories;Phase;Phenotype;Prevention;Regulation;Reporting;Research;Rewards;Risk;Risk-Taking;Speed (motion);Techniques;Testing;United States;United States National Institutes of Health;Vehicle crash;Wit;addiction;alcohol effect;alcohol response;alcohol sensitivity;distraction;drinking;driving behavior;driving under influence;high risk;impaired driving performance;improved;innovation;offender;programs;public health medicine (field);public health relevance;recidivism;response;success;theories;trafficking;trait;treatment program;willingness

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  One in every 127 licensed drivers is arrested for driving under the influence (DUI) and recidivism rates are high with over one-third of DUI offenders re-offending within three years. The proposed project examines DUI drivers from a cognitive dysfunction perspective that targets deficits in specific mechanisms of behavioral regulation. Identification of specific cognitive deficits in DUI offenders is critical for guiding new interventions that will move treatment beyond general addiction counseling. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page


application_id: 8713655
project_number: 3P01HL078825-08S1
project_title: Protection of Ischemic Myocardium
administering_ic: NHLBI
award_notice_date: 2013-08-09
opportunity_number: PAR-10-285
application_type: 3
activity_code: P01
ic: HL
serial_number: 078825
suffix: S1
program_official: WONG, RENEE P
project_start_date: 2005-04-15
project_end_date: 2015-05-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
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
project_abstract:
Lack of understanding of basic stem cell mechanisms limits current therapeutic approaches. In this renewal application we will focus on the use of c-kit* cardiac progenitor cells (CPCs) to protect the heart against post-myocardial infarction (Ml) remodeling and heart failure (HF). The overall goal is to elucidate the molecular mechanisms that regulate the properties of CPCs and to evaluate the therapeutic utility of enhancing CPC function in order to optimize cardiac repair. Four closely inter-related and inter-dependent Projects will address different facets of this theme. Project 1 (Belli) will elucidate the role of CO and NO in regulating CPC function and therapeutic efficacy. The central hypothesis is that these gases are kev determinants of CPC competence and that augmenting their levels will dramatically enhance CPC-mediated cardiac repair. Project 2 (Prabhu) will illuminate the deleterious effects of TNF on CPC competence and reparative ability. This project will test the hypothesis that differential TNF signaling via TNFR1 TNFR2 and NF-KB plavs a critical role in determining adrenergic versus cardiomyogenic fate and consequently the reparative capacity of CPCs following Ml. Project 3 (Jones) will examine the role of protein 0-GlcNAcylation in modulating the fundamental properties of CPCs and will test the hypothesis that the 0-GlcNAc alarm signal plays a critical role in regulating CPC proliferation survival differentiation and paracrine function. Project 4 (Bhatnagar) will determine how diabetes affects CPC-mediated myocardial repair and how CPC therapy can be optimized for the diabetic heart. The central hypothesis is that diabetes undermines CPC competence by inducing insulin resistance. Thus all four Projects focus cohesively on CPCs. These Projects will be supported by four Cores that will provide expertise in mouse surgery cell transplantation CPC culture and phenotyping pathology flow cytometry and cell sorting. This highly-focused PPG will be led by investigators who have collaborated productively for many years. Their long history of collaboration has resulted in closely integrated Projects that are ideally suited for a PPG. These will be the first studies to examine the role of CO and NO TNF 0-GlcNAcylation and type 2 diabetes on CPC function: consequently the results will be entirely new and will advance our understanding of CPC biology. In addition these studies may lay the groundwork for new translational investigations of CPC therapy in patients with HF. Since we have already initiated the first-in-humans clinical trial of unmodified CPCs in patients with HF we are well positioned to rapidly translate any insights derived from this Program into new clinical investigations.

project_terms:
Acute;Address;Adrenergic Agents;Affect;Aftercare;Apoptotic;Biology;Carbon Monoxide;Cardiac;Cell Culture Techniques;Cell Proliferation;Cell Separation;Cell Survival;Cell Therapy;Cell Transplantation;Cell Transplants;Cell physiology;Cells;Cellular biology;Cessation of life;Clinical Research;Clinical Trials;Collaborations;Competence;Cytoprotection;Diabetes Mellitus;Effectiveness;Engraftment;Environment;Flow Cytometry;Funding;Gases;Goals;Heart;Heart failure;Human;Hypoxia;Infarction;Inflammatory;Instruction;Insulin Resistance;Investigation;Ischemia;Knowledge;Lead;Left Ventricular Remodeling;Length;Manuscripts;Mediating;Molecular;Motivation;Mus;Muscle Cells;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Natural regeneration;Nitric Oxide;Non-Insulin-Dependent Diabetes Mellitus;Operative Surgical Procedures;Outcome;Pathology;Patients;Phenotype;Play;Positioning Attribute;Progress Reports;Property;Proteins;Proto-Oncogene Protein c-kit;Recording of previous events;Regulation;Reperfusion Injury;Research Infrastructure;Research Personnel;Resistance;Role;Signal Pathway;Signal Transduction;Stem cells;Stress;TNF gene;TNFRSF1A gene;TNFRSF1B gene;Testing;Therapeutic;Therapeutic Uses;Tissues;Translating;Translations;Transplantation;Treatment Efficacy;Work;abstracting;adrenergic;base;cardiac repair;cytokine;diabetic;experience;improved;insight;paracrine;programs;repaired;response;stem

public_health_relevance:
RELEVANCE (See instructions): In 2009 we started SCIPIO the first-in-humans study of c-kit+ cardiac progenitor cells (CPCs). The initial results are encouraging. This Program builds on SCIPIO and seeks to optimize the effectiveness of these promising CPCs therapies. If our hypotheses are confirmed the results will lead to the use of more efficacious cell therapies in patients with heart failure. Since we have developed the infrastructure to launch new clinical studies of CPCs any new insights gained in this Program will be rapidly translated.


application_id: 8713455
project_number: 1R44HL123120-01
project_title: Development of SVAD System for HF Therapy
administering_ic: NHLBI
award_notice_date: 2014-06-25
opportunity_number: PA-13-234
application_type: 1
activity_code: R44
ic: HL
serial_number: 123120
program_official: BALDWIN, TIM
project_start_date: 2014-07-01
project_end_date: 2015-06-30
study_section: Special Emphasis Panel[ZRG1 SBIB-Y (12)]
contact_pi_person_id: 8385495
contact_pi: SPENCE, PAUL A
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 610420817
duns_number: 610420817
fips: US
organization_id: 10006385
organization_name: SCR, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402022445
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-07-01
budget_end_date: 2015-06-30
project_abstract:
DESCRIPTION (provided by applicant): The objective of this proposal is to complete the engineering development and pre-clinical testing of the SCR SVAD system to provide partial cardiac assist in patients with less advanced stage heart failure (HF). HF is increasing worldwide and represents a major burden in terms of health care resources and costs. Despite advances in medical care prognosis with HF remains poor especially in advanced stages. Currently it requires a major operative intervention and cardiopulmonary bypass (CPB) which have been associated with significant adverse event rates and long recovery. The high cost of the intervention and patient follow-up has limited widespread acceptance. The SVAD system consists of a miniaturized axial flow pump (platinum alloy impeller and vane diffuser) inflow cannulation to the left atrium and outflow graft anastomosis to axillary artery. The SVAD pump (6 cm length 2 cm diameter 40 g weight) is implanted through a right lateral mini-thoracotomy. The clinical benefits of the SVAD include: eliminates major surgery (sternotomy) LV apical coring and aortic anastomosis; performed 'off pump' (no CPB); pump placement in subclavicular pocket facilitates implant (and explant) procedure(s); and superior hydrodynamic performance (5 lpm @ 100 mmHg) with low power requirements. In this phase I-II proposal we will demonstrate feasibility and complete engineering development and pre- clinical testing of the SVAD to support a FDA submission for phase one (n=10) and phase two (n=300) clinical trials. To achieve this objective we will complete the engineering development and design freeze of the SVAD system with Good Manufacturing Practices (GMP) specifications for a human implant quality system; demonstrate efficacy and biocompatibility by completing Validation and Verification (V&V) testing (fatigue) anatomical fit and surgical procedure study (human cadaver n=4) and in vivo acute (n=4) chronic 7-day (n=6) and chronic 45-day (n=8) Good Laboratory Practices (GLP) study. The pre-clinical V&V GMP and GLP study data will be used to support an IDE application for a clinical trial in HF patients. Our long-term goal is to
clinically translate the SCR SVAD to treat earlier stage HF patients using miniaturized partial support device and less invasive surgical tools and procedures to improve patient outcomes and restore quality of life.

project_terms:
Acute;Adverse event;Alloys;Anastomosis - action;Animal Model;Animals;Apical;Biomedical Engineering;Cadaver;Caliber;Cannulas;Cannulations;Cardiac;Cardiopulmonary Bypass;Cardiovascular system;Caring;Cattle;Chronic;Clinical;Clinical Engineering;Clinical Trials;Data;Development;Devices;Engineering;Fatigue;Freezing;Goals;Healthcare;Heart Atrium;Heart failure;Hospital Costs;Human;Implant;Institutes;Intervention;Lateral;Left;Left atrial structure;Legal patent;Length;Medical;Modeling;Motion;Muscle;Myocardial Ischemia;Obstruction;Operative Surgical Procedures;Outcome;Patients;Pectoralis major muscle structure;Performance;Phase;Physicians;Physiological;Platinum;Polyesters;Postoperative Period;Procedures;Pump;Quality of life;Recovery;Research Personnel;Resources;Risk;Safety;Shapes;Silicones;Staging;Sternotomy;Structure of subclavian artery;Suction;Surgical sutures;System;Target Populations;Technology;Testing;Thoracotomy;Thrombus;Time;Translating;Weight;arm;axillary artery;biomaterial compatibility;commercialization;cost;design;follow-up;good laboratory practice;implantation;improved;in vivo;industry partner;innovation;meetings;miniaturize;nitinol;outcome forecast;pre-clinical;product development;prototype;public health relevance;research clinical testing;tool;ventricular assist device;verification and validation

public_health_relevance:
SCR (Louisville KY) is developing the SVAD system in partnership with HeartWare (Miami Lakes FL). TheSVAD is a miniaturized left ventricular assist device (6 cm length 2 cm diameter 40 g weight) with atrial inflowand aortic outflow cannulation (SVAD) implanted via a mini-thoracotomy with pump placement in a rightsubclavicular pocket and provide partial support (1-5 lpm) to treat patients with less advanced heart failure.The clinical benefits of this technology are less invasive surgical procedure that will shorten recovery time andlower hospital costs while improving patient outcomes and restoring quality of life.


application_id: 8712853
project_number: 1R41AT008312-01
project_title: Harvesting specific plant metabolites from hairy root cultures using magnetized n
administering_ic: NCCIH
award_notice_date: 2014-05-21
opportunity_number: PA-13-235
application_type: 1
activity_code: R41
ic: AT
serial_number: 008312
program_official: WILLIAMSON, JOHN S
project_start_date: 2014-06-01
project_end_date: 2016-05-31
study_section: Special Emphasis Panel[ZRG1 IMST-M (13)]
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION:  Plants produce a wide variety of valuable bioactive metabolites but these are commonly present in low concentrations in the wild-type plant. This makes the separation and purification of these compounds complicated and expensive. The applicant company Naprogenix Inc has developed a technology for increasing the yields of specific bioactive metabolites in mutant plant cell cultures which promises to lessen this problem. However the value of this or any other approach using genetically-modified plant cells is limited by the necessity of the wasteful destruction of the plant cells in order to extract the required products.
The process would be more efficient if products could be harvested from cells in continuous culture. Nanoparticles are taken up by cells by endocytosis and subsequently exocytosed. They can also be engineered to adsorb specific chemicals. This suggests that specifically-engineered (functionalized and magnetized) nanoparticles could be used to repeatedly "harvest" specific metabolites from living plant cell cultures. One of the company's major projects is designed to generate novel flavonoids in goldenrod hairy root cultures. The applicants have shown that functionalized silica nanoparticles adsorb similar flavonoids and that they are taken up and removed from these plant cell cultures without compromising the viability of the cultures. The objective is now to engineer optimally-functionalized magnetized silica nanoparticles (by collaborators at the University of Kentucky) to harvest specific flavonoids from these hairy roots.
The specific aims of phase I are to show that (a) exposure to these nanoparticles translocate flavonoids from the intracellular compartment of hairy roots to the extracellular medium (b) these extracellular magnetized nanoparticles can be concentrated in a magnetic field (c) significant amounts of flavonoids can be eluted and collected from these nanoparticles following their passage through plant cells. If this is successful then in phase II the applicants will design ad test nanoparticles for harvesting other bioactive metabolites from optimized plant cell cultures. These will include very high value chemotherapeutic agents such as the taxoids and vinca alkaloids. If successful this approach should make a major impact on the use of plant cell cultures for the production and isolation of high value natural products. The nanoparticles and the harvesting technologies as applied to plant cells are patentable and have major commercial implications for the applicant company and the University.

project_terms:
Address;Area;Binding (Molecular Function);Biological Factors;Biotechnology;Cell Culture Techniques;Cell Survival;Cells;Characteristics;Chemical Engineering;Chemicals;Collaborations;Complex Mixtures;Devices;Drug Industry;Endocytosis;Engineering;Exposure to;Faculty;Fermentation;Flavonoids;Funding;Genetically Modified Plants;Harvest;High Pressure Liquid Chromatography;Individual;Industry;Kentucky;Licensing;Life;Mammalian Cell;Marketing;Measures;Medicine;Methods;Nutrient;One-Step dentin bonding system;Pharmacologic Substance;Phase;Plant Roots;Plants;Preparation;Process;Production;Protocols documentation;Quercetin;Research;Research Personnel;Schedule;Silicon Dioxide;Small Business Technology Transfer Research;Solidago;Specificity;Surface;System;Taxoids;Technology;Testing;Time;Tissues;Universities;Vinca Alkaloids;chemotherapeutic agent;commercialization;cytotoxicity;design;extracellular;improved;in vitro testing;magnetic field;microbial;mutant;nanoparticle;novel;prototype;public health relevance;radioligand;response;tissue culture

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Many valuable plant compounds can be produced in tissue culture but their isolation requires destruction of the plant tissue before chemically separating the required compounds from others. This project aims to develop magnetized nanoparticle devices that can be used to remove specific types of compounds from living plant tissue. This is predicted to greatly increase the efficiency of producing medicines or nutrients in plant tissue culture. These devices will also increase the commercial value of the proprietary biotechnology used by the applicant company which is designed to optimize plant cell cultures for their ability to produce specific natural products.


application_id: 8712716
project_number: 1P30GM110788-01
project_title: Center for the Biologic Basis of Oral/Systemic Diseases (Phase III)
administering_ic: NIGMS
award_notice_date: 2014-08-15
opportunity_number: PAR-13-238
application_type: 1
activity_code: P30
ic: GM
serial_number: 110788
program_official: DOUTHARD, REGINE
project_start_date: 2014-08-15
project_end_date: 2019-07-31
study_section: Special Emphasis Panel[ZGM1 TWD-C (C3)]
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Applied Research;Area;Basic Science;Centers of Research Excellence;Chronic;Clinical;Clinical Research;Clinical Sciences;Collaborations;Communities;Core Facility;County;Dental;Dentistry;Diagnostic;Disease;Educational aspects;Environment;Event;Faculty;Fostering;Funding;Funding Agency;Future Generations;Genetic;Genomics;Goals;Grant;Health;Healthcare;Housing;Immune response;Individual;Infection;Inflammatory;Institutes;Interdisciplinary Study;Investigation;Kentucky;Laboratories;Link;Mentors;Metric;Modeling;Molecular;Mouth Diseases;Oral;Oral cavity;Oral health;Periodontal Diseases;Phase;Population;Positioning Attribute;Postdoctoral Fellow;Productivity;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Research Support;Research Training;Resources;Role;Rural Population;Science;Services;Source;Structure;Systemic disease;Tissues;Translational Research;United States National Institutes of Health;Universities;base;burden of illness;career development;college;craniofacial complex;design;graduate student;health disparity;improved;population health;programs;public health relevance


application_id: 8712075
project_number: 1R43HL120370-01A1
project_title: Development of TransApical to Aorta Double Lumen Cannula for a Neonate LVAD
administering_ic: NHLBI
award_notice_date: 2014-03-29
opportunity_number: PA-13-234
application_type: 1
activity_code: R43
ic: HL
serial_number: 120370
suffix: A1
program_official: BALDWIN, TIM
project_start_date: 2014-04-01
project_end_date: 2015-09-30
study_section: Special Emphasis Panel[ZRG1 CVRS-C (10)]
contact_pi_person_id: 11058700
contact_pi: TOPAZ, STEPHEN R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 832402486
primary_uei: RK1ZDCXE3LJ7
duns_number: 832402486
uei: RK1ZDCXE3LJ7
fips: US
organization_id: 10024870
organization_name: W-Z BIOTECH, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Left ventricular assist device (LVAD) support allows the neonate with congenital heart disease or cardiomyopathy to grow to a larger body weight that is more feasible for complex surgical correction or heart transplant. A paracorporeal LVAD the Berlin heart ExCor is FDA-approved for pediatric application. Although this device is outside the body the outflow graft may still create coronary artery/heart compression. Our ultimate goal is to develop a less invasive and dependable LVAD system for the neonate. The enabling technology will be a small (16-18 Fr) double lumen cannula (DLC) which is inserted from the apex though the LV and aortic valve into the aorta with the drainage lumen opening in the LV and the infusion lumen in the aorta. Coupled with a blood pump blood is withdrawn from the LV and infused into the aorta to unload the LV though a single cannulation. This DLC-based LVAD: 1) has only one apex cannulation avoiding heart/coronary artery compression 2) has a much smaller apex cannulation eliminating cardiopulmonary bypass 3) requires a less traumatic left thoracotomy replacing traumatic medium sternotomy and 4) has a flexible configuration allowing a bigger paracorporeal pump for stronger performance and the addition of a gas exchanger for cyanotic heart diseases. Our DLC-based LVAD is much simpler less invasive more powerful and very suitable for neonate application. Our objective in this Phase I SBIR is to develop and fabricate a working prototype of a DLC assembly for a neonate LVAD and to test the prototype's performance in neonate sheep. Our hypothesis is that this new DLC coupled with a commercial blood pump will provide total LV support and save the life of sick neonate. It will bridge the patient to recovery transplant or further advanced heart surgery. Specific Aim 1:
To develop a new TransApical to Aorta (TAA) DLC assembly. A. To design and fabricate a new working prototype of a TAA DLC for a neonate LVAD. The DLC main body outer wall will be constructed with wire reinforced polyurethane. The inner infusion lumen will use an eccentric membrane sleeve. The DLC membrane sleeve infusion lumen extends out of DLC main body to the extension infusion cannula (EIC). The EIC will be reinforced by stainless steel wires across the aortic valve into the ascending aorta. A sewing plate will be designed for sewing the DLC onto the apex preventing TAA DLC dislodgement. B. Bench testing of the TAA DLC assembly. Bench testing will be done in an ex vivo circuit to measure DLC flow performance. Specific Aim 2: To test our prototype TAA DLC for ease of deployment and 6 hr. in vivo performance. The TAA DLC prototype will be coupled with a CentriMag pump to form a TAA LVAD system. The in vivo new born lamb experiments (n=5) will test the DLC for TAA deployment and in vivo performance. The 16 Fr DLC- based TAA LVAD will pump the blood at a flow rate up to 1 L/min against 200 mmHg ?P. Animal testing results will be used to optimize the TAA DLC design for best performance/reliability for the Phase II grant. Upon this SBIR grant completion the commercialized TAA DLC will provide a less invasive neonate LVAD.

project_terms:
Acute;Adult;American;Animal Testing;Anticoagulation;Aorta;Applications Grants;Area;Berlin;Biomedical Engineering;Blood;Body Weight;Businesses;Cannulas;Cannulations;Carbon Dioxide;Cardiac;Cardiac Surgery procedures;Cardiogenic Shock;Cardiomyopathies;Cardiopulmonary Bypass;Chest;Childhood;Complex;Coronary artery;Coupled;Deposition;Development;Devices;Diaphragm (Anatomy);Drainage procedure;Excision;FDA approved;Fibrin;Gases;Goals;Grant;Heart;Heart Diseases;Heart Transplantation;Heart failure;Hemoglobin;Infusion procedures;Kentucky;Laboratory Animal Production and Facilities;Left;Life;Liquid substance;Lung;Measurement;Measures;Membrane;Morbidity - disease rate;Mortality Vital Statistics;Neonatal;Operative Surgical Procedures;Patients;Performance;Phase;Plasma;Platelet Activation;Play;Polyurethanes;Pump;Recovery;Resistance;Sheep;Small Business Innovation Research Grant;Stainless Steel;Sternotomy;Surgeon;System;Technology;Test Result;Testing;Thoracotomy;Thrombelastography;Transplantation;Universities;Ventricular;Work;aortic valve;artificial lung;ascending aorta;base;blood pump;congenital heart disorder;design;experience;flexibility;improved;in vivo;multidisciplinary;neonate;novel;prevent;prototype;public health relevance;research and development;research study;respiratory;total artificial heart;ventricular assist device

public_health_relevance:
PUBLIC HEALTH RELEVANCE: We are proposing to develop a simple less invasive double lumen cannula-based left ventricular assist device (LVAD) for the neonate. The enabling technology is the novel double lumen cannula which is coupled with a blood pump to form a LVAD system to provide total left ventricular support thereby saving the life of the sick neonate.
This neonate LVAD system will bridge the patient to recovery transplant or further advanced heart surgery.


application_id: 8711883
project_number: 3P42ES007380-16S1
project_title: Nutrition and Superfund Chemical Toxicity
administering_ic: NIEHS
award_notice_date: 2013-08-07
opportunity_number: RFA-ES-06-003
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S1
program_official: HENRY, HEATHER F
project_start_date: 1997-04-07
project_end_date: 2014-03-31
study_section: ZES1-JAB-C(S7)
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_abstract:
The University of Kentucky is unique among land grant universities in that all colleges including Medicine and Agriculture are located on the same campus. This constellation of programs has enabled the UK-SBRP to develop uniquely productive collaborations across diverse disciplines. Such an environment will allow to study the overall theme of the SBRP research which focuses on the toxicology of Superfund chemicals and how health effects of exposure can be modulated by both intrinsic and extrinsic factors namely genetics and nutrition respectively. Given the abundance of Superfund chemicals and widespread distribution in the ecosystem it is unlikely that remediation alone will be sufficient to address their health risks. Nutritional intervention thus becomes a sensible way to address health problems associated with environmental pollutants. In the competing renewal the investigators recognize this dual need for sensing/remediation and biomedical intervention through nutrition by proposing five integrated projects. The investigators will concentrate on chlorinated organics (e.g. polychlorinated biphenyls) prevalent in most Superfund sites including those found in Kentucky. Preliminary findings by this group suggest that nutrition and dietary habits can markedly influence mechanisms of toxicity of the above-mentioned Superfund chemicals. Thus a major objective of our SBRP is to explore the paradigm that nutrition can modify Superfund chemical toxicity. All biomedical projects will focus on chronic diseases associated with vascular dysfunction such as cardiovascular disease cancer metastasis and obesity-related abdominal aortic aneurysms and will utilize a similar dietary fat regimen to study nutrient/toxicant interactions. There will be significant cross-talk with non-biomedical projects which will explore novel techniques for both remediation (detoxification) and biosensors associated with detection of PCBs and other chlorinated organics. Results from interdisciplinary research will be utilized for information/education technology transfer training policy and translational purposes as part of the objectives of the Research Translation Community Outreach and Training Cores. Nutrition may be the most sensible means to develop primary prevention strategies of diseases associated with many environmental toxic insults. Thus research proposed by the investigators may lead to novel dietary recommendations at the national level for populations at risk thus improving the health of people residing near Superfund sites.

project_terms:
Abdominal Aortic Aneurysm;Address;Agriculture;Biosensor;Blood Vessels;Cardiovascular Diseases;Chronic Disease;Collaborations;Community Outreach;Detection;Diet;Diet Habits;Dietary Fats;Dietary Intervention;Discipline;Disease;Drug Metabolic Detoxication;Ecosystem;Educational aspects;Environment;Environmental Pollutants;Functional disorder;Genetic;Grant;Health;Interdisciplinary Study;Intervention;Kentucky;Lead;Medicine;Neoplasm Metastasis;Nutrient;Obesity;Policies;Polychlorinated Biphenyls;Populations at Risk;Prevention strategy;Primary Prevention;Recommendation;Regimen;Research;Research Personnel;Risk;Techniques;Technology Transfer;Toxic effect;Toxicology;Training;Translational Research;Universities;college;improved;novel;nutrition;programs;remediation;superfund chemical;superfund site;toxicant interaction


application_id: 8711514
project_number: 5P20GM103492-07
project_title: Project 5 - Metabolomic Analysis of Atherothrombosis
administering_ic: NIGMS
award_notice_date: 2014-07-14
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5010
contact_pi_person_id: 9847182
contact_pi: DEFILIPPIS, ANDREW
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-07-01
budget_end_date: 2015-06-30
project_terms:
Biological Markers;Cardiovascular Diseases;Cause of Death;Clinical Management;Coronary;Coronary Thrombosis;Development;Diabetes Mellitus;Diagnosis;Diagnostic;Diagnostic tests;Effectiveness;Event;Goals;Individual;Intervention;Lead;Lesion;Measurement;Measures;Mortality Vital Statistics;Myocardial;Myocardial Ischemia;Necrosis;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Patients;Production;Research;Safety;Thrombus;Treatment Protocols;acute coronary syndrome;atherothrombosis;cardiovascular disorder risk;cohort;diagnostic accuracy;improved;metabolomics;oxidized lipid;young adult


application_id: 8711513
project_number: 5P20GM103492-07
project_title: Project 4 - Cardiac Stem Cell Dysfunction in Diabetes
administering_ic: NIGMS
award_notice_date: 2014-07-14
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5009
contact_pi_person_id: 11675369
contact_pi: HONG, KYUNG UK
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-07-01
budget_end_date: 2015-06-30
project_terms:
Adult;Affect;Antigens;Apoptotic;Attenuated;Blood Vessels;Cardiac;Cardiac Myocytes;Cardiomyopathies;Cardiovascular Diseases;Cell Count;Cell physiology;Cells;Characteristics;Competence;Complex;Congenital Heart Defects;Coronary Arteriosclerosis;Data;Defect;Development;Diabetes Mellitus;Diabetic mouse;Differentiation and Growth;Endocrine;Epidemiologic Studies;Etiology;Fatty Acids;Functional disorder;Gene Expression;Genes;Glucose;Growth;Health;Heart;Heart failure;Hyperglycemia;Hypertension;In Situ;In Vitro;Individual;Lead;Left;Left Ventricular Dysfunction;Measurement;Measures;Mediating;Mus;Myocardial;Myocardial dysfunction;Myocardium;Natural regeneration;Non-Insulin-Dependent Diabetes Mellitus;Nutrient;Obesity;Oxidative Stress;Pathogenesis;Patients;Play;Proto-Oncogene Protein c-kit;Research;Risk;Risk Factors;Role;Stem cells;Structure;System;Techniques;Testing;Time;Transgenic Mice;Vascular Diseases;Ventricular;atherogenesis;attenuation;cardiac repair;cardiovascular disorder risk;cell growth;db/db mouse;diabetic;diabetic cardiomyopathy;genetic element;heart preservation;hemodynamics;in vivo;innovation;insight;insulin sensitivity;interest;mouse model;non-diabetic;novel;novel therapeutic intervention;pandemic disease;prevent;progenitor;recombinase;repaired;senescence;stem cell biology;stem cell population


application_id: 8711511
project_number: 5P20GM103492-07
project_title: Project 2 - Effects of Particulate Matter on Insulin Resistance and Endothelial
administering_ic: NIGMS
award_notice_date: 2014-07-14
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5007
contact_pi_person_id: 11375489
contact_pi: HABERZETTL, PETRA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-07-01
budget_end_date: 2015-06-30
project_terms:
Accounting;Aerosols;Affect;Air;Air Pollution;Arrhythmia;Biological;Biological Markers;Blood Vessels;Body Composition;Breathing;Cardiovascular Diseases;Centers of Research Excellence;Cessation of life;Chemicals;Chronic;Data;Deposition;Developing Countries;Development;Diabetes Mellitus;Diet;Dose;Environmental Pollutants;Environmental Risk Factor;Epidemic;Epidemiologic Studies;Epidemiology;Exposure to;Fatty acid glycerol esters;Funding;Future;Health;Human;IL18 gene;Incidence;Inflammation;Inflammatory;Injury;Insulin;Insulin Resistance;Interruption;Intervention;Knockout Mice;Laboratories;Lead;Link;Longevity;Maintenance;Measures;Mediating;Metabolic Diseases;Metabolic syndrome;Modeling;Molecular;Mortality Vital Statistics;Mus;Myocardial Infarction;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Organ;Particulate Matter;Pathway interactions;Patients;Policies;Prevalence;Prevention;Process;Property;Prospective Studies;Regulation;Research;Risk;Risk Factors;Role;Stem cells;System;Testing;Tissues;Vascular Diseases;Vascular Endothelium;ambient particle;base;cardiovascular disorder risk;chemical property;diabetes risk;dosimetry;endothelial dysfunction;feeding;high efficiency particulate air filter;improved;indexing;insight;insulin sensitivity;mouse model;novel;particle;physical property;prevent;repaired;research study;response;stroke


application_id: 8711506
project_number: 5P20GM103492-07
project_title: Core B - Flow Cytometry Core
administering_ic: NIGMS
award_notice_date: 2014-07-14
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5002
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-07-01
budget_end_date: 2015-06-30
project_terms:
Antigens;Area;Arts;Cardiovascular system;Cell Separation;Cells;Centers of Research Excellence;Clinical Trials;Commit;Complex;Coupled;Data Analyses;Development;Diabetes Mellitus;Equipment;Evaluation;Event;Flow Cytometry;Foundations;Future;Goals;Health Hazards;Human Resources;Metabolism;Nature;Obesity;Population;Property;Research;Research Infrastructure;Research Personnel;Services;Signal Transduction;Sorting - Cell Movement;Tissues;Training;Universities;Work;analytical tool;experience;improved;instrument;interest;meetings;member;operation;theories


application_id: 8711503
project_number: 5P20GM103492-07
project_title: Center for Excellence in Diabetes and Obesity Research
administering_ic: NIGMS
award_notice_date: 2014-07-14
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
program_official: CANTO, MARIA TERESA
project_start_date: 2008-09-26
project_end_date: 2018-06-30
study_section: ZGM1-TWD-Y(C2)
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Air Pollution;Biological Markers;Biomedical Research;Cardiology;Cardiovascular Diseases;Cardiovascular system;Carnosine;Centers of Research Excellence;Chemistry;Clinical;Clinical Trials;Core Facility;Data;Development;Diabetes Mellitus;Diet;Disease;Epidemiology;Event;Faculty;Flow Cytometry;Fostering;Foundations;Functional disorder;Funding;Goals;Health;Image;Individual;Insulin Resistance;Interdisciplinary Study;Investigation;Knowledge;Mentors;Modality;Molecular;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Particulate;Pathology;Patients;Phase;Phenotype;Physiology;Postdoctoral Fellow;Prevention;Principal Investigator;Reagent;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Role;Stem cells;Universities;Work;animal model development;career;design;graduate student;novel;prevent;programs;public health relevance


application_id: 8711462
project_number: 5U01ES022564-03
project_title: Countermeasures for chlorine-induced airway fibrosis
administering_ic: NIEHS
award_notice_date: 2014-07-28
opportunity_number: PAR-11-155
application_type: 5
activity_code: U01
ic: ES
serial_number: 022564
program_official: NADADUR, SRIKANTH
project_start_date: 2012-09-25
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1-MDCN-J(50)R]
contact_pi_person_id: 2736750
contact_pi: HOYLE, GARY W.
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Chlorine gas is a highly toxic respiratory irritant that is considered a chemical threat agent because of the possibility that it could be released in industrial accidents or terrorist attacks. Acute effects of chlorine inhalation include dyspnea hypoxemia pneumonitis and pulmonary edema. Longer term consequences of chlorine inhalation include pulmonary function impairment and airway structural changes that have been observed in some exposed individuals. We have developed a mouse chlorine inhalation model in which animals develop pulmonary edema inflammation airway obstruction and airway hyperreactivity within one day after exposure. In new studies related to the current application we have characterized injury and repair of the lung at longer times after chlorine inhalation. We have observed that airways with a partial loss of epithelium are repaired quickly by the proliferation and differentiation of epithelial cells that survive chlorine exposure. In contrast portions of airways with few surviving epithelial cells are repaired inefficiently and fibroproliferative lesions develop at such sites within a week after chlorine exposure. This development of airway fibrosis is associated with impaired lung function including increased respiratory system resistance and airway hyperreactivity to inhaled methacholine. In the current application we propose to develop countermeasures that can be administered following a chemical attack or accidental release to prevent chlorine-induced airway disease. The hypothesis to be tested in the proposed studies is that inefficient repair of airway epithelium following chlorine lung injury leads to airway fibrosis and impaired lung function; agents that mimic anti-fibrotic effects of airway epithelium or stimulate airway repair will ameliorate chlorin- induced airway disease. Specific Aim 1 will characterize airway epithelial repair airway fibrosisand lung function impairment following chlorine exposure in mice. Specific Aims 2-5 will evaluate the efficacy of the following potential countermeasures for the treatment of chlorine-induced airway disease: the prostanoid receptor agonists butaprost and iloprost; the long-lasting ss-agonist formoterol and the type 4 phosphodiesterase inhibitor rolipram; stimulation of plasminogen activation with urokinase-type plasminogen activator or the plasminogen activator inhibitor-1 inhibitor tiplaxtinin; and manipulation of Wnt/ss-catenin signaling with lithium chlorie or pyrvinium. Specific Aim 6 will involve development of a ferret model of chlorine-induced airway disease and testing of countermeasures in this non-rodent species. The proposed studies are expected to identify a countermeasure for prevention of chronic airway disease that develops as a result of an acute high level exposure to chlorine.

project_terms:
Acute;Adrenergic Agonists;Affect;Agonist;Airway Obstruction;Animals;Breathing;Cell Proliferation;Chemical Warfare;Chemicals;Chlorine;Chronic;Cyclic AMP;Development;Disease;Dyspnea;Epithelial;Epithelial Cells;Epithelium;Exposure to;Ferrets;Fibrosis;Goals;Human;Hypoxemia;Iloprost;Impairment;Individual;Industrial Accidents;Inflammation;Irritants;Kinetics;Lesion;Lithium;Lithium Chloride;Lung;Measurement;Modeling;Mus;Non-Rodent Model;Phosphodiesterase Inhibitors;Plasminogen;Plasminogen Activator;Plasminogen Activator Inhibitor 1;Pneumonia;Poisons;Prevention;Production;Prostaglandins;Pulmonary Edema;Recording of previous events;Research;Resistance;Resolution;Respiratory System;Respiratory physiology;Rodent;Rolipram;Signal Pathway;Signal Transduction;Site;Structure;Structure of respiratory epithelium;Symptoms;Testing;Time;Toxic effect;Unconscious State;United States;Urokinase;airway epithelium;airway hyperresponsiveness;animal rule;butaprost;chemical threat;chlorin;chlorine gas;efficacy testing;formoterol;inhibitor/antagonist;injury and repair;lung development;lung injury;methacholine;novel;phosphoric diester hydrolase;prevent;prostaglandin EP2 receptor;public health relevance;pulmonary function;receptor;repaired;research study;respiratory;restoration

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The goal of the proposed experiments is to develop novel ways to treat chronic airway disease caused by acute high level exposure to chlorine gas. This type of research is important because of concerns that U.S. civilians could be adversely affected by the accidental or intentional release of highly toxic chemicals such as chlorine.


application_id: 8711418
project_number: 5U01DA033276-03
project_title: A Phase 3 Double-Blind Efficacy Safety and Dose-Response Study of Lofexidine (S
administering_ic: NIDA
award_notice_date: 2014-07-16
opportunity_number: PAR-11-109
application_type: 5
activity_code: U01
ic: DA
serial_number: 033276
program_official: ANDERSON, ANN
project_start_date: 2012-09-30
project_end_date: 2016-07-31
study_section: ZDA1-JXR-D(05)S
contact_pi_person_id: 2408657
contact_pi: GORODETZKY, CHARLES W.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 087875626
primary_uei: NKGSYBV5UGN1
duns_number: 087875626
uei: NKGSYBV5UGN1
fips: US
organization_id: 10003722
organization_name: US WORLDMEDS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40241
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The proposed research is aimed at characterizing the safety and efficacy profiles to address FDA-defined gaps in the clinical development program for lofexidine hydrochloride an alpha-2 adrenergic agonist under development for the treatment of acute withdrawal from short-acting opioids. The program includes two linked studies to be conducted consecutively at the same sites: Study 1 will generate pivotal efficacy/safety data for two doses of lofexidine hydrochloride in 600 subjects about to undergo total and abrupt withdrawal from short- acting opioids who will be randomized under double-blind conditions to either placebo (N=150) or lofexidine (2.4 mg or 3.2 mg total daily dose; N=225/group) for 7 days of inpatient treatment. Subsequently all subjects will be permitted to continue under open-label conditions for up to an additional 7 days of inpatient/outpatient variable-dose treatment depending on the wishes of the Site Investigator and subject. Safety will be assessed by evaluation of adverse event (AE) clinical laboratory electrocardiogram (with special attention toQTc) vital signs and physical exam data. Efficacy will be evaluated daily by subject- and observer-completed scales including the Short Opiate Withdrawal Scale of Gossop (SOWS-G) (the primary outcome measure is SOWS-G score area under the curve for Days 1-7) the Objective Opiate Withdrawal Scale (OOWS-Handelsman) the Visual Analog Scale for Efficacy (VAS-E) and the Modified Clinical Global Impressions scales for efficacy and side effects. Efficacy will also be evaluated by study retention completion rates concomitant medication use incidence of withdrawal-related AEs and subject treatment status 30 days post discharge. Study 2 will follow a similar 14-day dosing format but will be entirely open-label; and 200 to 400 subjects (different from those in Study 1) will receive lofexidine at a variable dose not to exceeda total of 3.2 mg per day or a single dose of 0.8 mg in an inpatient outpatient or a combination of settings as per the normal standard of care at the enrolling site. Study 2 is a translational research design aimed at gathering "real-world" effectiveness and safety data to supplement the existing lofexidine safety database and enable appropriate product labeling for end-users. Safety will be evaluated for all treated subjects and for two cohorts: those with urines negative and those with urines positive for drugs of abuse so that all possible causes of reported AEs may be considered for analysis. Effectiveness will be evaluated by the Clinical Opiate Withdrawal Scale (COWS) rate of detoxification completion and subject treatment status 30 days post discharge. An open-label variable-dose real-world design as planned in Study 2 is common in Phase 3 drug development and together with Study 1 which will provide pivotal efficacy data needed to support the proposed product indication the program has been designed to address FDA registration requirements for lofexidine. On approval of an NDA lofexidine will be the first approved non-narcotic non-addictive drug indicated for treatment of opioid withdrawal in the US providing an important alternative therapy for this indication.

project_terms:
Abstinence;Acute;Address;Adrenergic Agonists;Adverse effects;Adverse event;Alternative Therapies;American;Applications Grants;Area Under Curve;Attention;Buprenorphine;Clinical;Data;Databases;Development;Dose;Double-Blind Method;Drug Metabolic Detoxication;Effectiveness;Electrocardiogram;Enrollment;Evaluation;FDA approved;Hydrochloride Salt;Incidence;Inpatients;Laboratories;Life;Link;Literature;Marketing;Medical;Methadone;Narcotics;Opiates;Opioid;Outcome Measure;Outpatients;Pharmaceutical Preparations;Phase;Placebo Control;Placebos;Product Labeling;Program Development;Publishing;Randomized;Reporting;Research;Research Design;Research Personnel;Safety;Severe Adverse Event;Signs and Symptoms;Site;Symptoms;Translational Research;United Kingdom;United States Food and Drug Administration;Urine;Visual;Withdrawal;Work;analog;base;cohort;design;drug development;drug of abuse;experience;impression;lofexidine;meetings;open label;opioid withdrawal;phase 3 study;primary outcome;programs;public health relevance;response;standard of care;therapy development;treatment duration;trend

public_health_relevance:
PUBLIC HEALTH RELEVANCE: With a growing trend of millions of Americans becoming dependent on prescription and other short-acting opioid narcotics there is an unmet medical need for new detoxification treatments. The only drugs approved by the FDA for this indication (methadone and buprenorphine) are opioid replacement or substitution therapies which themselves have abuse potential. The proposed research program on lofexidine hydrochloride will: i) establish the dose range by examining the safety and efficacy of two different doses of lofexidine; ii) confirm that lofexidine may be used until the acute phase of opioid withdrawal is complete (i.e. up to 14 days); and iii) increase the safety database by employing a "real-world" strategy to study additional subjects and increase the likelihood of identifying potential safety issues that may be present in only a small percentage of users. NIDA's support of this development work on lofexidine is necessary to enable FDA approval of the first non-narcotic non-addictive treatment for opioid withdrawal.


application_id: 8711292
project_number: 5R01CA091901-12
project_title: Novel aureolic acid type antitumor agents
administering_ic: NCI
award_notice_date: 2014-06-13
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 091901
program_official: FU, YALI
project_start_date: 2001-06-01
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1-BCMB-B(02)M]
contact_pi_person_id: 2257319
contact_pi: ROHR, JURGEN T
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
ABCG2 gene;Address;Adverse effects;Affect;Anabolism;Anti-HIV Agents;Antineoplastic Agents;Arthritis;Biochemical;Biological Factors;Cancer Cell Growth;Child;Chromomycins;Cleaved cell;DNA;Developmental Therapeutics Program;Disease;Drug resistance;EWS-FLI1 fusion protein;Engineering;Enzymatic Biochemistry;Enzymes;Ewings sarcoma;Funding;Generations;Goals;Hypercalcemia;Investigation;Lead;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of lung;Methods;Methyltransferase;Modification;Oxygenases;Pathway interactions;Pattern;Pharmaceutical Preparations;Play;Plicamycin;Positioning Attribute;Process;Production;Proteins;Proto-Oncogenes;Reaction;Refractory;Research;Research Project Grants;Role;SRC gene;Side;Signal Transduction Pathway;Specificity;Stem cells;Structure-Activity Relationship;Techniques;Therapeutic Index;Toxic effect;Trisaccharides;Tumorigenicity;Work;analog;anticancer activity;antitumor agent;base;c-myc Genes;chemotherapy;chromomycin;cigarette smoke-induced;combinatorial;crosslink;design;digitoxose;drug modification;efflux pump;glycosylation;glycosyltransferase;improved;interest;malignant phenotype;mycarose;nervous system disorder;novel;protein structure;public health relevance;sugar;tool;transcription factor;tumor


application_id: 8710869
project_number: 2R01HL073085-10A1
project_title: Angiotensin - A link between obesity and hypertension
administering_ic: NHLBI
award_notice_date: 2014-04-30
opportunity_number: PA-11-260
application_type: 2
activity_code: R01
ic: HL
serial_number: 073085
suffix: A1
program_official: OH, YOUNGSUK
project_start_date: 2003-06-03
project_end_date: 2018-04-30
study_section: Special Emphasis Panel[ZRG1 VH-F (02)]
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Adipocytes;Adipose tissue;Angiotensin II;Angiotensinogen;Angiotensins;Blood Pressure;Body mass index;Castration;Cleaved cell;Data;Development;Epidemic;Equilibrium;Estrogen Therapy;Estrogens;Excision;Exhibits;Female;Gender;Gonadal Steroid Hormones;Hypertension;Kentucky;Knock-out;Left;Link;Mediator of activation protein;Menopause;Messenger RNA;Modeling;Mus;NHANES;Obese Mice;Obesity;Ovarian;Peptides;Peptidyl-Dipeptidase A;Pharmacotherapy;Phenotype;Plasma;Prevalence;Production;Regulation;Renin-Angiotensin System;Resistance;Source;Testing;Translating;Vasodilator Agents;Women's Rights;angiotensin I (1-7);male;normotensive;novel;novel therapeutics;prevent;public health relevance;receptor


application_id: 8710359
project_number: 5R24OD010435-14
project_title: Research Resources for Model Amphibians
administering_ic: OD
award_notice_date: 2014-06-21
opportunity_number: PAR-10-289
application_type: 5
activity_code: R24
ic: OD
serial_number: 010435
program_official: CONTRERAS, MIGUEL A
project_start_date: 2001-10-01
project_end_date: 2016-06-30
study_section: ZRR1-CM-8(01)
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Salamanders are important vertebrate model organisms in biomedical research. The Salamander Genome Project (SGP) is developing applying and making available genomic and bioinformatics resources for salamanders and in particular the Mexican axoloti (Ambystoma mexicanum). This renewal application proposes two objectives to further enhance axoloti genome resources. First a 3x Bacterial Artificial Chromosome (BAC) library will be created and screened to identify clones that contain axoloti genes of interest. This list of clones will be made available via the SGP website (Sal-Site) and 25 BACs will be prioritized by the community for isolation and sequencing. A second objective will innovate an approach to sequence the large axoloti genome. Whole axoloti chromosomes that correspond to the third largest chromosome (Chr3) in the karyotype will be isolated by laser capture microscopy. DNA fragment libraries will be generated from the captured chromosomes and these will be sequenced to yield a Chr3 draft assembly whose contiguity and conceptual context will be increased by integrating paired-end sequences from fosmids protein-coding sequences deriving from expressed sequence tags and markers defining linkage group 3 of the Ambystoma meiotic map. Accomplishment of these objectives will yield resources to enable functional studies of genes and epigenetic mechanisms. Also the project will innovate a 'one-chromosome-at- a time' approach to sequence the large axoloti genome. As a final objective of the application a historically significant collection of axolotis in the Ambystoma Genetic Stock Center (AGSC) will be maintained and distributed to NIH-funded researchers. Since 1969 the AGSC axoloti collection has been supported by funds received from the National Science Foundation. An increasing number of NIH researchers are requesting axoloti living stocks for regeneration research and at the same time there is need to develop a stable long term funding model to maintain this irreplaceable resource. A dual NIH-NSF funding model is proposed where costs associated with the maintenance and distribution of axoloti stocks will be split equally between the NSF and NIH.

project_terms:
Ambystoma;Ambystoma mexicanum;Amphibia;Animal Model;Bacterial Artificial Chromosomes;Bioinformatics;Biological;Biomedical Research;Chromosome Mapping;Chromosomes;Chromosomes Human Pair 3;Code;Collection;Communities;Community Surveys;Complex;Custom;DNA;DNA Sequence;Databases;Development;Embryonic Development;Ensure;Epigenetic Process;Expressed Sequence Tags;Foundations;Functional RNA;Funding;Funding Mechanisms;Future;Gene Chips;Genes;Genetic;Genetic Polymorphism;Genome;Genome Mappings;Genomics;Grant;Human;Karyotype;Lasers;Libraries;Life;Location;Maintenance;Maps;Meiosis;Methods;Mexican;Microscopy;Modeling;Natural regeneration;Phenotype;Process;Proteins;Quantitative Trait Loci;Research;Research Personnel;Resources;Salamander;Science;Shotgun Sequencing;Site;Technology;Time;Transcript;Translating;United States National Institutes of Health;Update;comparative;cost;gene function;genetic linkage;genome sequencing;innovation;interest;laser capture microdissection;mutant;organ regeneration;sex;tissue repair;web site

public_health_relevance:
(provided by applicant): Fundamental genome and living stock resources are needed for salamanders so that biomedical researchers can translate biological information to humans. In particular salamanders are primary vertebrate models for organ regeneration tissue repair and post-embryonic development.


application_id: 8710000
project_number: 5R01AR060701-05
project_title: The role of satellite cells in adult skeletal muscle growth and maintenance
administering_ic: NIAMS
award_notice_date: 2014-08-15
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AR
serial_number: 060701
program_official: BOYCE, AMANDA T
project_start_date: 2010-09-17
project_end_date: 2015-07-26
study_section: Special Emphasis Panel[ZRG1-MOSS-R(02)M]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: MCCARTHY, JOHN JOSEPH
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The loss of skeletal muscle mass is of clinical importance because it is associated with increased morbidity and mortality as well as a marked deterioration in the quality of life. A broad patient population is affected by significant losses in muscle mass including those afflicted by various systemic diseases (cancer sepsis HIV- AIDS) chronic physical inactivity as a result of long term bed rest rheumatoid arthritis and limb immobilization and sarcopenia the age associated loss in muscle mass and strength. Satellite cells are currently an attractive therapeutic target given their stem cell characteristics and essential role in post-natal muscle growth and regeneration. What remains controversial is the necessity of satellite cells in other aspects of muscle plasticity such as hypertrophy re-growth following atrophy and muscle maintenance with aging. In an effort to resolve this fundamental issue a novel mouse line was created which enables the specific ablation of satellite cells in mature skeletal muscle. The Pax7-DTA mouse will be used to investigate the physiological function of satellite cells in skeletal muscle hypertrophy (Aim 1) and re-growth following muscle atrophy (Aim 2). The results from the proposed experiments are expected to provide fundamental knowledge on the function of satellite cells in adult skeletal muscle plasticity which will help define the therapeutic value of satellite cells in treating the loss of muscle mass in various clinical conditions.

project_terms:
A Mouse;Ablation;Accounting;Acquired Immunodeficiency Syndrome;Adult;Affect;Age;Aging;Apoptotic;Area;Atrophic;Bed rest;Biology;Cell Separation;Cessation of life;Characteristics;Chronic;Chronic Disease;Clinical;Collagen;Consensus;Deterioration;Diphtheria Toxin;Disease;Elderly;Extracellular Matrix;Fiber;Fluorescence;Gene Expression;Goals;Grant;Growth;HIV;Hindlimb Suspension;Homeostasis;Hypertrophy;Immobilization;Immunohistochemistry;Knowledge;Label;Lead;Limb structure;Maintenance;Malignant Neoplasms;Measures;Mechanics;Mediating;Modeling;Molecular Profiling;Morbidity - disease rate;Morphology;Mortality Vital Statistics;Mus;Muscle;Muscle function;Muscle satellite cell;Muscular Atrophy;Natural regeneration;Outcome Measure;Persons;Physiological;Population;Predisposition;Property;Quality of life;Recovery;Research;Resources;Rest;Rheumatoid Arthritis;Risk;Role;Sepsis;Signal Transduction;Skeletal muscle structure;Soleus muscle structure;Staging;Stem cells;Symptoms;Systemic disease;Technical Expertise;Testing;Therapeutic;Weight;base;in vivo;insight;member;muscle form;muscle hypertrophy;muscle strength;novel;patient population;prevent;public health relevance;research study;response;restoration;sarcopenia;satellite cell;skeletal muscle growth;skeletal muscle plasticity;therapeutic target;therapy design;tool;wasting

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Loss of muscle a common symptom associated with many chronic diseases physical inactivity or aging negatively impacts a person's quality of life increases the susceptibility to other complications of disease and can even lead to death. Treatments designed to restore or prevent muscle loss have in part focused on using muscle stem cells referred to as satellite cells. The goal of the proposed research is to determine if satellite cells are necessary for adult muscle growth and thus are an appropriate target for therapy for skeletal muscle loss.       RelevanceLoss of muscle a common symptom associated with many chronic diseases physical inactivity or agingnegatively impacts a person's quality of life increases the susceptibility to other complications of disease andcan even lead to death. Treatments designed to restore or prevent muscle loss have in part focused on usingmuscle stem cells referred to as satellite cells. The goal of the proposed research is to determine if satellitecells are necessary for adult muscle growth and thus are an approprioate target for therapy for skeletal muscleloss. __SpecificAimsTextDelimiter__ Specific AimsThere is a general consensus in the field that satellite cells are required for post-natal muscle growth andregeneration. What remains controversial is the necessity of satellite cells in other aspects of muscle plasticitysuch as hypertrophy re-growth following atrophy and muscle maintenance with aging. At the center of thiscontroversy is the inability to specifically ablate satellite cells in adult skeletal muscle. In an effort to resolve thisfundamental issue a novel mouse line was created which enables the conditional ablation of satellite cells inmature skeletal muscle.The Pax7-DTA mouse line was generated by crossing two established mouse lines the Pax7CreER line and aRosa26DTA line. The Pax7-DTA mouse allows temporal control of satellite cell ablation by restricting Cre-mediated activation of diphtheria toxin A (DTA) gene expression to satellite cells. The Pax7-DTA mouse wasused to test the hypothesis that satellite cells are necessary for skeletal muscle hypertrophy in response tomechanical overload induced by synergist ablation. Contrary to this hypothesis evidence showed the primaryhypertrophic response which occurred within the first two weeks and accounted for the majority of the growth(doubling of muscle mass) did not require satellite cells. After four weeks of overload however notabledifferences were observed in muscle weight and myonuclear number suggesting continued growth and/ormaintenance of the increased muscle mass may require satellite cells. Moreover expression profilingsuggested that satellite cells may be necessary for extracellular matrix homeostasis as evidenced by increasedcollagen expression under both resting and hypertrophic conditions in muscle devoid of satellite cells. Thesenovel findings demonstrate the unique utility of the Pax7-DTA mouse to study the in vivo function of satellitecells in adult skeletal muscle. The following specific aims will be pursued using this powerful new model:Specific Aim 1. Quantify the hypertrophic response of adult skeletal muscle following depletion ofsatellite cells. The purpose of this aim is to definitively determine the role of satellite cells in different stages ofmuscle hypertrophy in mature mice as well as in the maintenance of the hypertrophic state. Synergist ablationwill be used to induce muscle hypertrophy of the plantaris and soleus muscles in adult mice with or withoutsatellite cells. The efficacy of satellite cell ablation will be assessed by immunohistochemistry (IHC)Fluorescence Assisted Cell Sorting (FACS) and single fiber analyses. The effect of satellite cell depletion onmuscle hypertrophy will be determined by measuring muscle mass fiber cross-sectional area fibermorphology myonuclear number and fiber-type composition. Muscle function at the whole muscle and singlefiber levels will be measured to determine if the loss of satellite cells affects the contractile properties of controland hypertrophied muscle. FACS expression profiling and cell signaling analyses will be performed todetermine if a compensatory mechanism(s) such as expansion of an alternative progenitor cell populationoccurs upon satellite cell ablation at rest and during different stages of hypertrophy. Satellite cells will then beablated at increasingly advanced age and muscle properties quantified following synergist ablation asdescribed above to determine if there are age-associated alterations in the muscle hypertrophic response.Specific Aim 2. Determine if satellite cells are necessary for skeletal muscle re-growth followingmuscle atrophy. Evidence suggests satellite cells are required for the restoration of muscle mass followingatrophy by replacing apoptotic myonuclei. To test this hypothesis the recovery of muscle mass with reloadingfollowing two weeks of hindlimb suspension will be analyzed in soleus muscle with and without satellite cells.The effect of satellite cell ablation on soleus muscle at rest during atrophy and with re-growth will bedetermined using the same outcome measures as described in Aim 1 and with advancing age as well.The loss of skeletal muscle mass and function observed with prolonged physical inactivity aging and disease-related wasting leads to a deterioration in the quality of life as well as increased risk of morbidity and mortality.It is critical to have a fundamental understanding of the physiological function of satellite cells in skeletalmuscle plasticity in order to make a meaningful assessment of the value of satellite cells as the basis oftherapies to treat these conditions. Acquiring this fundamental knowledge has been hampered by the inabilityto specifically eliminate satellite cells from adult skeletal muscle - the Pax7-DTA mouse line removes thisbarrier and provides a powerful new tool for the muscle plasticity field to use for the in vivo study of satellitecells. Results of this project combined with results from ongoing satellite cell labeling and tracking experimentsusing the same growth models will provide new insight into the potential utility of targeting satellite cells topromote adult muscle growth and maintenance particuarly during aging. An additional strength of the grant isthat as members of the UK Center for Muscle Biology the broad technical expertise and resources tosuccessfully perform all of the proposed experiments are currently in place.


application_id: 8708852
project_number: 5R01DK093832-03
project_title: Computational Approach to Personalized Anemia Management
administering_ic: NIDDK
award_notice_date: 2014-08-19
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: DK
serial_number: 093832
program_official: ROY, CINDY
project_start_date: 2012-09-01
project_end_date: 2016-07-31
study_section: Biomedical Computing and Health Informatics Study Section[BCHI]
contact_pi_person_id: 8145755
contact_pi: GAWEDA, ADAM E
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Effective anemia management in End-Stage Renal Disease (ESRD) is a complex task due to large variation in erythropoietic response among the ESRD patients. Evidence shows that excessive doses of Erythropoiesis Stimulating Agents (ESA) used in hypo-responsive patients coincide with increased cardiovascular complications. In addition to health risks reimbursement restrictions imposed by Medicare demand additional vigilance in ESA administration. Iron is one of the most important elements affecting the erythropoietic response. The ongoing blood losses associated with hemodialysis treatments increased risk of gastrointestinal bleeding and access complications as well as poor iron absorption lead to iron depletion in ESRD patients. Standard anemia management protocols do not fully address the synergistic nature of interactions between erythropoietin and iron. Personalized strategies for coordinated ESA and iron dosing are therefore necessary to achieve the desired clinical outcome reduce patient risk exposure and improve the cost-effectiveness of treatment. Our long-term goal is the advancement of biomedical computing to personalize medicine and pharmacologic management of chronic conditions. The objective of this project is to address the challenge of multiple drug dosing personalization with a specific application to ESA and iron management in anemia of ESRD. The central hypothesis is that a computational approach can be developed to perform coordinated personalized dosing of erythropoiesis stimulating agents and iron in order to achieve desired clinical outcomes and minimize patient exposure resulting in optimal care. The rationale behind the proposed research is that computational models quantifying the interaction between iron and erythropoietin can be applied through the principles of control theory and machine learning to derive personalized dosing strategies for both agents. The main objective will be accomplished through three specific aims: 1) quantification of the erythropoietin-iron interaction through clinically relevant computational models 2) application of such models to derive algorithms for coordinated personalized ESA and iron dosing 3) validation of these algorithms through an "in sillico" trial for a wide range o simulated subjects and clinical conditions. The expected outcome of this project is a new systematic approach to the management of ESRD anemia using multiple agents resulting in improved patient care and decreased cost which will be broadly applicable to other therapeutic areas.

project_terms:
Address;Affect;Algorithms;Anemia;Area;Biomedical Computing;Blood Vessels;Cardiovascular system;Caring;Chronic;Chronic Kidney Failure;Clinical;Complex;Complication;Computer Simulation;Computing Methodologies;Data;Dialysis procedure;Dose;Elements;End stage renal failure;Erythropoiesis;Erythropoietin;Exposure to;Goals;Health;Hemodialysis;Hemorrhage;Intestines;Iron;Lead;Machine Learning;Medicare;Medication Management;Medicine;Mission;Modeling;Mortality Vital Statistics;Nature;Outcome;Patient Care;Patients;Pharmaceutical Preparations;Population;Prevention;Protocols documentation;Quality of life;Research;Risk;Risk Factors;Simulate;Therapeutic;Therapeutic Agents;United States National Institutes of Health;Validation;Variant;Work;absorption;base;clinically relevant;cost;cost effectiveness;design;efficacy testing;gastrointestinal;improved;mathematical model;public health medicine (field);response;theories;vigilance

public_health_relevance:
The proposed research is relevant to public health because personalized dosing of multiple therapeutic agents broadly applicable to many chronic conditions is ultimately expected to improve cost-effectiveness of treatment and minimize patient risk. The proposed research is relevant to the NIH mission because it contributes toward advancement of personalized medicine one of the top priorities of the NIH.


application_id: 8708714
project_number: 5R01AA016959-08
project_title: Ethanol alteration of the neurogenic niche
administering_ic: NIAAA
award_notice_date: 2014-08-01
opportunity_number: PA-05-074
application_type: 5
activity_code: R01
ic: AA
serial_number: 016959
program_official: REILLY, MATTHEW
project_start_date: 2007-09-30
project_end_date: 2016-08-31
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 1869834
contact_pi: NIXON, KIMBERLY
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:
Alcohol use disorders remain as one of the nation's major public health problems with over 17 millionAmericans meeting the diagnostic criteria for alcohol abuse or dependence. Chronic alcoholics demonstratecognitive impairments that are related to a loss of brain mass or neurodegeneration effects that may recoverwith abstinence. Many assumed that the mechanism of this recovery was due to glial regeneration howeverrecent discoveries from our laboratory show that alcohol-induced regulation of neural stem cells (NSCs)parallels the changes in brain mass and cognition during active alcoholism (decrease) versus abstinence(increase) in the hippocampus. The regulation of NSCs relies on the milieu of the local environment orneurogenic niche. Microglial one of three types of glia contribute to this niche. Though microglial eventshistorically were synonymous with cytotoxicity a new role in neurogenesis is emerging. Some activatedmicroglia secrete growth factors and anti-inflammatory cytokines an effect that is consistent with recent datathat certain types of microglia promote NSC proliferation and adult neurogenesis. Thus when we observed amicroglial response that precedes the neurogenic response in our model of chronic alcoholism wesuspected a causal link between microglial events and the promotion of neurogenesis. Therefore thisproposal will test the hypothesis that binge alcohol exposure produces a graded microglial response thatdrives the recruitment of quiescent NSCs into proliferation and neurogenesis in abstinence. Three specificaims address this hypothesis by asking: (1) whether binge alcohol exposure recruits additional NSCs (2)whether microglia show a graded nonphagocytic phenotype predictive of a proneurogenic microenvironmentand (3) whether can we modulate this phenotype to alter neurogenesis in a model of chronic alcoholism.Multiple approaches will be used namely immunohistochemistry to assess the recruitment and proliferativedynamics of NSCs the morphology of microglia as well as in situ hybridization receptor autoradiographyand Enzyme-Linked ImmunoSorbant Assaysto determine microglia phenotype and cytokine expression. Andfinally neuroanatomical and behavioral work will confirm the role of microglia phenotype in neurodegnerationand regeneration following binge alcoholexposure.Relevance to public health: This proposal will uncover a mechanism of brain regrowth in abstinence fromalcohol by investigating the role of activated microglia on neural stem cells and the neurogenic environment.The results will lead to a novel approach in our long term goal of treating brain damage associated withchronic alcoholism: Identifying agents or behaviorsthat promote protective actions of microglia in recruitingNSCs to repair sites of damage with the hope of reversing or preventing cognitive deficits associated withalcoholic neurodegeneration.

project_terms:
Abstinence;Address;Alcohol abuse;Alcohol dependence;Alcoholic Intoxication;Alcoholism;Alcohols;American;Anti-Inflammatory Agents;Anti-inflammatory;Autopsy;Autoradiography;Behavioral;Brain;Brain Injuries;Brain Mass;Cell Death;Cell Proliferation;Cells;Cellular Morphology;Chronic;Cognition;Cognitive deficits;Data;Diagnostic;Environment;Enzymes;Ethanol;Event;Future;Goals;Growth Factor;Hippocampus (Brain);Image;Immunohistochemistry;Impaired cognition;In Situ Hybridization;Intention;Laboratories;Lead;Link;Microglia;Modeling;Morphology;Natural regeneration;Nerve Degeneration;Neuroglia;Neuroprotective Agents;Outcome;Pathway interactions;Pharmacotherapy;Phenotype;Population;Proliferating;Recovery;Recruitment (Neurology);Recruitment Activity;Regulation;Research Personnel;Role;Site;Stem cells;Structure;Testing;Work;adult neurogenesis;alcohol abstinence;alcohol abuse therapy;alcohol exposure;alcohol use disorder;binge drinking;cognitive function;cytokine;cytotoxicity;macrophage;meetings;nerve stem cell;neurogenesis;neuroprotection;new therapeutic target;novel;novel strategies;preconditioning;prevent;problem drinker;public health medicine (field);receptor;relating to nervous system;repaired;response;stem


application_id: 8708512
project_number: 5R25CA153954-05
project_title: The University of Kentucky Cancer Nanotechnology Training Center (UK CNTC)
administering_ic: NCI
award_notice_date: 2014-07-30
opportunity_number: RFA-CA-09-014
application_type: 5
activity_code: R25
ic: CA
serial_number: 153954
program_official: FARRELL, DOROTHY F
project_start_date: 2010-09-03
project_end_date: 2015-11-30
study_section: ZCA1-RTRB-2(M1)
contact_pi_person_id: 7875468
contact_pi: ANDERSON, BRADLEY D
other_pis: EVERS, BERNARD MARK
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The University of Kentucky Cancer Nanotechnology Training Center (UK CNTC) will provide advanced multidisciplinary training for predoctoral students and postdoctoral fellows toward the goal of creating a new type of cancer researcher who is skilled and ready to pursue a career in cancer nanotechnology research. Nationally and internationally recognized faculty members at the University of Kentucky will collaborate to create a fertile environment for the novel exploration of nanotechnology and cancer. Expertise covers a broad multidisciplinary range of scientific areas in gastrointestinal cancer lung cancer gliomas radiation medicine surgery cancer screening imaging and pharmacokinetics and dynamics. Among these faculty are 16 nanotechnology researchers in the Departments of Chemical Engineering Materials Engineering Electrical Engineering Chemistry and Pharmaceutical Sciences and 18 biomedical scientists or clinical oncologists in the Colleges of Pharmacy or Medicine. Based on existing research collaborations we propose cancer nanotechnology projects composed of multidisciplinary focus area teams with the goal of training future leading researchers in the field of cancer nanotechnology in the following four areas: (1) early detection and diagnosis in lung colon and ovarian cancer; (2) treatment of gastrointestinal tumors and metastases; (3) lung cancer treatment; and (4) glioma therapy. Specific Aim 1 is to expand the core expertise of participants in the UK CNTC through cross-disciplinary laboratory research training projects of up to two years involving innovative applications of nanotechnology to address specific unmet needs in cancer detection and therapy. Our trainees will be at the forefront of research that will be driven toward developing novel cancer therapies and diagnostic strategies based on nanotechnology. Through these activities the trainees will obtain a detailed understanding of the molecular basis of cancer the unresolved clinical problems in treating and diagnosing the disease and acquire expertise in the field of nanotechnology. In Specific Aim 2 the CNTC will provide trainees with problem-based and experiential training through seminars workshops short courses clerkships and laboratory training modules that will build their research skills and confidence as members of multi-disciplinary research teams. Each trainee will be immersed in individualized problem-based instruction and a broad multidisciplinary training through core courses short courses participation in seminars undergraduate and early graduate student mentoring and outreach activities designed to educate the public. Trainees will be guided through these programs with effective mentorship and an evaluation program (Specific Aim 3) that will assess the effectiveness of trainee progress and development. Finally Specific Aim 4 is to highlight the accomplishments of CNTC trainees both regionally and nationally. As such our trainees will learn to envision articulate and perform nanotechnology-centered research focused on developing novel solutions to the outstanding clinical problems associated with cancer.

project_terms:
Address;Applied Research;Archives;Area;Basic Science;Cancer Biology;Cancer Center;Cancer Detection;Cancer Diagnostics;Chemical Engineering;Clinical;Collaborations;Colon Carcinoma;Development;Diagnosis;Discipline;Doctor of Pharmacy;Drug Delivery Systems;Drug Kinetics;Early Diagnosis;Early treatment;Educational workshop;Effectiveness;Electrical Engineering;Engineering;Ensure;Environment;Environment Design;Ethics;Evaluation;Faculty;Feedback;Fostering;Funding;Future;Gastrointestinal Neoplasms;Glioma;Goals;Grant;Hour;Image;Immersion Investigative Technique;Instruction;International;Intervention;Journals;Kentucky;Knowledge;Laboratories;Laboratory Finding;Laboratory Research;Learning;Link;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of lung;Malignant neoplasm of ovary;Medicine;Mentors;Mentorship;Mission;Molecular;Monitor;Nanotechnology;Neoplasm Metastasis;Oncologist;Participant;Performance;Pharmaceutical Chemistry;Pharmacy facility;Postdoctoral Fellow;Program Effectiveness;Program Evaluation;Published Comment;Publishing;Radiation;Research;Research Personnel;Research Project Grants;Research Training;Rotation;Science;Screening for cancer;Solutions;Students;Suggestion;System;Therapeutic Human Experimentation;Time;Training;Translating;Universities;Update;Work;Writing;anticancer research;base;biomedical scientist;cancer diagnosis;cancer surgery;cancer therapy;cancer type;career;clinical conference;college;design;disease diagnosis;graduate student;improved;in vivo;innovation;interest;meetings;member;molecular imaging;multidisciplinary;novel;outreach;outreach program;pre-doctoral;programs;public health relevance;skills;training project;web site

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The University of Kentucky Cancer Nanotechnology Center will provide a systematic and unique multidisciplinary training environment focusing on laboratory hands-on research to create a workforce capable of using nanotechnology for solving intractable cancer research problems. Trainees of the Center will be immersed in a research environment designed to take advantage of the multiple research strengths of faculty at the University of Kentucky and will emerge with a broad yet detailed knowledge of cancer diagnostics interventions and related nanotechnology applications including drug delivery early detection and treatment.       The University of Kentucky Cancer Nanotechnology Center will provide a systematic and uniquemultidisciplinary training environment focusing on laboratory hands-on research to create aworkforce capable of using nanotechnology for solving intractable cancer research problems.Trainees of the Center will be immersed in a research environment designed to take advantageof the multiple research strengths of faculty at the University of Kentucky and will emerge with abroad yet detailed knowledge of cancer diagnostics interventions and related nanotechnologyapplications including drug delivery early detection and treatment. __SpecificAimsTextDelimiter__ SPECIFIC AIMSThe UK Cancer Nanotechnology Training Center (UK CNTC) will provide advanced multidisciplinary trainingfor predoctoral students and postdoctoral fellows in a highly collaborative environment comprised of eminentfaculty and productive laboratories in four Colleges located in close proximity to each other on one campus.The 34 faculty members include 16 nanotechnology researchers in the Departments of Chemical EngineeringMaterials Engineering Electrical Engineering Chemistry and Pharmaceutical Sciences and 18 biomedicalscientists or clinical oncologists in the Colleges of Pharmacy or Medicine with expertise in gastrointestinalcancer lung cancer gliomas radiation medicine surgery cancer screening imaging and pharmacokineticsand dynamics. Multidisciplinary focus area teams are proposed which build on relationships already developedamong the faculty through existing collaborations. Our overall goal is to foster the development of a new genreof cancer nanotechnology researcher who will fully appreciate the breadth of disciplines involved in translatingnovel laboratory findings to cancer diagnosis and treatment. This will be accomplished through their immersionin cross-disciplinary mentored laboratory training projects individualized problem-based instruction andfocused laboratory training participation in seminars undergraduate and early graduate student mentoringand outreach activities designed to educate the public. Trainees will acquire a clear understanding of themolecular basis of cancer and the unresolved clinical problems plus sufficient expertise in nanotechnology toenvision articulate and carry-out research to find realistic nanotechnology solutions to these problems.Aim 1: Expand the core expertise of participants in the UK CNTC through cross-disciplinary laboratoryresearch training projects of up to two years involving innovative applications of nanotechnology toaddress specific unmet needs in cancer detection and therapy. We envision a steady-state of 8 trainees atany given time with 6 advanced predoctoral participants and 2 postdoctoral fellows. Participants may havebasic science applied science or clinical backgrounds (i.e. PharmD and MD residents). Two of thepredoctoral trainees will be supported by matching funds provided by the Markey Cancer Center. Based on hisor her specific training and interests each participant will become an active member of one of fourcollaborative teams seeking nanotechnology solutions in: (1) early detection and diagnosis in lung colon andovarian cancer; (2) treatment of gastrointestinal tumors and metastases; (3) lung cancer treatment; and (4)glioma therapy. The nanotechnology faculty members of these focus area teams have particular strengths inmolecular imaging and early detection in vivo nanotechnology imaging systems multifunctional therapeuticsand research enablers all of which have been identified as critical nanotechnology platform needs in themission statement of the NCI Alliance for Nanotechnology in Cancer.Aim 2: Provide trainees with problem-based and experiential training through seminars workshopsshort courses clerkships and laboratory training modules that will build their research skills andconfidence as members of multi-disciplinary research teams. Depending on their backgroundspredoctoral students tracking into the CNTC program will be required to complete certain core courses as pre-requisites to diversify their backgrounds (e.g. a nanotechnology or cancer biology course). During the programstudents will receive training in ethics and grant writing. In addition participants will select a set of shortcourses hands-on lab modules clinical rotations etc. tailored to their research project and focus areabackgrounds and interests. All trainees and mentors will be expected to participate in a combinedCNTC/Experimental Therapeutics research seminar.Aim 3: Evaluate the progress of CNTC participants and the effectiveness of the program. Traineeprogress will be evaluated on a regular basis to ensure that the trainee and the program are meeting theirobjectives. The participants will work with their primary mentor and focus area team co-mentors to preparewritten goals with milestones that will be reviewed and updated during monthly meetings with the team. TheMentoring and Development Committee will meet with trainees at six-month intervals to monitor the trainee'sprogress and to invite suggestions from the trainee on ways to improve the program. A written evaluation andsummary of the participant's comments will be prepared and discussed with the participants' mentors.Aim 4: Highlight the accomplishments of CNTC trainees both regionally and nationally. CNTC traineesand participating faculty will be expected to present their research findings at international national and localbasic science and clinical conferences/meetings and publish in appropriate scientific journals. We will establisha dedicated website for our program and the websites of our affiliate Outreach programs will provide links toour announcements and archived information. CNTC trainees will be expected to participate in 20 hours ofoutreach and mentoring activities during their training period and feedback on their performance will beprovided.


application_id: 8708259
project_number: 7K08DA032296-03
project_title: African American Offenders: Drug Use Mental Health and HIV Risk
administering_ic: NIDA
award_notice_date: 2013-08-22
opportunity_number: PA-11-193
application_type: 7
activity_code: K08
ic: DA
serial_number: 032296
program_official: JONES, DIONNE
project_start_date: 2012-05-01
project_end_date: 2017-04-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 10667839
contact_pi: STEVENS-WATKINS, DANELLE J
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The primary goal of this K08 award is to further develop a productive independent research career in drug abuse research. The training and career development plan will enhance Dr. Stevens-Watkins's research experience in primary data collection with prisoners focused on drug use mental health and HIV thus resulting in the clarification of the specific aims of an R01 submission in years 4 and 5. The proposed training objectives are: (1) to receive training in the epidemiology of drug abuse mental health and HIV as they relate to health disparities among African Americans; (2) to further develop expertise in research with special populations biostatistics and advanced quantitative analyses including non-linear categorical models and structural equation modeling; (3) to use the data collected in the proposed research plan as pilot data for an R01 research proposal. The specified training goals are aligned with the research aims and compliment the clinical experience of the candidate. Dr. Stevens-Watkins will be sponsored by her established mentors Drs. Carl Leukefeld and Carrie Oser both with expertise in drug abuse and HIV research. Of high significance HIV has recently been termed a "crisis" in the African American community. The overall goal of the proposed research plan is to better understand the complex and dynamic relationship between drug use mental health and HIV risk among African American male prisoners nearing community re-entry. The specific aims are (1) to explore drug use symptoms of depression and anxiety and HIV risk behaviors among African American male inmates by conducting a thorough literature review and devising an analytical model using biostatics multivariate analytic techniques with available data; (2) to identify prevalence incidence and predictors of drug use disorders anxiety depressive disorders and HIV sexual risk behaviors among 205 incarcerated African American men; (3) to examine the knowledge patterns and perceived cultural and community barriers to utilizing individual and health resources and their relationship to substance abuse recovery and HIV risk behaviors among 205 African American men upon release from prison. Baseline data will be collected in prison and follow-up data collection will occur when participants have been released in the community after 3-months. The proposed research plan will offer HIV testing and counseling to an at-risk population that has historically been difficult to engage in research and HIV testing subsequently significantly impacting public health by possibly preventing the spread of HIV. The candidate's immediate career goals include published manuscripts and R01 funding by the end of K08 funding with an ultimate career goal of becoming an independent clinical drug abuse researcher. This proposal includes an outstanding mentoring team as well as a feasible training and research plan utilizing resources offered by both Spalding University and the University of Kentucky.

project_terms:
African American;Anxiety;Award;Biometry;Chronic;Clinical;Communities;Complex;Counseling;Data;Data Analyses;Data Collection;Depressive disorder;Development Plans;Drug Use Disorder;Drug abuse;Drug usage;Environment;Epidemiology;Equation;Funding;Goals;HIV;HIV Infections;HIV risk;Health;Health Resources;Housing;Human immunodeficiency virus test;Imprisonment;Incidence;Individual;Intervention;Interview;Kentucky;Knowledge;Life;Manuscripts;Mediating;Mental Depression;Mental Health;Mental Health Services;Mentors;Methods;Modeling;Outcome;Participant;Pattern;Phase;Populations at Risk;Pre-Post Tests;Prevalence;Prisoner;Prisons;Process;Protocols documentation;Psychologist;Publishing;Recording of previous events;Recovery;Research;Research Personnel;Research Proposals;Research Training;Resources;Review Literature;Risk;Risk Behaviors;Social support;Specific qualifier value;Structural Models;Substance abuse problem;Symptoms;Techniques;Testing;Training;Universities;Unsafe Sex;Writing;career;career development;community reentry;correctional system;depressive symptoms;drug testing;experience;follow-up;health care service utilization;health disparity;high risk;high risk sexual behavior;impression;improved;intravenous drug use;male;men;men who have sex with men;named group;offender;prevent;psychologic;public health medicine (field);public health research;racism;sex risk

public_health_relevance:
The proposed project has significant public health implications for reducing the spread of HIV among the African American community by offering testing and by targeting men exiting prison re-entering the community. The proposed project will generate an improved understanding of the complex relationship between drug use mental health and HIV risk among an at-risk group.


application_id: 8707876
project_number: 5R01HL113494-02
project_title: Treatment of Skeletal Muscle Dysfunction in ICU Patients
administering_ic: NHLBI
award_notice_date: 2014-06-26
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: HL
serial_number: 113494
program_official: HARABIN, ANDREA L
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;Diaphragm (Anatomy);Disease;Drug Combinations;Eicosapentaenoic Acid;Enhancers;Exercise;Exercise Tolerance;Financial cost;Functional disorder;Hospitals;Hyperglycemia;Intensive Care Units;Leg;Length of Stay;Limb structure;Measurement;Measures;Mechanical ventilation;Medical;Morbidity - disease rate;Mortality Vital Statistics;Muscle;Muscle Weakness;Muscle function;Outcome;Patient Care;Patients;Performance;Pharmaceutical Preparations;Pharmacotherapy;Physicians;Pilot Projects;Placebos;Pneumonia;Quadriceps Muscle of the Thigh;Randomized;Reporting;Respiratory Failure;Respiratory Muscles;Skeletal muscle structure;Testing;Thick;Training;Ventilator;Work;base;cytokine;design;improved;indexing;muscle strength;patient population;pressure;prevent;public health relevance;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: 8706799
project_number: 5R01AR060964-03
project_title: Modulating Inflammation and Fibrosis to Control Scarring in Muscle Wounds
administering_ic: NIAMS
award_notice_date: 2014-07-31
opportunity_number: PA-10-009
application_type: 5
activity_code: R01
ic: AR
serial_number: 060964
program_official: TSENG, HUNG H
project_start_date: 2012-08-01
project_end_date: 2016-07-31
study_section: Musculoskeletal Tissue Engineering Study Section[MTE]
contact_pi_person_id: 1874927
contact_pi: PULEO, DAVID A.
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Muscle injuries occurring recreationally as well as in the workplace and home are among the most common musculoskeletal conditions in the U.S. Satellite cells provide muscle with the potential for regeneration but for large defects slow healing and excessive proliferation of fibroblasts frequently results in fibrosis and scarring thatcan create a mechanical barrier that delays or restricts myofibers from bridging the injury gap. Recent findings have begun to elucidate differences between inflammatory processes that promote muscle repair and regeneration following injury and those that disrupt muscle homeostasis. In light of the multiple demands needed for preventing fibrotic scarring a multidisciplinary team has been assembled to apply a proactive strategy in which multiple biomolecules are delivered in a site-specific and temporally orchestrated manner to treat different aspects of the inflammatory and wound healing processes. Aim 1 will develop and characterize a mechanically flexible controlled release system for localized delivery of anti- inflammatory anti-oxidant pro-resolution and anti-fibrotic biomolecules. With respect to this Aim it is hypothesized that the devices can be tailored to deliver anti-inflammatory anti-oxidant pro-resolution and anti-fibrotic molecules with discrete profiles that roughly follow the kineticsof the wound healing process. Aim 2 will determine the efficacy of controlled localized sequential release of anti-inflammatory anti- oxidant pro-resolution and anti-fibrotic components to enhance structural/histological biochemical and functional properties in vivo in a rodent skeletal muscle defect model. The working hypothesis is that sequential treatment devices i.e. materials that resolve inflammation and then prevent fibrosis will not only enhance muscle regeneration but these films will be more effective than those releasing only one of the components or that deliver them without regard to the sequence of events during wound healing. Furthermore the methods may be applicable not only to repair of skeletal muscle defects but also for treatment of many other diseases in which control of inflammation and subsequent wound healing processes is needed.

project_terms:
Adhesions;Affect;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Biochemical;Biocompatible Materials;Biological Response Modifier Therapy;Chronic;Cicatrix;Contracture;Data;Defect;Devices;Disease;Event;Excision;Fibroblasts;Fibrosis;Film;Gel;Generations;Goals;Healed;Home environment;Homeostasis;Inflammation;Inflammation Mediators;Inflammatory;Injury;Killings;Kinetics;Laceration;Lead;Light;Location;Mechanics;Membrane;Methods;MicroRNAs;Military Personnel;Modeling;Muscle;Musculoskeletal;Natural regeneration;Operative Surgical Procedures;Outcome;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Polymers;Process;Property;Recovery;Resolution;Rodent;Sequential Treatment;Site;Skeletal muscle structure;Surface;System;Testing;Tissues;Trauma;Ursidae Family;Vent;Work;Workplace;Wound Healing;base;combat;controlled release;design;experience;flexibility;healing;in vivo;microorganism;multidisciplinary;muscle regeneration;prevent;public health relevance;repaired;response;satellite cell;stem cell population;tissue regeneration;tissue repair;vehicular accident;wound

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Muscle injuries occurring recreationally as well as in the workplace and home are among the most common musculoskeletal conditions in the U.S. Although muscle has the potential to regenerate slow healing of large defects frequently results in scarring and incomplete recovery. This project will develop bioerodible films that control different phases of wound healing to enhance muscle regeneration.


application_id: 8706748
project_number: 5R01AG039732-04
project_title: The Role of Adipose Tissue in Age-dependent Sensitivity to Critical Illness
administering_ic: NIA
award_notice_date: 2014-05-22
opportunity_number: PA-10-042
application_type: 5
activity_code: R01
ic: AG
serial_number: 039732
program_official: GUO, MAX
project_start_date: 2011-08-01
project_end_date: 2016-05-31
study_section: Special Emphasis Panel[ZRG1-BDCN-M(02)M]
contact_pi_person_id: 8163817
contact_pi: SAITO, HIROSHI
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Aging is characterized by an altered stress response that underlies a compromised resistance to disease or injury. Activation of inflammatory and coagulant pathways is a frequent consequence of severe critical illnesses and results in the progression of systemic inflammatory response syndrome (SIRS). Recent evidence suggests that adipose tissue-derived signaling proteins including cytokines coagulation factors and hormones may play an important role in the inflammatory response. Our long-term goals are to identify the mechanisms by which adipose tissue contributes to age-dependent severity of SIRS and to develop therapeutic strategies for decreasing vulnerability to critical illnesses in the aged. For these studies we will use two widely accepted mouse models of SIRS - acute endotoxemia induced by injection with bacterial endotoxin lipopolysaccharide and an intra-abdominal sepsis model induced by cecal ligation and puncture. The objective of this project is to identify and evaluate the expression of adipose-derived inflammatory and coagulant factors that differ by aging upon inflammatory stress. Our central hypothesis is that expression patterns of inflammatory / coagulant factors in the adipose tissue during SIRS are significantly altered by aging and that this alteration contributes to age-dependent severity of critical illnesses. To achieve the above goals we will pursue the following three specific aims: (1) To define the role of adipose tissue in age-related alterations of coagulation during critical illness. (2) To understand the mechanisms of age-related inflammatory cytokine production in the adipose tissue during critical illness. (3) To evaluate methods of body fat loss as potential therapies and preventative measures for reducing severity of critical illness in the aged. These studies will provide significant insight into the association of the previously neglected adipose organ in aging and critical illness.

project_terms:
Abbreviations;Acute;Adipose tissue;Age;Age Reporting;Aging;Animal Model;Blood Coagulation Factor;Body fat;Burn Trauma;Cessation of life;Coagulants;Coagulation Process;Complication;Critical Illness;Death Rate;Development;Disease Resistance;Disseminated Intravascular Coagulation;Elderly;Endotoxemia;Endotoxins;Excision;Foundations;Functional disorder;Gene Chips;Genes;Genetic;Goals;Growth Factor;Health Care Costs;Hormones;In Vitro;Incidence;Inflammation;Inflammatory;Inflammatory Response;Injection of therapeutic agent;Injury;Interleukin-1;Interleukin-1 Receptors;Interleukin-6;Intra-abdominal;Knockout Mice;Ligation;Link;Lipopolysaccharides;Lung;Measures;Mediating;Mediator of activation protein;Methods;Modeling;Mortality Vital Statistics;Mus;Operative Surgical Procedures;Organ;Organ Culture Techniques;Pathway interactions;Patients;Pattern;Plasminogen Activator Inhibitor 1;Plasminogen Activator Inhibitor 2;Plasminogen Inactivators;Play;Predisposition;Preventive;Process;Production;Puncture procedure;Role;Sepsis;Sepsis Syndrome;Severities;Signaling Protein;Source;Stress;System;TNF gene;Testing;Therapeutic;Thromboplastin;Thrombosis;Transgenic Organisms;Transplantation;Visceral;Visit;Wild Type Mouse;acute pancreatitis;age related;aged;biological adaptation to stress;cytokine;dietary restriction;effective therapy;improved;insight;middle age;mouse model;mutant;neglect;older patient;public health medicine (field);research study;therapy development

public_health_relevance:
This project is relevant to public health because it will enhance our understanding of the roles of adipose tissue in increased severity of critical illness in the elderly. This project will also provide information for the development of treatments and preventative therapies to decrease incidence rates and deaths related to critical illness in the aged. Preventative therapies will likely result in reduced patient visits and decreased health care costs. The development of effective treatments for systemic inflammation of which there are currently none available will be beneficial to elderly patients who suffer from critical illnesses.


application_id: 8706708
project_number: 5R01NR013430-04
project_title: Nutrition Intervention to Reduce Symptoms in Patients with Advanced Heart Failure
administering_ic: NINR
award_notice_date: 2014-07-23
opportunity_number: RFA-NR-11-006
application_type: 5
activity_code: R01
ic: NR
serial_number: 013430
program_official: HUSS, KAREN
project_start_date: 2011-09-27
project_end_date: 2016-07-31
study_section: ZNR1-REV-T(07)
contact_pi_person_id: 1906096
contact_pi: LENNIE, TERRY A
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): For a majority of patients with advanced heart failure medical treatment is only partially effective in relieving heart failure symptoms. Therefore it isrecommended that palliative care be initiated soon after diagnosis. There is a need for complementary nonpharmacologic interventions that could be easily implemented by health care providers to provide palliative care. Three major pathologic pathways underlying heart failure symptoms have been identified: fluid overload inflammation and oxidative stress. Prior research has demonstrated that three nutrients-sodium omega-3 fatty acids and lycopene-can alter these pathologic pathways. Clinical trials to date have only tested each nutrient individually. There is strong theoretical rationale that a combined intervention targeting all thre nutrients would have substantial benefit in relieving symptoms in advanced heart failure. Therefore the purposes of this study are to test the effects of a 6-month nutrition intervention o dietary sodium reduction combined with supplementation of lycopene and omega-3 fatty acids on heart failure symptoms health-related quality of life and time to heart failure rehospitalization or all-cause death. The aims of this double blind-placebo controlled study are 1) to determine the effects of a 6-month nutrition intervention on symptom burden (edema shortness of air and fatigue) and health related quality of life at 3 and 6 months and time to heart failure rehospitalization or all-cause death over 12 months from baseline; 2) compare dietary sodium intake inflammation and markers of oxidative stress between the nutrition intervention group and a placebo group at 3 and 6 months; and 3) compare body weight serum lycopene and erythrocyte omega-3 index between the nutrition intervention group and a placebo group at 3 and 6 months. A total of 175 patients with advanced heart failure will be randomized to either the nutrition intervention or placebo group (75 per group). The nutrition intervention group will receive a theory based education and skill building intervention designed to decrease dietary sodium intake to ~2 g per day. A research nurse will make 4 home visits and one follow-up telephone call over 6 months to provide the education-skill building intervention. The intervention group will take 3 omega-3 fatty acid capsules (350 mg eicosahexaenoic acid and 50 mg docosahexaenoic acid) and consume tomato juice or other tomato-based products containing 20-25 mg of lycopene daily for six months. The placebo group will receive the same number of visits and phone calls but only general nutrition information will be provided. They will take 3 placebo capsules containing soybean oil (500 mg/capsule) and consume their choice of fruit juices that do not contain lycopene daily for six months. Data will be collected in person at baseline 3 months and 6 months by a research assistant blinded to the group assignment. Patients will be followed for an additional 6 months by telephone to collect longer term data on symptom burden and quality of life as well as heart failure hospitalization and all-cause mortality at 9 and 12 months.

project_terms:
Acids;Address;Adherence (attribute);Air;Anorexia;Anti-Inflammatory Agents;Anti-inflammatory;Area;Attention;Blinded;Blood Vessels;Body Weight;Caring;Carotenoids;Cause of Death;Clinical Trials;Coupled;Data;Diagnosis;Diet;Dietary Intervention;Dietary Sodium;Docosahexaenoic Acids;Double-Blind Method;Edema;Educational aspects;Erythrocytes;Event;Fatigue;Fluid Balance;Fluid overload;Fruit;Funding Opportunities;Guidelines;Health;Health Personnel;Healthcare;Heart failure;Home visitation;Hospitalization;Hour;House Call;Human;Inflammation;Intake;Interleukin-10;Intervention;Isoprostanes;Juice;Knowledge;Link;Malondialdehyde;Medical;Mortality Vital Statistics;Myocardial;Nursing Research;Nutrient;Omega-3 Fatty Acids;Oxidative Stress;Palliative Care;Pathologic;Pathway interactions;Patients;Persons;Pharmacotherapy;Placebos;Play;Quality of life;Randomized;Research;Research Personnel;Risk;Role;Serum;Serum Markers;Severities;Sodium;Soybean Oil;Supplementation;Symptoms;Syndrome;TNF gene;Telephone;Testing;Time;Tomatoes;Tumor Necrosis Factor Receptor;Tumor Necrosis Factor-alpha;United States National Institutes of Health;Urine;Visit;base;blind;capsule (pharmacologic);cost;cytokine;follow-up;group intervention;health related quality of life;improved;indexing;inflammatory marker;interest;lycopene;nutrition;placebo controlled study;response;skills;sound;symptom management;theories;therapy design

public_health_relevance:
Despite optimal drug therapy most patients with heart failure remain symptomatic leading to poor quality of life and frequent rehospitalizations. The proposed study is aimed at improving symptoms and quality of life in patients with advanced heart failure through a low cost easily administered intervention of dietary sodium restriction coupled with lycopene and omega-3 fatty acid supplementation. The knowledge to be gained by defining the role of dietary interventions in heart failure is invaluable and will pave the way forfuture research in this area.


application_id: 8706077
project_number: 5U01CA151648-06
project_title: RNA Nanotechnology in Cancer Therapy
administering_ic: NCI
award_notice_date: 2014-08-18
opportunity_number: RFA-CA-09-013
application_type: 5
activity_code: U01
ic: CA
serial_number: 151648
program_official: MORRIS, STEPHANIE A
project_start_date: 2010-08-25
project_end_date: 2016-01-16
study_section: ZCA1-SRLB-X(M1)
contact_pi_person_id: 1878565
contact_pi: GUO, PEIXUAN
other_pis: LI, HENRY ;ROSSI, JOHN JOSEPH
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This project is to organize an interdisciplinary team to work on RNA nanotechnology by constructing polyvalent RNA nanoparticles for specific targeting and delivery to cancer cells. RNA molecules can down-regulate specific gene expression in cancer cells. RNA is particularly attractive as a building block for bottom-up assembly in nanotechnology and nanomedicine. RNA can be manipulated as easily as DNA but possesses the versatility in structure and function similar to that of proteins. RNA contains single-stranded stem-loops for intra- or inter-RNA interactions which can serve as mounting dovetails providing advantages over external linking dowels in nanomachine assembly. This CNPP operation comprises of three major functions: the fundamental studies on therapeutic RNA nanoparticle construction; the conjugation and incorporation of therapeutic and targeting moieties to RNA nanoparticles; and the specific delivery of therapeutics to cancer cells. The team includes basic scientists with strong backgrounds in biomedical engineering chemistry and RNA and DNA nanotechnology; cancer biologists with extensive experience in ribozyme and siRNA delivery; and pharmaceutical cooperation focusing on RNA therapeutics with expertise in animal trials. The team will elucidate the principles underlying the RNA/RNA interactions in RNA nanoparticle assembly using phi29 motor pRNA system and RNA junction motifs to build polyvalent RNA oligomers containing aptamer siRNA ribozyme ligand imaging markers or drugs for cancer cell recognition and gene silencing. A new methodology of SELEX will be developed to screen for stable and high affinity RNA aptamers that target and enter cancer cells specifically. Simultaneous delivery and detection will be designed combining therapy and detection of subsequent therapeutic effects on apoptosis. Approaches of crossover chemical modification and cross-linking will be applied to make RNA nanoparticles stable in vivo. Novel fermentation approaches and industry scale production methods will be developed to produce large-scale stable RNA for clinical applications. Animal trials on pharmacokinetics bio-distribution toxicity gene silencing effects and cancer cell killing will be carried out on animal models of lung cancer ovarian cancer liver cancer and leukemia.

project_terms:
Affinity;Animal Model;Animals;Apoptosis;Biological Models;Biomedical Engineering;Catalytic RNA;Cell Culture Techniques;Cells;Chemicals;Chemistry;DNA;Detection;Drug Kinetics;Fermentation;Gene Expression;Gene Silencing;Healthcare;Image;Industry;Investigation;Ligands;Link;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of ovary;Methodology;Methods;Modification;Motor;Nanotechnology;Ovarian;Pharmaceutical Preparations;Pharmacologic Substance;Primary carcinoma of the liver cells;Procedures;Production;Proteins;RNA;Ribosomes;Scientist;Small Interfering RNA;Structure;System;Therapeutic;Therapeutic Effect;Toxic effect;Work;Xenograft procedure;aptamer;cancer cell;cancer therapy;cell killing;clinical application;crosslink;design;experience;in vivo;leukemia;nanomachine;nanomedicine;nanoparticle;novel;operation;stem;targeted delivery;therapeutic RNA;therapeutic siRNA;therapeutic target

public_health_relevance:
Cancer is a current and long term health care crisis and treatments necessitate the investigation of specific delivery to target cells. This application proposes to fabricate RNA nanoparticles to incorporate therapeutic SiRNA aptamers and ribosomes to accomplish targeted delivery. Therapeutic constituents will be selected for the treatment of lung cancer ovarian cancer liver cancer and leukemia.


application_id: 8705330
project_number: 5R01AG026307-08
project_title: Self-Regulation Immunological Aging and Health in Older Adults
administering_ic: NIA
award_notice_date: 2014-07-18
opportunity_number: PA-09-216
application_type: 5
activity_code: R01
ic: AG
serial_number: 026307
program_official: NIELSEN, LISBETH
project_start_date: 2006-07-15
project_end_date: 2017-04-30
study_section: Special Emphasis Panel[ZRG1-BBBP-T(02)M]
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): Older adults are at high risk for a number of health problems including cardiovascular disease infectious disease and cancer. Underlying at least part of this risk is immunological aging but not all older adults experience immunological aging to the same degree nor do they experience the same health risk and health problems. The purpose of this project is to measure individual differences and changes in self-regulation over time in older adults and to link self-regulation to subjective health health risks and clinicallyrelevant markers of immunological aging including inflammation and markers of lymphocyte terminal differentiation and replicative senescence. This is a competing renewal of this longitudinal study which began in 2001 and received R01 funding in 2006 submitted by a research team with expertise in aging self-regulation neuropsychology autonomic and inflammatory biology immunology and longitudinal design and analysis. The first period of the study focused on risk factors especially stress and repetitive thought and their effects on psychological well-being subjective health and immune response to vaccination. The renewal continues assessment of these risk factors to provide continuity in this longitudinal dataset and adds innovation in the assessment of factors that may promote healthy aging and mitigate against effects of risks. Specifically the aims of the study are first to test the effects of a elf-regulatory constellation (comprising self-regulation executive cognitive function and heart rate variability [HRV]) on subjective psychological social and physical health and markers of immunological aging. Second we will test the relationships between this constellation and risk factors such as age and stress. Third we will test the ability of the constellation to moderate rik effects. A further aim is to support a "call for collaboration" in which we propose to work with other investigators whose hypotheses can be tested with study data from 2001 through the current renewal. At 6- month intervals older adults (N = 150) will complete measures of the self-regulatory constellation: behavioral emotional social and cognitive self-regulation; executive cognitive functions including inhibition shifting and working memory; and resting HRV. They will complete measures of risk including stress pain physical activity BMI and waist circumference. Finally they will complete measures of psychosocial health including depression perceived cognitive and physical health and marital satisfaction. Blood draws will be synchronized with these visits and assays performed on these samples will capture two aspects of immunological aging: increases in serum proinflammatory cytokines and their soluble receptors and increases in markers of terminal differentiation and senescence in T cells and NK cells. This renewal will be innovative in its comprehensive assessment of self-regulation as well as risk; the longitudinal design that allows for the study of change and lagged mediational and bidirectional effects; and the focus on the role of self-regulation in healthy aging.

project_terms:
Accounting;Age;Aging;Back;Behavioral;Biological Assay;Biological Markers;Biology;Blood;Cardiovascular Diseases;Cell Aging;Cognitive;Collaborations;Communicable Diseases;Data;Data Set;Elderly;Emotional;Funding;Health;Immune;Immune response;Immune system;Immunology;Individual;Individual Differences;Inflammatory;Influenza vaccination;Informal Social Control;Interleukin-6;Link;Longitudinal Studies;Lymphocyte;Malignant Neoplasms;Measures;Mental Depression;Mental Health;Natural Killer Cells;Neuropsychology;Outcome;Pain;Personal Satisfaction;Physical activity;Psychological Factors;Research;Research Personnel;Resistance;Rest;Risk;Risk Factors;Role;Sampling;Serum;Short-Term Memory;Stress;T-Lymphocyte;Testing;Time;Vaccination;Visit;Work;age related;clinically relevant;cognitive function;cohort;cytokine;experience;feeding;healthy aging;heart rate variability;high risk;indexing;inflammatory marker;innovation;longitudinal analysis;longitudinal design;member;physical conditioning;prospective;psychologic;psychosocial;public health relevance;receptor;satisfaction;senescence;shift work;social;waist circumference

public_health_relevance:
PUBLIC HEALTH RELEVANCE: With age come changes in the immune system that can increase the risk of poor health. However not all older adults experience these changes to the same degree. This project will continue to track a cohort of older adults examining psychological factors that may be protective for psychological and physical health and delay immunological aging as well as those factors that may confer risk and the interactions between protective and risk factors.


application_id: 8705326
project_number: 5R01AA020005-04
project_title: Alcohol Myopia and Aggression
administering_ic: NIAAA
award_notice_date: 2014-07-31
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AA
serial_number: 020005
program_official: GRAKALIC, IVANA
project_start_date: 2011-08-10
project_end_date: 2016-07-31
study_section: Risk, Prevention and Intervention for Addictions Study Section[RPIA]
contact_pi_person_id: 7876958
contact_pi: GIANCOLA, PETER R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This application has 2 main goals: 1) to test a psychological model [the Alcohol Myopia Model (AMM); Steele & Josephs 1990] that can explain the relation between alcohol intoxication and aggression and 2) to understand how established risk factors for intoxicated aggression operate within the AMM. The AMM contends that alcohol intoxication disrupts cognitive functioning thus creating a "myopic" or a narrowing effect on attentional capacity. This myopic effect facilitates aggression by restricting one's attention onto more salient provocative cues inherent in a hostile situation rather than less salient non-provocative or inhibitory cues. STUDY 1 will examine how distraction from provocation influences aggression under the influence of alcohol. It will also determine whether key trait risk factors (i.e. hostile rumination beliefs about aggression anger self-awareness and empathy) moderate the alcohol-aggression relation within the context of the AMM. Subjects will be 420 adult male and female social drinkers randomly assigned to 1 of 3 alcohol dose groups (alcohol placebo sober) and 1 of 2 distraction groups (distraction no-distraction). Trait risk factors will be measured using validated self-report measures. Aggression will then be assessed using a version of the well- established Taylor Aggression Paradigm (TAP; Taylor 1967) in which subjects administer and receive electric shocks to/from a fictitious opponent under the guise of a competitive reaction-time task. Aggression will be operationalized as a composite index of the shock intensity and duration administered by the subject to the fictitious opponent. STUDY 2 builds on Study 1 by testing the external validity of the AMM (to the extent possible in a laboratory setting) in explaining alcohol's effects on aggression by assessing the effectiveness of a contextual cue manipulation designed to mimic a more real-world setting. Its results will lend further credence to the AMM as it will demonstrate that a more externally valid distraction (i.e. a contextual manipulation comparing aggression-inhibiting vs. aggression-promoting cues) will also be effective in suppressing aggression. Subjects will be 240 adult male and female social drinkers randomly assigned to 1 of 3 beverage groups (alcohol placebo sober) and 1 of 2 cue manipulation groups (aggression-inhibiting or aggression-promoting). Aggression will be measured using the TAP.

project_terms:
Acute;Adult;Aggressive behavior;Alcohol consumption;Alcoholic Intoxication;Alcohols;Anger;Attention;Behavioral;Belief;Beverages;Cues;Development;Dose;Effectiveness;Empathy;Exhibits;Female;Goals;Health;Intervention;Laboratories;Measures;Modeling;Myopia;Nature;Patient Self-Report;Persons;Placebos;Process;Psychological Models;Randomized;Reaction Time;Relative (related person);Research Personnel;Risk;Risk Factors;Self Perception;Shock;Sports;Testing;Translating;Violence;alcohol effect;cognitive function;college;design;directed attention;distraction;indexing;innovation;male;psychologic;public health medicine (field);sobriety;social;therapy design;trait

public_health_relevance:
This project will provide a new understanding of the causes of alcohol-related violence. It will have significant implications for the development of public health interventions designed to reduce the negative consequences particularly violence associated with alcohol consumption. Support for these hypotheses will encourage public health researchers to develop new and innovative interventions marked by frequent and highly salient positive anti-violence and health-promoting cues in situations where violence is often the result of alcohol intoxication (e.g. bars sports venues college campuses etc).


application_id: 8703706
project_number: 5R01EY021769-03
project_title: The role of Insm1a in photoreceptor differentiation
administering_ic: NEI
award_notice_date: 2014-08-06
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: EY
serial_number: 021769
program_official: NEUHOLD, LISA
project_start_date: 2012-08-01
project_end_date: 2017-07-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 10184513
contact_pi: MORRIS, ANN C
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Retinitis pigmentosa (RP) and allied inherited retinal dystrophies are a leading cause of blindness for which there is currently no cure. One potential treatment for retinal degenerative diseases is cell-based transplantation therapy whereby progenitor cells are transplanted into the diseased eye to replace the lost photoreceptors. While this is an exciting possibility several challenges to the implementation of transplantation therapies must be overcome including the inefficient integration of retinal progenitor cells (RPCs) into the recipient retina and the difficulty of obtaining sufficient numbers of photoreceptor precursors for clinical application. Protocols for the in vitro culture of RPCs must be developed that will produce large numbers of photoreceptor precursors and will promote their survival and differentiation once transplanted. Defining the transcriptional networks that promote specification of photoreceptor precursors is a necessary next step for the evolution of therapeutic strategies. One of the long-term goals of our laboratory is to contribute to these efforts by studying photoreceptor development and regeneration in the zebrafish. The zebrafish is especially useful for studying photoreceptor biology because its retina contains numerous cone subtypes in addition to rods. Furthermore unlike mammals the zebrafish retina is able to regenerate neurons in response to experimental damage. We have recently identified the transcriptional repressor Insm1a as a candidate regulator of photoreceptor differentiation and regeneration. The experiments described in this proposal will define the role of Insm1a during retinal neurogenesis through the application of genetic and molecular genetics approaches. Our specific aims are as follows: Specific Aim I: Determine the role of Insm1a in regulating photoreceptor differentiation during retinal development at the cellular level using both loss- and gain-of-function experiments to place Insm1 within the genetic hierarchy of known photoreceptor development genes and to determine whether it is required for retinal progenitor cell cycle exit; Specific Aim II: Identify the molecular targets of Insm1 regulation in the retinausing a combination of gene expression profiling digital gene expression analysis in vitro reporter assays and in vivo chromatin immunoprecipitation. Completion of our proposal will bridge important gaps in our understanding of the molecular mechanisms of vertebrate photoreceptor differentiation and reveal underlying principles relevant to the development of approaches for the effective treatment of human retinal disease.

project_terms:
Address;Adoption;Ally;Animal Model;Animals;Biological Assay;Biology;Blindness;Cell Cycle;Cell Cycle Progression;Cell Survival;Cell Transplants;Cells;Cone;Data;Development;Disease;Embryo;Evolution;Eye;Gene Expression;Gene Expression Profile;Gene Expression Profiling;Gene Targeting;Genes;Genetic;Goals;Human;Immunohistochemistry;In Situ Hybridization;In Vitro;Inherited;Injury;Investigation;Laboratories;Luciferases;Mammals;Methods;Modeling;Molecular;Molecular Genetics;Molecular Target;Mus;Mutation;Natural regeneration;Nerve Regeneration;Neurons;Pathway interactions;Photoreceptors;Population;Promotor (Genetics);Protocols documentation;Regulation;Reporter;Retina;Retinal;Retinal Degeneration;Retinal Diseases;Retinal Dystrophy;Retinitis Pigmentosa;Rods (Retina);Role;Staging;Stem cells;System;Therapeutic;Transcription Repressor/Corepressor;Transplantation;Vertebrate Photoreceptors;Visual impairment;Zebrafish;Zinc Fingers;base;blastocyst;cell type;chromatin immunoprecipitation;clinical application;digital;effective therapy;gain of function;gene therapy;in vivo;neurogenesis;photoreceptor degeneration;research study;response;retinal neuron;retinal progenitor cell;retinogenesis;stem;therapy development;transcription factor

public_health_relevance:
The development of therapies to treat visual impairment resulting from photoreceptor degeneration will directly benefit from studies of animal models such as the zebrafish which develops ex utero remains optically transparent throughout development and which displays the capacity for injury-induced neural regeneration. The goal of our proposal is to define the role of a transcriptional regulator Insm1 in the development of photoreceptor cells and to identify the genes that are controlled by Insm1 in the developing retina. This information will facilitate efforts to guide photoreceptor differentiation from stem clls in vitro and in vivo for therapeutic purposes.


application_id: 8703632
project_number: 5K08CA155764-04
project_title: The Significance of Isocitrate Dehydrogenase Mutations in Gliomas
administering_ic: NCI
award_notice_date: 2014-07-29
opportunity_number: PA-10-059
application_type: 5
activity_code: K08
ic: CA
serial_number: 155764
program_official: LIM, SUSAN E
project_start_date: 2011-08-12
project_end_date: 2015-06-30
study_section: Transition to Independence Study Section (I)[NCI-I]
contact_pi_person_id: 9285753
contact_pi: HORBINSKI, CRAIG MICHAEL
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The goal of this research proposal is to determine the mechanism(s) by which mutant isocitrate dehydrogenase 1 (IDH1) causes brain tumors to be less aggressive. The most common type of brain tumor is the diffusely infiltrative glioma; these tumors cannot be completely excised surgically and are difficult to treat with radiation and chemotherapy. Thus infiltrative gliomas are incurable. A specific point mutation in IDH1 (and a less common analogous mutation in IDH2) has been found to be quite frequent in these gliomas. When present it is a powerful favorable prognostic factor being strongly associated with longer patient survival. Mutant IDH1 has recently been shown to produce a novel compound 2-hydroxyglutarate (2-HG). However the effects of mutant IDH1 and 2-HG on glioma cells are unknown. Other work showed that 2-HG causes oxidative stress in nonneoplastic tissue models and our preliminary data indicate that 2-HG is toxic to glioma cells and induces autophagy ERK activation and reactive oxygen species production. We therefore hypothesize that the improved survival imparted by mutant IDH1 in diffuse gliomas is due to 2-HG-induced production of reactive oxygen species leading to oxidative damage and cell death. We also hypothesize that the cell death is primarily by autophagy a form of programmed cell death involving lysosomes that has been shown to be prominent in many gliomas. To test these hypotheses glioma cells will be treated with 2-HG or transfected with mutant IDH1 and multiple well-described markers of autophagy and reactive oxygen species will be measured. Response of glioma cells to autophagy and reactive oxygen species modulation will be assessed. For patient-derived tumor biopsies and human-mouse xenografts immunohistochemical markers of autophagy and oxidative stress will be quantified and correlated with IDH mutation status. Success in this project would determine whether mutant IDH1 causes increased oxidative stress and autophagy in gliomas thereby producing a less aggressive glioma compared to tumors that are wild type for IDH1. This knowledge could then be exploited to develop novel ways of treating gliomas. I am fortunate to have been mentored by exceptional scientists and physicians thus instilling in me a desire to pursue a career that synthesizes what I have learned as a scientist and neuropathologist.My graduate and postdoctoral work in neuroscience and my work in neuro-oncology have given me a diverse array of techniques and approaches that will be used in this project. My current position as an Assistant Professor in the Department of Pathology in the University of Kentucky offers the ideal opportunity to pursue my goal of being an independent investigator. I have nine person-months (75%) of guaranteed protected time for research separate laboratory space that has been fully equipped a full-time technician to increase output and sufficient funds to conduct experiments for the next four years. All this has been put in place by my chairman Dr. Paul Bachner independent of my success in securing extramural funding. I also benefit from a collaborative environment superb mentorship by Drs. Natasha Kyprianou Arie Perry and Jeremy Rich and excellent technical resources. Now that I have completed my clinical training the funding provided by this K08 award would allow me to develop as an independent investigator. Furthermore the project described in this proposal provides a superb opportunity to discover why mutant IDH1 imparts a more favorable survival in patients afflicted with gliomas in turn helping to identify pathways and targets for effective therapeutic interventions.

project_terms:
Affect;Antioxidants;Apoptosis;Arginine;Autophagocytosis;Award;Binding Sites;Biology;Biopsy;Brain Neoplasms;Cell Death;Cell Survival;Cells;Cessation of life;Chairperson;Clinical;Codon Nucleotides;Data;Detection;Diffuse;Environment;Enzymes;Extramural Activities;Funding;Future;Genetic;Glioma;Gliomagenesis;Goals;Human;In Vitro;Isocitrate Dehydrogenase (NAD+);Isocitrates;Kentucky;Knowledge;Laboratories;Lead;Learning;Lesion;Lysosomes;Measurement;Measures;Mentors;Mentorship;Metabolic;Methods;Mus;Mutate;Mutation;NADP;Neurosciences;Output;Oxidative Stress;Pathology;Pathway interactions;Patients;Persons;Physicians;Point Mutation;Positioning Attribute;Primary Neoplasm;Production;Prognostic Factor;Radiation;Reactive Oxygen Species;Research;Research Personnel;Research Proposals;Resources;Scientist;Secure;Techniques;Testing;Therapeutic Intervention;Time;Tissue Model;Tissues;Training;Tumor-Derived;Universities;Work;Xenograft procedure;career;chemotherapy;clinically relevant;clinically significant;expectation;glioma cell line;improved;inhibition of autophagy;isocitrate;mutant;neuro-oncology;novel;outcome forecast;oxidative damage;professor;prognostic;research study;response;success;tumor

public_health_relevance:
This research explores why mutant isocitrate dehydrogenase 1 an abnormal enzyme found in many brain tumors is such a powerful marker of longer patient survival. Discovering why this is so will help find new ways to treat these incurable tumors.      The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the "Critique" section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The "Resume and Summary of Discussion" section above summarizes the final opinions of the committee.


application_id: 8703081
project_number: 5R44DK085810-04
project_title: Hollow Fiber Catheter for Drug Delivery into the Prostate
administering_ic: NIDDK
award_notice_date: 2014-07-08
opportunity_number: PA-12-088
application_type: 5
activity_code: R44
ic: DK
serial_number: 085810
program_official: KIRKALI, ZIYA
project_start_date: 2010-06-01
project_end_date: 2016-06-30
study_section: Urologic and Genitourinary Physiology and Pathology[UGPP]
contact_pi_person_id: 8714039
contact_pi: STICE, JIM
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 079228773
duns_number: 079228773
fips: US
organization_id: 10035571
organization_name: TWIN STAR TDS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405071968
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-07-01
budget_end_date: 2016-06-30
project_abstract:
DESCRIPTION (provided by applicant): The significance of the proposed research is based on the growing demand for healthcare resources to treat and manage prostatic disease particularly benign prostatic hyperplasia (BPH) and cancer. Both the incidence and cost of treatment for BPH and its complications are growing rapidly with the aging U.S. population; prostate cancer is the second-leading cause of cancer deaths among men in the U.S. There is a clear need for minimally invasive cost-effective therapies to match the outcomes of surgical treatment options which are associated with significant morbidity and complications. Prostate injections have not become standard of care due to inadequate drug distribution with needles. The Applicants have developed a microporous hollow fiber catheter (MiHFC) for improved injection distribution in the prostate. Phase II innovations focus on further developing MiHFC and combining existing treatment planning methods for drug delivery injections into human prostates with the objective to develop a system that is ready for human clinical use. The same MiHFC device with small changes would be adaptable for use in many other human clinical applications needing improved injection systems such as liver kidney and other solid organs. This would allow researchers to use MiHFC devices for other research projects involving human drug injections either with or without treatment planning. Hypothesis: The MiHFC injection system being developed in Phase II will give urologists and researchers a more reliable tool to plan and deliver injection therapies into the human prostate. Preliminary Data: In Phase I research the innovative use of applicant's MiHFC to improve injection drug delivery into the prostate was successful with MiHFC significantly improving ethanol distribution in canine prostates as compared to needle injections. Specific Aims: The objective of this Phase II proposal is to further develop the applicant's innovative drug delivery system for improved prostate disease therapies and to provide the bench and animal study data to accelerate its clinical use. Aim 1: Finalize human use MiHFC design. The Phase I MiHFC design will be optimized to meet human use specifications established from user requirements. Aim 2: Infusion studies and analysis. Human ex vivo and baboon in vivo studies will be conducted to assess MiHFC safety and agent distribution and to develop of a prostate specific treatment planning system. Aim 3: Design verification and 510(k) submission. Design verification test data and FDA 510(k) clearance will facilitate clinical adoption and commercialization.

project_terms:
Adoption;Aging;Animals;Area;Benign Prostatic Hypertrophy;Cancer Etiology;Canis familiaris;Catheters;Cessation of life;Clinical;Computer software;Data;Development;Devices;Disease;Drug Delivery Systems;Dyes;Ethanol;Evaluation;Fiber;Healthcare;Human;Image;Incidence;Infusion procedures;Injection of therapeutic agent;Kidney;Knowledge;Lead;Light;Liver;Magnetic Resonance;Malignant Neoplasms;Malignant neoplasm of prostate;Methods;Methylene blue;Modeling;Modification;Morbidity - disease rate;Needles;Operative Surgical Procedures;Oral;Organ;Outcome;Papio;Performance;Pharmaceutical Preparations;Phase;Population;Prostate;Prostatic Diseases;Research;Research Methodology;Research Personnel;Research Project Grants;Resources;Safety;Science;Solid;Structure;System;Testing;Therapeutic;Time;Treatment Cost;Urethra;Urologist;aging population;base;clinical application;clinical practice;commercialization;cost effective;design;drug distribution;effective therapy;human study;improved;in vivo;innovation;insight;meetings;men;minimally invasive;public health relevance;standard of care;tool;treatment planning

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  There is a significant demand for healthcare resources to treat and manage prostate diseases. The objective of this Phase II proposal is to develop an innovative drug delivery system for improved prostate disease therapies and to provide the bench and animal study data to accelerate its clinical use.


application_id: 8702712
project_number: 1R21NS084088-01A1
project_title: Novel Biomarkers of TBI Identified Using Phage Display
administering_ic: NINDS
award_notice_date: 2014-01-28
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: NS
serial_number: 084088
suffix: A1
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2014-02-01
project_end_date: 2016-01-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W.
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): Traumatic brain injury (TBI) can be frustratingly difficult to diagnose particularly for mild cases which can result in inadequate or improper treatment. As a result there has been considerable interest in identifying biochemical markers of TBI to aid in diagnosis and evaluation of treatment efficacy. CSF and serum alterations in several proteins have been investigated in both animal models and clinical studies but these appear to be best suited for severe TBI cases. Urgently needed are biomarkers for mild TBI which represents the majority of the cases and which are the most difficult to diagnose. To identify novel serum and CSF biomarkers for mild and moderate TBI we propose an unbiased approach utilizing phage display. Phage display is a powerful tool for selecting peptides proteins or antibodies with specific binding properties. It uses bacteriophages in which DNA encoding a peptide or protein is inserted into the gene encoding a coat protein of a filamentous phage such as M13 phage. The encoded protein or peptide is expressed on the cell surface of the phage and used to attract and bind proteins of interest. We propose to use engineered phage display peptide libraries in which >2 million independent clones express random sequences of 7 or 12 amino acid peptides. In Aim 1 three different phage libraries will be screened to identify phages that bind to the serum and CSF obtained from rats with mild TBI produced using the lateral fluid percussion model. The biofluids will be collected at 6h and 24h after injury. We will utilize a subtractive panning technique in which phage libraries are first bound to the biofluid (CSF or serum) from uninjured mice to remove non- specific phages then incubated with injury biofluids to identify injury-selective phages. Preliminary data demonstrate the feasibility of this approach using serum from a mouse TBI model at 6h postinjury. Aim 2 will use sequence and identify the proteins which bind to the phages selective for the injury biofluids. Together the above results will identify novel biomarkers of mild TBI to assist in the diagnosis of TBI determination of injury severity evaluation of recovery and therapeutic efficacy and prediction of outcomes.

project_terms:
Address;Amino Acids;Animal Model;Antibodies;Bacteriophage M13;Bacteriophages;Binding (Molecular Function);Binding Proteins;Biochemical Markers;Biological Markers;Biomechanics;Brain Concussion;Brain Injuries;Capsid Proteins;Cell surface;Clinical;Clinical Research;DNA;DNA Sequence;Data;Diagnosis;Diagnostic;Discrimination (Psychology);Disease;Dizziness;Engineering;Evaluation;Genes;Head;Headache;Image;Incubated;Individual;Inflammatory;Injury;Inovirus;Lateral;Libraries;Link;Liquid substance;Magnetism;Mass Spectrum Analysis;Modeling;Mus;Nausea;Nervous System Physiology;Outcome;Peptide Phage Display Library;Peptides;Percussion;Phage Display;Phase;Post-Concussion Syndrome;Property;Proteins;Protocols documentation;Radiology Specialty;Rattus;Recombinants;Recovery;Sensitivity and Specificity;Serum;Severities;Symptoms;Techniques;Technology;Time;Translating;Translations;Traumatic Brain Injury;Treatment Efficacy;Unconscious State;base;diagnosis evaluation;fluid percussion injury;injured;instrument;interest;mouse model;novel;public health relevance;research study;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Over 1 million individuals sustain a traumatic brain injury in a given year with the majority being concussions or similar mild forms. However diagnosis of such brain injury is difficult. Biomarkers with sufficient sensitivity and specificity would assistnot only with the diagnosis of brain injury but also with determination of injury severity evaluationof recovery and therapeutic efficacy and prediction of outcomes.


application_id: 8702281
project_number: 1R21AA022416-01A1
project_title: FGF21 and adipose lipolysis in alcoholic fatty liver
administering_ic: NIAAA
award_notice_date: 2014-06-11
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: AA
serial_number: 022416
suffix: A1
program_official: JUNG, KATHY
project_start_date: 2014-07-01
project_end_date: 2016-06-30
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 8029790
contact_pi: FENG, WENKE
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Alcoholic fatty liver is considered as the earliest pathological alteration of progression in alcoholic liver disease (ALD) from hepatic steatosis to hepatitis fibrosis cirrhosis and even hepatocellular carcinoma. Hepatic reverse transport of free
fatty acids (FFAs) derived from adipose hyperlipolysis resulting from alcohol ingestion plays a critical role in fatty liver formation. However the mechanisms by which alcohol regulates adipose tissue lipolysis are unclear. Recently fibroblast growth factor 21 (FGF21) has emerged as a hepatic regulatory factor that acts on multiple targets including the liver itself in an autocrine fashion and importantly on white adipose tissue to regulate lipid homeostasis. We have found that FGF21 plays a critical role in alcohol-induced adipose lipolysis and in hepatic fat accumulation in animal models of ALD and circulating FGF21 levels are significantly increased in patients with ALD and in experimental animal models. However how FGF21 regulates adipose tissue lipolysis during alcohol exposure is not known. The aims of this project are to investigate the role of FGF21 in adipose tissue lipolysis in response to alcohol exposure to improve our understanding of the molecular mechanisms in the regulation and action of this hormone in ALD and to assess the therapeutic potential in alcohol-induced fatty liver formation. To achieve this goal we will carry out the following specific aims. In aim 1 we will determine whether FGF21 plays a stimulatory role in adipose tissue lipolysis and the underlying mechanisms associated with hormone sensitive lipase and perilipin pathway during alcohol exposure using FGF21 knockout and transgenic overexpression mouse models. In the second aim we will test our hypothesis that adipose tissue specific disruption of FGF21 decreases FFA release and hepatic uptake and attenuates alcohol-induced fatty liver formation using adipose selective -klotho knockout mice.

project_terms:
Adipose tissue;Alcohol consumption;Alcoholic Fatty Liver;Alcoholic Liver Diseases;Alcohols;Animal Model;Attenuated;Body fat;Calories;Capsid Proteins;Catecholamines;Chronic;Cirrhosis;Cyclic AMP;Data;Deuterium;Development;Endocrine;Epidemiologic Studies;Ethanol;Experimental Animal Model;Exposure to;Fatty Liver;Fatty acid glycerol esters;Fibroblast Growth Factor;Fibrosis;Goals;Hepatic;Hepatitis;Hepatocyte;Homeostasis;Hormones;Hyperlipidemia;Incubated;Insulin;Knock-out;Knockout Mice;Label;Lipids;Lipolysis;Liver;Liver diseases;Mediating;Mediator of activation protein;Metabolic;Molecular;Nicotinic Acids;Nonesterified Fatty Acids;Pathway interactions;Patients;Phosphorylation;Plasma;Play;Primary carcinoma of the liver cells;Recombinant Fibroblast Growth Factor;Regulation;Reporting;Resistance;Rodent;Role;Serum;Signal Transduction;Testing;Therapeutic;Transgenic Mice;Transgenic Organisms;Triglycerides;Wild Type Mouse;alcohol exposure;alcohol response;autocrine;base;deprivation;fatty acid transport;feeding;fibroblast growth factor 21;improved;lipid biosynthesis;lipid metabolism;meetings;member;mouse model;overexpression;oxidation;perilipin;problem drinker;public health relevance;receptor;response;sterol esterase;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Alcoholic fatty liver is considered as the earliest pathological alteration of progression in alcoholic liver disease (ALD) from hepatic steatosis to hepatitis fibrosis cirrhosis and even hepatocellular carcinoma. Using animal models we will investigate the role of FGF21 in response to alcohol exposure to improve our understanding of the molecular mechanisms in the regulation and action of this hormone in ALD and to assess the therapeutic potential in alcohol- induced fatty liver formation.


application_id: 8701631
project_number: 1R21DC013343-01A1
project_title: Odorant Receptor Gene Regulation
administering_ic: NIDCD
award_notice_date: 2014-02-06
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: DC
serial_number: 013343
suffix: A1
program_official: SULLIVAN, SUSAN L
project_start_date: 2014-03-01
project_end_date: 2016-02-28
study_section: Special Emphasis Panel[ZRG1 SCS-N (09)]
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_abstract:
DESCRIPTION (provided by applicant): This project investigates the actions of two homeodomain transcription factors that help control expression of nearly all of the more than 1000 mouse odorant receptor genes expression so finely regulated that each olfactory nerve cell expresses just one allele of one odorant receptor gene. The overarching hypothesis for the project proposes that homeodomain transcription factor stimulation of odorant receptor gene transcription triggers local positive feedback acting through active chromatin modifications while simultaneously enhancing global negative feedback acting through repressive chromatin modifications competing events capable of explaining the singularity of odorant receptor expression. This project tests whether the transcription factors act directly at promoters and enhancers of odorant receptor genes and whether these events are associated with selected active chromatin modifications at odorant receptor genes.

project_terms:
Afferent Neurons;Alleles;Back;Binding (Molecular Function);Cells;Chemicals;Chromatin;Code;Complex;Data;Development;Discrimination (Psychology);Disease;Enhancers;Equilibrium;Event;Family;Feedback;Future;Gene Expression;Gene Expression Regulation;Gene Family;Genes;Genetic Predisposition to Disease;Genetic Transcription;Histones;In Vitro;Mammals;Modeling;Modification;Molecular;Mus;Mutant Strains Mice;Mutation;Neurons;Odorant Receptors;Odors;Olfactory Nerve;Outcome;Process;Promotor (Genetics);Property;Receptor Gene;Recruitment Activity;Reporter Genes;Repression;Role;Site;Specificity;Testing;Transcription Initiation;Work;afferent nerve;base;cancer genetics;chromatin modification;coping;emx2 protein;genetic discrimination;homeodomain;in vivo;interest;neuron development;public health relevance;receptor expression;selective expression;transcription factor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Expression of odorant receptors which are the largest family of mammalian genes is so specific that each olfactory sensory nerve cell expresses only one allele of one odorant receptor gene. Mechanisms controlling gene expression are broadly interesting given their fundamental involvement in normal development cancer and genetic susceptibility to diseases and the odorant receptors represent the most extreme and exquisite example of how cells achieve specificity of expression from a large gene family. Though poorly understood odorant receptor gene expression does appear to depend on two homeodomain transcription factors whose actions are the focus of this project.


application_id: 8701482
project_number: 1R21CA177359-01A1
project_title: Promoting Colorectal Cancer Screening in Rural Emergency Departments
administering_ic: NCI
award_notice_date: 2014-09-23
opportunity_number: PAR-13-132
application_type: 1
activity_code: R21
ic: CA
serial_number: 177359
suffix: A1
program_official: BRESLAU, ERICA S
project_start_date: 2014-09-23
project_end_date: 2016-08-31
study_section: Health Disparities and Equity Promotion Study Section[HDEP]
contact_pi_person_id: 8003903
contact_pi: HATCHER, JENNIFER
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Rural Appalachian Kentuckians suffer a disproportionate incidence and mortality from colorectal cancer (CRC) the second leading cause of cancer death. The Centers for Disease Control estimate that as many as 60 percent of CRC related deaths could be prevented if everyone age 50 and older were screened regularly. Rural Appalachian residents are currently being screened at suboptimal rates. The proposed intervention builds on our successful cancer prevention projects: Faith Moves Mountains: A CBPR Appalachian Wellness and Cancer Prevention Program and Promoting Mammography among African American Women Visiting the Emergency Departments. Both projects involve lay health advisor (LHA) delivered motivational interviewing interventions that have been culturally tailored. We propose to pilot test a culturally tailored intervention using brief motivational interviewing by LHAs to promote CRC screenings in an emergency department (ED) serving rural Appalachian Kentucky in order to (1) evaluate the feasibility of the intervention in this rurl Appalachian setting; and (2) assess the effects of the intervention on perceived barriers to CRC screening and subsequent cancer screening engagement.  Consistent with our current Faith Moves Mountains and Promoting Mammography projects we will train carefully selected community members (LHAs) to deliver a brief motivational interview while participants wait for non-urgent care in the ED or wait with a family member who is receiving care. Each participant in conjunction with the LHA will develop a written plan of action that addresses their identified barriers to screening. The brief intervention will take about 15 minutes and will be delivered in a
private area of the ED. Control group participants will receive standard-of-care ED services that include brochure information identifying general cancer screening services provided by the hospital. Outcome measures will include assessment of barriers and receipt of CRC screening and will be measured at three and six months post intervention. The results will serve as preliminary data for a multisite rural ED-based clinical trial evaluating the cancer promotion intervention.

project_terms:
Accident and Emergency department;Address;Advisory Committees;Affect;African American;Age;Appalachian Region;Area;Cancer Burden;Cancer Etiology;Caring;Centers for Disease Control and Prevention (U.S.);Cessation of life;Clinical Trials;Colorectal Cancer;Communities;Control Groups;County;Data;Educational aspects;Family member;Goals;Guidelines;Health;Health Services Accessibility;Healthcare Systems;Hospitals;Incidence;Individual;Intervention;Intervention Trial;Kentucky;Malignant Neoplasms;Mammography;Measures;Mortality Vital Statistics;Outcome Measure;Pamphlets;Participant;Patients;Population;Prevention program;Preventive;Primary Health Care;Provider;Randomized Controlled Trials;Readiness;Recommendation;Recruitment Activity;Research;Risk;Rural;Screening for cancer;Services;Staging;Survival Rate;Targeted Research;Testing;Training;Visit;Vulnerable Populations;Woman;Writing;base;behavioral/social science;brief intervention;cancer prevention;colorectal cancer screening;disorder prevention;experience;health disparity;high risk;innovation;intervention effect;member;motivational enhancement therapy;post intervention;prevent;programs;public health relevance;screening;social science research;therapy design

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  This project will be the first to address the disproportionate incidence and mortality from CRC in rural Appalachia by providing an innovative CRC screening intervention in a rural ED.


application_id: 8701458
project_number: 1R21NS083692-01A1
project_title: Leptin Obesity and Stroke
administering_ic: NINDS
award_notice_date: 2014-02-03
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: NS
serial_number: 083692
suffix: A1
program_official: CORRIVEAU, RODERICK A
project_start_date: 2014-02-15
project_end_date: 2016-01-31
study_section: Special Emphasis Panel[ZRG1 BINP-Y (08)]
contact_pi_person_id: 8535896
contact_pi: MURPHY, MICHAEL PAUL
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Metabolic disease is linked to obesity - especially mid-life obesity - a persistent problem in our society. An unexplained connection exists between type 2 diabetes mellitus and neurologic disorders such as vascular dementia (VaD) and Alzheimer's disease (AD). The biological mechanism underlying this link is not known. As our population demographics shift towards an older average age the potential confluence of obesity diabetes and age related neurological dysfunction represents a potential public health disaster. The form of dementia afflicting individuals with a history of obesity and diabetes combines vascular pathology strokes and AD related neuropathology including amyloid deposits. It is not known if amyloid either in the brain parenchyma or deposited within the cerebrovasculature causes the vascular pathology or if some other aspect of diabetes and obesity is reponsible. This proposal grew out of the possibility that this connection may be related to leptin resistance. Leptin is an adipocyte-derived peptide hormone that regulates satiety and hunger via signaling through the leptin receptor which is expressed throughout the brain. Obese individuals are resistant to leptin. In preliminary experiments we discovered that leptin is a strong regulator of -secretase particularly PS1 expression at the mRNA level. To investigate this problem we created a line of knock-in mice that become rapidly obese and diabetic and develop amyloid pathology with increasing age. The most remarkable feature of this unique mouse model (db/AD) is that it develops a striking phenotype of cerebrovascular pathology including aneurysms and strokes and displays a profound cognitive impairment. This mouse line does not overexpress disease related proteins or use artificial promoter systems making it an ideal system for the study of how aberant gene regulation in metabolic disease can influence brain pathology. We believe that we have created a mouse model of VaD an understudied neurological disorder with limited treatment options. We propose to use our unique db/AD model to determine the mechanistic connection between aberrant leptin signaling and the development of aneurysms strokes and other aspects of cerebrovascular pathology. We will track the development of pathology longitudinally using state-of-the-art magnetic resonance imaging combined with two approaches currently in human clinical trials to treat dementia. Since these approaches have been shown to have a good safety profile in human trials the clinical implications for the outcome of this study are significant. The major strengths of this proposal are the use of a novel mouse model with unique features and an innovative approach to determine the mechanism driving the development of pathology. This project has the potential to significantly advance our understanding of the major underlying causes of VaD and has significant implications for the treatment and prevention of age-related cerebrovascular disease.

project_terms:
Adipocytes;Affect;Age;Alzheimer's Disease;Alzheimer's disease model;Amyloid;Amyloid deposition;Aneurysm;Automobile Driving;Biological;Biological Factors;Blood Vessels;Brain;Brain Pathology;Cell Density;Cerebrovascular Disorders;Characteristics;Clinical;Clinical Trials;Dementia;Deposition;Development;Diabetes Mellitus;Disasters;Disease;Electron Microscopy;Employee Strikes;Endothelial Cells;Excision;Exhibits;Foundations;Functional disorder;Future;Gene Expression Regulation;Health;Human;Hunger;Image;Impaired cognition;Individual;Knock-in Mouse;Leptin;Leptin resistance;Lesion;Link;Magnetic Resonance Imaging;Messenger RNA;Metabolic Diseases;Modeling;Mus;Neurodegenerative Disorders;Neurologic Dysfunctions;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Outcome Study;Pathology;Peptides;Phenotype;Population;Prevention;Prevention strategy;Production;Promotor (Genetics);Proteins;Recording of previous events;Resistance;Risk;Role;Safety;Satiation;Signal Transduction;Societies;System;Testing;Vascular Dementia;age related;amyloid pathology;angiogenesis;base;cerebrovascular;demographics;density;diabetic;inhibitor/antagonist;innovation;leptin receptor;light microscopy;middle age;mouse model;nervous system disorder;neuropathology;notch protein;novel;overexpression;peptide hormone;presenilin-1;prevent;public health medicine (field);research study;secretase;small molecule;stroke;therapeutic development

public_health_relevance:
PUBLIC HEALTH RELEVANCE: A strong connection exists between risk for vascular dementia Alzheimer's disease type 2 diabetes and obesity but the mechanisms are unknown. The connection may involve strokes and other forms of cerebrovascular pathology. This project will explore the mechanism of this link and provide a strong foundation for future therapeutic development.


application_id: 8701451
project_number: 1R21AG045809-01A1
project_title: Leptin Signaling and Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2014-08-29
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: AG
serial_number: 045809
suffix: A1
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2014-09-01
project_end_date: 2016-05-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 8535896
contact_pi: MURPHY, MICHAEL PAUL
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common age-related neurodegenerative disease currently affecting more than five million people in the U.S.A. The vast majority of AD cases are sporadic with no clear etiology. It is well-documented that lifestyle and overall health play a role in the development of the disease. A connection exists between risk for AD and Type 2 Diabetes Mellitus (T2DM) a metabolic disease that is linked to obesity. The mechanism that underlies this epidemiological connection is unknown. Recent neuropathology studies have shown that AD cases that have a history of T2DM and obesity have substantially more cerebrovascular pathology but have either the same or lesser amounts of neuritic plaques and neurofibrillary tangles. It may be that changes in the cerebrovasculature alter the threshold for the development of AD or that individuals with AD and a history of obesity represent cases of mixed AD and vascular dementia (VaD). This proposal considers the possibility that these elements are connected through defective leptin signaling since individuals with a history of obesity and diabetes are leptin resistant. Leptin is an adipocyte-derived peptide hormone that regulates satiety and hunger via signaling through the leptin receptor (LepR) and these receptors are expressed throughout the brain. To explore the connection between leptin resistance obesity and AD we created a unique mouse line (db/AD) that combines features of these pathophysiologic states. These mice are resistant to leptin (the LepR is inactivated) become rapidly obese and diabetic and develop AD-related neuropathology. These mice also develop a striking phenotype of cerebrovascular pathology and display a profound cognitive impairment. In recent years several studies have linked leptin with cognitive function. It has even been suggested that leptin treatment may be a viable therapeutic approach towards alleviating age-related cognitive decline. This project proposes to directly test the role of leptin in cognitive function in our novel model by selectively replacing he defective LepR in the brain with a functional version via adeno-associated virus thereby restoring leptin sensitivity. Preliminary tests indicate that we are able to replace the receptor without affecting the hypothalamus and the animals remain hyperphagic and retain their metabolic disease phenotype. We therefore believe that this approach will allow us to separate the effects of leptin on the development of neurologic dysfunction from the many complex problems associated with obesity and systemic metabolic disease. If leptin resistance is the cause of the cognitive dysfunction in the db/AD mice then restoring leptin sensitivity will improve function. This project utilizing a novel and innovative mouse model has the potential to significantly advance our understanding of the association between obesity diabetes and dementia. If there is a clear connection between leptin leptin resistance and neuropathology patients may one day benefit from preventative of therapeutic strategies targeting leptin pathways.

project_terms:
Adipocytes;Affect;Age;Age-associated memory impairment;Alzheimer's Disease;Alzheimer's disease risk;Amyloid;Amyloid beta-Protein;Aneurysm;Animals;Beryllium;Biological;Biological Process;Brain;Case Mixes;Characteristics;Clinical;Complex;Data;Dementia;Dependovirus;Deposition;Development;Diabetes Mellitus;Disasters;Disease;Electron Microscopy;Employee Strikes;Endothelial Cells;Epidemiology;Etiology;Exhibits;Foundations;Functional disorder;Future;Genotype;Health;Hunger;Hypothalamic structure;Image;Impaired cognition;Individual;Injury;Knock-in Mouse;Knowledge;Leptin;Leptin resistance;Lesion;Life Style;Link;Magnetic Resonance Imaging;Mediator of activation protein;Metabolic;Metabolic Diseases;Modeling;Mus;Neurodegenerative Disorders;Neurofibrillary Tangles;Neurologic Dysfunctions;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathologic;Pathology;Pathway interactions;Patients;Peptides;Phenotype;Play;Population;Predisposition;Recording of previous events;Resistance;Risk;Risk Factors;Role;Satiation;Senile Plaques;Serum;Signal Transduction;Societies;System;Testing;Therapeutic;Variant;Vascular Dementia;Weight;age related;aging brain;angiogenesis;cerebrovascular;cognitive function;demographics;diabetic;disease phenotype;high risk;improved;improved functioning;innovation;leptin receptor;light microscopy;middle age;mouse leptin receptor;mouse model;nervous system disorder;neuronal survival;neuropathology;novel;peptide hormone;prevent;public health medicine (field);receptor;repaired;stroke;therapeutic development

public_health_relevance:
PUBLIC HEALTH RELEVANCE: A strong connection exists between risk for vascular dementia Alzheimer's disease type 2 diabetes and obesity but the mechanisms are unknown. The connection may involve strokes and other forms of cerebrovascular pathology. This project will explore the mechanism of this link and provide a strong foundation for future therapeutic development.


application_id: 8700284
project_number: 5R01AG042419-02
project_title: Modulation of microRNA pathways by gemfibrozil in predementia Alzheimer disease
administering_ic: NIA
award_notice_date: 2014-06-24
opportunity_number: PAR-11-100
application_type: 5
activity_code: R01
ic: AG
serial_number: 042419
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
arra_indicator: N
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 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;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;cost;design;drug discovery;human subject;mild cognitive impairment;novel;peptide A;placebo controlled study;pre-clinical;primary outcome;public health relevance;secondary outcome;tau Proteins

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: 8699847
project_number: 5R01NS045734-11
project_title: Vascular responses as therapeutic targets after SCI
administering_ic: NINDS
award_notice_date: 2014-07-03
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: NS
serial_number: 045734
program_official: JAKEMAN, LYN B
project_start_date: 2004-05-03
project_end_date: 2016-07-31
study_section: Special Emphasis Panel[ZRG1-BDCN-W(02)M]
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: HAGG, THEO
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:
DESCRIPTION (provided by applicant): The endoplasmic reticulum (ER) stress response (ERSR) is one of the major defense mechanisms that protect against cellular insult but if unchecked leads to apoptotic cell death. The ERSR has three arms initiated by PERK IRE1 ATF6 respectively. Preliminary data show the acute activation of all three ERSR signaling pathways in endothelial cells (ECs) after SCI. Most importantly we show that attenuation of PERK signaling in CHOP-/- (the downstream effector of PERK) mice or after i.v. salubrinal (which sustains protein synthesis inhibition) leads to enhanced functional recovery after SCI in WT mice. We found an acute vasoconstrictive phase following SCI and can enhance EC protection by the vasodilator nimodipine plus the vasoprotector glibenclamide in WT mice. Specifically Aim 1 will delineate the specific effectors that underlie ERSR-mediated EC death by PERK signaling. We will determine if reducing PERK or ATF4 signaling in ECs after SCI will enhance functional recovery after SCI. This will be done using available transgenic mice (Aim 1a) and siRNA methods (Aim 1b). We hypothesize that the earlier in the ERSR pathway that inhibition occurs the more extensive the vasoprotection and recovery. Aim 2 will characterize the acute activation profile of the ERSR in FACS purified ECs when one signaling pathway is deleted (Aim 2a) their effects on spinal cord microvasculature (Aim 2b) and the functional consequences (Aim 2c). Aim 3 will test whether EC rescue by ER stress inhibitors can be improved when combined with the vasodilators nimodipine or MgSO4 the mainstay treatments for CNS vasospasm. Aim 3a will optimize vasodilation protocols. Aim 3b will optimize treatment regimens for salubrinal and two chemical chaperones that influence ERSR signaling: TUDCA (in clinical trials for ALS) and PBA (FDA-approved). We will then test whether optimized vasodilation would further improve the efficacy of those drugs using both pharmacological and genetic approaches. Aim 3c will define determine the therapeutic window. Collectively the experiments outlined in these 3 Aims delineate a strategy to optimally inhibit ER stress in ECs to maximize functional recovery after SCI and determine whether this approach is clinically relevant.

project_terms:
Acute;Apoptosis;Apoptotic;Binding Proteins;Blood Vessels;Blood flow;CD47 gene;Cell Death;Cell Survival;Cells;Chemicals;Clinic;Clinical Trials;Cytoprotection;Data;Defense Mechanisms;Dimerization;Drug Kinetics;Drug usage;Endothelial Cells;Event;FDA approved;Funding;Genes;Genetic;Glyburide;Goals;Grant;Hypoxia;Inflammation;Integrins;Ligands;Mediating;Methods;Molecular Chaperones;Mus;Nervous System Physiology;Nimodipine;Notch Signaling Pathway;Outcome;Oxidative Stress;Pathway interactions;Peptides;Pharmaceutical Preparations;Phase;Phosphorylation;Promotor (Genetics);Protein Dephosphorylation;Protein Synthesis Inhibition;Protocols documentation;Recovery;Recovery of Function;Role;Safety;Signal Pathway;Signal Transduction;Small Interfering RNA;Spinal Cord;Spinal cord injury;Stress Response Signaling;TNFRSF10B gene;Testing;Therapeutic;Therapeutic Agents;Thinking function;Thoracic spinal cord structure;Thrombospondin 1;Tissues;Transgenic Mice;Translations;Traumatic CNS injury;Treatment Protocols;Vascular constriction (function);Vasodilation;Vasodilator Agents;Vasospasm;Work;angiogenesis;arm;attenuation;biological adaptation to stress;clinically relevant;cytotoxic;endoplasmic reticulum stress;excitotoxicity;improved;inhibitor/antagonist;nervous system disorder;offspring;research study;response;tauroursodeoxycholic acid;therapeutic target

public_health_relevance:
This grant examines the role of the endoplasmic reticulum stress response a cellular defense mechanism induced in every spinal cord cell after SCI which if unchecked leads to cell loss after SCI causing the loss of neurological functions. Our previous data show the crucial role of endothelial cell death of blood vessels in the spinal cord in the ensuing secondary loss of spinal cord tissue. Using both genetic approaches and current FDA approved and/or in clinical trial drugs to rescue the endothelial cells we expect to identify new acute therapeutic targets that will hopefully extend beyond SCI to other CNS trauma and neurological disease treatment.


application_id: 8699686
project_number: 5R41AR064596-02
project_title: Intelligent and Automatic Image Segmentation Software for High ThroughputAnalysi
administering_ic: NIAMS
award_notice_date: 2014-07-30
opportunity_number: PAR-09-221
application_type: 5
activity_code: R41
ic: AR
serial_number: 064596
program_official: WANG, XIBIN
project_start_date: 2013-07-15
project_end_date: 2015-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-Q(14)B]
contact_pi_person_id: 8263548
contact_pi: ESSER, KARYN A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078357046
primary_uei: LA54LAMKQ5A6
duns_number: 078357046
uei: LA54LAMKQ5A6
fips: US
organization_id: 10032028
organization_name: CYTOINFORMATICS, LLC
organization_city: NICHOLASVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403568852
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): It is well established that aging and many chronic diseases such as cancer and heart failure are associated with significant losses in skeletal muscle mass and strength in humans. There is agreement across the muscle biology community that important morphological characteristics of muscle fibers such as fiber area the number and position of myonuclei cellular infiltration and fibrosis are critical factors that determine the health and function of the muscle. However at this time quantification of muscle characteristics from standard histological and immunohistological techniques is still a manual or at best a semi-automatic process. This process is labor intensive and can be prone to errors leading to high inter-observer variability. On the other hand when muscle characteristics are calculated by computer-aided image analysis data acquisition times decrease and objectivity improves significantly. The objective of this Phase I STTR project is to build a fully automatic intelligent and high throughput image acquisition and analysis software for quantitative muscle morphological analysis on digitized muscle cross-sections. We propose to utilize the most recent technical advances in machine learning and biomedical image analysis. This includes a newly developed deformable model and mean-shift based seed detection algorithm for better segmentation accuracy; an asymmetric online boosting based machine learning algorithm which allows the software to learn from errors and adjust its segmentation strategies adaptively; and a data parallelization schema using the graphic processing unit (GPU) to handle the computational bottleneck for extremely large scale image such as whole slide scanned specimens. We believe that this software equipped with the most advanced technical innovations will be commercially attractive for the skeletal muscle research community including basic scientists clinician scientists and the pharmaceutical industry. The specific aim are: 1) Develop implement and validate an automatic biological image analysis software package for skeletal muscle tissue; 2) Develop a novel online updated intelligent artificial intelligence unit to enable the software to learn from errors; 3) Build a novel high performance computing unit to enable fast and high throughput automatic image analysis which is capable of processing whole slide scanned muscle specimens. The analysis approach proposed will provide more consistent accurate and objective quantification of skeletal muscle morphological properties and the time for data analysis will be reduced by over a factor of 100 for standalone version and 2000 for parallel version. The long-term goal of Cytoinformatics LLC for the Phase II stage is to apply the software to analyze histology/pathology from human muscle biopsy samples and extension of the software to other biological tissues such as adipose tissue.

project_terms:
Adipose tissue;Aging;Agreement;Algorithms;Appearance;Area;Artificial Intelligence;Basic Science;Biological;Biology;Biometry;Biopsy Specimen;Cell Nucleus;Cellular Infiltration;Characteristics;Chronic Disease;Clinical Research;Communities;Computational Science;Computer Assisted;Computer software;Data;Data Analyses;Defect;Detection;Drug Industry;E-learning;Eosine Yellowish;Exhibits;Fiber;Fibrosis;Freezing;Future;Goals;Health;Heart failure;Hematoxylin;High Performance Computing;Histology;Human;Human Pathology;Image;Image Analysis;Interobserver Variability;Intervention;Learning;Machine Learning;Malignant Neoplasms;Manuals;Marketing;Methods;Modeling;Morphologic artifacts;Muscle;Muscle Fibers;Muscle function;NIH Program Announcements;Performance;Phase;Pilot Projects;Positioning Attribute;Process;Property;Research;Research Personnel;Resources;Sampling;Scanning;Science;Scientist;Seeds;Shapes;Site;Skeletal muscle structure;Slide;Small Business Technology Transfer Research;Specimen;Speed (motion);Staging;Staining method;Stains;Techniques;Technology;Time;Tissues;United States National Institutes of Health;Update;Yang;base;bioimaging;biomedical informatics;cohort;computer science;data acquisition;design;fluorescence imaging;imaging Segmentation;improved;innovation;muscle form;muscle strength;novel;public health relevance

public_health_relevance:
Important features of muscle fibers such as fiber area the number and position of myonuclei cellular infiltration and fibrosis are critical factors that determine the health of the muscle. However quantification of muscle features from digitized images is still a manual or at best a semi-automatic process. The objective of this Phase I STTR project is to build software using the most recent technical advances in machine learning and biomedical image analyses to significantly move the skeletal muscle basic and clinical research fields ahead.


application_id: 8699312
project_number: 1R21DK100258-01A1
project_title: Dietary fat lipoproteins and lipopolysaccharide: role in insulin resistance
administering_ic: NIDDK
award_notice_date: 2014-04-08
opportunity_number: PA-12-157
application_type: 1
activity_code: R21
ic: DK
serial_number: 100258
suffix: A1
program_official: CHAN, KEVIN E
project_start_date: 2014-04-15
project_end_date: 2016-03-31
study_section: Special Emphasis Panel[ZRG1 EMNR-P (03)]
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
project_abstract:
DESCRIPTION (provided by applicant): Obesity is associated with insulin resistance and chronic inflammation in adipose tissue muscle and liver and the mechanisms underlying this inflammation is not well understood. Endotoxin (lipopolysaccharide LPS) is carried on gut-derived lipoproteins (chylomicrons) and provides a link between dietary fat and inflammation. During chylomicrons assembly LPS and LPS binding protein (LBP) are attached to the particle. Plasma LPS in the chylomicron fraction transiently increases following a fatty meal. Chylomicron triglyceride is cleared from plasma by adipose and muscle lipoprotein lipase (LpL); remnant lipoproteins are then cleared by the liver. Strong associations between insulin resistance/diabetes and plasma LPS have been found. Further links between gut bacteria and insulin resistance are illustrated by many experiments in germ-free mice or in mice with microbiota transplants which show changes in diet-induced obesity and insulin resistance. We hypothesize that the LPS on chylomicrons is delivered to adipose tissue muscle and liver during chylomicron TG lipolysis and the released LPS initiates a low-grade inflammatory reaction in these tissues that contributes to tissue inflammation and insulin resistance. A slow process of chylomicron lipolysis with persistent remnant lipoproteinemia may be associated with high exposure to LPS and consequent tissue inflammation. There is already an extensive literature in rodents demonstrating alterations in obesity inflammation and insulin resistance with various immune modulations or manipulations of microbiota. These questions have not been well tested in humans. This study is intended to determine whether alteration of gut microbiota can impact human lipoprotein associated LPS and insulin resistance. Specific Aim 1. We will determine whether an alteration in the gut microbiota achieved with rifaximin will decrease circulating LPS. We will measure plasma LPS both in the fasting state and after a lipid-rich meal in obese MetS subjects. The subjects will then be treated with the antibiotic rifaximin for 8 weeks to substantially reduce gut bacteria which can be detected by current techniques. Specific Aim 2. We will determine whether a change in the gut microbiota from rifaximin treatment will decrease adipose inflammation and improve insulin resistance. Subjects will undergo a baseline fat biopsy and a euglycemic clamp to measure peripheral and hepatic insulin sensitivity. They will then be treated with rifaximin and the insulin sensitivity testing ad biopsies will be repeated to determine if disruption of the microbiota reduces tissue inflammation and improves insulin sensitivity.

project_terms:
Abbreviations;Adipose tissue;Aftercare;Antibiotic Therapy;Antibiotics;Area Under Curve;Bacteria;Binding (Molecular Function);Biopsy;Chronic;Chylomicrons;Diabetes Mellitus;Diet;Dietary Fats;Endotoxins;Euglycemic Clamping;Exposure to;Extracellular Matrix;Fasting;Fatty acid glycerol esters;Germ-Free;Glucose Clamp;Hepatic;Human;Immune system;Inflammation;Inflammatory;Infusion procedures;Insulin;Insulin Resistance;Intervention;Limulus;Link;Lipids;Lipolysis;Lipopolysaccharides;Lipoproteins;Literature;Liver;Measures;Metabolic syndrome;Methods;Mus;Muscle;Nonesterified Fatty Acids;OGTT;Obesity;Peripheral;Plasma;Play;Process;Reaction;Research;Rodent;Role;Safety;Serum amyloid A protein;Techniques;Testing;Tissues;Transplantation;Triglycerides;bacterial resistance;gut microbiota;immunoregulation;improved;insulin sensitivity;lipopolysaccharide-binding protein;lipoprotein lipase;particle;public health relevance;research study;rifaximin

public_health_relevance:
Narrative:Obesity is closely linked with insulin resistance and diabetes and current research suggests that inflammationof fat plays a causal role in insulin resistance. Dietary fat causes an increase in plasma lipopolysaccharidewhich circulates bound to lipoproteins and we hypothesize that the LPS is transported to tissues and isresponsible for much of the tissue inflammation associated with insulin resistance.


application_id: 8699257
project_number: 5R00HL105577-04
project_title: Role of MP-HBEGF-EGFR signaling for inflammatory action of oxidized phospholipids
administering_ic: NHLBI
award_notice_date: 2014-07-25
opportunity_number: PA-10-063
application_type: 5
activity_code: R00
ic: HL
serial_number: 105577
program_official: CHEN, JUE
project_start_date: 2011-08-01
project_end_date: 2016-07-31
study_section: NSS
contact_pi_person_id: 10232950
contact_pi: LEE, SANGDERK
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:
Project Summary/Abstract:This K99/R00 will support candidate's career goal to become a researcher in the area of cardiovasculardisease with a focus on atherosclerosis. The candidate has past educational background related with cellbiology and pharmacology mainly on receptor signaling projects and simple array analysis. The candidate iscurrently a postdoctoral fellow at UCLA and the K99 training will be executed under mentor Dr. Judith A.Berliner and co-mentor Dr. Aldons J. Lusis at UCLA. The university system is well equipped with highlyproductive and supportive research facilities including systemized training of conduct of research. Theuniversity administrative system is very supportive for the success of new investigators. Dr. Berliner is apioneering researcher who identified important roles of oxidized phospholipids in the vascular inflammatoryresponses. Her experience with analysis of immuno-histochemistry will be important to the success of theproposed studies. Dr. Lusis is an outstanding researcher in the field of systems genetics whose work has beenimportant in identifying genetic factors and novel signaling pathways controlling the development ofatherosclerosis. During this K99 training phase the candidate will meet frequently with mentor and co-mentor.The candidate will also meet with advisory board committee every 6 months. During the K99 mentoring phasethe candidate will focus on mastering immuno-histochemistry and lesion analysis methods which is one of bigadvantages of current lab and associated Core labs. Another important aspect of the K99 will be learning theanalytical tools to do analyze high-throughput transcript and genotyping datasets; these studies are beingperformed by a large number of those in the Lusis group. During the independent R00 phase the candidatewill mainly focus on the in-depth mechanistic studies for MP activation by Ox-PAPC in the endothelial cellsand the validation study of the significance of the genetic factors and cellular pathways identified via systemsgenetics approach. The main goal of this proposed study is to define proximal events in oxidized phospholipid(Ox-PAPC) activation of this inflammatory pathway. In this study in Aim 1 candidate will identify themechanism by which Ox-PAPC induces activation of the MPs using in vitro culture of endothelial cells. In Aim2 candidate will determine if this pathway is activated for inflammation and lesion formation in mouse model ofatherosclerosis. Finally in Aim 3 a systems genetics approach will be used to identify genetic factors andnovel pathways controlling proximal inflammatory responses in vascular endothelium. For this study thecandidate will use transcript and genotyping data sets of the aortic endothelial cells isolated from 96 humandonors which datasets and cells are currently available. The K99 training phase under mentor and co-mentorin the current lab clearly fill the technical gaps to execute the projects proposed. After the training phase thecandidate will be equipped with more diverse tools and approaches to study the cardiovascular disease forsuccessful transit to the independent R00 phase.

project_terms:
Animal Model;Area;Atherosclerosis;Binding (Molecular Function);Blood Vessels;CCL2 gene;Cardiovascular Diseases;Cell surface;Cells;Cellular biology;Cholesterol;Chronic;Cysteine;Data Set;Development;Disease;Educational Background;Endothelial Cells;Endothelium;Epidermal Growth Factor Receptor;Event;Gene Expression;Generations;Genes;Genetic;Genetic Polymorphism;Genotype;Goals;Histocytochemistry;Human;IL8 gene;In Vitro;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Kinetics;Knockout Mice;Learning;Lesion;Life Expectancy;Lipids;Mediating;Membrane Microdomains;Mentors;Metalloproteases;Methods;Modification;Mus;Oxidative Stress;Pathway Analysis;Pathway interactions;Pharmacology;Phase;Phospholipids;Population;Postdoctoral Fellow;Predisposition;Preventive;Reagent;Receptor Activation;Receptor Signaling;Research;Research Personnel;Role;Signal Pathway;Signal Transduction;Structure;System;Testing;Training;Transcript;Universities;Variant;Vascular Endothelial Cell;Vascular Endothelium;Vascular System;Weight;Work;abstracting;aged;analytical tool;career;cytokine;experience;heparin-binding EGF-like growth factor;in vivo;macrophage;meetings;mouse model;novel;oxidation;oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine;public health medicine (field);research facility;response;success;therapeutic target;tool;validation studies;vascular inflammation

public_health_relevance:
Relevance to Public Health: This study is to find preventive and therapeutic targets for the chronic vascular inflammatory diseaseslike atherosclerosis. The primary aim is to contribute to the development of reagents targeting critical step ofvascular inflammation to increase life expectancy of human population especially for aged people. Oxidativestress and the oxidation products of lipids have been shown to be involved in the development ofcardiovascular diseases. This study will test the hypothesis that the oxidized phospholipids produced byvascular oxidative stress will activate metalloproteinases on the endothelial cell surface for proinflammatorycytokine expression leading to chronic inflammatory conditions in the vessel. These studies also have thepotential to identify additional therapeutic targets and identify genetic factors that increase susceptibility ofatherosclerosis.


application_id: 8698405
project_number: 5R21DE023207-02
project_title: Blocking of IL-6 function to prevent Pg mediated Th17 response
administering_ic: NIDCR
award_notice_date: 2014-06-26
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: DE
serial_number: 023207
program_official: MELILLO, AMANDA A
project_start_date: 2013-07-09
project_end_date: 2016-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-B(02)M]
contact_pi_person_id: 6947603
contact_pi: POTEMPA, JAN S
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): Th17 cells are emerging as critical players in many chronic inflammatory diseases including chronic periodontitis. Periodontal disease besides being the most prevalent form of bone pathology in humans is a risk factor for life-threatening conditions such as cardiovascular diseases and diabetes. Attempts to describe the pathogenesis of periodontal disease within the conceptual framework of Th1/ Th2 model have been inconclusive. Several human studies in CP have shown elevated levels of IL-17 signature cytokine of Th17 cells and presence of Th17 cells in the inflamed gingiva. However underlying mechanism of Th17 differentiation and their role in the pathogenesis of CP is not known. In this regard pro-inflammatory pleotropic cytokine IL-6 plays a critical role in differentiation of Th17cells and inhibition of regulatory T cells. Due to this role of IL-6 blocking of IL-6 function ha become an attractive target for treatment of chronic inflammatory and autoimmune diseases. Many clinical trials involving blocking of IL-6 signaling molecules are currently ongoing. In line with this CP although is initiated by microbes which include P. gingivalis disease pathogenesis and progression is immune mediated with high levels of IL-6. P. gingivalis implicated in CP relies on multiple virulence factors like fimbriae LPS and cysteine proteinases ginipains (RgpA and RgPB) which use different signaling receptors to exert their influence. While fimbriae FimA/ Pg LPS targets TLR2 gingipains (RgpA RgpB) signal through PAR-2. Both the receptors are expressed by human dendritic cells. In view of this information major hypothesis of the proposal is that Pg PAMP's adhesins and gingipains which use different PRR's have distinct immune-modulatory roles in TH17 differentiation and blocking of IL-6 signaling molecules represents an important therapeutic target to prevent Pg initiated Th17 differentiation. The major objective of this proposal is to identify molecular therapeutic targets o inhibit Pg and its PAMP's mediated Th17 differentiation and bone loss. To address this we will focus on two approaches first we will investigate the potential of Pg and it PAMP's in induction of IL-6 regulation of IL-6 signaling molecules and in Th17 differentiation by in-vitro cultured monocyte derived dendritic cells (MoDCs).Second we will target IL-6 signaling molecules: a) IL-6 receptor (IL-6R) with anti- IL-6R antibodies b) signal transducing protein gp130Fc and c) Jak2 inhibitor which have been proven to be effective in many chronic inflammatory and autoimmune diseases. The Long term goal of this study is to develop immune-modulatory intervention strategies for fine- tuning the host response to maximize the protective response and minimize the destructive aspects of the periodontal host response. Positive findings will establish the regulation of human Th17 cells by P. gingivalis adhesins and gingipains. Results of the present investigation will be useful in design of novel therapeutic targets.

project_terms:
Address;Alveolar Bone Loss;Animal Model;Antigens;Arginine;Autoimmune Diseases;Bacterial Adhesins;CD4 Positive T Lymphocytes;Cardiovascular Diseases;Cells;Chronic;Clinical Trials;Cysteine Protease;Degenerative polyarthritis;Dendritic Cells;Development;Diabetes Mellitus;Disease;Fc Receptor;Genes;Genetic Polymorphism;Gingiva;Gingival Crevicular Fluid;Goals;Gram-Negative Anaerobic Bacteria;Human;Immune;Immune response;In Vitro;Inflammatory;Interleukin 6 Receptor;Interleukin-1;Interleukin-12;Interleukin-17;Interleukin-6;Intervention;Investigation;Lead;Life;Maintenance;Mediating;Microbe;Modeling;Molecular;Mus;Myocardial Infarction;Oral;Oral mucous membrane structure;PAR-2 Receptor;Pathogenesis;Pathology;Patients;Pattern;Periodontal Diseases;Periodontitis;Phase;Physiologic pulse;Plasma;Play;Porphyromonas gingivalis;Process;Production;Proteins;Receptor Signaling;Regulation;Regulatory T-Lymphocyte;Reporting;Rheumatoid Arthritis;Risk Factors;Role;Signal Transduction;Signaling Molecule;Symptoms;T-Lymphocyte;TNFSF11 gene;Therapeutic Agents;Toll-Like Receptor 2;Tooth Loss;Virulence Factors;base;bone;bone loss;cardiovascular disorder risk;cost;cytokine;design;fimbria;gingipain;human disease;inhibitor/antagonist;interleukin-21;interleukin-23;microbial;monocyte;new therapeutic target;novel therapeutics;oral bacteria;pathogen;prevent;public health relevance;receptor;response;therapeutic target

public_health_relevance:
Periodontitis is a chronic inflammatory disease that can lead to not only tooth loss at a cost estimated to be $70 billion but also are associated with risk ofcardiovascular disease and myocardial infarction. Periodontitis is initiated by oral bacteria present in the gums and symptoms of disease are a result overproduced immune response. Thus identifying and blocking critical bacterial and host responses involved in the disease process is the key to cure the gum disease.


application_id: 8698337
project_number: 5R01CA125454-07
project_title: Regulation of Snail in breast cancer progression and metastasis
administering_ic: NCI
award_notice_date: 2014-04-08
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 125454
program_official: WOODHOUSE, ELIZABETH
project_start_date: 2007-09-13
project_end_date: 2018-04-30
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
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:
Address;Affect;BRCA1 gene;Binding Proteins;Boxing;Brain;Breast;Breast Cancer Cell;CCL2 gene;Caenorhabditis elegans;Cancer cell line;Cancer stem cell;Cells;Cellular Stress;Characteristics;Chromatin;Clinical;Complex;Data;Development;Disease;Distant Metastasis;Down-Regulation;E-Cadherin;Endoplasmic Reticulum;Environment;Enzymes;Epithelial;Exhibits;Fostering;Gene Silencing;Glycogen Synthase Kinase 3;Goals;Growth Factor;Homeostasis;Human;IL8 gene;Immune;Infiltration;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Interleukin-6;Intervention;Intestines;Intrinsic factor;Knowledge;Leukocytes;Location;Lung;Lymphocyte;Malignant Neoplasms;Mammary Neoplasms;Mediating;Medical Oncologist;Mesenchymal;Molecular;Mus;Mutation;Neoplasm Metastasis;Outcome;Pathologist;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Play;Promotor (Genetics);Proteins;Reagent;Recording of previous events;Recruitment Activity;Recurrence;Regulation;Repression;Research;Role;Sampling;Signal Pathway;Signal Transduction;Site;Snails;Stromal Neoplasm;Testing;Therapeutic Intervention;Tissues;Up-Regulation (Physiology);cancer therapy;cell injury;chemokine;chromatin modification;coping;cytokine;endoplasmic reticulum stress;epithelial to mesenchymal transition;gene repression;genome wide association study;in vivo;inhibitor/antagonist;innovation;insight;macrophage;malignant breast neoplasm;multidisciplinary;neoplastic cell;novel;novel therapeutics;outcome forecast;paracrine;prevent;programs;public health medicine (field);public health relevance;research study;response;success;trait;tumor;tumor microenvironment;tumor progression;ubiquitin isopeptidase;ubiquitin-protein ligase;wound;young woman

public_health_relevance:
Our proposal is innovative since we will have a significant impact to public health through its potential to influence cancer treatment. The knowledge gained will expand our understanding of the co-evolvement between tumor cells and their microenvironments in tumor progression and metastasis. When successfully completed these studies will provide insights for the development of novel interventions to prevent and treat metastatic basal-like breast cancer.


application_id: 8697066
project_number: 5R01GM094155-05
project_title: Mechanism of Neuropilin Dependent Angiogenesis
administering_ic: NIGMS
award_notice_date: 2014-06-25
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 094155
program_official: DUNSMORE, SARAH
project_start_date: 2010-09-06
project_end_date: 2016-06-30
study_section: Macromolecular Structure and Function C Study Section[MSFC]
contact_pi_person_id: 9627039
contact_pi: VANDER KOOI, CRAIG
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Angiogenesis the production of new blood vessels from existing vasculature is required for normal development wound repair and vascular homeostasis. Neuropilin is an essential mammalian cell surface receptor for one of the most potent pro-angiogenic molecules vascular endothelial growth factor (VEGF) and functions in synchrony with VEGFR receptor tyrosine kinases. Neuropilin is of particular medical importance because it is critical to the pathology of VEGF dependent hyper-vascularization in tumor angiogenesis.  We propose a series of parallel and complementary structural and functional studies to understand the physical interactions and receptor coupling at the heart of the VEGF signaling complex. Unlike many other kinase systems VEGF binding to VEGFR in the absence of neuropilin is insufficient to induce angiogenesis. We seek to first understand the molecular mechanism(s) underlying neuropilin's unique role in VEGF dependant angiogenesis. In Aim 1 we will determine the basis for competitive binding of ligands to neuropilin and the role that this competition plays in regulating angiogenesis. In Aim 2 we will explore the structural and conformational changes that neuropilin undergoes in its transition from inactive monomer to activated dimer. More globally we seek to define the physical basis for the coordinated action of VEGF neuropilin and VEGFR. Aim 3 is focused on utilizing multiple structural and biochemical tools coupled with endothelial cell signaling assays to determine the physical interactions and conformational changes necessary to couple extracellular ligand binding to receptor activation. Taken together these studies will provide a molecular understanding of the physical mechanisms underlying the critical first step connecting VEGF ligand binding to receptor activation.

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

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


application_id: 8696452
project_number: 1R01AG045775-01A1
project_title: Translating CD33 genetic mechanism into a novel Alzheimers therapeutic
administering_ic: NIA
award_notice_date: 2014-04-14
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: AG
serial_number: 045775
suffix: A1
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
project_terms:
Alleles;Alzheimer disease prevention;Alzheimer's Disease;Alzheimer's Disease Pathway;Alzheimer's disease risk;Antibodies;Apolipoprotein E;Apoptotic;Asses;Binding (Molecular Function);Brain;Critical Pathways;Exons;Fab Immunoglobulins;Family member;Foundations;Future;Genes;Genetic;Genetic Polymorphism;Genotype;Goals;Half-Life;Human;Immunoglobulins;In Vitro;Individual;Lectin;Length;Leukemia Myelocytic Acute;Ligands;Mediator of activation protein;Messenger RNA;Microglia;Minor;Molecular;Mus;Mutate;NR0B2 gene;Neurons;Odds Ratio;PTPN11 gene;Phagocytosis;Pharmaceutical Preparations;Preventive;Process;Production;Protein Isoforms;Proteins;RNA Splicing;Relative (related person);Reporting;Sialic Acids;Signal Transduction;Single Nucleotide Polymorphism;Staging;Testing;Therapeutic;Therapeutic Agents;Transgenic Model;Translating;Work;cohort;cytokine;genome wide association study;humanized monoclonal antibodies;in vivo;inhibitor/antagonist;novel;novel therapeutics;pre-clinical;public health medicine (field);public health relevance;receptor;sulfated glycoprotein 2;uptake


application_id: 8694031
project_number: 5U01ES015673-10
project_title: Novel Therapies for Chlorine-Induced Lung Injury
administering_ic: NIEHS
award_notice_date: 2014-05-07
opportunity_number: PAR-10-180
application_type: 5
activity_code: U01
ic: ES
serial_number: 015673
program_official: NADADUR, SRIKANTH
project_start_date: 2006-09-29
project_end_date: 2016-04-30
study_section: Special Emphasis Panel[ZRG1-MDCN-J(50)R]
contact_pi_person_id: 2736750
contact_pi: HOYLE, GARY W.
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Chlorine gas is a highly toxic respiratory irritant that is considered a chemical threat agent. The goal of the research proposed in this renewal application is to develop a medical countermeasure to treat lung injury induced by chlorine inhalation. During the previous U01 award a mouse model of chlorine gas inhalation was developed a detailed characterization of lung injury following chlorine exposure was performed signaling pathways representing possible targets for therapeutic intervention were investigated strategies for manipulating signaling pathways of interest were tested and compounds that significantly inhibited lung injury or inflammation in chlorine-exposed mice were identified. Rolipram a type 4 phosphodiesterase inhibitor was shown to stimulate alveolar fluid transport decrease pulmonary edema and inhibit airway hyperreactivity. Triptolide a diterpenoid anti-inflammatory compound inhibited chlorine-induced lung inflammation. In the present application formulations of rolipram and triptolide will be developed for intramuscular (i.m.) injection a preferred delivery route for potential mass casualty situations. In addition methylprednisolone an FDA-approved anti-inflammatory compound will be evaluated as an alternative to triptolide. The overall hypothesis to be tested is that i.m. injection of an encapsulated formulation of rolipram in combination with an anti-inflammatory compound will represent the most effective countermeasure for chlorine-induced lung injury. Countermeasure formulations will be tested in mice to determine efficacy against chlorine-induced acute lung injury to assess longer term effects on airway remodeling and airway hyperreactivity and to measure the length of effective post-exposure treatment window. The most effective countermeasure formulation will be evaluated in rabbits to demonstrate efficacy in a non-rodent animal model. An optimized countermeasure formulation with efficacy against chlorine-induced lung injury in mice and rabbits will be subject to additional studies necessary for progression toward regulatory approval including collection of pharmacokinetic/pharmacodynamic and toxicity data and production of the countermeasure using current good manufacturing practices.   Public Health Relevance: The goal of the proposed experiments is to develop novel ways to treat acute lung injury caused by chlorine gas inhalation. The research will focus on medical countermeasures that can be easily and rapidly administered in a mass casualty situation. This type of research is important because of concerns that U.S. civilians could be adversely affected by the accidental or intentional release of highly toxic chemicals.

project_terms:
Affect;Alveolar;Animal Model;Anti-Inflammatory Agents;Anti-inflammatory;Award;Breathing;Chlorine;Collection;Data;Development;Diterpenes;Drug Formulations;Drug Kinetics;Encapsulated;FDA approved;Gases;Goals;Human;Inflammation;Intramuscular Injections;Irritants;Length;Liquid substance;Long-Term Effects;Lung Inflammation;Lung Injury Acute;Maximum Tolerated Dose;Measures;Medical;Methylprednisolone;Mus;No-Observed-Adverse-Effect Level;Oryctolagus cuniculus;Pathway interactions;Pharmacodynamics;Phosphodiesterase Inhibitors;Poisons;Principal Investigator;Production;Pulmonary Edema;Research;Research Institute;Rodent;Rolipram;Route;Signal Pathway;Testing;Therapeutic Intervention;Toxic effect;Universities;airway hyperresponsiveness;airway remodeling;chemical threat;chemokine;chlorine gas;efficacy testing;interest;lung injury;mass casualty;mouse model;neutrophil;novel;pre-clinical;prevent;public health relevance;research study;respiratory;triptolide


application_id: 8693911
project_number: 5R01AI090048-05
project_title: Chemoenzymatic studies of aminoglycoside-resistance enzymes towards new drugs
administering_ic: NIAID
award_notice_date: 2014-06-30
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AI
serial_number: 090048
program_official: XU, ZUOYU
project_start_date: 2011-08-01
project_end_date: 2016-07-31
study_section: Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section[DDR]
contact_pi_person_id: 8970083
contact_pi: GARNEAU-TSODIKOVA, SYLVIE
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Aminoglycosides are broad-spectrum antibiotics used for treatment of serious bacterial infections including the deadly tuberculosis and those accompanying AIDS cystic fibrosis and cancer. The emergence of pathogens resistant to these drugs represents a major threat to public health and underscores the need for new antimicrobial agents. In Aim 1 we propose to utilize aminoglycoside-modifying enzymes of the aminoglycoside acetyltransferase (AAC) family in conjunction with a newly developed 6'-N-acylation protecting group-free chemical methodology (i) to generate in vitro libraries of new and more potent N-acylated aminoglycoside antibiotics and (ii) to develop aminoglycoside probes that will serve as baits for identification of novel therapeutic protein targets/pathways for these antibiotics. Our chemoenzymatic and chemical strategies offer an effective solution to the following problems: (i) there are no existing general synthetic methodologies for the creation of N-acylated aminoglycosides and (ii) there are no efficient methods to chemically modify specific amine groups on an aminoglycoside that contains a series of chemically identical amines. A few existing examples that use solely chemical syntheses are too demanding on research time and cost and are limited to very specific cases. In Aim 2 we propose biochemical and structural studies of the mechanism of action and inhibition of a major determinant of aminoglycoside resistance in extensively drug-resistant strains of M. tuberculosis (XDR-TB). We expect this work to (i) advance the basic understanding of AG resistance of a variety of pathogenic bacteria including M. tuberculosis and (ii) provide a potential solution to overcome the aminoglycoside resistance problem in majority of XDR- TB. Relevance to public health: We expect that this work will contribute to the development of novel antibiotics with a potential to combat existing and newly emerging drug-resistant bacteria.

project_terms:
Acetylation;Acetyltransferase;Acquired Immunodeficiency Syndrome;Acute;Acyl Coenzyme A;Affinity;Amines;Aminoglycoside Antibiotics;Aminoglycoside resistance;Aminoglycosides;Anti-Bacterial Agents;Antibiotics;Bacillus anthracis;Bacteria;Bacterial Infections;Biochemical;Biological;Chemicals;Chemistry;Clinic;Clinical;Coenzyme A;Collaborations;Complement;Complex;Cystic Fibrosis;Development;Disease;Drug Targeting;Drug resistance;Drug resistance in tuberculosis;Enterococcus faecalis;Enzymes;Extreme drug resistant tuberculosis;Family;Health;Homologous Gene;Human;In Vitro;Kanamycin A;Kinetics;Klebsiella pneumonia bacterium;Lead;Libraries;Malignant Neoplasms;Methodology;Methods;Michigan;Modification;Multi-Drug Resistance;Mycobacterium tuberculosis;N acylation;One-Step dentin bonding system;Parents;Pathway interactions;Pharmaceutical Preparations;Positioning Attribute;Proteins;Research;Resistance;Resistance development;Ribosomes;Series;Solutions;Structure;Testing;Therapeutic;Time;Toxic effect;Tuberculosis;Universities;Work;aminoglycoside acetyltransferase;analog;antimicrobial drug;bacterial resistance;chemical synthesis;combat;cost;drug resistant bacteria;fascinate;improved;inhibitor/antagonist;innovation;insight;novel;novel therapeutics;pathogen;pathogenic bacteria;prevent;public health medicine (field);resistance mechanism;resistant strain;therapeutic protein

public_health_relevance:
The proposed research is relevant to public health as an improved understanding of aminoglycoside- resistance enzymes is expected to lead to the discovery and development of new drugs and also in identifying drug targets. This research will enable us to better handle the problem of resistance of infectious bacteria to aminoglycoside antibiotics. The proposed research will have a major impact in two ways: (1) our novel chemical and chemoenzymatic methodologies for the rapid and facile regio- selective N-acylation of aminoglycosides will greatly reduce the cost and effort generally associated with such modifications and (2) our study of the mechanism of action and inhibition of the major determinant of aminoglycosdie resistance in extensively drug-resistant M. tuberculosis will advance our understanding of drug resistance and also set a new paradigm of aminoglycoside acetyltransferase in the antibiotics field.


application_id: 8693376
project_number: 1R01EY023561-01A1
project_title: Mid-level mechanisms of surface and binocular perception
administering_ic: NEI
award_notice_date: 2014-07-08
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: EY
serial_number: 023561
suffix: A1
program_official: WIGGS, CHERI
project_start_date: 2014-08-01
project_end_date: 2019-07-31
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 1965646
contact_pi: HE, ZIJIANG
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
3-Dimensional;Affect;Aging;Amblyopia;Attention;Behavioral;Clinical;Code;Color;Complex;Crowding;Diagnosis;Ensure;Environment;Eye;Feedback;Frequencies (time pattern);Functional disorder;Goals;Grant;Human;Image;Knowledge;Link;Location;Measurement;Motion;Occupations;Ownership;Pattern;Perception;Perceptual learning;Play;Process;Property;Protocols documentation;Psychophysics;Research;Resolution;Retinal;Role;Space Perception;Strabismus;Surface;System;Testing;Texture;Time;Training;Visual;Visual Perception;Visual system structure;base;detector;falls;feeding;improved;luminance;neurophysiology;object perception;object shape;operation;public health relevance;research study;visual information;visual process;visual processing;visual stimulus


application_id: 8693314
project_number: 7R01DK095662-07
project_title: Regulation of Intestinal Stem Cell Activation in Colitis
administering_ic: NIDDK
award_notice_date: 2013-09-11
opportunity_number: PA-12-270
application_type: 7
activity_code: R01
ic: DK
serial_number: 095662
program_official: CARRINGTON, JILL L
project_start_date: 2013-09-20
project_end_date: 2016-06-30
study_section: Clinical, Integrative and Molecular Gastroenterology Study Section[CIMG]
contact_pi_person_id: 1883566
contact_pi: BARRETT, TERRENCE 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): Induction of mucosal healing in inflammatory bowel disease (IBD) is associated with reduced hospitalizations and surgeries. Healing of the mucosal barrier requires control of the destructive inflammatory response as well as restitution of the epithelial barrier through enhanced proliferation and generation of new crypt structures.  Although it is clear that induction of Wnt/B-catenin activation is a key factor in intestinal stem ell (ISC) and progenitor cell (PC) activation there are few researchers that examine the regulation of B-catenin activation in colitis where mucosal healing and inflammation-induced dysplasia are major clinical concerns. Studies performed during the prior award period demonstrated that Akt phosphorylation of B-catenin increases in ISCs during colitis and colitis-induced cancer. The present proposal makes use of a novel genetic model for reducing PI3K signaling in colonic intestinal epithelial cells (IEC) during colitis. Data already produced in VilCre/pik3r1fl/fl mice given DSS colitis suggest that PI3K-mediated B-catenin activation plays a major role in wound healing. Acute and chronic forms of DSS colitis will be generated in VilCre/pik3r1fl/fl mice for invivo studies in AIM 1 to examine the role of IEC class 1A PI3K in mucosal healing B-catenin activation and ISC/PC gene expression (using novel enteroid cultures). Studies in AIM 2 utilize bone marrow chimera (BMC) mice to examine TNF-induced IEC B-catenin signaling in radioresistant epithelial populations in DSS colitis mice. AIM 3 studies examine the role of Nox1 in B-catenin activation using B6->Nox1-/- BMC DSS colitis mice. Together the studies propose that TNF-induced NOX1 stimulates PI3K-mediated B-catenin activation and ISC/PC gene expression to determine crypt responses in IBD. The underlying hypothesis is that inflammation-induced B-catenin signaling enhances epithelial regeneration and induces chronic architectural distortion by increasing ISC and progenitor cell expansion during colitis. The clinical relevance of these studies is great given that we hope to identify novel approaches to IBD therapy and chemoprevention.

project_terms:
Acute;Attenuated;Award;Biopsy;Bone Marrow;Cell Culture Techniques;Cell Line;Chemoprevention;Chicago;Chimera organism;Chronic;Clinical;Clinical Trials;Colitis;Colon;Colon Carcinoma;Colorectal Cancer;Crohn's disease;Data;Dysplasia;Enrollment;Epithelial;Epithelial Cells;Figs - dietary;Gene Expression;Generations;Genes;Genetic Models;Goblet Cells;Grant;Healed;Hospitalization;In Vitro;Inflammation;Inflammatory Bowel Diseases;Inflammatory Response;Inflammatory disease of the intestine;Intestines;Leukocytes;Malignant Neoplasms;Mediating;Modeling;Monoclonal Antibodies;Mucositis;Mus;Mutate;Natural regeneration;Operative Surgical Procedures;Pathway interactions;Patients;Phosphorylation;Phosphotransferases;Play;Population;Proteins;Publishing;Reactive Oxygen Species;Regulation;Research Personnel;Residual state;Risk;Role;Sampling;Severities;Severity of illness;Signal Transduction;Sodium Dextran Sulfate;Stem cells;Structure;Study models;Systemic infection;TNFRSF1A gene;Testing;Time;Tissues;Tumor Necrosis Factor-alpha;Ulcer;Ulcerative Colitis;Universities;Wound Healing;base;carcinogenesis;clinical remission;clinically relevant;colitis associated cancer;healing;in vivo;kinase inhibitor;member;myoinositol;novel;novel strategies;repaired;response;stem;therapy outcome

public_health_relevance:
The proposal presented plans to examine how patients heal from ulcers (sores) in the bowel during colitis (ulcerative colitis and Crohn's disease). We find that in colitis small protein molecules made by white blood cells cause stimulation of epithelial cells that line the colon. In this grant we will examine mechanisms that control how inflammation in colitis stimulates epithelial stem cells and increases their risk of turning into colon cancer.


application_id: 8692790
project_number: 5R21EY023767-02
project_title: Psychophysical Research on Auditory/Visual Space Perception and Navigation
administering_ic: NEI
award_notice_date: 2014-06-09
opportunity_number: RFA-EY-13-001
application_type: 5
activity_code: R21
ic: EY
serial_number: 023767
program_official: WIGGS, CHERI
project_start_date: 2013-07-01
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1-BBBP-T(52)R]
contact_pi_person_id: 1965646
contact_pi: HE, ZIJIANG
other_pis: ZAHORIK, PAVEL A
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Our normal everyday perception of 3-dimensional space and our abilities to interact and navigate within the space require integration of information from multiple sensory modalities. The integration of distance/depth information in the intermediate range (2 - 20 m) where visual and auditory modalities provide the primary inputs is not well understood however. The long-term goal of this project is a complete understanding of how auditory and visual information is integrated to form distance percepts that can support accurate orientation and navigation in both normal and sensory-impaired populations. The objective of this application is to test and refine an innovative conceptual framework that represents the integration processes in a normal-hearing normal-vision population. The central hypothesis guiding this framework is that distance perception unlike the perception of direction requires additional contextual or background information about the environment that is beyond that provided by the object itself. This background representation can act like a frame of reference for coding distance. For multisensory distance input object contextual and background information must be integrated across modalities. But since all the information is not necessarily available at the same time memory must be involved in the integration process. The rationale that underlies the proposed research is that once a conceptual framework for auditory/visual distance integration has been specified and validated for normal populations new and innovative approaches can be applied to understanding and minimizing the impact of sensory impairments on spatial perception and navigation. This hypothesis will be tested by pursuing two specific aims: 1) Reveal an integrated auditory and visual reference frame for distance perception based on the environmental background. 2) Determine the role of working memory in auditory/visual distance perception. These aims will be addressed by testing human distance judgment and navigation performance under conditions in which the contributions of the contextual information background information or working memory are manipulated. Virtual and real stimulus manipulation techniques will allow for novel pairing of auditory and visual information that will be used to evaluate and refine the proposed framework. Development and validation of this framework will be a significant contribution because it will provide a better understanding of how humans are able to successfully integrate auditory and visual information to perform spatial tasks in the environment. Moreover it will provide a vehicle for future studies to advance the field of multisensory space perception. The proposed research is relevant to public health because it will lead to a better understanding of how auditory or visual impairment affects multisensory space perception. Ultimately this knowledge may inform the development of new strategies for assisting or enhancing degraded spatial information to improve orientation and navigation abilities in visually- and/or hearing-impaired populations.

project_terms:
3-Dimensional;Address;Affect;Auditory;Auditory system;Basic Science;Code;Development;Distance Perception;Environment;Equilibrium;Future;Goals;Hearing;Human;Impairment;Individual;Judgment;Knowledge;Lead;Location;Memory;Methods;Modality;Outcome;Outcomes Research;Perception;Performance;Play;Population;Process;Psychophysics;Relative (related person);Research;Resolution;Role;Sensory;Short-Term Memory;Space Perception;Specific qualifier value;Stimulus;Techniques;Technology;Testing;Time;Translational Research;Validation;Vision;Visual;Visual impairment;Visual system structure;Visuospatial;Work;base;directed attention;improved;innovation;interest;multisensory;novel;public health medicine (field);public health relevance;spatial integration;virtual;visual information;way finding

public_health_relevance:
Space perception in the intermediate distance range (2-20 m) depends on both the auditory and visual systems and plays a crucial role in everyday activities including navigation. The proposed psychophysical research investigates how auditory and visual spatial information is integrated for distance perception. The research outcomes will advance our scientific understanding of how humans perceive and interact in the world and also improve non-invasive methods for assessing malfunctions of space perception in the hearing- and/or visually impaired populations.


application_id: 8692774
project_number: 5T32ES007266-25
project_title: TRAINING GRANT IN MOLECULAR MECHANISMS OF TOXICITY.
project_terms: Grant;Molecular;Toxic effect;Training
administering_ic: NIEHS
award_notice_date: 2014-06-20
application_type: 5
activity_code: T32
ic: ES
serial_number: 007266
program_official: SHREFFLER, CAROL A
project_start_date: 1990-07-01
project_end_date: 2016-06-30
study_section: Environmental Health Sciences Review Committee[EHS(01)]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant)    The objectives of the Molecular Mechanisms of Toxicity Training Program are to provide trainees with an education in the cellular and molecular mechanisms by which environmental agents induce human disease. The training program is based on an understanding of biochemistry molecular/cell biology pharmacology and toxicology and is coupled with in-depth laboratory research training. The Training Program is based in the Graduate Center for Toxicology (GCT) a basic science department in the College of Medicine that grants the Ph.D. in Toxicology and provides an administrative and teaching nucleus of 11 Core Faculty. Joint faculty from Medicine Pharmacy Agriculture and Arts & Sciences enrich the diversity of training opportunities; 25 of these Core and Joint Faculty with strong research programs make up the Training Grant Faculty. This competitive renewal application requests support for 4 pre- and 2 postdoctoral trainees; it is focused on three disease areas with an environmental basis: Cancer Cardiovascular Disease and Neurodegenerative Disease. Oxidative stress and DNA damage and repair are mechanistic themes that underlie many of the research programs providing opportunities for collaborations and multidisciplinary approaches that enrich the research training. The pre-doctoral training program requires biomedical (25 credits) and toxicology bases (13 credits) and an elective (2-4 credits). Pre-doctoral trainees will be supported for a maximum of 3 years (e.g. years 2-4 of doctoral training; Postdoctoral trainees will be supported for a minimum of 2 years.  Ph.D. fellows will be recruited within 3 years of their degree while M.D. fellows will be recruited upon completion of their residency training; the investigators anticipate a ratio of 2 Ph.D.s to 1 M.D. Postdoctoral trainees are required to enroll and participate in 2 credits of Environmental Exposure and Human Disease in addition to a rigorous laboratory experience.  Currently 28 students are enrolled in the Toxicology Ph.D. program including 6 minority students most of whom were recruited from the University of Puerto Rico and supported by summer research/education grants. The University provides strong support for the GCT in the form of student fellowships supplementation to this Training Grant and faculty lines space and equipment to enhance and sustain a strong toxicology program.     Relevance: The Training Program in Molecular Mechanisms of Toxicity will provide pre- and postdoctoral fellows with a fundamental understanding of the molecular and cellular processes by which environmental agents impact human health and cause disease. The long-term goal is to prepare and inspire the next generation of scientists to address the ever-present environmental challenges to human health by the prevention of disease either by nutritional intervention or by otherwise exploiting human defense systems.


application_id: 8691771
project_number: 5K02DA035116-02
project_title: Social Networks and HIV Risk Behaviors of Special Populations of Drug Users
administering_ic: NIDA
award_notice_date: 2014-06-10
opportunity_number: PA-11-191
application_type: 5
activity_code: K02
ic: DA
serial_number: 035116
program_official: DEEDS, BETHANY
project_start_date: 2013-07-01
project_end_date: 2018-06-30
study_section: Behavioral and Social Consequences of HIV/AIDS Study Section[BSCH]
contact_pi_person_id: 6264981
contact_pi: OSER, CARRIE BETH
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_abstract:
DESCRIPTION (provided by applicant): The primary goal of this resubmitted K02 application is to further develop Dr. Carrie Oser's productive independent research career and to augment her research focus on HIV substance abuse treatment crime and health disparities by gaining new training on social networks and HIV intervention development. The K02 builds upon her focus on special populations including both rural drug users and African American drug users. The proposed training goals will provide new instruction in social networks HIV intervention development and the responsible conduct of research. The specific aims are: (1) to identify HIV and HCV risk and longitudinal changes in risk in the social networks of 503 rural out-of-treatment drug using women as compared to men; and (2) to examine the effect of social networks including structure (e.g. size density) function (e.g. emotional and instrument support) and content (e.g. attitudes towards physicians) on HIV and HCV risk behaviors and health services utilization among African American drug using women as compared to men across criminal justice status. This significant and innovative study will have strong public healt impacts and will support NIDA's Health Disparities Initiative because of its potential to contribut to our understanding of the cultural and social network correlates of health disparities among both rural and African American drug users. In addition this study improves upon the methodological limitations of previous research findings by examining various social networks (e.g. egocentric dyadic and sociocentric) and using longitudinal data in multilevel models. This
proposed project will allow for a practical application of the substantive knowledge and analytical skills acquired from the K02 training activities and will ultimately culminate in the development of forthcoming investigator initiated NIDA grant applications. Specifically these findings will be used as a foundation for future HIV social networks based intervention to increase special populations' use of preventative health care and subsequently reduce the need for expensive medical services as well as to decrease HIV risk behaviors including drug use unprotected sex and recidivism.

project_terms:
Accounting;African American;Applications Grants;Attitude;Biological Assay;Centers for Disease Control and Prevention (U.S.);Communities;Crime;Criminal Justice;Data;Data Collection;Development;Drug Prescriptions;Drug abuse;Drug usage;Drug user;Emotional;Female;Foundations;Future;Gender;Goals;Grant;HIV;HIV Infections;HIV diagnosis;HIV risk;Health;Health Services;Healthcare;Hepatitis C virus;Imprisonment;Independent Scientist Award;Individual;Instruction;Intervention;Kentucky;Knowledge;Life;Link;Measures;Medical;Methodology;National Institute of Drug Abuse;Network-based;Oxycodone;Pathway Analysis;Patient Self-Report;Pharmaceutical Preparations;Physicians;Population;Prevalence;Prisons;Race;Research;Research Personnel;Risk;Risk Behaviors;Rural;S-nitro-N-acetylpenicillamine;Services;Social Network;Spirituality;Strategic Planning;Structure;System;Training;Training Activity;United States National Institutes of Health;Unsafe Sex;Woman;career;density;disorder prevention;experience;falls;health care service utilization;health disparity;high risk;high risk sexual behavior;improved;injection drug use;innovation;instrument;male;men;multilevel analysis;named group;practical application;probation;public health medicine (field);public health relevance;recidivism;responsible research conduct;rural area;skills;social;substance abuse treatment;therapy development;urban area;willingness


application_id: 8691753
project_number: 5R01CA175003-02
project_title: Activating Bax as a therapeutic strategy for lung cancer
administering_ic: NCI
award_notice_date: 2014-05-16
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 175003
program_official: SALNIKOW, KONSTANTIN
project_start_date: 2013-08-01
project_end_date: 2018-05-31
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 6950638
contact_pi: LI, CHI
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): Most human cancer cells are resistant to apoptosis. Among the major regulators of apoptosis are the Bcl-2 family of proteins. An emerging cancer therapeutic strategy is directly activating the apoptotic pathways by inhibiting the activity of ani-apoptotic Bcl-2 proteins or promoting the function of pro-apoptotic Bcl-2 proteins. However many of these strategies target the interaction among various Bcl-2 proteins particularly the interaction between pro- apoptotic and anti-apoptotic Bcl-2 proteins. Due to functional redundancy among Bcl-2 proteins these approaches are likely effective only on limited tumor types or display non-specific killing activities. As an important pro-apoptotic Bcl-2 protein Bax s involved in the development of tumors and Bax activation has been linked to apoptosis in lung tumors. Given that Bax alone is sufficient to initiate apoptosis in almost all apoptotic paradigms
direct activation of Bax by small molecule compounds could induce death of Bax-expressing tumor cells. Our preliminary studies using in silico screening of large chemical libraries identifid a small molecule predicted to bind to the Bax hydrophobic groove. This compound is able to activate Bax leading to Bax-dependent tumor cell apoptosis and inhibition of mouse tumor growth. The following specific aims are proposed: 1) Examine the mechanisms by which the Bax activator inhibits tumor growth in mice. We will test the ability of the Bax activator to inhibt the growth of transplanted human tumors in mice as well as spontaneous mouse lung tumors. Furthermore we will investigate whether the active compound acts synergistically with other therapeutic drugs to inhibit the growth of tumors. 2) Improve the ability of Bax activators to activate Bax induce apoptosis and inhibit tumor growth. Ligand-based analyses will be used to identify potential compounds with greater biological activities and the compounds will be experimentally examined. 3) Investigate the mechanism of Bax activation on biological membranes by the Bax activators. We will use a novel patch-clamp technique combined with biochemical and cell biology approaches to investigate how the Bax activators induce Bax permeation channels on native biological membranes in vitro. We will also study how Bax permeation pore formation is regulated by the anti-apoptotic Bcl-2 protein Bcl-XL. As dysregulation of Bax expression has been implicated in lung tumor development inducing apoptosis in tumor cells by directly activating Bax holds promise as a novel therapeutic strategy to treat lung cancer patients.

project_terms:
Address;Alleles;Anus;Apoptosis;Apoptosis Regulator;Apoptotic;BCL-2 Protein;BCL2 gene;Bax protein;Binding (Molecular Function);Biochemical;Biological;Cancer Patient;Carboplatin;Cell Death;Cells;Cellular biology;Cessation of life;Computer Simulation;Development;Generations;Growth;Human;In Situ;In Vitro;Inhibition of Apoptosis;Killings;Lead;Ligands;Link;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Membrane;Mus;Neoplasm Transplantation;Organelles;Patch-Clamp Techniques;Pathway interactions;Pharmaceutical Preparations;Process;Property;Protein Family;Relative (related person);Resistance;Role;Structure;Structure-Activity Relationship;Synthesis Chemistry;Testing;Therapeutic;Time;Toxic effect;Transplantation;Tumor Cell Line;Xenograft Model;base;cancer cell;cancer therapy;cytotoxic;cytotoxicity;design;improved;in vivo;inhibitor/antagonist;neoplastic;neoplastic cell;novel;novel therapeutics;pharmacophore;preclinical study;pro-apoptotic protein;public health relevance;research study;screening;small hairpin RNA;small molecule;small molecule libraries;tumor;tumor growth;tumor xenograft;virtual


application_id: 8690806
project_number: 5U01DA013519-12
project_title: Development of Novel Therapies or Methamphetamine Abuse
administering_ic: NIDA
award_notice_date: 2014-06-26
opportunity_number: PA-10-067
application_type: 5
activity_code: U01
ic: DA
serial_number: 013519
program_official: APPEL, NATHAN M
project_start_date: 2000-08-15
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1-MDCN-C(56)S]
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Methamphetamine (METH) abuse continues to escalate and effective treatments are not currently available. METH interacts with the vesicular monoamine transporter-2 (VMAT2) promoting both dopamine (DA) release into the cytosol and reversal of the DA transporter to increase extracellular DA concentrations which is thought to be associated with its abuse liability. The overall objective of this project is to provide a clinical candidate for the treatment of METH abuse. Recently we identified a novel small molecule (GZ-793A) which potently and selectively inhibits DA uptake by VMAT2 inhibits METH-evoked DA release from synaptic striatal vesicles and slices and exhibits selectivity does not interact with nicotinic receptors or DA transporters. Off-target evaluation at a cadre of neurotransmitter-related steroid and ion channel sites second messenger prostaglandin growth factor and hormones brain/gut peptides and enzymes revealed outstanding selectivity. Translation to whole animals models revealed that GZ-793A specifically decreases METH self-administration without altering responding for sucrose does not produce tolerance to the decrease in METH self- administration upon repeated administration and decreases METH seeking in the cue-induced reinstatement. Acute GZ793A pretreatment also protects against the neurotoxic effects of METH as measured by striatal DA depletion. Although the physicochemical properties of GZ-793A are favorable in terms of druggability GZ-793A has only 2-3% oral bioavailability likely due to the presence of the hydroxyl functionalities in the molecule which are likely sites for high first-pass metabolism. Thus new optimized analogs of GZ-793A are the focus of the current application with the goal of identifying analogs with the required pharmacological properties druggability increased oral bioavailability and acceptable pharmacokinetic profile. Compounds with these characteristics would be high value preclinical candidates for advancement toward clinical trials as treatments for METH abuse. Thus we propose to expand our existing molecular library of analogs by performing the final steps of optimization of GZ-793A to identify a high value preclinical candidate as a potential therapeutics for METH abuse. In future work the best candidate will undergo comprehensive toxicological evaluation for subsequent preparation of an Investigational New Drug application to the FDA as a proposed treatment for methamphetamine abuse.

project_terms:
Acute;Affinity;Animal Model;Behavioral;Binding Sites;Bioavailable;Biological Availability;Brain;CYP2C19 gene;CYP2D6 gene;Characteristics;Chemical Structure;Clinical;Clinical Trials;Collaborations;Corpus striatum structure;Cues;Cytosol;Data;Development;Dopamine;Dose;Drug Kinetics;Enzymes;Evaluation;Event;Exhibits;Food;Future;Generations;Goals;Growth Factor;Half-Life;Hepatic;Hydroxyl Radical;Ilex vomitoria;In Vitro;Intravenous;Investigational New Drug Application;Ion Channel;Lead;Libraries;Lobeline;Measures;Metabolism;Methamphetamine;Modification;Molecular Bank;National Institute of Drug Abuse;Neurotransmitters;Nicotinic Receptors;Oral;Oral Administration;Outcome;Peptides;Pharmaceutical Preparations;Phase;Plasma;Preparation;Prodrugs;Property;Prostaglandins;Rattus;Rewards;Route;Safety;Salts;Second Messenger Systems;Self Administration;Site;Slice;Somatotropin;Specificity;Steroids;Structure-Activity Relationship;Sucrose;Synapses;Synaptic Vesicles;Therapeutic;Therapeutic Agents;Translations;Variant;Vesicle;Work;analog;base;dihydrotetrabenazine;dopamine system;dopamine transporter;effective therapy;extracellular;improved;inhibitor/antagonist;methamphetamine abuse;neurotoxic;neurotoxicity;new therapeutic target;novel;piperidine;pre-clinical;preference;public health relevance;second messenger;small molecule;sulfation;uptake;vesicular monoamine transporter 2;water solubility

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Currently there is no pharmacotherapeutic available for methamphetamine abuse. The overall objective of this project is to provide a clinical candidate for the treatment of methamphetamine abuse. Recently we identified a novel small molecule (GZ-793A) which potently and selectively interacts with the vesicular monoamine transporter-2 and which exhibits potency and specificity in decreasing responding for intravenous methamphetamine in an animal model of self-administration. We propose to expand our existing molecular library by performing the final steps of optimization of the chemical structure of GZ-793A with the aim of providing additional leads that are druggable orally-bioavailable high value preclinical candidates. The outcome of the proposed project is to bring the best candidate to comprehensive toxicological evaluation for preparation of an Investigational New Drug application to the FDA as a proposed treatment for methamphetamine abuse.


application_id: 8690764
project_number: 5R01AR061939-03
project_title: BetaCatenin Regulation of Skeletal Muscle Hypertrophy
administering_ic: NIAMS
award_notice_date: 2014-08-22
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AR
serial_number: 061939
program_official: BOYCE, AMANDA T
project_start_date: 2012-07-01
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-C(90)S]
contact_pi_person_id: 8263548
contact_pi: ESSER, KARYN A
other_pis: MCCARTHY, JOHN JOSEPH
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  As the "house-building" macromolecule of the cell ribosome biogenesis is essential for cell growth. Despite this central role in cell growth there remains a fundamental gap in our understanding of the role of ribosome biogenesis in adult skeletal muscle hypertrophy. Studies from our laboratory have provided evidence which supports a role for increased ribosome biogenesis in skeletal muscle hypertrophy. The current proposal will begin to directly examine the importance of ribosome biogenesis to muscle hypertrophy by testing the hypothesis that -catenin is necessary for muscle hypertrophy by increasing protein synthesis through c-myc activation of ribosome biogenesis. To conditionally manipulate -catenin or c-myc gene expression in adult skeletal muscle we generated the HSA-MerCreMer mouse. Aim 1 will determine if -catenin expression is necessary for skeletal muscle hypertrophy using a mechanical overload model of the plantaris muscle following catenin gene inactivation. Aim 2 will determine if increased expression of -catenin is sufficient to stimulate skeletal muscle hypertrophy. -catenin will be over-expressed in adult skeletal muscle by using the HSA- MerCreMer strain to generate a stabilized form of -catenin. Aim 3 will determine if c-myc expression is necessary for skeletal muscle hypertrophy following the conditional inactivation of c-myc in adult skeletal muscle using the HSA-MerCreMer strain. The effect of gene inactivation on the hypertrophic response will be assessed by measuring morphometric (muscle weight fiber CSA) biochemical (total protein RNA and DNA) molecular (Western blot RT-PCR promoter analysis chromatin immunoprecipitation (ChIP) and electrophorectic mobility shift assay (EMSA)) and metabolic (rates of protein synthesis and degradation) variables. The results of the proposed studies are expected to have important clinical implications by identifying new molecular targets for promoting skeletal muscle protein synthesis and hypertrophy. In the long- term the ability to manipulate ribosome biogenesis represents a promising novel strategy to attenuate or ameliorate muscle atrophy associated with aging bed rest and cachexia.

project_terms:
Adult;Aging;Atrophic;Attenuated;Bed rest;Biochemical;Biogenesis;Biology;Body Weight;Cachexia;Cartoons;Catabolism;Cells;Clinical;Complement;DNA;DNA Polymerase I;DNA-Directed RNA Polymerase;Electrophoretic Mobility Shift Assay;Event;Fiber;Gene Expression;Gene Silencing;Genes;Genetic Transcription;Growth;Health;Hindlimb Suspension;Housing;Human;Hypertrophy;In Vitro;Insulin-Like Growth Factor I;Knowledge;Laboratories;Malignant Neoplasms;Measurement;Measures;Mechanics;Metabolic;Modeling;Molecular;Molecular Target;Morbidity - disease rate;Mortality Vital Statistics;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscle Proteins;Muscular Atrophy;Outcome;Pathway interactions;Plantaris muscle;Promotor (Genetics);Protein Biosynthesis;Proteins;Publishing;Quality of life;RNA;Regulation;Research;Reverse Transcriptase Polymerase Chain Reaction;Ribosomal RNA;Ribosomes;Rodent;Role;Skeletal muscle structure;Stimulus;System;Testing;Translations;Weight;Western Blotting;Work;c-myc Genes;cell growth;chromatin immunoprecipitation;in vitro Model;in vivo;macromolecule;muscle form;muscle hypertrophy;muscle strength;novel;novel strategies;overexpression;prevent;protein degradation;research study;response;sedentary

public_health_relevance:
Skeletal muscle mass makes up almost 50% of the total body weight in healthy adults and it is now recognized as an important health factor. The findings from the proposed research are expected to reveal whether or not b-catenin regulation of protein synthesis is necessary for muscle growth. If confirmed such results will be of medicinal value by providing new targets for promoting muscle growth during periods of muscle loss associated with inactivity cancer and aging.


application_id: 8690762
project_number: 5R01AR059810-04
project_title: TAK1/TRAF6 Signaling in Skeletal Muscle
administering_ic: NIAMS
award_notice_date: 2014-06-21
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AR
serial_number: 059810
program_official: BOYCE, AMANDA T
project_start_date: 2011-07-01
project_end_date: 2016-06-30
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1917770
contact_pi: KUMAR, ASHOK
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Skeletal muscle atrophy/wasting is a devastating complication of a wide range of diseases and conditions such as aging disuse chronic obstructive pulmonary disease space travel chronic heart failure sepsis and cancer. Myogenesis is the process that is required not only for the embryonic development of skeletal muscle but it is also an important element of certain types of postnatal growth and repair of injured myofibers. Impairment in myogenesis is the critical determinant of skeletal muscle-wasting in several chronic diseases and also development of rhabdomyosarcoma in children. Although significant progress has been made to understanding the processes of skeletal muscle formation and wasting the upstream signaling events regulating skeletal muscle mass in various physiological and pathophysiological conditions remain poorly understood. We have accumulated strong evidence that supports a crucial role of TAK1/TRAF6 signaling complex in the acquisition and maintenance of skeletal muscle mass. Our preliminary studies have shown that both TRAF6 and TAK1 stimulate myogenic differentiation through novel Lysine-63-linked poly-ubiquitination mechanisms. TAK1 and TRAF6 are also required for MyoD-induced transformation of non-muscle cells into skeletal muscles. In adult skeletal muscle the activation of TAK1/TRAF6 leads to inflammation impairment in myofiber regeneration and atrophy. To clearly establish the role and delineate the mechanisms of action of TAK1/TRAF6 complex in skeletal muscle we will use genetic approaches including conditional knockout mice. Based on our preliminary data we hypothesize that signaling through TAK1 and TRAF6 is required for the development of skeletal muscle but not for maintaining differentiated phenotype. Under stress conditions the activation of TAK1 and TRAF6 stimulates catabolic pathways leading to skeletal muscle atrophy. To test this hypothesis we propose to address the following three specific aims: 1) Investigate the signaling mechanisms by which TAK1 and TRAF6 regulate myogenic differentiation in cultured myoblasts; 2) Investigate the role and cellular mechanisms by which TAK1 and TRAF6 regulate skeletal muscle development in vivo; and 3) Delineate the mechanisms by which TAK1 and TRAF6 regulates regeneration and atrophy in adult skeletal muscles. Successful completion of this project will provide critical insights into the signaling mechanisms and establish TAK1 and TRAF6 as novel molecular targets to prevent skeletal muscle loss in various muscular disorders.

project_terms:
Address;Adult;Affect;Aging;Apoptosis;Area;Atrophic;Biochemical;Biology;Calcineurin;Cell Culture Techniques;Cell Cycle Arrest;Cell Line;Cell Surface Proteins;Cells;Child;Chronic;Chronic Disease;Chronic Obstructive Airway Disease;Complex;Complication;Cytoplasmic Tail;Data;Denervation;Development;Disease;Drug Targeting;Elements;Embryonic Development;Endocrine;Event;Family;Fiber;Genetic;Growth;Health;Heart failure;Human;Impairment;Inflammation;Knockout Mice;Laboratories;Lead;Link;Lysine;MAP Kinase Gene;MAP3K7 gene;MAPK14 gene;Maintenance;Malignant Neoplasms;Mediating;Methods;Molecular Target;Muscle;Muscle Development;Muscle Fibers;Muscular Atrophy;Myoblasts;Myopathy;Natural regeneration;Neonatal;Nude Mice;Pathway interactions;Perinatal;Phenotype;Phosphotransferases;Physiological;Play;Polyubiquitin;Process;Protein Biosynthesis;Proteins;Regulation;Rhabdomyosarcoma;Role;Sepsis;Signal Transduction;Signal Transduction Pathway;Skeletal muscle structure;Staging;Stem cells;Stimulus;Stress;System;TRAF6 gene;Testing;Transforming Growth Factors;Travel;Tumor Necrosis Factor Receptor;Ubiquitination;autocrine;base;human morbidity;human mortality;improved;in vivo;injured;insight;mouse model;muscle form;muscle regeneration;myogenesis;novel;paracrine;postnatal;prevent;protein degradation;repaired;response to injury;sarcopenia;satellite cell;skeletal muscle growth;skeletal muscle wasting;transcription factor NF-AT c3;ubiquitin-protein ligase;wasting

public_health_relevance:
Skeletal muscle formation and wasting are well-orchestrated processes regulated by autocrine paracrine and endocrine factors via multiple signal transduction pathways. Our proposed studies are aimed to dissect the signaling mechanisms underlying the regulation of muscle differentiation with a focus on TAK1/TRAF6 complex. In addition to muscle formation our study will also delineate the signaling mechanisms responsible for accelerated protein degradation that causes rapid atrophy of mature skeletal muscles. Results of these studies will contribute to the understanding of skeletal muscle biology which will have a significant impact on health-related issues such as sarcopenia disease- induced muscle atrophy muscle regeneration and rhabdomyosarcoma.


application_id: 8690718
project_number: 5P30AG028383-09
project_title: Education and Information Transfer Core
administering_ic: NIA
award_notice_date: 2014-06-13
opportunity_number: RFA-AG-11-005
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_start_date: 2006-07-15
study_section: ZAG1-ZIJ-5
subproject_number: 6079
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-07-01
project_abstract:
PROJECT SUMMARY (See instructions): The Education and Information Transfer Core (EITC) functions as a vital link between the UK-ADC and the local and state communities. EITC programs and activities have created and will maintain an educated local community eager to receive updated information on AD and to participate in our Center's research. Through EITC efforts the UK-ADC will continue to work with both the Commonwealth of Kentucky and UK in directing state and institutional response to meeting Kentucky's dementia health care needs. Over the past five years the EITC has taken a lead in developing innovative products to support research participation by African Americans the largest minority group in Kentucky. The EITC will continue strong relationships with the Council of Ministers and the Community Action Council so that activities and products developed such as the Book of Alzheimer's for African-American Churches and Granny Pearl a film to educate African- American adolescents about AD are responsive to local needs. EITC recruitment and outreach activities will be closely coordinated with the Clinical Core and the Gateway Satellite Clinic to ensure that appropriate participants are identified for ADC cohorts clinical trials and other research studies. Work in the EITC forthe five-year grant period will be designed to meet three specific aims. Aim 1 is to support recruitment and retention activities for our Center's research protocols clinical trials and NIH/NIA initiatives. The core places a special emphasis on minority recruitment and retention strategies and will continue its innovative and successful strategies for African American participants. An expanded goal is to increase research participation including brain donation in this population. Aim 2 is to increase community awareness of AD with an emphasis on maintaining a strong presence in the African-American community. Awareness efforts will be focused on the importance of early disease identification to support our Center theme of transitions and translation. Aim 3 is to expand UK community and regional partnerships to meet the educational needs of community and professional audiences and UK researchers. Strong collaborations with the local Alzheimer's Association and Geriatric Education Center will continue. Based on needs assessment and survey data our current and future professional educational efforts will focus on the following three areas: caregiver education medical student education and scientific conferences including a new William R. Markesbery scientific symposium in honor of our former director.

project_terms:
Administrative Supplement;Adolescent;African American;Aging;Alzheimer's Disease;Area;Awareness;Books;Brain;Caucasians;Caucasoid Race;Church;Clinic;Clinical;Clinical Research;Clinical Research Protocols;Clinical Trials;Clinical trial protocol document;Collaborations;Communities;Community Actions;Data;Dementia;Development;Disease;Education and Outreach;Educational aspects;Elderly;Enrollment;Ensure;Event;Film;Focus Groups;Future;Goals;Grant;Healthcare;Indiana;Instruction;Kentucky;Lead;Link;Medical Education;Medical Students;Medicine;Minority;Minority Groups;Mission;Needs Assessment;Outreach Research;Participant;Play;Poa plant;Population;Protocols documentation;Public Relations;Research;Research Personnel;Research Support;Role;Rural;Scientist;Students;Surveys;Telemedicine;Translations;United States National Institutes of Health;Universities;Update;Work;base;caregiver education;cohort;college;combat;community organizations;design;innovation;meetings;outreach;programs;research study;response;symposium

public_health_relevance:
The EITC plays a critical role in the UK-ADC by supporting recruitment and retention activities for research protocols clinical trials and NIA initiatives; by increasing community awareness of AD and maintaining a strong presence in the African-American community; and by supporting educational initiatives in collaboration with key partners. These functions are vital to the UK-ADC mission to catalyze outstanding and innovative research outreach education and clinical programs.


application_id: 8690717
project_number: 5P30AG028383-09
project_title: Neuropathology Core
administering_ic: NIA
award_notice_date: 2014-06-13
opportunity_number: RFA-AG-11-005
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_start_date: 2006-07-15
study_section: ZAG1-ZIJ-5
subproject_number: 6077
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-07-01
project_abstract:
PROJECT SUMMARY (See instructions): The overall objective of the Neuropathology Core of the University of Kentucky Alzheimer's Disease Center (UK-ADC) is to support research on normal brain aging presymptomatic Alzheimer's disease (pAD) mild cognitive impairment (MCI) early and late AD mixed dementia syndromes and other dementing disorders. Autopsies will be performed by our Rapid Autopsy Team on longitudinally followed subjects from our Clinical Core. We will perform short post-mortem interval autopsies in relation to our clinical cohort and we will maintain a high autopsy rate. This Core is optimally tailored to help address important research questions. The Core will provide brain tissue specimens CSF and synaptosomes for investigators at UK other ADCs and outside investigators. The Core will also provide consensus conference determined diagnoses quantitation of neurofibrillary tangles (NFT) neuritic plaques and diffuse plaques from 8 brain regions AB 1-40 and 1-42 quantitation Braak staging CERAD and NIA-Reagan Institute staging on all autopsied cases to investigators. Since the brain bank has been operating continuously for over two decades with a strong track record special care will be taken to ensure diagnostic excellence consistency and continuity. The Core will maintain a tissue bank of the above specimens and frozen serum plasma buffy coats and CSF from living patients. Special emphasis will be placed on defining the neuropathological findings in the brains of the oldest old (>85 years) and providing investigators with specimens from cognitively intact control subjects with no AB deposition and sparse tau pathology (successful cerebral aging) and also cognitively intact subjects with abundant plaques and neurofibrillary tangles. Providing these samples will contribute to clinical-pathological correlation studies and cutting-edge research that include sponsored studies related to AD genomics oxidative stress hippocampal sclerosis dementia with Lewy bodies amyloid precursor protein processing Down syndrome and neuroinflammation. Frequent consensus conferences will be held with the Clinical Core and Biostatistics Core to help define clinicalpathological diagnoses on all autopsied subjects. This Core is strongly integrated with other Cores of the UK-ADC and exploits unique opportunities to conduct clinical-pathological correlative studies on longitudinally followed subjects. Through these methods we will better understand normal brain aging and the transition to dementia with the focused goal of contributing to therapeutic or preventive measures.

project_terms:
Address;Aged 80 and over;Aging;Alzheimer's Disease;Autopsy;Biochemical;Biometry;Biostatistics Core;Brain;Brain Diseases;Brain region;Caring;Centenarian;Cerebrospinal Fluid;Cerebrum;Clinical;Clinical Data;Cognition Disorders;Collaborations;Complement;Consensus;Correlation Studies;Correlative Study;Country;Data;Databases;Degenerative Disorder;Dementia;Deposition;Diagnosis;Diagnostic;Disease;Down Syndrome;Elderly;Enrollment;Ensure;Freezing;Frontotemporal Dementia;Genomics;Goals;Hippocampus (Brain);Individual;Institutes;Instruction;Investigation;Kentucky;Lesion;Lewy Body Dementia;Life;Measures;Methodology;Methods;Metric;MicroRNAs;Mission;National Institute on Aging;Neurodegenerative Disorders;Neurofibrillary Tangles;Oxidative Stress;Parkinson Disease;Pathology;Patients;Plasma;Preparation;Preventive;Process;Protocols documentation;Relative (related person);Religion and Spirituality;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Sampling;Sclerosis;Senile Plaques;Services;Specimen;Staging;Synapses;Synaptosomes;Syndrome;Therapeutic;Tissue Banking;Tissue Banks;Tissue Sample;Universities;age related;aged;aging brain;amyloid precursor protein processing;brain tissue;cohort;data management;experience;genome wide association study;innovation;meetings;mild cognitive impairment;mixed dementia;neuroinflammation;neuropathology;normal aging;pre-clinical;symposium;synucleinopathy;tau Proteins;tool

public_health_relevance:
RELEVANCE (See instructions): The Neuropathology Core complements the other Cores of the University of Kentucky Alzheimer's Disease Center to provide extremely essential diagnoses and tissue samples that are required for many cutting-edge researchers at the University of Kentucky and elsewhere. We will build on our track record of excellence using innovative tools related to brain autopsies neuropathological diagnoses tissue banking and state-of the-art clinical-pathological correlation.


application_id: 8690716
project_number: 5P30AG028383-09
project_title: Biostatistics and Data Management Core
administering_ic: NIA
award_notice_date: 2014-06-13
opportunity_number: RFA-AG-11-005
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_start_date: 2006-07-15
study_section: ZAG1-ZIJ-5
subproject_number: 6075
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-07-01
project_abstract:
PROJECT SUMMARY (See instructions): The Biostatistics and Data Management Core (BDMC) can be conceptualized as the lynchpin for integration of the ADC Cores and is vital to the success of the UK-ADC. Its critical roles include managing a large centralized database consulting with ADC-affiliated researchers and working to develop and apply innovative statistical methodology for data analysis. Data management efforts focus on collecting and storing high quality data. This focus begins with the leadership and vision and attention to detail provided by the BDMC. This core has an enviable track record of timely and accurate reporting of a high volume of data to NACC. Further weekly Core meetings are popular with UK-ADC investigators who find that the expert advice provided by our seasoned investigators improves their success in pilot studies grant applications and publications. This core also participates as a full partner to the research mission of the UK-ADC emphasizing transitions and translations. One such partnership with the Clinical and Neuropathology Cores relates to clinico-pathological models of mixed dementias. A key element of this BDMC is the well established track record of developing novel methodology to analyze data collected at the UK-ADC and from other cohorts with a focus on elderly subjects' transitions to MCI and eventually dementia. The BDMC also provides training for students enrolled in the graduate programs in Gerontology Public Health Epidemiology and Biostatistics Psychology and Statistics. In keeping with the mission of the UK-ADC faculty in this core also contribute to the dementia research community at large through service on external advisory committees study sections manuscript reviews and data safety monitoring boards. The BDMC will continue these critical responsibilities through the following specific aims. 1. Maintain a centralized database of the information collected by all ADC Cores and affiliated research projects in an integrated manner. 2. Provide expertise on experimental design and statistical analysis (and developing new analytical approaches). 3. Interact dynamically with other Cores to contribute to the clinical neuropathological and educational/outreach missions of the ADC.

project_terms:
Advisory Committees;Aging;Alzheimer's Disease;Applications Grants;Area;Attention;Autopsy;Biometry;Clinical;Clinical Trials Data Monitoring Committees;Collaborations;Commit;Communities;Computer Assisted;Consult;Consultations;Data;Data Analyses;Data Collection;Data Quality;Data Set;Databases;Dementia;Development;Elderly;Elements;Enrollment;Ensure;Epidemiology;Equipment and supply inventories;Experimental Designs;Extramural Activities;Faculty;Funding;Gerontology;Image;Instruction;Kentucky;Laboratories;Leadership;Link;Logic;Manuscripts;Methodology;Methods;Mission;Modeling;Outcome;Pathology;Pilot Projects;Policies;Postdoctoral Fellow;Procedures;Process;Psychology;Publications;Quality Control;Records;Reporting;Research;Research Design;Research Personnel;Research Project Grants;Resources;Role;Seasons;Series;Serum;Services;Students;Study Section;System;Time;Tissue Sample;Training;Translations;Universities;Vision;Work;cohort;data management;graduate student;high standard;improved;innovation;meetings;mixed dementia;neuropathology;novel;outreach;programs;public health medicine (field);relational database;statistics;success

public_health_relevance:
RELEVANCE (See instructions): This core provides data management and analysis support that meets the highest standards of scientific conduct. The Core is also involved facilitating AD research through collaborations with investigators and development of new methods for analyzing data.


application_id: 8690715
project_number: 5P30AG028383-09
project_title: Clinical Core
administering_ic: NIA
award_notice_date: 2014-06-13
opportunity_number: RFA-AG-11-005
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_start_date: 2006-07-15
study_section: ZAG1-ZIJ-5
subproject_number: 6071
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-07-01
project_abstract:
PROJECT SUMMARY (See instructions): Central to the success of the UK-ADC over the past 25 years is Clinical Core productivity that has allowed the development and perpetuation of a large longitudinally-followed well-characterized continuously-replenishing cohort focused on normal aging and early transitional disease states. All subjects undergo autopsy at death supporting clinical-pathologic research in aging and dementia. This practice has allowed major contributions in the area of clinical-pathological correlative studies and our understanding of early preclinical and predementia disease states such as mild cognitive impairment (MCI). UK-ADC productivity in terms of contributions to national collaborative initiatives such as NACC (2nd in overall productivity) ADCS (2nd in overall productivity) ADNI (2nd in overall productivity) NCRAD (597 normal control cell lines) and GWAS/ADGC is well recognized by involved researchers participating in these initiatives. The Clinical Core of the UK-ADC has contributed to the success of 31 independent research studies using living subjects (in addition to the many that rely on our data for work in the area of biospecimens and neuropathology) and has led to an impressive 159 publications supported by this core over the last funding cycle. In the upcoming cycle under the leadership of Dr. Greg Jicha we will focus our efforts on supporting investigations in the detection and treatment of preclinical AD and MCI of the AD-type as outlined in the new proposed NIA criteria released at ICAD 2010. As such our center is in critical transition developing and expanding biomarker capabilities (target normal to MCI/dementia transitions n=270 over the next funding period and n=50 high risk normals for the development of preclinical AD) while maintaining the size of our existing cohort to ensure sufficient transitions from normal to MCI and dementia (n=500 normals and n=300 impaired) continuing to work towards the development of more sensitive cognitive measures recommended by the NIA proposed criteria for preclinical AD and fully supporting our continued leadership position in the area of clinical-pathological correlative studies under the NR Core leadership of Dr. Peter Nelson. The clinical core fully supports the leadership role of Dr. Linda Van Eldik as center director after the loss of Dr. Markesbery earlier this year. We are committed to remaining one of the top ADCs in the nation and across the globe. We have further strengthened our resolve and commitment to advancing research and moving diagnostic strategies and therapeutic development forward as we transition into a new era of research with the NIA..

project_terms:
Age;Aging;Alzheimer's Disease;Area;Autopsy;Biological Markers;Biometry;Cell Line;Cessation of life;Clinic;Clinical;Clinical Data;Clinical Trials;Cognition;Cognitive;Collaborations;Commit;Correlative Study;Data;Data Collection;Data Set;Dementia;Detection;Development;Diagnosis;Diagnostic;Disease;Education and Outreach;Ensure;Environment;Funding;Future;Health;Healthcare Systems;Image;Impaired cognition;Industry;Instruction;International;Investigation;Kentucky;Leadership;Life;Measures;Minority;Mission;Pathologic;Patients;Pharmaceutical Preparations;Phase;Pilot Projects;Play;Positioning Attribute;Prevention;Productivity;Psychometrics;Publications;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Subjects;Role;Sampling;Therapeutic;Translational Research;Translations;United States National Institutes of Health;Universities;Work;base;cohort;data management;drug development;drug discovery;genome wide association study;high risk;innovation;mild cognitive impairment;multidisciplinary;neuropathology;normal aging;novel;pre-clinical;programs;research clinical testing;research study;stem;success;therapeutic development;tool;translational study

public_health_relevance:
RELEVANCE (See instructions): Alzheimer's disease is a major health concern for the nation as the number of patients with AD in the US approaches 6 million and the baby boomers are just reaching the age of high nsk for developing AD foretelling an impending inundation of the health care system by this ravaging disease. Targeting sporadic AD through the development of strategies for eady diagnosis and prevention is the only way we can abort the catastrophe we all see coming. The UK-ADC will continue to play a leading role in such initiatives.


application_id: 8690714
project_number: 5P30AG028383-09
project_title: Administrative Core
administering_ic: NIA
award_notice_date: 2014-06-13
opportunity_number: RFA-AG-11-005
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_start_date: 2006-07-15
study_section: ZAG1-ZIJ-5
subproject_number: 6070
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-07-01
project_abstract:
PROJECT SUMMARY (See instructions): The primary mission of Core A is to provide leadership coordination and integration of all the components of the UK-ADC so that our programmatic and scientific goals are achieved. Our overall scientific objective is to support and facilitate research aimed at elucidating the pathogenic mechanisms underlying the transitions from normal cognitive aging to the development of AD with a long-term goal of enabling more effective translation of this mechanistic knowledge to intervention strategies. The UK-ADC has historically been at the forefront of supporting research in identification of the early manifestations of disease and the pathogenic mechanisms underlying the transitions from normal cognitive aging to the development of AD. In the renewal period we will build upon this highly successful focus as well as leverage several recent positive developments at UK that will expand our translational research capability and thereby help to increase the rate of progress toward new therapies to delay or prevent AD. The UK-ADC functions in a multidisciplinary integrated and supportive environment that catalyzes high-quality AD research within the UK community and throughout Kentucky and beyond. The ADC also enhances education and outreach within UK and in the community and provides clinical diagnoses and care of patients with cognitive impairment. The ADC serves as the focal point of all AD-related activities in Kentucky providing the infrastructure and resources to enhance scientific interactions and develop new collaborations. The ADC also reaches beyond Kentucky to enhance AD research education and clinical practice on a national level through its interactions with other ADCs as well as other regional and national institutions including the Alzheimer's Association NIA and industry. An effective Administrative Core is essential for transforming ADC goals into accomplishments. Therefore Core A will continue to support the ability of our UK-ADC to serve as a critical resource for the university community state region and nation through a set of integrated and intertwined specific aims.  Aim 1: Provide leadership and an organizational framework for management and coordination of all ADC activities to ensure optimal resource utilization to meet the overall goals of the ADC. Aim 2: Enable the ADC to serve as the focal point of AD-related activities in Kentucky by continuing to coordinate facilitate and promote scientific interactions. Aim 3: Contribute to and interact with other ADCs and other national collaborative activities and the lay community to increase visibility of the ADC and maximize progress in AD research throughout the country.

project_terms:
Advisory Committees;Affect;Aging;Alzheimer's Disease;Basic Science;Caregivers;Clinical;Clinical Research;Clinical Trials;Cognitive aging;Collaborations;Communication;Communities;Country;Development;Diagnosis;Disease;Disease Progression;Early identification;Education and Outreach;Educational aspects;Ensure;Environment;Ethics;Evaluation;Faculty;Fostering;Foundations;Funding;Future;Goals;Growth;Human;Human Volunteers;Impaired cognition;Industry;Institution;Instruction;Intervention;Kentucky;Knowledge;Leadership;Medical;Mission;Patient Care;Patients;Pilot Projects;Policies;Productivity;Research;Research Activity;Research Infrastructure;Research Personnel;Research Support;Resources;Training;Translational Research;Translations;Universities;beneficiary;clinical Diagnosis;clinical care;clinical practice;meetings;multidisciplinary;outreach;prevent;programs;successful intervention

public_health_relevance:
RELEVANCE (See instructions): Our goal is to catalyze outstanding AD research while ensuring more rapid progress toward new therapies to delay or prevent AD so that our human volunteers patients and caregivers become the beneficiaries of our advances in knowledge. Our well integrated center is moving the field of cognitive aging and AD forward and supporting the elucidation of mechanisms of disease progression so that successful interventions can be developed in the future to treat or prevent this most dehumanizing disorder to affect humans.


application_id: 8690713
project_number: 5P30AG028383-09
project_title: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2014-06-13
opportunity_number: RFA-AG-11-005
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
program_official: SILVERBERG, NINA B
project_start_date: 2006-07-15
project_end_date: 2016-06-30
study_section: ZAG1-ZIJ-5(M2)
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This application seeks to renew the Alzheimer's Disease Core Center (P30 AG028383) at the University of Kentucky (UK-ADC) a mature and experienced ADC that was originally funded in 1985. Our principal mission is to serve as the focal point for all AD-related activities at UK and the Commonwealth of Kentucky by providing an environment and core resources that catalyze innovative research outreach and education and clinical programs that benefit elderly Kentuckians. Over the past 25 years we have developed a vigorous program in the clinical neuropathological educational and research aspects of AD that serves as a critical resource for the university community state region and nation. UK-ADC initiatives are innovative and are shifting the current research and clinical practice paradigms. Two of the historically outstanding facets of our ADC are: 1) a strong program in clinical-neuropathological correlations and short postmortem interval autopsies and 2) a unique normal control group of -500 subjects followed longitudinally with all committed to brain autopsy upon death. These resources have contributed to us becoming one of the premier Centers in defining pathogenic mechanisms underlying the transitions from normal cognitive aging to AD. With the recent change in leadership of our ADC we are poised to build on these strengths and capitalize on emerging opportunities to more effectively translate this knowledge into therapeutic strategies aimed at slowing progression or preventing development of AD. Thus the UK-ADC will focus on two interrelated themes: Transitions and Translation. Our emphasis moving forward will be to more effectively bridge the gap between basic research and clinical studies by providing support and the necessary infrastructure to facilitate translational efforts. Efforts are focused across the spectrum of cognitive impairment (normal/ preclinical AD/ MCI/ dementia) with an overall goal of more effective translation of knowledge to intervention strategies. The UK-ADC provides an infrastructure and environment that focuses on these integrated themes and advances multidisciplinary innovative AD research through five highly interactive and effective Cores: A: Administrative B: Clinical (including our successful Minority Gateway Satellite) C: Biostatistics and Data Management D: Neuropathology and E: Education and Information Transfer Cores.

project_terms:
African American;Aging;Alzheimer's Disease;Autopsy;Awareness;Basic Science;Biometry;Brain;Cessation of life;Clinic;Clinical;Clinical Research;Cognitive;Cognitive aging;Commit;Communities;Community Health Education;Continuing Education;Control Groups;Databases;Dementia;Development;Disease;Education and Outreach;Educational aspects;Elderly;Environment;Evaluation;Experimental Designs;Funding;Goals;Housing;Impaired cognition;Intervention;Kentucky;Knowledge;Leadership;Life;Minority;Mission;Neurodegenerative Disorders;Outreach Research;Recruitment Activity;Research;Research Design;Research Infrastructure;Research Project Grants;Research Support;Resources;Serum;Services;Structure;Therapeutic;Tissue Banking;Tissue Banks;Translating;Translational Research;Translations;Universities;aging brain;brain tissue;clinical practice;cohort;data management;experience;experimental analysis;follow-up;innovation;knowledge translation;multidisciplinary;neuropathology;normal aging;novel therapeutic intervention;pre-clinical;prevent;programs;ranpirnase;research clinical testing;research study;success;translational clinical trial

public_health_relevance:
The UK-ADC has historically been at the forefront of supporting research to identify the early manifestations of disease and the pathogenic mechanisms underlying the transitions from normal aging to the development of AD. We propose to build upon this highly successful focus as well as leverage several recent positive developments at UK that will expand our translational research capability and thereby help to increase the rate of progress toward new therapies to delay or prevent AD.


application_id: 8690405
project_number: 1R21CA179283-01A1
project_title: Regulation of Par-4 Secretion in Normal Cells for Paracrine Action in Tumor Cells
administering_ic: NCI
award_notice_date: 2014-03-28
opportunity_number: PAR-13-146
application_type: 1
activity_code: R21
ic: CA
serial_number: 179283
suffix: A1
program_official: SALNIKOW, KONSTANTIN
project_start_date: 2014-04-01
project_end_date: 2016-03-31
study_section: Special Emphasis Panel[ZCA1 RPRB-O (J1)]
contact_pi_person_id: 1883986
contact_pi: RANGNEKAR, VIVEK M
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: 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): Lung cancer is a leading cause of cancer death in men and women in the United States. Mutations leading to activation of the Ras oncogenes and inactivation of the p53 tumor suppressor gene are two of the most common alterations in lung cancer. As the tumor growth inhibitory action of chemotherapy and radiation therapy generally requires wild-type p53 function lung tumors with p53 mutations or deletions develop resistance to therapy resulting in ultimate death of the patients. Moreover oncogenic Ras activation and p53 inactivation results in elevated NF-kB activity that contributes to cell survival and therapeutic resistance. Tumor growth is regulated by a complex network of interactions between normal cells and cancer cells. In addition to local interactions tumor growth may be influenced by growth-promoting and growth-inhibiting factors produced systemically by the host. Accordingly cancer therapeutics can be aptly utilized to regulate the systemic environment in order to directly target aberrant growth. Understanding the mechanisms associated with systemic secretion of pro-apoptotic proteins by normal cells and their effect on tumor epithelial cells is a critical facet of such investigations. A majority of the cells throughout the body of lug cancer patients are normal and have wild type p53 status. This proposal will explore whether p53 activation in normal cells triggers paracrine cell death in p53-deficient lung tumors. As p53 activation only partially inhibits NF-kB activity our Preliminary Studies used co-parallel activation of p53 and inhibition of NF-kB in normal cells to identify secreted protein(s) that can cause a paracrine apoptotic effect in p53-deficient lung cancer cells. Based on our findings we hypothesize that p53 regulates the secretion of the pro-apoptotic tumor suppressor protein Par-4 from normal cells for paracrine effect in cancer cells and that maximum induction of Par-4 protein by p53 activation and NF-kB inhibition from normal cells should effectively induce apoptosis in p53-deficient lung tumors in mice. The proposed study will explore the feasibility of this novel area of investigation by pursuing two Specific Aims. (Aim 1) Determine the mechanism by which p53 activation in normal cells induces tumor cell apoptosis. We will study the kinetics and mechanism of Par-4 secretion induced by p53 in diverse normal cell types leading to apoptosis of p53-deficient lung cancer cells. (Aim 2) Determine the paracrine effect of Par-4 secretion which is induced by p53 activation in normal cells on p53-deficient lung tumors. After concomitant activation of p53 and inhibition of NF-kB activity we will test the kinetics of systemic elevation of Par-4 protein and its effect on apoptosis and regression of lung tumors in K-rasLSL-G12Dp53Fl/Fl mice. Moreover mechanistic studies will be undertaken to gain deeper insights into the functional role of Par-4 in the paracrine action on these tumors in mice. Collectively these studies will uncover the feasibility and mechanism of the paracrine effects of p53 activation in normal cells for apoptosis and regression of p53-deficient lung cancer. As p53 is mutated in diverse cancers the findings of this study will have broad translational implications.

project_terms:
Apoptosis;Apoptotic;Area;B-Lymphocytes;Binding (Molecular Function);Binding Sites;Blood Cells;Breeding;Cancer Etiology;Cancer Patient;Cancer cell line;Cell Culture Techniques;Cell Death;Cell Survival;Cell surface;Cells;Cessation of life;Complex;Conditioned Culture Media;Consensus;Coupled;Cytokine Activation;Data;Endothelial Cells;Environment;Epithelial Cells;Fibroblasts;GRP78;Growth;Human;Investigation;Kinetics;Lung Neoplasms;MDM2 gene;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Molecular;Mus;Mutate;Mutation;NF-kappa B;Normal Cell;Oncogenic;PAWR gene;PAWR protein;Pathway interactions;Patients;Protein Secretion;Protein p53;Proteins;Radiation therapy;Regulation;Relative (related person);Resistance;Resistance development;Role;Serum;TP53 gene;Testing;Therapeutic;Therapeutic Agents;Tumor Suppressor Genes;Tumor Suppressor Proteins;United States;Woman;base;cancer cell;cancer diagnosis;cell type;chemotherapy;functional status;in vivo;inhibitor/antagonist;insight;men;mouse model;neoplastic cell;novel;paracrine;pro-apoptotic protein;public health relevance;ras Genes;ras Oncogene;receptor;response;secretory protein;small molecule;therapy resistant;tumor;tumor growth

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  The proposed studies will examine the paracrine effect of co-parallel activation of p53 and inhibition of NF-kB in normal cells on p53-deficient lung cancer cel lines and tumors. Both cell culture and mouse models will be used to determine the mechanism of tumor suppressor Par-4 protein secretion by normal cells. The findings will validate the role of
Par-4 in mediating the paracrine tumor suppressor effect of p53.


application_id: 8690171
project_number: 5R01NS039041-14
project_title: Neurogenic Amplification of Pancreatitis Pain
administering_ic: NINDS
award_notice_date: 2014-06-25
opportunity_number: PA-10-006
application_type: 5
activity_code: R01
ic: NS
serial_number: 039041
program_official: OSHINSKY, MICHAEL L
project_start_date: 2000-04-01
project_end_date: 2016-06-30
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 6346300
contact_pi: WESTLUND-HIGH, KARIN 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): For patients with inflamed or cancerous pancreas the precipitating complaint is pain generated by local tissue inflammation fibrosis ductal stenosis edema and fluid pressure. The pain relayed by visceral afferent nerves from chronically inflamed pancreas can become severe and intractable with no effective long-term treatment options. The studies proposed in this competitive renewal extend the original aims of the parent grant with two serendipitously discovered novel and potentially related findings. Discovery #1: Our recent unpublished findings indicate that high fat diet and alcohol induce increased expression of transient receptor potential vanilloid 4 (TRPV4) channels on pancreas cells. TRPV4 channels are non-selective cation channels responsive to conditions present in the local cellular microenvironment after tissue injury including lipid mediators and tissue edema. Some alcohol metabolites are lipid mediators that can activate TRPV4. Excessive TRPV4 activation initiates cellular influx of calcium that initiates damaging intracellular cascades and pancreas afferent nerve activation. Discovery #2: We found that pancreatic tissue damage inflammation and pain-related behaviors are significantly reduced by gene therapy inducing overexpression of the endogenous opioid peptide met- enkephalin. We propose new studies using a chronic pancreatitis model in rats and clonal pancreatic cells to further investigate significant tissue injury-induced changes in the cell microenvironment that are relevant to inducible TRPV4 expression and activation responses during the development of chronic pain. Hypothesis: Alcohol-induced injury in pancreas cells increases TRPV4 expression and activation which are reduced by met-enkephalin protection Aim 1 Determine the effects of alcohol injury on TRPV4 expression and activation in the pancreas. Aim 2 Determine if alcohol-induced TRPV4 expression and activation is reduced by met-enkephalin. Our overall goal is to discover local cellular microenvironment interactions that impact chronic pain and that provide inroads for development of future clinical treatments for chronic inflammatory visceral pain. The impact of TRPV4 induced in local reactive cells after tissue damage and the role of TRPV4 in chronic pain have not been well studied. The findings will provide knowledge about analgesic protective and reparative effects of met-enkephalin related to TRPV4. Expected outcomes of challenging pancreatic cells in vitro with TRPV4 activators are that TRPV4 expression and activation responses will increase except in the presence of met- enkephalin. Further TRPV4 inhibitors and met-enkephalin will reduce pain-related behaviors in the rat model of chronic pancreatitis. The findings will extend understanding of TRPV4 mediated events in the local microenvironment that impact both peripheral and central sensitization during the transition from acute to chronic visceral pain. Study of the transition to chronic pain is a mission of the NIH Blueprint and NINDS.

project_terms:
Acetaldehyde;Acinar Cell;Action Potentials;Acute;Alcohol abuse;Alcohol-Induced Disorders;Alcohols;Analgesics;Animal Model;Arachidonic Acids;Behavior;Blood alcohol level measurement;Calcium;Cancerous;Cations;Cell membrane;Cells;Chronic;Chronic inflammatory pain;Clinical Treatment;Development;Diet;Dose;Ductal;Edema;Endogenous Opiates;Event;Exposure to;Fatty acid glycerol esters;Fibrosis;Future;Goals;Homeostasis;Human;In Vitro;Inflammation;Inflammatory;Injury;Ischemia;Knowledge;Lipids;Liquid substance;Malignant neoplasm of pancreas;Mediating;Methionine Enkephalin;Mission;Modeling;National Institute of Neurological Disorders and Stroke;Nerve;Nerve Endings;Neuropeptides;Neurosciences;Nociception;Opioid;Opioid Peptide;Organ;Outcome;Outcome Study;Oxygen;Pain;Pancreas;Pancreatitis;Patients;Peripheral;Proteins;Rattus;Research;Role;Signal Transduction;Stenosis;Study models;Testing;Tissues;United States National Institutes of Health;Vanilloid;Visceral Afferents;Visceral pain;afferent nerve;alcohol effect;alcohol exposure;alcohol induced pancreatic injury;base;cell type;central sensitization;chronic pain;chronic pancreatitis;gene therapy;improved;inflammatory pain;inhibitor/antagonist;lipid mediator;novel;overexpression;parent grant;pressure;receptor;research study;response;response to injury;stellate cell;visceral afferent nerve

public_health_relevance:
We propose that alcohol and other related injurious agents present in the inflamed pancreas increase expression and activation of the cation channel protein transient receptor protein vanilloid 4 (TRPV4). We propose studies to confirm this preliminary finding and to determine if the endogenous opioid peptide met-enkephalin can interfere with the destructive actions induced by alcohol injury on TRPV4 expression and activation. Our novel findings have implications for improved pancreatic function and reduction of pain for patients with pancreatitis and pancreatic cancer.


application_id: 8689198
project_number: 5R01NS084823-02
project_title: Mechanisms of Homocysteine-Induced Fibrinogen-Amyloid Plaque Formation
administering_ic: NINDS
award_notice_date: 2014-04-28
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: NS
serial_number: 084823
program_official: CORRIVEAU, RODERICK A
project_start_date: 2013-07-01
project_end_date: 2018-04-30
study_section: Special Emphasis Panel[ZRG1-VH-B(03)]
contact_pi_person_id: 6869069
contact_pi: LOMINADZE, DAVID
other_pis: TYAGI, SURESH C.
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 plaques in the brain during Alzheimer's diseases (AD) are primarily composed of amyloid-b (Ab) peptide. Although a strong association between Ab fibrinogen (Fg) and elevated level of homocysteine (Hcy) i.e. hyperhomocysteinemia (HHcy) during AD is well- documented the mechanism of amyloid plaque formation is unclear. The long-term goal of this project is to understand the mechanisms of cerebrovascular permeability leading to amyloid plaque formation. We have shown that elevated levels of Hcy and Fg i.e. hyperfibrinogenemia (HFg) increase cerebrovascular permeability and Fg can cross vascular endothelial cell (EC) layer secondary to activation of matrix metalloproteinase-9 (MMP-9). In addition increased levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) which enhances collagen content in subendothelial matrix (SEM) are associated with AD. In pilot studies we found that while HHcy enhances vascular permeability through mainly the paracellular pathway HFg activates mainly the transcellular transport. We also found that blood level of Fg is increased during HHcy. Therefore Fg can have an additive effect in HHcy-induced cerebrovascular permeability. We found that HHcy increases collagen level in SEM and Fg and Ab depositions in brain vasculature. While HHcy increases MMP-9 activity and enhances the paracellular transport as well as homocyteinylates Fg (making fibrin clots more rigid) Fg enhances the transcellular transport through caveolin-1 (Cav-1) signaling (via phosphorylation of Cav-1). However the role of Hcy and Fg in Hcy-Fg-Ab-collagen complex formation is unclear. The hypothesis of this proposal is that HHcy increases vascular permeability by primarily affecting the endothelial cell (EC) junction proteins and activating MMP-9 and indirectly by increasing blood content of Fg which enhances transcellular transport leading to an enhanced Hcy- Fg-Ab-collagen complex formation. We will test this hypothesis with three specific aims: 1) To determine whether the HHcy instigates cerebrovascular permeability via paracellular transport leading to enhanced cerebrovascular crossing of fibrinogen 2) To determine whether the fibrinogen deposition enhances cerebrovascular permeability mainly through caveolar transcytosis via Cav-1 signaling secondary to MMP-9 activation 3) To determine whether the HHcy increases fibrinogen-Ab-collagen complex accumulation in mouse brains secondary to increasing tissue inhibitor of metalloproteinase-1. To define specific causative effects of Hcy Fg MMP-9 Cav-1 and TIMP-1 in Fg-Ab-collagen complex formation the studies will be done on pial vessels of wild type (WT) Cystathionine b-Synthase heterozygote (CBS+/-) mice (a model of HHcy) MMP-9 gene knockout (MMP9-/-) CBS and MMP-9 double knockout (CBS+/-/MMP9-/-) Cav-1 gene knockout (Cav1-/-) Fg g-chain-deficient (Fg-/-) CBS+/-/Fg-/- HFg transgenic (HFg) HFg/MMP9-/- CBS+/-/Cav1-/-/MMP9-/- CBS+/- /HFg CBS+/-/HFg/MMP9-/- TIMP-1 gene knockout (TIMP1-/-) CBS+/-/TIMP1-/- double knockout Fg-/-/MMP1-/- and CBS+/-/Fg-/-/TIMP1-/- mice using a newly developed dual-tracer probing method that allows separation of paracellular from transcellular transport. Formation of Fg-Ab-collagen complex in brain cortex will be assessed with immunohistochemical analysis. The results of the proposed research should uncover the molecular mechanisms regulating Hcy-Fg-Ab-collagen complex formation and lead to effective strategies for the treatment of cerebrovascular complications during diseases such as AD.

project_terms:
Affect;Aging;Alzheimer's Disease;Amyloid;Binding (Molecular Function);Blood;Brain;CAV1 gene;Caveolae;Coagulation Process;Collagen;Complex;Cryoultramicrotomy;Cystathionine;Dementia;Deposition;Development;Disease;Endothelial Cells;Extravasation;Fibrin;Fibrinogen;Gelatinase B;Goals;Heterozygote;Homocysteine;Homocystine;Hyperhomocysteinemia;Immunohistochemistry;Intercellular Junctions;Interstitial Collagenase;Knock-out;Knowledge;Lead;MMP9 gene;Matrix Metalloproteinases;Measures;Methods;Mission;Modeling;Molecular;Mus;Neurodegenerative Disorders;Pathway interactions;Peptides;Permeability;Phosphorylation;Pilot Projects;Presenile Alzheimer Dementia;Proteins;Research;Role;Sampling;Secondary to;Senile Plaques;Signal Transduction;TIMP1 gene;Testing;Therapeutic;Tissue Inhibitor of Metalloproteinase-1;Tracer;Transgenic Organisms;United States National Institutes of Health;Vascular Endothelial Cell;Vascular Permeabilities;caveolin 1;cerebrovascular;design;knockout gene;novel;occludin;public health medicine (field);public health relevance;transcytosis;treatment strategy;vascular endothelial cadherin-2;venule

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Alzheimer's Disease (AD) is the most common form of dementia and it is not a normal part of aging. Up to 5 percent of people with the disease have early onset AD. The plaques in the brain during AD are primarily composed of amyloid-b (Ab) peptide. Although a strong association between Ab fibrinogen (Fg) and homocysteine (Hcy) is well-documented the mechanism is unclear. Our findings show that at elevated levels Hcy increases cerebrovascular permeability to proteins leading to Fg deposition in brain cortical vessels. We also found that this Fg is associated with increased levels of Ab and collagen in brain vasculature. These effects of Hcy and Fg were diminished in the absence of matrix metalloproteinase-9 (MMP-9) activity. The long-term goal of this project is to understand mechanisms leading to brain Fg-Ab-collagen complex formation. The knowledge of mechanisms that control the amyloid plaque formation will lead to the design of therapeutic strategies for the control of this devastating neurodegenerative disease. The proposed research is relevant to public health and to the mission of NIH because it will clarify a novel pathogenic causal relationship into the role of Hcy Fg and MMPs in development of AD.


application_id: 8688978
project_number: 5U01DA036158-02
project_title: Kentucky TRIALS Research Center
administering_ic: NIDA
award_notice_date: 2014-06-25
opportunity_number: RFA-DA-13-009
application_type: 5
activity_code: U01
ic: DA
serial_number: 036158
program_official: JONES, DIONNE
project_start_date: 2013-07-01
project_end_date: 2018-06-30
study_section: ZDA1-EXL-T(11)S
contact_pi_person_id: 1873108
contact_pi: LEUKEFELD, CARL G
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:
AIDS prevention;Address;Adolescence;Adolescent;Adoption;Area;Clinical Research;Commit;Communities;Community Services;Continuity of Patient Care;Criminal Justice;Data;Data Analyses;Disease;Drug Controls;Drug abuse;Environmental Risk Factor;Evidence based intervention;Evidence based practice;Federal Hospitals;HIV;Intervention;Justice;Kentucky;Knowledge;Legal system;Letters;Measures;National Institute of Drug Abuse;Organizational Change;Outcome;Pharmaceutical Preparations;Policies;Positioning Attribute;Provider;Publications;Research;Research Personnel;Research Project Grants;Services;Site;Staging;Substance abuse problem;Supervision;Testing;Translational Research;U-Series Cooperative Agreements;United States Public Health Service;Universities;Vision;Youth;adolescent substance abuse;alcohol research;base;behavioral health;cooperative study;data management;design;experience;implementation research;implementation science;improved;innovation;juvenile justice system;prevention service;response;success;theories


application_id: 8688861
project_number: 5R01AG029623-09
project_title: Role of TWEAK in skeletal muscle metabolism
administering_ic: NIA
award_notice_date: 2014-06-30
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AG
serial_number: 029623
program_official: WILLIAMS, JOHN
project_start_date: 2007-02-01
project_end_date: 2017-05-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 1917770
contact_pi: KUMAR, ASHOK
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): During last funding period we identified and established that TWEAK cytokine is a major regulator of skeletal muscle mass during aging and disuse conditions. We have now obtained strong evidence suggesting that the TWEAK causes insulin resistance in skeletal muscle. However the mechanisms by which TWEAK induces muscle atrophy or insulin resistance remain less well understood. PGC-1 cofactor plays a major role in regulation of skeletal muscle mass fiber-type composition and mitochondrial biogenesis. Our preliminary studies have shown that TWEAK suppresses the expression of PGC-1 and mitochondrial content and inhibits insulin signaling in skeletal muscle. We have also found that disuse conditions or type II diabetes involve the inducible expression of TWEAK receptor Fn14 (but not TWEAK itself) in skeletal muscle. Our initial analysis has revealed that both human and mouse Fn14 promoter contains CpG rich regions and that demethylation of Fn14 promoter could be a crucial event for the induction of Fn14 expression in skeletal muscle. In the next phase of this project we will investigate the mechanisms by which TWEAK causes sarcopenia disuse-related muscle atrophy and insulin resistance and how the expression of Fn14 gets up regulated in skeletal muscle in different conditions. We will address the following three specific aims: AIM I. Investigate the role of PGC-1 in TWEAK-mediated skeletal muscle atrophy in vivo. Hypothesis 1: TWEAK causes muscle atrophy and fiber-type switching through down-regulation of PGC-1 expression. AIM II. Investigate the key mechanisms by which TWEAK-Fn14 system induces insulin-resistance in adult and/or aged skeletal muscle. Hypothesis 2: TWEAK induces insulin resistance by inhibiting insulin receptor substrate (IRS1) phosphorylation and diminishing oxidative phosphorylation in skeletal muscle. AIM III: Investigate the molecular events leading to increased expression of TWEAK receptor Fn14 in skeletal muscle. Hypothesis 3: Demethylation of CpG islands in Fn14 promoter followed by binding of SP1 transcription factor triggers the expression of Fn14 in skeletal muscle in catabolic
states. Successful completion of this project will provide critical insights about sarcopenia durin aging and type II diabetes and provide novel avenues for therapeutic interventions.

project_terms:
Ablation;Acquired Immunodeficiency Syndrome;Address;Adult;Age;Aging;Atrophic;Binding (Molecular Function);Binding Sites;Biogenesis;Chronic Disease;Computer Simulation;Consensus;CpG Islands;Denervation;Development;Diabetes Mellitus;Disease;Down-Regulation;Drug Targeting;Epigenetic Process;Etiology;Event;Fiber;Funding;GLUT4 gene;Genetic;Glucose;HDAC5 gene;Heart failure;Human;IRS1 gene;Immobilization;In Vitro;Injury;Insulin;Insulin Receptor;Insulin Resistance;Lead;MAP3K7 gene;Malignant Neoplasms;Mediating;Mediator of activation protein;Medicine;Methyltransferase;Mitochondria;Modeling;Molecular;Morbidity - disease rate;Mus;Muscle;Muscle Fibers;Muscle Proteins;Muscle function;Muscular Atrophy;NF-kappa B;Natural regeneration;Non-Insulin-Dependent Diabetes Mellitus;Oxidative Phosphorylation;PPAR gamma;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Phase;Phosphorylation;Physiological;Play;Population;Promotor (Genetics);Proteins;Regulation;Reporting;Role;Signal Transduction;Skeletal muscle structure;Specificity;Syndrome;System;TRAF6 gene;Testing;Therapeutic Intervention;Transcription Initiation Site;Transgenic Organisms;Ubiquitin;Up-Regulation (Physiology);aged;cofactor;cytokine;demethylation;glucose uptake;human HDAC4 protein;improved;in vivo;insight;insulin sensitivity;insulin signaling;multicatalytic endopeptidase complex;muscle aging;muscle form;muscle metabolism;neuromuscular activity;novel;older patient;overexpression;prevent;public health relevance;receptor;research study;sarcopenia;skeletal muscle wasting;transcription factor;wasting

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Skeletal muscle wasting is a debilitating consequence of aging and many chronic diseases such as type II diabetes common at older age. However there is still no approved therapy for treatment of this disorder/syndrome. It is essential to develop new medicines that can preserve skeletal muscle mass during aging. The proposed studies will identify the mechanisms of action of TWEAK cytokine a recently identified mediator of muscle wasting. Successful completion of this project will improve the basic understating of etiology of muscle wasting and type II diabetes and will lead to the identification of a novel drug
target to preserve muscle mass and function in aging human population.


application_id: 8688712
project_number: 1R01CA185972-01
project_title: Chemoprevention of metastatic colorectal cancer
administering_ic: NCI
award_notice_date: 2014-07-24
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: CA
serial_number: 185972
program_official: CHEN, WEIWEI
project_start_date: 2014-08-01
project_end_date: 2019-07-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 7649061
contact_pi: DAMODARAN, CHENDIL
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
AKT Signaling Pathway;AKT inhibition;Affinity;Animal Model;Animals;Apoptosis;BCL2 gene;Binding (Molecular Function);Biological Assay;Biotin;Cancer Etiology;Cause of Death;Cell Culture Techniques;Cell Line;Cell Proliferation;Cells;Cessation of life;Chemoprevention;Chemopreventive Agent;Clinical;Clinical Trials;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Data;Development;Diagnosis;Dietary Supplements;Disease;Disseminated Malignant Neoplasm;Docking;E-Cadherin;Epithelial;Event;Fluorouracil;Goals;Growth;Human;In Vitro;Investigation;Label;Laboratories;Large Intestine Carcinoma;Lead;Malignant Epithelial Cell;Mediating;Mesenchymal;Modeling;Molecular;Neoplasm Metastasis;Oral;Oral Administration;Patients;Pattern;Phenotype;Phosphotransferases;Polyps;Pre-Clinical Model;Prevention;Proteins;Proto-Oncogene Proteins c-akt;Radiosurgery;Regimen;Relapse;Research Personnel;Role;SW620;Sampling;Signal Transduction;Snails;Staging;Survival Rate;Therapeutic;Time;Transcription factor genes;Tumor Tissue;Withania somnifera;Woman;Xenograft Model;Xenograft procedure;analog;angiogenesis;base;cell growth;chemotherapy;high risk;insight;interest;meetings;men;metastatic colorectal;migration;neoplastic cell;novel;novel strategies;overexpression;pre-clinical;prevent;public health relevance;slug;survivin;tumor;tumor growth;tumor progression


application_id: 8688439
project_number: 3R01NS069633-03S1
project_title: Mitochondrial-Targeted Therapeutics for Treatment of Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2013-06-25
opportunity_number: PA-10-067
application_type: 3
activity_code: R01
ic: NS
serial_number: 069633
suffix: S1
program_official: JAKEMAN, LYN B
project_start_date: 2011-06-15
project_end_date: 2015-04-30
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: RABCHEVSKY, ALEXANDER GEORGE
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Spinal cord injury (SCI) is a long-term health care problem in the United States and with the exception of the modestly effective methylprednisolone there is currently no neuroprotective intervention clinically available for treatment of acute SCI. Our published data and preliminary results demonstrate that oxidative damage to key mitochondrial enzymes and subsequent mitochondrial dysfunction is key to the neuropathological sequalae following SCI. This proposal focuses on directly targeting mitochondrial dysfunction as a novel therapeutic intervention for contusion SCI the fundamental concept being that SCI-induced excitotoxicity increases mitochondrial Ca2+ cycling/overload and the production of reactive oxygen species (ROS) ultimately leading to mitochondrial dysfunction and glutathione (GSH) depletion. Our approach is two-pronged aimed at reducing mitochondrial ROS production utilizing a novel cell-permeant antioxidant and GSH precursor NACA (the amide form of N-acetylcysteine) as well as an alternative biofuel substrate for energy production acetyl-l-carnitine (ALC) following SCI. Our published and preliminary data signify that both NACA and ALC improve mitochondrial bioenergetics following contusion SCI in rats and that prolonged NACA or ALC treatment increases tissue sparing following injury. The planned experiments are designed to test the novel hypothesis that reducing oxidative damage to key mitochondrial proteins will maintain mitochondrial bioenergetics thus leading to increased neuroprotection and improved functional recovery following contusion SCI. Specifically we will: 1) Characterize oxidative damage to specific mitochondrial proteins involved in bioenergetics and test the hypothesis that NACA treatment ameliorates mitochondrial oxidative damage following SCI 2) Test the hypothesis that a combinatorial treatment with NACA and ALC will act synergistically to preserve mitochondrial homeostasis following SCI and 3) Test the hypothesis that a combinatorial treatment with NACA and ALC will increase tissue sparing and promote long-term functional recovery following SCI. Critically this application is built around the utilization of several novel techniques we have developed for isolating synaptic (neuronal) and non-synaptic (soma and glia) mitochondria from the injured spinal cord as well as an L1/L2 contusion SCI paradigm that demonstrates a significant correlation between neuroprotection and remarkable improvements in recovery of hind limb function. Collectively the proposed experiments will pinpoint key mitochondrial events that could be potential novel targets for pharmacological interventions to more effectively treat SCI and perhaps other CNS injuries.

project_terms:
Acetylcysteine;Acute;Amides;Antioxidants;Behavioral;Bioenergetics;Carnitine;Cell Count;Cells;Collaborations;Contusions;Data;Dose;Enzymes;Event;Glutathione;Healthcare;Histopathology;Homeostasis;Impairment;Injury;Intervention;Levocarnitine Acetyl;Limb structure;Maintenance;Methylprednisolone;Mitochondria;Mitochondrial Proteins;N-Acetylcysteinamide;Neuroglia;Neurons;Outcome Measure;Oxidative Phosphorylation;Population;Production;Publishing;Rattus;Reactive Oxygen Species;Recovery;Recovery of Function;Reporting;Site;Source;Spinal cord injury;Synapses;Techniques;Testing;Therapeutic;Tissues;United States;Universities;Work;base;cell body (neuron);central nervous system injury;combinatorial;design;dosage;excitotoxicity;improved;kinematics;mitochondrial dysfunction;neuroprotection;novel;novel therapeutic intervention;oxidative damage;prevent;research study;response;therapeutic target

public_health_relevance:
Spinal cord injury (SCI) is a serious health care problem in the United States. However with the exception of the modestly effective methylprednisolone no neuroprotective intervention is clinically available for treatment of acute SCI. This proposal focuses on directly targeting mitochondrial dysfunction as a novel therapeutic intervention following spinal cord injury (SCI).


application_id: 8688329
project_number: 5R01HL103750-04
project_title: Respiratory motor control and blood pressure regulation after spinal cord injury
administering_ic: NHLBI
award_notice_date: 2014-06-23
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: HL
serial_number: 103750
program_official: LAPOSKY, AARON D
project_start_date: 2011-06-07
project_end_date: 2016-05-31
study_section: Clinical and Integrative Cardiovascular Sciences Study Section[CICS]
contact_pi_person_id: 9348839
contact_pi: OVECHKIN, ALEXANDER VLADIMIROVICH
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:
DESCRIPTION (provided by applicant):   Many individuals with chronic spinal cord injury (SCI) face the challenge of managing their unstable blood pressure which frequently results in persistent hypotension due to decreased cardiac output and autonomic nervous system dysfunction. In addition blood pooling in the lower body during upright posture leads to a further decrease in blood pressure known as orthostatic hypotension. These conditions severely impact the overall health of SCI individuals delay their participation in rehabilitative treatment limit the effectiveness of such treatment and significantly interfere with activities of daily living. In our clinic that utilizes activity-based therapy programs we have observed that one of the most common impediments to full participation in these programs was orthostatic hypotension. Further orthostatic intolerance increases the cost and decreases the efficacy of rehabilitative treatment. Another common impediment to rehabilitation after SCI is respiratory insufficiency due to paresis and paralysis of respiratory muscles. Physiologically these respiratory and cardiovascular dysfunctions are closely related. Data from our laboratory show that resting blood pressure correlates positively with pulmonary function outcomes and the location and severity of spinal cord lesion. These relationships could be due to better venous return to the heart as a result of higher negative intrapleural pressure and/or higher sympathetic tone due to better baroreflex response in individuals with better inspiratory and expiratory motor control. Our preliminary data showed that respiratory motor function after SCI can be improved by respiratory muscle training (RMT) a rehabilitative technique based on the breathing with resistance exercise. We observed that resting blood pressure and orthostatic tolerance were also improved after RMT in individuals with SCI. Therefore for the current proposal we hypothesize that RMT will improve blood pressure regulation in individuals with chronic SCI. We will examine the response of physiological regulatory mechanisms to RMT. Based on statistical power analysis forty five individuals who have chronic SCI will be recruited for this study over a four-year period. All subjects will have been diagnosed as having respiratory function deficits and orthostatic hypotension. We will evaluate pulmonary and cardiovascular function using spirometry respiratory muscle strength sympathetic skin response tests and surface electromyography of respiratory muscles. In addition we will use continuous beat-to-beat recording of systemic arterial blood pressure heart rate cardiac output and the measurements of blood catecholamines level during orthostatic stress test. Autonomic regulation outcomes will be calculated from beat-to-beat blood pressure and heart rate frequency composition analysis. We will also evaluate Spinal Cord Injury Independence (SCIM-III) and quality of life (CHART) measures. These outcomes will be obtained before a total of 20 RMT sessions lasting 45 minutes each / 5 days per week immediately after RMT and during 6-month follow-up period in 35 research participants forming the experimental group. Another 10 individuals serving as a control group will undergo the same procedures except the RMT intervention during the same time course. This technique as a therapeutic intervention in order to improve the blood pressure regulation and investigate its mechanisms in individuals with SCI has never been tested before. The results of this study will have direct effect on the SCI population by improving our understanding of the mechanisms of pulmonary function and blood pressure regulation and offering a pathophysiologically based rehabilitation strategy.

project_terms:
Activities of Daily Living;Affect;Area;Autonomic nervous system;Baroreflex;Blood;Blood Pressure;Breathing;Cardiac Output;Cardiovascular Physiology;Cardiovascular system;Catecholamines;Cause of Death;Chronic;Clinic;Control Groups;Data;Diagnosis;Diastolic blood pressure;Educational Intervention;Effectiveness;Electromyography;Exercise;Face;Frequencies (time pattern);Functional disorder;Goals;Health;Heart;Heart Rate;Hypotension;Individual;Injury;Laboratories;Location;Lung;Measurement;Measures;Motor;Muscle;Muscle Weakness;Neurologic;Orthostatic Hypotension;Outcome;Outcome Measure;Paralysed;Paresis;Participant;Performance;Persons;Physiological;Play;Population;Posture;Procedures;Pulmonary Function Test/Forced Expiratory Volume 1;Quality of life;Recovery;Recruitment Activity;Regulation;Rehabilitation therapy;Research;Resistance;Respiration;Respiratory Insufficiency;Respiratory Muscles;Respiratory Paralysis;Respiratory physiology;Response Latencies;Rest;Role;Secondary to;Severities;Skin;Spinal Cord Lesions;Spinal cord injury;Spirometry;Stress;Stress Tests;Surface;Techniques;Testing;Therapeutic Intervention;Time;Training;Training Technics;Venous;Vital capacity;base;blood pressure regulation;cardiopulmonary system;clinically relevant;cost;density;experience;follow-up;functional outcomes;improved;motor control;motor function improvement;muscle strength;novel;novel therapeutic intervention;pressure;programs;pulmonary function;rehabilitation strategy;respiratory;response

public_health_relevance:
Spinal cord injury (SCI) is commonly associated with paralysis resulting in pulmonary and cardiovascular dysfunctions which are listed among the leading causes of death in SCI population. The overall goal of this project is use a respiratory to muscle training to enhance respiratory motor function improve blood pressure regulation and to investigate the mechanisms of such improvement in persons with chronic SCI. The results of this study will have direct effect on the SCI population by providing the opportunity to significantly improve the overall health in individuals with SCI using novel rehabilitative approaches.


application_id: 8688311
project_number: 5P01HL078825-09
project_title: Stem Cell and Pathology Core
administering_ic: NHLBI
award_notice_date: 2014-05-08
opportunity_number: PAR-10-285
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
project_start_date: 2005-04-15
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7462
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-06-01
project_abstract:
The Stem Cell and Pathology Core will be a critical resource to this PPG. It will provide the four Projects with access to a wide array of reagents procedures and analyses including i) CPC isolation sorting and characterization ii) assays of CPC function in vitro and iii) histopathology of cardiac samples obtained in vivo. It will provide the facilities and expertise necessary to isolate maintain and manipulate CPCs from several genetically engineered mice. The individual Projects do not have the facilities or expertise needed to isolate and characterize CPCs consistently or to perform the extensive histopathological analyses required. Consolidation of all CPC work into a Core facilitv will decrease the costs of supplies and eguipment because the Core will make bulk purchases of supplies (thereby reducing expenses) and because waste and unnecessary duplication of supplies reagents and equipment will be eliminated with the maintenance of centralized stocks and inventories. Consolidating CPC work into a Core facilitv is also time-effective because the techniques involved in this work are very labor intensive and require dedicated skilled personnel. The Core staff a full-time team of six dedicated individuals under the immediate supervision of the Core Leaders will provide consistency and reproducibility of analvsis. This is crucial because it will ensure that all four Proiects will use CPCs isolated expanded and sorted the same way thereby making the results comparable. A single source of CPCs with rigorous standardization to ensure consistency will result in transplantation of uniform CPC populations in all four Proiects and thus is extremely important for the integration and comparison of results from each of the Projects. Similarly the uniform histopathologic analyses conducted by the Core in a blinded and rigorously standardized fashion will make it possible to compare results of different experiments within the same Project and among different Projects.   The methods used by the Core to prepare CPCs are extremely efficient; CPCs in culture as determined by c-kit expression (FACS). average 953% at passages 2 to 10 and remain at -95% at passage 10. In summary the Core will ensure guality control and by eliminating duplication of effort and maximizing the use of personnel and supplies will enable an efficient use of resources.

project_terms:
Actins;Apoptotic;Biological Assay;Blinded;Blood capillaries;Bromodeoxyuridine;Cardiac;Cell Count;Cell Death;Endothelium;Ensure;Equipment;Equipment and supply inventories;Fibrosis;Fixatives;Genetically Engineered Mouse;Heart;Histocytochemistry;Histopathology;Human Resources;Image;Image Analysis;In Situ Nick-End Labeling;In Vitro;Individual;Isolectin;Maintenance;Methods;Mortality Vital Statistics;Mus;Muscle Cells;Myocardial Ischemia;PECAM1 gene;Paraffin;Pathology;Perfusion;Population;Preparation;Procedures;Proto-Oncogene Protein c-kit;Reagent;Reproducibility;Resources;Sampling;Sirius Red F3B;Slide;Smooth Muscle Actin Staining Method;Smooth muscle (tissue);Sorting - Cell Movement;Source;Staining method;Stains;Standardization;Stem cells;Supervision;Techniques;Time;Tissues;Transplantation;Trichrome stain;Wheat Germ Agglutinins;Work;capillary;cost;density;in vivo;research study;tissue processing;von Willebrand Factor;wasting


application_id: 8688310
project_number: 5P01HL078825-09
project_title: Surgery and Physiology Core
administering_ic: NHLBI
award_notice_date: 2014-05-08
opportunity_number: PAR-10-285
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
project_start_date: 2005-04-15
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7461
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-06-01
project_abstract:
The function of the Surgery and Physiology Core (Core B) is to provide the expertise equipment and facilities needed for all of the in vivo murine studies. Specifically Core B will be responsible for all surgical procedures (coronary artery occlusion/reperfusion and CPC delivery) echocardiographic analyses invasive hemodynamic studies and maintenance and genotyping of transgenic and knockout mouse lines. Accurate physiological measurements and surgical procedures in mice represent technically demanding tasks that cannot and should not be attempted in every laboratory but rather should be performed by a group of dedicated investigators who focus on studies in mice and thereby acquire extensive experience with this difficult model. One of the main advantages of this Program Project is that it provides all four Proiects with access to complex and technically challenging in vivo mouse models of mvocardial infarction (Ml) and ceil therapy expert physiology and surgery and state-of-the-art technigues that otherwise would not be available to these investigators. This is a major benefit to all investigators. Core B consists of a team of skilled highly- experienced investigators who have worked together cohesively for many years focusing exclusively on murine studies (they have performed >16.000 surgical procedures in mice) have developed and perfected murine models of Ml and cell therapy utilizing state-of-the-art facilities and equipment and have collaborated extensively with the other investigators in this PPG.  An important feature of Core B is that it will use a new technique for delivering CPCs - intracoronary infusion in the mouse which has never been used before in this species. Compared with standard intramyocardial injection intracoronary infusion is much more clinically relevant. Furthermore it enables uniform distribution of CPCs throughout the infarct and in the noninfarcted region which is not possible with intramyocardial injection and produces superior results as shown by our data. Another feature is that all echocardiographic and hemodynamic analvses will be performed off-line by blinded observers. The capacity of the Core has been tested in the preparation of this submission. To produce the preliminary data needed for this application. Core B has operated upon >300 mice and performed 231 studies of CPC transplantation 390 echocardiographic studies and 108 hemodynamic studies. All of this has been done in the past 10 months. These numbers eloquently illustrate the research output that the Core can produce.

project_terms:
Blinded;Cell Therapy;Complex;Coronary artery;Data;Equipment;Genotype;Infarction;Infusion procedures;Injection of therapeutic agent;Knockout Mice;Laboratories;Maintenance;Measurement;Modeling;Mus;Myocardial Ischemia;Operative Surgical Procedures;Output;Physiological;Physiology;Preparation;Reperfusion Therapy;Research;Research Personnel;Techniques;Testing;Transgenic Mice;Transplantation;Work;artery occlusion;clinically relevant;experience;hemodynamics;in vivo;mouse model;programs


application_id: 8688307
project_number: 5P01HL078825-09
project_title: Regulation of CPC Function via Protein O-GlcN Acylation
administering_ic: NHLBI
award_notice_date: 2014-05-08
opportunity_number: PAR-10-285
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
project_start_date: 2005-04-15
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7458
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-06-01
project_abstract:
The myocardium is largely unable to effecfively repair itself following an infarcfion. Recent work indicatesthat resident cardiac progenitor cells (CPCs) represent an under-developed therapeutic target.Unfortunately the post-ischemic myocardium is an unfavorable environment for the survival and potenfialcardiomyogenic differentiation of CPCs thereby limlfing effective post-ischemic myocardial repair ofexogenously administered CPCs. Project 3 will address the biological regulation of stress signaling and itsimpact on CPC function. Recently several reports indicated a unique stress response (0-GlcNAc) in theheart that allows differenfiated cardiac myocytes to withstand the violent environment of the post-ischemicmyocardium. Protein 0-GlcNAcylafion occurs in every mulficellular organism that has been examined; yetnothing is known about the role of this stress signal in CPCs. This Project will directly address thisdeficiency to create new biological insights. Project 3 will test the central hypothesis that a unique alarmsignal (0-GlcNAc) plays a fundamental role in regulafing CPC function and that it promotes CPC survivalbut may limit bona fide post-ischemic cardiomyogenesis by maintaining CPCs in a persistent state of alarm.Project 3 will establish the impact of the pro-adaptive stress signal 0-GlcNAc on CPC function byspecifically focusing on proliferation (Aim 1) survival (Aim 2) and differenfiafion (Aim 3). This Project willuse an exhausfive series of carefully controlled loss- and gain-of-function approaches. Regardless of thespecific outcomes of the Alms this Project will provide completely novel Insights into an exclfing area ofcardiovascular medicine because of the significance of the quesfions being pursued. Project 3 will confinueto collaborate with Projects 1 2 and 4 to understand innovafive inter-regulatory mechanisms between O-GlcNAcylation and: the NO-CO axis (Project 1) TNF-NFkB induced inflammation (Project 2) andhyperglycemic suppression of CPC function (Project 4). The role of protein 0-GlcNAcylafion in CPCs iscompletely unknown. This Project will undoubtedly establish new biological insights by assuming aninnovative approach to understanding CPC regulation and pathophysiology.RELEVANCE (See instructions):Project 3 will establish completely innovafive insights into the regulation of the proliferation survival anddlfferenfiation of primitive cells in the heart and translate the findings into a clinically relevant model of heartfailure. Regardless of the specific outcomes of the Aims Project 3 will provide completely novel insights intoa unique form of stress signaling as a previously unrecognized regulator of progenitor cell function.

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

public_health_relevance:
RELEVANCE (See instructions): Project 3 will establish completely innovative insights into the regulation of the proliferation survival and differentiation of primitive cells in the heart and translate the findings into a clinically relevant model of heart failure. Regardless of the specific outcomes of the Aims Project 3 will provide completely novel insights into a unique form of stress signaling as a previously unrecognized regulator of progenitor cell function.


application_id: 8688306
project_number: 5P01HL078825-09
project_title: Tumor Necrosis Factor Modulation of CPCs
administering_ic: NHLBI
award_notice_date: 2014-05-08
opportunity_number: PAR-10-285
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
project_start_date: 2005-04-15
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7457
contact_pi_person_id: 1914941
contact_pi: PRABHU, SUMANTH D
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-06-01
project_abstract:
The overarching objective of this project is to establish the mechanistic relationships between pathologicalinflammation and cardiac progenitor cell (CPC)-mediated tissue repair. After myocardial infarction (Ml)CPCs are increased in number but fail to produce sufficient endogenous healing suggesting that factors inthe microenvironment compromise their reparative capacity. During LV remodeling there is sustainedelaboration of the pro-inflammatory cytokine tumor necrosis factor-a (TNF). The effects of TNF in the post-MIheart are heterogeneous and depend on its two cell-surface receptors (TNFRs) - TNFRl promotes LVremodeling and activation of nuclear factor (NF)-KB and p38 MAPK whereas TNFR2 opposes these effectsand is beneficial. However whether divergent TNFR-specific effects extend to CPCs and modulate theirreparative capacity is unknown. In our preliminary studies we have uncovered the novel finding that TNFinhibits cardiomyocyte differentiation of CPCs and instead promotes an adrenergic phenotype that canpotentiate remodeling. This response is dependent on TNFR1 and associated with NF-KB and can beopposed by TNFR2 Hence we hypothesize that differential TNF signaling via TNFR1 TNFR2 and NF-KBplavs a critical role in determining adrenergic versus cardiomyogenic fate and conseguentiv the reparativecapacity of CPCs following Ml. We propose three Aims. In Aim 1 we will determine the effects of TNFR-dependent signaling on CPC competence and adrenergic versus cardiogenic differentiation in vitro usingGFP-labeled lin-/c-kit+ CPCs from wild-type (WT) TNFRl-/- TNFR2-/- dominant-negative (DN)-lKBatransgenic (Tg) and Tg-DN-p38a MAPK mouse hearts. We will also establish that neuroadrenergic-typecells are derived from cardiac and not resident neural progenitors. In Aim 2 we will delineate the role ofCPC-localized TNFR-signaling during cardiac repair in vivo. In a murine reperfused Ml model we will deliverGFP-labeled lin-/c-kit+ WT TNFR1-/- TNFR2-/- or Tg-DN-kBa CPCs and determine cell fate and theireffects on LV remodeling and tissue adrenergic activation. In Aim 3 we will determine the effects of TNF inthe tissue microenvironment on CPC-mediated repair and adrenergic differentiation by defining remodelingresponses upon transplantation of GFP-labeled WT lin-/c-kit+ CPCs following reperfused Ml in WT and TNF-/- mice or upon circumscribed systemic TNF inhibition with etanercept. Collectively these studies will: 1)uncover a novel role for TNF as an inhibitor of CPC function and CPC-mediated repair via TNFR1 and NF-KB; 2) define a heretofore unknown CPC-derived origin for adrenergic cells in the failing heart; and 3) targetpotential therapeutic avenues related to TNF signaling to enhance the efficacy of CPC transplantationRELEVANCE (See instructions):These studies will establish the novel paradigm that tumor necrosis factor-a (TNF) profoundly influencescardiac progenitor cell (CPC) behavior through the divergent effects of its two receptors and channels thesecells toward either beneficial (cardiac cell) or detrimental (adrenergic cell) fates for tissue repair. The resultswill shed light on potential therapeutic avenues related to TNF signaling that can both enhance the efficacyof exogenous progenitor cell transplantation and augment the heart's intrinsic capacity to repair itself aftermyocardial infarction in the absence of progenitor cell therapy.

project_terms:
Adrenergic Agents;Arrhythmia;Biological;Cardiac;Cardiac Myocytes;Catecholamines;Cell Density;Cell Differentiation process;Cell Surface Receptors;Cell Therapy;Cell Transplantation;Cell membrane;Cell physiology;Cells;Clinical;Competence;Cytoprotection;Disease;Doctor of Medicine;Dominant-Negative Mutation;Etanercept;Healed;Heart;Heart failure;Human;In Vitro;Inflammation;Inflammatory;Injury;Instruction;Label;Left Ventricular Remodeling;Left ventricular structure;Light;MAP Kinase Gene;MAPK14 gene;Mediating;Mediator of activation protein;Modeling;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Nuclear;Phenotype;Play;Principal Investigator;Process;Promotor (Genetics);Proteins;Proto-Oncogene Protein c-kit;Role;Secondary to;Signal Transduction;Staging;Stem cell transplant;Stem cells;TNFRSF1A gene;TNFRSF1B gene;Testing;Therapeutic;Tissues;Transgenic Organisms;Transplantation;Tumor Necrosis Factor Receptor;Tumor Necrosis Factor-alpha;Tyrosine 3-Monooxygenase;adrenergic;cardiac repair;cell behavior;cell type;cytokine;healing;improved;in vivo;indexing;inhibitor/antagonist;injured;nerve stem cell;nestin protein;novel;receptor;repaired;research study;response;time use;tissue repair


application_id: 8688200
project_number: 5P50DA005312-24
project_title: Examining Urgency from Neurobiology to Prevention
administering_ic: NIDA
award_notice_date: 2014-06-20
opportunity_number: PAR-10-189
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
study_section: ZDA1-EXL-T
subproject_number: 6590
contact_pi_person_id: 3122080
contact_pi: LYNAM, DONALD R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-07-01
budget_end_date: 2015-06-30
project_abstract:
Impulsive behavior is an important contributor to substance misuse which is prevalent in college samples.Our center (CDART) has identified four distinct personality traits that underlie impulsive behaviors: NegativeUrgency (NU) lack of Premeditation (PRE) lack of Perseverance (PSV) and Sensation Seeking (SS). Ourprevious work clarified the roles of SS and PRE in substance misuse in the college population. In our morerecent work NU has emerged as an important and independent contributor to substance misuse. Even aftercontrolling for SS and PRE NU is related to the onset and escalation of substance misuse and other riskybehaviors and the relation between NU and alcohol use is mediated through different mechanisms than therelations for PRE and SS. Thus our previous work clearly shows that understanding NU is criticallyImportant to the prevention of substance misuse in college populations. The four proposed studies will use arange of methods to investigate the nature of NU and the mechanisms through which it exerts its effects.Study 1 will identify underlying biological substrates of NU using fMRI. It is predicted that regions in theprefrontal cortex associated with inhibitory control will show less activation in high NU participants whenparticipants are experiencing negative affect. Study 2 will identify the affective contexts and responsecharacteristics most important to NU. It is predicted that affect will be more important to NU than to otherimpulsivity traits and that NU will manifest in impulsive behavior on tasks that include prepotent responsesand/or tasks in which an impulsive response is negatively reinforced. Study 3 will examine the interactionsamong impulsivity traits affective contexts and interpersonal contexts in predicting impulsive behavior indaily life. It is predicted that NU will be related to impulsive behavior when high NU participants are under theinfluence of negative mood. Other impulsivity traits like SS may be more responsive to interpersonalcontexts. Study 4 will test whether an intervention designed to help high NU participants respond moreadaptively to their negative affect can reduce future impulsive behavior. It is predicted that mindfulnesstraining will reduce impulsive behaviors among high NU individuals but not among high SS individuals.RELEVANCE (See instructions):Prevention of substance misuse in college samples is important because of the associated public healthrisks including death injury long-term illness and disability. Negative urgency is a strong but understudiedpredictor of substance misuse. The proposed studies will contribute to prevention research by clarifying thenature of negative urgency and the mechanisms through which it exerts its effects on substance misuse.

project_terms:
Address;Adolescent;Affect;Affective;Aggressive behavior;Alcohol consumption;Alcohol or Other Drugs use;Amygdaloid structure;Attention deficit hyperactivity disorder;Behavior;Behavioral;Biological;Borderline Personality Disorder;Boredom;Cessation of life;Characteristics;Child;Clinical;Conduct Disorder;Consensus;Crime;Dimensions;Disinhibition;Drug abuse;Drug usage;Eating Disorders;Esthesia;Functional Magnetic Resonance Imaging;Future;Impulsive Behavior;Impulsivity;Individual;Injury;Instruction;Knowledge;Laboratories;Life;Marijuana Smoking;Mediating;Methodology;Methods;Modeling;Nature;Neurobiology;Participant;Personality Traits;Population;Predisposition;Prefrontal Cortex;Prevention;Prevention Research;Preventive;Preventive Intervention;Principal Investigator;Problem behavior;Process;Regulation;Research;Rewards;Risk;Risk Behaviors;Risk Factors;Risk-Taking;Role;Running;Sampling;Specific qualifier value;Stimulus;Substance Use Disorder;Syndrome;Testing;Thinking function;Training;Translational Research;Violence;Work;anti social;base;college;disability;distraction;experience;high risk drinking;high risk sexual behavior;improved;intimate partner violence;mindfulness;negative mood;neural circuit;operation;preference;psychological stressor;public health medicine (field);response;theories;therapy design;trait;willingness


application_id: 8688199
project_number: 5P50DA005312-24
project_title: Indivicual Differences in Drug abuse Liability
administering_ic: NIDA
award_notice_date: 2014-06-20
opportunity_number: PAR-10-189
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
study_section: ZDA1-EXL-T
subproject_number: 6589
contact_pi_person_id: 1901822
contact_pi: KELLY, THOMAS H.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-07-01
budget_end_date: 2015-06-30
project_abstract:
Prevention investigators in our Center and elsewhere have demonstrated that drug abuse preventionefficacy can be significantly enhanced by targeting individuals who are most vulnerable to developingproblems and tailoring message content and format based on the characteristics of these individuals. Ourprevious work focused on drug use initiation and identified behavioral mechanisms (neurobehavioralresponse to reinforcing novel and emotional stimuli) whereby the sensation seeking dimension of impulsivityis associated with vulnerability to drug use initiation and high sensation-value contexts enhance the efficacyof prevention interventions designed to reduce drug use initiation. Further development of laboratory modelsto identify individuals who are vulnerable to drug use escalation and development of associated problemsand identifying the characteristics of these individuals that predispose them to vulnerability and/or influencethe efficacy of targeted intervention materials is of critical importance for informing and advancing the field ofdrug abuse prevention. This application proposes five years of research to continue laboratory investigationsof individual differences associated with drug use escalation and associated exposure to heavy drug use.Growing evidence suggests that vulnerability to drug-use escalation is associated with self-controlmechanisms. A multidisciplimary approach combining personality measurement with laboratory abuseliability assessment behavioral inhibition task performance and brain imaging methodologies will be used toexamine impulsivity among matched groups of tobacco and marijuana users who have either maintainedstable patterns of intermittent/light use (escalation resistant) or who have escalated to heavy use with andwithout extended histories of heavy use (escalation; escalation + extended drug exposure) to test thehypothesis that drug use escalation is associated with inhibitory neurobehavioral dimensions of impulsivity.Knowledge of the association between component dimensions of impulsivity and drug-use escalation willenhance understanding of vulnerability to and consequences of drug use escalation and thus our ability todesign more efficacious tailored and targeted drug abuse prevention interventions.RELEVANCE (See instructions):Drug abuse prevention efficacy is improved by targeting at-risk individuals and tailoring interventions basedon the characteristics of those individuals. Impulsivity is closely linked with drug abuse vulnerability. Thisproject will support prevention science by identifying the neurobehavioral dimensions of impulsivity that areassociated with vulnerability to and adverse consequences of tobacco and marijuana use escalation.

project_terms:
Alcohols;Automobile Driving;Behavior;Behavioral;Behavioral Mechanisms;Behavioral inhibition;Brain imaging;Characteristics;Clinical;Dependence;Development;Dimensions;Disinhibition;Drug Exposure;Drug abuse;Drug usage;Drug user;Esthesia;Exposure to;Impairment;Impulsivity;Individual;Individual Differences;Instruction;Intervention;Investigation;Knowledge;Laboratories;Laboratory Study;Light;Link;Marihuana;Marijuana Smoking;Matched Group;Measurement;Mediating;Methodology;Modeling;Motivation;Nicotine;Pattern;Personality;Pharmaceutical Preparations;Prevention;Preventive Intervention;Process;Psychological reinforcement;Recording of previous events;Research;Research Personnel;Resistance;Risk;Role;Science;Self Administration;Self-control as a personality trait;Staging;Task Performances;Testing;Tetrahydrocannabinol;Tobacco;Tobacco use;Translational Research;Vulnerable Populations;Work;adverse outcome;alcohol effect;alcohol measurement;base;behavioral impairment;design;drinking;drug abuse prevention;drug reinforcement;emotional stimulus;improved;marijuana user;neurobehavioral;novel;prevent;programs;public health medicine (field);response;success;therapy design;young adult


