# projects

application_id: 8928142
project_number: 5U01DK074007-10
project_title: Continuation: UMMC's Clinical Center in NIDDK's Gastroparesis Research
administering_ic: NIDDK
award_notice_date: 2015-09-09
opportunity_number: RFA-DK-10-502
application_type: 5
activity_code: U01
ic: DK
serial_number: 074007
program_official: HAMILTON, FRANK A
project_start_date: 2006-04-15
project_end_date: 2016-08-31
study_section: ZDK1-GRB-8(J2)S
contact_pi_person_id: 8264660
contact_pi: ABELL, THOMAS LYMAN
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The University of Mississippi Medical Center proposes to continue its participation as a Clinical Center in NIDDK's Gastroparesis Clinical Research Consortium. Our study team headed by Thomas Abell MD a recognized expert in research and clinical experience in the area of gastroparesis will now include as co- investigator Michael Griswold PhD an expert in biostatistics and as collaborator Filip To PhD an expert in data automation signal analysis data fusion and instrumentation along with key members of our initial research team and two UMC collaborators from Surgery and Pathology respectively. The multidisciplinary expertise provided by this team will further our ability to investigate the complex pathophysiological pathways and symptoms associated with gastroparesis. The UMMC Vice Chancellor for Health Affairs and the Associate Vice Chancellor for Research continue to provide strong support for and the resources necessary to conducting the Clinical Center's research.  With respect to Consortium-wide contributions UMMC is well positioned to increase the study population already enrolled in the Gastroparesis Registry through its Clinical Center. Approximately 1000 patients with gastroparesis annually seek their treatment at this site; over the past 5 years we have evaluated new patients for the disorder identifying on the average 300 new patients with gastroparesis each year. In addition to furthering Consortium-wide protocols two new-efforts have been proposed for the present funding period at UMMC. The first is to assess and compare associations between presenting Gl symptoms histological counts of interstitial cells of Cajal and electrophysiology measures for patients with GP of diabetic and idiopathic etiology as well as to compare ICC counts in these biopsy specimens with counts in gastric tissue specimens from controls. The second is to demonstrate that Gastric Electrical Stimulation (GES) can reduce Gl symptoms by at least 50% for individual patients to assess the impact of temporary GES on gastric emptying times EGG values neuro-hormonal and autonomic status markers and HRQOL measures and to evaluate EGG values at varied GES energy levels in predicting likely usefulness with GES.

project_terms:
Area;Automation;Biometry;Biopsy Specimen;Clinical;Clinical Research;Complex;Data;Data Analyses;Diagnosis;Disease;Doctor of Philosophy;Electric Stimulation;Electrophysiology (science);Enrollment;Etiology;Funding;Gastric Emptying;Gastric Tissue;Gastroparesis;Head;Health;Hormonal;Individual;Interstitial Cell of Cajal;Measures;Medical center;Mississippi;Operative Surgical Procedures;Pathology;Pathway interactions;Patients;Population Study;Positioning Attribute;Protocols documentation;Registries;Research;Research Personnel;Resources;Signal Transduction;Site;Specimen;Stomach;Symptoms;Time;Universities;diabetic;experience;instrumentation;member;multidisciplinary;young woman

public_health_relevance:
In 2004 over 10000 patients were hospitalized in the U.S. with gastroparesis a devastating disease mainly seen in younger women as a primary diagnosis; for 134000 further patients it was a secondary diagnosis. We propose to continue and extend the systematic concerted approaches developed under initial funding to maintain and analyze long-term data so as to determine reliable treatments that decrease the toll of GP.


application_id: 8928039
project_number: 5R01AG046920-02
project_title: Novel Actions of Metformin to Augment Resistance Training Adaptations in Older Ad
administering_ic: NIA
award_notice_date: 2015-06-17
opportunity_number: PA-12-271
application_type: 5
activity_code: R01
ic: AG
serial_number: 046920
program_official: DUTTA, CHHANDA
project_start_date: 2014-09-30
project_end_date: 2019-05-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: BAMMAN, MARCAS M;KERN, PHILIP A
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adjuvant;Adult;Aging;Anti-Inflammatory Agents;Anti-inflammatory;Area;Biopsy;Blinded;Cell Culture System;Clinical Research;Coculture Techniques;Conditioned Culture Media;Cytokine Gene;Development;Disabled Persons;Effectiveness;Elderly;Environment;Exercise;Gene Expression;Goals;Growth;Health;Human;Hypertrophy;In Vitro;Individual;Inflammatory;Insulin;Insulin Resistance;Intervention;Life;Mediating;Metabolic;Metformin;Modeling;Molecular;Muscle;Muscle Cells;Muscle Fibers;Muscular Atrophy;Myoblasts;Nuclear;Organ;Participant;Persons;Pharmaceutical Preparations;Phenotype;Physiological;Placebo Control;Placebos;Positioning Attribute;Quality of life;Randomized;Recruitment Activity;Refractory;Regulation;Relative (related person);Research;Resistance;Risk;Signal Pathway;Skeletal muscle structure;Stretching;System;Testing;Time;Training;Training Programs;age related;cell type;combat;cost;effective intervention;frailty;glucose uptake;improved;improved functioning;in vivo;insulin sensitivity;macrophage;monocyte;muscle form;muscle hypertrophy;muscle strength;novel;prevent;programs;prospective;response;sarcopenia;satellite cell;strength training;vastus lateralis


application_id: 8928005
project_number: 5R01GM102129-04
project_title: In Search of Mannolipid Intermediate Flippases
administering_ic: NIGMS
award_notice_date: 2015-07-09
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: GM
serial_number: 102129
program_official: DEATHERAGE, JAMES F
project_start_date: 2012-09-20
project_end_date: 2017-07-31
study_section: Intercellular Interactions Study Section[ICI]
contact_pi_person_id: 7875239
contact_pi: WAECHTER, CHARLES J
other_pis: RUSH, JEFFREY STEWART
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): During the past 35 years this laboratory has been studying the function of polyisoprenol-linked intermediates in glycan synthesis in prokaryotes and eukaryotes. A long-standing interest in the topological issues involved in the biosynthesis of extracellular saccharides has led us to focus on the proteins that mediate the transbilayer movements of the lipid-linked intermediates utilized as glycosyl donors in these pathways. The current proposal is aimed at identifying the proteins that mediate the transbilayer movement of dimannosyldiacylglycerol and mannosylphosphoryldolichol two mannolipid intermediates in the assembly of the lipomannan of Micrococcus luteus. These studies will provide important clues to the identification of related proteins functioning in protein N-glycosylation C- and O-mannosylation of proteins and biosynthesis of glycosylphosphatidylinositol anchors in humans. The discovery of genes encoding membrane proteins functioning as flippases in these assembly processes will be valuable in the diagnosis of potential genetic errors referred to as Congenital Disorders in Glycosylation (CDGs).

project_terms:
12-diacylglycerol;Anabolism;Benzophenones;Biological Assay;Cell membrane;Cells;Chemistry;Collection;Congenital Disorders;Defect;Diagnosis;Diffuse;Diglycerides;Dolichol;Dolichol Monophosphate Mannose;Endoplasmic Reticulum;Eukaryota;Eukaryotic Cell;Face;GPI Membrane Anchors;Genes;Genetic;Genomic Library;Glycolipids;Goals;Human;In Vitro;Insulin Receptor;Label;Laboratories;Lead;Link;Lipids;Mammalian Cell;Mannose;Mediating;Membrane;Membrane Glycoproteins;Membrane Proteins;Metabolic;Micrococcus luteus;Movement;Mutation;Oligosaccharides;Pathway interactions;Play;Polysaccharides;Process;Prokaryotic Cells;Protein Biosynthesis;Protein C;Proteins;Proteomics;Protoplasts;Research Design;Rhodopsin;Scheme;Sodium Channel;Suicide;Surface;Temperature;Vesicle;Yeasts;analog;experience;extracellular;gene discovery;glycosylation;interest;lipomannan;man;monolayer;mutant;novel;protein function;seal;temperature sensitive mutant;voltage

public_health_relevance:
This application proposes studies designed to identify the membrane proteins (flippases) in Micrococcus luteus that mediate the transbilayer movements of dimannosyl-diacylglycerol and mannosylphosphorylundecaprenol two mannolipid intermediates in bacterial lipomannan synthesis. These studies on micrococcal lipomannan assembly will provide important new clues to the identification of related membrane proteins functioning in protein N-glycosylation C- and O-mannosylation of proteins and the biosynthesis of glycosylphosphatidylinositol (GPI) anchors in humans. Since N-linked oligosaccharides play a key role in the proper folding and intracellular routing of important membrane glycoproteins e.g. rhodopsin voltage-sensitive sodium channels and the insulin receptor the identification of the genes encoding mammalian flippases is relevant to the diagnosis of potential genetic errors referred to as Congenital Disorders in Glycosylation (CDGs).


application_id: 8927921
project_number: 1R21ES025669-01
project_title: Mitochondrial Metabolic Reprogramming and DNA Damage in Arsenic Carcinogenesis
administering_ic: NIEHS
award_notice_date: 2015-06-15
opportunity_number: RFA-ES-14-006
application_type: 1
activity_code: R21
ic: ES
serial_number: 025669
program_official: BALSHAW, DAVID M
project_start_date: 2015-06-15
project_end_date: 2017-04-30
study_section: Special Emphasis Panel[ZES1 LWJ-D (ME)]
contact_pi_person_id: 7213583
contact_pi: FAN, TERESA WHEI-MEI
other_pis: IZUMI, TADAHIDE ;SHI, XIANGLIN
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): Although epidemiological studies have associated arsenic (As) exposures with increased risk of lung cancer the molecular mechanisms involved in lung cancer development by arsenite exposure remain poorly defined. Recent literature has implicated altered mitochondrial (mt) metabolism oxidative stress and DNA damage in environmental As carcinogenesis but the biochemical dysregulations that underlie these processes and their interactions are unknown. It is also unclear if benchside understanding of As carcinogenesis in model systems can be translated into bedside understanding of human cancer. In this R21/R33 proposal this team of investigators will address these issues by adopting an integrated `omics approach that uses stable isotope-resolved metabolomics (SIRM) to define mt and cellular metabolic networks central to proliferation redox homeostasis and oxidative DNA damage/repair response in lung cells as perturbed by As transformation and carcinogenesis. This approach will reveal pathway changes for further testing on their dysregulations (e.g. key enzymes and related regulatory proteins) at the gene mutational epigenetic and transcriptional level by querying into genomic epigenomic and transcriptomic sequencing data. The investigators will fulfill their goal with two specific aims (SA1 & 2) in the R21 phase followed by SA3 & 4 in the R33 phase and SA1 to determine if and how mt and cellular metabolic networks are altered in As-transformed lung cells using SIRM. Transformed lung cells will be studied in vitro and in mouse xenografts using SIRM. The reprogrammed metabolic networks obtained will be related to those separately acquired in vivo from human lung cancer patients. SA2) to link ROS production mt and nuclear DNA damages/repair processes to metabolic reprogramming in As-transformed lung cells. Correlations of SA1&2 data will enable hypothesis generation for further testing of cause-and-effect relationships in SA3&4. SA3) to reveal cause-and-effect relations among altered Mt/cellular metabolic networks ROS production and DNA damage during As-induced transformation by their time-dependence. SA4) to map corresponding genetic epigenetic and gene expression changes in As-transformed lung cells for hypothesis testing on As action. Next-generation sequence data will be acquired and queried for mutational signatures epigenetic status and mRNA expression of key genes involved in the reprogrammed metabolic networks redox balance and DNA repair. These data will help delineate how As-induced genetic or epigenetic lesions lead to metabolic reprogramming or vice versa. Such integration of genomic epigenomic transcriptomic and metabolomics analysis of As action in model lung cell systems should provide unprecedentedly detailed insights into metabolic dysregulation and DNA damage in the mitochondria and how they may be linked to nuclear DNA damage and altered gene expression. The integrated `omics information will facilitate full-scale validation studies on the molecular mechanism for As-induced
carcinogenesis and translation of such basic insights into human lung cancer resulting from As exposure (e.g. discovery of mechanistic and robust biomarker patterns).

project_terms:
Acetylcysteine;Address;Adopted;Arsenic;Arsenites;Biochemical;Biochemical Pathway;Biological Assay;Biological Markers;Biological Models;Cancer Patient;Cells;Citric Acid Cycle;Complex;Coupled;DNA;DNA Damage;DNA Repair;Data;Data Correlations;Dependence;Development;Electron Transport;Environmental Carcinogens;Enzymes;Epidemiologic Studies;Epigenetic Process;Epithelial Cells;Equilibrium;Etiology;Event;Fumarate Hydratase;Future;Gene Expression;Gene Mutation;Generations;Genes;Genetic;Genomic DNA;Genomics;Genus Hippocampus;Glucose;Glutamine;Goals;Health;Homeostasis;Human;In Vitro;Kidney;Knowledge;Lead;Lesion;Link;Literature;Lung;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Mammalian Cell;Maps;Measures;Mediating;Metabolic;Metabolism;Mitochondria;Mitochondrial DNA;Modeling;Molecular;Mus;Mutation;Nuclear;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Pattern;Phase;Poly(ADP-ribose) Polymerases;Populations at Risk;Preventive;Process;Production;Protocols documentation;RNA;RNA Sequences;Research Personnel;Respiration;Risk;Role;Succinate Dehydrogenase;System;Testing;Therapeutic;Time;Tracer;Translating;Translations;Xenograft procedure;arsenic-induced carcinogenesis;base;carcinogenesis;cell transformation;environmental carcinogenesis;enzyme activity;epigenomics;genetic regulatory protein;in vivo;insight;mRNA Expression;metabolomics;mitochondrial dysfunction;next generation;next generation sequencing;oxidative DNA damage;public health relevance;repaired;respiratory;response;stable isotope;transcriptome sequencing;transcriptomics;tumor;validation studies

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Environmental carcinogenesis is an important and yet difficult issue to resolve in human health in the US and worldwide due to its extreme complexity. This proposal will take advantage of the latest advances in metabolomics genomics epigenomics and transcriptomics and applies them in an integrated fashion to decipher the molecular etiology of As-induced carcinogenesis. The molecular insights to be acquired will help resolve long-standing gaps of mechanistic knowledge in As action while facilitating the discovery of robust biomarkers as well as preventive and therapeutic measures for at risk populations.


application_id: 8927881
project_number: 2U60OH008483-11
project_title: Kentucky Occupational Safety and Health Surveillance
administering_ic: NIOSH
award_notice_date: 2015-08-26
opportunity_number: PAR-14-275
application_type: 2
activity_code: U60
ic: OH
serial_number: 008483
program_official: INSERRA, STEVE
project_start_date: 2005-07-01
project_end_date: 2020-06-30
study_section: Special Emphasis Panel[ZOH1 GGB (52)]
contact_pi_person_id: 7931539
contact_pi: BUNN, TERRY LEE
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
public_health_relevance:
PUBLIC HEALTH RELEVANCE: This proposed project is relevant to public health by 1) identifying industries occupations and worker populations at high risk for work injuries and illnesses; 2) identifying risk factors trends and emerging issues; and 3) identifying gaps in and
improving occupational injury and illness surveillance systems. When injury prevention knowledge is attained by the worker injuries will decrease and the economic costs of injuries will decrease because there will be fewer worker compensation claims.


application_id: 8927542
project_number: 5R21HS022583-02
project_title: Trial of Aggregate Data Extraction for Maintenance of Certification and Raising Q
administering_ic: AHRQ
award_notice_date: 2015-09-09
opportunity_number: PAR-08-269
application_type: 5
activity_code: R21
ic: HS
serial_number: 022583
program_official: KIM, BRYAN
project_start_date: 2014-09-30
project_end_date: 2017-12-31
study_section: Health Care Technology and Decision Science[HTDS]
contact_pi_person_id: 11733013
contact_pi: PHILLIPS, ROBERT
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 079659108
primary_uei: GEBSQDRBMFN5
duns_number: 079659108
uei: GEBSQDRBMFN5
fips: US
organization_id: 4602601
organization_name: AMERICAN BOARD OF FAMILY MEDICINE, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 405111338
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Most Family Physicians are now participating in Maintenance of Certification (MOC) measuring and reporting quality measures from limited patient samples before and after a quality improvement effort (Part IV requirement). It is time to take next steps towards broader and more regular assessment of quality and to simultaneously reduce reporting burden. This intention is consistent with AHRQ's aims for HIT and Quality and with those of the Office of the National Coordinator for Health Information Technology (Direct Project and Nationwide Health Information Network Exchange). The objective of the TRADEMARQ study is to make quality reporting a byproduct of ambulatory care and ongoing quality improvement. It has four aims: 1) To test the capacity for exchange of whole-panel family physician quality measures from clinical networks; 2) To study whether viewing quality measures and comparison to peers will affect the types of self-assessment modules and quality improvement efforts that are chosen by family physicians (randomized); 3) To study whether viewing quality measures and comparison to peers will influence the degree of change in outcomes after quality improvement efforts (randomized) We have developed partnerships with three clinical systems for this study: Kaiser Permanente Colorado the Oregon Community Health Information Network (now OCHIN) and the South East Texas Medical Associates (SETMA). All three use standardized physician-level quality measures and are willing to test ways to securely share these. We will develop project leadership and secure data exchange pathway to all three entities to iteratively test means of automating direct transmission of familyphysician measures exploring both technical and legal solutions (Aim1). For Aim 2 physicians will be randomized within system to exposure to their measures and comparisons to peers before or after they choose their self-assessment and quality improvement projects. Within each randomization arm we will conduct a formal correlation analysis between SAM and Part IV selection and quality measures using hierarchical logistic regression adjusting for propensity of providers to select a SAM / Part IV. For Aim 3 we will assess changes in crude rates of quality measures from baseline to study completion using a difference in difference analysis which controls for physician characteristics via the propensity score calculated for Aim 2 and a longitudinal hierarchical logistic regression model fit to account for dependence of observations. This application is the first stage of three to which the ABFM has made a $2 million commitment. The partnership with AHRQ will help support our collaborators and offers critical federal data protections for the study.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The objective of the TRADEMaRQ study is to make quality reporting a byproduct of care and ongoing quality improvement. More than 84500 family physicians are already reporting limited quality measures to the American Board of Family Medicine before and after conducting a quality improvement project. This study is the first stage of a larger project to improve care through more comprehensive whole-patient panel quality measure reporting feedback quality improvement and assessment-integrated into routine provision of care. It is expected that this will make Maintenance of Certification a more robust support for quality improvement and a partner in reducing reporting burden.


application_id: 8927339
project_number: 5R01CA140605-06
project_title: Dietary prevention of prostate cancer
administering_ic: NCI
award_notice_date: 2015-07-08
opportunity_number: PA-14-078
application_type: 5
activity_code: R01
ic: CA
serial_number: 140605
program_official: MALONE, WINFRED F
project_start_date: 2014-06-01
project_end_date: 2017-05-31
study_section: Special Emphasis Panel[ZRG1-OTC-B(02)M]
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_abstract:
DESCRIPTION (provided by applicant): Our research focuses on natural compounds that possess chemotherapeutic and/or chemopreventive properties with respect to cancer. In the proposed study we will characterize the mechanism of action of the compound Withaferin-A (WA) a bioactive compound of Withania somnifera which is extensively used in Asian and African traditional medicine. WA displays impressive and selective activity against androgen- dependent and androgen-independent prostate cancer (ADPC and AIPC respectively) of which the latter is refractory to all current forms of treatment. Our preliminary in vitro and in vivo data indicate WA targets ADPC and AIPC cells by inhibiting the activity of Akt a protein kinase that activates cell survival pathways. Our preliminary data demonstrate that concomitant to Akt inhibition in ADPC and AIPC cells WA activates FOXO3a which in turn activates prostate apoptosis response-4 (Par-4) a protein that selectively induces apoptosis in cancer cells Based on our results we hypothesize WA overrides the negative effects of Akt on CREB/Par-4 signaling to achieve chemopreventive and/or chemotherapeutic effects on AIPC. To address this hypothesis we propose the following aims: investigate the interaction between Akt/CREB and Par-4 signaling (Aim 1); and how WA modulates the pro-apoptotic signaling in AIPC (Aim 2); evaluate the effects of WA on androgen- -independent prostate tumor growth in the transgenic adenocarcinoma of mouse prostate (TRAMP) model (Aim 3); and examine the mechanisms of WA-mediated tumor inhibition in TRAMP and/or TRAMP cell lines (Aim 4). For the in vitro arm of our studies we will use a variety of approaches (immunoprecipitation siRNA strategies immunofluorescence Western blot Northern blots Chip assays siRNA strategies pull down assays pharmacological blocking) in order to determine the molecular junction at which Akt/CREB 3aand Par-4 converge. For our in vivo studies we will conduct tumor regression studies yet we will also examine histopathology cell death expression patterns of pro-survival proteins and pro-apoptotic proteins in the tumor tissues and WA levels in the serum and prostate tissue. Our long term goal is to promote natural compounds to a clinical environment where these agents can be thoroughly assessed for their chemopreventive and chemotherapeutic properties. Our preliminary data indicate WA is a potential candidate for such clinical evaluation and our proposed studies will elucidate at a mechanistic level its potency against prostate cancer both from a chemopreventive and chemotherapeutic standpoint.

project_terms:
Address;African Traditional Medicine;Age;Androgens;Animal Model;Animals;Apoptosis;Apoptotic;Area;Ashwagandha;Asians;Binding (Molecular Function);Biological Assay;Cancer Etiology;Cancer Model;Cell Culture Techniques;Cell Death;Cell Line;Cell Survival;Cells;Cessation of life;Chemoprevention;Chemopreventive Agent;Clinical;Clinical Trials;Cyclic AMP Response Element;Cyclic AMP-Responsive DNA-Binding Protein;Data;Development;Diet;Dietary Supplements;Environment;Event;Exposure to;Gap Junctions;Goals;Growth;Health;Histopathology;Immunofluorescence Immunologic;Immunoprecipitation;In Vitro;Induction of Apoptosis;Inhibition of Apoptosis;Intervention;Lead;Lesion;Lipids;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Modality;Modeling;Molecular;Mus;Northern Blotting;Outcome;Outcome Study;PTEN gene;Pathway interactions;Pattern;Phosphoric Monoester Hydrolases;Phosphorylation;Prevention;Prevention approach;Promotor (Genetics);Property;Prostate;Prostatic Neoplasms;Protein Kinase;Proteins;Refractory;Research;Resistance;Role;S-Phase Fraction;Serum;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Small Interfering RNA;Specimen;Staging;Tissues;Trans-Activation (Genetics);Tumor Suppressor Proteins;Tumor Tissue;Western Blotting;androgen independent prostate cancer;angiogenesis;arm;base;cancer cell;cell growth;chemotherapy;chromatin immunoprecipitation;design;feeding;in vivo;insight;novel therapeutics;prevent;pro-apoptotic protein;prostate cancer cell;prostate cancer prevention;research clinical testing;research study;response;transgenic adenocarcinoma of mouse prostate;tumor;tumor growth;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Prostate cancer (PCa) remains a major cause of cancer-related death and at advanced stages current therapy is ineffective. Intervention with dietary compounds for the prevention and/or treatment of prostate cancer is a relatively new area of research focused on signal transduction pathways which has resulted in the development of important new therapeutics for specific malignancies. The proposed study of dietary supplement Withaferin-A (WA) the major bioactive compound from Withania somnifera) is designed to provide essential insights at the molecular level into the mechanism of action of Withaferin-A against prostate cancer and may ultimately lead to clinical evaluation of its potential for chemoprevention and/ or chemotherapy in prostate cancer.


application_id: 8926871
project_number: 5R01CA138797-06
project_title: Targeting AR and Akt for the Treatment of Prostate Cancer
administering_ic: NCI
award_notice_date: 2015-07-08
opportunity_number: PA-14-078
application_type: 5
activity_code: R01
ic: CA
serial_number: 138797
program_official: ARYA, SURESH
project_start_date: 2014-05-15
project_end_date: 2018-04-30
study_section: Developmental Therapeutics Study Section[DT]
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_abstract:
DESCRIPTION (provided by applicant): The androgen receptor (AR) plays an important role in the development and progression of prostate cancer (PCa). Most PCa specimens express high levels of AR which is necessary and sufficient to convert androgen-dependent (AR+) PCa to the clinically more aggressive androgen-independent (AR-) PCa. Although inhibition of AR activity is a mainstay of AR+ PCa treatment there are no effective therapies for AR- PCa which is uniformly lethal. Studies reveal AR and Akt mutually activate one another and that together AR and Akt inhibit pro-apoptotic signaling and enhance the conversion of AR+ to AR- PCa. Targeting both AR and Akt signaling represents a powerful therapeutic approach for treating AR+ PCa and preventing the emergence of AR- PCa. We recently demonstrated Withaferin-A (WA) a natural compound specifically targets AR- PCa cells by inhibiting phosphorylated Akt; this inhibition leads to the activation of prostate apoptosis response-4 (Par-4)-dependent apoptosis in cell culture and in animal models. Similarly inhibition of AR in AR+ PCa cells facilitates WA-induced Par-4 activation and apoptosis. Over-expression of either Akt or AR inhibits WA-mediated Par-4 activation and blocks apoptosis in AR+ PCa suggesting both AR and Akt negatively regulate the pro-apoptotic functions of Par-4 in PCa cells. We hypothesize that WA in combination with hormone ablation is an effective strategy to control the progression of PCa. To address this hypothesis we will: Aim 1. Characterize the molecular link between AR signaling and Par-4 and determine the effects of WA on AR+ PCa cells (investigating AR binding to the Par-4 promoter via reporter constructs ChIP assays using AR antibodies and Western analysis of pro- and anti-apoptosis proteins); Aim 2. Examine the relationship between Par-4 and FOXO 3a which is regulated by Akt and how WA modulates this interaction in AR+ PCa (studying FOXO3a binding to the Par-4 promoter via reporter constructs ChIP assays using FOXO3a antibodies mobility shift assays Western analysis of pro- and -anti-apoptosis proteins and TUNEL and annexin-V assays following FOXO3a over-expression); and Aim 3. Determine the chemotherapeutic effects of WA on the development of PCa in prostate specific PTEN knockout mice (PS PTEN-KO; performing in vivo WA efficacy studies on PCa histopathology immunohistochemistry of pro-survival and pro-apoptotic proteins proliferation index apoptosis and serum WA levels). We anticipate these studies will provide molecular insight into the mechanism of WA action against AR+ PCa and will ultimately lead to novel therapeutic strategies for the treatment of PCa.

project_terms:
Ablation;Address;Androgen Antagonists;Androgen Receptor;Androgens;Animal Model;Antibodies;Apoptosis;Apoptotic;Area;Binding (Molecular Function);Bioavailable;Biological Assay;Cell Culture Techniques;Cell Death;Cells;Development;Diet;Disease Progression;Dominant-Negative Mutation;Dose;Electrophoretic Mobility Shift Assay;Health;Histopathology;Hormonal;Hormones;Immunohistochemistry;In Situ Nick-End Labeling;In Vitro;Induction of Apoptosis;Killings;Knockout Mice;LNCaP;Lead;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Modeling;Molecular;Mus;PC3 cell line;PTEN gene;Pattern;Play;Prevention;Promotor (Genetics);Prostate;Prostatic Neoplasms;Proteins;Radiation therapy;Receptor Cell;Receptor Signaling;Refractory;Regulation;Reporter;Research;Role;S-Phase Fraction;Sampling;Serum;Signal Transduction;Small Interfering RNA;Specimen;Therapeutic;Traditional Medicine;Tumor Tissue;Xenograft procedure;androgen independent prostate cancer;annexin A5;base;cancer therapy;chromatin immunoprecipitation;effective therapy;in vivo;in vivo Model;inhibitor/antagonist;insight;novel therapeutics;prevent;pro-apoptotic protein;prostate cancer cell;receptor binding;research study;response;transgenic adenocarcinoma of mouse prostate;treatment strategy;tumor;tumor growth

public_health_relevance:
This proposal focuses on the effect of a non-toxic dietary compound Withaferin-A (WA)on androgen-dependent (AR+) prostate cancer (PCa) and how WA in combination withandrogen inhibitors selectively kills AR+ PCa. Establishing an effective and safeapproach for treating AR+ PCa is an important health issue as AR+ PCa frequentlytransitions to AR-independent PCa which is a lethal cancer that is uniformly refractory toknown therapeutics. In this proposal we will further characterize the therapeutic merit ofWA which is used in traditional medicine for the prevention and treatment of cancer.


application_id: 8925099
project_number: 5R01GM105977-02
project_title: Exploring Post-Type II PKS Frame Modifications
administering_ic: NIGMS
award_notice_date: 2015-07-14
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: GM
serial_number: 105977
program_official: GERRATANA, BARBARA
project_start_date: 2014-09-10
project_end_date: 2018-07-31
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 2257319
contact_pi: ROHR, JURGEN T
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Natural products have a major impact on drug discovery. They have contributed to approximately 50% of new chemical entities between 1940 and 2006 because they offer a unique richness in structural skeletons combined with a high degree of chirality that has the potential to selectively match bio-receptors. Natural products have been particularly useful for the treatment of cancer and infectious diseases nonetheless new drugs are urgently needed because current drug regimens inevitably lose their effectiveness due to resistance mechanisms. Many important natural product drugs are generated by polyketide synthases (PKS multiple enzyme complexes) and various frame-modifying reactions called post-PKS tailoring steps. Type II PKSs assembling multicyclic aromatic intermediates together with the respective tailoring enzymes are responsible for the generation of important drugs such as the clinically used tetracycline antibiotics or anthracycline and aureolic acid anticancer drugs. While type II PKSs are well studied the post-PKS steps are much less understood although the frame modifying enzymes typically render an inert scaffold into a bioactive drug. The primary goal of this proposal is to functionally and mechanistically characterize uniquely reacting and organized frame modifying post-PKS enzymes involved in the biosynthesis of anticancer polyketide drugs of the angucycline and aureolic acid groups. It is our expectation that uncovering the molecular details of catalysis willhelp to evolve these critical enzymes so that they can be exploited to modify type II PKS scaffolds. This could lead to novel second-generation 'unnatural' natural products and/or derivatives of natural products via combinatorial biosynthesis mutasynthesis or chemo-enzymatic synthetic strategies. The studies also will help to generate new mithramycin and gilvocarcin analogues that will be useful to further study and steer the interactions of these drugs with their recently discovered specific targets.

project_terms:
Address;Anabolism;Anthracyclines;Antibiotics;Antineoplastic Agents;Biochemical;Biological;Biological Factors;Catalysis;Characteristics;Chemicals;Chemotherapy-Oncologic Procedure;Clinical;Collaborations;Communicable Diseases;Complex;Development;Drug Interactions;Effectiveness;Engineering;Enzyme Interaction;Enzymes;Epirubicin;Event;Evolution;Future;Generations;Goals;Health;In Vitro;Investigation;Kentucky;Laboratories;Lead;Methods;Methylation;Michigan;Modeling;Modification;Molecular;Multienzyme Complexes;National Institute of Diabetes and Digestive and Kidney Diseases;Natural Product Drug;Nature;Oxidoreductase;Oxygenases;Parents;Pathway interactions;Pharmaceutical Preparations;Pharmacy facility;Plicamycin;Proteins;Reaction;Recombinant Proteins;Regimen;Resistance;Side;Skeleton;System;Tetracyclines;United States National Institutes of Health;Universities;Vertebral column;Work;analog;antineoplastic antibiotics;base;cancer therapy;catalyst;chemotherapy;college;combinatorial;cost;drug discovery;drug synthesis;expectation;glycosylation;glycosyltransferase;improved;interest;member;novel;overexpression;polyketide synthase;protein structure;receptor;resistance mechanism;scaffold;screening;tigecycline;tool;transamination

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed work aims to study key enzymes and enzyme complexes of the type II post-polyketide synthase (PKS) machinery found in the biosynthesis of natural product anticancer drugs which are essential to turn primary polyketide scaffolds into bioactive drugs. Uncovering the molecular details of catalysis will help to evolve these critical enzymes so that they can be exploited to modify primary PKS scaffolds. This could lead to novel second-generation 'unnatural' natural products and/or derivatives of natural products via combinatorial biosynthesis mutasynthesis or chemo-enzymatic synthetic strategies. The studies also will help to generate new mithramycin and gilvocarcin analogues that will be useful to further study and steer the interactions of these drugs with their recently discovered specific targets.


application_id: 8925039
project_number: 5R01DA036827-02
project_title: Topiramate-Phentermine Combinations for Cocaine Dependence
administering_ic: NIDA
award_notice_date: 2015-06-29
opportunity_number: PA-10-268
application_type: 5
activity_code: R01
ic: DA
serial_number: 036827
program_official: HAMPSON, AIDAN
project_start_date: 2014-09-15
project_end_date: 2018-03-31
study_section: Special Emphasis Panel[ZRG1-RPIA-N(09)]
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cocaine (COC) dependence is a significant public health concern. A widely effective pharmacotherapy has not yet been identified for COC dependence. Innovative strategies are needed to identify an effective pharmacotherapy for COC dependence. Testing medications effective for disorders that share neurobiological substrates with drug dependence for example could yield treatments for managing COC dependence. Obesity is also a significant public health concern. While obesity and COC dependence are typically considered distinct clinical entities both involve perturbations of central biogenic amie systems. The obesity epidemic has spurred development of medications to promote weight loss. The Food and Drug Administration (FDA) recently approved a combination of topiramate (TOP) and phentermine (PHEN) for obesity. The overarching goal of this application is to demonstrate the initial efficacy safety and tolerability of TOP-PHEN combinations for COC dependence. A mixed-model experiment will be conducted in which separate cohorts of non-treatment-seeking COC-dependent participants will be randomized to different TOP maintenance doses (i.e. TOP is a between-subject factor). Participants (N=12) in each TOP cohort will be maintained concurrently on PHEN (i.e. PHEN is a within-subject factor). The reinforcing effects of COC will be determined after participants in each TOP cohort are maintained for 7 days on each PHEN dose (i.e. COC is a within-subject factor). COC (4 [placebo] 40 80 mg) will be tested with each dose combination of TOP (0 100 200 mg/day) and PHEN (0 15 30 mg/day). The proposed study will therefore identify the optimal TOP-PHEN dose combination that most effectively attenuates the reinforcing effects of COC. This research will provide critical information regarding the initial efficacy and optimal doses of a novel drug combination TOP and PHEN for COC dependence which will enhance the probability of success when advanced to a clinical trial. Innovations of the proposal include: 1) testing a drug combination effective for a disorderobesity that shares neurobiological and behavioral substrates with COC addiction; 2) the use of drug self-administration procedures; 3) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of TOP-PHEN combinations for COC addiction; 4) demonstrating the initial efficacy of commercially available drugs as opposed to waiting for novel molecules to be available for testing in humans thereby impacting clinical research and practice more quickly; 5) facilitating communications between scientists studying distinct clinicalentities (e.g. obesity and COC addiction); and 6) spurring sponsor interest in addiction pharmacotherapy because demonstrating the efficacy of the TOP-PHEN combination would support a novel indication for this product in a new population and extend patent life. The proposed project will shift the current research paradigm in pharmacotherapy development and have a significant impact on COC abuse treatment.

project_terms:
Abstinence;Adverse effects;Attenuated;Behavior Therapy;Behavioral;Biogenic Amines;Body Weight;Body Weight decreased;Clinical;Clinical Research;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependences;Combination Drug Therapy;Communication;Development;Disease;Dose;Drug Addiction;Drug Combinations;Drug usage;Enrollment;Epidemic;Excitatory Amino Acid Antagonists;Food;GABA Agonists;Goals;Health;Human;Inpatients;Investigation;Laboratory Study;Legal patent;Life;Maintenance;Modeling;Mono-S;Neurobiology;Obesity;Outcome Measure;Participant;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phase II Clinical Trials;Phentermine;Physiological;Placebos;Population;Probability;Procedures;Questionnaires;Randomized;Relative (related person);Research;Research Design;Safety;Scientist;Self Administration;System;Testing;United States Food and Drug Administration;Work;addiction;clinical practice;cocaine use;cohort;double-blind placebo controlled trial;indexing;innovation;interest;monoamine;novel;programs;public health medicine (field);reinforcer;research study;secondary outcome;success;topiramate

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The research proposed in this application will determine the initial efficacy safety and tolerability of a novel drug combination topiramate and phentermine as a pharmacotherapy for cocaine dependence. A rigorous inpatient human laboratory study will be conducted. The proposed study is innovative and important because it will provide the impetus for the conduct of double blind placebo-controlled trials to further demonstrate the efficacy of topiramate-phentermine combinations for managing cocaine dependence.


application_id: 8921840
project_number: 5F31HL123315-02
project_title: Protection from Aortic Aneurysm by Bmal1 deletion from Smooth Muscle Cells
administering_ic: NHLBI
award_notice_date: 2015-08-13
opportunity_number: PA-11-112
application_type: 5
activity_code: F31
ic: HL
serial_number: 123315
program_official: WANG, WAYNE C
project_start_date: 2014-09-05
project_end_date: 2016-09-04
study_section: Special Emphasis Panel[ZRG1-F10A-S(20)L]
contact_pi_person_id: 10915630
contact_pi: LUTSHUMBA, JENNY
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): Protection from Aortic Aneurysm by Bmal1 deletion from Smooth Muscle Cells Recognized as an important cause of death in the aging population aortic aneurysm is a disease that is currently treated only through surgery. Therefore a thorough understanding of the molecular mechanism of aortic aneurysm is a pressing matter. Bmal1 is a basic helix loop helix (bHLH) transcription factor and is an indispensable core clock gene. Bmal1 is expressed in vascular smooth muscle but its function remains mostly unknown.The current study is designed to test a potential role of Bmal1 in aortic aneurysm. Our preliminary data have shown that deletion of Bmal1 from smooth muscle cells has been protective from DOCA plus salt induced aortic aneurysm formation in 8 to 9 months old mice. This protection is independent of increase in blood pressure. We have also found that smooth muscle specific knockout mice have an increase of Tissue inhibitor of mellaproteinases 4(TIMP4) at basal level and a further increase in TIMP4 after DOCA plus salt with no gelatinases activities. TIMP4 is the fourth member of endogenous inhibitors of matrix metalloproteinases (MMPs). TIMP4 expression is restricted to cardiovascular tissues and has been shown to be a strong inhibitor of MMP2. TIMP4 role in aortic aneurysm formation is unknown. MMPs are proteases that degrade component of the extracellular matrix (ECM). Many MMPs have been identified and classified depending on their substrates. An imbalance between MMPs and TIMPs has been shown to be a major cause of vascular diseases such as aortic aneurysm. Gelatinases MMP2 and MMP9 have been shown to be upregulated in patients with aortic aneurysm. Our hypothesis has been that Bmal1 regulates TIMP4 expression therefore playing a role in aneurysm formation. To test this hypothesis we have constructed two specific aims: 1) to test the hypothesis that deletion of Bmal1 in smooth muscle cells will protect from other model of aortic aneurysm such as angiotensin II and CaPO4 through TIMP4 upregulation. 2) To test the hypothesis that upregulation of TIMP4 mediates the protective effect observed in SMC-Bmal1 KO mice. To determine whether SMC-Bmal1 KO mice will be protected from other models of aortic aneurysm we will first induced aortic aneurysm using AngII+salt then compare the relative aortic aneurysm incidence. Second we will induce aortic aneurysm using CaPO4 in SMC-Bmal1 KO mice. To look at the role of TIMP4 in aortic aneurysm we will use TIMP4 KO mice and TIMP4-Bmal1 KO mice and induce aortic aneurysm using the DOCA plus salt model which we will then compare the incidence of aortic aneurysm. We will use different staining to distinguish the pathology among the different mice that will be used. The results from this proposed study will provide new insights to the molecular mechanisms underlying aortic aneurysm and may lead to a new therapeutic target for the aortic aneurysm treatment.

project_terms:
ARNT gene;Abdominal Aortic Aneurysm;Acetates;Affect;Aneurysm;Angiotensin II;Aorta;Aortic Aneurysm;BHLH Protein;Behavior;Biological Clocks;Blood Pressure;Blood Vessels;Brain;Breeding;Cardiovascular system;Cause of Death;Circadian Rhythms;Data;Deoxycorticosterone;Dilatation - action;Disease;Elderly;Emergency Situation;Extracellular Matrix;Extracellular Matrix Degradation;Gelatinases;Genes;Hypertension;Hypothalamic structure;In Situ;Incidence;Infusion procedures;Inhibition of Matrix Metalloproteinases Pathway;Injury;Knockout Mice;Laboratories;Lead;MMP2 gene;MMP9 gene;Matrix Metalloproteinase Inhibitor;Matrix Metalloproteinases;Mediating;Metalloproteases;Modeling;Molecular;Mortality Vital Statistics;Mus;Muscle;Muscle Smooth Vascular;Mutation;Operative Surgical Procedures;Pathology;Patients;Peptide Hydrolases;Peripheral;Pharmaceutical Preparations;Physiology;Play;Proteins;Rattus;Relative (related person);Role;Ruptured Abdominal Aortic Aneurysm;Smooth Muscle Myocytes;Smooth muscle (tissue);Sodium Chloride;Staining method;Stains;Testing;Tissue Inhibitor of Metalloproteinases;Tissues;Up-Regulation (Physiology);Vascular Diseases;age related;aging population;design;inhibitor/antagonist;insight;mRNA Expression;male;member;mouse model;neointima formation;new therapeutic target;novel;prevent;protective effect;protein expression;public health relevance;response;salt sensitive hypertension;suprachiasmatic nucleus;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Aortic aneurysm is a disease that affects the aging population is one of the leading causes of death among the elderly with no treatment but surgery. In our study we would like to know whether genes that regulate the internal biological clock are involved in the formation of aortic aneurysm. This study would bring in more information to what is already known about aortic aneurysm and bring about a more focus target for a new drug for aortic aneurysm


application_id: 8921242
project_number: 5R01HG006838-02
project_title: Harmonizing Privacy Laws to Enable International Biobank Research
administering_ic: NHGRI
award_notice_date: 2015-09-16
opportunity_number: PA-11-250
application_type: 5
activity_code: R01
ic: HG
serial_number: 006838
program_official: MCEWEN, JEAN
project_start_date: 2014-09-05
project_end_date: 2016-12-31
study_section: Societal and Ethical Issues in Research Study Section[SEIR]
contact_pi_person_id: 6098284
contact_pi: ROTHSTEIN, MARK A
other_pis: KNOPPERS, BARTHA MARIA M.
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): In recent years researchers from around the world have begun developing repositories of tissues and socio-demographic data for genetics and other biomedical research. These biobanks often linked with patient health care records have been an invaluable resource in helping to understand cancer diabetes and various genetic-related disorders. The specimens and data are especially valuable when combined and analyzed with specimens and data from other countries because rare variations can be detected and examined. Sharing by researchers of specimens and data across international borders may be hampered by privacy laws in several countries that limit disclosure or receipt of certain specimens or health information. The study relying on a worldwide team of experts will compile and analyze the privacy laws in 23 countries undertaking substantial biobank development. It will then propose legal and technical strategies to accommodate important privacy interests while facilitating international access and use for research.   
   
PUBLIC HEALTH RELEVANCE: Biobanks often with linked clinical records have been established in numerous countries to facilitate genetic and genomic research. International collaborations of researchers using biobanks have been hampered by privacy laws in various countries. Developing an expert compilation of privacy laws in countries performing biobank-based research and recommending measures to harmonize these laws will enable international research cooperation and coordination.

project_terms:
Administrator;Affect;Area;Biomedical Research;Clinical;Code;Collaborations;Complex;Confidentiality;Consent;Country;Data;Databases;Development;Diabetes Mellitus;Disclosure;Disease;Ensure;Environment;Europe;European Union;Fostering;Genetic;Genome;Genomics;Growth;Health;Healthcare;Individual;Information Technology;International;Laws;Lead;Legal;Link;Malignant Neoplasms;Maps;Measures;Modeling;Monograph;Nature;Other Genetics;Participant;Patients;Policies;Policy Maker;Population Study;Privacy;Records;Regulation;Research;Research Methodology;Research Personnel;Resources;Role;Sampling;Security;Specimen;Structure;Tissues;Translational Research;Variant;Work;base;biobank;comparative;data integration;development policy;interest;next generation sequencing;privacy protection;public health relevance;repository;sharing data;tool

public_health_relevance:
Biobanks often with linked clinical records have been established in numerous countries to facilitate genetic and genomic research. International collaborations of researchers using biobanks have been hampered by privacy laws in various countries. Developing an expert compilation of privacy laws in countries performing biobank-based research and recommending measures to harmonize these laws will enable international research cooperation and coordination.


application_id: 8921108
project_number: 5R01AA017226-08
project_title: Alcohol and Breast Cancer
administering_ic: NIAAA
award_notice_date: 2015-08-05
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AA
serial_number: 017226
program_official: JUNG, KATHY
project_start_date: 2008-03-05
project_end_date: 2019-08-31
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
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): Alcohol consumption promotes the development of human cancers and environmental factors play an important role in the etiology. Epidemiological studies indicate that alcohol consumption not only increases breast cancer risk but also enhances the progression and the aggressiveness of existing breast tumors. Nonetheless the mechanism by which alcohol contributes to breast tumor initiation or progression has yet to be established. ErbB2 is a member of epidermal growth factor receptor family. Amplification of ErbB2 is found in 20-30% of breast cancer patients and is associated with poor prognosis. We have previously demonstrated that over-expression of ErbB2 sensitized breast cancer cells to alcohol-induced tumor promotion. Recently we identified a novel component in ErbB2 signaling pathways that may regulate cancer cell aggressiveness the p38?. We hypothesized that alcohol enhances NOX-dependent production of ROS which activates ErbB2 or MKK6. The activation of ErbB2 and MKK6 causes selective phosphorylation of p38? which recruits SAP97/DLG. The activated SAP97/DLG promotes epithelial to mesenchymal transition (EMT) increase cancer stem cells (CSC) population and invasiveness of breast cancer cells. This leads to an enhanced aggressiveness. There will be three specific aims. Specific Aim 1 will determine the role of p38? in alcohol- induced aggressiveness in vitro. Specific Aim 2 will investigate the mechanisms underlying alcohol-induced p38? activation as well as the mechanisms how p38? mediates aggressiveness of breast cancer cells. Specific Aim 3 will investigate the role of p38? in alcohol-induced tumor aggressiveness in animal models. The study will not only explore the basic cell biology of breast cancer aggressiveness but also elucidate the mechanisms of alcohol's tumor promotion action. The outcomes will help developing new therapeutic strategy for breast cancer treatment and alcohol-mediated tumor promotion.

project_terms:
Alcohol consumption;Alcohols;Amino Acid Sequence;Animal Model;Animals;Attention;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Treatment;Cancer Etiology;Cancer stem cell;Cell Culture System;Cell Polarity;Cells;Cellular biology;Characteristics;DLG1 gene;Data;Development;Diet;Environmental Risk Factor;Epidemiologic Studies;Epidermal Growth Factor Receptor;Etiology;Family;Funding;Genes;Health;Heavy Drinking;Human;Human Development;In Vitro;Knockout Mice;Liquid substance;MAP2K6 gene;MAPK14 gene;MAPK8 gene;Malignant Neoplasms;Mammary Neoplasms;Mammary Tumorigenesis;Mediating;Mediator of activation protein;Mitogen-Activated Protein Kinase Kinases;Mitogen-Activated Protein Kinases;Molecular;Mus;Neoplasm Metastasis;Outcome;Patients;Phosphorylation;Phosphotransferases;Physiological;Play;Production;Protein Tyrosine Kinase;Reactive Oxygen Species;Recruitment Activity;Risk;Role;Signal Pathway;Signal Transduction;Stream;Testing;Time;Transgenic Organisms;Tumor Promoters;Tumor Promotion;Xenograft Model;alcohol effect;alcohol exposure;alcohol sensitivity;anticancer research;cancer cell;cancer risk;cancer therapy;epithelial to mesenchymal transition;feeding;human MAPK14 protein;in vivo;indexing;malignant breast neoplasm;member;mitogen-activated protein kinase p38;novel;novel therapeutics;outcome forecast;research study;stem;stem cell population;therapeutic target;tumor;tumor initiation;tumor progression;tumor xenograft

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Excessive alcohol consumption is associated with advanced and aggressive breast cancers suggesting that alcohol may enhance mammary tumor progression and metastasis. We found that p38? signaling is down stream of ErbB2 and hypothesize that alcohol activates p38? which promotes tumor aggressiveness and accelerates mammary tumor development. This proposal will elucidate the mechanisms by which alcohol promotes the progression of mammary tumors and identify therapeutic targets for alcohol-associated tumor promotion.


application_id: 8920527
project_number: 5R00DA033373-04
project_title: Tonic and Phasic Glutamate Release in Incentive Salience and Cocaine Reinforcemen
administering_ic: NIDA
award_notice_date: 2015-08-24
opportunity_number: PA-11-197
application_type: 5
activity_code: R00
ic: DA
serial_number: 033373
program_official: SORENSEN, ROGER
project_start_date: 2014-09-15
project_end_date: 2017-08-31
study_section: NSS
contact_pi_person_id: 9713925
contact_pi: BECKMANN, JOSHUA
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:
The proposed career development plan is designed to provide the PI with a unique skill set and experience tomeet the short-term goal of becoming a productive independent researcher and long-term goal of becoming asignificant contributor to the understanding and treatment of substance abuse disorders. The plan will becarried out at the University of Kentucky an institution with a rich history of interdisciplinary substance abuseresearch. The PI will be mentored by Dr.Michael Bardo and co-mentored by Dr. Greg Gerhardt establishedexperts in neuropsychopharmacology and neurochemistry respectively. The plan proposes to use enzyme-based microelectrode arrays to uncover the role of sub-second tonic/phasic mesocorticolimbic glutamaterelease in individual differences in incentive salience/value attribution to reward-related cues and cocainereinforcement in a preclinical rat model. When a stimulus reliably predicts reward some animals attributeincentive value to the stimulus and thus will approach and contact it (sign-trackers); other animals use thestimulus as a simple signal of forthcoming reward and thus will approach the receptacle into which reward willbe delivered (goal-trackers). Recently it has been demonstrated that differences in sign and goal tracking arerelated to novelty seeking impulsivity initial vulnerability to cocaine reinforcement and relapse vulnerability.In addition to mesocorticolimbic dopamine stimulus-reward learning and drugs of abuse are known to altermesocorticolimbic glutamate signaling. The overall proposed hypothesis is that differences in incentive valueattribution are mediated by differential mesocorticolimbic glutamate release upon cue exposure; thisdifferential release is then exacerbated by repeated cocaine self-administration giving rise to differentialsubstance abuse vulnerability and relapse. Specific Aim 1 will determine if second-by-second tonic/phasicglutamate signaling is differentially affected by food-associated cues in sign- vs. goal-tracking animals.Specific Aim 2 will determine the role of dopaminergic receptor function on the expression of sign-/goal-tracking and underlying tonic/phasic glutamate signaling. Specific Aim 3 will determine if second-by-secondtonic and phasic glutamatergic signaling in sign- and goal-tracking animals changes differentially withrepeated cocaine self-administration. Specific Aim 4 will then determine the role of dopaminergic receptorfunction on cocaine self-administration and tonic/phasic glutamate signaling in sign- and goal-trackers.Collectively these results will provide insight into the role of tonic/phasic glutamate signaling in stimulus-reward learning incentive value attribution to reward-associated stimuli and cocaine reinforcement whileproviding the PI with unique training in neuropsychopharmacology and neurochemistry by experts in bothfields.

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

public_health_relevance:
Although many people may experiment with drugs of abuse few come to develop a substance use disorders.These individual differences suggest that some people may be more or less prone to develop such disorders.These individual differences may be related to differential attribution of incentive value to reward-relatedstimuli; the broad goal of this research is to identify the underlying neurochemical basis for individualdifferences in substance abuse vulnerability and will be beneficial in identifying novel pharmacological targetsfor the development of substance abuse pharmacotherapies.


application_id: 8919848
project_number: 5R21AR064896-02
project_title: Ribosome specialization in adult skeletal muscle
administering_ic: NIAMS
award_notice_date: 2015-08-06
opportunity_number: PA-12-209
application_type: 5
activity_code: R21
ic: AR
serial_number: 064896
program_official: BOYCE, AMANDA T
project_start_date: 2014-09-01
project_end_date: 2017-08-31
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1873134
contact_pi: MCCARTHY, JOHN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The ribosome has generally been considered to have no cell-specific function but rather serves in a "housekeeping" capacity. This view has been challenged by evidence showing heterogeneity in the protein composition of the ribosome resulting in the functional specialization of the ribosome. Ribosome specialization alters the intrinsic translational activity of the ribosome thereby affecting the translation of a particular et of mRNAs. Expression profiling of ribosomal proteins in adult tissues showed that ribosomal protein L3 (Rpl3) is highly expressed in all tissues except in striated muscle; in contrast the expression of the Rpl3-like is exactly the opposite being highly expressed only in striated muscle skeletal muscle in particular. Preliminary data revealed that during periods of significantmuscle hypertrophy such as post-natal development and in response to synergist ablation the expression pattern of these two genes is completely reversed such that Rpl3 is highly-expressed and Rpl3-like is dramatically down-regulated in skeletal muscle. Consistent with these observations we found that over-expression of RPL3-like promotes significant myotube atrophy associated with a lower fusion index. While Rpl3 is necessary for ribosome assembly and peptidyl transferase activity of the ribosome the ribosomal function of Rpl3-like remains completely unknown. Based on our preliminary data we hypothesize that Rpl3-like acts to limit muscle size by altering the intrinsic translational activity of skeletal muscle ribosomes. To test the idea of ribosome specialization in skeletal muscle and its regulation the following objectiveswill be pursued: 1) Determine how muscle-specific Rpl3-like alters ribosome function and 2) Determine the mechanisms regulating the muscle-specific pattern of expression of Rpl3 and Rpl3-like. We have developed a Tet-On system to compare translational fidelity of ribosomes containing Rpl3 versus Rpl3- like. Ribosome function will be examined by assessing programmed ribosomal frameshifting stop codon read- through near- and non-cognate tRNA utilization and IRES-mediated translation. Based on preliminary data we will test the hypothesis that the muscle-specific microRNA-1 represses Rpl3 expression in skeletal muscle by using 32-UTR reporter assay with mutagenesis in gain- and loss-of-function studies using miR-1 mimic and antimiR respectively. Next we will test the hypothesis that MyoD regulates the muscle-specific expression of Rpl3-like through promoter analysis mutagenesis EMSA and ChIP assay. The fact that there is a muscle- specific Rpl3 strongly suggests ribosomes have become specialized in skeletal muscle - understanding why this is so is the long-term goal of this project In the short-term the goal is to better understand the function and regulation of Rpl3-like as thebasis for a future R01 grant application investigating the role of ribosome specialization in skeletal muscle plasticity and disease.

project_terms:
Ablation;Acquired Immunodeficiency Syndrome;Adult;Affect;Aging;Applications Grants;Atrophic;Biological Assay;Cachexia;Cells;Clinical;Congestive Heart Failure;Data;Databases;Deterioration;Development;Disease;EMSA;Embryonic Development;Future;Gene Expression;Gene Expression Regulation;Genes;Genetic Translation;Goals;Growth;HIV;Health;Heterogeneity;Housekeeping;Immobilization;In Vitro;Internal Ribosome Entry Site;Limb structure;Malignant Neoplasms;Mammals;Mediating;Messenger RNA;MicroRNAs;Molecular;Molecular Profiling;Morbidity - disease rate;Mortality Vital Statistics;Mus;Muscle;Muscle Fibers;Muscle function;Mutagenesis;Myogenic Regulatory Factors;Nature;Pattern;Peptidyltransferase;Play;Process;Promotor (Genetics);Proteins;Quality of life;Reading;Regulation;Reporter;Repression;Rheumatoid Arthritis;Ribosomal Frameshifting;Ribosomal Proteins;Ribosomes;Risk;Role;Sepsis;Skeletal muscle structure;Striated Muscles;System;Systemic disease;Terminator Codon;Testing;Tetanus Helper Peptide;Tissues;Transcript;Transfer RNA;Translating;Translations;Untranslated Regions;base;chromatin immunoprecipitation;effective therapy;indexing;interest;loss of function;muscle form;muscle hypertrophy;neurotensin mimic 1;novel;patient population;prevent;programs;research study;response;sarcopenia;skeletal muscle plasticity

public_health_relevance:
PUBLIC HEALTH RELEVANCE: 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 n muscle mass including those afflicted by various systemic diseases (cancer sepsis HIV- AIDS heart failure) chronic physical inactivity rheumatoid arthritis limb immobilization and sarcopenia. A better of understanding of the molecular mechanisms that regulate skeletal muscle mass will provide the basis for more effective therapies to prevent or restore muscle mass. The focus of the current proposal is to investigate the regulation and function of ribosome specialization in adult skeletal muscle and the role it plays in skeletal muscle health and disease.


application_id: 8919198
project_number: 5R21AG045809-02
project_title: Leptin Signaling and Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2015-06-08
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: AG
serial_number: 045809
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
arra_indicator: N
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 isan 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;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;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;amyloid peptide;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 A;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: 8918563
project_number: 5R01DA036553-02
project_title: Selective Monoamine Release as a Treatment for Cocaine Use Disorders
administering_ic: NIDA
award_notice_date: 2015-05-14
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DA
serial_number: 036553
program_official: HAMPSON, AIDAN
project_start_date: 2014-09-01
project_end_date: 2017-11-30
study_section: Special Emphasis Panel[ZRG1-RPIA-N(09)F]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cocaine (COC) addiction is an unrelenting public health concern. An effective medication has not been identified for COC dependence despite being a high priority for the National Institute on Drug Abuse for nearly 30 years and extensive efforts by the scientific and treatment communities. The results of preclinical studies have shown that monoamine releasers attenuate the reinforcing effects of COC. The results of human laboratory studies also suggest that monoamine releasers attenuate the reinforcing effects of COC although the effects are small in magnitude and dependent on the methods used to assess drug reinforcement. The results of clinical trials that tested monoamine releasers for COC abuse are mixed. Monoamine releasers vary along a continuum from DA/NE selective to 5-HT selective. Theoreticians have postulated that the 5-HT/DA releasing ratio is a critical determinant of the efficacy and specificity of a monoamine releaser to attenuate the reinforcing effects of COC. Compounds with intermediate 5-HT/DA release ratios (i.e. 30-40) were the most effective and specific in terms of reducing cocaine taking. For example methamphetamine (5-HT/DA ratio = 31) completely and specifically eliminated responding for COC. Consistent with these findings methamphetamine dramatically reduced COC use in a clinical trial although it is NOT a viable option for managing COC abuse because of its high abuse and diversion potential. Compounds with a desirable 5- HT/DA releasing ratio and minimal abuse potential need to be tested for COC dependence. Phendimetrazine (PHEN) is indicated for treating obesity. After oral administration PHEN is converted to phenmetrazine which is largely responsible for its behavioral and neuropharmacological effects. Consistent with the notion that compounds with intermediate 5-HT/DA release ratios selectively attenuate the reinforcing effects of COC phenmetrazine (5-HT/DA ratio = 37) also completely and specifically eliminated COC-maintained responding. Moreover PHEN reduces COC-maintained responding but does not maintain self-administration or produce high magnitude positive subjective effects suggesting that its abuse potential is low. Although PHEN has not yet been tested as a potential pharmacotherapy for COC dependence in human laboratory experiments or clinical trials to our knowledge the results of extant preclinical experiments suggest it may be a viable option. We will conduct two rigorous within-subject experiments to fill this gap. These studies will 1) establish the safety and tolerability of PHEN-COC combinations and 2) demonstrate that PHEN reduces COC self- administration. The results of this project will provide critical information regarding the initial efficacy of PHEN for COC dependence which will enhance the probability of success when advanced to a clinical trial.

project_terms:
Abstinence;Amphetamines;Attenuated;Behavior Therapy;Behavioral;Binding (Molecular Function);Cardiovascular system;Clinical Research;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependences;Cocaine Users;Communities;Data;Development;Dextroamphetamine;Disease;Dopamine;Dose;Enrollment;Goals;Health;Human;Laboratories;Laboratory Procedures;Laboratory Study;Maintenance;Methamphetamine;Methods;Modeling;Monkeys;National Institute of Drug Abuse;Norepinephrine;Obesity;Oral Administration;Outcome Measure;Parents;Participant;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phase II Clinical Trials;Phenmetrazine;Placebos;Presynaptic Terminals;Probability;Procedures;Psychostimulant dependence;Research;Safety;Schedule;Self Administration;Serotonin;Specificity;Testing;clinical efficacy;clinical practice;cocaine use;drug reinforcement;indexing;innovation;meetings;monoamine;novel;pre-clinical;preclinical study;prevent;primary outcome;programs;public health medicine (field);reinforcer;research study;reuptake;success

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Preclinical data indicate that maintenance on selective monoamine releasers reduces cocaine taking. The goal of this project is to demonstrate that maintenance on a selective monoamine releaser with limited abuse potential phendimetrazine reduces cocaine taking in a sophisticated predictive human laboratory self- administration model.


application_id: 8918562
project_number: 5R01DA036550-02
project_title: Human Laboratory Screening of Pregabalin and Tiagabine for Cannabis Dependence
administering_ic: NIDA
award_notice_date: 2015-06-29
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DA
serial_number: 036550
program_official: HAMPSON, AIDAN
project_start_date: 2014-09-01
project_end_date: 2020-06-30
study_section: Special Emphasis Panel[ZRG1-RPIA-N(09)F]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Abstinence;Acute;Admission activity;Adult;Adverse effects;Aminobutyric Acids;Attenuated;Award;Basic Science;Behavior;Behavior Therapy;Calcium Channel;Cannabis;Characteristics;Choice Behavior;Clinical;Clinical Treatment;Clinical Trials;Cost Savings;Data;Dependence;Development;Dose;Double-Blind Method;Drug Addiction;Drug Kinetics;Drug usage;Effectiveness;Environment;Exclusion;Goals;Health;Human;Hybrids;Illicit Drugs;Independent Scientist Award;Intervention;Laboratories;Ligands;Maintenance;Marijuana Dependence;Measures;Methods;Modeling;Monitor;Motivation;Outpatients;Patients;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacotherapy;Placebo Control;Principal Investigator;Procedures;Process;Psychological reinforcement;Qualifying;Randomized;Relapse;Relative (related person);Research;Resources;Role;Schedule;Self Administration;Statistical Models;Study Subject;Techniques;Technology;Testing;Therapeutic;Therapeutic Effect;Time;Translating;Treatment Efficacy;United States;career development;cost effectiveness;drug maintenance;experience;gabapentin;gamma-Aminobutyric Acid;improved;inhibitor/antagonist;innovation;marijuana use;marijuana use disorder;marijuana user;next generation;novel;pregabalin;primary outcome;public health medicine (field);reinforcer;response;reuptake;screening;secondary outcome;success;therapy development;tiagabine


application_id: 8918091
project_number: 3R43HL121970-01S1
project_title: Wireless Vagal Nerve Stimulation System for Treating Atrial Fibrillation
administering_ic: NHLBI
award_notice_date: 2014-09-15
opportunity_number: PA-13-088
application_type: 3
activity_code: R43
ic: HL
serial_number: 121970
suffix: S1
program_official: KRULL, HOLLY
project_start_date: 2014-07-21
project_end_date: 2015-12-31
study_section: Special Emphasis Panel[ZRG1-CVRS-C(10)B]
contact_pi_person_id: 10313138
contact_pi: DUKE, AUSTIN ROBERT
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 968130778
duns_number: 968130778
fips: US
organization_id: 10032915
organization_name: ROSELLINI SCIENTIFIC, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405111162
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-09-15
project_abstract:
DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with substantial risk of morbidity and mortality. AF currently affects more than 2.5 million Americans and the affected population is steadily growing with our aging society. AF independently increases the risk of stroke by 4- to 5-fold is an independent risk factor for stroke recurrence and is responsible for at least 15-20% of all ischemic strokes. In addition to its associated health risks and diminished quality of life AF is a financial burdenon the US Healthcare system with annual Medicare costs currently estimated at $16 billion. Over the past decade neuromodulator emerged as an alternative to antiarrhythmic medications and ablative procedures for the treatment of some forms of AF. Applying low levels of electrical stimulation to the vagus nerves inhibits AF inducibility. This innovative form of neural cardiac control is a non-pharmacological non- ablative modality for the treatment of AF that maintains healthy myocardium. The ultimate goal of this project is to enhance the quality of life for individuals with AF by translating this recent cutting edge research into a clinically viable technology. To date the majority of studies investigating neuromodulation as a treatment for AF were acute procedures. To progress this approach towards clinical application will require the development of suitable devices capable of chronic stimulation. Rosellini Scientific has partnered with Stimwave Technologies Inc. to apply their wireless spinal cord stimulation technology to a form factor and therapeutic treatment protocol suitable for low-level vagus nerve stimulation (LL-VNS) to treat AF. The goal of the proposed study is to evaluate the therapeutic value of LL- VNS for treating AF in a long-term study. To accomplish this goal we will implant our system in a high-yield canine model of AF and evaluate changes in AF frequency as a result of LL-VNS for a period of 4 weeks. During the experimental period an implantable pulse generator (IPG) will deliver rapid atrial pacing (RAP) to the left atrial appendage for 6 hours/dayto induce AF. Concurrent with RAP the experimental group will receive LL-VNS from the Rosellini Scientific VNS system while the control group will receive sham stimulation. The weekly AF burden defined as the sum of the duration of all spontaneous AF episodes during the period without RAP will be calculated and compared between groups. For our treatment to be indicated as feasible we must see e 50% reduction in AF burden for the treatment group versus control. If feasibility is achieved we will apply to the NIH for Phase 2 funding to determine the appropriate treatment protocol in a chronic study and will submit a U44 to further develop the device.

project_terms:
Accounting;Acute;Affect;Aging;American;Animals;Arrhythmia;Atrial Fibrillation;Autonomic nervous system;Biomedical Engineering;Canis familiaris;Cardiac;Cessation of life;Chronic;Computational Biology;Control Groups;Development;Device or Instrument Development;Devices;Doctor of Philosophy;Electric Stimulation;Electrodes;Electronics;Frequencies (time pattern);Funding;Goals;Health;Healthcare Systems;Heart Atrium;Heart Rate;Hour;Human Resources;Implant;Individual;Intervention;Ischemic Stroke;Left;Legal patent;Longitudinal Studies;Medical Device;Medicare;Methods;Metric;Modality;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Multi-Institutional Clinical Trial;Myocardium;Nerve;Neuromodulator;Neurosciences;Neurostimulation procedures of spinal cord tissue;Pathology;Pharmaceutical Preparations;Phase;Physiologic pulse;Population;Procedures;Publishing;Quality of life;Recurrence;Research;Risk;Risk Factors;Societies;Sum;System;Techniques;Technology;Testing;Therapeutic;Tinnitus;Translating;Treatment Protocols;United States National Institutes of Health;Vagus nerve structure;Wireless Technology;auricular appendage;austin;clinical application;cost;implantable device;innovation;nervous system disorder;neuroregulation;neurotechnology;novel;pre-clinical;relating to nervous system;stroke;vagus nerve stimulation

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Atrial Fibrillation (AF) is the most common cardiac arrhythmia affecting more than 2.5 million Americans. AF independently increases the risk of stroke and stroke recurrence and is associated with an increase in the risk of death. This is a proposal to develop a device to provide treatment for AF.


application_id: 8917833
project_number: 5K01AG040164-04
project_title: Neuroimaging Assessments of Brain Integrity in Aging Mice
administering_ic: NIA
award_notice_date: 2015-07-16
opportunity_number: PA-14-078
application_type: 5
activity_code: K01
ic: AG
serial_number: 040164
program_official: WISE, BRADLEY C
project_start_date: 2014-07-01
project_end_date: 2017-06-30
study_section: Basic Neuroscience of Aging Study Section[NIA-N]
contact_pi_person_id: 10518078
contact_pi: LIN, AI-LING
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of my research career is to use state-of-the-art non-invasive brain imaging methods (magnetic resonance imaging and spectroscopy (MRI/MRS) and positron emission tomography (PET)) to assess brain metabolic hemodynamic and neuronal (structural and functional) integrity and its associations with cognitive function in animal models of healthy aging and of age-related neurodegenerative disorders. The goals of my training program are: 1) to "reversely translate" the neuroimaging methods for assessing hemodynamics and metabolism from humans to rodent models; 2) to receive training in the biology of aging using rodent models with an emphasis on metabolic physiology; 3) to apply these newly found skills to the investigation of the mechanisms of action of aging and potential protective effects of caloric restriction (CR); and 4) to have hands-on training in behavioral testing for rodents and identify the association between imaging and behavioral results. The research objective of this proposal is to use high-field MRI/MRS and PET to investigate the brain integrity of aging mice and identify possible protective effects of CR.  In the brain mitochondrial oxidative phosphorylation of glucose is the predominant source of energy (ATP production) supporting energy demands (maintaining neuronal integrity and basal firing rates). A widely accepted cause of the functional losses that accompany aging both in the brain and in other organs is decreased brain metabolism. In support of this viewpoint a host of neuroimaging studies show that cerebral metabolic rates of oxygen (CMRO2) glucose (CMRGlc) and cerebral blood flow (CBF) decline with age and decline still more rapidly and profoundly in neurodegenerative disorders such as Alzheimer's Disease (AD). It is generally believed therefore that preserving bioenergetics (i.e. glucose oxidative capacity) is critical fr optimizing lifespan and healthspan. Interventions have been introduced to preserve metabolism in aging process. CR perhaps is the most well-studied one for various model organisms of extended longevity including Saccharomyces cerevisiae Caenorhabditis elegans rodents and monkeys. In the neuronal system CR has shown to attenuate age-related metabolic dysfunction and neuromuscular synaptic loss and to enhance cognitive function.  The rationale of the study therefore is to characterize the effect of CR on in vivo brain metabolic hemodynamic and neuronal (structural and functional) integrity in aging using non-invasive multimodal neuroimaging methods and the association of the neuroimaging indices with the cognitive testing. The central hypothesis of this proposal is that cerebral metabolic function will decline i normal aging and consequently reduce brain structural functional and cognitive integrity; mice with CR intervention will demonstrate: preserved CMRO2 CBF CMRGlc total ATP concentration; and thus preserved brain structure functional connectivity and cognition during aging. The hypothesis will be tested by pursuing three specific aims: 1) Determine effects of normal aging on brain metabolic and hemodynamic integrity and possible protective effects of CR; 2) Determine effects of normal aging on neuronal (structural and functional) integrity and possible protective effects of CR; and 3) Determine effects of normal aging on cognitive integrity and possible protective effects of CR. The approach is innovative because it investigates the CR protective effect on in vivo brain metabolism in aging process with non-invasive neuroimaging methods; it uses complementary multi- parametric non-invasive imaging methods (MRI MRS and PET) to explore the physiological effects of mitochondrial alterations for the first time; it uses quantitative imaging techniques (developed by the PI for humans) at ultra-high field (11.7T) and in rodents the first time this has been done; and it willbe the first study to investigate the correlation between cognitive effects (memory and spatial information processing) and brain imaging results in the CR mouse model. The proposed research is significant because 1) physiological effects of metabolic alterations in aging and age-related neuronal disorders disease progression and treatment efficacy can be monitored non-invasively and nondestructively; 2) the interplay between brain metabolic structural and cognitive functions in aging can be identified; and 3) these multi-metric imaging methods can be translated seamlessly from rodents to non-human primates and to humans.  Collectively the training provide by the Career Development Award will place me at the cutting edge of aging research of animal neuroimaging and of their combination: translational neuroimaging of aging. Translational neuroimaging is an emerging field with extraordinary promise. My ambition is to become pioneer in this emerging discipline.

project_terms:
Age;Age-Months;Aging;Aging-Related Process;Alzheimer's Disease;Animal Experimentation;Animal Model;Area;Atrophic;Attenuated;Behavioral;Biochemical Pathway;Bioenergetics;Biological Preservation;Biology of Aging;Brain;Brain imaging;Brain region;Caenorhabditis elegans;Caloric Restriction;Cerebrovascular Circulation;Cerebrum;Cognition;Cognitive;Discipline;Disease;Disease Progression;Dopamine D2 Receptor;Energy-Generating Resources;Exhibits;Functional disorder;Glucose;Glutamates;Goals;Health;Hippocampus (Brain);Human;Image;Imaging Techniques;Impaired cognition;Intervention;Investigation;K-Series Research Career Programs;Learning;Life;Longevity;Magnetic Resonance Imaging;Measurement;Measures;Memory;Metabolic;Metabolism;Methods;Mitochondria;Monitor;Monkeys;Mus;Neurodegenerative Disorders;Neurons;Organ;Outcome;Oxidative Phosphorylation;Oxygen;Performance;Physiological;Physiology;Positron-Emission Tomography;Production;Prosencephalon;Published Comment;Relative (related person);Research;Resolution;Rest;Rodent;Rodent Model;Saccharomyces cerevisiae;Structure;Synapses;System;Technology;Testing;Time;Training;Training Programs;Translating;Treatment Efficacy;age related;aged;aging brain;anti aging;behavior test;brain metabolism;brain volume;career;cognitive function;cognitive testing;functional loss;gray matter;healthy aging;hemodynamics;imaging modality;in vivo;indexing;information processing;innovation;interest;metabolic rate;morris water maze;mouse model;neuroimaging;neuromuscular;non-invasive imaging;nonhuman primate;normal aging;protective effect;quantitative imaging;skills;spatial memory;spectroscopic imaging;white matter

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The purpose of the study is to use multimodal neuroimaging methods (PET MRI and MRS) to investigate the brain integrity of aging mice and identify possible protective effects of caloric restriction (CR). The findings from the study will advance our understanding on the interplay between brain metabolic structural and cognitive functions in aging. In addition brain metabolism observed in long-lived animal models (e.g. with CR) might predict positive cognitive outcomes in humans. The findings are thus expected to be applicable to the health of human beings especially for aging and age-related neurodegenerative disorders.


application_id: 8917643
project_number: 3UL1TR000117-04S1
project_title: Kentucky Center for Clinical and Translational Science
administering_ic: NCATS
award_notice_date: 2014-09-06
opportunity_number: RFA-RM-10-001
application_type: 3
activity_code: UL1
ic: TR
serial_number: 000117
suffix: S1
program_official: BRAZHNIK, OLGA
project_start_date: 2011-06-01
project_end_date: 2016-02-29
study_section: ZRR1-CR-1(01)
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:
At the University of Kentucky (UK) we have established the Center for Clinical and Translational Science (CCTS) as a home for clinical and translational research. UK is located in Lexington on the western edge of mid-Appalachia one ofthe poorest areas ofthe country where there are unprecedented disparities in disease and mortality. Many of these disparities stem from risky behaviors such as smoking drug abuse and obesity. In this proposal our overarching goal is to transform the pace effectiveness and quality of translational research at UK which will result in better health for the people of mid-Appalachia. Scientific discovery offers the potential for improved care with community-based research offering a faster impact on health through a better dissemination of optimal medical care. However scientific discoveries often do not reach the community due to the many difficulties with navigating the complex process of clinical and translational research. In this application we will capitalize on our strengths in education basic and clinical sciences as well as our outstanding programs in practice- and community- based participatory research. These efforts will result in scientific discovery that will impact the health ofthe Appalachian rural community in the near term and prime the pipeline for the future. To accomplish these goals UK will form a collaboration with Marshall University which is 2 hr away in Huntington WV. In addition we will form an Appalachian Translational Reseach Network involving not only Marshall but also the CTSAs at the Ohio State University University of Cinncinati Morehead University and Pikeville School of Osteopathic Medicine. This network will be especially important in the further development of our strong programs in community based participatory research. To help integrate our efforts we have developed an innovative group of faculty CATalysts who will build collaborative team science programs backed by generous pilot funding that will target novel ideas at all levels of science. New CCTS programs in "Drug Development" "Novel Methodologies" and "Risk-Related Behavior Research" will capitalize on our strengths engage investigators with diverse areas of expertise and will more quickly impact the health of the Appalachian community. We have recently recruited a new leader in Biomedical Informatics and have invested heavily in this program which will greatly improve our ability to transform data into knowledge throughout the CCTS. Through these initiatives UK will fulfill its mandate as Kentucky's flagship university to improve the health of Central Appalachia and thereby add unique value to improvements in the health ofthe nation.

project_terms:
Address;Appalachian Region;Area;Back;Basic Science;Behavior;Caring;Chronic;Clinical;Clinical Research;Clinical Sciences;Collaborations;Communities;Complex;Country;Data;Development;Disease;Drug abuse;Educational aspects;Effectiveness;Ensure;Faculty;Foundations;Funding;Future;Goals;Health;Home environment;Huntington Disease;Instruction;Kentucky;Knowledge;Marshal;Medical;Methodology;Methods;Mortality Vital Statistics;Obesity;Ohio;Osteopathic Medicine;Pathway interactions;Process;Recruitment Activity;Research;Research Personnel;Risk;Risk Behaviors;Rural;Rural Community;Rural Health;Schools;Science;Scientist;Smoking;Solutions;Translational Research;Universities;base;biomedical informatics;catalyst;community based participatory research;drug development;improved;innovation;next generation;novel;outreach;programs;stem

public_health_relevance:
RELEVANCE (See instructions): The CCTS at UK has developed well-integrated relationships with University programs in Central Appalachia and with rural health programs. We routinely apply a foundation principal of community based participatory research where the lay community identifies ttie research issues and co-develops solutions. This proposal seeks to make research more relevant by breaking down bamers to research translation and greatly improving the pace by which science discoveries drive improvements in health in Kentucky and the nation.


application_id: 8917144
project_number: 5K07CA181351-02
project_title: The Dynamics of Smoking Cessation After Cancer Diagnosis: A Naturalisitic Study
administering_ic: NCI
award_notice_date: 2015-08-11
opportunity_number: PAR-12-067
application_type: 5
activity_code: K07
ic: CA
serial_number: 181351
program_official: PERKINS, SUSAN N
project_start_date: 2014-09-01
project_end_date: 2019-08-31
study_section: Career Development Study Section (J)[NCI-J]
contact_pi_person_id: 9524802
contact_pi: BURRIS, JESSICA L
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Abstinence;Affective;Alcohol consumption;Attention;Behavior;Belief;Biochemical;Cancer Control;Cancer Patient;Cancer Survivor;Cereals;Clinical;Clinical Investigator;Clinical Research;Cognitive;Complement;Complex;Cotinine;Data;Data Analyses;Data Collection;Distress;Educational workshop;Electronic cigarette;Ensure;Environment;Ethics;Event;Eye;Future;Goals;Head and Neck Cancer;Health;Health Status;High-Risk Cancer;Home environment;Hour;Individual;Intention;Intervention;Journals;Knowledge;Lead;Life;Measures;Medical;Mentors;Modeling;Motivation;Nature;Newly Diagnosed;Nicotine Dependence;Outcome;Outcome Study;Participant;Perception;Play;Prevention;Process;Recurrence;Relapse;Research;Research Design;Research Training;Resources;Risk;Risk Behaviors;Risk Factors;Role;Saliva;Sampling;Second Primary Cancers;Self Concept;Smoke;Smoker;Smoking;Smoking Behavior;Smoking Cessation Intervention;Social Environment;Social support;South Carolina;Survival Rate;Techniques;Technology;Testing;Time;Tobacco;Tobacco Use Cessation;Training;Universities;Voice;Withdrawal;Withholding Treatment;Work;behavioral outcome;cancer complication;cancer diagnosis;cancer prevention;cancer recurrence;cancer therapy;career;career development;cigarette smoking;craving;design;dissemination research;emotional distress;factor A;head and neck cancer patient;innovation;longitudinal design;novel;programs;psychologic;public health medicine (field);response;skills;smoking cessation;smoking restriction;success;symposium;therapy development;tobacco control;treatment response


application_id: 8917034
project_number: 5R44CA136017-06
project_title: SapC-DOPS Nanovesicles for Treating Glioblastoma Multiforme
administering_ic: NCI
award_notice_date: 2015-08-17
opportunity_number: RFA-CA-12-023
application_type: 5
activity_code: R44
ic: CA
serial_number: 136017
program_official: HAIM, TODD E
project_start_date: 2008-09-25
project_end_date: 2016-08-31
study_section: ZCA1-SRLB-V(M1)
contact_pi_person_id: 8717940
contact_pi: XU, KEVIN
other_pis: QI, XIAOYANG
congressional_district: 04
department: Unavailable
primary_duns: 782233501
primary_uei: HJPDQTK95NS8
duns_number: 782233501
uei: HJPDQTK95NS8
fips: US
organization_id: 10010035
organization_name: BEXION PHARMACEUTICALS, INC.
organization_city: COVINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 410112312
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Our goal is to develop a new molecular entity with a novel mechanism of action for targeting and eliminating glioblastoma multiforme (GBM high grade glioma) a deadly and invasive brain tumor with no effective treatment. Of the 12000 patients expected to be diagnosed with GBM this year most will succumb within a year. There is an urgent demand for an efficacious anti-glioma drug. We are developing a new class of therapeutic proteolipid nanovesicle that can target and destroy glioma tumors. Composed of the small lysosomal sphingolipid activator protein saposin C (SapC 80 aa) and the phospholipid dioleoylphosphatidylserine (DOPS); the stable 200 nm SapC-DOPS nanovesicles (clinical formulation is called BXQ-350) have unusually high affinity for phosphatidylserine-enriched membrane surfaces that occur widely in many types of tumor cells and tumor neovasculature. Consistent with sphingolipid activator function BXQ-350 appear to selectively induce tumor cells to undergo ceramide-mediated cell death apparently sparing non-tumor cells. In Phase I of this proposal we demonstrated the feasibility of using SapC-DOPS to target and kill intracranial gliomas. Intravenous administration of SapC-DOPS in mice with orthotopically implanted gliomas resulted in dose-dependent improvement in survival. In Phase II a GMP compliant formulation of SapC-DOPS (i.e. BXQ-350) was developed and potency was confirmed in additional orthotopic preclinical GBM models. IND-enabling studies are in progress. Pharmacokinetics and toxicity studies thus far indicate favorable distribution and safety profiles in rodent and non-rodent studies. In this three-year Phase IIB proposal the key objectives are to file the IND for BXQ-350 complete a Phase 1 clinical trial and prepare for Phase 2. Recognizing that gliomas are highly heterogeneous another objective is to identify and link biochemical factors (e.g. cell surface PS levels; genetic markers) to the degree of BXQ-350 tumoricidal activity. Understanding of these factors will improve dosing strategies and reduce the risk of variable therapeutic response. Specific Aims are: (1) Scale- up GMP production of BXQ-350; (2) File the IND and complete the Phase 1 clinical trial; and (3) Correlate susceptibility to killing by BXQ-350 with molecular and cellular characteristics of glioma cell lins (from a tumor bank). BXQ-350 offers an innovative and potentially powerful approach for slowing tumor growth and eliminating deep-seated brain tumors. Ultimately we will progress this technology for treating other tumors and for developing tumor-targeted imaging diagnostics.

project_terms:
Activator Appliances;Affinity;Animal Model;Animals;Antineoplastic Agents;Behavioral;Biochemical;Biological Assay;Biological Markers;Brain Neoplasms;Catabolism;Cell Death;Cell surface;Cells;Ceramides;Characteristics;Chemistry;Clinical;Clinical Trials;Data;Diagnosis;Diagnostic;Dose;Drug Formulations;Drug Kinetics;Genetic;Genetic Markers;Glioblastoma;Glioma;Glucosylceramides;Goals;Grant;Growth;Health;Heterogeneity;Human;Implant;Investigational Drugs;Investigational New Drug Application;Killings;Link;Mediating;Membrane;Methods;Modeling;Molecular;Morbidity - disease rate;Mus;Normal Cell;Nude Mice;Outcome;Patients;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Phosphatidylserines;Phospholipids;Plasmids;Predisposition;Primates;Procedures;Production;Property;Proteins;Proteolipids;Protocols documentation;Qualifying;Radiosurgery;Research;Risk;Rodent;Safety;Small Business Innovation Research Grant;Solid Neoplasm;Sphingolipid Activator Proteins;Sphingolipids;Surface;Techniques;Technology;Testing;Therapeutic;Toxic effect;Tumor Bank;Tumor-Derived;Xenograft Model;analytical method;annexin A5;beta-Glucosidase Stimulating Protein;cancer cell;cell bank;chemotherapy;differential expression;drug candidate;effective therapy;efficacy trial;expression vector;glioma cell line;improved;in vivo;innovation;intravenous administration;lysosomal proteins;meetings;nanovesicle;neoplastic cell;neovasculature;nonhuman primate;novel;oncology;phase 1 study;phase II trial;pre-clinical;preclinical study;response;scale up;success;targeted imaging;treatment strategy;tumor;tumor growth

public_health_relevance:
PUBLIC HEALTH RELEVANCE: We are developing a new treatment for glioblastoma multiforme a deadly form of brain tumor that kills over 90% of afflicted patients. Current treatment methods consisting of surgery radiation and chemotherapy have not been effective in significantly reducing morbidity. Our strategy involves using new proteolipid nanovesicles that can penetrate the tumors and selectively destroy malignant cells without harming normal cells. Success in clinical trials will enable us to offer an effective new strategy to treat patients withaggressive brain tumors.


application_id: 8916845
project_number: 5R01NS089515-02
project_title: The Role of Perlecan Domain V in Vascular Dementia
administering_ic: NINDS
award_notice_date: 2015-08-11
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 089515
program_official: CORRIVEAU, RODERICK A
project_start_date: 2014-09-01
project_end_date: 2019-07-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 7568819
contact_pi: BIX, GREGORY JAYE
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
APP-PS1;Acute;Aftercare;Age;Alzheimer's Disease;Alzheimer's disease model;Animal Model;Animals;Arteriovenous malformation;Astrocytes;Autopsy;Bilateral;Biochemical;Blood;Blood Vessels;Brain;Brain Part;Brain region;Carotid Stenosis;Cell Communication;Cell physiology;Cerebral Amyloid Angiopathy;Cognitive;Complex;Coupling;Dementia;Development;Endothelial Cells;Etiology;Experimental Animal Model;Extracellular Matrix;Failure (biologic function);Functional disorder;Gene Expression;Generations;Growth;Growth Factor;Health;Heparan Sulfate Proteoglycan;Homo;Human;Immunohistochemistry;Impaired cognition;Infarction;Injury;Integrins;Ischemic Stroke;Knock-in Mouse;Methods;Mus;Neurons;Outcome;Pathologic;Pathology;Patients;Pericytes;Phenotype;Play;Prevalence;Process;Protein Fragment;Proteins;Relative (related person);Replacement Therapy;Role;Therapeutic;Time;Vascular Dementia;angiogenesis;blood vessel development;cerebrovascular;cognitive function;combat;diabetic;gray matter;hypoperfusion;improved;mouse model;neurovascular unit;novel;perlecan;post stroke;prevent;receptor;response;response to injury;stroke;white matter


application_id: 8916721
project_number: 5R01ES022191-05
project_title: Integrated Chemoselective and Informatic Platform for Large-Scale Metabolomics
administering_ic: NIEHS
award_notice_date: 2015-08-14
opportunity_number: RFA-RM-11-019
application_type: 5
activity_code: R01
ic: ES
serial_number: 022191
program_official: BALSHAW, DAVID M
project_start_date: 2014-04-26
project_end_date: 2017-08-31
study_section: Special Emphasis Panel[ZRG1-BST-P(50)R]
contact_pi_person_id: 7213583
contact_pi: FAN, TERESA WHEI-MEI
other_pis: HIGASHI, RICHARD M;MOSELEY, HUNTER NATHANIEL;NANTZ, MICHAEL H
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Recent advances in metabolomics technologies especially those that combine the complementarily of mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) enables rapid analysis of thousands of peaks representing hundreds of metabolites. Yet key barriers remain for large-scale metabolomics applications most notably: even higher throughput with robust metabolite assignment and quantification; identification of unknown metabolites; analysis of low abundance/labile metabolites; and reconstruction of metabolic networks and regulation. Here we propose an integrated approach that uses chemoselective (CS) tagging of key metabolite functional groups to boost the speed and accuracy of metabolite identification and enhance detection. Such tagged metabolites are inherently amenable for multiplexed analysis and reliable relative quantification via stable isotope encoding. This approach will accelerate analytical throughput while widening the classes of analytes including metabolically enriched isotopologues far beyond current limits. We will achieve our goals via the following specific aims: SA1. To develop CS probes for tagging metabolites by targeting functional groups: Hydrophobic quaternary ammonium (QA)-based CS probes will be developed for tagging carbonyl amino thiol & diol functional groups (FG) in metabolites optimized for direct infusion FT- ICR-MS detection & assignment; SA2. To develop a set of isotope-encoded CS probes for metabolite identification and multiplexed quantification by FT-ICR-MS and NMR: Developing 13C-encoded QA-CS probes will facilitate integrated structural analysis of metabolites by 13C edited 2D NMR and FT-ICR-MS & multiplexed analysis by FT-ICR-MS; SA3. To develop web-based software for large-scale CS-adducted metabolite assignment & pathway reconstruction: Algorithm for robust automated MS assignment of metabolite & labeled isotopologues will be developed based on isotopologue cliques FG profile & molecular formula (MF). NMR- derived substructure & MF will be combined with MS data for semi-automated assignment of metabolite isotopomers & unknowns. Atom-resolved human metabolic database will be refined and tools developed for pathway reconstruction based on labeled metabolite profiles; SA4. To demonstrate the integrated CS profiling and biochemo-informatic approach in three basic and translational projects: Metabolic reprogramming driven by oncogenic gene defects or enzyme deletion in human lung and kidney cancers will be mapped using Stable Isotope-Resolved Metabolomics (SIRM) enhanced by newly developed CS tagging chemistry and automated assignment tools. Our long-term goal is to decipher human disease metabolic networks for drug discovery & early diagnosis.

project_terms:
A549;Aldehydes;Algorithms;Ammonium;Binding (Molecular Function);Biochemical Pathway;Cell Extracts;Chemistry;Clinical;Computer software;Crude Extracts;Data;Data Analyses;Databases;Defect;Detection;Development;Diagnosis;Early Diagnosis;Enzymes;Fourier transform ion cyclotron resonance;Fumarate Hydratase;Future;Gene Expression;Genes;Glycols;Goals;Hereditary Leiomyomatosis and Renal Cell Cancer;Human;Human Cell Line;Informatics;Infusion procedures;Isomerism;Isotopes;Ketones;Label;Malate dehydrogenase (decarboxylating);Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mass Spectrum Analysis;Metabolic;Molecular;Molecular Profiling;Mus;Mutation;NMR Spectroscopy;Nature;Network-based;Oncogenic;Online Systems;Pathway interactions;Pattern;Plasma;Reaction;Regulation;Relative (related person);Renal carcinoma;Role;Sampling;Speed (motion);Sulfhydryl Compounds;System;Technology;Tissues;Tracer;Transgenic Mice;adduct;base;cancer cell;chemical property;design;drug discovery;functional group;human disease;improved;ionization;metabolomics;nano-electrospray;novel;outcome forecast;programs;protein expression;reconstruction;research study;software development;stable isotope;tandem mass spectrometry;tool;ultra high resolution

public_health_relevance:
The proposed chemoselective tagging of metabolites with integrated informatics tools will enhance both metabolite profiling and elucidation of human disease metabolic networks far beyond current limits. The information gained from these tools will help accelerate at an unprecedented rate our functional understanding of human disease development and progression while improving our ability to diagnose prognose and treat intractable human diseases such as cancer.


application_id: 8916704
project_number: 5U24DK097215-03
project_title: OUTREACH CORE
administering_ic: NIDDK
award_notice_date: 2015-09-14
opportunity_number: RFA-RM-11-016
application_type: 5
activity_code: U24
ic: DK
serial_number: 097215
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZRG1-BST-F]
subproject_number: 6292
contact_pi_person_id: 8656419
contact_pi: HIGASHI, RICHARD M
other_pis: FAN, TERESA WHEI-MEI;LANE, ANDREW N.;MOSELEY, HUNTER NATHANIEL
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: 2015-09-01
project_abstract:
PROJECT SUMMARY (See instructions): Despite rapid advances in metabolomics technologies and the need for understanding the human metabolome metabolomics applications in biomedical research remain limited. This is partly due to the combination of lack of awareness in the value of large-scale metabolic understanding inadequate access to high end instrumentation lack of experience in experimental design sample handling/processing complex data analysis and biochemical interpretation. Since the inception of our Center for Regulatory and Environmental Analytical Metabolomics (CREAM) in 2007 we have learned that proper outreach training and educational efforts can overcome most barriers to integrating metabolomics approaches into mainstream basic and translational research. Thus with the proposed addition of resources for the new RCMRC-CREAM we will greatly expand our outreach and educational efforts in the Outreach & Education Core led by PI Fan. These goals will be achieved with the following Specific Aims: SA1. Provide education on metabolomics research via distance learning workshops symposia and a wiki. In addition to metabolomics education means for integration with other 'omics information will be illustrated. SA2. Provide hands-on training on how to acquire metabolomics information for integration into systems biological understanding. Hands-on training will complement the education component in SA1 and provides the most effective way for transferring metabolomics expertise and for its adoption by the research community. SA3. Collaborate with investigators of Pilot & Feasibility projects and others who wish to engage metabolomics research. There will be $1.5M available (with $0.5M match from UofL) over 5 years for funding at least 30 P&F projects. SA4. Disseminate metabolomics research achievements via scientific meetings and publications. We will hold two special symposia in addition to attending appropriate scientific meetings and writing manuscripts as warranted. We believe by applying metabolomics technologies in collaborative projects to address pressing health issues with high quality and breakthrough research results will facilitate the wide acceptance of this approach by the biomedical research community.

project_terms:
Achievement;Address;Adoption;Animal Model;Award;Awareness;Basic Science;Biochemical;Biochemical Pathway;Biochemistry;Biological;Biomedical Research;Cell model;Collaborations;Communities;Complement;Complex;Data;Data Analyses;Diagnosis;Disease;Distance Learning;Education and Outreach;Educational aspects;Educational process of instructing;Educational workshop;Experimental Designs;Funding;Generations;Goals;Grant;Health;Human;Informatics;Instruction;Joints;Knowledge;Learning;Letters;Mainstreaming (Education);Manuscripts;Metabolic;Online Systems;Pathway interactions;Patients;Process;Publications;Research;Research Infrastructure;Research Personnel;Resources;Sampling;Science;Scientist;Specific qualifier value;Students;System;Technology;Textbooks;Time;Tracer;Training;Training and Education;Translational Research;Travel;Universities;Visit;Work;Writing;advanced system;biological systems;experience;handbook;human disease;instrumentation;interest;meetings;metabolomics;next generation;novel;outreach;programs;research and development;research study;stable isotope;symposium;wiki

public_health_relevance:
RELEVANCE (See instructions): It is now recognized that understanding human metabolome and disease-elicited perturbations is crucial to our ability to effectively diagnose and treat human diseases. The Outreach core will overcome current barriers to integrating metabolomics approaches into mainstream basic and translational research by proper outreach training and educational efforts along with demonstration of high quality and breakthrough research.


application_id: 8916703
project_number: 5U24DK097215-03
project_title: INFOMRATICS CORE
administering_ic: NIDDK
award_notice_date: 2015-09-14
opportunity_number: RFA-RM-11-016
application_type: 5
activity_code: U24
ic: DK
serial_number: 097215
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZRG1-BST-F]
subproject_number: 6291
contact_pi_person_id: 8656419
contact_pi: HIGASHI, RICHARD M
other_pis: FAN, TERESA WHEI-MEI;LANE, ANDREW N.;MOSELEY, HUNTER NATHANIEL
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: 2015-09-01
project_abstract:
PROJECT SUMMARY (See instructions): Recent advances in metabolomics technologies especially those that combine the complementarity of mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) enables rapid analysis of tens of thousands of peaks representing thousands of metabolites. Yet the need for metabolite detection identification quantitative analysis and interpretation for reconstructing metabolic networks still represents key barriers to the optimal use of this flood of high quality interrelated data. The interpretability is substantially enhanced when atom-resolved pathway tracing with the use of stable isotope tracers (e.g. stable isotope resolved metabolomics or SIRM) is part of the experimental design but this imposes additional demands on the informatics and statistical analyses. The major goals of the Informatics Core are to provide the necessary bioinformatics biostatistical and systems biochemical analyses of metabolomics data from the Analytical Core as a set of automated and interactive services for the Clients of the RCMRCCREAM. These informatics capabilities will have broad applications from straightforward profiling for e.g. biomarker discovery to elucidation of metabolic reprogramming in response to disease pathogenesis or therapeutic interventions. We will achieve these goals by coordinating our efforts with the Administrative Sample Analytical Cores and the Clients via the following Specific Aims: Specific Aim 1. Support all RCMRC-CREAM's data handling needs via a web-based informatics platform. Specific Aim 2. Provide tools for raw data analysis and quality control of MS and NMR analytical data. Specific Aim 3. Provide basic biostatistical analysis of refined data. Specific Aim 4. Expand metabolic pathway reconstruction flux modeling tools and data integration for mechanism-based analysis.

project_terms:
Basic Science;Biochemical;Biochemical Pathway;Bioinformatics;Biological Markers;Client;Collaborations;Communities;Data;Data Analyses;Data Quality;Data Set;Databases;Deposition;Detection;Development;Disease;Doctor of Philosophy;Documentation;Elements;Experimental Designs;Floods;Funding;Goals;Imagery;Informatics;Instruction;Linux;Machine Learning;Maintenance;Mass Spectrum Analysis;Metabolic;Metabolic Pathway;Metadata;Methods;Modeling;NMR Spectroscopy;Online Systems;Pathogenesis;Pathway interactions;Procedures;Process;Production;Proteomics;Quality Control;Relative (related person);Resources;Sampling;Series;Services;System;Technology;Testing;Therapeutic Intervention;Time;Tracer;Translational Research;base;case control;computerized tools;data integration;experience;functional group;human disease;innovation;interest;metabolomics;novel;outreach;reconstruction;research study;response;sound;stable isotope;success;therapeutic target;tool;transcriptomics;ultra high resolution;virtual;web-accessible;wiki

public_health_relevance:
RELEVANCE (See instructions): The unprecedented richness of metabolomics data and particularly SIRM data requires sophisticated informatics and statistical analysis to optimize the range and accuracy of metabolite determination for systems biochemical interpretation. The Informatics Core will provide such crucial developments and services for RCMRC-CREAM thereby facilitating large-scale understanding of disease pathogenesis for the discovery of novel biomarkers and therapeutic targets


application_id: 8916702
project_number: 5U24DK097215-03
project_title: ANALYTICAL CORE
administering_ic: NIDDK
award_notice_date: 2015-09-14
opportunity_number: RFA-RM-11-016
application_type: 5
activity_code: U24
ic: DK
serial_number: 097215
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZRG1-BST-F]
subproject_number: 6290
contact_pi_person_id: 8656419
contact_pi: HIGASHI, RICHARD M
other_pis: FAN, TERESA WHEI-MEI;LANE, ANDREW N.;MOSELEY, HUNTER NATHANIEL
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: 2015-09-01
project_abstract:
PROJECT SUMMARY (See instructions): Metabolomics requires identification and quantification of a large number of metabolites of many different biochemical classes from diverse biological samples including cells culture media tissue and biofluids. Where biochemical mechanism is desired it is imperative that metabolomic approach be coupled with stable isotope (e.g. 0-13 or N-15) tracer labeling for robust metabolic network reconstruction which increase the number of analytes to be determined by orders of magnitude. The goals of the Analytical Core of the RCMRC-CREAM are to provide analytical services for a wide coverage of metabolites including isotopomer and isotopologue analysis as efficiently as possible. To achieve this we use of a number of analytical platforms including high-resolution mass spectrometry with or without liquid chromatography gas. chromatography MS high resolution and in vivo NMR. The Core will continue to develop and implement improved methods of data collection and reduction to increase the overall metabolite coverage and analytical throughput. These include 1) upgrade existing and install new high throughput instrumentation dedicated to metabolomics; 2) incorporate chemoselective tagging approach for improved metabolite coverage and assignment. The Core will continue to update its databases and refines its standard operating procedures. The Core will consult with users on experimental design analytical methods and additional technologies that may be needed to identify and quantify "unknowns" that appear to be biologically important. The Analytical Core thus works closely with the Sample and the Informatics Cores to achieve these goals by the following Specific Aims. SA1. To provide access and expertise across a wide range of NMR and MS technologies to the Clients. SA2. To provide data processing support to the Clients in coordination with the Informatics Core for statistical analysis metabolic pathway and biochemical mechanism analyses. SA3. To implement additional hardware capabilities for enhanced sample throughput. SA4. To develop and implement new methods to enhance metabolomic capabilities.

project_terms:
Age;Biochemical;Biochemical Pathway;Biological;Biomass;Cell Culture Techniques;Cells;Chromatography;Client;Collaborations;Communities;Complement;Consult;Consultations;Coupled;Culture Media;Data;Data Analyses;Data Collection;Databases;Detection;Development;Diagnosis;Experimental Designs;Fourier transform ion cyclotron resonance;Gas-Liquid Chromatography;Goals;Human Resources;Informatics;Infusion procedures;Instruction;Isotopes;Journals;Label;Letters;Mass Spectrum Analysis;Measures;Metabolic;Metabolic Pathway;Methods;Mole the mammal;NMR Spectroscopy;Pathway interactions;Procedures;Process;Protocols documentation;Research;Resolution;Resources;Running;Sampling;Services;Study Section;System;Techniques;Technology;Therapeutic;Therapeutic Intervention;Tissues;Tracer;United States National Institutes of Health;Update;Work;analytical method;base;computerized data processing;coping;data acquisition;data reduction;human disease;imaging system;improved;in vivo;instrument;instrumentation;meetings;metabolomics;operation;outcome forecast;outreach;pre-clinical;reconstruction;research study;response;stable isotope;wiki

public_health_relevance:
RELEVANCE (See instructions): The Analytical Core serves the vital function of large-scale metabolite analyses to promote metabolomic research in biomedical community. In particular stable isotope-resolved metabolomic data procured by the Core will facilitate systems biochemical understanding of human diseases for the purpose of diagnosis prognosis therapeutics and response to therapeutic interventions.


application_id: 8916701
project_number: 5U24DK097215-03
project_title: SAMPLE CORE
administering_ic: NIDDK
award_notice_date: 2015-09-14
opportunity_number: RFA-RM-11-016
application_type: 5
activity_code: U24
ic: DK
serial_number: 097215
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZRG1-BST-F]
subproject_number: 6289
contact_pi_person_id: 8656419
contact_pi: HIGASHI, RICHARD M
other_pis: FAN, TERESA WHEI-MEI;LANE, ANDREW N.;MOSELEY, HUNTER NATHANIEL
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: 2015-09-01
project_abstract:
PROJECT SUMMARY (See instructions): Recent advances in metabolomics technologies have made possible simultaneous analysis of hundreds of metabolites by mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR). As the "gateway" to meaningful metabolomics analysis sample processing has critical issues not widely addressed in metabolomics studies such as 1) sample integrity; 2) reproducibility and range of metabolite recovery; 3) tools for extending metabolite coverage enabling high throughput & robust metabolite analysis and facilitating de novo structure elucidation of unknowns. Our Center (CREAM) has developed test-proven protocols for processing a wide selection of biospecimens with the aim of maintaining biochemical integrity and reproducible recovery of metabolites in large-scale. These protocols have been applied to many stable isotope-resolved metabolomics (SIRM) studies to reveal key reprogrammed metabolic events in human diseases. We have also shown the utility of chemoselective (CS) tagging in enriching low-level labile and volatile carbonyl metabolites for high throughput analysis by direct infusion Fourier transform-ion cyclotron resonance-mass spectrometry (FTICR-MS). Our protocols can be further enhanced in terms of throughput and coverage of previously inaccessible metabolites. We will support sample processing activities for the U24 RCMRC with three Specific Aims: SA1. To process a wide range of biospecimens researched by Clients. These range from cells tissues media biofluids to animals. We have provided this service since 2007 and will greatly expand the operation with added resources including sample preparation for in vivo NMR. SA2. To implement microfluidics-based subcellular/cell separation and metabolite extraction. We will test and refine microfiuidic platforms for separation of subcellular particles cell sorting and metabolite extraction to offer more efficient speedy and high throughput sample processing than existing methods. SA3. To implement profiling and multiplexed quantification of metabolites and their labeling patterns by FTICR- MS in a wide range of biological systems using chemoselective (CS) tagging of functional groups (FG). We will implement the CS capture approach (funded by a separate Common Funds R01) for enriching previously inaccessible metabolites with carbonyl amino thiol and diol FG for robust identification and multiplexed analysis by FTICR-MS and NMR.

project_terms:
A549;Address;Aldehydes;Ammonium;Animals;Aspirate substance;Base Pairing;Biochemical;CD3 Antigens;Cell Extracts;Cell Separation;Cells;Chromatography;Client;Computer software;Consult;Coupled;Crude Extracts;Cultured Cells;Detection;Development;Diagnosis;Disease;Event;Factor V;Fourier Transform;Fourier transform ion cyclotron resonance;Fractionation;Funding;Glycols;Goals;Human Resources;Informatics;Infusion procedures;Instruction;Internet;Ions;Isomerism;Isotopes;Ketones;Label;Leukocytes;Link;Lipids;Lymphocyte;Magnetic Resonance Imaging;Malignant Neoplasms;Mass Spectrum Analysis;Metabolic;Methods;Microfluidics;Molecular;Mus;NMR Spectroscopy;Nipples;Nucleotides;Parents;Pattern;Phase;Plasma;Population;Preparation;Process;Proteins;Protocols documentation;Reaction;Recovery;Reproducibility;Research;Resources;Rodent;Sample Size;Sampling;Scheme;Secure;Services;Solvents;Specimen;Speed (motion);Structure;Subcellular Fractions;Sulfhydryl Compounds;Surface;Technology;Testing;Tissues;Urine;Weight;Work;adduct;base;biological systems;design;functional group;granulocyte;high throughput analysis;human disease;human tissue;improved;in vivo;instrument;macrophage;meetings;metabolomics;nano-electrospray;operation;particle;prevent;sound;stable isotope;tandem mass spectrometry;tool;ultra high resolution

public_health_relevance:
RELEVANCE (See instructions): Sound sample processing is a prerequisite to metabolomic studies which have tremendous potential for promoting large-scale functional understanding of human diseases. Such understanding will ultimately enhance our ability to prevent diagnose and treat intractable diseases such as cancer. The proposed sample processing plan should help expand and facilitate meaningful metabolomic analysis and interpretation.


application_id: 8916700
project_number: 5U24DK097215-03
project_title: ADMINISTRATIVE
administering_ic: NIDDK
award_notice_date: 2015-09-14
opportunity_number: RFA-RM-11-016
application_type: 5
activity_code: U24
ic: DK
serial_number: 097215
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZRG1-BST-F]
subproject_number: 6288
contact_pi_person_id: 8656419
contact_pi: HIGASHI, RICHARD M
other_pis: FAN, TERESA WHEI-MEI;LANE, ANDREW N.;MOSELEY, HUNTER NATHANIEL
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: 2015-09-01
project_abstract:
PROJECT SUMMARY (See instructions): In this NIH Metabolomics Common Fund center proposal for a Regional Comprehensive Metabolomics Resource Core (RCMRC) "Resource Center for Stable Isotope-Resolved Metabolomics" we aim to continue and expand on our current successful Center for Regulatory and Environmental Analytical Metabolomics (CREAM). The role of the Administrative Core is to provide overall administration budgetary management oversee analytical services (e.g. sample tracking analysis status and billing) and oversight for the other 4 Cores' operations. The Core PI list comprises the current directorship of CREAM ensuring smooth personnel and management transition to the NIH RCMRC version of CREAM. This section describes both current and expanded operations with regards to administration of the proposed center and to ensure complete operational and policy harmony with the Common Funds goals. The Administrative Core will be responsible for all aspects of service scheduling and recharges financial management of the annually awarded Pilot and Feasibility projects maintaining all budgets and cost reporting of Cores organizing outreach workshops and symposia as well as coordinating annual reports regular meetings among the project personnel and all interactions with other RCMRC's program wide Executive Committee the Data Repository and Coordinating Center (DRCC) NIH Project Scientist & staff and any other appropriate entities. The specific aims of the Administrative Core are as follows: SA1. Establish the RCMRC-CREAM and evolve a tiered set of services for users. SA2. Coordinate with Clients and manage sample analytical and data workflow across all Cores. SA3. Provide administrative and budgetary oversight for the RCMRC-CREAM and across all Cores. SA4. Coordinate external efforts with other RCMRC facilities the Executive Committee NIH Project Scientists and staff NIH Common Fund programs and any other appropriate entities. SA5. Plan and implement transition to self-sustaining operations.

project_terms:
Annual Reports;Award;Biochemical;Biological Markers;Budgets;Charge;Client;Clinical;Complex;Consultations;Contracts;Core Facility;Core Grant;Cost Effectiveness Analysis;Data;Data Analyses;Databases;Development;Diagnostic;Distance Learning;Doctor of Philosophy;Educational workshop;Ensure;Fees;Funding;Goals;Grant;Health;Health Services Research;Human Resources;Income;Informatics;Instruction;Legal patent;Letters;Occupational activity of managing finances;Personnel Management;Pharmaceutical Preparations;Phase;Policies;Reporting;Resources;Role;Sampling;Schedule;Scientist;Services;Source;Stream;Structure;System;Technology;Training;Translating;Travel;United States National Institutes of Health;base;commercialization;cost;human disease;meetings;metabolomics;novel;operation;outreach;programs;research study;stable isotope;symposium;therapeutic target;web interface;web site

public_health_relevance:
RELEVANCE (See instructions): The Administrative Core is necessary to operate this complex metabolomics center for accelerating systems biochemical understanding of human diseases from which novel biomarkers and therapeutic targets for many critical health issues can be uncovered and translated into clinical development.


application_id: 8916696
project_number: 5U24DK097215-03
project_title: Resource Center for Stable Isotope-Resolved Metabolomics
administering_ic: NIDDK
award_notice_date: 2015-09-14
opportunity_number: RFA-RM-11-016
application_type: 5
activity_code: U24
ic: DK
serial_number: 097215
program_official: MARUVADA, PADMA
project_start_date: 2013-09-11
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZRG1-BST-F(50)R]
contact_pi_person_id: 8656419
contact_pi: HIGASHI, RICHARD M
other_pis: FAN, TERESA WHEI-MEI;LANE, ANDREW N.;MOSELEY, HUNTER NATHANIEL
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: The human metabolome represents the functional display of the human genome and proteome. The regulation of its homeostasis is highly sensitive to both intrinsic and external factors the perturbation of which can lead to disease development. Advances in mass spectrometry (MS) NMR informatics and sample processing have made possible large-scale interrogation of the human metabolome ("metabolomics") and is being increasingly applied to a variety of diseases such as cancer diabetes neurodegenerative and cardiovascular disorders for diagnosis and therapeutic purposes. The existing Center for Regulatory and Environmental Analytical Metabolomics (CREAM) conducts training and provides advice and full analytical resources from sample processing MS and NMR instrumentation to informatics which match with the major goals of the Common Fund. Moreover CREAM is now in its 6th year of self- sufficiency through client fees and conducts translational clinical research both of which are critical fifth-year exit goals of the Common Fund. Building on this solid foundation with added resources the proposed Common Fund Regional Comprehensive Metabolomics Resource Core (RCMRC) at the University of Louisville will greatly expand CREAM's capabilities in sample processing analytical/informatics developments and services and outreach efforts under the leadership of the PD and Pis who collectively have more than 95 years of experience in metabolomics. The Overall Goals of the RCMRC-CREAM are to facilitate and promote metabolomics research with an emphasis on stable isotope tracing for pathway elucidation in studies ranging from laboratory bench cell cultures model animals to human subjects and to provide the state-of-art analytical and informatics resources education and training for the biomedical research community. These goals will be achieved via the following specific aims: SA1: To administer comprehensive Metabolomics resources for bench to bedside research; SA2: To develop and implement integrated Metabolomics platforms to enhance performance sample & information throughput and scientific relevance; SA3: To provide outreach and education of the wider community in Metabolomics approaches.

project_terms:
Address;Adoption;Algorithms;Animal Model;Animals;Arts;Award;Biochemical Pathway;Biomedical Research;Cardiovascular Diagnostic Techniques;Cell Culture Techniques;Cells;Client;Clinical Research;Communities;Consultations;Data;Data Analyses;Detection;Development;Devices;Diabetes Mellitus;Disease;Distance Learning;Education and Outreach;Educational workshop;Ensure;Experimental Designs;Fees;Foundations;Fractionation;Freezing;Fresh Tissue;Funding;Goals;Grant;Homeostasis;Human;Human Genome;Informatics;Infusion procedures;Instruction;International;Internet;Joints;Laboratories;Laboratory Research;Lead;Leadership;Learning;Malignant Neoplasms;Mass Spectrum Analysis;Metabolism;Methodology;Microfluidics;Modeling;Neurodegenerative Disorders;Outcome;Paper;Pathway interactions;Performance;Preparation;Procedures;Process;Proteome;Publications;Publishing;Qualifying;Regulation;Research;Research Personnel;Resected;Resource Informatics;Resources;Sampling;Services;Slice;Solid;Structure;System;Techniques;Technology;Therapeutic;Tissues;Tracer;Training;Training and Education;Transplantation;United States National Institutes of Health;Universities;Work;Xenograft procedure;base;bench to bedside;computerized data processing;cost;data acquisition;design;disease diagnosis;experience;handbook;human subject;instrumentation;meetings;metabolomics;network models;new therapeutic target;operation;outreach;prevent;programs;software development;stable isotope;symposium;tandem mass spectrometry;therapeutic development;ultra high resolution

public_health_relevance:
RELEVANCE (See instructions): It is increasingly recognized that perturbations to the human metabolome is crucial to the development and therapeutic outcome of many major intractable diseases. The integrated metabolomic technologies and outreach efforts offered by the proposed RCMRC-CREAM will help promote adoption of metabolomic approaches in basic and translational biomedical research thereby accelerating our ability to prevent and diagnose diseases as well as to uncover novel therapeutic targets.


application_id: 8916620
project_number: 5R25CA134283-05
project_title: University of Louisville Cancer Education Program
administering_ic: NCI
award_notice_date: 2015-08-28
opportunity_number: PAR-08-120
application_type: 5
activity_code: R25
ic: CA
serial_number: 134283
program_official: RADAEV, SERGEY
project_start_date: 2011-09-14
project_end_date: 2017-03-31
study_section: Education Study Section (G)[NCI-G]
contact_pi_person_id: 1924912
contact_pi: HEIN, DAVID W
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cancer incidence morbidity and mortality in the Commonwealth of Kentucky are among the highest in the nation. The James Graham Brown Cancer Center's mission is to reduce cancer incidence morbidity and mortality particularly within the Commonwealth and the region we serve. The clinical and research programs of the James Graham Brown Cancer Center have experienced tremendous growth in faculty recruitment and in the development of scientific and clinical programs and shared use facilities. The long-term objective of the University of Louisville Cancer Education Program is to recruit educate and motivate outstanding undergraduate and professional students to pursue further training and future careers in cancer research. The program fits exceptionally well within the strategic plans of the University of Louisville and we will implement novel recruitment evaluation and dissemination strategies to achieve the objectives of the program.

project_terms:
American Association of Cancer Research;Benchmarking;Cancer Center;Cancer Research Project;Clinical;Clinical Research;Development;Educational Curriculum;Evaluation;Faculty;Future;Growth;Health Professional;Incidence;Kentucky;Malignant Neoplasms;Mentors;Mission;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Motivation;Outcome;Recruitment Activity;Research;Research Project Grants;Selection Criteria;Strategic Planning;Students;Time;Training;United States;Universities;anticancer research;cancer education;career;experience;medical schools;meetings;novel;programs;research and development;skills;symposium;undergraduate student

public_health_relevance:
Cancer incidence morbidity and mortality in the Commonwealth of Kentucky are among the highest in the nation. The James Graham Brown Cancer Center's mission is to reduce cancer incidence morbidity and mortality particularly within the Commonwealth and the region we serve. The clinical and research programs of the James Graham Brown Cancer Center have experienced tremendous growth in faculty recruitment and in the development of scientific and clinical programs and shared use facilities. The long-term objective of the University of Louisville Cancer Education Program is to recruit educate and motivate outstanding undergraduate and professional students to pursue further training and future careers in cancer research.


application_id: 8916069
project_number: 5R01DA033394-03
project_title: Targeting GABA and Opioid Systems for a Pharmacotherapy for Methamphetamine Abuse
administering_ic: NIDA
award_notice_date: 2015-08-20
opportunity_number: PA-10-268
application_type: 5
activity_code: R01
ic: DA
serial_number: 033394
program_official: HAMPSON, AIDAN
project_start_date: 2013-09-30
project_end_date: 2018-08-31
study_section: Special Emphasis Panel[ZRG1-RPIA-N(09)]
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Methamphetamine (MA) abuse and dependence are significant public-health concerns. Treatment admissions for MA use increased at an alarming rate from 1998 to 2007 in the US. Behavioral treatments reduce MA use. However many patients enrolled in behavioral treatment programs are unable to achieve a significant period of abstinence suggesting other strategies like pharmacotherapy are urgently needed. G-Aminobutyric-acid (GABA) and opioid systems modulate dopamine. GABAA receptor modulators (e.g. oxazepam [OXP]) and opioid antagonists (e.g. naltrexone [NTX]) attenuate the abuse-related effects of amphetamines. The attenuation of the abuse-related effects of amphetamine by GABAA receptor modulators or opioid antagonists while statistically significant is modest in magnitude. Novel strategies are needed to enhance the efficacy of these drugs. Targeting GABA and opioid systems simultaneously is an innovative strategy in that combining NTX and OXP may produce greater attenuation of the abuse-related effects of MA. A rigorous within-subject experiment will be conducted in non-treatment-seeking MA-abusing participants. NTX (0 and 50 mg/day) and OXP (0 and 40 mg/day) alone and in combination will be tested with MA (0 10 20 and 30 mg). The four NTX-OXP maintenance conditions will be tested in random order. Similarly within each NTX-OXP condition the MA doses will be tested in random order. The reinforcing effects of intranasal MA doses will be determined after four days of maintenance on each of the NTX-OXP conditions using a sensitive progressive-ratio procedure. The ability to attenuate the reinforcing effects of drugs isa reliable predictor of an effective pharmacotherapy. We hypothesize that combining NTX and OXP will produce an additive or supra-additive reduction in the reinforcing effects of MA relative to the constituent drugs alone. This research will provide critical information regarding the initil efficacy a novel drug combination NTX and OXP for MA dependence. Innovations of the proposed research include: 1) testing a combination of marketed drugs that demonstrated some efficacy when tested as mono-therapies; 2) testing a GABAA receptor modulator that has minimal abuse potential and dependence liability which will likely be more acceptable to clinicians; 3) the use of a sensitive drug self-administration procedure; 4) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of NTX-OXP combinations for MA dependence; and 5) demonstrating the initial efficacy of commercially available drugs as opposed to waiting for novel molecules to be available for testing in humans thereby impacting clinical research and practice more quickly. In these ways the proposed project will shift the current clinical research paradigm in pharmacotherapy development and have a significant impact on the treatment of MA dependence.

project_terms:
Abstinence;Admission activity;Adverse effects;Alprazolam;Aminobutyric Acids;Amphetamines;Animals;Attenuated;Behavior Therapy;Behavioral;Cardiovascular system;Chronic;Clinical Research;Clinical Trials;Cocaine Dependences;Cognitive Therapy;Communicable Diseases;Crime;Data;Data Analyses;Dependence;Development;Dopamine;Dose;Drug Combinations;Drug-sensitive;Enrollment;Health;Human;Impaired cognition;Laboratories;Maintenance;Mediating;Medical;Methamphetamine;Methamphetamine dependence;Mono-S;Naltrexone;Narcotic Antagonists;National Institute of Drug Abuse;Opioid;Outcome Measure;Oxazepam;Participant;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phase II Clinical Trials;Physiological;Play;Premature Mortality;Probability;Procedures;Productivity;Questionnaires;Relative (related person);Reporting;Research;Role;Safety;Self Administration;System;Testing;United States;addiction;attenuation;clinical practice;contingency management;cost;dopamine system;double-blind placebo controlled trial;drug efficacy;drug market;drug reinforcement;indexing;innovation;methamphetamine abuse;methamphetamine use;novel;novel strategies;public health medicine (field);receptor;research study;secondary outcome;stimulant abuse;success;tool;treatment program

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The research proposed in this application will provide critical information regarding the initial efficacy safety and tolerability of a novel drug combination naltrexone and oxazepam as a pharmacotherapy for methamphetamine dependence. The proposed research is innovative because it will demonstrate the initial efficacy of commercially available drugs as opposed to waiting for novel molecules to be available for testing in humans thereby impacting clinical research and practice more quickly. The proposed study is important because it will provide the impetus for the conduct of double blind placebo-controlled trials to further demonstrate the efficacy of naltrexone-oxazepam combinations for managing cocaine dependence. If these trials demonstrate efficacy they will provide clinicians with a pharmacological tool for managing methamphetamine dependence.


application_id: 8916018
project_number: 5R01AR061939-04
project_title: BetaCatenin Regulation of Skeletal Muscle Hypertrophy
administering_ic: NIAMS
award_notice_date: 2015-08-01
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: 2016-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-C(90)S]
contact_pi_person_id: 1873134
contact_pi: MCCARTHY, JOHN JOSEPH
other_pis: ESSER, KARYN A
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;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;metabolic rate;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: 8915177
project_number: 5K08EY021757-05
project_title: Endothelial Cell Dysregulation in Neovascular AMD
administering_ic: NEI
award_notice_date: 2015-08-19
opportunity_number: PA-10-059
application_type: 5
activity_code: K08
ic: EY
serial_number: 021757
program_official: AGARWAL, NEERAJ
project_start_date: 2011-09-01
project_end_date: 2016-08-31
study_section: ZEY1-VSN(11)
contact_pi_person_id: 8784086
contact_pi: KLEINMAN, MARK E
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The candidate is applying for a Mentored Clinical Scientist Research Career Development Award (K08) to  support a 5 year research career training program that will significantly bolster his transition to faculty  independence as a fellowship trained clinician-scientist specializing in vitreoretinal and macular diseases. The  rigorous training program has been designed with extensive input and unyielding support from the candidate's  mentor co-mentor chairman and advisory committee. All training will take place in the excellent scientific and  academic environment of the University of Kentucky Department of Ophthalmology and Visual Sciences which  includes an ocular angiogenesis research consortium consisting of four independent investigators. The  applicant will spend the first 3 years of the program as a Research Assistant Professor and Clinical Fellow. The  specific design of the fellowship is precisely detailed in the Career Development section and accompanied by a  very strong institutional commitment that allows the candidate at least 80% effort performing research and 20%  performing clinical duties. After completion of the fellowship the candidate will transition to a full-time faculty  position as Assistant Professor at University of Kentucky with the same institutional commitment of 80%  research and 20% clinical effort. The long-term goal of the award is to offer the candidate the critical career  development support to establish a pathway to faculty independence that will extensively train him as a  biomedical researcher confident and masterful specialist in the diagnosis and treatment of vitreoretinal and  macular diseases and leading academician. The candidate aims to have an independent laboratory up and  running within the initial 12-18 months of the award period in order to gain early independence with his  research project and develop critical principal investigator skills with guidance from his established mentors  and advisory committee. The research plan has been devised by the candidate and his mentors and aims to  extend his scientific expertise beyond basic vascular biology with a rich experience to develop new techniques  and to utilize such methods in experimental designs to obtain critical data that expand his current fund of  knowledge in order to yield fundamental insights on endothelial cell dysregulation immuno-modulation in  vascular growth and therapeutic targets in neovascular age-related macular degeneration (AMD).  AMD is a devastating blinding disease that affects as many as 10 million Americans a number that rivals the  prevalence of all cancers combined and is unfortunately expected to double by 2020. The overwhelming cause  of severe vision loss in AMD is choroidal neovascularization (CNV) the growth of abnormal blood vessels  beneath the retina. Despite the use of recently approved molecular therapeutics targeting vascular endothelial  growth factor (VEGF)-A the majority of patients do not regain functional vision and a significant fraction  progress to legal blindness. This treatment failure is attributed to the frequent clinical situation in which patients  present to eye physicians after vision is already lost and irreversible structural and functional tissue damage  has already occurred. Moreover while patients with AMD often undergo at least one or more dilated eye  examinations per year the physician is often not able to detect CNV before it grows beneath the retina and  wreaks havoc. Fortunately there is an exciting development that may provide the first available technique for  detecting incipient CNV in patients with AMD thereby allowing for earlier detection and treatment to prevent  loss of vision and quality of life. This discovery was recently reported in the journal Nature and described as  the first molecular marker that is specific for human CNV (Takeda et al. Nature 2009). It is an immune receptor  called chemokine receptor 3 (CCR3) that is involved in allergic response and recruitment of white blood cells  but may also be found on inflamed and growing blood vessels.  The identification of CCR3 as a molecular signature has opened a gateway to a new understanding in vascular  disease in AMD. CCR3 expression is found on the surface of the specialized endothelial cells that line the  abnormal blood vessels. In this proposal rigorous basic science investigations of the cellular circuitry that  mediates this pathogenic switch will be explored in conjunction with the biological relationships between  endothelial cell dysregulation aging immune activation and oxidative stress. The initial aim of the study is to  decipher how these established AMD risk factors regulate the progression of disease through chemokine and  other immune signaling pathways in order to develop appropriately targeted diagnostics and therapeutics that  will enable clinicians to offer improved care of patients suffering from AMD. A second aim focuses specifically  on CCR3 biology with scientific exploration of its pathogenetic induction expression patterns and signaling  effects during endothelial cell dysregulation in neovascular AMD. In a final aim optimized fluorescent CCR3-  targeting probes will be engineered and applied to pre-clinical animal models of CNV and human cellular  toxicology studies in order to obtain necessary data to proceed with future clinical studies. These specific  experimental aims will provide fundamental insights into the modulatory function of the immune system  chemokine signaling and the role of CCR3 as a molecular switch during the endothelial cell dysregulation that  heralds vision loss in neovascular AMD.

project_terms:
Ablation;Accounting;Advisory Committees;Affect;Age related macular degeneration;Aging;American;Animal Model;Architecture;Area;Automobile Driving;Award;Basic Science;Biological;Biological Markers;Biology;Biomedical Research;Blindness;Blood;Blood Vessels;Bone Marrow Transplantation;Cell Line;Cells;Chairperson;Choroidal Neovascularization;Chromatin Remodeling Factor;Clinical;Clinical Research;Complement Activation;Coupled;Data;Detection;Development;Diagnosis;Diagnostic;Disease;Disease Progression;Drusen;Dyes;Early Diagnosis;Early Intervention;Early treatment;Endothelial Cells;Engineering;Environment;Experimental Designs;Exudative age-related macular degeneration;Eye;Faculty;Fellowship;Fluorescein Angiography;Funding;Future;Gene Expression Profile;Genetic;Goals;Grant;Growth;Human;Hypersensitivity;Imaging Techniques;Immune;Immune system;Immunoglobulin Fragments;Immunologic Receptors;In Vitro;Inflammation;Interleukins;Invaded;Investigation;Journals;K-Series Research Career Programs;Kentucky;Knowledge;Laboratories;Lead;Legal;Legal Blindness;Lesion;Leukocytes;Ligands;Malignant Neoplasms;Maps;Mediating;Medicine;Mentors;Methods;Molecular;Molecular Profiling;Molecular Target;Mus;Nature;Nonexudative age-related macular degeneration;Ophthalmic examination and evaluation;Ophthalmology;Outcome;Oxidative Stress;Pathogenesis;Pathologic Processes;Pathway interactions;Patient Care;Patients;Pattern;Physicians;Positioning Attribute;Prevalence;Principal Investigator;Process;Progressive Disease;Quality of life;Regulation;Relative (related person);Reporting;Research;Research Personnel;Research Project Grants;Research Training;Retina;Retinal Diseases;Risk Factors;Role;Running;Safety;Scientist;Sensitivity and Specificity;Signal Pathway;Signal Transduction;Signaling Molecule;Specialist;Specimen;Staging;Structure of retinal pigment epithelium;Sum;Surface;Symptoms;Techniques;Testing;Therapeutic;Therapeutic Uses;Time;Tissues;Toxicology;Training;Training Programs;Transgenic Mice;Treatment Efficacy;Treatment Failure;United States;Universities;Uveal Melanoma;Vascular Diseases;Vascular Endothelial Growth Factor A;Vision;Visual;Work;allergic response;base;bioimaging;career;career development;cell type;chemokine;chemokine receptor;cost;cytokine;cytotoxicity;design;disorder of macula of retina;experience;imaging probe;immune activation;improved;in vivo;insight;molecular marker;mouse model;nanocrystal;neutralizing antibody;next generation;normal aging;ocular angiogenesis;pre-clinical;prevent;professor;programs;research study;response;skills;small molecule;targeted treatment;therapeutic development;therapeutic target;vision science

public_health_relevance:
The abnormal growth of blood vessels beneath the retina results in devastating vision loss in  age-related macular degeneration (AMD) yet the specific molecular and cellular mechanisms  by which this process occurs are an area of active scientific investigation. The proposal aims to  provide fundamental insights into the dysregulation of the specialized endothelial cells that line  the abnormal blood vessels during AMD progression. Importantly this award will grant the  candidate a critical opportunity to gain essential research training while greatly enhancing  career development and a confident transition to faculty independence.


application_id: 8914931
project_number: 3R01ES019217-04S1
project_title: Endothelial Progenitor Cells and Particulate Air Pollution
administering_ic: NIEHS
award_notice_date: 2014-09-10
opportunity_number: PA-10-067
application_type: 3
activity_code: R01
ic: ES
serial_number: 019217
suffix: S1
program_official: SCHUG, THADDEUS
project_start_date: 2011-09-23
project_end_date: 2016-04-30
study_section: Special Emphasis Panel[ZRG1-CVRS-C(02)M]
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: BHATNAGAR, ARUNI ;POPE, ARDEN
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): Multiple epidemiological and experimental studies report that acute or chronic exposure to air pollution is associated with adverse cardiovascular events including myocardial ischemia stroke arrhythmias heart failure sudden cardiac arrest and atherogenesis. These effects of air pollution are most strongly correlated with fine and ultrafine particulate matter (PM) fractions which are generated directly from the combustion of fossil fuels and are found in automobile exhaust wood or coal smoke and industrial emission from smelters paper or steel mills or cement plants. A common feature of PM-associated cardiovascular disorders is the establishment and maintenance of a dysfunctional endothelium. Because endothelial dysfunction is an early symptom of cardiovascular disease and an important factor in acute thrombotic complications of atherosclerosis such as stable and unstable angina myocardial infarction and ischemic stroke it could be a key mediator of the cardiovascular toxicity associated with PM exposure. The adult endothelium is a differentiated cell layer that provides a non-thrombotic interface between parenchymal cells and peripheral blood. Damages due to normal "wear-and-tear" in this layer are repaired by the mobilization and homing of bone-marrow resident pluripotent cells or endothelial progenitor cells (EPCs) which also promote angiogenesis and wound healing. We have recently identified a negative correlation between PM exposure and circulating EPC level. Here we hypothesize that defects in EPC mobilization or function are a consequence of PM-induced systemic inflammation induced by oxidative stress. We will test this hypothesis in three aims. First we will examine PM-induced changes in EPC populations in the peripheral blood and bone marrow of mice exposed to concentrated ambient air particles (CAPS) or filtered air. We will determine the time course of these effects whether there is a mobilization defect per se whether specific populations and locations of EPC are affected and whether this response is selective to EPCs or other stem cells such as the hematopoietic stem cells and mesenchymal stem cells are affected as well. In addition we will measure circulating levels of EPC-derived microparticles to test whether exposure to PM increases EPC activation or cell death. The second aim is to delineate the mechanisms by which PM exposure affects EPC function. For this we will assess how exposure to CAPs affects the ability of EPCs to grow differentiate migrate and promote wound healing. We will examine whether these changes in EPC are accompanied by an increase in systemic inflammation and oxidative stress and whether antioxidant interventions or strategies to increase NO availability would prevent PM-induced deficits in EPC number and function. Finally Aim 3 is to examine whether PM-induced changes in human peripheral blood EPC number and function are accompanied by an increase in systemic inflammation oxidative stress and microparticle or miRNA biomarkers and whether anti-oxidant intervention could reverse such changes. Successful completion of this project will provide novel insights into the cardiovascular toxicity of PM and how it affects the abundance and the reparative capacity of stem cells. Findings of this project could also form the basis for the development of new biomarkers of PM exposure or new strategies to mitigate PM toxicity.

project_terms:
Acetylcholine;Acute;Admission activity;Adult;Affect;Air;Air Pollution;Animals;Antioxidants;Aorta;Arrhythmia;Atherosclerosis;Automobile Exhaust;Biological Markers;Blood Cells;Blood Pressure;Blood Vessels;Bone Marrow;Breathing;Cardiotoxicity;Cardiovascular Diseases;Cardiovascular Pathology;Cardiovascular system;Cell Count;Cell Death;Cell Survival;Cell physiology;Cells;Cessation of life;Chronic;Coagulation Process;Coal;Defect;Deposition;Development;Endothelium;Epidemiologic Studies;Event;Exposure to;Flow Cytometry;Fossil Fuels;Free Radicals;Generations;Goals;Health;Heart Arrest;Heart failure;Hematopoietic;Hematopoietic stem cells;Homing;Hospitals;Human;Inflammation;Inflammatory Response;Injury;Intervention;Ischemic Stroke;Lead;Location;Maintenance;Measures;Mediator of activation protein;Mesenchymal Stem Cells;MicroRNAs;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Oxidation-Reduction;Oxidative Stress;Paper;Particulate;Particulate Matter;Plants;Plasma;Population;Reaction;Relaxation;Reporting;Risk;Smoke;Steel;Stem cells;Symptoms;Testing;Thrombosis;Time;Toxic effect;Ultrafine;Unstable angina;Wood material;Wound Healing;air filter;angiogenesis;atherogenesis;base;cardiovascular disorder risk;cardiovascular risk factor;cell growth;endothelial dysfunction;human tissue;insight;novel;particle;peripheral blood;prevent;repaired;research study;response;stroke;tissue repair;young adult

public_health_relevance:
Exposure to particulate matter (PM) air pollution is strongly correlated with the initiation and progression of atherosclerosis increased thrombosis myocardial infarction and stroke. These cardiovascular pathologies are characterized by a dysfunctional endothelium and its inefficient repair by pluripotent cells or endothelial progenitor cells (EPCs). Thus in this proposal we test the hypothesis that the cardiotoxicity resulting from PM exposure is a consequence of PM-induced deficits in EPC number or function.


application_id: 8914605
project_number: 5R01DK098176-02
project_title: Thrombospondin 1 in obesity associated inflammation and insulin resistance
administering_ic: NIDDK
award_notice_date: 2015-05-12
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 098176
program_official: ABRAHAM, KRISTIN M
project_start_date: 2014-08-20
project_end_date: 2018-05-31
study_section: Integrative Physiology of Obesity and Diabetes Study Section[IPOD]
contact_pi_person_id: 7837422
contact_pi: WANG, SHUXIA
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Increased accumulation of adipose tissue macrophages (ATMs) promotes obesity-associated chronic inflammation and insulin resistance. Although there have been some advances in the study of ATMs in obese condition the mechanisms underlying ATMs recruitment and activation remain to be determined. Thrombospondin 1 (TSP1) has been identified to be an adipokine and its expression levels correlate positively with human obesity adipose tissue inflammation and insulin resistance. By using TSP1 deficient mice preliminary studies revealed a novel role for TSP1 in stimulating macrophage recruitment and activation in adipose tissue that contributes to inflammation and insulin resistance resulting from high fat diet-induced obesity (DIO). Moreover TSP1 promoting macrophage migration and activation is through the N-terminal domain and the type 1 repeats to interact with receptors LRP1 and CD36 respectively. Blocking the interactions of TSP1/LRP1 and TSP1/CD36 inhibited TSP1 stimulation of macrophage function. Based on these data we hypothesize that blockade of the stimulatory effect of TSP1 on macrophage function prevents/ameliorates obesity-associated inflammation and insulin resistance. To test this hypothesis in Aim 1 tissue specific TSP1 knockout mice will be used to definitively answer the question of whether adipocyte-derived TSP1 serves as a primary chemokine to stimulate macrophage accumulation in adipose tissue and promotes the development of obesity-associated inflammation and insulin resistance. In Aim 2 utilizing the identified stimulatory domains on TSP1 as targets based on their available x-ray crystal structures new decoy peptides will be designed by structure-based computational design strategy. The inhibitory effect of decoy peptides on TSP1stimulation of macrophage function will be tested. In Aim 3 whether blocking of TSP1/CD36 interaction can prevent/ameliorate obesity-associated inflammation and insulin resistance in vivo will be tested. Together these proposed studies may lead to novel therapeutics for obesity-induced insulin resistance and metabolic complications and therefore have significant clinical relevance.

project_terms:
Address;Adipocytes;Adipose tissue;Binding (Molecular Function);CD36 gene;Cardiovascular Diseases;Cells;Chemotactic Factors;Chronic;Data;Development;Diet;Disease;Fatty acid glycerol esters;Fibrosis;Genotype;Health;Human;Hypertension;In Vitro;Infiltration;Inflammation;Inflammatory;Injury;Insulin Resistance;Kidney;Kidney Diseases;Knockout Mice;Lead;Macrophage Activation;Mediating;Mediator of activation protein;Metabolic;Modeling;Molecular;Mus;N-terminal;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Obesity;Peptides;Phenotype;Play;Proteins;Reporting;Resistance development;Rodent;Role;Signal Transduction;Structure;TLR4 gene;Testing;Thrombospondin 1;Tissues;Visceral;Wild Type Mouse;Work;base;chemokine;clinically relevant;clinically significant;design;glucose tolerance;human subject;improved;in vivo;insulin sensitivity;macrophage;migration;novel;novel therapeutics;obesity treatment;prevent;receptor;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Obesity is prevalent worldwide and is associated with insulin resistance and the development of type 2 diabetes. The proposed studies will provide novel information on the mechanisms of obesity-induced adipose tissue macrophage infiltration and activation and importantly will develop novel therapeutic strategies in the treatment of obesity-induced insulin resistance a problem of immense clinical significance.


application_id: 8914596
project_number: 5R01DK093832-04
project_title: Computational Approach to Personalized Anemia Management
administering_ic: NIDDK
award_notice_date: 2015-07-14
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: 2018-07-31
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;Mission;Modeling;Mortality Vital Statistics;Nature;Outcome;Patient Care;Patient risk;Patients;Pharmaceutical Preparations;Population;Prevention;Protocols documentation;Quality of life;Research;Risk;Risk Factors;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;personalized medicine;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: 8914400
project_number: 5P01CA163223-03
project_title: Stable Isotope Resolved Metabolomics Analytical Shared Core
administering_ic: NCI
award_notice_date: 2015-02-27
opportunity_number: PAR-12-005
application_type: 5
activity_code: P01
ic: CA
serial_number: 163223
study_section: ZCA1-RPRB-0
subproject_number: 7605
contact_pi_person_id: 8656419
contact_pi: HIGASHI, RICHARD M
other_pis: FAN, TERESA WHEI-MEI;YAN, JUN
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-03-01
budget_end_date: 2016-02-29
project_abstract:
PROJECT SUMMARY (See instructions): The Stable Isotope Resolved (SIRM) Analytical Shared Core will provide high information throughput (HIT) bioanalytical support for the groups with special emphasis on stable isotope-based metabolic pathway tracing. The basis for this Core already exists in the form of the NSF-initiated UofL Center for Regulatory and Environmental Analytical Metabolomics (CREAM) established expressly for SIRM metabolomic bioanalytical services and collaborations on sample preparation and handling high field NMR mass spectrometry and biochemoinformatics since 2002. CREAM houses state of the art instrumentation that has profoundly influenced experimental design for several research groups. Therefore many Core interactions are by their nature long-standing collaborative efforts. The main goals of the SIRM Shared Core are to provide a set of shared resources for all three Research Projects and seamlessly integrate experimental design data collection and data analysis spanning tissue culture mouse models and human subjects. The Core will provide a combination of experimental methods to determine metabolic phenotypes of cancerous and non-cancerous lung cells and tissue using our state of the art analytical platforms in both NMR and mass spectrometry. In consultation with individual project leaders specific experimental design for stable isotope analysis will be tailored to individual project needs but with consistency across projects to facilitate integrated analyses. We have 3 specific aims to achieve our goals: Specific Aim 1. Provide infrastructure and expert sample handling that ensures consistent handling processing and archiving of samples across all three Research Projects; Specific Aim 2. Provide access and expertise across a wide range of NMR and MS technologies to the three Research Projects: A) Provide access to instrumentation and expertise for robust and consistent SIRM-based analytical experimental design and B) Provide expert data collection and analysis across a wide range of NMR and MS technologies. Specific Aim 3. Provide data analytical support to the Research Projects including data metabolic pathway and biochemical mechanism analyses that include: A) Implement a web-based platform for data reduction quality control and data analytical support; B) Provide methodologies for identifying and quantifying metabolites; C) Provide a bridge between the Projects data acquisition and biochemical analysis in Gore A. Core B provides extensive interoperability handling and advising all aspects of sample preparation data collection data analysis & quality control ensuring consistency of data across all 3 research projects.

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


application_id: 8914399
project_number: 5P01CA163223-03
project_title: Administration Bioinformatics and Biostatistics Core
administering_ic: NCI
award_notice_date: 2015-02-27
opportunity_number: PAR-12-005
application_type: 5
activity_code: P01
ic: CA
serial_number: 163223
study_section: ZCA1-RPRB-0
subproject_number: 7604
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
other_pis: FAN, TERESA WHEI-MEI;YAN, JUN
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-03-01
budget_end_date: 2016-02-29
project_abstract:
In this Program Project "Systems Biochemistry in Lung Cancer: toward a mechanistic understanding of NSCLC" we aim to achieve a better understanding of the basic biochemistry of lung cancers as a prerequisite to mechanism-based reliable early detection of the disease and to improved approaches to treatment. The role of the Administrative Bioinformatics and Biostatistics Core is to provide overall administration and oversight to the project directors and core leaders (T. W-M. Fan Ph.D. Project 1; J. Yan M.D. Ph.D. Project 2; A. N. Lane Ph.D. Project 3; R. M Higashi Ph.D. Core B Analytical) on this Program Project. In addition Biostatistics and Informatics support (leaders S. N. Rai Ph.D. and H. N. B Moseley Ph.D.) for the Projects will be provided through this Core. To ensure smooth interoperability of the program the administrative core will be responsible for maintaining the budgets and cost reporting of the projects and cores as well as coordinating annual reports regular meetings among the project personnel and the internal and external advisory committees. The primary objective of the Bioinformatics / Biostatistics portion of this core is to provide support for investigators performing translational research and Informatics for biochemical pathway reconstruction and flux modeling. The core services are matched to the needs of each project and cover a full range of services from collaboration and routine service; protocol preparation and review; development of informatics approaches to ensure interoperability; and biochemical network analysis.

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


application_id: 8914397
project_number: 5P01CA163223-03
project_title: Determining Molecular Mechanisms of NSCLC and Response to beta-glucan
administering_ic: NCI
award_notice_date: 2015-02-27
opportunity_number: PAR-12-005
application_type: 5
activity_code: P01
ic: CA
serial_number: 163223
study_section: ZCA1-RPRB-0
subproject_number: 7603
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
other_pis: FAN, TERESA WHEI-MEI;YAN, JUN
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-03-01
budget_end_date: 2016-02-29
project_abstract:
The gold standard for understanding the connection between tumor metabolism tumor progression and ultimately therapeutic efficacy is the human subject but more detailed information is needed from appropriate better controlled models. We have begun a Stable Isotope Resolved Metabolomics (SIRM) study of non-small cell lung cancer (NSCLC) from patients who underwent surgical resection. In our pilot study we capitalized on the inherent power of the matched pairs of malignant and benign lung tissue and the use of "C-labeled glucose administered iv prior to surgery to map in situ intracellular metabolic pathways for the first time. This led to the discovery that mitochondrial pyruvate carboxylase (PCB) is activated to replenish Krebs cycle intermediates required for biosynthesis (i.e. anaplerosis) in tumors. This was further corroborated by increased mRNA and protein expression of PCB in the tumors compared with the paired benign lung tissue as well as growth inhibition of NSCLC cells by PCB knockdown. Critical to the interpretation of these studies was the additional detailed information that we obtained on cell culture and mouse models which provided metabolic signatures to look for in the tumor tissue.). Our preliminary findings also indicate that there are many more metabolic distinctions in lung tumors; the underlying pathways and regulation have yet to be defined. We now seek to extend the approach to a larger cohort of NSCLC and added a new ex vivo "Warburg" tissue slice approach to better define in large-scale the metabolic reprogrammings in NSCLC with prevailing driver gene defects. These direct human studies will be conducted in parallel with model cell (Project 1) and animal studies (Project 2) to facilitate interpretation. We will also apply this integrated approach to explore the metabolic mechanism underlying the tumor-regressive effect of a pre-operative treatment with beta-glucans. We hypothesize that this effect may be in part mediated by beta-glucan's activation of glucose and Gin metabolism in resident macrophages a key immune modulator in the tumor microenvironment based on our most recent data and the literature (cf. Project 2). We will further explore the linkage of lung tumor tissue to blood plasma metabolism via the lipidic microvesicles (MV) known to be released by lung cancer cells with metastasis-promoting capacity. We have new evidence that the lipid profile of plasma MV is distinct among early stages of lung and breast cancer patients and healthy subjects. We will test if beta-glucan treatment can alter MV metabolic signatures for future application as clinical indicators. These goals will be achieved via the three specific aims.

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


application_id: 8914396
project_number: 5P01CA163223-03
project_title: Determining Tumor Metabolism and Biochemical Mechanism of beta-glucan Action in
administering_ic: NCI
award_notice_date: 2015-02-27
opportunity_number: PAR-12-005
application_type: 5
activity_code: P01
ic: CA
serial_number: 163223
study_section: ZCA1-RPRB-0
subproject_number: 7602
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: FAN, TERESA WHEI-MEI;YAN, JUN
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-03-01
budget_end_date: 2016-02-29
project_abstract:
Deaths from lung cancer are the highest of all cancers in the US. The complexity of lung cancer (LC) development suggests that a combination of approaches is needed to understand the mechanism of LC biology and tumor cell interactions with other cells such as immune cells within the tumor microenvironment. The concept of "cancer immunoediting" recognizes the complex and dynamic interactions between the tumor and host during tumor development progression and metastasis. Although how the immune system plays a role in development and progression of human non-small cell lung carcinoma (NSCLC) is still elusive innate macrophages are abundant in the NSCLC tumors. These macrophages are of immune suppressive M2 phenotype promote tumor angiogenesis and metastasis and limit efficacy of chemotherapy for NSCLC. beta-Glucans polysaccharides derived from various sources can stimulate both innate and adaptive immune responses. Our preliminary data further demonstrate that beta-glucan treatment in vitro converts immune suppressive M2 macrophages into tumoricidal M1 phenotype and significantly decreases tumor-associated macrophage (TAM)-mediated immune suppression on CD4 and CDS T cells. Using the stable isotope resolved metabolomics (SIRM) approach we show that glutamine (Gin) uptake and subsequent metabolism to glucose glutathiones and lactate are enhanced when immune suppressive M2 macrophages are converted into an Ml phenotype. The central hvpothesis of this proposal is that differential human NSCLC subtypes may have distinct metabolic profiles and p-glucan treatment modulates TAM activity and metabolism leading to the alterations of metabolic networks in NSCLC. We will use stable isotopic (13C 15N) nutrient tracers in combination with the SIRM approach and metabolomics-edited transcriptomic analysis (META) to define key metabolic components of human NSCLC in vivo and investigate how beta-glucan treatment influences TAM phenotype function metabolism and subsequently tumor microenvironmental metabolic events. Three Specific Aims are proposed to determine the: 1 specific metabolic patterns of human NSCLC cells in xenografted tumors in severe combined immunodeficient (SCID) mice; 2) biochemical mechanisms of beta-glucan action in murine lung carcinoma models; 3) biochemical and phenotypic characteristics of human primary tumors implanted in N0D/SCID/IL-2gcNULL mice in response to beta-glucan administration. These investigations will advance our understanding of the biochemical underpinnings of tumor microenvironment nutrient utilization by NSCLC and how these processes are related to tumor immune evasion and immunomodulation.

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


application_id: 8914395
project_number: 5P01CA163223-03
project_title: Microenvironmental Nutrient Availability and Immunomodulation in Lung Cancer Cel
administering_ic: NCI
award_notice_date: 2015-02-27
opportunity_number: PAR-12-005
application_type: 5
activity_code: P01
ic: CA
serial_number: 163223
study_section: ZCA1-RPRB-0
subproject_number: 7601
contact_pi_person_id: 7213583
contact_pi: FAN, TERESA WHEI-MEI
other_pis: FAN, TERESA WHEI-MEI;YAN, JUN
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-03-01
budget_end_date: 2016-02-29
project_abstract:
. PROJECT SUMMARY (See instructions); We propose a systems biochemical study of lung cancer (LC) cell nutrient metabolism of importance to LC development survival and progression in the tumor microenvironment (TME). The primary approach is to utilize stable isotopic (13C and 15N) nutrient tracers in conjunction with stable isotope-resolved metabolomics (SIRM) and metabolomics-edited transcriptomic analysis (META) to discern key metabolic events in LC cells that govern their behavior and vulnerability in response to major TME factors such as hypoxia and nutrient deficiency. A central focus of this cell-based project is to understand the interaction of nutrient availability and hypoxia in modulating LC cell metabolism and how this may affect its ability to grow survive and progress. This focus is in part motivated by our recent finding from the gene array data of paired cancerous and benign lung tissues resected from human patients regarding the dysregulations of key enzymes (e.g. arginase glutaminase hyaluronan synthase 2) involved in metabolism of glutamine and glucose. It is also driven by our recent discovery of arginase suppression in lung tumor xenograft and activation of Gin metabolism in murine macrophages by a natural immune activator B-glucan. We will accomplish this with the following specific aims: SAI: SIRM profiling of lung cells for reconstructing biochemical pathways involved in utilization of glucose and glutamine. Biochemical pathways of these nutrients relevant to energy anabolism immunomodulatory sensors and cell migration-related extracellular matrix factors will be mapped in LC cells harboring major driver gene anomalies normal epithelial cells and relevant stromal cells for comparison. SA2: Probe interactions of nutrient availability in combination with hypoxia. We will focus on 2 key questions: 1) How does Gin alleviate glucose demand by LC cells?; 2) Is Gin metabolism crucial to hypoxic LC cells?. SAS: Examine Arg metabolism in human tumor-associated macrophages as a function of Gin and Arg availability. Gin and Arg utilization pathways of relevance to immunomodulation in tumor-associated human macrophages will be probed in response to immune activator (B-glucans) and M2 to Ml polarization. The knowledge gained from this project will be used to help interpret data obtained from Projects 2 and 3.

project_terms:
Affect;American;Anabolism;Behavior;Benign;Biochemical;Biochemical Pathway;Biochemistry;Cancerous;Cells;Cessation of life;Clinical;Colon Carcinoma;Data;Development;Early Diagnosis;Enzymes;Epithelial Cells;Event;Extracellular Matrix;Food Interactions;Genes;Glucans;Glucose;Glutaminase;Glutamine;Human;Hypoxia;Immune;Instruction;Killings;Knowledge;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Maps;Medicine;Metabolic;Metabolism;Modification;Mortality Vital Statistics;Mus;Non-Small-Cell Lung Carcinoma;North America;Nutrient;Pathway interactions;Patients;Research;Resected;Stromal Cells;Structure of parenchyma of lung;System;Therapeutic;Tracer;arginase;base;cancer cell;cell motility;hyaluronan synthase 1;immunoregulation;improved;macrophage;malignant breast neoplasm;metabolomics;novel;novel strategies;nutrient metabolism;outcome forecast;response;sensor;stable isotope;transcriptomics;tumor;tumor microenvironment;tumor xenograft


application_id: 8914385
project_number: 5P01CA163223-03
project_title: Systems Biochemistry in Lung Cancer: Toward a Mechanistic Understanding of NSCLC
administering_ic: NCI
award_notice_date: 2015-02-27
opportunity_number: PAR-12-005
application_type: 5
activity_code: P01
ic: CA
serial_number: 163223
program_official: SPALHOLZ, BARBARA A
project_start_date: 2014-08-19
project_end_date: 2018-02-28
study_section: ZCA1-RPRB-0(O1)
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
other_pis: FAN, TERESA WHEI-MEI;YAN, JUN
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Deaths from lung cancer are the highest of all cancers in North America and elsewhere and because of the long incubation time are likely to remain so for the foreseeable future. Furthermore although the 5-year survival rate of stage I lung cancer is 60-70% later stage disease has a very poor prognosis. Accurate detection of asymptomatic early stage lung cancer in individuals at risk is currently unreliable. A better understanding of the basic biochemistry of lung cancers is a prerequisite to mechanism-based reliable early detection of the disease and to improved approaches to treatment. The very complexity of the transformed cells and the variable host-tumor interactions makes the problem refractory to any single approach. A systems biochemistry approach in which lung cancers are studied at the mechanistic level in the laboratory in mouse models and in human subjects offers the opportunity to address the complexity of cancer development and progression. The use of stable isotope resolved metabolomics provides the necessary direct biochemical information about lung cancer with minimal processing that is not otherwise available. This program will address the problem in a 3-pronged approach based on the following integrated projects: Project 1: Cellular Systems Biochemistry. Microenvironmental nutrient availability and immune modulation in lung cancer cells. Project 2; Preclinical Systems Biochemistry. Using SIRM in Human NSCLC xenograft mouse to determine biochemical mechanisms of immunomodulator -glucan.    
Project 3: Translational Systems Biochemistry. Molecular mechanisms of NSCLC and response to -glucan by SIRM. The three projects will use a common mechanistic approach to understanding cancer biochemistry namely stable isotope resolved metabolomics (SIRM) that we have been developing over the last eight years. The analytical requirements will be met in the SIRM Analytical Core which also supplies the necessary sample handling and bioinformatics support for the three projects. Core A provides overall administrative support.

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

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


application_id: 8913358
project_number: 1R01DC014658-01
project_title: Repair of mechano-electrical transduction in mammalian auditory hair cells
administering_ic: NIDCD
award_notice_date: 2015-02-11
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: DC
serial_number: 014658
program_official: FREEMAN, NANCY
project_start_date: 2015-02-15
project_end_date: 2020-01-31
study_section: Auditory System Study Section[AUD]
contact_pi_person_id: 8360158
contact_pi: FROLENKOV, GREGORY I
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Actins;Affect;Auditory;Cells;Data;Deafness;Exposure to;Freezing;Genes;Hair;Hair Cells;Health;Hearing;Human;Immunogold Technics;Individual;Inner Hair Cells;Knock-in Mouse;Labyrinth;Link;Mechanical Stimulation;Mechanics;Microscopy Electron Scanning;Modeling;Molecular;Mus;Mutation;Myosin ATPase;Natural regeneration;Noise;Noise-Induced Hearing Loss;PCDH15 gene;Point Mutation;Predisposition;Probability;Process;Recovery;Regulation;Research;Rest;Role;Sampling;Sensory;Solutions;Stereocilium;Techniques;Time;Transmission Electron Microscopy;extracellular;gamma Actin;hearing impairment;human CDH23 protein;mouse model;nanoscale;novel;overexpression;postnatal;public health medicine (field);repaired;research study;response


application_id: 8913225
project_number: 5P30GM110788-02
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2015-08-05
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110788
study_section: ZGM1-TWD-C
subproject_number: 8147
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-08-01
budget_end_date: 2016-07-31
project_terms:
Administrator;Adoption;Award;Bioinformatics;Centers of Research Excellence;Clinical Sciences;Communities;Dental;Dental Faculty;Dental Students;Education and Outreach;Grant;Health;Health Services Research;Housing;Kentucky;Knowledge;Link;Oral;Oral health;Phase;Play;Population;Research;Research Personnel;Resources;Role;Systemic disease;Technology Transfer;Training and Education;Translational Research;Work;base;design;improved;organizational structure;outreach program;public health medicine (field)


application_id: 8912769
project_number: 2R01HL074185-11
project_title: Reversing diabetic muscle myopathy by exercise and exosomes
administering_ic: NHLBI
award_notice_date: 2015-03-09
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: HL
serial_number: 074185
program_official: SCHWARTZ, LISA
project_start_date: 2003-09-05
project_end_date: 2019-01-31
study_section: Special Emphasis Panel[ZRG1 MOSS-C (02)]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
3' Untranslated Regions;Acetylcholine;Adult;Adverse effects;Binding (Molecular Function);Blood capillaries;Cardiac;Cardiomyopathies;Chimeric Proteins;Clinical Trials;Collagen;Complications of Diabetes Mellitus;Connexin 43;Connexins;Consumption;Coupling;Cytochromes;Cytosol;Diabetes Mellitus;Electron Microscopy;Endothelium;Exercise;Extravasation;FVB Mouse;Fibrosis;Funding;Gelatinase B;Goals;In Situ Hybridization;Label;Laboratories;Matrix Metalloproteinases;Measures;Mediating;MicroRNAs;Mitochondria;Mitochondrial Matrix;Mus;Muscle;Muscle Cells;Myocardial Infarction;Myopathy;Nitroprusside;PECAM1 gene;Perivascular Fibrosis;Plasma;Preparation;Proteins;Reverse Transcriptase Polymerase Chain Reaction;Role;Swelling;Techniques;Testing;Therapeutic;Tissues;Ultracentrifugation;Untranslated Regions;capillary;connexin 37;diabetic;inhibitor/antagonist;innovation;interstitial;male;nanovesicle;public health relevance;response;treatment strategy


application_id: 8912686
project_number: 1R01ES025515-01
project_title: Oxidative stress Cr(VI) carcinogenesis and prevention
administering_ic: NIEHS
award_notice_date: 2015-04-28
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: ES
serial_number: 025515
program_official: SHAUGHNESSY, DANIEL
project_start_date: 2015-05-01
project_end_date: 2020-01-31
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: ZHANG, ZHUO
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_terms:
2 year old;Adult;Animal Model;Animals;Antioxidants;Apoptosis;Apoptotic;BCL2 gene;Binding (Molecular Function);Breeding;Cell Death;Cells;Chemopreventive Agent;Chronic;Data;Development;Diet;Elements;Environmental Carcinogens;Epidemiologic Studies;Epithelial;Event;Exhibits;Exposure to;Female;Gene Expression;Gene Targeting;Generations;Genes;Life;Literature;Lung;Luteolin;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mediating;Metal exposure;Molecular;Mus;Nutritional;Occupational;Oncogenic;Oxidative Stress;Pathway interactions;Pregnancy;Premalignant;Prevention;Prevention strategy;Promotor (Genetics);Property;Proteins;Reactive Oxygen Species;Resistance;Role;Signal Pathway;Signal Transduction;Source;Staging;Stress;Superoxide Dismutase;Time;Tumor Tissue;Tumorigenicity;Up-Regulation (Physiology);angiogenesis;antioxidant enzyme;cancer cell;carcinogenesis;carcinogenicity;cell transformation;chromium hexavalent ion;combat;drinking water;exposed human population;in vivo;insight;male;malignant state;novel;offspring;pregnant;prevent;public health relevance;tumor;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE:    
NARRATIVE The study will show that luteolin protects Cr(VI) carcinogenesis by activation of inducible Nrf2 in pre-malignant stage to prevent cell transformation and by inactivation of constitutive expression of Nrf2 in later stage to prevent tumorigenesis. The expected results will demonstrate the roles of oxidative stress and Nrf2 in the mechanism of Cr(VI) carcinogenesis and the strategy for prevention.


application_id: 8912681
project_number: 3R01HL106843-03S1
project_title: Regulation of Blood Pressure Circadian Rhythm by Vascular Smooth Muscle BMAL1
administering_ic: NHLBI
award_notice_date: 2014-08-29
opportunity_number: PA-10-067
application_type: 3
activity_code: R01
ic: HL
serial_number: 106843
suffix: S1
program_official: LAPOSKY, AARON D
project_start_date: 2012-05-15
project_end_date: 2016-04-30
study_section: Special Emphasis Panel[ZRG1-VH-B(02)]
contact_pi_person_id: 6625920
contact_pi: GONG, MING C
other_pis: GUO, ZHENHENG
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):  The well-known blood pressure (BP) circadian rhythm is important to human health and BP circadian rhythm disruption in diabetes is emerging as an index for future target organ damage and cardiovascular outcomes. Recent discoveries that clock genes are expressed in all of the tissues examined challenges the dogma that BP circadian rhythm is solely controlled by central pacemaker. However it is completely unknown which specific clock gene(s) in which peripheral tissue(s) are important for BP circadian rhythm. We have generated a novel smooth muscle specific clock gene BMAL1 knockout mice SM-bmal1-/- to investigate the role of vascular smooth muscle in BP circadian rhythm under physiological and diabetic conditions. We found that vascular smooth muscle BMAL1 is essential for normal BP circadian rhythm as well as normal vascular smooth muscle contractile circadian variation. Moreover our preliminary study implicates rho kinase ROCK2 links BMAL1 to contraction. Importantly we found that in type 2 diabetic db/db mice loss of BMAL1 protein and activity circadian oscillations is associated with loss of vascular smooth muscle circadian variation and BP circadian rhythm. Thus we hypothesize that BMAL1 regulates ROCK2 thus controlling vascular smooth muscle contractile circadian variation thereby significantly contributing to normal BP circadian rhythm and its disruption in diabetes. We propose to use in vitro and in vivo approaches to test the hypothesis in three specific aims: 1) test the hypothesis that under physiological conditions BMAL1 regulates the vascular smooth muscle contractile circadian variation and BP circadian rhythm via ROCK2. 2) Test the hypothesis that under diabetic conditions BMAL1 is required for disruptions in vascular smooth muscle contractile circadian variation. 3) Determine the role of vascular smooth muscle BMAL1 in diabetes-associated disruption of BP circadian rhythm. Results from the proposed studies may modify the dogma that central pacemaker is solely responsible for the physiological BP circadian rhythm by providing the first direct experimental evidence that peripheral vascular smooth muscle BMAL1 play an important role. Moreover our results may identify vascular smooth muscle BMAL1 as a potential therapeutic target for control of 24-h BP in diabetic patients by providing evidence thatBMAL1 is a significant contributor linking diabetes to disruptions of BP circadian rhythm.

project_terms:
Affect;Animals;BMAL1 protein;Blood Pressure;Blood Vessels;Cardiovascular system;Circadian Rhythms;Conscious;Data;Diabetes Mellitus;Diabetic mouse;Event;Exhibits;Future;Genes;Goals;Health;Human;In Situ;In Vitro;Knockout Mice;Life;Link;Mediating;Mesenteric Arteries;Molecular;Motor Activity;Mus;Muscle Contraction;Muscle Smooth Vascular;Organ;Outcome;Pacemakers;Pathway interactions;Peripheral;Phenylephrine;Physiological;Physiology;Play;Radial;Regulation;Rho-associated kinase;Role;Smooth muscle (tissue);Streptozocin;Testing;Time;Tissues;Variant;blood pressure regulation;db/db mouse;diabetic;diabetic patient;in vivo;indexing;novel;response;suprachiasmatic nucleus;therapeutic target;transcription factor;type I diabetic

public_health_relevance:
The well-known blood pressure (BP) circadian rhythm is important for human health and the disruption of BP circadian rhythm in diabetes is emerging as an index of future target organ damage and cardiovascular outcomes. However molecular mechanisms linking diabetes with disruption in BP circadian rhythm are unknown. The goals of this application are to elucidate the molecular mechanisms responsible for normal BP circadian rhythm and its disruptions in diabetes.


application_id: 8912277
project_number: 5F31DE022679-04
project_title: MicroRNAs and Parotid Acinar Cell Differentiation
administering_ic: NIDCR
award_notice_date: 2015-07-01
opportunity_number: PA-11-111
application_type: 5
activity_code: F31
ic: DE
serial_number: 022679
program_official: FRIEDEN, LESLIE A
project_start_date: 2012-09-01
project_end_date: 2016-08-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 11005944
contact_pi: METZLER, MELISSA A
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long term goal of this fellowship project is to be able to provide clinical intervention to patients suffering from salivary gland loss of function. Parotid gland dysfunction affects millions of people across the nation and stems from several causes. Sjogren's syndrome (which affects 2 - 4 million Americans) for instance results in hypofuction of the gland. Also radiation damage severely affects the parotid gland and is common among patients receiving treatment for head and neck carcinomas. Loss of function in patients results in chronic xerostomia. This leads to a reduction in quality of life for these patients as well as a reduction in overall oral health as the incidence of dental caries and periodontal disease increases. The ability to regenerate or restore function to damaged parotid glands would greatly increase patient health and quality of life. This requires further knowledge of how the gland develops and differentiates into its different cell types. Defining the molecular mechanisms of parotid differentiation is a significant goal. Specifically the parotid acinar cellsare responsible for producing and secreting the salivary proteins amylase parotid secretory protein (PSP) and others in response to parasympathetic nerve stimulation. Parotid salivary proteins contribute to defense against bacteria and yeast and initiation of digestion. These cells are highly specialized; however the terminal differentiation of this cell type is poorly understoo. Within the last decade the importance of microRNAs on the process of development and differentiation has been identified in many cell types. This suggests that microRNAs are a common mechanism used by the cell to control differentiation. However the role of microRNAs in acinar terminal differentiation has yet to be explored. It remains to be investigated if microRNA levels correlate with acinar differentiation in vivo and which microRNAs are important. This project addresses the hypothesis that microRNA expression drives gene networks that are important for parotid acinar differentiation through two separate aims. Aim one is to determine if microRNAs are differentially expressed during parotid acinar differentiation in vivo and as compared to undifferentiated acinar cells. And to identify potential microRNA target genes and networks. MicroRNA (and well as mRNA) levels will be measured throughout the course of parotid acinar differentiation in the rat with the goal of using bioinformatics techniques to identify potentially biologically relevant miRNA:mRNA interactions and gene regulatory networks. Aim 2 will experimentally test the function of the predicted interactions by determining if microRNAs drive expression of differentiation associated gene networks in parotid acinar cells. This project contributes to the long term goal of understanding salivary gland biology to the point that clinical interventions can be developed to regenerate or restore glands to those patients suffering from parotid hypofunction.

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

public_health_relevance:
The long term goal of this fellowship project is to be able to provide clinical intervention to patients suffering from salivary gland loss of function. The abiliy to regenerate or restore function to damaged parotid glands would greatly increase patient health and quality of life. This requires further knowledge of how the gland develops and differentiates into its different cell types. Defining the molecular mechanisms of parotid differentiation is the goal of this proposal.


application_id: 8912218
project_number: 1R01NS089324-01A1
project_title: Functional consequences of silencing propriospinal pathways after SCI in the adult rat
administering_ic: NINDS
award_notice_date: 2015-01-20
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: NS
serial_number: 089324
suffix: A1
program_official: JAKEMAN, LYN B
project_start_date: 2015-02-01
project_end_date: 2020-01-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 1932676
contact_pi: MAGNUSON, DAVID SK
other_pis: WHITTEMORE, SCOTT R
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
project_terms:
Address;Adult;Animals;Behavior;Behavioral;Beryllium;Bilateral;Cervical;Contusions;Data;Development;Dissection;Doxycycline;Excision;Forelimb;Gait;Grant;Hindlimb;Histology;Injury;Interneurons;Locomotion;Locomotor Recovery;Lumbar Regions;Molecular;Motor Activity;Movement;Neural Pathways;Neurons;Neurotransmitters;Outcome;Pathway interactions;Phenotype;Physiological;Play;Population;Presynaptic Terminals;Process;Rattus;Recovery;Recovery of Function;Role;Severities;Spinal;Spinal Cord;Spinal cord injury;Subfamily lentivirinae;Synaptic Transmission;System;Testing;Tetracycline Control;Time;Virus;Walking;Weight-Bearing state;Work;arm;cell body (neuron);central pattern generator;drinking water;insight;kinematics;limb movement;neural circuit;neurotransmission;neurotropic;novel;public health relevance;research study;tool;vector;white matter


application_id: 8911843
project_number: 5R01GM104123-03
project_title: Functional analysis of programmed genome rearrangement
administering_ic: NIGMS
award_notice_date: 2015-08-27
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: GM
serial_number: 104123
program_official: CARTER, ANTHONY D
project_start_date: 2013-09-01
project_end_date: 2016-08-31
study_section: Genetic Variation and Evolution Study Section[GVE]
contact_pi_person_id: 9381521
contact_pi: SMITH, JERAMIAH JAMES
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):    This proposal stems from our recent discovery that the sea lamprey (unlike other vertebrates) undergoes large- scale genome rearrangements during the normal course of its embryonic development. Programmed genome rearrangement (PGR) results in the highly reproducible elimination of ~20% of the lamprey's genome during the establishment of somatic cell lineages in the early embryo. Recent work has revealed that: 1) hundreds of gene-coding fragments are eliminated 2) human homologs of lost genes generally possess "pluripotency" functions 3) computational analysis of "next-gen" sequence datasets identify predicted recombination sites that mediate deletion events which have been validated experimentally indicating that PGR is mediated in part by recombination and 4) proteins expressed in the early embryo show sequence-specific binding to validated recombination sites. With the advent of extensive sequence resources for lamprey and methods for gene knockdown and transcript replacement lamprey will continue to provide unique insights into the rearrangement biology of vertebrate genomes and the genetics of somatic vs. germline cell fate. As such this research is broadly relevant to NIGMS research programs in genetics and developmental biology particularly towards understanding the biology of genomes chromosomes and epigenetics vertebrate developmental genetics stem cell biology genetic mechanisms of DNA recombination/repair and oncogenesis. The specific aims of this proposal will seek to further characterize lamprey PGR at the genetic level in order to deduce its molecular mechanisms and use this information to guide functional studies of the biological causes and consequences of genome rearrangement. Specific Aim 1 will allow us to further refine our functional models of PGR by developing a meiotic map for the lamprey genome and integrating this with existing somatic and germline genome assemblies. Analyses of this map will shed critical light on the scale distribution biological function and likely mechanisms of deletion. Specific Aim 2 dissects the biological function of genes that are deleted through PGR. Experiments performed under this aim will use morpholino mediated gene knockdowns and transcript replacement to elucidate the function of somatically deleted genes and their human homologs. Specific Aim 3 identifies genes that mediate PGR and characterizes their molecular function. Experiments performed under this aim will use morpholino-mediated knockdown to elucidate the function of genes that bind recombination sites during PGR then use transcript replacement to test whether human homologs can partly or completely replace these functions. This will provide a direct assay for the capacity of identified human homologs to participate in somatic recombination. Critically these approaches do not rely on pre-existing knowledge regarding the function of human genes and therefore hold great potential for the discovery of new gene functions. These studies are expected to provide unique insight into vertebrate genome biology and yield information that might not be achievable outside of the context of PGR.

project_terms:
Binding (Molecular Function);Biological;Biological Assay;Biological Process;Biology;Candidate Disease Gene;Cell Death;Cell Lineage;Cell Proliferation;Cells;Chromosomes;Code;Computer Analysis;Control Animal;DNA;Data;Data Set;Development;Developmental Biology;Disease;Embryo;Embryonic Development;Epigenetic Process;Event;Fertility;Fertilization in Vitro;Gene Deletion;Genes;Genetic;Genetic Polymorphism;Genetic Recombination;Genome;Genome Stability;Genomics;Health;Homologous Gene;Human;Human Genome;Individual;Knowledge;Lampreys;Light;Maintenance;Maps;Mass Spectrum Analysis;Measures;Mediating;Meiosis;Methods;Modeling;Molecular;National Institute of General Medical Sciences;Outcome;Pattern;Petromyzon marinus;Play;Population;Promotor (Genetics);Property;Protein Binding;Proteins;Regulation;Research;Resistance;Resolution;Resources;Role;Site;Somatic Cell;Specificity;Staging;Study models;Testing;Transcript;Vertebrates;Work;analog;base;comparative;design;developmental genetics;gene function;genome sequencing;genome-wide;germline stem cells;insight;next generation sequencing;novel;pleiotropism;pluripotency;programs;recombinational repair;research study;scaffold;stem;stem cell biology;tumorigenesis;vertebrate genome

public_health_relevance:
PUBLIC HEALTH RELEVANCE:    Programmed rearrangement of the lamprey genome provides a highly reproducible model for studying the causes and consequences of genome rearrangement especially as it relates to the biology of germline stem cells. Proposed research will use the lamprey as a model for studying 1) the genetic consequences of programmed gene deletions 2) the molecular basis of rearrangement and 3) the capacity of specific human genes to mediate rearrangement. This work will shed new light on the molecular basis of genome stability/instability and fundamental molecular properties of germline stem cells focusing on genes with human homologs.             __SpecificAimsTextDelimiter__ SPECIFIC AIMSThis proposal stems from our recent discovery that the sea lamprey (Petromyzon marinus) undergoesdevelopmentally programmed genome rearrangements (PGRs). These rearrangements result in the loss of~20% of the germline genome during the establishment of somatic cell lineages in the early embryo. Excisedregions include hundreds of genes and other single-copy DNAs many of which have vertebrate homologs thatcontribute to germline pluripotency (or oncogenesis if misexpressed). The discovery of PGR in lamprey (avertebrate) therefore fills an important gap in our understanding of dysregulated rearrangement of vertebrategenomes that are often associated with disease vs. the capacity for tight regulation of genome rearrangementthat is known for a few diverse metazoan and protist lineages. The specific aims of this proposal will seek tofurther characterize lamprey PGR at the genetic level in order to deduce its molecular mechanisms and usethis information to aid in the development of functional studies that will dissect the biological causes andconsequences of genome rearrangement. Functional studies will focus on resolving the developmental(maintenance of pluripotency / regulation of somatic pleiotropy) and recombinational functions of PGR both ofwhich are highly relevant toward understanding the biology of the human genome. Functional studies ofrecombination will aim to discover and characterize human genes that mediate recombination.Specific Aim 1) Define chromosome-scale patterns of gene loss: The current lamprey genome assemblyprovides kilobase to megabase resolution of somatic genome sequences sufficient to identify genespromotors and local gene syntenies (preliminary studies). Our preliminary studies indicate that deletion eventsinvolve segments of DNA that may exceed the upper end of this range. In order to understand the true scale ofindividual deletion events and refine our functional models of deletion we will generate long-range linkageinformation for lamprey via recombinational mapping. Mapping information will be rapidly generated using asite-anchored (RAD-tag) sequencing approach that leverages the high fecundity of lampreys the abundance ofsegregating polymorphisms in natural populations of sea lampreys and ease of performing controlled crossesvia in vitro fertilization. This information will be used to 1) scaffold the germline assembly to form chromosome-scale ultrascaffolds 2) identify broad-scale regions that differ between germline and somatic genomes and 3)define transitions (breakpoints) between deleted and retained sequence. This information will facilitate studiescarried out under Specific Aims 2 and 3 and will provide invaluable information for comparative genetic andgenomic studies that use lamprey for its unique evolutionary perspective.Specific Aim 2) Characterize the biological effects of gene loss: We will use the genomic data alreadycollected through our preliminary studies and supplemented by Specific Aim 1 to dissect the biological effectsof gene loss (a major outcome of PGR). Genes that are lost from somatic cell lineages during PGR will beanalyzed using morpholino (MO)-mediated knockdown in lamprey embryos and will therefore focus particularlyon genes that are expressed during lamprey embryonic development. We will also perform rescue experimentswith synthetic analogs of lamprey transcripts and their human homologs to confirm the specificity ofknockdowns and test for functional equivalence of lamprey and human homologs. These experiments will beused to elucidate both the function of somatically deleted genes in the developing germline and the effects oftheir somatic misexpression. Preliminary studies have led to the hypothesis that many of these genes areimportant for regulating cell proliferation and the maintenance of pluripotency. We will generate phenotypicinformation for MO-treated rescue and control animals using markers for cell death proliferation and cell fatein order to test this hypothesis and elucidate the function of PGR-eliminated genes and their human homologs.Specific Aim 3) Characterize the molecular underpinnings of gene loss: Our validated backgroundstudies indicate that site-specific recombination plays a role in PGR. Under this aim we will isolate the proteinsthat mediate PGR and functionally characterize human gene homologs in the context of PGR. Probesdesigned from experimentally validated sites of recombination will be used to isolate the proteins that bindthese sequences during the embryonic stages in which PGR occurs (Specific Aim 3.1). Isolated proteins will becharacterized by mass spectrometry in order to further develop a panel of candidate genes that arehypothesized to contribute to PGR. These candidate genes will be then be targeted for morpholino-mediatedknockdown (Specific Aim 3.2). As morpholinos will be designed to inhibit PGR machinery the effects of theseknockdowns will be measured using molecular assays for several PGR events. For lamprey genes that areidentified as contributing to recombination we will attempt to rescue experiments with morpholino-resistantlamprey transcripts and their human homologs which will provide a direct assay for the capacity of identifiedhuman genes to participate in somatic recombination. Critically this approach does not rely on pre-existingknowledge regarding the function of human genes and therefore holds great potential for the discovery of novelgene functions. Such assays will provide unique insight into the biological function of human genes andprovide functional information that might not be achievable outside of the context of PGR.


application_id: 8911751
project_number: 5R21AG046762-02
project_title: Vitamin D Contribution to Muscle Metabolic Function in the Elderly
administering_ic: NIA
award_notice_date: 2015-05-11
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: AG
serial_number: 046762
program_official: JOSEPH, LYNDON
project_start_date: 2014-08-15
project_end_date: 2018-05-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 10544123
contact_pi: THOMAS, DAVID TRAVIS
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: ORGANIZED RESEARCH UNITS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Metabolic dysfunction is a major contributor to age-related co-morbidities; however the mechanisms underlying muscle metabolic dysfunction have not been fully elucidated in the elderly and there is a need to discover complementary interventions that could be easily and inexpensively implemented for treatment. With a novel strategy to address this knowledge gap our objective is to investigate synergy between vitamin D repletion and short-term aerobic training (AT) on lipid repartitioning and local muscle oxygen metabolism in the elderly with the use of non-invasive techniques (magnetic resonance imaging (MRI) and hybrid diffuse optical spectroscopies). We suggest based on growing theoretical rationale that a beneficial relationship exists when vitamin D repletion is accompanied by AT in the elderly. A potentiating relationship will prove to have substantial inexpensive merit for relieving metabolic dysfunction associated with aging. The aims of this study are to 1) Identify the magnitude of lipid redistribution in gastrocnemius muscle following vitamin D repletion + AT compared to vitamin D repletion or AT alone in 65-80 year olds and 2) Quantify local muscle tissue oxygen consumption rate (VO2) using hybrid diffuse optical spectroscopy to elucidate how local muscle tissue metabolism is related to muscle lipid measures. Our central hypothesis is that vitamin D repletion combined with AT will promote a greater shift from EMCL to IMCL depots than either treatment alone and that these changes will correspond to improved oxygen extraction (metabolic function) at the local muscle level. The delineation of the impact of vitaminD repletion combined with AT on maintaining muscle health by altering muscle lipid content using novel and non-invasive techniques has the potential to refine our knowledge of the effect vitamin D and exercise have on muscle biology in aging. The positive impact of this project is consistent with our long-term objectives and are twofold 1) provide the framework to advance our use of non-invasive diffuse optical spectroscopy to efficiently characterize muscle metabolic function and nutrition/exercise treatment response and 2) generate novel data describing the interrelationships between vitamin D exercise muscle lipid and metabolic function in aging muscle.

project_terms:
2 year old;Address;Aerobic;Aerobic Exercise;Affect;Age;Aging;Biological Preservation;Biology;Chronic Disease;Clinical Trials;Combined Modality Therapy;Comorbidity;Coupled;Data;Development;Diffuse;Economic Burden;Elderly;Enrollment;Exercise;Exercise Tolerance;Fatigue;Fatty acid glycerol esters;Functional disorder;Gastrocnemius muscle structure;Goals;Health;Hybrids;Imaging Techniques;Individual;Insulin Resistance;Intervention;Knowledge;Life Style;Link;Lipids;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Measures;Metabolic;Metabolism;Mitochondria;Monitor;Muscle;Muscle function;Nutritional;Optical Instrument;Optics;Oxygen;Oxygen Consumption;Pharmacotherapy;Physical Function;Population;Protocols documentation;Quality of life;Recovery;Reporting;Retrieval;Role;Spectrum Analysis;Techniques;Technology;Tissues;Training;Vitamin D;Work;age related;aged;base;body physical activity;combat;design;improved;instrumentation;insulin sensitivity;lipid metabolism;mitochondrial dysfunction;muscle aging;muscle metabolism;non-invasive imaging;novel;novel strategies;nutrition;nutritional guideline;oxidation;post intervention;response;sedentary;tissue oxygenation;tool;treatment response

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Despite drug therapy many aged individuals with chronic disease associated with metabolic dysfunction remain symptomatic leading to poor quality of life and significant economic burden. This proposed study is aimed at 1) investigating synergy between vitamin D repletion and moderate aerobic training to potentiate improvements in muscle metabolic function and 2) the development of a portable assessment tool capable of identifying the most effective combined nutrition-exercise intervention in aged individuals to combat metabolic dysfunction. The knowledge to be gained by advancing the utility of our assessment tool in elderly who suffer from metabolic decline is invaluable and will pave the way for inexpensive non-invasive future research.


application_id: 8911617
project_number: 2R13GM058252-16A1
project_title: Interactive Learning Modules for Writing Grant Proposals
administering_ic: NIGMS
award_notice_date: 2015-08-14
opportunity_number: PA-13-347
application_type: 2
activity_code: R13
ic: GM
serial_number: 058252
suffix: A1
program_official: SESMA, MICHAEL A
project_start_date: 1998-09-01
project_end_date: 2017-08-31
study_section: Training and Workforce Development Study Section - D[TWD-D]
contact_pi_person_id: 8535385
contact_pi: FRAZIER, DONALD T
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): The climate surrounding federal funding for biomedical research has become increasingly competitive lending considerable importance to the development of grantsmanship skills by higher education faculty as a whole and by faculty from underrepresented groups in particular. The proposed conference series Interactive Learning Modules for Writing Grant Proposals offers a highly focused program of grant-writing training that directly addresses issues of diversity in biomedical research through an active participatory training sequence resource modules and post-workshop mentored support. The overall objectives are to empower faculty at institutions with a significant enrollment of underrepresented minorities to develop and submit competitive research proposals and to build capacity at minority-serving institutions to support those efforts. The original goal of our trainig partnership with NIGMS was to translate an innovative proven grant-writing workshop into an interactive hypermedia course on the internet for wide dispersal to eligible faculty and research support staff. That project concept evolved into a highly effective model of direct workshop training on proposal development that was supported by the online course modules. We now propose a new model that engages trainers and participants in direct proposal development activities through guided writing and mentored support. Building on our past experience with faculty research administrators and students the competing renewal has the following specific aims: 1) develop and host active-learning style grant-writing retreats for selected faculty poised to submit proposals ranging from developmental and exploratory research awards to R01s; 2) update the internet course modules as a resource to facilitate active post-workshop learning by incorporating new media content developed using the Echo360 active learning technology platform; 3) provide a pipeline to the writing retreat by conducting off-site regional faculty workshops to motivate mentor and engage prospective faculty in pursuing competitive extramural funding opportunities; and 4) assist faculty workshop participants through invited site visits focused on institution-specific proposal development and submission issues. Through our ongoing scientific and administrative mentoring (via video and/ or teleconferencing and webinars) we will sustain a relationship with our participants well beyond the workshops and internet course. We anticipate that the proposed workshop series will motivate participants and improve the grant-seeking skills and abilities of researchers from institutions that serve significant numbers of underrepresented groups increase the number of scientists from these groups engaged in biomedical research and thereby strengthen the overall research environment at participating campuses.

project_terms:
Active Learning;Address;Administrator;Applications Grants;Attention;Award;Behavior;Behavioral Research;Biomedical Research;Climate;Consult;Consultations;Development;Dimensions;Discipline;Educational aspects;Educational workshop;Elements;Enrollment;Environment;Event;Extramural Activities;Faculty;Faculty Workshop;Funding;Funding Opportunities;Goals;Grant;Health;Hypermedia;Institution;Internet;Kentucky;Learning;Learning Module;Mentors;Minority;Minority-Serving Institution;Mission;Modeling;National Institute of General Medical Sciences;Participant;Personal Satisfaction;Persons;Principal Investigator;Process;Research;Research Personnel;Research Project Grants;Research Proposals;Research Support;Research Training;Resources;Rest;Scientist;Series;Site;Site Visit;Specialist;Students;Technology;Teleconferences;Training;Translating;Underrepresented Minority;United States National Institutes of Health;Universities;Update;Writing;base;career;design;empowered;experience;graduate student;improved;innovation;programs;prospective;public health relevance;research and development;skills;symposium;tool;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  A diverse workforce in biomedical and behavioral research is essential for exploring socially and culturally sensitive health-related issues concerning underrepresented populations. Our proposed program is designed to motivate and improve the competitiveness of researchers/grant writers at minority institutions and thereby have a substantial impact on the well-being of our citizens.


application_id: 8911456
project_number: 1F31CA196219-01
project_title: Erbin-mediated regulation of colon cancer progression
administering_ic: NCI
award_notice_date: 2015-03-03
opportunity_number: PA-14-147
application_type: 1
activity_code: F31
ic: CA
serial_number: 196219
program_official: SCHMIDT, MICHAEL K
project_start_date: 2015-03-03
project_end_date: 2018-03-02
study_section: Special Emphasis Panel[ZRG1 F09B-B (20)]
contact_pi_person_id: 12351385
contact_pi: STEVENS, PAYTON D
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Approximately 136000 new cases and 50310 deaths are predicted for the year 2014; this mortality is predominantly due to metastasis to other organs. If advances are to be made in the survival of colorectal cancer patients a better understanding of the molecular mechanisms involved in CRC metastasis is required. In this proposed study I plan to investigate the role of Erbin a basolateral-localized scaffolding protei in inhibiting CRC invasion and metastasis. This proposal centers on a novel discovery that Erbin plays an important role in suppressing epithelial-mesenchymal transition (EMT) of CRC cells by controlling cell polarity. The proper establishment of epithelial polarity allows cells to sense an respond to signals that arise from the microenvironment in a spatiotemporally controlled manner. Increasing evidence has suggested that disruption of this cellular polarity promotes the malignant progression of cancer cells. However the molecular mechanism underlying polarity regulation in the initiation and progression of CRC remains largely unknown. In my preliminary experiments I have found that knockdown of Erbin induces an EMT-like phenotype and promotes migration in CRC cells. In addition silencing Erbin resulted in the disruption of cell polarity in 3D cultures mislocalization of EGF receptors (EGFRs) and an increase in the activation of EGFR signaling. To begin to elucidate the underlying molecular mechanism we identified PHLPP a novel tumor suppressor in CRC as an interacting protein of Erbin. Interestingly loss of Erbin expression resulted in an increase in both Akt and ERK activation similar to that observed in PHLPP knockdown cells. I hypothesize that Erbin serves as a scaffolding protein bringing PHLPP in close proximity with its substrates. This interaction between PHLPP and Erbin could provide the spatial-temporal control necessary to suppress oncogenic Akt and RAS/RAF signaling. Furthermore the analysis of Erbin mRNA expression in two large sets of CRC patient samples revealed that Erbin is significantly down regulated in cancer specimens compared to normal controls thus supporting the role of Erbin as a tumor suppressor in CRC. In light of our preliminary findings the central hypothesis driving this proposal is that Erbin plays a critical role in inhibiting CRC metastasis and it functions by maintaining cell polarity to inhibit Akt- and RAS/RAF-mediated oncogenic signaling. The following specific aims are proposed: 1) to define the functional effects of Erbin in inhibiting CR invasion and metastasis. We will elucidate the molecular mechanism by which loss of Erbin promotes CRC invasion and metastasis both in vitro and in vivo; 2) to determine the role of Erbin in regulating PHLPP-dependent inhibition of Akt and RAS/RAF pathways. Defining the role of Erbin in tumor metastasis will have sustained impact on improving CRC patient care. Working on this project I will not only gain more research experience but also master the problem solving and communication skills needed to fulfill my career goals.

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

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


application_id: 8911346
project_number: 5P20GM103527-08
project_title: Role of Adipose Tissue TGF-b signaling on Adipose Dysfunction in Obesity
administering_ic: NIGMS
award_notice_date: 2015-09-01
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103527
project_start_date: 2015-08-01
project_end_date: 2016-07-31
study_section: ZGM1-TWD-Y
subproject_number: 5043
contact_pi_person_id: 12406059
contact_pi: HANAOKA, BEATRIZ
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:
Obesity is associated with adipose dysfunction which contributes to insulin resistance diabetes and heart disease. It has been proposed that adipose dysfunction is caused by an inappropriate response to hypoxia that results in increased ECM expression and reduced angiogenesis. Our data indicate that adipocytemacrophage crosstalk results in increased expression of thrombospondin-1 (TSP-1) a multifunctional protein that promotes fibrosis by activating TGF-beta signaling. TGF-beta has multiple effects on adipose in addition to inducing fibrosis including inhibiting adipogenesis and complicated effects on angiogenesis. Recently a whole-body knockout of SMAD3 to block TGF-beta signaling resulted in mice with improved metabolic function and browning of their white adipose; this was due in part to reversing the inhibition of TGF-beta on the expression of PGC-1 alpha. Our overall hypothesis is that increased TSP-1 expression and TGF-beta signaling in white adipose with obesity cause increased fibrosis reduced capillary density reduced PGC-1 alpha and reduced UCP-1 expression hence less "browning" and impaired WAT function. Thus inhibiting the TGF-beta pathway in humans may improve adipose function and reverse the effects of obesity on insulin resistance. The first aim will characterize the white adipose ECM and capillary density of TSP-1 knockout mice and their littermate controls challenged with a high fat diet. The second aim will knockout TGF-beta in adipose using cre/lox technology to elucidate the role of TGF-beta signaling on adipose function is response to high fat feeding. The third aim will determine whether the dramatic reduction in adipocyte PGC-1 alpha by macrophage coculture is TGF-beta dependent. The fourth aim will determine whether toll-like receptor (TLR) signaling is involved in the adipocyte-macrophage crosstalk that induces TSP-1 and TGF-beta signaling in macrophages. Thus the two mouse models will indicate the contribution of TSP-1 and TGF- beta to adipose dysfunction with obesity. The coculture studies will begin to define the mechanisms by which adipocytes and macrophages communicate with each other to induce TSP-1 expression by both cells types and to decrease PGC-1 alpha expression in adipocytes.

project_terms:
Adipocytes;Adipose tissue;Blood capillaries;Brown Fat;Cardiovascular Diseases;Coculture Techniques;Complex;Data;Diabetes Mellitus;Diet;Docosahexaenoic Acids;Euglycemic Clamping;Extracellular Matrix;Fatty acid glycerol esters;Fibrosis;Fish Oils;Functional disorder;Gene Expression;Glucose Clamp;Heart Diseases;Human;Hypoxia;Immune;Insulin Resistance;Interleukin-10;Knock-out;Knockout Mice;MADH3 gene;Measures;Mediating;Metabolic;Methods;Mus;Obesity;Pathway interactions;Process;Proteins;Receptor Signaling;Research;Role;Signal Transduction;Small Interfering RNA;TLR2 gene;TLR4 gene;Technology;Testing;Thrombospondin 1;Toll-like receptors;Transforming Growth Factor beta;angiogenesis;capillary;cell type;combat;density;feeding;glucose tolerance;improved;inhibitor/antagonist;insulin tolerance;lipid biosynthesis;macrophage;mouse model;receptor;response

public_health_relevance:
Adipose tissue becomes dysfunctional with obesity by a complex process. We hypothesize that TGF-beta signaling contributes to this by promoting adiopose fibrosis and by inhibiting the ability of adipose to metabolize fat; inhibiting TGF-beta signaling may be an effective method to combat obesity.


application_id: 8911345
project_number: 5P20GM103527-08
project_title: Role of bioactive lipids in the protective pathways of obesity in ischemic cardi
administering_ic: NIGMS
award_notice_date: 2015-09-01
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103527
project_end_date: 2016-07-31
study_section: ZGM1-TWD-Y
subproject_number: 5042
contact_pi_person_id: 11330155
contact_pi: ABDEL LATIF, AHMED
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: 2015-08-01
project_abstract:
Obesity is approaching epidemic state in the western worid and is a known risk factor for acute myocardial infarction (AMI). AMI and the subsequent ischemic heart disease (IHD) are often complicated with high mortality and poor overall prognosis despite significant advances in medical therapy and revascularization strategies. Currently short of heart transplantation with all of its inherit limitations there are no available treatment strategies that replace the infracted myocardium and therapies are largely palliative. Paradoxically obesity may also confer a protective effect against AMI-associated remodeling which leads to IHD. The molecular kiasis for this protection is poorly understood. AMI initiates poorly understood innate reparatory mechanisms through which BMSPCs are mobilized and home towards the ischemic myocardium contributing to myocardial regeneration and correlating with cardiac recovery. Our preliminary data indicates that bioactive lipids such as sphingosine-1 phosphate (SIP) but not traditional chemokines play a quintessential role in this mobilization and homing. Interestingly obesity and the associated metabolic syndrome are associated with alterations in bioactive lipids' metabolism. Our objective in this application therefore is to develop better understanding ofthe obesity-associated alterations in AMI-induced stem cell mobilization pathways specially those involving bioactive lipids and devise therapies that hamess this process for therapeutic myocardial regeneration strategies. Our central hypothesis has been formulated based upon the existing literature and our strong preliminary data demonstrating that BMSPCs express SIP receptors and will migrate towards plasma from AMI patients in an SI P dependent fashion. Our rationale for these studies is that understanding the protective role of bioactive lipids and stem cell mobilization during AMI in obesity would help establish a strong scientific framework for eventual generalizable human myocardial regenerative clinical trials utilizing the available and new pharmacological modulators of bioactive lipids and their receptors. In addition to clinical studies our approach will exploit small molecule-strategies in mouse models through examining the obesity associated molecular and cellular pathways specially those involving bioactive lipids that are activated by myocardial infarction (Aim 1); and examine the modulation of bioactive lipids' metabolism and receptor expression to enhance cardiac recovery following AMI (Aim 2).

project_terms:
Acute myocardial infarction;Adipose tissue;Bone Marrow;Cardiac;Cardiac Myocytes;Cardiovascular Diseases;Clinical Research;Clinical Trials;Data;Development;Diet;Epidemic;Exhibits;Goals;Heart;Heart Transplantation;Hematopoietic Stem Cell Mobilization;Hematopoietic stem cells;Home environment;Homing;Human;Individual;Inherited;Injury;Laboratories;Lipids;Literature;Longevity;Medical;Metabolic syndrome;Molecular;Mortality Vital Statistics;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Natural regeneration;Obesity;Overweight;Pathway interactions;Patients;Pharmacologic Substance;Plasma;Play;Population;Positioning Attribute;Process;Recovery;Research;Review Literature;Risk;Risk Factors;Role;Signal Pathway;Signal Transduction;Sphingosine-1-Phosphate Receptor;Staging;Stem cells;System;Therapeutic;Western World;Work;base;chemokine;expectation;improved;lipid mediator;lipid metabolism;mouse model;outcome forecast;palliative;peripheral blood;protective effect;receptor;receptor expression;regenerative;regenerative therapy;response;small molecule;sphingosine 1-phosphate;stem;treatment strategy

public_health_relevance:
Obesity increases the risk for acute myocardial infarction but may paradoxically exert protective effect from the subsequent cardiac remodeling. Our objective is to develop better understanding of obesity-associated alterations in myocardial infarction-induced stem cell mobilization pathways specially those involving bioactive lipids and devise therapies that'harness this process for myocardial regeneration strategies.


application_id: 8911343
project_number: 5P20GM103527-08
project_title: Role of lipinl in skeletal muscle mitochondrial homeostasis and oxidative energy
administering_ic: NIGMS
award_notice_date: 2015-09-01
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103527
project_start_date: 2015-08-01
project_end_date: 2016-07-31
study_section: ZGM1-TWD-Y
subproject_number: 5041
contact_pi_person_id: 10792635
contact_pi: SUBRAMANIAN, VENKATESWARAN
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:
Body weight is determined by the balance between energy input and expenditure. Skeletal muscle is major site of mitochondrial oxidative metabolism of fatty acids and glucose and thereby plays a central role in whole body energy expenditure. Accordingly preservation or promotion of skeletal muscle metabolism could play a critical role in protection from diet induced obesity. Understanding the mechanisms that regulate skeletal muscle metabolism and their relationship to those controlling fatty storage and mobilization is therefore a critical goal in metabolic disease research. Lipinl is a phosphatidic acid (PA) phosphatase enzyme that catalyzes the penultimate step in triglyceride synthesis at the cytoplasmic surface of the endoplasmic reticulum and also serves as a nuclear transcriptional co-activator of PPAR-a responsive genes. Lipinl deficient mice (fatty liver dystrophy mice fid mice) exhibit impaired adipocyte differentiation circulating hyperlipidemia and neonatal hepatic steatosis associated with diminished rates of hepatic fatty acid oxidation. Lipinl is also expressed in skeletal muscle and transgenic overexpression of lipinl in this tissue reverses many ofthe phenotypes of lipinl deficient fid mice. Interestingly humans with heritable lipinl null mutations present with severe rhabdomyolysis (skeletal muscle degeneration) characterized by impaired carnitine palmitoyi acyltransferase (CPT) activity decreased mitochondrial fatty oxidation and respiratory chain function and the consequent destruction of skeletal muscle fibers. We made the seminal observation that lipinl is recruited to the mitochondrial surface where it promotes mitochondrial fission and remodels mitochondrial lipids suggesting that lipinl deficiency impacts directly on mitochondrial function. Based on these observations we propose that lipinl is poised to function as a link between fatty acid and carbohydrate metabolism in muscle and fat. Accordingly we hypothesize that recruitment of lipinl to mitochondria directly promotes mitochondrial respiratory function and beta-oxidation through effects on mitochondrial homeostasis and lipid composition and that this is particularly important for skeletal muscle function in energy metabolism. In direct support of our hypothesis we found mitochondrial respiratory function is impaired in lipinl deficient mouse embryo fibroblasts and mitochondria isolated from skeletal muscle of lipinl deficient rnice. The broad goal of this research is to define the role of Lipinl in mitochondrial function and skeletal muscle physiology. Aim 1 defines the role of muscle cell lipinl PA phosphatase activity in regulating mitochondrial lipid composition and function while Aim 2 examines deletion of skeletal muscle lipinl in lean and obese mice.

project_terms:
Activator Appliances;Acyltransferase;Adipose tissue;Alleles;Animals;Biological Preservation;Blood Pressure;Body Weight;Cardiovascular Diseases;Carnitine;Cell Culture System;Cell Respiration;Cells;Consumption;Defect;Diabetes Mellitus;Diet;Down-Regulation;Embryo;Endoplasmic Reticulum;Energy Metabolism;Enzymes;Equilibrium;Exhibits;Expenditure;Fatty Acids;Fatty Liver;Fatty acid glycerol esters;Fibroblasts;Gene Expression;Genes;Genetic Polymorphism;Glucose;Goals;Hepatic;Homeostasis;Human;Hyperlipidemia;In Vitro;Individual;Link;Lipids;Messenger RNA;Metabolic;Metabolic Diseases;Metabolism;Mitochondria;Morphology;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscle Weakness;Muscle function;Mutation;Myoblasts;Neonatal;Neuropathy;Nuclear;Obese Mice;Obesity;Oxidative Phosphorylation;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Phenotype;Phosphatidate Phosphatase;Phosphoric Monoester Hydrolases;Physiology;Play;Predisposition;Process;Recruitment Activity;Regulation;Research;Respiratory Chain;Respiratory physiology;Rhabdomyolysis;Role;Seminal;Site;Skeletal muscle structure;Small Interfering RNA;Surface;System;Tissues;Transcription Coactivator;Transgenic Organisms;Transportation;Triglycerides;Variant;adipocyte differentiation;base;carbohydrate metabolism;fatty acid oxidation;in vivo;insight;insulin sensitivity;lipine;mitochondrial dysfunction;muscle degeneration;muscle metabolism;null mutation;overexpression;oxidation;research study

public_health_relevance:
Lipin l is emerging as a master regulator of metabolism. Inter-individual variation in lipinl expression and alterations in lipinl mRNA processing have been associated with human susceptibility to diet induced obesity. Our proposed studies promise to reveal a new facet of lipinl function in skeletal muscle and to define the role of lipinl as a link between fat storage in adipose tissue and consumption of mobilized fatty acids by skeletal muscle mitochondrial oxidative metabolism.


application_id: 8911342
project_number: 5P20GM103527-08
project_title: Quantifying the effect of obesity and comorbid hypertension on cardiac function
administering_ic: NIGMS
award_notice_date: 2015-09-01
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103527
project_start_date: 2015-08-01
project_end_date: 2016-07-31
study_section: ZGM1-TWD-Y
subproject_number: 5039
contact_pi_person_id: 11817133
contact_pi: VANDSBURGER, MORIEL
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:
Obesity is a major public health problem affecting over one third of adults in the United States and one in five children. Obesity is related to an increased risk of cardiovascular mortality which may in part be mediated through a direct effect on the heart leading to dysfunction. However the time course over which obesity leads to cardiac dysfuncfion the underlying mechanisms of myocardial dysfunction in obesity and potential treatments have not been fully elucidated. Our preliminary data ufilizing cardiac magnefic resonance imaging (MRI) show abnormalifies in the magnitude of contracfion synchrony of contraction and myocardial mass in the hearts of mice fed a high-fat Western diet. The objective of this project is to define the time course over which this dysfunction occurs in mice evaluate the role of hypertension in the development of this dysfunction and to translate this work into humans by determining whether children in our pediatric obesity clinic have evidence of cardiac dysfunction. This project has 3 specific aims as follows: 1) Determine the time course over which myocardial dysfunction develops in mice fed a high-fat Western diet. We will quantify advanced measures of cardiac function assessing mass contraction and relaxation and synchrony overtime in a longitudinal study using magnetic resonance imaging. 2) Determine the effect of anti-hypertensive therapy on the development of hypertrophy and cardiac dysfunction in mice fed a high-fat Western diet. Mice on a high-fat Western diet develop obesity-related hypertension that is reversible with anti-hypertensive therapy. However the effect of anti-hypertensive therapy on cardiac function in obese mice has not been studied and may elucidate underiying mechanisms. We will compare cardiac function measured in the'mice on a high-fat Western diet in specific aim 1 to a group of mice on a high-fat Western diet and hydralazine. 3) Quantify cardiac function in children with obesity using advanced MRI. State-of-the-art technology at the University of Kentucky enables us to directly translate our findings in mice into our pediatric obesity clinic with over 800 patients. The effect of obesity on myocardial function in children is largely unknown.

project_terms:
Adult;Affect;Animals;Antihypertensive Agents;Blood Pressure;Cardiac;Cardiac Function Study;Cardiovascular Diseases;Child;Clinic;Computer software;Data;Development;Diet;Fat-Restricted Diet;Fatty acid glycerol esters;Functional disorder;Heart;Heart Hypertrophy;Human;Hydralazine;Hypertension;Hypertrophy;Image;Kentucky;Longitudinal Studies;Magnetic Resonance Imaging;Measures;Mediating;Mortality Vital Statistics;Mus;Myocardial;Myocardial Contraction;Myocardial dysfunction;Obese Mice;Obesity;Obesity Related Hypertension;Patients;Pharmaceutical Preparations;Protocols documentation;Relaxation;Research;Role;Technology;Time;Translating;Translations;United States;Universities;Weight;Work;cardiovascular risk factor;feeding;heart function;mouse model;normotensive;obesity in children;public health medicine (field);western diet

public_health_relevance:
Obesity affects over one third of adults in the United States and one in five children. The objective of this project is to understand the effects of obesity on the function of the heart using advanced magnetic resonance imaging (MRI) of the hearts of both mice and humans. Part of this project will also investigate the specific role of blood pressure medications on helping to protect the heart from the effects of obesity.


application_id: 8911341
project_number: 5P20GM103527-08
project_title: The role of IKKB in linking obesity to adipose tissue inflammation and adipogene
administering_ic: NIGMS
award_notice_date: 2015-09-01
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103527
project_start_date: 2015-08-01
project_end_date: 2016-07-31
study_section: ZGM1-TWD-Y
subproject_number: 5038
contact_pi_person_id: 10353515
contact_pi: YIANNIKOURIS, FREDERIQUE
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:
The goal of this project is to investigate the role of IKB kinase beta (IKKB) a central coordinator of innate immunity and inflammation through activation of NF-KB in linking obesity to adipose tissue inflammation and adipogenesis. Obesity is associated with a state of chronic low-grade inflammation that has been considered to be a major contributor to diabetes and atherosclerosis. The transcriptional factor NF-KB is a primary mediator of inflammatory pathways that are linked to the development of obesity-associated insulin resistance and atherosclerosis. IKKB is the predominant catalytic subunit ofthe IKK complex that is required for canonical activation of NF-KB by inflammatory mediators. Given the defined role of IKKB in regulating NF-KB-mediated inflammation in several cell types it is unclear whether IKKB contributes to obesity-induced inflammation in adipocytes. In the proposed studies we will define the role of adipocyte-derived IKKB in high fat (HF) diet-induced obesity adipose inflammation and insulin resistance. In preliminary studies during Phase I support of this project we also defined the role of smooth muscle cell (SMC) IKKB in the development of obesity-associated atherosclerosis in LDL receptor (LDLR) deficient mice. To delete IKKB in SMCs we used SM22-Cre transgenic male mice carrying floxed IKKB alleles that were mated to female LDLR-/- mice carrying floxed IKKB alleles. During the course of these studies we made the novel finding that deficiency of IKKB in SMCs rendered mice resistant to the development of diet-induced obesity. Preliminary results demonstrate that SM22 is expressed in primary adipose stromal/vascular (SV) cells consistent with recent reports that SM22-Cre is active in mesenchymal stem cells (MSCs) that give rise to adipose tissue. Notably SV cells from SMC IKKB-deficient mice exhibited impaired adipogenic potential. These results implicate a previously unrecognized role of IKKB in the regulation of adipogenesis. The central hypothesis of this proposal is that HF-diet induced activation of IKKB promotes adipocyte differentiation adipocyte inflammation and insulin resistance. In the proposed studies we will define mechanisms for IKKB-mediated regulation of adipogenesis. We will also define the effect of adipocyte IKKB deficiency on the development of obesity adipose inflammation and insulin resistance in response to a HF diet. The proposed studies will elucidate new aspects of adipocyte biology and metabolic control and may lead to novel therapeutic targets for obesity and diabetes.

project_terms:
Ablation;Adipocytes;Adipose tissue;Affect;Alleles;Atherosclerosis;Blood Vessels;Cardiovascular Diseases;Catalytic Domain;Cells;Chronic;Complex;Country;Data;Development;Diabetes Mellitus;Diet;Disease;Epidemic;Exhibits;Fatty acid glycerol esters;Female;Goals;Hematopoietic;Human;Hypertrophy;I-kappa B Proteins;Immune response;Inflammation;Inflammation Mediators;Insulin Resistance;Intervention;Lead;Link;Low Density Lipoprotein Receptor;Mediating;Mesenchymal Stem Cells;Metabolic Control;Metabolic Diseases;Modeling;Mus;Natural Immunity;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Partner in relationship;Pathway interactions;Phase;Phosphotransferases;Play;Promotor (Genetics);Regulation;Reporting;Research;Resistance;Risk;Role;Signal Transduction;Smooth Muscle Myocytes;Stem cells;Testing;Transgenic Organisms;adipocyte biology;adipocyte differentiation;cell type;feeding;gain of function;lipid biosynthesis;loss of function;male;new therapeutic target;novel;nutrition;obesity treatment;population health;progenitor;response;stem cell differentiation;therapeutic target

public_health_relevance:
Obesity is a rapidly growing epidemic representing a serious threat to the health of the population in almost every country around the world. There is an urgent need to understand the mechanisms underlying the diet induced obesity and associated metabolic disorders. The proposed study will investigate a novel mechanism that links over nutrition and obesity.


application_id: 8911338
project_number: 5P20GM103527-08
project_title: Analytical Core B
administering_ic: NIGMS
award_notice_date: 2015-09-01
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103527
project_end_date: 2016-07-31
study_section: ZGM1-TWD-Y
subproject_number: 5035
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW 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: 2015-08-01
project_abstract:
The Analytical Core (B) will be located in the Biomedical Biological Sciences Building University of Kentucky. The Analytical Core will consist of the Director and research personnel for performing services of resolution and profiling of analytes using mass spectroscopy and for quantifying analytes using luminex platforms. An important part of Core activities will include methods development to analyze speciflc molecules of interest and for profiling lipids within animal and human tissue.

project_terms:
Area;Award;Biological;Biological Sciences;Cardiovascular Diseases;Centers of Research Excellence;Computers and Advanced Instrumentation;Consultations;Detection;Diagnosis;Electrospray Ionization;Fatty Acids;Fee-for-Service Plans;Fees;Flame Ionization;Funding;Gases;Goals;Grant;High Pressure Liquid Chromatography;Human;Human Resources;Individual;Institution;International;Investigation;Investments;Kentucky;Life;Lipids;Lipolysis;Mass Fragmentography;Mass Spectrum Analysis;Measurement;Measures;Mediator of activation protein;Mentors;Metabolic;Methods;Monitor;Mus;National Center for Research Resources;Obesity;Participant;Peptides;Phase;Positioning Attribute;Proteins;Publications;Reader;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Resolution;Series;Services;Solutions;Suspension substance;Suspensions;Training;United States National Institutes of Health;Universities;Work;animal tissue;base;biomedical facility;carbohydrate metabolism;cost;detector;human tissue;instrument;instrumentation;interest;lipid biosynthesis;lipid metabolism;mass spectrometer;metabolomics;method development;operation;small molecule;stable isotope;success;synthetic polymer Bioplex;tandem mass spectrometry

public_health_relevance:
The Analytical Core provides services and methods development to investigators of the Center to quantify profile and resolve various analytes with a focus on lipids.


application_id: 8911191
project_number: 5R01HL120746-03
project_title: Tobacco Products and Atherosclerotic Disease
administering_ic: NHLBI
award_notice_date: 2015-08-07
opportunity_number: PAR-12-267
application_type: 5
activity_code: R01
ic: HL
serial_number: 120746
program_official: PUNTURIERI, ANTONELLO
project_start_date: 2013-09-19
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZRG1-HDM-Q(54)R]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION: Smoking is the leading cause of preventable deaths. Although cigarette smoking increases the risk of several chronic diseases nearly half of smoking related mortality could be linked to cardiovascular deaths. Therefore regulation of cigarettes and other tobacco products could significant lower the global burden of cardiovascular disease (CVD). The Family Smoking Prevention and Tobacco Control Act gives the FDA the authority to regulate the manufacturing marketing and distribution of tobacco products to protect public health. However to set standards for tobacco products it is important to know how cardiovascular effects of new and emerging tobacco products could be measured and which components of tobacco products induce cardiovascular injury. Because CVD is a chronic disease that develops over several years biomarkers of tobacco-induced cardiovascular injury are urgently needed to assess CVD risk in a time-frame sufficient for product evaluation. Moreover to relate biomarkers of injury with exposure to specific harmful and potentially harmful (HPHC) tobacco constituents it is essential to identify biomarkers that reflect exposure to specific constituents of tobacco products. Elucidation of the relationship between biomarker of exposure and biomarkers of injury will enable comparisons between the toxicities of different tobacco products and inform the design of future human studies for evaluating the cardiovascular effects of tobacco product use. Accordingly the overall goal of our project is to identify biomarkers of exposure to tobacco products and to relate them to atherosclerosis the underlying cause of several cardiovascular diseases. To accomplish this goal we will examine tobacco-induced injury in apoE-null mice and apoE-null rats. We will expose animals to varying intensities of tobacco smoke and smokeless tobacco we will identify urinary metabolites of exposure-derived aldehydes and determine how they relate to the extent and duration of exposure as well as to atherosclerotic lesion formation and lesion stability and how the relationship between the biomarkers of injury and biomarkers of exposure is affected by gender and the species and duration of exposure. In these experiments we will identify specific indices of atherosclerosis and thrombosis and how these biomarkers of injury are related to the biomarkers of exposure. To delineate the contribution of HPHCs we will identify which constituents of tobacco and tobacco smoke contribute to atherogenesis we will examine atherogenesis in mice exposed to individual constituents of exposure - nicotine acrolein and crotonaldehyde and determine how removal of these constituents affects atherosclerosis due to tobacco smoke and whether increases in the extent of exposure to these aldehydes and related reactive chemicals exacerbate atherosclerosis. Successful completion of this project will lead to the development of validated animal models to establish standard toxicitychanges and the discovery of novel biomarkers of cardiovascular injury that can be associated with measures of tobacco exposure. The findings of this project will provide new information regarding the contribution of reactive aldehydes such as acrolein and crotonaldehyde to the cardiovascular toxicity of cigarette smoke and smokeless tobacco. These findings will be useful in evaluating the contribution of HPHCs to tobacco product toxicity in humans; assessing the extent of harm reduction in PREPs and in developing policies for regulating HPHCs in smokeless tobacco cigarettes and emerging tobacco products. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

project_terms:
2-butenal;Acrolein;Affect;Aldehydes;Animal Model;Animals;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Biological Markers;Blood Platelets;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Chemicals;Cholesterol Homeostasis;Chronic Disease;Cigarette;Development;Doctor of Philosophy;Evaluation;Excision;Exposure to;Family Smoking Prevention and Tobacco Control Act;Future;Gender;Goals;Harm Reduction;Health;Heart Diseases;Heart failure;Human;Individual;Injury;Ischemia;Knockout Mice;Lead;Lesion;Link;Marketing;Measures;Mediating;Mortality Vital Statistics;Mus;Nature;Nicotine;Policies;Principal Investigator;Rattus;Regulation;Reperfusion Therapy;Risk;Risk Factors;Smoke;Smokeless Tobacco;Smoking;Surrogate Markers;Thrombosis;Time;Tobacco;Tobacco smoke;Tobacco use;Toxic effect;atherogenesis;authority;cardiovascular disorder risk;cardiovascular injury;cigarette smoke;cigarette smoking;design;indexing;novel;programs;public health medicine (field);research study;stroke;tobacco exposure;urinary

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Smoking is the leading cause of preventable deaths. Although cigarette smoking increases the risk of several chronic diseases nearly half of smoking related mortality could be linked to cardiovascular deaths. In the proposed studies we will identify biomarkers of exposure to tobacco products and relate them to atherosclerosis in experimental animals the underlying cause of several cardiovascular diseases. These studies will lead to the development of validated animal models to establish standard toxicity changes and the discovery of novel biomarkers of cardiovascular injury that can be associated with measures of tobacco exposure. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page


application_id: 8909642
project_number: 3R01ES021502-03S1
project_title: FRESH: Dual Home Screening for Lung Cancer Prevention
administering_ic: NIEHS
award_notice_date: 2014-08-12
opportunity_number: PA-10-067
application_type: 3
activity_code: R01
ic: ES
serial_number: 021502
suffix: S1
program_official: DILWORTH, CAROLINE H
project_start_date: 2012-09-01
project_end_date: 2017-05-31
study_section: Psychosocial Risk and Disease Prevention Study Section[PRDP]
contact_pi_person_id: 1906116
contact_pi: HAHN, ELLEN J
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):    The purposes of this randomized controlled trial are to test the effectiveness of Freedom from Radon Exposure and Smoking in the Home (FRESH) a dual home screening and tailored environmental feedback intervention designed to reduce environmental risks for lung cancer and to identify factors associated with monetary incentives for radon mitigation. The combination of firsthand smoke secondhand smoke (SHS) and radon exposure increases the risk of lung cancer nearly tenfold. The long-term goals are to foster environmental justice by reducing home exposure to radon and SHS and to promote equity in radon mitigation by policy change to provide tax credits. A randomized controlled trial enrolling 550 primary care patients will test four hypotheses controlling for contextual factors of age gender home smoking and socioeconomic status (SES): 1) Those who receive FRESH will be more likely to take action to test and mitigate for radon and institute and enforce a smoke-free home policy compared to the control group; 2) Those receiving FRESH will have lower radon and home SHS levels at 15 months post-intervention compared to the control group; 3) Those who receive FRESH will have greater increases in perceived risk of lung cancer and synergistic risk perception (SHS x radon) health-related self-concept readiness to change and self-efficacy to prevent lung cancer and a greater decrease in lung cancer worry compared to controls at 15 months post-intervention; and 4) Those with at least one smoker in the home will be less likely to take action to reduce exposure to radon and SHS. The Treatment group (n = 275) will receive free test kits in the primary care clinic to measure their homes for radon and SHS at baseline receive their test results and the tailored environmental feedback intervention and take part in baseline and three follow up online surveys and home testing 15 months post-intervention. Those with high radon will receive a voucher for 30% of the cost up to $600 for radon mitigation. The Control group (n = 275) will receive information on how to request test kits for radon and SHS and a brochure on radon and SHS and take part in all study surveys. Participants in both groups will be asked to test their homes for radon and SHS 15 months post-intervention. Project      The proposal is directly relevant to public health in that it has the potential to prevent lung cancer by reducing exposure to radon and secondhand smoke in the home.

project_terms:
Address;Adopted;Adoption;Age;Area;Behavior;Clinic;Clinical;Control Groups;Counseling;Effectiveness;Enrollment;Environmental Risk Factor;Environmental Tobacco Smoke;Event;Exposure to;Feedback;Fostering;Freedom;Gender;Goals;Government;Health;Home environment;Housing;Incentives;Institutes;Intervention;Malignant neoplasm of lung;Measures;Modeling;Non-smoker;Pamphlets;Participant;Patients;Policies;Preventive;Primary Health Care;Process;Psychosocial Factor;Radon;Randomized Controlled Trials;Readiness;Research;Risk;Risk Factors;Safety;Screening for Lung Cancer;Secondary Prevention;Self Concept;Self Efficacy;Services;Simulate;Smoke;Smoker;Smoking;Socioeconomic Status;Staging;Surveys;Taxes;Test Result;Testing;Tobacco Use Cessation;Tobacco smoke;base;behavior change;cancer diagnosis;contextual factors;cost;environmental justice;follow-up;heuristics;high risk;innovation;intervention effect;lung cancer prevention;neglect;post intervention;prevent;prospective;public health medicine (field);remediation;risk perception;screening;therapy design;voucher

public_health_relevance:
The proposal is directly relevant to public health in that it has the potential to prevent lung cancer by reducing exposure to radon and secondhand smoke in the home


application_id: 8908767
project_number: 1R01ES024757-01A1
project_title: Coal Ash and Neurobehavioral Symptoms in Children Aged 6-14 Years Old.
administering_ic: NIEHS
award_notice_date: 2015-04-17
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: ES
serial_number: 024757
suffix: A1
program_official: GRAY, KIMBERLY A
project_start_date: 2015-05-01
project_end_date: 2020-01-31
study_section: Behavioral Genetics and Epidemiology Study Section[BGES]
contact_pi_person_id: 8476117
contact_pi: ZIEROLD, KRISTINA MARIE
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Coal ash is generated when power plants burn coal for energy. Coal ash is not classified as a hazardous waste so there are no federal regulations that govern its use storage or disposal. Most coal ash is stored in open landfills or in ponds. There are over 800 coal ash storage sites in the U.S. and many are located near residential communities. Coal ash includes many components but fly ash which is comprised of small spherical particles is the greatest component. Composition of fly ash varies but it frequently contains toxic metals (e.g. arsenic cadmium chromium copper lead manganese and mercury) polycyclic aromatic hydrocarbons (PAHs) and radioactive elements. Neurobehavioral disorders in children are associated with exposure to many of the metals that are contained in fly ash. Thus children exposed to fly ash are potentially at risk of developing neurobehavioral disorders. Children are exposed to fly ash via inhalation and ingestion from fugitive dust emissions that come off the landfills and the ponds.  This project will investigate the effect of fy ash on children who live in neighborhoods near two coal ash storage sites in Louisville Kentucky. Some children live in homes within 150 feet of coal ash landfills and ponds. Working with neighborhoods within 10 miles of the coal ash storage sites we will complete four specific aims: (1) Characterize indoor exposure from fly ash and heavy metals in homes of children residing near coal ash store sites compared to children living further away from coal ash storage sites (2) Determine if the heavy metal body burden differs from children residing near coal ash storage sites compared to children living further away from storage sites (3) Assess if increased fly ash exposure and greater heavy metal body burden is associated with poorer neurobehavioral performance and more neurobehavioral symptoms (4) Utilize mapping spatial analysis and modeling applications of geographic information systems (GIS) for household recruitment analysis of distance decay effects surface interpolation of Aims 1 and 2 results and fate and transport modeling of fly ash.  Three hundred and sixty children aged 6-14 will be recruited for this study. Neurobehavioral performance will be tested using the Behavioral Assessment Research System and neurobehavioral symptoms will be assessed by the Child Behavior Checklist (CBCL). Any child who has a CBCL t score =7 will be further assessed through a Structured Clinical Interview for the Diagnosis of DSM Disorders (SCID). Environmental sampling in the homes will be completed to determine the presence of fly ash and metals. Toenail samples will be collected from the children and analyzed for heavy metals. Questionnaires and an in-home assessment will help to characterize environmental exposure history and health history of the children. The results will provide evidence to define the environmental health impact of coal ash.

project_terms:
14 year old;Area;Aromatic Polycyclic Hydrocarbons;Arsenic;Attention deficit hyperactivity disorder;Autistic Disorder;Behavior Disorders;Behavior assessment;Blood Circulation;Body Burden;Breathing;Burn injury;Cadmium;Caliber;Child;Child Behavior Checklist;Chromium;Clinical;Coal;Communities;Copper;Developmental Delay Disorders;Diagnosis;Diagnostic and Statistical Manual of Mental Disorders;Disease;Dust;Emotional disorder;Environmental Exposure;Environmental Health;Exposure to;Focus Groups;Geographic Information Systems;Hazardous Substances;Hazardous Waste;Health;Heavy Metals;Home environment;Household;Human;Ingestion;Interview;Kentucky;Lead;Learning;Life;Low income;Lung;Manganese;Maps;Mercury;Metals;Methods;Modeling;Neighborhoods;Parents;Participant;Particle Size;Pathway interactions;Performance;Power Plants;Principal Investigator;Property;Questionnaires;Radioactive;Radioactive Elements;Recording of previous events;Recruitment Activity;Regulation;Research;Research Personnel;Residual state;Risk;Sampling;Site;Structure;Structure of nail of toe;Surface;Surveys;Symptoms;Testing;Time;Toxic effect;United States;Work;aged;base;coal ash;fly ash;follow-up;foot;hazard;improved;indoor exposure;junior high school;landfill;neurobehavioral;neurobehavioral disorder;neurotoxic;particle;pollutant;public health medicine (field);public health relevance;remediation;systems research;toxic metal

public_health_relevance:
PUBLIC HEALTH RELEVANCE: An estimated 1.54 million children in the U.S. are exposed to coal ash yet the research investigating the health impacts from exposure is scarce. Children exposed to coal ash which is comprised of small particles containing multiple heavy metals are potentially at risk for developing neurobehavioral symptoms. This study which will be the first to
document coal ash exposure heavy metal body burden and neurobehavioral performance and symptoms in children may provide evidence of the environmental and health impact of coal ash.


application_id: 8908750
project_number: 1F30AI114194-01A1
project_title: Elucidating binding fusion and entry of HMPV in cell culture and host tissue
administering_ic: NIAID
award_notice_date: 2014-12-29
opportunity_number: PA-14-150
application_type: 1
activity_code: F30
ic: AI
serial_number: 114194
suffix: A1
program_official: KIM, SONNIE
project_start_date: 2015-05-01
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1 F13-C (20)]
contact_pi_person_id: 12024712
contact_pi: KLIMYTE, EDITA MARIA
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): Human metapneumovirus (HMPV) is a recently discovered respiratory pathogen in the Paramyxoviridae family that infects nearly 100% of the world population. This enveloped virus causes severe viral respiratory disease in infants the elderly and immunocompromised patients worldwide. In fact HMPV is estimated to be the second most common cause of pediatric lower respiratory illness following the closely related respiratory syncytial virus. Furthermore the rate of hospitalization for respiratory disease caused by HMPV in adults over the age of 65 is near that of influenza. Despite its clinical significance there is no antiviral treatment or vaccine available at this time. Since its discovery several key factors have been identified to play a role in HMPV entry but much of the mechanisms of binding fusion and entry remain unsolved. It has been previously shown by our group that heparan sulfate is a required moiety for HMPV binding and infectivity; however it is not known if heparan sulfate proteoglycans (HSPGs) serve as a receptor or mediate other necessary cellular factors on the plasma membrane. Furthermore the route of entry has not been identified for HMPV. Thus to elucidate the role of HSPGs we will utilize a collection of currently available HMPV strains from laboratory strains and clinical isolates to determine the effects of heparan sulfate blocking molecules and knockdown studies on specific HSPGs; in order to identify the route of entry we will utilize viral particles with fluorescent labeled envelopes to track if membrane fusion is occurring at the plasma membrane or within intracellular compartments. Finally we propose to study HMPV entry in the context of traditional cell culture utilizing physiologically relevant cell lines derived from human lung tissue such as Beas-2B Calu-3 and A549 as well as novel human airway epithelial tissue to elucidate important details about its life cycle in this model and identify potential factors that may affect
HMPV infection in vivo. We hypothesize heparan sulfate proteoglycans specifically the syndecan moieties serve as an attachment factor for HMPV which is required for internalization and membrane fusion occurs in intracellular compartments. We expect heparan sulfate is also critical for viral infectivity in human airway epithelium. We also anticipate tissus derived from patients with chronic respiratory disease will show an increased permissibility to HMPV infection.

project_terms:
A549;Address;Adult;Affect;Antigens;Antiviral Agents;Area;Asthma;Binding (Molecular Function);Biological Models;Bronchiolitis;Caveolins;Cell Culture Techniques;Cell Line;Cell membrane;Cells;Chemicals;Child;Childhood;Chimeric Proteins;Chronic;Chronic Disease;Clathrin;Clinical;Collection;Complex;Dendrimers;Dependence;Development;Disease;Dynamin;Elderly;Endocytosis;Endosomes;Epithelial;Epithelium;Escherichia coli;Excision;Family;Glycoproteins;HIV;Heparan Sulfate Proteoglycan;Heparitin Sulfate;Hospitalization;Human;Human Metapneumovirus;Human respiratory syncytial virus;Immunocompromised Host;Infant;Infection;Influenza;Inorganic Sulfates;Intervention;Label;Laboratories;Life Cycle Stages;Lipids;Lung;Lung diseases;Mediating;Membrane Fusion;Modeling;Molecular;Mortality Vital Statistics;Mucous body substance;Paramyxoviridae;Paramyxovirus;Pathway interactions;Patients;Peptides;Play;Pneumonia;Pneumovirinae;Population;Predisposition;Production;RNA Viruses;Respiratory Tract Diseases;Respiratory syncytial virus;Role;Route;Site;Structure of parenchyma of lung;Surface;Symptoms;System;Time;Tissue Model;Tissues;Trypsin;Unspecified or Sulfate Ion Sulfates;Vaccines;Viral;Virus;airway epithelium;airway hyperresponsiveness;cell type;cellular targeting;clinically significant;in vivo;inhibitor/antagonist;member;monolayer;novel;particle;pathogen;public health relevance;receptor;reconstitution;respiratory;syndecan;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Human metapneumovirus is a prevalent cause of respiratory disease in children and adults all over the world. It is important to understand how the virus gets
into the cells of the lungs in order to develop treatments and vaccines for this virus.


application_id: 8907368
project_number: 1F31AG048697-01A1
project_title: Testing a Values-Based Approach to Healthcare Decision-Making in Older Adults
administering_ic: NIA
award_notice_date: 2015-03-05
opportunity_number: PA-14-147
application_type: 1
activity_code: F31
ic: AG
serial_number: 048697
suffix: A1
program_official: NIELSEN, LISBETH
project_start_date: 2015-07-01
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1 F16-L (20)]
contact_pi_person_id: 11980340
contact_pi: GEIGER, PAUL 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 ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The purpose of this proposal is to provide research training in the intersecting fields of emotion regulation aging and decision-making in healthcare. Despite natural declines in physical and cognitive function older adults maintain good emotion regulation abilities leading to emotional wellbeing and resilience. This phenomenon can partially be explained by socio-emotional selectivity theory (SST) which posits that when time is perceived as a limited resource emotional wellbeing becomes a top priority. Although this positivity effect maintains emotional wellbeing it may disrupt information
processing related to healthcare decision-making. Older adults request less information from their doctors are less likely to ask for a second opinion make their decisions more quickly and devote more attention to positive medical information compared with younger adults. Although these strategies fulfill goals of emotional wellbeing they do not allow for fully informed decisio-making. Research has shown these SST effects are malleable and temporarily reversible when older adults are primed to reduce their emotional focus or increase the amount of information they gather. However older adults do not normally gather extensive information because it does not support present-moment emotional wellbeing; instead it reduces positive affect and may reduce self-regulatory capacities required for emotion regulation. The research component of this proposal will investigate a personal values-based strategy for reducing the positivity effect n information processing related to healthcare decision-making. Writing about personal values increases positive affect counteracts self-regulatory fatigue and reduces defensiveness while reading threatening health information. Values-based interventions have been extensively studied but rarely applied to older adults. This study will integrate two broad areas of research (aging emotion and decision- making and the role of values in decision-making) that has great promise in improving decision-making across the lifespan. Didactic and experiential training in aging and values-based research will include (1) regular meetings with University of Kentucky Sanders Brown Center for Aging faculty members (2) coursework covering aging decision-making and advanced statistics (3) intensive statistics training program (4) visiting scholar training with leaders in the field of aging and decision-making. In order to foster professional development proposed activities include (1) attending and presenting research at multiple national conferences and (2) pursuing additional research questions with access to an R01-funded longitudinal dataset of community-dwelling older adults. Finally a substantial emphasis will be placed on ethical training including (1) a course on ethical research with older adults (2 a course based on NIH guidelines for Responsible Conduct of Research and (3) regular meetings with advisors to discuss ethical issues. This proposal provides extensive training to build a research career devoted to the development of novel emotion regulation interventions that enhance the lives of older adults.

project_terms:
Address;Affect;Age;Aging;Area;Attention;Cognitive;Communities;Data Set;Decision Making;Development;Elderly;Emotional;Emotions;Ethical Issues;Ethics;Faculty;Failure (biologic function);Fatigue;Fostering;Funding;Goals;Guidelines;Health;Healthcare;Informal Social Control;Intervention;Kentucky;Laboratories;Laboratory Study;Lead;Length;Life;Literature;Longevity;Maintenance;Measures;Medical;Medicare;Memory;Motivation;Participant;Patient Self-Report;Personal Satisfaction;Physical Function;Population;Process;Psyche structure;Reading;Research;Research Training;Resources;Role;Second Opinions;Techniques;Testing;Time;Training;Training Programs;United States National Institutes of Health;Universities;Visit;Well in self;Writing;age effect;age related;base;career;cognitive function;computerized;cost;design;effective intervention;emotion regulation;improved;information gathering;information processing;meetings;member;novel;positive emotional state;psychosocial;public health relevance;resilience;responsible research conduct;satisfaction;skills;statistics;symposium;theories;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Older adults use a variety of cognitive techniques to focus their attention primarily on positive information. Despite effectively maintaining emotional wellbeing these techniques lead to incomplete information processing which can be problematic when making important decisions related to healthcare and medical treatment. The purpose of the proposed project is to: (1) study the effects of a values-based induction on the process of healthcare decision-making in older adults and (2) provide didactic and experiential training in psychosocial functioning and decision-making in older adults ethical issues in research with this population and the methodological and statistical skills necessary to investigate emotion regulation strategies to improve healthcare-related information processing in older adults.


application_id: 8906868
project_number: 5R01EY021769-04
project_title: The role of Insm1a in photoreceptor differentiation
administering_ic: NEI
award_notice_date: 2015-06-26
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: 2016-07-31
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;genetic approach;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: 8906836
project_number: 5K12DA035150-04
project_title: Kentucky BIRCWH Program: Training the Next Generation of Women's Health Scholars
administering_ic: NIDA
award_notice_date: 2015-07-01
opportunity_number: RFA-OD-11-002
application_type: 5
activity_code: K12
ic: DA
serial_number: 035150
program_official: BABECKI, BETH
project_start_date: 2012-08-01
project_end_date: 2016-07-31
study_section: Special Emphasis Panel[ZRG1-PSE-K(50)R]
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The University of Kentucky (UK) is uniquely positioned to continue using exceptional and outstanding research infrastructure to train the next generation of women's health scholars. We choose to focus our scholarship efforts on those health challenges unique to Appalachian Kentucky. Because the Appalachian region is disproportionately affected by drug abuse violence and poor health we will actively engage women living in Appalachian Kentucky in our research agenda with research flowing bidirectionally between communities and researchers. This approach will continue to provide our BIRCWH scholars with state-of-the-art multidisciplinary training leading to their development as faculty with independent NIH funding. The focused areas targeted towards improving women's health in this application include: 1) substance abuse 2) violence against women and 3) hormonal regulation across a woman's lifespan. UK is uniquely position to address violence against women because UK has the only US Center focusing on research to prevent violence against women. Through this BIRCWH program strengthening the capacity for women's health research will be accomplished by the following Specific Aims: 1) to provide the environment mentorship and facilities to enhance the ability of BIRCWH scholars to compete for NIH research grants in diverse areas of women's health research 2) to deepen our understanding of the unique role of gender in the manifestation of health and disease 3) to stimulate new collaborations in focused interdisciplinary and interactive research areas that are essential forimproving women's health; and 4) to use a thematic multidisciplinary focus as a platform for enhancing translational research between basic clinical and public health scientists. Key aspects of training will include: (a) pairing the BIRCWH scholar with senior level scientists and former BIRCWH scholars forming a research team and thus modeling interdisciplinary collaboration (b) providing these teams with access to cutting edge technologies and (c) providing scholars with training in concepts relevant to women's health. A strength of our BIRCWH program is its multidisciplinary cross-departmental and interactive nature positioned in an area with unique health needs. As evident by the success of our former BIRCWH scholars we are well positioned to continue the tradition of excellence in mentoring our scholars to become independent researchers in women's health.

project_terms:
Address;Affect;Appalachian Region;Area;Clinical;Collaborations;Communities;Development;Disease;Drug abuse;Environment;Faculty;Funding;Gender Role;Health;Kentucky;Life;Longevity;Mentors;Mentorship;Modeling;Nature;Positioning Attribute;Research;Research Infrastructure;Research Personnel;Research Project Grants;Scholarship;Scientist;Substance abuse problem;Technology;Training;Training Programs;Translational Research;United States National Institutes of Health;Universities;Violence;Woman;Women's Health;hormone regulation;improved;interdisciplinary collaboration;multidisciplinary;next generation;programs;public health medicine (field);success;violence against women;violence prevention

public_health_relevance:
Emphasizing gender differences in effective health care research and treatment is critical. We must train the next generation of scientists to recognize and apply these differences. This proposal will provide a platform to mentor and train promising young scientists in focused areas of women's health research to address the unique needs in women's health especially for those who are underserved.


application_id: 8906501
project_number: 5R01CA166499-04
project_title: A role for c-Abl/Arg in melanoma progression
administering_ic: NCI
award_notice_date: 2015-08-12
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 166499
program_official: SATHYAMOORTHY, NEERAJA
project_start_date: 2012-09-12
project_end_date: 2016-08-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1918859
contact_pi: PLATTNER, RINA
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): Despite 35 years of clinical trials there has been little improvement in five-year survival rates with any chemotherapeutic regimen for the treatment of metastatic melanoma. Here we demonstrate a previously unrecognized role for Abl kinases in melanoma cells. We found that c-Abl/Arg non-receptor tyrosine kinases are activated in primary melanomas and in melanoma cell lines and promote proliferation survival cell-cell adhesion migration invasion and lung colonization/metastasis. In addition c-Abl/Arg promote matrigel invasion via STAT3 and MMP-dependent pathways; increase cell-cell adhesion; and dramatically induce degradation of a metastasis suppressor. Moreover drugs targeting c-Abl/Arg and Raf/MEK/ERK pathways cooperate to decrease melanoma viability. Based on these novel findings we hypothesize that c-Abl/Arg activate novel pathways that cooperate with B-Raf to promote melanoma cell-cell adhesion migration invasion and metastasis. We propose a comprehensive hypothesis-driven experimental design that will establish Abl kinases as novel and exploitable drug targets for metastatic melanoma. Aim 1 will define molecular pathways by which Abl kinases promote cell-cell adhesion migration and invasion. To achieve our objective we will combine biochemical molecular and cell biological approaches using RNAi pharmacological inhibitors constitutively active forms of c-Abl/Arg rescue experiments 2D/3D cell culture and melanoma- endothelial co-cultures to identify migration invasion and cell-cell adhesion signaling pathways driven by c- Abl/Arg. Aim 2 will test the prediction that c-Abl/Arg cooperates with Abl-independent pathways (e.g. B-Raf) to promote melanoma cell-cell adhesion migration and invasion. Finally three complementary approaches will be utilized in Aim 3 to identify mechanisms by which c-Abl/Arg promote metastasis. A novel GEM model that develops metastatic UV-induced melanomas and lung colonization and spontaneous metastasis xenograft models will be used to test the prediction that blocking c-Abl/Arg-dependent signaling pathways inhibits metastatic progression. We also will test whether B-Raf and c-Abl/Arg inhibitors cooperate to prevent metastasis of melanomas harboring B-Raf mutations. The data obtained from this proposal not only will allow us to gain insight into the fundamental mechanisms by which c-Abl/Arg drive invasion and metastasis but also will lead to clinical studies testing the efficacy of c-Abl/Arg inhibitors for treating metastatic disease.

project_terms:
ABL1 gene;Anoikis;Biochemical;Biological;Cathepsin L;Cathepsins;Cell Adhesion;Cell Communication;Cell Culture Techniques;Cell Line;Cell Survival;Cell-Cell Adhesion;Cells;Clinic;Clinical;Clinical Research;Clinical Trials;Coculture Techniques;Data;Dermal;Detection;Development;Disease;Disease remission;Drug Combinations;Drug Targeting;Endothelial Cells;Environment;Experimental Designs;Extravasation;FDA approved;Fibroblasts;Genetic Transcription;Goals;Imatinib;In Vitro;Killings;Lead;Lung;MEKs;Matrix Metalloproteinases;Mean Survival Times;Mediating;Melanoma Cell;Metastatic Melanoma;Modeling;Molecular;Mouse Strains;Mutation;N-Cadherin;NME1 gene;Neoplasm Metastasis;Outcome;Pathway interactions;Patients;Peptide Hydrolases;Phosphotransferases;Play;Positioning Attribute;Prevention;Protein Tyrosine Kinase;RNA Interference;Ras/Raf;Regimen;Research;Residual state;Resistance;Role;STAT3 gene;STI571 (Gleevec);Scientist;Seminal;Signal Pathway;Signal Transduction;Solid Neoplasm;Staging;Survival Rate;Testing;Transcriptional Activation;Treatment Protocols;UV-induced melanoma;Universities;Xenograft Model;base;c-abl Proto-Oncogenes;chemotherapeutic agent;design;efficacy testing;gain of function;inhibitor/antagonist;innovation;insight;leukemia;loss of function;matrigel;melanoma;migration;mutant;novel;novel therapeutics;prevent;research study;tool

public_health_relevance:
Melanomas are essentially untreatable if they metastasize because they are resistant to all known chemotherapeutic agents. This proposal will solidify Abl kinases as novel druggable targets in melanoma by identifying mechanisms by which Abl kinases promote invasion and metastasis; determining which type of melanomas contain active Abl kinases; and testing whether Abl inhibitors cooperate with B-Raf inhibitors to kill melanoma cells and prevent metastatic progression. Data obtained from this proposal are likely to lead to the initiation of a clinical trial to test these novel drug combinations for treatment of metastati disease. 1


application_id: 8905682
project_number: 3R44AA018226-04S1
project_title: Selection-driven plant metabolites for treatment of CNS diseases
administering_ic: NIAAA
award_notice_date: 2015-03-23
opportunity_number: PA-14-077
application_type: 3
activity_code: R44
ic: AA
serial_number: 018226
suffix: S1
program_official: EGLI, MARK
project_start_date: 2010-08-20
project_end_date: 2017-02-28
study_section: Special Emphasis Panel[ZRG1(11)-B]
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
project_abstract:
DESCRIPTION (provided by applicant): This project aims to demonstrate that the evolution of plant biosynthetic pathways can be accelerated and driven to favor the synthesis of ligands which interact with a specific human target protein. This is achieved by subjecting mutant plant cells to selection pressures favoring the survival of mutants with the phenotype of interest. As an example this approach will be used to optimize pharmacological activity in Lobelia cardinalis which inhibits the human dopamine transporter (hDAT) putatively by its ability to synthesize the complex alkaloid lobinaline. A stable transgenic line of L. cardinalis plant cells expressing the hDAT has been established. These cells show increased sensitivity to toxins transported into the cell by the hDAT including the neurotoxin MPP+. A large genetically diverse population of gain-of-function mutants expressing the hDAT has now been generated and selected on medium containing 100uM MPP+ which kills the vast majority of the transgenic mutants. However individual mutants that are over-producing inhibitors of the hDAT have a survival advantage so that the MPP+-resistant population is greatly "enriched" in clones with this bioactivity. Preliminary GC/MS analysis of individual MPP+-resistant mutants with increased hDAT inhibitory activity indicates that many of these are overproducing lobinaline but the rest are generating other metabolites some of which are not detectable in the wild-type plant. Phase II is designed to demonstrate that this biotechnology can be used to (a) generate novel natural products with a specific valuable pharmacology (b) provide a biosynthetic production system for these compounds in mutant plants. The process should be of particular value when a plant-derived lead compound such as lobinaline is too complex for chemical synthesis. The first specific aim is to analyze the remaining MPP+-resistant population to determine those individuals in which lobinaline content cannot explain increased hDAT inhibitory activity. Separation (assay-guided preparative HPLC) and tentative identification (GC/MS) of active compounds will be followed by pharmacological evaluation in vitro in comparison with lobinaline and a synthetic inhibitor of the hDAT. The most active compounds will then be tested for functional effects on the DAT in rat brain in vivo using electrochemistry. In parallel studies themutant clonal cultures which are overproducing active metabolites to the greatest extent will be regenerated to intact mutant plants and extracts analyzed to establish whether the pharmacological /chemical phenotype is retained. The ultimate aim is to commercialize the technology as a platform for discovering and producing novel plant-derived natural products targeted on specific human CNS proteins.

project_terms:
1-Methyl-4-phenylpyridinium;Agonist;Alkaloids;Amphetamines;Antioxidants;Award;Biological Assay;Biological Factors;Biotechnology;Brain;Cell Culture Techniques;Cell Line;Cells;Central Nervous System Diseases;Chemicals;Complex;Computer Simulation;Corpus striatum structure;Development;Drug Addiction;Drug Industry;Electrochemistry;Evaluation;Evolution;Free Radical Scavenging;Guanine + Cytosine Composition;High Pressure Liquid Chromatography;Hormonal;Human;In Vitro;Individual;Killings;Lead;Ligands;Lobelia;Medicine;Methods;Mitochondria;Modification;National Institute on Alcohol Abuse and Alcoholism;Natural regeneration;Neurodegenerative Disorders;Neurotoxins;Nicotine;Nicotinic Receptors;Norepinephrine;Nucleus Accumbens;Pathway interactions;Pharmaceutical Preparations;Pharmacology;Phase;Phenotype;Plant Extracts;Plants;Population;Population Heterogeneity;Predisposition;Preparation;Process;Production;Proteins;Rattus;Resistance;Rest;Serotonin;Small Business Innovation Research Grant;Small Business Technology Transfer Research;Source;Structure;System;Techniques;Technology;Testing;Therapeutic Uses;Toxin;Transgenic Organisms;United States National Institutes of Health;base;chemical synthesis;design;directed evolution;dopamine transporter;gain of function;gain of function mutation;high throughput screening;improved;in vivo;inhibitor/antagonist;interest;mutant;novel;pre-clinical;pressure;programs;public health relevance;radioligand;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Plants are a major source of existing medicines but the pharmaceutical industry has now almost abandoned this source in favor of synthetic chemicals. One reason is that plant metabolites are often too complex for synthetic methods to be used for their modification or production. The technology being developed by Naprogenix uses the plants own biosynthetic capacity to modify the active chemicals contained in the plant. It is also capable of increasing the amounts of the active chemicals that are present. The "directed evolution" of a plant species using this technology is capable of generating novel compounds that may be of value in many CNS diseases for example the targets in this project are important in drug dependence and neurodegenerative disease.


application_id: 8905107
project_number: 1R43DK105692-01
project_title: A new technique for diabetic foot ulcers
administering_ic: NIDDK
award_notice_date: 2015-03-26
opportunity_number: PA-14-058
application_type: 1
activity_code: R43
ic: DK
serial_number: 105692
program_official: ARREAZA-RUBIN, GUILLERMO
project_start_date: 2015-04-01
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZRG1 SBIB-Q (11)]
contact_pi_person_id: 1885914
contact_pi: CHIEN, SUFAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 968792007
primary_uei: DHTASEX58M16
duns_number: 968792007
uei: DHTASEX58M16
fips: US
organization_id: 10029830
organization_name: NOVERATECH, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021959
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal is submitted in response to the new NIDDK announcement (PA-14- 058) calling for development of new diagnostic monitoring and therapeutics technologies for the complications of type 1 diabetes (T1D). An estimated 15-25% of the 25.8 million diabetic patients in this country will develop diabetic foot ulcers (DFU) at some point in their lives. Currently even the best available treatments achieve only a 50% healing rate for these wounds-and this healing is often only temporary with a high chance of recurring.  Although the causes of non-healing chronic wounds are multifactorial one critical pathophysiology is ischemia-a deficient blood supply. Ischemia may not be the initiating factor for DFU because most ulcers start from a combination of neuropathy pressure loading and/or trauma. However tissue ischemia is the main cause that hinders healing-wounds do not heal in tissue that does not bleed whereas they always heal in tissue that bleeds extensively. The most critical consequence of ischemia is a decreased cellular energy supply because energy is required in every aspect of the wound healing process from protein synthesis to cell migration proliferation and functioning.  Our company has developed a technique to encapsulate Mg-ATP into very small unilamellar lipid vesicles for intracellular delivery (ATP-vesicles or VitaSolTM). When we use this new technique in animal wound models not only healing is enhanced but also produces an unprecedented result: Granulation tissue starts to appear in less than 24 hours. It continues to grow and covers the whole wound within 3-5 days. Massive cell accumulation and proliferation occur not only on the wound wall but also in the wound cavity where no blood supply exists. We have never seen this phenomenon in humans or any other land animals nor has it been reported in the literature by any other treatment strategy. The effect seems even more pronounced in long-term (12 months or longer) diabetic plus ischemic wounds. Although the granulation tissue growth is rapid it shows a self-limiting feature which results in no hypertrophic scar formation or any other overgrowth even after 2 years. Like many other wound care specialists when we first saw this unprecedented result we did not believe it because it seemed too good to be true. However this novel healing response has been confirmed in more than 130 rabbits (over 1040 wounds).  In this phase I proposal we will compare VitaSolTM with Regranex the only FDA- approved prescription growth factor for wound care in a diabetic wound model without skin contraction and perform a preliminary toxicity study. The accomplishment of these two goals will bring the project one step closer to IND application.  Our technique of intracellular energy delivery has consistently been viewed as innovative. If successful it will provide an inexpensive and easy to use dressing for DFU treatment something not yet achieved despite thousands of dressings developed or proposed. The potential impact is high.

project_terms:
Animal Testing;Animals;Area;Becaplermin;Calculi;Caring;Cell Proliferation;Cell Survival;Cell membrane;Cells;Characteristics;Chronic;Clinical;Complication;Country;Development;Diabetic Foot Ulcer;Diabetic wound;Drug Controls;Encapsulated;Energy Supply;FDA approved;Female;Functional disorder;Goals;Granulation Tissue;Growth;Growth Factor;Healed;Hemorrhage;Hemostatic function;Hour;Human;Hypertrophic Cicatrix;Inflammation;Insulin-Dependent Diabetes Mellitus;Ischemia;Lipids;Literature;Medicine;Modeling;Monitor;National Institute of Diabetes and Digestive and Kidney Diseases;Neuropathy;One-Step dentin bonding system;Oryctolagus cuniculus;Phase;Process;Proliferating;Protein Biosynthesis;Reporting;Skin;Specialist;Sterile coverings;Supporting Cell;Techniques;Technology;Testing;Therapeutic;Time;Tissues;Toxic effect;Toxicity Tests;Trauma;Ulcer;Use of New Techniques;Vascular blood supply;Vesicle;Wound Healing;anxious;cell motility;compare effectiveness;diabetic;diabetic patient;effective therapy;healing;innovation;macrophage;male;non-diabetic;novel;novel diagnostics;pressure;public health relevance;response;success;tissue regeneration;treatment strategy;wound

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Diabetic foot ulcer is a major and disabling complication but no effective treatment is currently available. We have developed an intracellular energy delivery technique for wound care. In animal tests it causes granulation tissue to appear in less than 24 hours and covers wound cavity quickly. The effect is more prominent in long-term diabetic plus ischemic wounds. The elimination of the traditional lag time in wound healing process and the ability to nourish massive cells in wound cavities devoid of blood supply are two features never achieved with any other treatments. This phase I project will compare the effectiveness of this new treatment with the only FDA-approved prescription growth factor for wound care--Regranex in diabetic wounds and perform a preliminary toxicity tests in male and female rabbits. The success of this phase I project will pave the way for more extensive tests in phase II and prepare the technique for IND application. The final success will benefit the millions of diabetic patients with unmanageable chronic wounds and will also have the potential to be applied to other areas of medicine where ischemia is involved.


application_id: 8903528
project_number: 1R56HL124266-01
project_title: Role of Bioactive Lipids in Stem Cell Mobilization and Homing in Cardiac Ischemia
administering_ic: NHLBI
award_notice_date: 2014-08-31
opportunity_number: PA-13-302
application_type: 1
activity_code: R56
ic: HL
serial_number: 124266
program_official: SOPKO, GEORGE
project_start_date: 2014-09-01
project_end_date: 2015-12-31
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 11330155
contact_pi: ABDEL LATIF, AHMED
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): Acute myocardial infarction (AMI) initiates innate immune and reparatory mechanisms through which Bone marrow-derived stem/progenitor cells (BMSPCs) are mobilized towards the ischemic myocardium and contribute to myocardial regeneration. Although it is clear that the magnitude of BMSPC mobilization following AMI correlates with cardiac recovery the molecular events driving BMSPC mobilization and homing are poorly understood. The long-term research goal is to contribute toward the development of new clinically useful myocardial regenerative therapies for injury caused by AMI. The objective for this application is to identify the role of bioactive lipids in the mobilization and homing of BMSPCs to the myocardium following AMI and their therapeutic utility. The central hypothesis is that bioactive lipids play an important role in BMSPCs mobilization and homing following AMI that can be utilized clinically to enhance cardiac recovery. The rationale for the proposed research is that its completion is expected to offer new methods for enhancing the mobilization and homing of BMSPCs to injured myocardium to promote tissue regeneration following AMI. Guided by strong preliminary data this hypothesis will be tested by pursuing two specific aims: 1) Establish the role of bioactive lipids in stem cell mobilization and homing after acute myocardial infarction; and 2) Develop clinically relevant strategies to improve the mobilization ofBMSPCs to the injured myocardium following acute ischemic insult. Under the first aim the approach will involve examining human subjects and the use of transgenic animal models with altered levels of bioactive lipids to determine their role in BMSPC mobilization. For the second aim the approach will entail using clinically relevant pharmacological agents to modulate the effects of bioactive lipids and thereby achieve the desired BMSPC mobilization and homing effect and subsequent myocardial recovery. The approach is potentially innovative in that it involves utilizing bioactive lipids and members of the immune system in BMSPC mobilization and homing to enhance the outcomes of patients post AMI. The proposed research is significant because it is expected to constitute an important first step in a continuum of research that will ultimately lead to improved mechanism-based myocardial regenerative therapies. Ultimately such knowledge has the potential to contribute meaningfully toward the ultimate development of novel mechanism-based strategies to treat AMI-induced heart failure.

project_terms:
Acute;Acute myocardial infarction;Adult;Animal Model;Automobile Driving;Bone Marrow;Cardiac;Cardiac Myocytes;Chimerism;Data;Development;Environment;Event;Future;Genetic;Goals;Health;Heart failure;Hematopoietic Stem Cell Mobilization;Homing;Human;Immune;Immune system;Individual;Inflammatory;Injury;Intervention;Ischemia;Knowledge;Lead;Lipids;Literature;Longevity;Mediating;Methods;Mission;Modeling;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Mus;Myocardial;Myocardial Ischemia;Myocardium;Natural regeneration;Outcome;Pathway interactions;Patients;Peptides;Physiological;Plasma;Play;Prevention;Recovery;Research;Role;Stem cells;Testing;Therapeutic;Transgenic Animals;Transplantation;United States;Work;base;chemokine;clinically relevant;defined contribution;expectation;human subject;improved;injured;innovation;lipid metabolism;member;novel;novel therapeutic intervention;paracrine;prevent;public health medicine (field);regenerative;regenerative therapy;sphingosine 1-phosphate;stem;tissue regeneration;translational study

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health in that ischemic heart disease following AMI is the leading cause of mortality and morbidity in the United States. A mechanism-based understanding of how bioactive lipids mediate BMSPC mobilization and homing following acute ischemic cardiac injury is expected to contribute to a framework whereby novel therapeutic approaches can be developed. Thus the proposed research is relevant to the part of the NIH's mission pertaining to developing and applying fundamental knowledge to protect and improve health.


application_id: 8902534
project_number: 2R56AI051517-11
project_title: Paramyxovirus F protein mediated membrane fusion
administering_ic: NIAID
award_notice_date: 2014-08-13
opportunity_number: PA-13-302
application_type: 2
activity_code: R56
ic: AI
serial_number: 051517
program_official: CASSETTI, CRISTINA
project_start_date: 2002-05-15
project_end_date: 2014-12-31
study_section: Virology - B Study Section[VIRB]
contact_pi_person_id: 8106840
contact_pi: DUTCH, REBECCA
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): Compelling work in the last decade has shown that transmembrane domains (TMDs) once thought to function solely as hydrophobic anchors are central players driving cellular protein oligomerization cell signaling and regulation of channel function. However the role of TMDs in viral glycoprotein stability and function remains poorly understood. During the previous funding period our studies of the Hendra virus (HeV) fusion (F) protein identified key roles for TMDs in regulation of F protein stability cellular trafficking ad fusion function. Our novel studies utilizing sedimentation equilibrium (SE) analysis established that F protein TMDs efficiently trimerize separate from the rest of the protein. Altered TM-TM association was found for multiple functionally important mutations implicating TM-TM interactions in regulation of F protein folding and function. The long-term goal of our research is to understand the molecular details and regulation of membrane fusion promoted by the paramyxovirus F proteins. The overall hypothesis of this proposal is that interactions of the TMD with itself and the lipid environment are critical for fusion protein stability and function makin these interactions potential targets for antiviral therapeutics. To test this important hypothesis we will pursue three specific aims. First we will define key elements driving F protein TM-TM interactions including defining the role of a L/I heptad in TM-TM association and Hendra F protein stability. Second we will determine how the TMD affects fusion triggering and promotion of membrane fusion with a focus on the role of C-terminal beta-branched residues and a determination of the conformational changes that can occur when TM-TM interactions cannot be released. Third we will dissect the role of the lipid environment in prefusion F stability in the context of cellular and viral membranes. These important experiments will provide critical new insight into the role of TMDs in regulation of F protein stability and fusion promotion.

project_terms:
Address;Affect;Antiviral Agents;Automobile Driving;C-terminal;Ca(2+)-Transporting ATPase;Cells;Characteristics;Chimeric Proteins;Cholesterol;Cytoplasmic Tail;Data;Development;Dissociation;Elements;Environment;Family;Funding;Glycoproteins;Goals;Health;Hendra Virus;Human Metapneumovirus;Individual;Infection;Kinetics;Lipids;Mediating;Membrane;Membrane Fusion;Membrane Fusion Activity;Molecular;Molecular Conformation;Mutation;Neuropilins;Paramyxovirus;Paramyxovirus Fusion Protein;Peptides;Play;Process;Proteins;Regulation;Research;Rest;Role;Sarcoplasmic Reticulum;Signal Transduction;Structure;System;Testing;Therapeutic;Time;Transmembrane Domain;Viral;Viral Fusion Proteins;Viral Proteins;Virus;Work;disulfide bond;fluidity;insight;mutant;novel;particle;prevent;protein folding;protein function;research study;sedimentation equilibrium;trafficking


application_id: 8902341
project_number: 1G20OD020297-01
project_title: Establishing a Bioexclusion Barrier in the Combs Cancer Research Building
administering_ic: OD
award_notice_date: 2015-03-27
opportunity_number: PAR-14-251
application_type: 1
activity_code: G20
ic: OD
serial_number: 020297
program_official: MCCULLOUGH, WILLIE
project_start_date: 2015-04-01
project_end_date: 2017-03-31
study_section: Scientific and Technical Review Board on Biomedical and Behavioral Research Facilities[STOD]
contact_pi_person_id: 1903578
contact_pi: STILLS, HAROLD F
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The University of Kentucky requests $500000 to be combined with a $441449 university contribution to establish a bioexclusion barrier capability on the east campus biomedical complex by renovating a portion of the Combs Cancer Research Building (CCRB) animal facility. The CCRB animal facility is a 5570 ft2 facility that is an integrl portion of the ~34000 ft2 contiguous east campus biomedical complex animal facility and contains the cage sanitation and sterilization support facilities for all rodents housed in the entre facility. The east campus biomedical complex animal facility is an older facility designed for conventional animal housing. The minimal sterilization capacity and lack of restricted entry barrier housing rooms with integral procedural rooms has severely limited our ability to prevent the exposure of rodents to endemic opportunistic pathogens including Pasteurella pneumotropica Helicobacter spp. and Norovirus. The result has been morbidity and mortality in unique immunocompromised transgenic mouse strains which has negatively impacted the research efforts of a number of NIH-funded investigators. The opening of the NIH-funded Sanders-Brown Embryo Cryopreservation and Rederivation Core has provided the University with in-house rederivation capability for the first time permitting the rederivation of unique transgenic rodent colonies to eliminate these opportunistic pathogens. While this facility can initially expand the colonies prior to return to the investigator there is a lack of sufficient barier housing and support facilities on the east campus biomedical complex to isolate these rederived "clean" colonies from conventional colonies and prevent re-infection. This project has three specific aims. The first aim is the expansion of the clean cage wash/cage prep area with redirection of cage flow from the tunnel washer to eliminate a burn hazard to personnel and permit the relocation of the remotely located bedding dispenser to improve efficiency. The installation of a dry-heat sterilizer will provide the capability to support the bioexclusion barrir. The second aim is the establishment of two bioexclusion barrier animal housing rooms with a dedicated ante/procedure room. The third aim is to reduce energy and maintenance demands improve cage microenvironment reduce odors and eliminate noise and vibrations by replacing the outdated Class 100 Vertical Laminar Flow (VLF) ventilation systems with a system designed to optimally support individually ventilated cage (IVC) systems. The renovation will provide the infrastructure needed for anticipated future expansion of the barrier facility and improve the flow
of caging through the entire facility improving efficiency and minimizing the potential for cross-contamination. This renovation will be the initial step in a long-term University effort to eliminae and exclude opportunistic pathogens that result in animal disease limit the interchange of unique strains among investigators and confound research results at the east campus biomedical complex the university's largest animal facility.

project_terms:
Animal Diseases;Animal Housing;Area;Beds;Burn injury;Comb animal structure;Complex;Cryopreservation;Embryo;Environmental air flow;Facility Designs;Funding;Future;Heating;Helicobacter;Housing;Human Resources;Immunocompromised Host;Infection;Kentucky;Maintenance;Morbidity - disease rate;Mortality Vital Statistics;Mouse Strains;Noise;Norovirus;Odors;Pasteurella pneumotropica;Procedures;Research;Research Infrastructure;Research Personnel;Rodent;Sanitation;Sterilization;System;Time;Transgenic Mice;Transgenic Organisms;United States National Institutes of Health;Universities;animal facility;anticancer research;design;hazard;improved;pathogen;prevent;supported housing;vibration


application_id: 8902195
project_number: 5P20GM103436-15
project_title: EKU Lead Faculty Award
administering_ic: NIGMS
award_notice_date: 2015-07-03
opportunity_number: PAR-12-205
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
study_section: ZGM1-TWD-7
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: 2015-05-01
budget_end_date: 2016-04-30
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;DNA Sequence Alteration;Data Analyses;Data Collection;Defect;Development;Educational workshop;Ensure;Event;Experimental Designs;Faculty;Funding;Gene Expression;Gene Expression Profile;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;Microarray Analysis;Molecular;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;miRNA expression profiling;next generation sequencing;operation;outreach;rapid growth;tool


application_id: 8902193
project_number: 5P20GM103436-15
project_title: Genomics Core
administering_ic: NIGMS
award_notice_date: 2015-07-03
opportunity_number: PAR-12-205
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
study_section: ZGM1-TWD-7
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: 2015-05-01
budget_end_date: 2016-04-30
project_terms:
Anatomy;Biochemistry;Bioinformatics;Biological Sciences;Biology;Biomedical Research;Biometry;Chemistry;Clinical Research;Clinical and Translational Science Awards;Collaborations;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: 8902192
project_number: 5P20GM103436-15
project_title: Bioinformatics Core
administering_ic: NIGMS
award_notice_date: 2015-07-03
opportunity_number: PAR-12-205
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
study_section: ZGM1-TWD-7
subproject_number: 7044
contact_pi_person_id: 7948398
contact_pi: ROUCHKA, ERIC C
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: 2015-05-01
budget_end_date: 2016-04-30
project_abstract:
We wish to provide the next generation of biomedical investigators with the correct tools and environment to help them succeed in the rapidly changing scientific enterprise. The omics approaches and bioinformatics tools are the tools for the biomedical research of today and we-have to insure that our undergraduate students understand their underlying strengths and weaknesses. We need to make sure that students in the Commonwealth of Kentucky are learning how to become competitive in a competitive world. It is our thesis that the best training ground will include some research training in competitive labs where investigators-mentors are themselves forging their independence through competition in the federal funding marketplace. Not all investigators will be able to market their ideas and not all students can be placed in competitive labs but the strategy of the Developmental Research Core is designed to maximize opportunities for both faculty mentors and student trainees.  The logic model below (Table 21) provides a schematic overview of our plan for the Developmental Research Core. Specifically reading from left to right this model provides a succinct description of the specific aims of the core the strategic activities planned to accomplish these aims the objective measurable outputs necessary to evaluate progress and the expected short- and long-term outcomes. It should be emphasized that while separately presented and discussed all aspects of the Developmental Research Core are well integrated into the overall KBRIN operational plan (see Network section) and the activities of other cores (e.g. genomics bioinformatics administrative) as well as evaluation processes are critical to the success of the core.  Consistent with INBRE goals the major objective of the Development Research Core is to provide an array of programs to develop a number of competitive biomedical research faculty in Kentucky's primarily undergraduate institutions (PUis). Moreover it is implicit in this endeavor that we have the intent to develop a sustainable research enterprise. The foundation of this core was developed during the initial BRIN planning grant in 2001 and has continued to evolve based upon annual outcomes assessment formative evaluation and changing needs. One of the critical components of our approach has always been the element of opportunistic flexibility the ability to change tactics as needed. This will be explained in more detail below. All along the primary assumption underlying this program is that each Kentucky institution needs a critical mass of independent biomedical researchers as faculty (who publish on a regular basis and are competitive for NIH grant programs) in order to provide the highest quality biomedical research training to undergraduate students. As noted in our Progress Report this core has been very successful in developing junior investigators to be competitive for NIH R15 funding (25 R15s since 2007) and equally important in assisting successful R15 investigators maintain their funding beyond their first R15 award. Indeed six Pis in the state are now working on their second and in two cases their third R15 award. This success has allowed us to support additional researchers at each network institution as well provide incentive funds to recruit ten new highly qualified biomedical researchers to faculty positions in network institutions. This progress in developing a critical mass of independent investigators has allowed the PUis to provide state-of-the-art training and research opportunities for students which has resulted in an increase in the number of students pursuing biomedical research careers and a better trained workforce (see Progress Report).  In the remainder of this section we first describe the history evolution and progress of our developmental research programs along with supporting data and the rationale for modifying these programs over time. Following this introduction the general guidelines and administrative procedures for all programs are presented including (1) Eligibility criteria; (2) Award conditions; (3) Solicitation procedures; (4) Application procedures; (5) Review and selection criteria; (6) Progress reports and evaluation; (7) Student research training; and (8) Mentoring services. Following this description of general guidelines and procedures the specific Developmental Research Programs proposed to build upon our past successes in the next five-year award period are described.

project_terms:
Application procedure;Award;Beryllium;Bioinformatics;Biomedical Research;Data;Development;Eligibility Determination;Environment;Evaluation;Evolution;Faculty;Foundations;Funding;Genome;Genomics;Goals;Grant;Guidelines;Incentives;Institution;Kentucky;Knowledge;Learning;Left;Logic;Marketing;Measurable;Mentors;Modeling;Outcome;Outcome Assessment (Health Care);Output;Positioning Attribute;Procedures;Process;Progress Reports;Publishing;Qualifying;Reading;Recording of previous events;Recruitment Activity;Research;Research Personnel;Research Training;Science;Selection Criteria;Services;Students;Technology;Time;Training;United States National Institutes of Health;Work;base;career;design;flexibility;forging;functional genomics;next generation;programs;research and development;success;tool;undergraduate student


application_id: 8902191
project_number: 5P20GM103436-15
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2015-07-03
opportunity_number: PAR-12-205
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
study_section: ZGM1-TWD-7
subproject_number: 7043
contact_pi_person_id: 1866398
contact_pi: COOPER, NIGEL G.F.
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: 2015-05-01
budget_end_date: 2016-04-30
project_terms:
Award;Biomedical Research;Development;Evaluation;Health;Leadership;Mentors;Research;Research Infrastructure;Research Training;Structure;Training;member;sound


application_id: 8902077
project_number: 5R21CA187345-02
project_title: Plasma DSC for early detection of disease and therapeutic efficacy in melanoma
administering_ic: NCI
award_notice_date: 2015-08-07
opportunity_number: PAR-13-146
application_type: 5
activity_code: R21
ic: CA
serial_number: 187345
program_official: THURIN, MAGDALENA
project_start_date: 2014-08-01
project_end_date: 2017-07-31
study_section: ZCA1-SRLB-Y(M2)
contact_pi_person_id: 11129807
contact_pi: GARBETT, NICHOLA C.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Stage IV melanoma kills approximately 40000 individuals per year globally. Early detection of new metastases is essential since up to three metastastic tumors can be resected for cure and patients with limited disease burden have improved clinical outcomes to immunotherapeutic agents such as ipilimumab (anti- CTLA4). As a result full-body FDG-PET and CT imaging assessments are routinely conducted every three months for surveillance and every two months for response assessment. However the utility of these scans is limited by both cost and the contribution of cumulative radiation exposure to secondary malignancies. The development of new non-invasive approaches for melanoma detection and frequent monitoring thus is expected to result in a marked reduction in melanoma-related deaths. The overarching goal of our research is the development of differential scanning calorimetry (DSC) analysis of blood plasma as a new non- invasive diagnostic to enable more frequent monitoring and facilitate early detection of recurrences and early assessment of therapeutic response. Importantly the University of Louisville's Melanoma Multi- Disciplinary Clinic and Tissue Repository has a large and growing collection of detailed de-identified clinical information and multiple longitudinal plasma specimens from stage I-IV melanoma patients (>3000 plasma samples and currently 219 resected melanoma metastases) which we propose to access in order to test this novel diagnostic approach. The application of DSC analysis to characterize the blood plasma proteome in our lab has provided an entirely new and complementary bioanalytical approach for the detection and monitoring of disease. DSC monitors heat changes associated with the thermal denaturation of biomolecules yielding a unique profile characteristic of the components their amounts and interactions. Preliminary data indicate that direct analysis of small volumes of plasma using DSC yields profiles (or thermograms) that are sensitive to differences in the thermodynamic properties of abundant plasma proteins related to health status. DSC thermograms show sensitivity to disease pathology and therapeutic response and therefore could have considerable utility as a new diagnostic approach. The goals of this proposal are to examine the performance of DSC thermograms alongside standard PET/CT imaging for the diagnosis the early detection of recurrence and the assessment of therapeutic efficacy in melanoma. If we are successful the proposed research has the potential to contribute to earlier clinical assessment that can directly impact the care of melanoma patients. We propose three aims. Aim 1 addresses the utility of DSC thermograms for the detection and stage differentiation of melanoma compared with PET/CT. Aim 2 will determine the diagnostic performance of DSC analysis of longitudinal plasma samples to detect disease recurrence following surgical resection in stage III patients. In Aim 3 we will determine the utility of DSC for the assessment of early response to treatment in BRAF+ stage IV melanoma patients.

project_terms:
Address;Aftercare;BRAF gene;Blood;Blood Plasma Volume;CTLA4 gene;Cancer Center;Caring;Cessation of life;Characteristics;Classification;Clinic;Clinical;Clinical assessments;Collection;Control Groups;Data;Databases;Deposition;Detection;Development;Diagnosis;Diagnostic;Differential Scanning Calorimetry;Discrimination (Psychology);Disease;Early Diagnosis;Enrollment;Excision;Exposure to;Goals;Health;Health Status;Heating;Image;Immunotherapeutic agent;Immunotherapy;Incidence;Individual;Killings;Link;Monitor;Neoplasm Metastasis;Operative Surgical Procedures;Outcome;PET/CT scan;Pathology;Patient Care;Patients;Performance;Plasma;Plasma Proteins;Positron-Emission Tomography;Property;Proteome;Proteomics;Protocols documentation;Radiation;Recurrence;Research;Resectable;Resected;Risk;Sampling;Scanning;Second Primary Cancers;Specimen;Staging;Systemic Therapy;Testing;Therapeutic;Therapeutic Agents;Thermodynamics;Time;Tissues;Treatment Efficacy;Tumor Burden;Universities;X-Ray Computed Tomography;burden of illness;clinical care;cost;disease diagnosis;effective therapy;high risk;imaging modality;improved;longitudinal analysis;melanoma;novel;novel diagnostics;novel strategies;repository;response;standard of care;tool;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Although effective treatment of melanoma is critically dependent on early and accurate detection PET/CT imaging is only used every 2-3 months as a result of radiation burden and expense. The goal of this proposal is to build upon our significant promising preliminary data to demonstrate the feasibility and utility of DSC analysis o blood plasma as a new non-invasive diagnostic tool. Our approach could enable more frequent monitoring and facilitate early detection of recurrences and early assessment of therapeutic response in melanoma that can directly impact the clinical care of patients.


application_id: 8901852
project_number: 5R01AA021722-03
project_title: Behavioral Dysregulation and Alcohol Sensitivity in Risky Drivers
administering_ic: NIAAA
award_notice_date: 2015-07-22
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: 2016-07-31
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;Health;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);recidivism;response;success;theories;trafficking;trait impulsivity;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: 8901836
project_number: 5R01AA016959-09
project_title: Ethanol alteration of the neurogenic niche
administering_ic: NIAAA
award_notice_date: 2015-08-26
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: 2017-08-31
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;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;behavioral outcome;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: 8901221
project_number: 5P30GM103507-05
project_title: Mechanisms of plasticity and repair after SCI
administering_ic: NIGMS
award_notice_date: 2015-07-27
opportunity_number: PAR-10-196
application_type: 5
activity_code: P30
ic: GM
serial_number: 103507
program_official: ZLOTNIK, HINDA
project_start_date: 2011-08-01
project_end_date: 2017-07-31
study_section: ZRR1-RI-B(01)
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The goal of this revised PSO grant is to expand the present COBRE-funded Kentucky Spinal Cord Injury Research Center (KSCIRC) Core facilities at the University of Louisville (UofL). We propose to broaden the scope of research that these Cores support in neural development and CNS injury and 2) bring additional PIs into the Center both to enhance their research programs and to bring their new techniques and approaches to the COBRE PIs. We will increase the number of involved PIs from 8 to 22. The Cores will facilitate the research programs of both NIH funded and non-funded junior and more senior PIs in directions that would not be possible without the highly trained Core personnel. Each Core will be directed by a funded PI and housed in independent dedicated laboratory space. All PIs will have access to these Cores. We will give priority access to junior and unfunded PIs. The UofL administration will make significant space and financial commitment to the COBRE/KSCIRC Core Facilities. The Cores are: A) Administration and Biostatistics B) Surgery and Animal Care C) Behavioral and Electrophysiological Assessment D) Cell and Tissue Imaging and Histology and E) Human Translational Studies. The specific aims are: 1. Support and enhance the scope of the strong ongoing UofL NINDS and non-NINDS funded research in the areas of nervous system injury and repair including our continuing development of innovative technology. 2. Make our technologies available to additional UofL neuroscientists working in other areas of nervous system development and repair to facilitate their individual research programs with novel approaches. 3. Facilitate the development of the research programs of junior and more senior unfunded Investigators. 4. Enhance collaborative opportunities between PIs that utilize these Core facilities.

project_terms:
Area;Behavioral;Biometry;Cancer Grant Supplements (P30);Centers of Research Excellence;Core Facility;D Cells;Development;Extramural Activities;Faculty;Funding;Goals;Grant;Histology;Housing;Human;Human Resources;Image;Individual;Investments;Kentucky;Laboratories;Life;Mentorship;Mortality Vital Statistics;National Institute of Neurological Disorders and Stroke;Nervous System Trauma;Neurosciences Research;Operative Surgical Procedures;Paralysed;Rattus;Rehabilitation Research;Rehabilitation therapy;Research;Research Infrastructure;Research Personnel;Resources;Rodent;Secure;Services;Spinal cord injury;Techniques;Technology;Therapeutic;Tissues;Training;Translating;United States;United States National Institutes of Health;Universities;Work;animal care;central nervous system injury;disability;injury and repair;innovation;innovative technologies;insight;nervous system development;neurodevelopment;novel;novel strategies;programs;rehabilitation strategy;repaired;research and development;translational study

public_health_relevance:
Each year over 10000 people in the United States suffer a traumatic spinal cord injury (SCI) and a recent estimate puts the number of people living with paralysis in the U.S. at 6 million. SCI continues to be a significant cause of disability and mortality. This grant proposes infrastructure that will allow insight into both mechanisms of injury and repair and novel rehabilitative strategies.


application_id: 8901173
project_number: 5R21ES024158-02
project_title: Lead Exposure in a Novel Mouse Model of Neurologic Disease
administering_ic: NIEHS
award_notice_date: 2015-07-14
opportunity_number: RFA-ES-13-007
application_type: 5
activity_code: R21
ic: ES
serial_number: 024158
program_official: HOLLANDER, JONATHAN
project_start_date: 2014-08-01
project_end_date: 2017-07-31
study_section: ZES1-LWJ-K(R)
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Environmental exposure to lead (Pb) has been linked to risk of late-onset Alzheimer's disease (AD) and dementia. Although Pb has long been known as a neurotoxic agent in children a recent and growing body of both toxicological and epidemiological research indicates that cumulative environmental Pb exposure is toxic to adults as well and may be a significant contributor to age-related neurologic dysfunction. The biological mechanism underlying this link is not known. It has been proposed based on a limited number of animal studies that the linkage is through epigenetic changes in the methylation state of DNA although evidence for this mechanism in human disease has been lacking. This proposal considers another possibility that the linkage is through a combination of Pb-driven neuropathologic change and that cerebrovascular pathology is the major contributor to this form of neurologic dysfunction. The amount of cerebrovascular pathology is a significant co-morbidity in all forms of age-related dementia. Most individuals with AD have some degree of comorbid cerebrovascular pathology although individuals with a history of obesity and T2DM have substantial amounts of this pathology. To investigate this problem we created a line of knock-in mice that co-develops amyloid pathology and cerebrovascular abnormalities with increasing age. The most remarkable feature of this novel mouse model (db/AD) is that it develops a striking phenotype of cerebrovascular pathology including aneurysms and strokes and also displays a profound cognitive impairment. We believe that we have created an innovative model of AD with significant cerebrovascular disease an understudied variant with limited treatment options. The unique db/AD mouse does not overexpress disease related proteins or use artificial promoter systems making it an ideal system for the study of how aberrant gene regulation in disease can influence brain pathology. This presents an unparalleled opportunity to study and potentially dissociate the role of Pb exposure at different times in an animal's lifespa and gauge the ultimate impact on neuropathology. This proposal thus seeks to answer three key questions relating to Pb exposure and neurologic disease that occurs later in life. First is early life Pb exposure more damaging than exposure as an adult? Second can Pb cause late-life cognitive dysfunction by increasing cerebrovascular pathology such as strokes through increased hypertension a well-known outcome of Pb exposure? Finally how much does Pb exposure affect the development of AD-related pathology by affecting the expression of AD related genes? We believe that our mouse model is uniquely suited to answering these questions. A major innovative feature of this proposal is the use of a novel mouse model with unique features exhibiting significant age associated AD-related amyloid deposition cerebrovascular pathology and cognitive dysfunction. This project not only has clear implications for the prevention and treatment of age-related cerebrovascular disease but also has the potential to advance our understanding of the major underlying causes of cerebrovascular disease as comorbidity in the AD brain.

project_terms:
Adult;Affect;Age;Alzheimer's Disease;Alzheimer's disease model;American;Amyloid deposition;Aneurysm;Animal Disease Models;Animal Model;Animals;Biological;Blood Pressure Monitors;Blood Vessels;Brain;Brain Pathology;Cerebrovascular Disorders;Child;Comorbidity;Complex;Cryopreservation;DNA;Dementia;Development;Disease;Elderly;Embryo;Employee Strikes;Ensure;Environmental Exposure;Epidemiology;Epigenetic Process;Exhibits;Experimental Designs;Exposure to;Gene Expression;Gene Expression Regulation;Genes;Goals;Grant;Health;Hypertension;Impaired cognition;Individual;Institution;Kentucky;Knock-in Mouse;Late Onset Alzheimer Disease;Life;Link;Longevity;Magnetic Resonance Imaging;Mediating;Methylation;Modeling;Mus;National Institute of Environmental Health Sciences;Neurodegenerative Disorders;Neurologic;Neurologic Dysfunctions;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Pathology;Phenotype;Play;Prevention;Promotor (Genetics);Proteins;Recording of previous events;Recovery;Relative (related person);Research;Resources;Risk;Risk Factors;Role;Specimen;System;Testing;Therapeutic;Time;Toxic effect;Universities;Variant;Vascular Dementia;age related;amyloid pathology;base;behavior test;cerebrovascular;chronic Pb exposure;cognitive function;environmental Pb exposure;human disease;innovation;lead exposure;mouse model;neuropathology;neurotoxic;novel;overexpression;response;sharing data;spectroscopic imaging;stroke;success

public_health_relevance:
PUBLIC HEALTH RELEVANCE: A strong connection exists between risk for vascular dementia Alzheimer's disease type 2 diabetes (T2D) and obesity but the mechanisms are unknown. The connection may involve strokes and other forms of cerebrovascular pathology. This project will investigate the role of environmental lead exposure as an underlying risk factor in this complex disease state.


application_id: 8900956
project_number: 5R01AR060964-04
project_title: Modulating Inflammation and Fibrosis to Control Scarring in Muscle Wounds
administering_ic: NIAMS
award_notice_date: 2015-07-15
opportunity_number: PA-10-009
application_type: 5
activity_code: R01
ic: AR
serial_number: 060964
program_official: PARK, HEIYOUNG
project_start_date: 2012-08-01
project_end_date: 2018-07-31
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;Health;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;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.


