# projects

application_id: 9325025
project_number: 5P30GM110788-04
project_title: OHPP Oral Health Pilot Program
administering_ic: NIGMS
award_notice_date: 2017-08-03
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110788
study_section: ZGM1-TWD-C
subproject_number: 8150
contact_pi_person_id: 1883677
contact_pi: MILLER, CRAIG S
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-08-01
budget_end_date: 2018-07-31
project_abstract:
The Oral Health Pilot Program (OHPP) is designed to identify and recruit research efforts from across UK that support the use of the unique core facilities supported by the Phase III CBBO/SD. This program will leverage resources from the COBRE grant and College of Dentistry to provide three types of pilot project funding: (1) Clinical research planning grants to aid investigators at UK in developing the initial concept and linkages for multi-investigator multi-site or multi-institutional clinical research investigations; (2) Bridge grants to support UK investigators with finite funds to enhance pilot data available for submission of a new grant resubmission success of a grant as well as to help in transition times between grant awards; and (3) Pilot/feasibility grants that are full pilot proposals for faculty to develop new areas of science or extend their existing scientific focus by obtaining substantial preliminary data to help effectively compete for new grants at NIH or other similar funding sources. This engages the centers' core directors. Steering Board and Scientific Advisory Committee members. Also linking this program with ongoing pilot programs in other UK centers and institutes will help leverage these funds. Finally use of existing systems for development and submission of these pilots through the CCTS and Office ofthe Vice President for Research will expedite marketing of the program to increase awareness and solicit high quality applications.

project_terms:
Advisory Committees;Area;Award;Awareness;Centers of Research Excellence;Clinical Research;Committee Members;Communities;Core Facility;Data;Dentistry;Faculty;Funding;Funding Agency;Grant;Institutes;Investigation;Link;Marketing;Oral;Oral health;Phase;Pilot Projects;Recruitment Activity;Research;Research Personnel;Resources;Science;Site;Systemic disease;Systems Development;Time;United States National Institutes of Health;base;college;design;improved;programs;research and development;success

public_health_relevance:
The OHPP core is primarily designed to be the starting point for development of research initiatives that will contribute mid-to long-term to improving oral health. Thus these activities will help effectively use the cores ofthe COBRE center and extend their value in contributing to the ability of these pilot projects to advance towards more directly impacting oral health. It is anticipated that certain of these will be community-based pilots.


application_id: 9325023
project_number: 5P30GM110788-04
project_title: DDKCRC Clinical Core
administering_ic: NIGMS
award_notice_date: 2017-08-03
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110788
study_section: ZGM1-TWD-C
subproject_number: 8148
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: 2017-08-01
budget_end_date: 2018-07-31
project_abstract:
The DDKCRC is the principal clinical research facility in the College of Dentistry at UK. It is partnered with the Clinical Research Development and Operations Center (CRDOC) medical clinical operations under the UK Centerfor Clinical and Translational Research. The facility is staffed by managers and multiple clinical coordinators that contribute to supporting investigators in the development of projects IRB application process marketing and recruiting for studies clinical evaluation biologic specimen collection and management and reporting requirements for UK and the federal government. Thjs 6-operatory facility will continue to provide these services as well as extending its interface with other clinical activities in the College of Dentistry.

project_terms:
Address;Clinical;Clinical Research;Dental Care;Dentistry;Development;Federal Government;Health Services Accessibility;Institutional Review Boards;Marketing;Medical center;Oral;Oral health;Patients;Phase;Process;Recruitment Activity;Reporting;Research Personnel;Research Project Grants;Services;Systemic disease;Time;Translational Research;college;improved;operation;research and development;research clinical testing;research facility;sample collection

public_health_relevance:
The DDKCRC is critical to the development and implementation of clinical and translational research in the College of Dentistry. The patients coming to the College of Dentistry for dental care are offered opportunities to participate in research projects that address their specific needs. This interaction takes place at the time of registration at the college. Thus this core helps provide greater opportunities for patients to access care and improve their oral health.


application_id: 9325021
project_number: 5P30GM110788-04
project_title: Center for the Biologic Basis of Oral/Systemic Diseases (Phase III)
administering_ic: NIGMS
award_notice_date: 2017-08-03
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110788
program_official: GAO, HONGWEI
project_start_date: 2014-08-15
project_end_date: 2019-07-31
study_section: ZGM1-TWD-C(C3)
contact_pi_person_id: 6200819
contact_pi: KYRKANIDES, STEPHANOS
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Systemic Diseases (CBBO/SD)" is to continue sustainability of a nationally competitive transdisciplinary research center focusing on oral healt sciences and systemic diseases within the University of Kentucky. This proposal builds upon the Phase l/ll funding for developing the research infrastructure in the College of Dentistry and supporting junior investigators to develop competitive research programs using this infrastructure. The CBBO/SD represents the concrete realization of the Specific Aims of the Phase l/ll funding that was designed to: (i) expand the critical mass of funded investigators at UK in the areas of oral and systemic health research; (ii) create and enhance cutting-edge scientific core resources that can continue to serve as platforms to increase the competitiveness of existing research faculty as well as for recruiting new faculty; and (iii) implement the range f infrastructure improvements in the research enterprise to successfully transition the COBRE funding into long-term competitive renewable support from a diverse array of federal and non-federal sources. The UKCD created a position for an Associate Dean for Research and a Center for Oral Health Research (COHR) housed in the college to develop and oversee a broad range of basic and applied research beginning in 2000. This was followed by events that created a vibrant environment for implementation of the CBBO/SD in 2003 with an explicit goal of developing a center conducting research on oral and systemic health and housed in the College of Dentistry. The CBBO/SD provides a strong thematic research focus and unique resources along with research training of graduate students post-doctoral fellows and junior faculty mentoring. From the outset this was accomplished in a collaborative framework that emphasized mentoring scientific advancement academic career development competitive grantsmanship and productivity. The Phase III proposal incorporates 4 interactive cores: Adminstrative/Educational Core Delta Dental of Kentucky Clinical Research Center (DDKCRC) Core; Core Translational Diagnostics Laboratory (CTDL); and Oral Health Pilot Program (OI-IPP) core. The CBBO/SD Phase Ill objectives are to: (1) focus efforts and resources towards creating a sustainable university-wide research center with unique clinical and translational scientific cores providing interdisciplinary research interactions in oral and general health investigations (2) continue to identify Stimulate and nurture investigators at the University of Kentucky to ascertain and pursue important questions related to diseases of the oral and craniofacial complex and (3) enhance the expansion of collaborative research programs by supplying structure and expertise in specialized core facilities supporting these research initiatives. The major research theme of the CBBO/SD generally remains similar to those throughout the Phase l/ll tenure of the center. This focused on chronic inflammatory diseases with infections and dysregulated host responses linking oral and systemic health. The CBBO/SD has a parallel goal in providing the fundamental basis for the research enterprise in the UK College of Dentistry (UKCD) to actively participate in the national clinical and translation research environment with a focus of moving clinical findings into improving health of the population with enhanced implementation of new clinical findings. As the flagship land-grant University of the Commonwealth of Kentucky the UKCD has a major role in helping to solve the massive health care needs of the Appalachian population inhabiting 54 counties in Kentucky by addressing multigenerational oral and general health disparities in Appalachian Kentucky. This will require effective interprofessional education collaborative research initiatives and emphasizing external funding from a wide array of NIH institutes other federal agencies and independent private and public funding sources. The Strategic Objectives of the Phase III aspect of the center include: understand the molecular mechanisms underlying periodontal disease; foster collaborations enabling definition of the biologic mechanisms linking periodontal disease with systemic disease(s); support collaborative efforts across the UK campus to engage additional research teams into the offering of the Genetics/Genomics services and the Mineralized Tissue services; and continue the research relationship with the Center for Clinical and Translational Sciences at UK to implement community-based initiatives to reduce oral disease burden.

project_terms:
Address;Appalachian Region;Applied Research;Area;Basic Science;Centers of Research Excellence;Chronic;Clinical;Clinical Research;Clinical Sciences;Collaborations;Communities;Core Facility;County;Dental;Dentistry;Disease;Education;Environment;Event;Faculty;Fostering;Funding;Funding Agency;Future Generations;Genetic;Genomics;Goals;Grant;Health;Healthcare;Immune response;Individual;Infection;Inflammatory;Institutes;Interdisciplinary Study;Investigation;Kentucky;Laboratories;Link;Mentors;Minerals;Modeling;Molecular;Mouth Diseases;Oral;Oral cavity;Oral health;Periodontal Diseases;Phase;Population;Positioning Attribute;Postdoctoral Fellow;Privatization;Productivity;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Research Support;Research Training;Resources;Role;Rural Population;Science;Services;Source;Structure;Systemic disease;Tissues;Translational Research;United States National Institutes of Health;Universities;base;burden of illness;career development;college;craniofacial complex;design;faculty mentor;faculty research;graduate student;health disparity;improved;population health;programs;public health relevance;translational diagnostics

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The COBRE core infrastructure will focus on supporting clinical and translational research that impacts health of the oral cavity and the individual. The substantially poor oral health metrics of the population of Kentucky particularly rural populations needs to be addressed with new science and new models to deliver improved health for future generations.


application_id: 9324719
project_number: 5F31NS093904-02
project_title: Mitochondria Transplantation for Functional Recovery after Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2017-03-15
opportunity_number: PA-14-147
application_type: 5
activity_code: F31
ic: NS
serial_number: 093904
program_official: JAKEMAN, LYN B
project_start_date: 2016-04-01
project_end_date: 2017-08-28
study_section: Special Emphasis Panel[ZRG1-F01A-F(20)L]
contact_pi_person_id: 12110259
contact_pi: GOLLIHUE, JENNA LEIGH
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): Contusion spinal cord injury (SCI) is a mechanical insult to the spinal cord which results in immediate tissue damage followed by excitotoxicity increased production of reactive oxygen species and compromised mitochondrial function. Each of these contributes to secondary pathophysiological cascades which are responsible for increasing the spread and severity of the injured tissue. Importantly the loss of mitochondrial function is implicated in most of the pathways in these cascades. As such this proposal will determine whether supplementation with exogenous healthy mitochondria after SCI can attenuate secondary injury damage possibly salvaging at-risk tissue that would have otherwise been compromised. Mitochondrial transplantation has been tested successfully in other tissue injuries but never following SCI. In doing so it may be possible to restore some functional recovery of the hind limbs over time after injury. A rat model of contusion SCI will be used to tes the overall hypothesis that supplementation of healthy mitochondria into an injured spinal cord will result in improved functional recovery via preservation of compromised tissues. In the first set of experiments mitochondria labeled with turbo green fluorescent protein (tGFP) will be isolated from cultured cells and transplanted directly into the injured rat spinal cord at three different concentrations and two time points after injury. To test the hypothesis that mitochondrial supplementation restores cellular bioenergetics and reduces oxidative stress molecular/biochemical outcome measures will be used including mitochondrial respiration calcium buffering capacity and markers of oxidative damage or inflammation. A second experiment is designed to determine which cell types are incorporating the exogenous tGFP mitochondria employing the injection concentration found to most closely maintain normal mitochondrial bioenergetics. Confocal microscopy of double and triple immunolabeling will allow visualization of cell-type colocalization with exogenous tGFP mitochondria as well as establish their rostral-caudal distribution. Most critically injections of isolated tGFP mitochondria after CI will be used to test the hypothesis that mitochondrial transplantation improves long-term hindlimb functional recovery after injury. The extent of hindlimb functional recovery will then be correlated with tissue sparing afforded by mitochondrial supplementation. Taken together results from these experiments will show that healthy mitochondria can be injected into an injured spinal cord and integrate into host cells thus increasing both mitochondrial function and cellular bioenergetics. Such maintenance of cellular homeostasis is expected to be correlated with increased tissue preservation and improved long-term hindlimb functional recovery. Once found to be a viable therapeutic mitochondrial supplementation therapy may be implemented as a novel bioenergetics medicine in the clinic to treat individuals after SCI.

project_terms:
Acute;Address;Adult;Americas;Animals;Attenuated;Autologous;Biochemical;Bioenergetics;Biological Preservation;Buffers;Calcium;Cardiac;Cell Survival;Cell Transplantation;Cell Transplants;Cells;Clinic;Confocal Microscopy;Contusions;Cultured Cells;Development;Evaluation;Female;Free Radical Scavengers;Green Fluorescent Proteins;Hindlimb;Histologic;Homeostasis;Hour;Imagery;Immune system;Immunohistochemistry;In Vitro;Individual;Infarction;Inflammation;Injectable;Injection of therapeutic agent;Injury;Intervention;Label;Laminectomy;Lateral;Limb structure;Locomotor Recovery;Macrophage Activation;Maintenance;Measures;Mechanics;Medial;Medicine;Mental Depression;Methods;Microglia;Mitochondria;Modeling;Molecular;Numbness;Organelles;Outcome Measure;Oxidative Stress;Oxygen Consumption;Paralysed;Pathway interactions;Play;Process;Production;Quality of life;Quantitative Reverse Transcriptase PCR;Rattus;Reactive Oxygen Species;Recovery;Recovery of Function;Reperfusion Therapy;Reporting;Respiration;Respiratory System;Risk;Rodent Model;Secondary to;Severities;Site;Spectrophotometry;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;Sprague-Dawley Rats;Supplementation;Testing;Therapeutic;Time;Tissue Preservation;Tissues;Toxic effect;Translations;Transplantation;United States;Work;cell type;clinically relevant;design;dosage;excitotoxicity;experimental study;gait examination;gray matter;improved;in vivo;injured;mitochondrial dysfunction;neuroprotection;novel;oxidative damage;prevent;public health relevance;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: There are a reported 12000 new cases of traumatic spinal cord injury (SCI) in the United States of America each year resulting in lifelong debilitating consequences including paralysis loss of sensation compromised immune and respiratory systems and depression. This project proposes that supplementing the acutely injured spinal cord with healthy mitochondria the major energy producing organelle in cells will rescue damaged tissue and prevent the injury from spreading in a rodent model of SCI. Translation of this therapy into the clinic may improve the potential for locomotor recovery and have a high impact on the long-term quality of life for individuals living with SCI.


application_id: 9324718
project_number: 5F30NS090714-02
project_title: Elucidating A Novel Mechanism for Dementia
administering_ic: NINDS
award_notice_date: 2017-11-15
opportunity_number: PA-14-150
application_type: 5
activity_code: F30
ic: NS
serial_number: 090714
program_official: CORRIVEAU, RODERICK A
project_start_date: 2016-12-15
project_end_date: 2018-12-14
study_section: NST-2 Study Section [NST-2]
contact_pi_person_id: 11942576
contact_pi: IGHODARO, ESEOSA T.
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Dementia is a devastating clinical syndrome that affects millions of elderly individuals worldwide. Treating patients with dementia is challenging because of the myriad number of pathologies underlying its clinical manifestation and progression. Therefore it is imperative to better understand the various mechanisms of dementia-inducing diseases in order to correctly diagnose and treat dementia patients. The focus of my proposed project is to study a common but relatively underappreciated and under-studied mechanism of dementia characterized by vascular abnormalities hippocampal shrinkage and abnormal protein accumulation (TDP-43) in the brain. Our lab has published several studies on two dementia-associated pathologies: hippocampal sclerosis of aging (HS-Aging) and brain arteriolosclerosis (B-ASC). HS-Aging is a common neurodegenerative pathology seen in up to 25% of individuals < 85 years at autopsy. B- ASC is a cerebrovascular pathology that increases in frequency and severity with advanced age. We have identified a common genetic risk variant in the ABCC9 gene with a polymorphism that changes risk for both B-ASC and HS-Aging pathologies. This phenomenon is exciting because it may point the way to a novel future therapeutic intervention related to ABCC9-modulating drugs. As a key step to better understanding the pathogenetic mechanism new experiments are required. My overall hypothesis is that genetic and pharmacological perturbations in ABCC9 or its gene product lead to B-ASC pathology which in turn lead to HS-Aging/TDP-43 resulting in the clinical presentation of dementia. We will address this hypothesis through the following specific aims: 1) Test the hypothesis that a SNP ABCC9.rs704180 is associated with altered vascular structure in aged individuals and 2) Test the hypothesis that chronic pharmacologic inhibition of ABCC9 gene product will cause B-ASC thus in turn exacerbating HS-Aging/TDP-43 pathology. In Aim 1 we will use human tissue samples from the University of Kentucky Alzheimer's Disease Center brain bio-bank to quantify vascular structures in individuals with varying ABCC9 SNP status. In Aim 2 we will treat mice with clinical and pathological HS-Aging characteristics (age-related TDP-43 pathology) to determine the effects of ABCC9 modifying drug treatment in these animals. Successful completion of this project will provide insight into a novel mechanism of dementia. In addition it will provide opportunities for me to diversify my skillset as I prepare for a future career as a physician-scientist in the field of translational neuroscience research.

project_terms:
ABCC9 gene;Address;Affect;Aging;Alzheimer's Disease;Animal Model;Animals;Autopsy;Binding;Bioethics;Blood Vessels;Brain;Breeding;Cessation of life;Characteristics;Chronic;Clinical;Computer software;Data;Dementia;Development;Diagnosis;Disease;Dissection;Early Diagnosis;Elderly;Family;Frequencies;Future;Genetic;Genetic Polymorphism;Genetic Risk;Hippocampus (Brain);Human;IACUC;Image Analysis;Immunohistochemistry;Individual;Journals;Kentucky;Knowledge;Lead;Learning;Maintenance;Measures;Mediating;Morphology;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neurology;Neurosciences Research;Paper;Pathologic;Pathology;Patients;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Physicians;Proteins;Publishing;Research;Risk;Sampling;Scientist;Severities;Single Nucleotide Polymorphism;Smooth Muscle Myocytes;Source;Structure;Sulfonylurea Compounds;Syndrome;Testing;Therapeutic Intervention;Thick;Tissue Sample;Training;Transcript;Universities;age related;aged;aging brain;biobank;brain arteriolosclerosis;career;cerebrovascular;cerebrovascular pathology;digital;effective therapy;experimental study;gene product;hippocampal sclerosis;human tissue;inhibitor/antagonist;insight;member;mouse model;neuron loss;neuropathology;novel;pre-clinical;protein TDP-43;risk variant;sulfonylurea receptor;therapeutic target;tissue processing;translational neuroscience;vascular abnormality

public_health_relevance:
Dementia is a devastating syndrome caused by a plethora of diseases in the brain. Understanding the underlying mechanisms and clinical presentations of these varying diseases will aid in early detection precise diagnosis and effective treatment of patients with this debilitating syndrome.


application_id: 9324104
project_number: 5R21AG050133-02
project_title: Can low blood glucose extend health
administering_ic: NIA
award_notice_date: 2017-03-29
opportunity_number: PA-13-156
application_type: 5
activity_code: R21
ic: AG
serial_number: 050133
program_official: FRIDELL, YIH-WOEI
project_start_date: 2016-05-01
project_end_date: 2019-04-30
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 1927079
contact_pi: EPSTEIN, PAUL N
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Aging of the world population has made prolongation of health a more important priority than ever.Several models of extended health and delayed aging such as caloric restriction and mouse models ofdwarfism demonstrate low blood glucose. However these models have complex physiology and it isnot known whether low blood glucose is important to their prolonged health and extended lifespan. Ofpotential value to understanding the relationship between blood glucose and aging is a transgenicmouse line designated Inshex with a healthy phenotype but permanently low blood glucose 25-50%lower than normal mice. The mouse was originally developed mice to study pancreatic -cells anddiabetes. The Inshex transgene produced a left shift in the pancreatic -cell insulin secretion responseto glucose but the final phenotype is hypoglycemia with almost normal serum insulin levels. Thisproposal will use Inshex mice to test if blood glucose influences aging. Inshex mice are healthy ofnormal size and fertile. Blood glucose is reduced at 500 days of age. The first goals of this project areto confirm that blood glucose stays low permanently and that reduced blood glucose extends longevity.Lifespan will be determined in cohorts of 30 male Inshex and 30 non-transgenic littermates that will befollowed undisturbed to determine the age when mice become moribund and require euthanasia. Aveterinary pathologist will assess the cause of morbidity. Over the course of their lives mice will beobserved daily and weighed monthly. In separate cohorts of Inshex and control mice blood and urinesamples will be obtained at 3 month intervals to measure blood glucose HbA1c plasma free fatty acidsand urine albumin to creatinine ratio. Groups of mice will be sacrificed at 5 10 and 20 months of age.The day before sacrifice mice will be placed in metabolic chambers to determine respiratory quotient byindirect calorimetry and simultaneously measure ambulatory activity. Unlike other mouse models withlow glucose initial results indicate that Inshex mice have a normal respiratory quotient. After themetabolic chamber animals will be anesthetized for DEXA scan measurement of body composition andfor obtaining a large blood sample to measure metabolic hormones implicated in modulation of aging(insulin IGF1 or growth hormone). Aging is the leading cause for loss of renal function in people. Apreliminary analysis indicated less glomerular scarring in 400-500 day Inshex kidneys. The beneficialeffect of Inshex low glucose on kidney structure and function will be confirmed by examining renalhistology of control and Inshex mice sacrificed at 5 10 and 20 months and by comparing ageassociated leakage of albumin into the urine. These studies will demonstrate whether low bloodglucose extends function of the kidney and lifespan of the mouse.

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

public_health_relevance:
Lowbloodglucoseiscommontoseveralcomplexmodelsofextendedhealthandlifebutitisnotknowniflowglucoseisimportanttoprolongedhealthoranonessentialbyproduct.Thisprojectwilltestanovelmousemodelwhichhaslowbloodglucoseastheprimarydifferencefromnormalmicetotestiflowbloodglucoseissufficienttoextendlongevity.


application_id: 9324023
project_number: 272201000033I-2-27200003-1
administering_ic: NIAID
project_start_date: 2015-06-20
project_end_date: 2017-04-19
contact_pi_person_id: 14145560
contact_pi: HIGDON, 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
funding_mechanism: R and D Contracts
project_title:
TASK A72: THERAPEUTICS TESTING IN A MURINE MODEL OF MULTIPLE DRUG RESISTANT (MDR) PSEUDOMONAS AERUGINOSA LUNG INFECTION

project_abstract:
This contract provides for the development and standardization of small animal models for infectious diseases and may include efficacy testing of candidate products.

project_terms:
Animal Model;Communicable Diseases;Contracts;Development;Drug resistant Pseudomonas aeruginosa;Infection;Lung;Multi-Drug Resistance;Standardization;Testing;Therapeutic;efficacy testing;mouse model;therapeutic development


application_id: 9323553
project_number: 5R21HL132263-02
project_title: 4D MR Imaging of Flow and Hemodynamics in Aortic Stenosis
administering_ic: NHLBI
award_notice_date: 2017-07-15
opportunity_number: PA-12-284
application_type: 5
activity_code: R21
ic: HL
serial_number: 132263
program_official: EVANS, FRANK
project_start_date: 2016-08-01
project_end_date: 2021-06-30
study_section: Medical Imaging Study Section[MEDI]
contact_pi_person_id: 1880208
contact_pi: AMINI, AMIR A
other_pis: Not Applicable
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Aortic Stenosis (AS) is a progressive valvular disease which has a 2 year survival rate of 50% in symptomaticpatients left untreated. Accurate characterization of stenosis severity is crucial in evaluating patients for valvereplacement. To determine severity of AS several clinical indices are typically determined from Doppler flow:these are effective orifice area (EOA) transvalvular pressure gradient (TVPG) ejection time peak out-flowtract velocity and peak aortic jet velocity. However Doppler flow can only derive components of velocities inthe direction of insonification and existence of air bone or surgical scar present impediments to accurateevaluation. A dilemma that occurs is that in as many as 30% of patients with severe AS who undergoechocardiographic assessment the indices measured from Doppler are discordant requiring additionalinvasive hemodynamic catheterization studies. This may have a physiologic basis but it may also have a rootcause in image noise and geometric assumptions. MRI is noninvasive and as with ultrasound has thecapability to image the anatomy as well as velocity and flow. Compared to ultrasound however the velocitiescan be measured in all 3D directions and due to its tomorgraphic nature do not require any geometricassumptions. Furthermore with the advent of 4D flow imaging MRI permits 3D visualization of flow as part ofa single scan. Despite these advances in MRI current 4D flow imaging techniques suffer from longscan times and when imaging flow distal to severe stenotic valves are hampered by artifacts. We haveaddressed these shortcomings through two 4D flow imaging techniques both adopting non-Cartesian k-spacetrajectories which significantly reduce echo times (TE): on the one hand using an Ultra-Short Echo Time (UTE)sequence with radial k-space trajectory (4D UTE Flow) and on the other hand with Spiral k-space trajectory(4D Spiral Flow). The specific aims of the study are as follows: 1) We will construct rigid and distensible flowphantoms of the aortic arch with a stenotic valve. This will permit study of stenotic valvular flows andhemodynamic indices calculated from velocity images at high resolution in idealized and realistic curvedgeometries. 2) 33 subjects with severe AS as determined by Doppler echocardiography will undergo a 4DFlow MRI a Doppler Ultrasound examination and a hemodynamic study in the cath lab in close succession.From Doppler and MRI all currently adopted clinical indices will be measured and correlated with cath-basedmeasures as the gold standard. We hypothesize that measures derived from the proposed MRI approachescorrelate more closely with cath alleviating the need for invasive catheterization to resolve discrepant echofindings in many patients. 3) In addition to standard indices the nature of MRI permits 3D measurement ofpressure based on a novel noniterative calculation involving harmonic analysis of pressure gradients resultingin improved accuracy and speed. This and a new index of flow recirculation vorticity will be tested on phantomand patient data.

project_terms:
4D MRI;Address;Adopted;Adult;Air;Anatomy;Aortic Valve Stenosis;Area;Atherosclerosis;Beds;Calcified;Catheterization;Catheters;Chronic;Cicatrix;Clinical;Color;Data;Data Quality;Diagnostic;Disease;Distal;Doppler Echocardiography;Doppler Ultrasound;Evaluation;Geometry;Gold;Heart Valves;Human;Image;Imagery;Imaging Techniques;In Vitro;Inflammation;Left;Lipids;Magnetic Resonance Imaging;Measurement;Measures;Mitral Valve;Morphologic artifacts;Motion;Nature;NavierStokes equations;Noise;Operative Surgical Procedures;Patients;Physiological;Plant Roots;Process;Radial;Resolution;Scanning;Severities;Severity of illness;Slice;Speed;Stenosis;Survival Rate;Techniques;Testing;Time;Ultrasonography;aortic arch;aortic valve;aortic valve disorder;base;bone;calcification;clinical imaging;clinical practice;hemodynamics;improved;indexing;novel;particle;pressure;prognostic;prospective;valve replacement

public_health_relevance:
Aortic Stenosis (AS) is a significant disease of the aortic valve of the heart which is chronicprogressive and has a 2 year survival rate of 50% in symptomatic patients who are untreated.The most common cause of AS in adults is calcification of a normal trileaflet or congenitalbicuspid valve. The proposal aims to develop a new and improved test based on MRI fordetermination of diagnostic indices of this disease in subjects with severe AS.


application_id: 9322664
project_number: 3U18FD004620-05S1
project_title: FDA Vet-LRN Veterinary Diagnostic Laboratory Cooperative Agreement Program fundin
administering_ic: FDA
award_notice_date: 2016-08-04
opportunity_number: PA-12-194
application_type: 3
activity_code: U18
ic: FD
serial_number: 004620
suffix: S1
project_start_date: 2012-09-01
project_end_date: 2017-08-31
study_section: ZFD1-SRC(99)
contact_pi_person_id: 11450267
contact_pi: GASKILL, CYNTHIA LYNN
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Gaskill UKVDL Project Summary/AbstractThe objective of this Food and Drug Administration (FDA) Veterinary Laboratory Response Network (Vet-LRN)Cooperative Agreement Program is to provide increased sample analysis capabilities for the FDA throughpartnership with Vet-LRN laboratories in the event of animal food or drug related illness or other large scaleanimal food/feed emergency events requiring surge capacity testing of implicated diagnostic or animal foodsamples. Testing will include microbiological and chemical analysis of samples such as animalfood/feed/drugs environmental samples related to animal food/feed/drug production and/or animal diagnosticnecropsy or clinical samples. In the event of a large-scale biological or chemical contamination affecting animalfood or drug products the UKVDL will perform selected analyses of diagnostic samples collected and suppliedto the laboratory by FDA or other government agencies. Federal or State surveillance assignments will also bea source of samples for analyses.The overall goal of the cooperative agreement is to complement develop improve and use university stateand federal veterinary diagnostic laboratory testing capabilities. The program will also be used to implementstandardized analysis through the usage of standardized methods equipment analytical worksheets andelectronic reporting. Training and proficiency testing will be provided for each method and Qualitymanagement systems will be enhanced. Small scale method development and method validation projects willbe performed as directed by the Vet-LRN Program Office. Funding will be used for supplies equipmentmaintenance and personnel time.

public_health_relevance:
Project Narrative This FDA Vet-LRN Cooperative Agreement Program will strengthen the overall food safety system by developing increased capacity and capabilities to detect adulteration which could affect animals raised for human consumption or companion animals consuming ingredients used in both animal and human food products.


application_id: 9322647
project_number: 3U18FD004619-05S1
project_title: CVM Vet-LRN Veterinary Diagnostic Laboratory Program
administering_ic: FDA
award_notice_date: 2016-08-03
opportunity_number: PA-12-194
application_type: 3
activity_code: U18
ic: FD
serial_number: 004619
suffix: S1
project_start_date: 2012-09-01
project_end_date: 2017-08-31
study_section: ZFD1-SRC(99)
contact_pi_person_id: 12682213
contact_pi: REED, DEBBIE
other_pis: Not Applicable
congressional_district: 01
department: VETERINARY SCIENCES
primary_duns: 041980632
primary_uei: LHC2S92MXG63
duns_number: 041980632
uei: LHC2S92MXG63
fips: US
organization_id: 5591701
organization_name: MURRAY STATE UNIVERSITY
organization_city: MURRAY
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 420712393
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract  The FDA CVM Vet-LRN desires to expand the national laboratory capacity to respond to animal food/drug related illnesses or other large-scale animal food/feed emergency events requiring surge capacity testing of implicated diagnostic or animal food samples.  The Breathitt Veterinary Center is a fully accredited (AAVLD) animal disease diagnostic laboratory strategically located in Western Kentucky.  The objective of this grant application is to provide a cooperative agreement between the FDA CVM Vet-LRN and the BVC whereby the BVC will participate in the Vet-LRN Veterinary Diagnostic Laboratory Program.  Funding provided through the cooperative agreement will be used to provide equipment supplies training and proficiency testing under the aegis of the Vet-LRN Veterinary Diagnostic Program on an annualized basis for a five year period.

public_health_relevance:
Project Narrative  Agriculture is Kentucky's number one industry contributing $5 billion to the state's economy  annually.  Livestock and livestock product sales generate 65% of the total agricultural revenues.   The Murray State University Breathitt Veterinary Center (BVC) is an animal disease diagnostic  laboratory dedicated to protecting the invaluable assets of the region by providing the fastest  most accurate and most dependable animal disease diagnostic services possible.  The BVC  with a staff of 45 employees is housed in a 44000 sq. ft. facility located on 15 acres of land in  Hopkinsville KY.  The facility is centrally located to serve a 200 mile radius including Western  Kentucky Southern Indiana and Illinois and Northwestern Tennessee.  The BVC professional  staff includes nine members with Doctorates in Veterinary Medicine and/or Masters and PhD  degrees in the fields of Pathology Microbiology Virology Immunology and Toxicology.  The  professional staff is supported by laboratory bench personnel each of who hold a minimum of a  Bachelor's degree and several have Masters degrees.  The laboratory provides full  administrative secretarial/clerical and maintenance staff in support of diagnostic and research  activities.  The BVC is accredited for all species by the American Association of Veterinary  Laboratory Diagnosticians (AAVLD) through December 2014.  The BVC is a member of the USDA  National Animal Health Laboratory Network (NAHLN) the Centers for Disease Control  Laboratory Response Network (LRN) and the FDA Vet-Laboratory Response Network (Vet-LRN)  (See attached FDA Vet-LRN Acceptance Letter).  The center's scope of activity includes the  scientific disciplines of Pathology Microbiology Molecular Diagnostics Clinical Pathology  Toxicology Serology and Virology.  The BVC processes 24000+ diagnostic cases per year to  include over 190000 tests.    The FDA CVM Vet-LRN desires to expand the national laboratory capacity to provide increased  sample analyses in the event of animal food or drug related illnesses or other large-scale animal  food/feed emergency events requiring surge capacity testing of implicated diagnostic or animal  food samples.    Objective:  The objective of this grant application is to provide a cooperative agreement  between the FDA CVM Vet-LRN and the BVC whereby the BVC will participate in the Vet-LRN  Veterinary Diagnostic Laboratory Program.  The FDA CVM Vet-LRN grant program is a mutually  beneficial opportunity in which the FDA CVM Vet-LRN adds to the national laboratory capacity  and the BVC receives support to advance its scope of activity.  Funding provided through the  cooperative agreement will be used to provide equipment supplies training and proficiency  testing under the aegis of the Vet-LRN Veterinary Diagnostic Program on an annualized basis for  a five year period.


application_id: 9322512
project_number: 5P30GM106396-05
project_title: PILOT PROJECT PROGRAM
administering_ic: NIGMS
award_notice_date: 2017-06-28
opportunity_number: PAR-10-196
application_type: 5
activity_code: P30
ic: GM
serial_number: 106396
study_section: ZGM1-TWD-C
subproject_number: 8531
contact_pi_person_id: 1882793
contact_pi: EATON, JOHN W
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
The overall goal of the Phase III MT COBRE is to ensure that the novel targets and compounds that have been identified by MT COBRE faculty are translated to pivotal human clinical trials. To that end the Pilot Grant Program will have as its major objective the identification and initial funding of research projects to develop novel pre-clinical therapeutic agents identified by MT COBRE Program investigators. Although the theme of this funding mechanism will be translational development of novel therapeutics and priority will be given to translational studies with a high potential for advancement to clinical studies other meritorious grants may be funded as well. It is the intent that these developmental projects will lead to R01 and other competitive grant funding through expansion or re-direction of prior COBRE projects. The Pilot Grant Program will have a total 5-year budget of $1725000; comprised of $575000 from the MT COBRE grant $500000 from the Executive Vice President for Research and $650000 from the James Graham Brown Cancer Center discretionary funds (see detailed description below). The applications will be solicited by an RFP process and will be reviewed by the MT COBRE Steering Committee.

project_terms:
Budgets;Cancer Center;Centers of Research Excellence;Clinical Research;Clinical Trials;Development;Ensure;Faculty;Funding;Funding Mechanisms;Goals;Grant;Human;Molecular Target;Phase;Pilot Projects;Process;Research;Research Personnel;Research Project Grants;Therapeutic Agents;Translating;novel;novel therapeutics;pre-clinical;programs;translational study


application_id: 9322511
project_number: 5P30GM106396-05
project_title: Animal Model Core
administering_ic: NIGMS
award_notice_date: 2017-06-28
opportunity_number: PAR-10-196
application_type: 5
activity_code: P30
ic: GM
serial_number: 106396
study_section: ZGM1-TWD-C
subproject_number: 8530
contact_pi_person_id: 1923745
contact_pi: CHESNEY, JASON A.
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
PROJECT SUMMARY (See instructions): The goal of the University of Louisville Molecular Targets COBRE Core D is to facilitate the rapid translation of novel approaches to cancer prevention diagnosis and treatment through the use of transgenic mouse models of cancer. In particular. Core D will facilitate the translational objectives of University of Louisville COBRE-related investigators by developing coordinated resources techniques expertise and several colonies of transgenic mice for the safety and efficacy testing of novel anti-cancer approaches. The initial goal will be to establish colonies of the transgenic mice and to develop methods for longitudinal monitoring of tumor progression or regression without the need to euthanize the animals. Once the core is established the long-term objectives will be to provide access of transgenic mouse models of cancer to junior and senior cancer researchers at the University of Louisville including past and present COBRE investigators in order to facilitate the testing of novel anti-cancer compounds and strategies. The specific objectives are to: (i) Maintain distribute and provide pre-clinical toxicity and efficacy support for transgenic mouse models of melanoma childhood neuroblastoma lung breast prostate colon pancreatic and hematological cancers; (ii) Provide technical support for transgenic mouse genotyping specimen collection and processing and PK analyses of novel anti-cancer agents; and (iii) Conduct state-of-the-art diagnostic imaging services for the detection of tumors and response to novel therapeutic agents. In summary we propose a core facility that will procure and breed transgenic mouse models of several common cancer types and that will provide technical services to facilitate the testing of novel strategies and drugs developed at the University of Louisville.

project_terms:
Animal Model;Animals;Cancer Model;Centers of Research Excellence;Childhood;Clinic;Colon Carcinoma;Core Facility;Detection;Diagnosis;Diagnostic Imaging;Genotype;Goals;Hematologic Neoplasms;Instruction;Laboratories;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Methods;Modality;Modeling;Molecular Target;Monitor;Neuroblastoma;Phase;Research Personnel;Resources;Safety;Services;Site;Specimen Handling;Techniques;Testing;Therapeutic Agents;Time;Toxic effect;Transgenic Mice;Translations;Universities;Xenograft Model;cancer prevention;cancer type;cost;efficacy testing;efficacy trial;experimental study;human disease;human subject;malignant breast neoplasm;melanoma;mouse model;novel;novel anticancer drug;novel strategies;novel therapeutics;phase I trial;pre-clinical;prevent;response;safety testing;sample collection;success;tumor;tumor progression

public_health_relevance:
RELEVANCE (See instructions): Core E will support pre-clinical safety and efficacy trials of novel compounds and strategies to detect prevent and treat cancer so that our COBRE investigators can rapidly move these agents and strategies from laboratory benches into cages and then phase I trials of human subjects suffering with cancer.


application_id: 9322510
project_number: 5P30GM106396-05
project_title: Molecular Modelling Core
administering_ic: NIGMS
award_notice_date: 2017-06-28
opportunity_number: PAR-10-196
application_type: 5
activity_code: P30
ic: GM
serial_number: 106396
study_section: ZGM1-TWD-C
subproject_number: 8529
contact_pi_person_id: 7821204
contact_pi: TRENT, JOHN O
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
PROJECT SUMMARY (See instructions):  One of the overriding goals of the Brown Cancer Center is translational research. One way to achieve this is to provide a conduit for investigators studying particular molecular targets to conduct structure-based drug design. The Molecular Modeling Core Facility is an integral part of the COBRE which is used by all the COBRE investigators and many NIH funded investigators. It provides a natural entryway for structural biological approaches developed by COBRE scientists and through its close interaction with the NMR Center biophysicists molecular biologists chemists medicinal chemists computer scientists and biochemists. The overall goal of the Facility is rationalization prediction and design i.e. the rationalization of experimental data the prediction of new empirical experiments and the structure-based drug design of new agents. The aims of the Core are to: 1. provide equipment and expertise for a variety of modeling applications 2. facilitate structure-based drug design for drug discovery and drug development including facilitating testing of targeted compounds. 3. provide a bridge between crystallography NMR medicinal chemistry and other disciplines 4. provide a collaborative environment for the BCC 5. inform the Structural Biology Program of advances in the field and to implement them 6. educate the Structural Biology Program and others on possible enhancements to their research 7. train students on "state of the art" molecular modeling These aims will be met by maintaining state-of-the-art software and computafional resources which will support collaborative interactions with COBRE and other investigators.

project_terms:
Biological;Cancer Center;Centers of Research Excellence;Chemicals;Code;Computational Biology;Computer Hardware;Computer Simulation;Computer software;Computers;Consult;Core Facility;Crystallography;Data;Data Analyses;Development;Discipline;Doctor of Philosophy;Drug Design;Educational Models;Equipment;Funding;Goals;Individual;Instruction;Maintenance;Mission;Modeling;Molecular;Molecular Models;Molecular Target;New Agents;Pharmaceutical Chemistry;Phase;Rationalization;Research;Research Personnel;Resource Allocation;Resources;Route;Scientist;Structure;System;Testing;Training;Translational Research;United States National Institutes of Health;Validation;base;collaborative environment;computing resources;design;drug development;drug discovery;experience;experimental study;molecular modeling;novel;novel therapeutics;operation;programs;screening;structural biology;student training;virtual

public_health_relevance:
RELEVANCE (See instructions): The Modeling Core is directly involved in drug discovery. It enables almost any investigator to determine if their system is targetable and provides potential compounds for testing as chemical probes or new drugs. This adds a new direct route for translational research that otherwise would not be available to many investigators.


application_id: 9322509
project_number: 5P30GM106396-05
project_title: NMR and Metabolomics Core
administering_ic: NIGMS
award_notice_date: 2017-06-28
opportunity_number: PAR-10-196
application_type: 5
activity_code: P30
ic: GM
serial_number: 106396
study_section: ZGM1-TWD-C
subproject_number: 8528
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
PROJECT SUMMARY (See instructions): The primary aims of the NMR core are to provide infrastructure and support for structural analysis of target macromolecules their mutual interactions and with candidate drug molecules obtained from in silico searches and optimization and metabolomics of cancer cells and tissue. This includes stable isotope labeling strategies including N-15 and C-13 precursors. Our goals continue to be to streamline both data collection and analysis as well as introduce new labeling strategies to provide more detailed information about specific metabolic pathways via Stable Isotope Resolved Metabolomics (SIRM). This includes NMR structural and biophysical analysis of macromolecules and their interactions with small molecules as well as extensive use of the metabolomics capabilities of the Core as a part of the drug discovery/development process. A large fraction of research projects that use the facility are translational using purified components as well as animal models and human subjects. The NMR-based studies operate in tandem with activates of other Cores especially the Modeling Core and in the future with the Transgenic Mouse Core. NMR is one of the few techniques that provides localized imaging and high resolution high information content spectroscopy in vivo. This will be a major new direction of the Core.  The overall goals of the Core will be achieved via the following Specific Aims: 1. Provide NMR instrumentation and expertise for characterizing macromolecules and their interactions; 2. Provide the instrumentation and expertise for metabolomics studies; 3. Facilitate structure-based drug design for drug discovery and drug development; 4. Develop and implement new experiments and capabilities including stable isotope resolved metabolomics on small animals in vivo; 5. Educate members of the community on the specific capabilities of NMR for their research projects; 6. Provide training of students and fellows in cancer biochemistry and drug development. These Aims complement those of the other Cores in terms of the overall research mission of the Cancer Center and the University.

project_terms:
Animal Model;Animals;Automation;Binding;Biochemical;Biochemistry;Biophysics;Cancer Center;Chemistry;Collaborations;Communities;Complement;Computer Simulation;Consultations;Core Facility;DNA;Data Analyses;Data Collection;Development;Drug Design;Drug Targeting;Enzymatic Biochemistry;Experimental Designs;Future;Goals;Image;Instruction;Isotope Labeling;Label;Malignant Neoplasms;Metabolic Pathway;Metabolism;Methods;Mission;Modeling;Molecular Models;Molecular Target;Nucleic Acids;Pathway Analysis;Pharmaceutical Preparations;Phase;Procedures;Process;Proteins;Research;Research Infrastructure;Research Project Grants;Resolution;Running;Sampling;Spectrum Analysis;Stable Isotope Labeling;Structure;Surface;Techniques;Technology;Tissues;Training;Transgenic Mice;Universities;Validation;base;biophysical analysis;cancer cell;data reduction;design;drug candidate;drug development;drug discovery;experimental study;human subject;in vivo;instrumentation;macromolecule;member;metabolomics;molecular modeling;novel;research facility;small molecule;stable isotope;student training;translational cancer research

public_health_relevance:
RELEVANCE (See instructions): NMR provides high resolution information about drug targets and their interactions as well as metabolomics analyses at the atomic level that are critical to basic understanding of cellular metabolism and drug discovery and development.


application_id: 9322508
project_number: 5P30GM106396-05
project_title: Microarray Core
administering_ic: NIGMS
award_notice_date: 2017-06-28
opportunity_number: PAR-10-196
application_type: 5
activity_code: P30
ic: GM
serial_number: 106396
study_section: ZGM1-TWD-C
subproject_number: 8527
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
PROJECT SUMMARY (See instructions): At the University of Louisville the instrument personnel and software resources for high-density microarray based gene expression and single nucleotide polymorphism (SNP) genotyping analyses are in place through an investment of the UofL James Graham Brown Cancer Center (JGBCC). Such global profiles can be obtained for tens of thousands of genes or SNP loci from cell populations or tissue material within one time saving and standardized experiment. Comparative analysis of global gene expression patterns on biological or pathologic material will provide crucial information on gene products and/or mutations which are involved in a cellular and/or disease process. The objective of the Microarray Core is to offer this highly advanced technology as well as sufficient opportunities for training and research applications for investigators. The Specific Aims of the Microarray Facility are to offer the following services to JGBCC investigators: 1. To provide high-quality services for microarray-based gene expression and genotyping analysis; 2. To continuously incorporate the newest array products and analysis tools into the menu of services provided; 3. To educate and train users in applications strengths and limitations of microarray technology; 4. To assist users in experimental design sample processing and data analysis; 5. To provide logistic support for project development grant applications and manuscript preparations applying microarray technology.  The Core presented here shall ensure that JGBCC investigators especially clinical faculty and research groups will be able to efficiently adopt this novel state-of-the-art technology for their research clinical and investigative goals using in vitro clinical specimen or animal model materials (using their approval protocols). It will be crucial for these investigators to have affordable access and expert support to the most advanced and sophisticated molecular technologies as part of the institutional resources provided to them.

project_terms:
Adopted;Animal Model;Applications Grants;Basic Science;Bioinformatics;Biological;Biometry;Cancer Center;Cells;Clinical;Clinical Research;Computer software;DNA;Data Analyses;Data Collection;Development;Disease;Educational workshop;Ensure;Experimental Designs;Gene Expression;Gene Expression Profile;Genes;Genetic Transcription;Genomic DNA;Genotype;Goals;Human;Human Resources;Hybridization Array;In Vitro;Individual;Instruction;Internet;Investments;Knowledge;Logistics;Malignant Neoplasms;Manuscripts;Microarray Analysis;Molecular;Molecular Target;Mus;Mutation;Nursing Faculty;Pathologic;Phase;Polymorphism Analysis;Population;Preparation;Procedures;Process;Protocols documentation;Provider;RNA;RNA amplification;Research;Research Personnel;Resources;Sample Size;Sampling;Savings;Services;Single Nucleotide Polymorphism;Specimen;Standardization;Technology;Time;Tissues;Training;Universities;base;comparative;density;experimental study;gene product;instrument;novel;novel diagnostics;tool;training opportunity;transcriptome

public_health_relevance:
RELEVANCE (See instructions): The Microarray Facility offers highly advanced microarray-based technologies for basic science and clinical research applications as well as opportunities for training to UofL investigators. This Facility has been and will be instrumental in advancing our knowledge on disease mechanisms and novel diagnostic tools for cancer.


application_id: 9322507
project_number: 5P30GM106396-05
project_title: ADMINISTRATIVE CORE
administering_ic: NIGMS
award_notice_date: 2017-06-28
opportunity_number: PAR-10-196
application_type: 5
activity_code: P30
ic: GM
serial_number: 106396
study_section: ZGM1-TWD-C
subproject_number: 8526
contact_pi_person_id: 1898718
contact_pi: MILLER, DONALD M.
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
PROJECT SUMMARY (See instructions): The Administrative Core (Core A) will be responsible for the day-to-day operation of the MT COBRE program. The overall goal of the Phase 111 application of the Molecular Targets COBRE (MT COBRE) is to ensure that the novel targets and compounds which have been identified by MT COBRE faculty are translated to pivotal human clinical trials. Under Dr. Miller's direction Core A will provide budgetary management core oversight manage the Pilot Grant Program and monitor progress of the MT COBRE faculty. The MT COBRE Administrative Assistant and the Program Coordinator will report to the MT COBRE PI and co-Director through this core. The Administrative Core will be responsible for organizing all committee meetings including those of the Steering Committee the Internal Advisory Committee and the External Advisory Committee. It will provide regular evaluations of research core function and fiscal status. Core A also will provide the requisite reports to the NIH Program administration on an annual basis. During the first ten years of MT COBRE funding. Core A has provided very important support to all of the MT COBRE faculty and has played an important role in the overall success of the program. This core will assume an even more important role during Phase III of the COBRE.

project_terms:
Advisory Committees;Antineoplastic Agents;Area;Cancer Center;Centers of Research Excellence;Clinical Trials;Core Facility;Ensure;Evaluation Research;Faculty;Funding;Goals;Grant;Growth;Human;Individual;Instruction;Laboratories;Leadership;Mentors;Molecular Target;Monitor;Phase;Physicians;Pilot Projects;Play;Program Development;Recruitment Activity;Reporting;Research;Research Infrastructure;Research Personnel;Resources;Retreatment;Role;Scientist;Structure;Testing;Therapeutic;Training;Translating;Translational Research;United States National Institutes of Health;Universities;design;drug development;medical schools;meetings;member;novel;oncology;operation;programs;success;tumor metabolism

public_health_relevance:
RELEVANCE (See instructions): Cancer metabolism and cancer drug development are currently very important areas of research. The MT COBRE program has trained leaders in this area; the funding of Phase III will ensure the continued success and growth of the JGBCC core facilities and thus it's faculty and this program.


application_id: 9322505
project_number: 5P30GM106396-05
project_title: Molecular Targets Phase III CoBRE
administering_ic: NIGMS
award_notice_date: 2017-06-28
opportunity_number: PAR-10-196
application_type: 5
activity_code: P30
ic: GM
serial_number: 106396
program_official: LIU, YANPING
project_start_date: 2013-07-01
project_end_date: 2018-06-30
study_section: ZGM1-TWD-C(C3)
contact_pi_person_id: 1898718
contact_pi: MILLER, DONALD M.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The Molecular Targets Center of Biomedical Research Excellence (MT COBRE) at the University of Louisville and the James Graham Brown Cancer Center has successful supported the early career of fourteen junior faculty members during its Phase I and il funding periods. The current application reflects the maturation of the Molecular Targets Program and its faculty. The overall goal of the Phase III application of the Molecular Targets COBRE will be to ensure that the novel targets and compounds which have been identified by MT COBRE faculty are translated to pivotal human clinical trials. Several strengths have enhanced the success of this program including: 1) Stability of program leadership; 2) Successful retention of all fourteen faculty members; 3) Institutional support for the program totaling over $30M; and 4) Creation of a University of Louisville-owned company dedicated to translating important discoveries of MT COBRE investigators. The ability of MT COBRE faculty to test their novel compounds in humans will distinguish this program from similar programs at other institutions.' To this end the MT COBRE has supported the development of a unique translational research infrastructure which has enabled the characterization of more than 30 novel targets. The Phase III application will support four closely
integrated core facilities which will support this goal; 1) Microarray Core; 2) Molecular Modeling Core; 3) NMR/Metabolomic Core and 4) Animal Model Core. Additionally the James Graham Brown Cancer Center has created complementary research cores which will be available to MT Program members during the Phase III component of the program including the Biostatistics Core Clinical Trials Office Biophysical Cancer Core Cell Sorting and Flow Cytometry Core. The MT COBRE administration will continue to provide intensive support for development of the fourteen faculty members many of whom have assumed leadership roles within the Cancer Center and University. The robust translational research infrastructure at the James Graham Brown Cancer Center and University of Louisville will ensure the success and sustainability of this unique program.

project_terms:
Animal Model;Antineoplastic Agents;Area;Biophysics;Biostatistics Core;Cancer Center;Cell Separation;Centers of Research Excellence;Clinical Trials;Core Facility;Development;Ensure;Faculty;Flow Cytometry;Funding;Goals;Growth;Human;Institution;Leadership;Malignant Neoplasms;Molecular Models;Molecular Target;Phase;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Role;Testing;Training;Translating;Translational Research;United States National Institutes of Health;Universities;career;drug development;drug discovery;inhibitor/antagonist;member;metabolomics;molecular modeling;novel;novel therapeutics;preclinical development;programs;public health relevance;success;targeted cancer therapy;tumor metabolism

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cancer metabolism and cancer drug development are currently very important areas of research. The MT COBRE program has trained leaders in this area; the funding of Phase III will ensure the continued success and growth of the core facilities and this program.


application_id: 9322360
project_number: 5R01GM107586-04
project_title: Light-responsive ruthenium compounds for applications in disease
administering_ic: NIGMS
award_notice_date: 2017-07-20
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: GM
serial_number: 107586
program_official: FABIAN, MILES
project_start_date: 2014-08-01
project_end_date: 2019-07-31
study_section: Synthetic and Biological Chemistry A Study Section[SBCA]
contact_pi_person_id: 8085279
contact_pi: GLAZER, EDITH C
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal seeks to develop a new class of light-responsive inorganic materials as chemotherapeutic agents. Cisplatin and its analogues remain the standard therapy for a variety of cancers despite their nonspecific mechanism of action with nucleic acids resulting in general cytotoxicity and debilitating side-effects. A promising approach that will provide several key advantages is to combine the reactivity of metal- based drugs with the selectivity of photodynamic therapy (PDT) to increase the targeting of malignant tissues and reducing side-effects. We have recently shown that structural distortion can be utilized to promote photochemical reactions to create reactive ruthenium species that are strongly electrophilic and highly photo-toxic in cell based assays. We hypothesize that distortion can be used to control light-activated cytotoxicity for the creation of selective and potent chemotherapeutics. We propose a new class of ruthenium-based compounds that have a readily modifiable modular design to facilitate rapidly incorporation of key molecular components to efficiently develop materials exhibiting selectivity and controlled reactivity. Coordination chemistry will be used to generate a structurally diverse family of three-dimensional chiral ruthenium compounds in a self-assembled manner. The structural variations in the materials will be correlated to cytotoxic efficacy using high-throughput cell survival assays and the most promising compounds will be assessed for Pharmacokinetic (PK) properties Maximum Tolerated Dose (MTD) and efficacy in mouse xenograft models of lung cancer and melanoma. Mechanism of action studies will be used to define the currently unknown process of cell killing. In order to accomplish this aim a novel chemical labeling strategy is proposed to facilitate imaging of the subcellular and potentially sub-organellar localization of active compounds using Electron Microscopy. If successfully validated this approach could be extended to additional imaging applications in tissues. Alternative approaches utilize biotin-labeled ruthenium materials for target pull-down with cellular targets identified through a process of gel electrophoresis chromatography and mass spectrometry. In vitro and in cell transcription and translation assays will support these findings. Cisplatin the benchmark inorganic chemotherapeutic will be used for comparison in all mechanism of action studies. The goal is to determine if the proposed ruthenium materials utilize the same biological target(s) as cisplatin or may be directed to different functional targets via structural modification. Upon completion of these studies we willhave expanded our knowledge of the fundamental photochemistry of ruthenium complexes developed potent and selective cytotoxic chemical entities identified their mechanism of action and developed a new tool for the imaging of small molecules in biological systems. 1

project_terms:
Adverse effects;Animals;Benchmarking;Biological;Biological Assay;Biotin;Cancer cell line;Cell Death;Cell Survival;Cell physiology;Cells;Cessation of life;Charge;Chemicals;Chemistry;Chromatography;Cisplatin;Combined Modality Therapy;Complex;DNA;DNA Damage;Development;Dimensions;Disease;Dose-Limiting;Drug Kinetics;Drug Utilization;Electron Microscopy;Engineering;Exhibits;Family;Genetic Transcription;Goals;Image;Imaging Device;In Vitro;Knowledge;Label;Lead;Ligands;Light;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Maximum Tolerated Dose;Metals;Modality;Modeling;Modification;Molecular;Motivation;Mus;Neutropenia;Nucleic Acids;PUVA Photochemotherapy;Pathway interactions;Patients;Pattern;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Photochemistry;Phototoxicity;Platinum;Process;Prodrugs;Property;Radiation;Reaction;Reducing Agents;Resistance;Resistance profile;Resolution;Ruthenium;Ruthenium Compounds;Sampling;Singlet Oxygen;Site;System;Therapeutic;Tissues;Toxic effect;United States;Variant;Xenograft Model;analog;base;biological systems;cancer cell;cancer therapy;cancer type;cell killing;cell type;cellular targeting;chemotherapeutic agent;chemotherapy;clinical application;crosslink;cytotoxic;cytotoxicity;design;gel electrophoresis;in vivo;innovation;melanoma;novel;oxidative damage;pre-clinical trial;public health relevance;screening;small molecule;systemic toxicity;targeted agent;therapy development;translation assay;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cisplatin received FDA approval in 1978 for the treatment of cancer and despite producing a wide range of debilitating side-effects; it is still one of the most prescribed chemotherapeutics today. With over 500000 cancer-related deaths in the United States each year it is essential to develop new broadly applicable therapeutic treatments for this disease. This proposal develops ruthenium materials as selective and potent chemotherapeutic agents that reduce off target toxic effects by acting as cytotoxic species only in a spatially controlled manner when "turned on" by light.


application_id: 9321959
project_number: 5R01DK107646-03
project_title: Cold Induced Changed in Human Subcutaneous White Adipose
administering_ic: NIDDK
award_notice_date: 2017-07-26
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 107646
program_official: HAFT, CAROL R
project_start_date: 2015-09-21
project_end_date: 2020-07-31
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The recent rediscovery of human brown adipose tissue through PET-CT has initiated more research on thermogenesis and defense defense against obesity. Many studies have demonstrated that white adipose tissue (WAT) in mice has the ability to upregulate its thermogenic capacity and become "beige". No studies have demonstrated browning of typical human WAT depots except for our recent studies. We have recently examined the subcutaneous (SC) WAT of humans and found a considerable ability to upregulate UCP1 and other mitochondrial genes in response to cold and to seasons and we have demonstrated this phenomenon with human adipocytes in culture. The seasonal changes in WAT are of particular interest since this indicates a physiologic response to colder weather without provocative and unphysiologic experimental conditions. In addition we found that obese humans with a high SC WAT macrophage burden do not upregulate SC WAT UCP1 as well suggesting that adipose inflammation inhibits the increased thermogenic capacity of WAT. A number of immune-mediate functions are involved in this process. Based on these data we propose the following hypotheses. Hypothesis 1. Repeated exposure to cold temperatures will amplify changes in human subcutaneous WAT beiging. These beiging effects are seen acutely in response to seasons and involve an activation of immune mediators. Hypothesis 2. The beiging of SC WAT involves an acute increase in adipose tissue immune mediators which may be a source of catecholamines that activate protein kinase A (PKA). This process is inhibited by -blockers in vivo. Hypothesis 3. Obese insulin resistant subjects are resistant to cold induced changes in WAT due to the proinflammatory milieu which inhibits local mediators of beiging. Hypothesis 4. Cold- and season-induced changes in SC WAT will lead to functional changes in the tissue characterized by increased mitochondrial uncoupling increased TG turnover (lipolysis) and increased resting metabolic rate.

project_terms:
Acute;Adipocytes;Adipose tissue;Area;Basal metabolic rate;Biological Response Modifiers;Brown Fat;Catecholamines;Cyclic AMP-Dependent Protein Kinases;Data;Diabetes Mellitus;Energy Metabolism;Exposure to;Genes;Glucose;Heart Diseases;Human;Immune;Inflammation;Inflammatory;Insulin Resistance;Lead;Link;Lipolysis;Mammals;Mediating;Mediator of activation protein;Metabolic syndrome;Mitochondria;Modernization;Mus;Neck;Obesity;Phenotype;Physiological;Positron-Emission Tomography;Process;Property;Regulation;Research;Resistance;Rodent;Seasons;Societies;Source;Temperature;Therapeutic;Thermogenesis;Tissues;Triglycerides;Vertebral column;Weather;base;cold temperature;glucose uptake;human tissue;immune activation;improved;in vivo;interest;macrophage;prevent;protein activation;response;subcutaneous

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


application_id: 9321363
project_number: 5R01DA040637-03
project_title: NK-1 Receptor Antagonism: A Role in Opioid Use Disorders
administering_ic: NIDA
award_notice_date: 2017-07-10
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DA
serial_number: 040637
program_official: ANDERSON, ANN
project_start_date: 2015-09-15
project_end_date: 2019-07-31
study_section: Risk, Prevention and Intervention for Addictions Study Section[RPIA]
contact_pi_person_id: 1877426
contact_pi: WALSH, SHARON L.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe United States has experienced a dramatic rise in non-medical use of prescription opioids leading toincreased demand for effective treatments for opioid use disorders. Recent evidence suggests thatinactivation of Substance P receptors either through genetic deletion or pharmacological blockadesignificantly attenuates the rewarding effects of opioids in an array of laboratory models and suppressesexpression of opioid withdrawal signs. Neurokinin 1 (NK1) receptors for Substance P may offer an attractivenovel target for a non-addictive treatment approach. This project proposes two inpatient laboratory studies thatwill enroll individuals with opioid use disorders. These studies will provide the proof-of-concept evidence ofNK1 receptor system involvement in mediating the response to opioids as related to abuse potentialreinforcing efficacy and opioid withdrawal in humans. These randomized placebo-controlled double-blindinpatient studies will both employ a within-subject design and enroll otherwise healthy volunteers with currentnon-medical opioid use with (Exp. 1) and without (Exp. 2) physical dependence on opioids. Both studies willcapitalize on the availability of a novel brain-penetrant NK-1 antagonist VLY-686 for which requisite clinicalsafety data are available and the sponsor (Vanda) has agreed to provide support and clinical drug supply.Experiment 1 will examine the effects of maintenance on VLY-686 (100 mg/day) versus placebo on opioidresponses with oxycodone on an array of physiological subjective and behavioral outcomes (self-administration and experimental pain). Experiment 2 will enroll opioid dependent volunteers who will bemaintained on oxycodone throughout the study using an established procedure. This study will examine theeffects of maintenance on VLY-686 (0 and 100 mg/day) for its ability to attenuate expression of opioidwithdrawal signs and symptoms and to attenuate the response to opioid agonist challenge. These studies willprovide preliminary safety and key pharmacodynamic data in individuals with opioid use disorders both withand without physical dependence and provide proof-of- concept data for the NK-1 receptor system role inmediating critical factors in opioid use disorders.

project_terms:
Acute;Admission activity;Agonist;Anxiety;Attenuated;Behavior;Brain;Buprenorphine;CD94 Antigen;Clinical;Clinical Trials;Cocaine;Crossover Design;Data;Dependence;Dose;Double-Blind Method;Enrollment;Formulation;Genetic;Heroin;Heroin Abuse;Human;Individual;Inpatients;Intravenous;Laboratories;Laboratory Study;Maintenance;Measures;Mediating;Mediation;Methadone;Modeling;Morbidity - disease rate;Naltrexone;Narcotic Antagonists;Nociception;Opiate Addiction;Opioid;Opioid Receptor;Oral;Outcome;Oxycodone;Pain;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Pharmacology;Pharmacotherapy;Phase;Physical Dependence;Physiological;Placebo Control;Placebos;Procedures;Randomized;Research;Rewards;Role;Safety;Self Administration;Signs and Symptoms;Specific qualifier value;Stress;Substance P;Substance P Receptor;System;Testing;United States;base;behavioral outcome;design;effective therapy;experience;experimental study;healthy volunteer;improved;laboratory experiment;mortality;mu opioid receptors;novel;opioid use;opioid use disorder;opioid withdrawal;overdose death;prescription opioid;response;volunteer

public_health_relevance:
PROJECT NARRATIVEThis research will provide important information regarding the potential utility of drugs which act through the NKreceptor system for a role in the treatment of opioid use disorders.


application_id: 9320943
project_number: 5R01NS091582-03
project_title: The role of macrophage phenotype and age in spinal cord injury
administering_ic: NINDS
award_notice_date: 2017-07-20
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 091582
program_official: JAKEMAN, LYN B
project_start_date: 2015-09-30
project_end_date: 2020-07-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 8201969
contact_pi: GENSEL, JOHN C
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Spinal cord injury (SCI) triggers a heterogeneous neuroinflammatory response consisting of macrophages with the potential to both aggravate tissue damage and promote wound healing and repair. These macrophages have been identified as pro-inflammatory pathological "M1" macrophages or anti-inflammatory alternatively activated pro-reparative "M2" macrophages. There is published evidence that driving M2 macrophage activation improves SCI recovery. The mechanisms underlying the reparative effects of M2 macrophages however are not well understood. As a result the development of clinically viable pharmacological interventions that harness the reparative potential of activated macrophages remains a critical challenge that is compounded by a changing SCI demographic. The incidence of SCI among older individuals has increased in recent years with a more equal balance of SCI across sexes. The purpose of this proposal is to investigate the mechanisms of M2 macrophage-mediated SCI repair and determine the effects of age and sex on SCI macrophage activation. Aim 1 will determine the role of arginase in M2 macrophage-mediated SCI repair processes through the use of genetically engineered mice with macrophages that lack arginase-1 (Arg1) and a newly identified treatment that increases M2-mediated arginase production. Parallel in vivo and in vitro SCI models of neurotoxicity axon growth/dieback and remyelination will test the hypothesis that the effects of M2 macrophages are dependent upon Arg1 production. In Aim 2 mice of different ages and sex will be used to determine the effect of these physiological factors on the acute SCI macrophage response. The macrophage response over time will be evaluated using newly developed focused gene profiling and flow cytometry techniques. The hypothesis to be tested is that aged males will have impaired M2 macrophage activation. In Aim 3 the effect of age and sex on M2 macrophage-mediated SCI repair and recovery will be evaluated using a clinically relevant mouse SCI model and a newly developed immunomodulatory SCI treatment. Forms of M2 macrophage activation occur in most CNS pathologies; therefore the current work is significant because it is expected to have broad translational impact on a wide range of neuroinflammatory conditions. This project is both conceptually and technically innovative. It will employ creative use of Arg1 knockout mice and a novel immunomodulatory agent. The investigation of the effects of age and sex on the macrophage response to SCI using a comprehensive focused gene array approach is novel. Collectively the completion of the proposed research will improve scientific knowledge regarding macrophage biology as it specifically relates to age and sex. This knowledge will improve clinical practice by leading to sophistication of treatment strategies that include sex andage as potential influences in the context of SCI treatment and recovery.

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

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The injured spinal cord does not heal properly resulting in chronic paralysis and expensive health care costs for patients with spinal cord injuries (SCI). The average age at the time of SCI in the United States is increasing but most clinical SCI therapies are being examined in individuals regardless of age and are based upon pre-clinical data generated almost exclusively using young female animals. The physiological factors of age and sex influence the inflammatory response to SCI therefore this proposal will examine treatment and inflammatory mechanisms in SCI models using both young and middle-aged male and female subjects in order to generate data of relevance to all SCI individuals.


application_id: 9320919
project_number: 5R01GM115261-02
project_title: Platform technologies for understanding and exploiting methylation
administering_ic: NIGMS
award_notice_date: 2017-07-20
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: GM
serial_number: 115261
program_official: FABIAN, MILES
project_start_date: 2016-08-01
project_end_date: 2020-07-31
study_section: Special Emphasis Panel[ZRG1-BCMB-W(02)M]
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: PHILLIPS, GEORGE NEAL
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): Methyltransferase (MT)-catalyzed S-adenosyl-L-methionine (AdoMet)-dependent methylation is essential to all walks of life and alterations in methylation-dependent processes have direct relevance to microbial/fungal/viral pathogenesis and human disease. Yet for many MTs there is a lack of correlative fundamental knowledge regarding specific MT function and corresponding impact upon cellular fate and/or pathogenesis/disease. In addition while simple chemical or MT-catalyzed methylation of a drug/drug lead can dramatically impact its corresponding ADMET (absorption distribution metabolism excretion and/or toxicity) the structural complexity of many natural products often prohibits doing so in the context of natural products-based drugs/lead development. This proposal seeks to develop general chemoenzymatic alkylation strategies and reagents for that are expected to broadly facilitate the fundamental study annotation and application of MTs. A centerpiece to the proposed universal platform development is the study engineering and application of permissive methionine adenosyltransferases (MATs) and MTs where the model MTs selected represent broad catalytic diversity (C-methylation O-methylation and N-methylation) and directly act upon a selected set of complex natural product-based drugs validated clinical candidates or marketed agricultural products. The proposed studies will integrate the chemical synthesis and application of unique methionine (Met) analogs MAT/MT structure determination high throughput MAT/MT assay development/application structure-guided MAT/MT directed evolution microbial strain engineering complex natural product (NP) structure elucidation and bioactivity assessment for NP analogs generated. The anticipated outcomes of this study include highly permissive/proficient MATs/MTs engineered for medicinal chemistry applications novel functional AdoMet orthologs designed as alternative alkyl donors and/or with improved stability an expanded understanding of MAT/MT structure-activity relationships of potential relevance to MAT/MT inhibitor design single vessel chemoenzymatic strategies to enable complex NP differential alkylation engineered microbial strains to enable complex NP differential alkylation and functional MT annotation and unprecedented differentially-alkylated NP analogs with potential therapeutic and/or agricultural applications. Within this context the proposed studies will also provide the first bioorthogonal strategy to functionally annotate interrogate or exploit a single MT within a cell containing a full complement of competing native MTs. While NP methylation has been selected as the model for platform development it is important to note that reagents and concepts developed will likewise enable the similar study annotation and application of other class I MTs relevant to cellular development human disease or microbial/fungal/viral pathogenesis.

project_terms:
Agriculture;Alkylation;Alpha Cell;Anabolism;Ansamycin Antineoplastic Antibiotic;Anti-Infective Agents;Biological Assay;Biological Process;Catalysis;Chemicals;Complement;Complex;Development;Directed Molecular Evolution;Disease;Elements;Engineering;Enzymes;Escherichia coli;Eukaryota;Evolution;Excretory function;Gene Deletion;Goals;Human;Immunosuppressive Agents;In Vitro;Insecticides;Isotope Labeling;Knowledge;Lead;Life;Ligands;Metabolism;Methionine;Methylation;Methyltransferase;Modeling;Mutation;Natural Products;Orthologous Gene;Outcome Study;Pathogenesis;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Polyketide Macrolides;Process;Prokaryotic Cells;Reaction;Reagent;S-Adenosylmethionine;Series;Sirolimus;Small Interfering RNA;Specificity;Structure;Structure-Activity Relationship;Substrate Specificity;System;Technology;Therapeutic;Toxic effect;Translating;Viral Pathogenesis;Walking;absorption;actionable mutation;analog;assay development;base;catalyst;cellular development;chemical genetics;chemical synthesis;clinical candidate;design;flexibility;high throughput screening;human disease;improved;in vivo;inhibitor/antagonist;innovation;loss of function;methionine adenosyltransferase;methylome;microbial;novel;permissiveness;practical application;prototype;public health relevance;tool;treatment response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Enzyme-catalyzed methylation is essential to normal function and development of all species. However disproportionate or aberrant methylation can also serve as a causative element in pathogenesis human disease and directly impact a patient's response to treatment. This proposal seeks to develop a universal platform and innovative reagents to facilitate the fundamental study and practical application of enzyme-catalyzed methylation and will also provide novel natural product analogs with potential anticancer immunosuppressant anti-infective and/or insecticide activities.


application_id: 9320722
project_number: 5R01DK104653-03
project_title: Hydrogen sulfide mechanism of renal hypertension
administering_ic: NIDDK
award_notice_date: 2017-08-24
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 104653
program_official: NIHALANI, DEEPAK
project_start_date: 2015-07-01
project_end_date: 2019-06-30
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 9501257
contact_pi: SEN, UTPAL
other_pis: TYAGI, SURESH C.
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): For decades hydrogen sulfide (H2S) was known only for its neurotoxicity and as an environmental hazard. Recent findings however suggest that endogenous H2S has a variety of physiological functions and a decrease in production can lead to vascular dysfunction atherosclerosis and hypertension. This discovery has stimulated further research into its development as a potential therapeutic agent in diseases attributed to diminished H2S synthesis. In chronic kidney disease low levels of plasma H2S is often associated with a concomitant increase in homocysteine (Hcy) known as hyperhomocysteinemia (HHcy). HHcy is well known to cause vascular dysfunction. The cause and effect relationship of HHcy in renal disease can therefore adversely affect the final outcome. Because Hcy is a precursor of H2S changes in the H2S metabolism can have a significant impact on HHcy-induced pathology. However the mechanism by which HHcy causes vascular dysfunction and the role of H2S in renal protection is incompletely understood. In the body Hcy is metabolized by three enzymes cystathionine -synthase (CBS) cystathionine y-lyase (CSE) and 3- mercaptopyruvate sulfurtransferase (3MST) and produce H2S. During HHcy an impairment in these enzymes leads to deficient H2S production. Our preliminary studies suggest that HHcy results in upregulation of caveolin-1 and homocysteinylation of eNOS thus decreasing NO production. The resulting imbalance in matrix metalloproteinases and their tissue inhibitors of metalloproteinases causes accumulation of extracellular matrix proteins leading to microvascular remodeling renal dysfunction and hypertension. In this proposal we hypothesize that H2S offers renal protection from HHcy-induced renal damage by inhibition of caveolin-1 and modulation of eNOS. We will test this hypothesis in vivo and in vitro. Wild type (C57BL/6J) and genetic model of HHcy (CBS+/-) mice will be supplemented without or with H2S. To determine whether HHcy effects are caveolin-1 dependent we will use caveolin-1-/- mice supplemented with high Hcy diet. To ameliorate the HHcy- induced injury single double or triple gene delivery system employing CBS CSE and 3MST enzymes will be used to enhance conversion of Hcy to H2S. In addition to confirming the preliminary findings further studies will be performed for a deeper understanding into H2S-mediated improvement in renovascular dysfunction caused by pro-fibrotic and pro-inflammatory effects of HHcy. This research is novel because it evaluates gene delivery as a therapeutic option to ameliorate HHcy-induced microvascular remodeling renal dysfunction and hypertension.

project_terms:
3-Mercaptopyruvate sulfurtransferase;Affect;Amino Acids;Angiography;Antihypertensive Agents;Antioxidants;Atherosclerosis;Blood Pressure;Blood Vessels;Blood capillaries;Cells;Chemicals;Chronic Kidney Failure;Co-Immunoprecipitations;Collagen;Connexins;Cystathionine;Cystathionine beta-Synthase;Development;Diet;Disease;Endothelial Cells;Environmental Hazards;Enzymes;Extracellular Matrix;Extracellular Matrix Proteins;Fibrosis;Functional disorder;Future;Gap Junctions;Gelatinase A;Gelatinases;Gene Delivery;Genes;Genetic Models;Glomerular Filtration Rate;Goals;Histologic;Homocysteine;Hydrogen Sulfide;Hyperhomocysteinemia;Hypertension;Impairment;In Vitro;Inflammatory;Injury;Intercellular Junctions;Interstitial Collagenase;Investigation;Kidney;Kidney Diseases;Knowledge;Lead;Lyase;Mass Spectrum Analysis;Matrilysin;Matrix Metalloproteinases;Measures;Mediating;Messenger RNA;Metabolism;Metalloproteases;Methods;Molecular;Mus;NOS3 gene;Nitric Oxide;Outcome;Outcomes Research;Oxidative Stress;Pathology;Perfusion;Physiological;Plasma;Process;Production;Renal Hypertension;Renal function;Renovascular Hypertension;Reporting;Research;Reverse Transcriptase Polymerase Chain Reaction;Roentgen Rays;Role;Structure;Sulfhydryl Compounds;Supplementation;Testing;Therapeutic;Therapeutic Agents;Tissue Inhibitor of Metalloproteinase-1;Tissue Inhibitor of Metalloproteinases;Tissues;Up-Regulation;Vascular Diseases;Vascular remodeling;Western Blotting;blood pressure regulation;capillary;caveolin 1;collagenase;connexin 37;density;gene delivery system;histological stains;in vivo;insight;kidney vascular structure;neurotoxicity;novel;prevent;public health relevance

public_health_relevance:
PUBLIC HEALTH RELEVANCE: A non-protein amino acid homocysteine at elevated levels cause vascular remodeling and dysfunction. Homocysteine however in the body metabolizes and produces hydrogen sulfide. Although high levels of hydrogen sulfide are toxic low levels are protective against varieties of vascular diseases. This study proposes to mitigate high homocysteine effects on renal vascular tissues either by hydrogen sulfide supplementation or through conversion of bad homocysteine to good hydrogen sulfide by gene manipulation. The research outcome will further our knowledge for future investigations of therapeutic potential of hydrogen sulfide in high homocysteine-associated renovascular diseases.


application_id: 9320011
project_number: 5R01CE002690-03
project_title: Randomized Trial Integrating Substance Abuse with Bystander-Based Violence Prevention
administering_ic: NCIPC
award_notice_date: 2017-07-26
opportunity_number: RFA-CE-15-001
application_type: 5
activity_code: R01
ic: CE
serial_number: 002690
program_official: WRIGHT, MARCIENNE
project_start_date: 2015-09-01
project_end_date: 2018-08-31
study_section: ZCE1-EEO(01)1
contact_pi_person_id: 9247640
contact_pi: BUSH, HEATHER M
other_pis: COKER, ANN L
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Rates of sexual violence (SV) or dating violence (DV) remain high among college students (22% in the past year for female undergraduates). Binge drinking commonly occurs (25% of undergraduates report binge drinking in the past month) and is a strong predictor of sexual risk taking and violent victimization and perpetration. Given connections between SV/DV risk and alcohol use and abuse many advocate prevention programming to jointly address SV/DV and alcohol abuse. Bystander interventions recognized as promising violence prevention strategies are unique in their engagement of all community members to 1) recognize situations that may become violent and 2) learn to safely and effectively intervene to reduce violence risk. Based on their promise the Campus Sexual Violence Elimination Act (SaVE) now requires all publicly-funded colleges to provide a bystander intervention aimed at reducing SV/DV. No randomized intervention trial to date has compared bystander interventions focused exclusively on SV/DV prevention with those that also address alcohol abuse prevention within the bystander context. We propose such an experimental trial at the University of Kentucky (UK) a nationally recognized leader in addressing SV through bystander intervention programming. This randomized intervention trial is designed to evaluate the relative efficacy of three bystander training conditions. Per UK policy all incoming undergraduates participate in mandatory online SV training and students recruited for this study will be randomized to a condition with one of the following additional elements: 1) Green Dot Intensive Bystander Training combined with Substance Abuse Prevention Training (SubINT); 2) Green Dot Intensive Bystander Training (INT) or 3) No add-on online bystander training alone (Online). Aim 1: Evaluate methods to capture bystander behaviors and diffusion of training through social media communications (e.g. Facebook Twitter and Instagram). Aim 2: Determine the relative efficacy of the three bystander training conditions to a) increase bystander efficacy and behaviors by domain (alcohol abuse and violence prevention) b) reduce acceptance of SV/DV alcohol's role in sexual behavior and alcohol use / abuse and c) reduce risk taking behaviors by domains of sexual behavior and alcohol use / abuse. Aim 3: Determine the relative cost of implementing bystander approaches and their cost effectiveness. Design: Incoming UK undergraduates will be recruited and randomized to one of the three conditions and followed for one academic year (9 months) (n=6000 total over 3 academic year cohorts). A mixed-method approach will measure intervention fidelity and costs over time and by condition. Value-Added: UK Analytics and Technology will serve as a trusted broker to link and aggregate by randomized condition available external data from mandatory Campus Attitudes Toward Safety (CATS) and other assessments and academic records. Using the most rigorous design available we seek to generate a new understanding of how novel bystander intervention approaches work to reduce not only SV/DV risk taking behaviors but also reduce alcohol abuse.

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


application_id: 9319907
project_number: 1R56DC015019-01A1
project_title: Gap Junctional Function in Hearing
administering_ic: NIDCD
award_notice_date: 2016-08-04
opportunity_number: PA-13-302
application_type: 1
activity_code: R56
ic: DC
serial_number: 015019
suffix: A1
program_official: WATSON, BRACIE
project_start_date: 2016-08-08
project_end_date: 2018-07-31
study_section: Auditory System Study Section[AUD]
contact_pi_person_id: 8536073
contact_pi: ZHAO, HONG-BO
other_pis: Not Applicable
congressional_district: 06
department: OTOLARYNGOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Summary The long-term goal of this project is to investigate the function of connexins in hearing and the deafnessmechanisms underlying connexin mutation-induced hearing loss. Connexin 26 (Cx26 GJB2) mutationsaccount for >50% of cases of nonsyndromic hearing loss ranging from profound congenital deafness at birthto mild progressive late-onset hearing loss in late childhood. However the underlying deafness mechanismsstill remain largely undetermined. Lack of detailed information about deafness mechanisms directly hampersefforts to develop efficient and practicable therapeutic interventions. In particular patients with progressivelate-onset hearing loss are good candidates for applying protective and therapeutic interventions. Recently wefound that Cx26 deficiency induced congenital deafness is associated with cochlear developmental disordersrather than cell degeneration whereas Cx26 deficiency induced late-onset hearing loss is associated with thereduction of active cochlear amplification by affecting outer hair cell electromotility despite the lack ofconnexin expression in outer hair cells. We also found that the hypothesized defect of K+-recycling is notresponsible for Cx26 deficiency induced hearing loss. Our working hypothesis in this project is that Cx26deficiency induced hearing loss may have different deafness mechanisms: congenital deafness mayresult from cochlear developmental disorders whereas late-onset hearing loss may result from thereduction of active cochlear amplification. Five specific aims (SAs) will be tested for this novel hypothesis.We will first investigate the mechanisms underlying Cx26 deficiency induced cochlear developmentaldisorders. Organ development relies on well-orchestrated intercellular communication to coordinate geneexpression. Gene expression can be regulated by many factors at many stages such as promoterstranscription factors and small non-coding RNAs (miRNAs/siRNAs). However none of these regulatory factorsis intercellularly exchangeable through gap junctions except miRNAs/siRNAs. We will test whethermiRNAs/siRNAs can pass through inner ear gap junctions and whether Cx26 deficiency can disruptmiRNA/siRNA intercellular communication in the cochlea to influence cochlear development (SA1-2). Then wewill investigate how Cx26 deficiency in the cochlear supporting cells reduces active cochlear amplification inlate-onset hearing loss (SA3). In SA4-5 we will further characterize and compare changes in channelproperties and functions associated with Cx26 R75W and M34T mutations which cause congenital deafnessand late-onset hearing loss respectively and create mutation knockin mice to identify pathological changes inthe cochlea. Undoubtedly this systematic study will reveal detailed molecular and cellular mechanismsunderlying Cx26 deficiency induced hearing loss and will also provide invaluable information for developingnew strategies for protecting against and treating this common nonsyndromic deafness.

project_terms:
Accounting;Affect;Birth;Cell Differentiation process;Cell Proliferation;Cell membrane;Cells;Childhood;Cochlear structure;Communication;Connexins;Cytoskeleton;Deafness;Defect;Development;Disease;GJB2 gene;Gap Junctions;Gene Expression;Genetic;Goals;Hair Cells;Hearing;Impairment;Incidence;Induced Mutation;Knock-in Mouse;Knockout Mice;Labyrinth;Mechanics;Mediating;Membrane Potentials;MicroRNAs;Molecular;Mutation;Nerve Degeneration;Outer Hair Cells;Patients;Permeability;Play;Property;Recycling;Role;Small Interfering RNA;Staging;Supporting Cell;Techniques;Testing;Therapeutic Intervention;Untranslated RNA;Work;congenital deafness;developmental disease/disorder;hearing impairment;in vivo;intercellular communication;novel;optogenetics;organ growth;promoter;public health relevance;research study;spiral ganglion;transcription factor

public_health_relevance:
Public Health Relevance Statement: Connexin 26 mutations can induce high incidences of nonsyndromic hearing loss. In thisproposal we will directly investigate the pathological mechanism underlying this common typeof nonsyndromic hearing loss. This study will provide invaluable clues for developing protectiveand therapeutic interventions for nonsyndromic hearing loss.


application_id: 9319801
project_number: 5U01HL121807-05
project_title: The Impact of Oxidative Stress on HIV-induced Lung Disease
administering_ic: NHLBI
award_notice_date: 2017-07-10
opportunity_number: RFA-HL-13-026
application_type: 5
activity_code: U01
ic: HL
serial_number: 121807
program_official: CALER, ELISABET V
project_start_date: 2013-09-26
project_end_date: 2018-11-30
study_section: ZHL1-CSR-S(S1)
contact_pi_person_id: 8816315
contact_pi: RAMIREZ, JULIO ALBERTO
other_pis: ROMAN, JESSE
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): Lung diseases are major causes of morbidity and mortality in patients infected with the Human Immunodeficiency Virus (HIV). Currently antiretroviral therapy (ART) has changed HIV into a chronic disease. In the pre-ART era pulmonary infections were very common. In patients with ART however pulmonary infections are less frequent and noninfectious lung disorders such as COPD pulmonary hypertension lung cancer and pulmonary fibrosis are emerging as important causes of illness. These are important cause of morbidity and mortality yet the mechanisms responsible for these disorders in HIV patients are unknown. All pulmonary disorders mentioned above are associated with among other things lung inflammation and tissue remodeling characterized by alterations in matrix expression deposition and degradation. Interestingly HIV infection is also associated with oxidant stress caused by oxidation of the thiol disulfide couple cysteine (Cys)/cysteine (CySS) redox potential (Eh); also termed Eh Cys/CySS. This is important because in vitro studies show that an oxidized Eh Cys/CySS stimulates lung cells to produce more fibronectin (a matrix glycoprotein implicated in tissue injury and repair) transforming growth factor b (a pro-fibrotic growth factor) and pro-inflammatory cytokines like interleukin-1b. It also stimulates theproliferation and epithelial- mesenchymal transformation of lung fibroblasts processes implicated in tissue remodeling. These data suggest that HIV-related oxidation of Eh Cys/CySS may promote lung tissue remodeling. We have shown that one mechanism by which oxidation of Eh Cys/CySS stimulates tissue remodeling is through the activation of nicotinic acetylcholine receptors (nAChRs). This is intriguing considering that HIV-1 proteins like gp120 bind and increase the expression and signaling of nAChRs expressed in brain and this mechanism has been implicated in HIV-related dementia. We hypothesize that patients with HIV infection have oxidation of the Eh Cys/CySS which together with gp120 activates nAChR-mediated signaling in lung cells and leads to their expression of cellular products with pro-inflammatory and pro-fibrotic effects such as cytokines and growth factors matrix glycoproteins and tissue proteases. The persistent and exaggerated production of these factors activates lung tissue remodeling thereby promoting HIV-related lung disease. The type of disease developed (e.g. COPD versus pulmonary hypertension) however is dependent on both the genetic makeup of the subject and external factors such as smoking and infection. It is important that this hypothesis be tested considering that diet and other interventions have been shown to influence Eh Cys/CySS (9). If found to be causal Eh Cys/CySS and nAChRs can be targeted for intervention in the hope of reducing the incidence and/or severity of HIV-related non-infectious lung disease.

project_terms:
AIDS Dementia Complex;Address;Binding;Blood;Brain;Bronchoalveolar Lavage Fluid;Cause of Death;Cells;Chronic Disease;Chronic Obstructive Airway Disease;Chronic lung disease;Clinical Research;Complement Factor B;Cysteine;Data;Databases;Dementia;Deposition;Deterioration;Diet;Disease;Disulfides;Epithelial;Fibroblasts;Fibronectins;Glycoproteins;Goals;Growth Factor;HIV;HIV Envelope Protein gp120;HIV Infections;HIV-1;Immunologist;In Vitro;Incidence;Individual;Infection;Inflammatory;Interleukin-1 beta;Interleukins;Intervention;Lung;Lung Inflammation;Lung diseases;Malignant neoplasm of lung;Mesenchymal;Morbidity - disease rate;Myofibroblast;Nicotinic Receptors;Oxidation-Reduction;Oxidative Stress;Oxides;Patients;Peptide Hydrolases;Physicians;Process;Production;Proteins;Pulmonary Fibrosis;Pulmonary Hypertension;Research Personnel;Scientist;Severities;Signal Transduction;Smoking;Structure of parenchyma of lung;Sulfhydryl Compounds;Testing;Tissues;Transforming Growth Factors;Universities;antiretroviral therapy;base;clinical investigation;cytokine;design;env Gene Products;epidemiology study;follow-up;genetic makeup;injury and repair;mortality;oxidant stress;oxidation;prevent;programs;public health relevance;pulmonary function;receptor-mediated signaling;research and development;transdifferentiation

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Lung diseases are major causes of death in patients with HIV infection. We are investigating what damages the lung in HIV infected patients compared to patients without HIV. Our ultimate goal is develop treatments to prevent lung diseases in these patients.


application_id: 9319737
project_number: 5R44DK089892-08
project_title: NOVEL ASSAY TO DETECT CHRONIC KIDNEY DISEASE
administering_ic: NIDDK
award_notice_date: 2017-07-21
opportunity_number: PA-14-071
application_type: 5
activity_code: R44
ic: DK
serial_number: 089892
program_official: GOSSETT, DANIEL ROBERT
project_start_date: 2010-09-20
project_end_date: 2020-03-31
study_section: Special Emphasis Panel[ZRG1-DKUS-L(11)B]
contact_pi_person_id: 1897474
contact_pi: CARRITHERS, STEPHEN L
other_pis: COUGHLIN, RICHARD THOMAS
congressional_district: 04
department: Unavailable
primary_duns: 189577070
primary_uei: DJ6WUEKKFBM8
duns_number: 189577070
uei: DJ6WUEKKFBM8
fips: US
organization_id: 10001287
organization_name: SEQUELA
organization_city: PEWEE VALLEY
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400569116
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant:  There are an estimated 26 million Americans with chronic kidney disease (CKD). Early diagnosis and treatment are the only cost-effective means to reverse this growing problem. NIH recognizes the challenge to diagnose CKD early during its initiation and development phases in order to prevent further renal damage reduce cardiovascular risk and minimize the economic impact of CKD. Currently two complimentary tests - estimated GFR (eGFR) and urine albumin-to-creatinine ratio (UACR) - are used to identify CKD and are effective once the onset of disease has occurred. We will produce a new ELISA for CKD to be employed as a diagnostic test based upon the use of a novel biomarker that reflects critical events in the pathophysiology of kidney disease. Preliminary results suggestthat our CKD-ASSAY could replace or compliment both predicate assays. Further the specificity and reproducibility of the results may reduce or eliminate the need for repeat testing.Aside from increased convenience and reduced time to treatment this may mean that the cost of screening for CKD may be greatly reduced.  Our CKD-ASSAY would give physicians the ability to evaluate patients that have been recently diagnosed with hypertension diabetes or a family history of CKD. In Phase I we evaluated the feasibility and proof-of principal of this testand found that the prototype assay in both at-risk populations was highly sensitive and specific. In Phase II we confirmed the specificity of our CKD-ASSAY established concordance with other assays and looked for other factors that might have impacted on assay performance. We request Phase IIB support so that we can prepare cGMP kits perform the pivotal clinical evaluations submit our 510(k) application to the FDA and prepare for commercial launch.

project_terms:
Acute Renal Failure with Renal Papillary Necrosis;Adult;Affect;Agreement;Albumins;American;Biological Assay;Biological Markers;Blinded;Calibration;Child;Chronic Kidney Failure;Clinical;Clinical Research;Clinical Trials;Code;Communities;Creatinine;Cyclic GMP;Detection;Development;Devices;Diabetes Mellitus;Diagnosis;Diagnostic;Diagnostic radiologic examination;Diagnostic tests;Disease;Doctor of Philosophy;Early Diagnosis;Early treatment;End stage renal failure;Enzyme-Linked Immunosorbent Assay;Equation;Event;Family history of;Focus Groups;Functional disorder;Funding;Goals;Health Insurance Portability and Accountability Act;Hemodialysis;Howard Temin Award;Hypertension;ICD-9;In Vitro;Injury;Intellectual Property;Kidney;Kidney Diseases;Legal patent;Measures;Methods;Minority Groups;Morbidity - disease rate;Onset of illness;Patients;Performance;Phase;Physicians;Polycystic Kidney Diseases;Populations at Risk;Premature Infant;Prevalence;Process;Publishing;Quality Control;Records;Regulatory Pathway;Reproducibility of Results;Series;Sickle Cell;Site;Specificity;System;Testing;Time;Transact;United States;United States National Institutes of Health;Urine;Work;base;cardiovascular risk factor;clinical material;cohort;commercialization;cost;cost effective;cost efficient;disorder risk;economic impact;high risk;high risk population;loss of function;manufacturing process;mortality;novel;novel marker;polyclonal antibody;post gamma-globulins;pre-clinical;prevent;programs;prototype;public health relevance;research clinical testing;risk minimization;screening;success;validation studies

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Chronic Kidney Disease affects nearly 26 million people in the United States which places them at higher risk of cardiovascular disease hemodialysis and end stage renal disease. We will develop an assay for identification of people with advanced kidney disease that are under-diagnosed by current methods and to aid physicians in earlier treatment and better assessment of chronic kidney disease.


application_id: 9319419
project_number: 3R01AG047297-02S1
project_title: Asthma in Older Adults: Identifying Phenotypes and Factors Impacting Outcomes
administering_ic: NIA
award_notice_date: 2016-09-19
opportunity_number: PA-16-225
application_type: 3
activity_code: R01
ic: AG
serial_number: 047297
suffix: S1
program_official: ZIEMAN, SUSAN
project_start_date: 2015-02-01
project_end_date: 2020-01-31
contact_pi_person_id: 11844758
contact_pi: POLIVKA, BARBARA J
other_pis: FOLZ, RODNEY J
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 NURSING
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Asthma is a common chronic inflammatory disorder of the distal airways characterized by recurring symptoms airway inflammation and reversible airflow constriction. It is considered a collection of various phenotypes (characteristics) instead
of a single disease. Currently there is no comprehensive phenotyping specific to older adults with asthma that considers multiple factors relevant to this population. Divergent asthma phenotypes and exposure to unique environmental triggers may affect asthma control in the elderly. In addition factors contributing to asthma quality of life in the elderly have not been wll explored. The aims of our study are to: (1) develop and systematically implement a phenotyping algorithm in older adults with asthma; (2) longitudinally investigate the effects of asthma phenotypes and volatile organic compounds (VOCs) exposures on asthma control in older adults with asthma; and (3) develop a predictive model for asthma quality of life for older adults with asthma. Sub-aims are to explore the impact on moving from community-based to congregate living settings (e. g assisted living) on the course of asthma in older adults and to identify barriers to successful asthma medication management. One hundred ninety participants 60 years of age or older will be enrolled. Inclusion criteria are: meet standard diagnostic criteri for asthma non-smokers have no other chronic respiratory diseases do not reside in a skilled nursing facility and have not recently had a major a medical illness. At baseline participants wil complete spirometry bronchodilator responsiveness fractional exhaled nitric oxide methacholine challenge (if not completed within past 5 years) allergic sensitization Immunoglobulin E (IgE) and sputum analysis as well as standardized questionnaires to assess asthma control quality of life knowledge and self-efficacy. Within 30 days an in-home environmental assessment will be conducted to obtain data on VOCs air particulates moisture temperature humidity pests and an asthma home environment checklist. At 9 and 18 months in-home data will be collected on participants' pulmonary status asthma control and asthma quality of life. At 9-months participants will also complete the measures of medication management. At 18-months we will conduct follow-up in-home environmental assessments collecting the same data we collected at baseline. Participants who have moved to congregate living facilities will be asked open-ended questions about their perception of the effects of the move on the course of their asthma. Using factor analysis we will perform a comprehensive phenotypic characterization that will include a wide range of demographics asthma-specific knowledge and self-efficacy and biomarkers. Predictive models for asthma control and asthma quality of life will be identified using generalized linear mixed-effects modeling. The findings of
this study will be used in future research to develop and test the efficacy of patient-centered interventions for older adults with asthma to improve asthma control and enhance quality of life.

project_terms:
4 year old;Acute;Address;Affect;Age;Age-Years;Air;Algorithms;Allergic;Area;Assisted Living Facilities;Asthma;Biological;Biological Markers;Bronchodilator Agents;Characteristics;Child;Chronic;Collection;Communities;Data;Diagnostic;Disease;Distal;Drug Interactions;Elderly;Emergency department visit;Enrollment;Environment;Environmental Exposure;Exhalation;Exposure to;Factor Analysis;Home environment;Hospitalization;Household Products;Humidity;IgE;Individual;Inflammatory;Intervention;Knowledge;Life;Life Style;Living Arrangement;Longitudinal Studies;Lung;Lung diseases;Measures;Medical;Medication Management;Methods;Modeling;NIH Program Announcements;Nitric Oxide;Non-smoker;Outcome;Paint;Participant;Particulate;Perception;Pesticides;Pharmaceutical Preparations;Phenotype;Physicians;Population;Prevalence;Quality of life;Questionnaires;Research;Research Personnel;Residential Facilities;Self Efficacy;Skilled Nursing Facilities;Spirometry;Sputum;Stress;Symptoms;Temperature;Testing;Therapeutic Intervention;Visit;airway inflammation;asthmatic;base;constriction;demographics;efficacy testing;experience;follow-up;improved;inclusion criteria;interest;meetings;methacholine;mortality;patient oriented;predictive modeling;public health relevance;residence;response;volatile organic compound

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This study will develop a method of categorizing asthma in older adults longitudinally investigate the effects of these categorizations on asthma control and identify factors such as environmental exposures and type of living arrangements that impact asthma quality of life for older adults. As the population ages and the percentage of older adults with asthma increases the information obtained from this study is needed to develop and test patient-centered interventions that will improve asthma control and quality of life in older adults with asthma.


application_id: 9319298
project_number: 5R01GM105977-04
project_title: Exploring Post-Type II PKS Frame Modifications
administering_ic: NIGMS
award_notice_date: 2017-07-19
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: GM
serial_number: 105977
program_official: BOND, MICHELLE RUEFFER
project_start_date: 2014-09-10
project_end_date: 2020-07-31
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;Biotechnology;C-glycoside;Catalysis;Characteristics;Chemicals;Chemotherapy-Oncologic Procedure;Clinical;Collaborations;Communicable Diseases;Complex;Cost Savings;Crystallization;Development;Effectiveness;Engineering;Enzyme Interaction;Enzymes;Epirubicin;Event;Evolution;Future;Generations;Goals;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;Natural Products;Nature;Oxidoreductase;Oxygenases;Parents;Pathway interactions;Pharmaceutical Preparations;Pharmacotherapy;Pharmacy facility;Plicamycin;Proteins;Reaction;Recombinant Proteins;Regimen;Resistance;Side;Skeleton;System;Tetracyclines;United States National Institutes of Health;Universities;Vertebral column;Work;analog;base;cancer therapy;catalyst;chemotherapy;college;combinatorial;drug discovery;drug synthesis;expectation;glycosylation;glycosyltransferase;improved;interest;member;novel;novel therapeutics;overexpression;polyketide synthase;protein structure;public health relevance;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: 9319273
project_number: 5R21EY027032-02
project_title: Identifying novel c-Cbl antagonists to promote corneal epithelial regeneration
administering_ic: NEI
award_notice_date: 2017-07-24
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: EY
serial_number: 027032
program_official: MCKIE, GEORGE ANN
project_start_date: 2016-08-01
project_end_date: 2019-01-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 1925445
contact_pi: CERESA, BRIAN P.
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:
PROJECT SUMMARY/ABSTRACT An intact and fully differentiated corneal epithelium is critical for proper vision and to keep foreign objects(bacteria viruses small particles) out of the eye. However damage to the corneal epithelium is one of themost common ocular problems presented in primary care facilities and arises from a variety of factorsincluding trauma disease and a side-effect of drugs. Despite the prevalence discomfort and potential forblindness associated with perturbation of the corneal epithelium there are no FDA-approved agents thatpromote the restoration and homeostasis of this tissue. The long-term goal of our research is to identify noveltools to modulate the molecular mechanisms that regulate and promote corneal epithelial wound healing andhomeostasis. The overall objective of this application is to identify novel compounds that prolong EGFRsignaling. To accomplish this we will test the central hypothesis that compounds that block c-Cbls ability toubiquitylate the EGFR will divert the activated EGFR from the lysosome for degradation. We believe inhibitionof this interaction will lead to greater EGFR activity and increase corneal epithelial cell migration proliferationand differentiation three cell biological responses that are central to the restoration and maintenance ofcorneal epithelial homeostasis. The rationale for these studies is based on our previous findings thatknockdown of c-Cbl and inhibition of ubiquitylation enhances EGFR-dependent corneal epithelial woundhealing. This research has the following specific aims: 1) Identify candidate compounds that bind with thehighest affinity for c-Cbl and 2) Determine whether the highest affinity compounds are the mostefficacious antagonists of EGFR ubiquitylation and best prolong EGFR signaling. We have completedan in silico screen of 28000000 compounds for their ability to disrupt EGFR:c-Cbl interactions. In Aim 1 wewill test the top 50 candidates for their ability to bind recombinant purified c-Cbl using a Thermofluor assayand Isothermal Titration Calorimetry. In Aim 2 we will use immortalized corneal epithelial cells to test whetherour highest affinity compounds are most effective in preventing ligand-dependent EGFR ubiquitylation slowingthe rate of receptor degradation and enhancing the rate of corneal epithelial wound healing. Our proposedstudies are innovative in our opinion because we will modulate novel ligand-independent molecularmechanisms to increase the magnitude and duration of EGFR activity as a means of accelerating restoration ofdamaged corneal epithelium. These studies are significant because accelerating re-epithelialization andhomeostasis of compromised corneas will decrease the duration of patient distress minimize the likelihood ofinfection and reduce the incidence of blindness. Corneal epithelial homeostasis is a significant public healthissue with limited treatment options. This research has the potential to identify new ways of treating damagedcorneas following trauma disease or as a side-effect of drug treatment as well as provide a betterunderstanding of the molecular mechanisms that regulate corneal epithelial homeostasis.

project_terms:
Advanced Development;Adverse drug effect;Adverse effects;Affinity;Antineoplastic Agents;Bacteria;Binding;Biological;Biological Assay;Biology;Biomedical Engineering;Blindness;Calorimetry;Cell Proliferation;Cells;Cetuximab;Chemical Injury;Chemicals;Complement;Complex;Computer Simulation;Cornea;Corneal Injury;Crystallization;Data;Development;Diabetes Mellitus;Disease;Distress;Drug Kinetics;EGF gene;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Epithelial;Epithelial Cells;Eye;Eye Infections;FDA approved;Foundations;Future;Goals;Growth Factor Receptors;Health;Homeostasis;Human;In Vitro;Incidence;Individual;Infection;Investigation;Kinetics;Laboratory Study;Lead;Ligands;Light;Lysosomes;Maintenance;Measures;Mediating;Mission;Modeling;Molecular;Natural regeneration;Operative Surgical Procedures;Oryctolagus cuniculus;Pain;Patients;Pharmacodynamics;Pharmacology;Pharmacotherapy;Prevalence;Primary Health Care;Property;Public Health;Reagent;Receptor Signaling;Recombinants;Recurrence;Replacement Therapy;Research;Retina;Rodent;Signal Transduction;Stem cells;Structure;Testing;Therapeutic;Tissues;Titrations;Trauma;Virus;Vision;Wound Healing;base;biophysical analysis;cancer therapy;cell growth;cell motility;corneal epithelial wound healing;corneal epithelium;cytokine;experience;heat injury;improved;in vivo;innovation;interest;knock-down;limbal;novel;particle;prevent;receptor;response;restoration;small molecule;tool;ubiquitin-protein ligase

public_health_relevance:
Project NarrativeThe proposed research is relevant to public health because the integrity of the corneal epithelium is frequentlycompromised as the result of trauma surgery side effects of anti-cancer drugs and secondary effects ofdiabetes. This innovative line of investigation seeks to identify new compounds that will extend the duration ofepidermal growth factor receptor signaling to maintain and promote a healthy corneal epithelium. This projectis relevant to the NEIs mission because these findings will advance the development of new strategies topromote corneal epithelial wound healing and minimize the chances of eye infection and subsequentblindness.


application_id: 9319133
project_number: 5K22AI118949-02
project_title: Contact-Dependent Interbacterial Signaling in Burkholderia
administering_ic: NIAID
award_notice_date: 2017-07-20
opportunity_number: PAR-14-341
application_type: 5
activity_code: K22
ic: AI
serial_number: 118949
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2016-08-01
project_end_date: 2019-07-31
study_section: Microbiology and Infectious Diseases B Research Study Section[MID-B]
contact_pi_person_id: 10751521
contact_pi: GARCIA, ERIN C
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Both non-pathogenic and pathogenic Burkholderia including members of the opportunistic infection-causing Burkholderia cepacia complex encode genes to produce contact-dependent growth inhibition (CDI) system proteins. CDI is a widespread phenomenon in which Gram-negative bacteria use the toxic C-terminus of a polymorphic surface-exposed exoprotein to inhibit the growth of susceptible bacteria upon cell-cell contact. The exoprotein toxin is delivered to the cytoplasm of target cells and autoinhibitionis prevented by production of a small immunity protein. We previously demonstrated that in addition to their role in interbacterial competition the CDI system proteins in Burkholderia thailandensis encoded by bcpAIOB mediate biofilm formation. This requires the putative nuclease activity of the BcpA toxic exoprotein but is independent of interbacterial killing suggesting that biofilm formation in B. thailandensis involves an uncharacterized function of BcpA. Preliminary data suggest that bcpAIOB mediate interbacterial signaling in B. thailandensis leading to a change in gene expression in immune target bacteria. Given these data and the conservation of CDI systems it seems likely that CDI systems in other Burkholderia also function in interbacterial signaling and could play a role during infection. Toward understanding the role of CDI system-mediated signaling this proposal will test the hypothesis that BcpA toxin delivered to an immune target cell interacts with specific periplasmic and cytoplasmic factors leading to global gene expression changes and represents a useful therapeutic target in pathogenic Burkholderia. Experiments proposed in Aim 1 will continue to investigate the mechanism of bcpAIOB-mediated interbacterial signaling in B. thailandensis defining the affected gene regulation pathways and identifying required regions of BcpA as well as other factors necessary for signaling. Studies in Aim 2 will explore the role of CDI systems and their potential for exploitation as therapies in pathogenic Burkholderia cepacia complex strains. These studies represent the first investigation of what may be a widespread phenomenon in Gram-negative bacteria and will work toward addressing an essential need for new drug targets and antimicrobials.

project_terms:
Address;Affect;Animal Model;Animals;Anti-Bacterial Agents;Bacteria;Behavior;Binding;Biochemical;Burkholderia;Burkholderia cepacia complex;Cells;Chronic;Chronic Granulomatous Disease;Communication;Communities;Complex;Congo Red;Cytoplasm;Data;Decontaminant;Development;Disease;Disease Outbreaks;Drug Targeting;Escherichia coli;FLP recombinase;Foundations;Future;Gene Expression;Gene Expression Regulation;Genes;Genome;Gram-Negative Bacteria;Growth;Human;Immune;Immune Targeting;Immunity;In Vitro;Infection;Infection prevention;Investigation;Killings;Knowledge;Life;Lung;Lung diseases;Mediating;Microbial Biofilms;Modeling;Molecular;Neisseria meningitidis;Opportunistic Infections;Organism;Pathogenicity;Pathway interactions;Phenotype;Pigments;Plants;Play;Production;Proteins;Reporter;Research;Role;Signal Pathway;Signal Transduction;Soil;Surface;System;Testing;Therapeutic;Toxic effect;Toxin;Work;antimicrobial;base;cystic fibrosis patients;experimental study;human disease;in vivo;insight;member;mouse model;new therapeutic target;nuclease;pathogen;periplasm;prevent;public health relevance;therapeutic target;transcriptome sequencing;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Burkholderia are a group of environmental bacteria that can cause life-threatening opportunistic infections in patients with cystic fibrosis or other lung disorders. This proposal focuses on understanding of how these and related bacteria interact with each other and how that interaction may affect disease. Additionally by studying antibacterial proteins produced by these bacteria this research will lay the foundation for the development of new antimicrobial therapies against Burkholderia.


application_id: 9318133
project_number: 5U48DP005014-04
project_title: Rural Cancer Prevention Center __ Early Detection of Colorectal Cancer and Polyps
administering_ic: NCCDPHP
award_notice_date: 2017-08-11
opportunity_number: RFA-DP-14-001
application_type: 5
activity_code: U48
ic: DP
serial_number: 005014
program_official: DARLING, NATALIE
project_start_date: 2014-09-30
project_end_date: 2019-09-29
study_section: ZDP1-EEO(01)
contact_pi_person_id: 8234905
contact_pi: CROSBY, RICHARD A
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This renewal application proposes to continue the cancer prevention programs of the University of Kentucky PRC the only PRC dedicated to cancer prevention in rural Appalachia. Known locally as the Rural Cancer Prevention Center (RCPC) our past focus has been on the prevention (through vaccination) and early detection of cervical cancer. Through social marketing and planned outreach the RCPC has successfully leveraged the trust of rural people residing in the most economically depressed area of Appalachia (southeastern KY). The proposed renewal offers plans to continue our community-based cancer prevention research and to extend our programs to other regions of Appalachia using sustainable models. Moreover the previous research pertaining to cervical cancer prevention created a strong basis for testing a novel approach to community-based screening for colorectal cancer (CRC). Based on new screening technology this approach will be effective and accessible to medically disenfranchised and under-served rural residents. The proposed plan has 5 general aims (A-E) and a specific research aim (F): A) Provide infrastructure and administrative services that support cancer prevention; B) Build community capacity and actively engage the community in partnerships for cancer prevention; C) Provide an efficient and effective communications network that ties cancer prevention activities together and disseminates health communication; D) Offer training and technical support to state and local agencies; E) Evaluate (process and outcome) all planned activities related to aims A-D; and F) Conduct an applied prevention research project that demonstrates the value of using community change agents to foster widespread adoption of annual colorectal cancer (CRC) screening with Fecal Immunochemical Test (FIT) followed by navigation to colonoscopy for those screening FIT-positive and by an intervention program that promote annual repeat use of FIT. All six aims are inter-related; however the final aim is a highly focused set of activities that occur in two phases: 1) the programs supporting this aim will be tested in Years 1-3 and 2) to benefit other rural Appalachian states dissemination and implementation activities will be conducted in Years 4-5. Programs to be tested in Years 1-3 include 1) a community-based intervention featuring a Diffusion of Innovations model standard RCPC outreach methods and academic detailing for health care providers tested using a non-equivalent comparison design; this trial will end when 500 FIT specimens have been returned in the intervention health district 2) a social network analysis (N = 64) used to provide interim feedback regarding key characteristics of effective change agents used in the diffusion model 3) a navigation program (based on current RCPC practices for cervical cancer) that will be applied to people testing FIT-positive (N = 60) and 4)
an internet-based program designed to foster annual repeat FIT screening tested using a randomized controlled trial design (N = 220). Programs will be designed for optimal sustainability and dissemination/implementation potential.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This renewal application proposes to continue the cancer prevention programs of the University of Kentucky PRC the only PRC dedicated to cancer prevention in rural Appalachia. The proposed renewal offers plans to continue our community-based cancer prevention research and to extend our programs to other regions of Appalachia using sustainable dissemination and implementation models.


application_id: 9318046
project_number: 1R21NS098186-01A1
project_title: Changing serotonin receptor 2C splice variants to combat spasticity after spinal cord injury
administering_ic: NINDS
award_notice_date: 2017-03-14
opportunity_number: PA-16-161
application_type: 1
activity_code: R21
ic: NS
serial_number: 098186
suffix: A1
program_official: JAKEMAN, LYN B
project_start_date: 2017-04-01
project_end_date: 2019-03-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 8899488
contact_pi: STAMM, STEFAN
other_pis: RABCHEVSKY, ALEXANDER GEORGE
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:
Project SummarySpinal cord injury (SCI) affects approximately 300000 Americans resulting in devastating neurologicaland physical limitations. SCI in the chronic phase is complicated by muscle spasms which are to alarge degree caused by hyperactivation of the serotonin receptor 2C (5HT2C) caudal to the injury.Through a combination of alternative splicing and editing the G-protein coupled receptor generates atleast 25 isoforms with different regulatory properties: one intracellular truncated receptor 5HT2C_tr onenon-edited full-length receptor 5HT2C_Fl_INI and 23 full length edited receptors 5HT2C_FL_ed. The ratio of these isoforms wherein the 5HT2C_FL shows constitutive activity plays a major partin the maladaptation after injury. SCI leads to a loss of editing activity of ADAR2 (adenosine deaminaseacting on RNA) which results in a downregulation of 5HT2C_FL_ed isoforms relative to the5HT2C_FL_INI. Extending our joint published work (Zhang et al. 2016 EMBO Mol. Med)1 weconcentrated on the novel 5HT2C_tr isoform that sequesters the 5HT2C_FL intracellularly. We foundan increase of the 5HT2C_tr isoform after SCI possibly as an adaptation to prevent the constitutivelyactive 5HT2C_FL_INI from hyperactivity. To intervene with the isoform ratios we developed a series of oligonucleotides that eitherincrease or decrease the 5HT2C_tr /5HT2C_FL_INI ratio as well as an antiserum that is specific for the5HT2C_tr protein. Using these tools we will test the hypothesis that SCI leads to an increase in bothconstitutively active 5HT2C_FL_INI and its downregulating 5HT2C_tr isoform. This change deregulatesspinal cord neuronal activity leading to spasms likely due to insufficient 5HT2C_tr isoform to stop the5HT2C_FL_INI activity. We will thus further test whether these spasms can be mitigated using ourdeveloped oligonucleotides that promote 5HT2C_tr. Using an established S2 spinal cord transection rat model we will map the spatial and temporalchanges in receptor isoforms and test the influence of splicing-changing oligonucleotides on thedevelopment of tail spasms. The oligonucleotides interfere with the serotonin system by changing thesurface localization of constitutive active 5HT2C_FL which is a novel approach compared to ligand-based drugs activating surface receptors. Using this innovative approach targeting the pre-mRNAthese studies are significant with great potential to treat spasticity which is a major co-morbidity of SCI.

project_terms:
Activities of Daily Living;Affect;Agreement;Alternative Splicing;American;Cells;Chronic Phase;Collaborations;Comorbidity;Contusions;Coupled;DRADA2b protein;Development;Down-Regulation;G-Protein-Coupled Receptors;G-substrate;GTP-Binding Proteins;Genes;Hyperactive behavior;Injury;Intervention;Intrathecal Injections;Joints;Laboratory Study;Lead;Length;Ligands;Maps;Membrane Proteins;Metabolism;Modeling;Molecular;Molecular Target;Motor Neurons;Neurologic;Neurons;Oligonucleotides;Persons;Pharmaceutical Preparations;Play;Property;Protein Isoforms;Proteins;Publishing;RNA;RNA Splicing;Rattus;Series;Serotonergic System;Serotonin Receptor 5-HT2C;Spasm;Spastic;Spinal Cord;Spinal Cord transection injury;Spinal cord injury;Surface;System;Tail;Testing;United States;Variant;Work;adenosine deaminase;base;combat;innovation;mRNA Precursor;novel;novel strategies;prevent;receptor;spasticity;tool;uptake

public_health_relevance:
Spinal cord injury affects more than 300000 Americans leading to spasms that interferewith living activities as they occur repeatedly on a daily basis. We will determine themolecular basis for the spasms and test a synthetic RNA as a possible drug intervention.


application_id: 9317445
project_number: 5R01CA185972-04
project_title: Chemoprevention of metastatic colorectal cancer
administering_ic: NCI
award_notice_date: 2017-07-19
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 185972
program_official: CHEN, WEIWEI
project_start_date: 2014-08-01
project_end_date: 2019-07-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 7649061
contact_pi: DAMODARAN, CHENDIL
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Colon cancer metastasis remains the leading cause of death due to this disease. It is important to identify the cause of events maneuvering it to a more advanced stage and metastasis. In the proposed study we have hypothesized that high level of AKT expression is CRC is responsible for developing an aggressive and metastatic disease by influencing epithelial-mesenchymal transitions (EMT) endowing cells with migratory and invasive phenotype hence targeting AKT activation can prevent metastasis in CRC. To prove the hypothesis we have checked the status of AKT in CRC cell lines and patient samples revealing high expression of AKT. In our cell culture and colon cancer xenograft models we have shown that overexpression of AKT leads to aggressive cell and tumor growth angiogenesis in tumors and EMT phenotype in tumor cells. The goal of the current project is to characterize and generate preclinical data on withaferin-A (WA) or ita potent analog as an oral agent for the prevention of colon cancer metastasis. To inhibit AKT signaling we have employed Withaferin-A (WA) an herbal molecule that overcomes AKT-mediated EMT in preclinical models of CRC. Based on these finding we hypothesize that CRC cells have adapted for the high-level of AKT expression to develop an aggressive phenotypes hence targeting AKT activation can prevent the development of aggressive CRC growth by inhibiting epithelial mesenchymal transition (EMT). We have proposed to identify and synthesize more potent molecules derived from WA which bind more strongly to AKT. These derivatives will be further characterized in cell culture and animal (metastatic xenograft and an APC mimicking advanced and metastatic human CRC) models. Preventing colon cancer using potent biomolecules targeting AKT specifically is a novel approach and may have significant impact on high-risk patients. In addition for the first time we have shown that AKT accumulation is a critical step towards EMT and we have proposed to develop biotin-labeled compounds to target AKT specifically. Chemoprevention of CRC by using these novel potent compounds may have a significant impact in high-risk patients or clinically relapsing patients by inhibiting AKT- induced EMT signaling and hence metastasis.

project_terms:
AKT Signaling Pathway;AKT inhibition;Affinity;Animal Model;Animals;Apoptosis;Ashwagandha;BCL2 gene;Binding;Biological Assay;Biotin;Cancer Etiology;Cause of Death;Cell Culture Techniques;Cell Line;Cell Proliferation;Cells;Cessation of life;Chemoprevention;Chemopreventive Agent;Clinical;Clinical Trials;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Data;Development;Diagnosis;Disease;Disseminated Malignant Neoplasm;Docking;E-Cadherin;Epithelial;Event;Fluorouracil;Genetic Transcription;Goals;Growth;HCT116 Cells;Human;In Vitro;Investigation;Label;Laboratories;Large Intestine Carcinoma;Lead;Malignant Epithelial Cell;Mediating;Mesenchymal;Modeling;Molecular;Neoplasm Metastasis;Oral;Oral Administration;Patient risk;Patients;Pattern;Phenotype;Phosphotransferases;Polyps;Pre-Clinical Model;Prevention;Proteins;Proto-Oncogene Proteins c-akt;Radiosurgery;Regimen;Relapse;Research Personnel;Role;SW620;Sampling;Signal Transduction;Snails;Survival Rate;Therapeutic;Time;Tumor Tissue;Woman;Xenograft Model;Xenograft procedure;analog;angiogenesis;base;beta catenin;cell growth;chemotherapy;dietary supplements;high risk;insight;interest;men;metastatic colorectal;migration;neoplastic cell;novel;novel strategies;overexpression;pre-clinical;prevent;public health relevance;relapse patients;slug;survivin;transcription factor;tumor;tumor growth;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The survival rate of metastatic colorectal carcinoma (CRC) is less than 5%. Use of 5-fluorouracil (5-FU) radiation and surgery are the primary treatments; however most metastatic cancers eventually cause death. Developing approaches to prevent progression to metastasis could therefore be part of an important therapeutic strategy especially for high-risk patients including those patients already diagnosed with high grade polyps or localized colon cancer. The goal of the current project is to characterize and generate preclinical data on withaferin-A (WA) as an oral agent for the prevention of colon cancer metastasis which is the third leading cause of cancer-related death for both men and women. The proposed study of the dietary supplement Withaferin-A (WA) the major bioactive compound from Withania somnifera) and its potent analog will provide molecular level insight into the mechanism of action of this agents against metastatic colon cancer and clarify the clinical potential of WA or its potent analog with respect to the chemoprevention and/ or chemotherapy of colon cancer.


application_id: 9316688
project_number: 5R01HL091357-07
project_title: Genomewide Association Study of Lipid Response to Fenofibrate and Dietary Fat
administering_ic: NHLBI
award_notice_date: 2017-02-19
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 091357
program_official: JAQUISH, CASHELL E
project_start_date: 2008-09-05
project_end_date: 2019-02-28
study_section: Special Emphasis Panel[ZRG1-PSE-Q(90)S]
contact_pi_person_id: 1876483
contact_pi: ARNETT, DONNA K
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 PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Dyslipidemias remain a critical determinant of cardiovascular disease risk. Effective dietary and therapeutic interventions to reduce dyslipidemia including elevated triglycerides (TGs) and high non-HDL-cholesterol exist yet there is much variation in lipid and lipoprotein level's response to these interventions. Genetics partially explain this variation. We hypothesize that by using improved lipid phenotyping techniques we will be able further characterize this interindividual variation of lipids in respone to diet and drug. Recent advances in mass spectrometry-based techniques allow metabolomic characterization in large populations. Detailed and precise measurement of lipid molecular species a field known as "lipidomics" now offers an unprecedented picture of lipid metabolism. The Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study provides an ideal context in which to pursue this work. GOLDN is the largest family study conducted to date that has sought to identify genetic factors that explain response to two short-term interventions one to raise lipids (i.e. ingestion of a high-fat meal the "post-prandial lipemia" (PPL) intervention and one to lower lipids (i.e. treatment with fenofibrate (FFB)). The goal of the "Genomewide Association Study (GWAS) of Lipid Response to Fenofibrate and Dietary Fat" (Arnett PI R01-HL091357) was to identify the common genetic variants that explain response to the interventions. In addition to this GOLDN is also conducting a genome- wide epigenomics study and exome sequencing through the NIH Pharmacogenomics Research Network (PGRN). The proposed work will leverage this wealth of genomic data in the context of state-of-the-art lipidomic phenotypes specifically phospholipids neutral lipids and sterols to identify rare andcommon variants and epigenetic marks that determine response to GOLDN's diet and drug interventions. Specifically we aim to: (1) Quantify pre- and post-FFB treatment/PPL response of 350 metabolites. GOLDN recruited and examined 1048 Caucasians from 186 families. Participants were given an 83% fat meal and three weeks of FFB treatment 250 mg/d. Blood was drawn at fasting and 6-hr post ingestion and again after 3 wk of FFB treatment. Plasma from each of these time points will be analyzed with for 350 lipidomic species. PPL response (estimated as the 6-hr TG response adjusted for baseline) and fenofibrate response (estimated by the ratio of post/pre TG values) of the new lipidomic phenotypes will be calculated. Responsive and heritable metabolites will be moved forward to Aim 2. (2) Test the association of these small molecules with (a) common (GWAS) and rare (WES) variants (b) methylation at CpG sites (EWAS). (3) Replicate PPL findings in 500 subjects selected from extremes of the PPL response in the HAPI Heart Study. (4) Use induced pluripotent stem cell- derived hepatocytes to functionally validate fenofibrate response variants identified in Aim 2. If successful GOLDN will identify novel lipidomic biomarkers to predict efficacy and adverse responses to a high-fat meal and fenofibrate treatment leading to more personalized approaches to diet and pharmacologic treatment.

project_terms:
Age;Biological Assay;Biological Markers;Biological Models;Blood;Body Surface Area;Calcium-Activated Potassium Channel;Calories;Caucasians;Chemicals;Cholesterol;Data;Diet;Dietary Fats;Dietary Intervention;Disease;Drug Prescriptions;Drug Targeting;Dyslipidemias;Eating;Epigenetic Process;Family;Family Study;Fasting;Fatty Acids;Fatty acid glycerol esters;Fenofibrate;Fibrates;Funding;Genes;Genetic;Genome;Genomics;Goals;Heart;Hepatic;Hepatocyte;Heritability;Human;Hypertension;Hypertriglyceridemia;Ingestion;Institutes;Intervention;Link;Lipids;Lipoproteins;Mass Spectrum Analysis;Measurement;Measures;Metabolism;Methodology;Methylation;Modeling;Molecular;Myocardial Infarction;Nuclear;PPAR alpha;Participant;Pharmaceutical Preparations;Pharmacogenomics;Pharmacological Treatment;Phase;Phenotype;Phospholipids;Plasma;Population;Process;Protocols documentation;Recruitment Activity;Reporting;Research;Sample Size;Sampling;Signal Transduction;Sister;Site;Standardization;Steroids;Sterols;Techniques;Testing;Therapeutic Intervention;Time;Triglycerides;United States National Institutes of Health;Universities;Validation;Variant;Washington;Work;base;blood lipid;cardiovascular disorder risk;density;disorder risk;epigenome-wide association studies;epigenomics;exome sequencing;gene environment interaction;genetic pedigree;genetic variant;genome wide association study;genome-wide;genomic data;improved;induced pluripotent stem cell;inter-individual variation;lipid I;lipid metabolism;member;metabolic profile;metabolomics;novel;personalized approach;prevent;programs;public health relevance;rare variant;response;sex;small molecule;stroke;tandem mass spectrometry;trait

public_health_relevance:
PUBLIC HEALTH RELEVANCE: People differ in the ways their bodies process dietary fats and in the ways they respond to drugs meant to lower elevated blood lipids (such as cholesterol and triglycerides factors that can increase the risk of cardiovascular disease). By studying the building blocks of lipids and the chemicals that lipids are broken down into this project seeks todetermine which genetic factors influence people's blood lipid concentrations after eating a high-fat meal or after taking a lipid- lowering drug. Ultimately this research may help doctors more accurately assess people's risk of cardiovascular disease and more effectively prescribe drugs to prevent disease.


application_id: 9316416
project_number: 5R01AA024102-02
project_title: The role of dietary unsaturated fat and inflammasome in alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2017-06-12
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AA
serial_number: 024102
program_official: RADAEVA, SVETLANA
project_start_date: 2016-07-15
project_end_date: 2021-06-30
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 10484237
contact_pi: KIRPICH, IRINA A.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Affect;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Animal Model;Animals;Arachidonate 15-Lipoxygenase;Attenuated;Cations;Clinical;Data;Development;Diet;Dietary Fats;Dietary Intervention;Enzymes;Experimental Animal Model;FDA approved;Fatty Acids;Genetic;Hepatic;Hepatocyte;Human;In Vitro;Inflammasome;Inflammatory;Inflammatory Response;Interleukin-1 beta;Interleukin-18;Intestines;Knock-in;Knockout Mice;Kupffer Cells;Laboratories;Ligands;Linoleic Acids;Mediating;Molecular;Morbidity - disease rate;Mus;Oxides;Pathogenesis;Pathway interactions;Patients;Permeability;Research;Role;Sampling;Severities;Signal Pathway;TRPV1 gene;Testing;Transgenic Organisms;United States National Institutes of Health;Unsaturated Fats;Up-Regulation;Vanilloid;Whole Blood;cytokine;in vivo;liver inflammation;liver injury;loss of function;macrophage;member;monocyte;mortality;new therapeutic target;octadecadienoic acid;overexpression;oxidation;peripheral blood;public health relevance;receptor;saturated fat;translational study


application_id: 9314011
project_number: 1UL1TR001998-01
project_title: Kentucky Center for Clinical and Translational Science
administering_ic: NCATS
award_notice_date: 2016-08-15
opportunity_number: PAR-15-304
application_type: 1
activity_code: UL1
ic: TR
serial_number: 001998
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2020-05-31
study_section: ZTR1-SRC(99)
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Abbreviations;Academic Medical Centers;Affect;Agriculture;Appalachian Region;Arts;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Clinical Trials Network;Collaborations;Communities;Data;Development;Discipline;Diverse Workforce;Education;Engineering;Environment;Fostering;Future;Goals;Health;Healthcare;Healthcare Systems;Home environment;Informatics;Institutes;Institution;Interdisciplinary Study;Kentucky;Lead;Leadership;Longevity;Marshal;Medical center;Methodology;Mission;Multi-Institutional Clinical Trial;Participant;Personal Satisfaction;Phase;Population;Positioning Attribute;Quality of life;Research;Research Training;Role;Rural;Rural Community;Rural Population;Scholarship;Science;Solid;Target Populations;Translational Research;Trust;Universities;West Virginia;Work;Workforce Development;abstracting;base;biomedical informatics;catalyst;collaborative environment;college;data management;drug development;food environment;health care quality;health care service organization;health disparity;healthcare community;improved;innovation;medical schools;medically underserved;meetings;named group;novel;novel therapeutics;programs;success


application_id: 9314009
project_number: 1TL1TR001997-01
project_title: NRSA Training Core
administering_ic: NCATS
award_notice_date: 2016-08-15
opportunity_number: PAR-15-304
application_type: 1
activity_code: TL1
ic: TR
serial_number: 001997
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2020-05-31
study_section: ZTR1-SRC(99)
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Anti-Retroviral Agents;Appalachian Region;Area;Basic Science;Biomedical Research;Clinical;Clinical Medicine;Clinical Research;Clinical Sciences;Collaborations;Communication;Communities;Complex;Dentistry;Development;Development Plans;Discipline;Discipline of Nursing;Doctor of Philosophy;Economics;Educational Status;Engineering;Environment;Ethics;Feedback;Fellowship;Foundations;Funding;Future;Goals;Grant;Growth;Health;Health Sciences;Healthcare;Human;Incubated;Individual;Interdisciplinary Study;Kentucky;Leadership;Learning;Manuscripts;Measures;Medical Students;Medicine;Mentors;Monitor;National Research Service Awards;Oral;Outcome;Pharmacy facility;Population;Positioning Attribute;Preparation;Process;Productivity;Psychology;Public Health;Publications;Qualifying;Research;Research Infrastructure;Research Personnel;Research Training;Residencies;Role;Rural Population;Science;Social Work;Solid;Structure;Students;TNFSF15 gene;Time Management;Training;Training Programs;Translational Research;Universities;Writing;base;biomedical informatics;career;career development;cohort;college;education research;experience;graduate student;innovation;instructor;meetings;multidisciplinary;patient oriented;posters;pre-doctoral;professor;programs;skills;success;training opportunity


application_id: 9314006
project_number: 1KL2TR001996-01
project_title: Institutional Career Development Core
administering_ic: NCATS
award_notice_date: 2016-08-15
opportunity_number: PAR-15-304
application_type: 1
activity_code: KL2
ic: TR
serial_number: 001996
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2020-05-31
study_section: ZTR1-SRC(99)
contact_pi_person_id: 1901822
contact_pi: KELLY, THOMAS H.
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_terms:
Academia;Accounting;Achievement;Address;Aptitude;Arts;Behavioral;Biomedical Research;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Communication;Communities;Complement;Complex;Dentistry;Development;Discipline;Discipline of Nursing;Doctor of Philosophy;Economics;Education;Educational Curriculum;Educational Technology;Engineering;Ensure;Environment;Equilibrium;Evaluation;Extramural Activities;Faculty;Foundations;Funding;Future;Good Clinical Practice;Growth;Health;Health Occupations;Health Psychology;Health Sciences;Healthcare;Human;Incubated;Industry;Instruction;Kentucky;Lead;Leadership;Link;Location;Medicine;Mentors;Methodology;NCI Scholars Program;Nursing Faculty;Outcome;Pharmacy facility;Policies;Population;Process;Productivity;Psychology;Public Health;Public Health Education;Recruitment Activity;Research;Research Training;Resources;Role;Scholarship;Science;Scientist;Self Efficacy;Social Work;Structure;Students;Teacher Professional Development;Technology;Time;Training;Training Programs;Training Support;Training and Education;Translational Research;United States National Institutes of Health;Universities;Work;base;biomedical informatics;career;career development;clinical practice;cohort;college;design;early-career faculty;evidence base;experience;improved;interest;member;next generation;novel;programs;skills;training opportunity;workforce needs


application_id: 9313218
project_number: 5R01DC007176-13
project_title: Neurotrophin receptor regulation of adult taste bud innervation and function
administering_ic: NIDCD
award_notice_date: 2017-06-13
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DC
serial_number: 007176
program_official: SULLIVAN, SUSAN L
project_start_date: 2005-03-01
project_end_date: 2021-06-30
study_section: Special Emphasis Panel[ZRG1-IFCN-B(03)]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adult;Agonist;Basic Science;Brain;Brain-Derived Neurotrophic Factor;Cells;Chemicals;Citric Acid;Clinical;Defect;Development;Disease;Electrophysiology (science);Excision;Eye;Fiber;Food;Ganglia;Genetic;Goals;Health;Ion Channel;Knock-out;Label;Location;Mus;Nerve;Nerve Fibers;Nerve Growth Factor Receptors;Nerve Regeneration;Neuromodulator;Neurons;Neurotransmitter Receptor;Pathway interactions;Pattern;Peripheral;Persons;Process;Quality of life;Receptor Cell;Regulation;Resolution;Role;Sensory;Signal Transduction;Sodium Chloride;Specificity;Stimulus;Structure of geniculate ganglion;Taste Bud Cell;Taste Buds;Taste Disorders;Taste Perception;Techniques;Testing;Therapeutic;Three-Dimensional Imaging;Three-dimensional analysis;Transgenic Mice;Tyrosine Kinase Inhibitor;base;cell type;chemical genetics;epithelial Na+ channel;experimental study;ganglion cell;genetic approach;imaging approach;nerve supply;neurotrophic factor;neurotropin;receptor;relating to nervous system;response;sensory system;small molecule;taste system


application_id: 9312897
project_number: 5R01NS091329-03
project_title: PERK as a central mediator of neurotoxicity in tauopathies
administering_ic: NINDS
award_notice_date: 2017-06-26
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 091329
program_official: CORRIVEAU, RODERICK A
project_start_date: 2015-09-30
project_end_date: 2020-06-30
study_section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND]
contact_pi_person_id: 10569691
contact_pi: ABISAMBRA, JOSE FRANCISCO
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Tauopathies are a group of nineteen known debilitating neurodegenerative disorders that affect nearly eight million people in the United States. Currently there is no cure for tauopathies and there are temporary and limited benefits to current therapeutic strategies. The endoplasmic reticulum (ER) stress sensor PERK (protein kinase R-like ER kinase) has been identified as a participant in the pathogenesis and progression of tauopathies. However the mechanism by which the PERK pathway causes neuronal dysfunction is still unknown. The long-term goal is to better understand the mechanism(s) that induce(s) neuronal dysfunction in tauopathies and the overall objective is to determine the mechanism by which tau and PERK synergize to induce neuronal dysfunction. The central hypothesis is that tau and PERK engage in a pathological cycle whereby aberrant accumulation of tau chronically activates PERK and active PERK activates enzymes that contribute to the production of pathogenic tau. The overall consequence of this cycle is potentiation of tau pathogenic pathways as well as chronic inhibition of protein synthesis. Characterizing the role of the PERK pathway in neuronal dysfunction will identify novel urgently needed therapeutic targets for tauopathies. The hypothesis will be tested in three specific aims. Aim 1 is designed to determine the extent to which the PERK pathway causes neuronal dysfunction in tauopathies. Aim 2 is designed to determine the mechanism by which PERK activity modulates tau pathology. Finally Aim 3 will determine the extent of PERK pathway activation in a newly described tauopathy called Primary Age-Related Tauopathy (PART). In Aim 1 we will use pharmacologic and genetic approaches to inhibit PERK in in vivo in situ and in vitro models of tauopathy; neuronal function will be measured by cognitive tests a novel and non-invasive imaging approach called manganese-enhanced MRI and electrophysiological measurements. Secondly we will use biochemical immunohistochemical and gene expression assays to determine the extent of PERK activity. In Aim 2 we will use pharmacologic and genetic approaches to activate and inhibit PERK in in vivo and in vitro models of tauopathy; we will measure changes to pathological tau and the PERK pathway. Finally in Aim 3 we will measure changes in the levels of PERK pathway markers and pathological tau in PART CSF and brain parenchyma. This will be the first extensive biochemical approach to PART which could unveil novel biomarkers of the disease. The identification of a pathogenic PERK-tau cycle is innovative because it departs from the status quo by identifying an effector of disease (PERK) that can cause neuronal dysfunction (downstream) while also potentiating tau aberrancies (upstream). Therefore the PERK pathway offers a unique repertoire of novel therapeutic targets that can modulate disease in multiple aspects. This approach is significant because of the central role the pathway plays in disease and therefore the potential to offer therapeutic solutions to tauopathies.

project_terms:
Acute;Affect;Alzheimer's Disease;Biochemical;Brain;CASP3 gene;Caspase;Cerebrospinal Fluid;Chemosensitization;Chronic;Cleaved cell;Code;Cognition;Cognitive;Data;Defect;Dementia;Development;Disease;Disease Progression;Distributional Activity;Electrophysiology (science);Endoplasmic Reticulum;Enzymes;Gene Expression Profiling;Genes;Goals;Homeostasis;Human;Impaired cognition;Impairment;In Situ;Individual;Lead;Link;Magnetic Resonance Imaging;Manganese;Measurement;Measures;Mediating;Mediator of activation protein;Modeling;Morphology;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neurofibrillary Tangles;Neurologic Deficit;Neuronal Dysfunction;Neurons;Outcome;Participant;Pathogenesis;Pathogenicity;Pathologic;Pathology;Pathway interactions;Patients;Pharmacology;Phosphotransferases;Play;Prion Diseases;Production;Progressive Supranuclear Palsy;Protein Biosynthesis;Protein Synthesis Inhibition;Proteins;Public Health;RNA;Reporting;Research;Risk;Role;Slice;Synapses;Tauopathies;Tenuate;Testing;Therapeutic;Time;Transgenic Mice;Translations;United States;Work;age related;aging population;attenuation;base;brain parenchyma;cell immortalization;cerebral atrophy;cognitive testing;design;effective therapy;endoplasmic reticulum stress;genetic approach;imaging approach;immortalized cell;improved;in vitro Model;in vivo;innovation;mouse model;neurotoxicity;new therapeutic target;non-invasive imaging;novel;novel marker;novel therapeutics;protein kinase R;public health relevance;sensor;tau Proteins;tau aggregation;tau mutation;therapeutic target

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


application_id: 9312726
project_number: 5R01AG054130-02
administering_ic: NIA
award_notice_date: 2017-04-18
opportunity_number: PAR-16-365
application_type: 5
activity_code: R01
ic: AG
serial_number: 054130
program_official: MCLINDEN, KRISTINA
project_start_date: 2016-07-15
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZRG1-BBBP-V(55)R]
contact_pi_person_id: 10700978
contact_pi: MOGA, DANIELA CLAUDIA
other_pis: JICHA, GREGORY A
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-05-01
project_terms:
AD pathology;Address;Adverse drug effect;Aerobic Exercise;Affect;Age;Alzheimer's Disease;Alzheimer's disease risk;American;Amyloid;Amyloid beta-Protein;Anti-Cholinergics;Beer;Biological;Brain;Clinical;Cognitive;Communities;Comorbidity;Complex;Data;Dementia;Diet;Disease;Disease Progression;Drug usage;Elderly;Enrollment;Expenditure;Health;Health Care Costs;Health Expenditures;Healthcare;Impaired cognition;Intervention;Intervention Trial;Measures;Medical;Medication Management;Neurocognitive;Neurofibrillary Tangles;Onset of illness;Outcome Measure;Pathologic;Pathology;Patients;Pharmaceutical Preparations;Pharmacists;Pharmacology;Pharmacy facility;Phase;Physicians;Placebos;Population;Positron-Emission Tomography;Prevalence;Prevention strategy;Public Health;Reporting;Research;Scopolamine;Senile Plaques;Societies;Standardization;Symptoms;Testing;Time;United States;aging population;base;clinical practice;cognitive reserve;disability;exhaust;functional decline;indexing;insight;non-demented;older patient;patient oriented;post intervention;pre-clinical;primary outcome;psychosocial;public health relevance;randomized placebo controlled trial;randomized trial;stressor;therapy design;uptake


application_id: 9312114
project_number: 5U01CE002668-03
project_title: BYSTANDER PROGRAM ADOPTION & EFFICACY TO REDUCE SV-IPV IN COLLEGE COMMUNITY
administering_ic: NCIPC
award_notice_date: 2017-07-27
opportunity_number: RFA-CE-15-003
application_type: 5
activity_code: U01
ic: CE
serial_number: 002668
program_official: WRIGHT, MARCIENNE
project_start_date: 2015-09-30
project_end_date: 2019-09-29
study_section: ZCE1-GXC(01)
contact_pi_person_id: 1894149
contact_pi: COKER, ANN L
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Rates of physically forced sex to dating violence remain high in college communities (22% of 10000 female undergraduates disclosed these forms of violence against women (VAW) in the past 12 months (2010-2013).  Bystander interventions recognized as promising violence prevention strategies are unique in their engagement of all community members to 1) recognize situations that may become violent and 2) learn to safely and effectively intervene to reduce violence risk.  Based on their promise the Campus Sexual Violence Elimination Act (SaVE) now requires all publicly-funded college to provide bystander intervention.  With SaVE's policy intervention requiring bystander intervention a "natural experiment" has arisen to determine the relative efficacy of students' bystander training across multiple colleges.  We propose a quasi-experimental design with fractional factorials to evaluate the relative efficacy of bystander interventions components to reduce violence in college communities.  Green Dot will be one of the bystander intervention components evaluated because our group has considerable experience rigorously evaluating Green Dot and we have recently found that this bystander intervention is associated with a 20-40% reduction in VAW in college and high school settings.  Aim 1.  Compare the relative efficacy of bystander interventions to 1) increase bystander efficacy and behaviors 2) reduce violence acceptance 3) reduce violence victimization and perpetration and 4) increase program cost effectiveness.  The three primary bystander groups compared will be:  a) exclusively online training Green Dot (speeches and intensive bystander training) and other skills-based by stander training.  Program efficacy data will be obtained from student surveys campus crime statistics and surveys with college staff and administrators responsible for selecting and implementing bystander interventions.  We will collect data at each college for the full 4 years ofthe project (~50000 students annually.  Infrastructure provided by the Kentucky Center for Clinical and Translational Science at the University of Kentucky and West Virginia University will support a VAW Research Coordinating Center for all electronic data collection and analyses from 24 recruited colleges comparing the different bystander interventions.  VAW researchers draw from multiple disciplines yet few training programs support this diverse field of highly relevant applied research.  Thus we seek to grow communities of VAW prevention researchers.  Researcher communities will form through researcher' engagement with college recruitment survey design data collection and analyses.  Aim 2.  Determine the efficacy of this program to increase VAW prevention research productivity defined as 1) increasing research skills and 2) increasing research communities measured as manuscript submissions presentations and publications.  This natural experiment will generate new understanding of how and what bystander components work to prevent violence.  It will also provide the VAW research community an opportunity to increase our skill-sets and share our experiences with and help grow the next generation of VAW prevention researchers.

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


application_id: 9311721
project_number: 1R01GM118541-01A1
project_title: A melatonin-sensitive circadian oscillator in the human gut commensal Enterobacter aerogenes
administering_ic: NIGMS
award_notice_date: 2017-09-15
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: GM
serial_number: 118541
suffix: A1
program_official: SESMA, MICHAEL A
project_start_date: 2017-09-15
project_end_date: 2019-07-31
study_section: Cellular Signaling and Regulatory Systems Study Section[CSRS]
contact_pi_person_id: 1862567
contact_pi: CASSONE, VINCENT M
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
project_abstract:
Circadian rhythms are fundamental features of many if not all organisms on Earth. Amonganimals the molecular mechanisms underlying these rhythms are remarkably conserved. Yetoutside animals known mechanisms among the few model systems are disparate which is notsurprising due to the billions of years of separation among these taxa. Among prokaryotes onlyone species has been shown to exhibit circadian rhythms the cyanobacterium Synechococcuselongatus whose clock derives from cycles of autophosphorylation and phosphatase activity inkey clock proteins Kai AB and C. We have discovered a new biomedically important modelbacterium Enterobacter aerogenes which expresses a temperature-compensated circadianclock which is synchronized by the gut hormone melatonin and is entrained by cycles oftemperature using swarming behavior and motA-driven luciferase bioluminescence. We proposeto fully characterize this exciting new clock system. We will determine whether the clock systemregulates multiple physiological processes in parallel by asking whether gene expression withdifferent promoter elements and luciferase are expressed rhythmically and/or respond tomelatonin similar to motA-driven rhythms. We will determine whether melatonin is a trueZeitgeber for this clock and we will characterize the effects of temperature cycles which entrainthis clock testing the hypotheses that host melatonin secretion and/or TB synchronize this entericbacterium. Secondly we will knock out candidate genes that bear molecular similarity to Kaiproteins characterize these knockouts and complement those that exhibit clock phenotypes. Inaddition we will conduct a broad mutant screen searching for clock mutants. Thirdly we willcharacterize the biological activity clock function and melatonin sensitivity of all knockout andmutant strains discovered here. If this clock does indeed share a common ancestor with thecyanobacterial clock the data have broad and important evolutionary significance placing theevolution of the circadian clock before the emergence of O2 generating photosynthesis some 3.5billion years ago. In addition these observations point to an integrated circadian organization inwhich master pacemakers in the brain synchronize peripheral oscillators which in turn mayregulate aspects of the microbiota through entrainment of the bacterial clock. This has importantimplications for biomedical science and therapeutics.

project_terms:
5'-Nucleotidase;Animals;Back;Bacteria;Behavior;Biological;Biological Models;Bioluminescence;Body Temperature;Brain;Candidate Disease Gene;Circadian Rhythms;Clock protein;Complement;Cyanobacterium;Data;Dephospho-CoA kinase;Disease;Elements;Enteral;Enterobacter aerogenes bacterium;Enterobacteriaceae;Evolution;Exhibits;Funding;Gene Expression;Genes;Hormones;Human;Knock-out;Lead;Luciferases;Manganese;Melatonin;Modeling;Molecular;Mutagenesis;Organism;Pacemakers;Pattern;Periodicity;Peripheral;Phase;Phase response curves;Phenotype;Phosphoric Monoester Hydrolases;Photosynthesis;Phylogenetic Analysis;Physiologic pulse;Physiological;Physiological Processes;Physiology;Planet Earth;Plasmids;Process;Prokaryotic Cells;Promoter Regions;Proteins;Protocols documentation;Regulation;Reporter;Science;Signal Transduction;Symbiosis;Synechococcus;System;TYRP1 gene;Temperature;Testing;Therapeutic;Ursidae Family;catalase;cell motility;circadian pacemaker;commensal microbes;gastrointestinal;knockout gene;microbiota;mutant;promoter;response

public_health_relevance:
The human biological circadian clock orchestrates a diverse array of processes throughthe coordination and entrainment of peripheral circadian oscillators whereby disruption ofcircadian organization can lead to disease. We have discovered that at least one commensalgut bacterium Enterobacter aerogenes also expresses an endogenous circadian clock that isresponsive to signals from the hosts circadian system the hormone melatonin and changes intemperature. This project is likely to identify the components of this first prokaryotic circadianclock outside of the cyanobacterial phylum and the first in an organism that interacts directlywith humans the results of which are likely to have broad implications for the regulation of thehuman microbiota and gut physiology.


application_id: 9311380
project_number: 1R01HL125877-01A1
project_title: A novel mechanism of stromal cell-derived factor 1 protection against diabetic cardiomyopathy
administering_ic: NHLBI
award_notice_date: 2017-04-18
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: HL
serial_number: 125877
suffix: A1
program_official: BUXTON, DENIS B
project_start_date: 2017-05-01
project_end_date: 2022-02-28
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 12101586
contact_pi: TAN, YI
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
5'-AMP-activated protein kinase;Adhesions;Apoptosis;Bone Marrow;CXCR4 Receptors;CXCR4 gene;Cardiac;Cardiac Myocytes;Cardiovascular Diseases;Cardiovascular system;Catalytic Domain;Cell Death;Cell physiology;Cells;Cessation of life;Chemotaxis;Chronic;Cytoskeletal Modeling;Data;Development;Diabetes Mellitus;Diabetic Angiopathies;Diabetic mouse;Dysplasia;Family;Future;G-substrate;GTP-Binding Proteins;Genes;Growth Factor;Heart;High Fat Diet;Hypertension;In Vitro;Infarction;Injection of therapeutic agent;Injury;Insulin-Dependent Diabetes Mellitus;Interleukin-6;Ischemia;Knock-out;Knockout Mice;Life Style;Lipids;MAP Kinase Gene;MAPK14 gene;Mediating;Modeling;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Non-Insulin-Dependent Diabetes Mellitus;Oxidative Stress;Palmitates;Paper;Pathogenesis;Pathogenicity;Pathologic;Pathology;Phosphorylation;Phosphotransferases;Prevention;Process;Production;Protein Kinase;Reperfusion Injury;Role;Signal Pathway;Signal Transduction;Site;Stem cells;Streptozocin;Stromal Cell-Derived Factor 1;System;Testing;Therapeutic;Tissues;Transgenes;Transgenic Organisms;Transplantation;Ventricular septum;antioxidant therapy;base;beta-arrestin;cardiac angiogenesis;cardiac regeneration;chemokine;clinical investigation;clinical practice;conventional therapy;diabetic;diabetic cardiomyopathy;diabetic patient;glycemic control;improved;in vivo;insight;new therapeutic target;novel;prevent;receptor;receptor expression;treatment strategy


application_id: 9310610
project_number: 1R01NS097781-01A1
project_title: Altered Motor Function & Force Feedback After Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2017-03-23
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: NS
serial_number: 097781
suffix: A1
program_official: JAKEMAN, LYN B
project_start_date: 2017-04-01
project_end_date: 2022-03-31
study_section: Special Emphasis Panel[ZRG1 BDCN-N (91)]
contact_pi_person_id: 1904515
contact_pi: HOWLAND, DENA R.
other_pis: NICHOLS, T. RICHARD
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:
Acute;Animals;Area;Behavior;Bilateral;Chest;Data;Data Collection;Databases;Decerebrate State;Decerebration procedure;Development;Distal;Dorsal;Extensor;Feedback;Felis catus;Gait;Goals;Golgi Targeting;Golgi Tendon Organs;Human;Immunohistochemistry;Injury;Joints;Laboratories;Lateral;Leg;Lesion;Limb structure;Link;Locomotion;Maps;Mediating;Methods;Modeling;Motor;Movement;Muscle;Normal Statistical Distribution;Pathway interactions;Pattern;Performance;Phase;Preparation;Procedures;Production;Publishing;Recovery;Reflex action;Rehabilitation therapy;Research;Silver;Spinal;Spinal Cord;Spinal cord injury;Staining method;Stains;System;Testing;Time;Walking;Weight;Work;base;design;experimental study;gait examination;gait rehabilitation;injured;innovation;insight;kinematics;locomotor tasks;motor control;motor disorder;nervous system disorder;novel;programs;receptor;relating to nervous system;response;spinal tract;treadmill;white matter


application_id: 9310552
project_number: 1R01CA207772-01A1
project_title: Roles of Hsp47 in breast cancer progression
administering_ic: NCI
award_notice_date: 2017-03-03
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: CA
serial_number: 207772
suffix: A1
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2017-03-03
project_end_date: 2022-02-28
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 10533977
contact_pi: XU, REN
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Adhesions;Adjuvant Therapy;Aftercare;Binding;Biology;Blood Circulation;Blood Platelets;Breast;Breast Cancer Cell;Breast Cancer Model;Breast Epithelial Cells;Cancer Relapse;Cell Survival;Cells;Clinical;Coculture Techniques;Collagen;Collagen Receptors;Deposition;Development;Disseminated Malignant Neoplasm;Distal;Distant;Early Diagnosis;Epithelial;Event;Extracellular Matrix;Extracellular Matrix Proteins;Extravasation;Gene Silencing;Genetic Transcription;Growth;Human;Incidence;Investigation;Knowledge;Lung;Mesenchymal;Metastatic breast cancer;Microfluidics;Migration Assay;Modeling;Molecular;Molecular Chaperones;Mus;Neoplasm Metastasis;Oncogenes;Organ;Pathologist;Pathway interactions;Phenotype;Platelet Activation;Positioning Attribute;Production;Prognostic Marker;Property;Proteins;Proteomics;Recruitment Activity;Regulation;Relapse;Research;Role;Signal Transduction;Site;Stromal Cells;System;Techniques;Testing;Tissue Microarray;Tumor Initiators;Tumor Tissue;Up-Regulation;Xenograft Model;base;cancer cell;carcinogenesis;chemotherapeutic agent;chemotherapy;discoidin domain receptor 2;discoidin receptor;experimental study;imaging system;in vivo;loss of function;malignant breast neoplasm;multidisciplinary;nano;novel;outcome forecast;protein expression;receptor;self-renewal;stemness;therapeutic target;three dimensional cell culture;triple-negative invasive breast carcinoma;tumor growth;tumor microenvironment;tumor progression


application_id: 9309884
project_number: 1R01CA208343-01A1
project_title: Altered Lipid Metabolism as a Novel Target for Colon Cancer Treatment
administering_ic: NCI
award_notice_date: 2017-07-28
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: CA
serial_number: 208343
suffix: A1
program_official: TIMMER, WILLIAM C
project_start_date: 2017-08-01
project_end_date: 2022-07-31
study_section: Clinical Oncology Study Section[CONC]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: GAO, TIANYAN
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Acute;Address;Apoptosis;Attention;Behavior;Benign;Biological Models;Biological Sciences;Cancer Cell Growth;Cancer Etiology;Carnitine;Cell Death;Cell Proliferation;Cell Survival;Cells;Cessation of life;Clinical Trials;Collaborations;Colon;Colon Carcinoma;Colorectal Cancer;Controlled Clinical Trials;DNA Sequence Alteration;Development;Dose;Enzymes;Epithelial Cells;Etiology;Excision;Fatty Acids;Fatty-acid synthase;Future;Glucose;Glycolysis;Goals;Growth;Hepatic;Individual;Laboratories;Lead;Lipids;Lung;Malignant - descriptor;Malignant Neoplasms;Measures;Mediating;Membrane Lipids;Metabolic;Metabolism;Mitochondria;Mucous Membrane;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Oncogenic;Oral;Ovarian;Oxidative Stress;Palmitates;Patients;Pharmacodynamics;Pharmacologic Substance;Phospholipids;Placebo Control;Production;RNA Interference;Randomized;Research;Resected;Respiration;Signal Pathway;Slice;Techniques;Technology;Therapeutic;Therapeutic Agents;Tissues;Triglycerides;Tumor Angiogenesis;United States;Up-Regulation;Warburg Effect;Xenograft Model;Xenograft procedure;antitumor effect;base;beta catenin;cancer cell;cancer therapy;cell growth;cell transformation;chemotherapy;colon cancer patients;experimental study;extracellular;fatty acid biosynthesis;fatty acid metabolism;in vivo;inhibitor/antagonist;innovation;lipid biosynthesis;lipid metabolism;membrane synthesis;metabolomics;multidisciplinary;neoplastic;neoplastic cell;new therapeutic target;novel;novel therapeutics;overexpression;patient subsets;personalized approach;response;small molecule inhibitor;stable isotope;treatment strategy;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor metabolism;tumor progression;tumorigenesis


application_id: 9309756
project_number: 1R01AR070313-01A1
project_title: Macrophage phenotype orchestrates mammalian tissue regeneration
administering_ic: NIAMS
award_notice_date: 2017-03-12
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: AR
serial_number: 070313
suffix: A1
program_official: TSENG, HUNG H
project_start_date: 2017-03-13
project_end_date: 2022-02-28
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 10345749
contact_pi: SEIFERT, ASHLEY WINN
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
project_terms:
Acomys;Address;African;Azithromycin;Biological Assay;Cartilage;Cicatrix;Clinical;Complex;Data;Disease;Ear;Environment;Exhibits;External Ear;Extracellular Matrix;Fibroblasts;Fibrosis;Genes;Genetic Transcription;Genetically Engineered Mouse;Genomics;Goals;Granulation Tissue;Hair follicle structure;Human;In Vitro;Inflammation;Inflammatory;Injury;Intervention;Knowledge;Laboratory mice;Mammals;Medicine;Modeling;Molecular;Mus;Muscle;Musculoskeletal;Natural regeneration;Nerve;Outcome;Pathology;Phenotype;Process;Production;Proteomics;Public Health;Publishing;Recruitment Activity;Regenerative response;Research;Role;Skin;Structure;System;Testing;Time;Tissue Model;Tissues;Trauma;Work;Wound Healing;arginase;base;comparative;cytokine;disability;extracellular;healing;immunoreaction;immunoregulation;improved functioning;in vivo;inhibitor/antagonist;injured;injury and repair;innovation;insight;macrophage;novel;organ regeneration;regenerative;response;response to injury;stem;targeted agent;tissue regeneration;tissue trauma


application_id: 9309326
project_number: 2R01HL056652-18A1
project_title: Molecular Mechanism of Platelet Exocytosis
administering_ic: NHLBI
award_notice_date: 2017-03-31
opportunity_number: PA-16-160
application_type: 2
activity_code: R01
ic: HL
serial_number: 056652
suffix: A1
program_official: SARKAR, RITA
project_start_date: 1996-07-01
project_end_date: 2021-03-31
study_section: Hemostasis and Thrombosis Study Section. Committee was terminated on 11/30/2020. [HT]
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
World-wide spurious thrombosis accounts for 1 in 4 non-communicable disease deaths.Normally platelets respond to vascular damage and secrete granule cargo that are essential forrecruiting more platelets their adhesion and thrombosis. This releasate promotes normalsequelae but can also contribute to disease. Do platelets actively control what they release?How much releasate is enough? These are key questions to understand how platelets affecttheir vascular microenvironments. Membrane proteins (v- and t-SNAREs) fuse granule andplasma membranes to allow cargo release. In platelets VAMPs SNAP-23 and Syntaxin-11form a membrane-spanning complex that mediates fusion. Formation of this complex requirespost-translational modifications and a host of SNARE-regulators. This controls the complexity ofthe platelet release reaction: its rate extent and content. We hypothesize that bymanipulating the platelet secretory machinery we can modulate thrombosis with onlymodest effects on hemostasis. We propose three Aims: 1) Determine how alterations inplatelet exocytosis affect thrombosis and hemostasis. Using our unique collection oftransgenic mice we will genetically titrate platelet secretory machinery to determine how muchsecretion is needed for thrombosis and hemostasis. 2) Determine if platelet exocytosis canbe controlled by targeting post-translational modifications of t-SNAREs. We will examinetwo post-translational modifications: SNAP-23 phosphorylation by IB kinase and t-SNAREacylation. We will test inhibitors to determine if they can be repurposed as anti-thrombotics. t-SNARE acylation is highly dynamic in platelets. We will alter its cycling with acyl transferase andthioesterase inhibitors to define its importance to secretion and whether acylation can betargeted to affect platelet exocytosis. 3) Determine the roles of new elements of the plateletexocytosis machinery. We will probe the roles of two novel secretory elements: -synucleinand RalA/B. Our proposal expands our knowledge of the molecular requirements and thesequence of protein-protein interactions controlling platelet exocytosis. Our work is significantbecause it provides the needed mechanistic insights to identify potential targets for therapeuticintervention and to evaluate the relevance of the increasing volume of gene/risk associations.

project_terms:
Acylation;Address;Adhesions;Affect;Agonist;Amino Acid Sequence;Biochemical;Biological Assay;Blood Coagulation Disorders;Blood Platelets;Blood Vessels;Cell membrane;Cessation of life;Clinical;Coagulation Process;Collection;Communicable Diseases;Complex;Cytoplasmic Granules;Data;Defect;Disease;Elements;Equilibrium;Event;Exocytosis;Fatty Acids;Funding;Goals;Health;Hemorrhage;Hemostatic function;Hyperactive behavior;Kinetics;Knowledge;Mediating;Membrane;Membrane Fusion;Membrane Proteins;Molecular;Mus;Myocardial Infarction;Pathology;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Physicians;Post-Translational Protein Processing;Process;Proteins;Public Health;Reaction;Recruitment Activity;Risk Factors;Role;S-nitro-N-acetylpenicillamine;SNAP receptor;Serine;Testing;Therapeutic;Therapeutic Intervention;Thrombosis;Transferase;Transgenic Animals;Transgenic Mice;Transmembrane Domain;Work;active control;alpha synuclein;alpha-SNAP;base;design;experimental study;genetic analysis;genetic manipulation;genetic regulatory protein;in vivo;inhibitor/antagonist;insight;kinase inhibitor;novel;response;risk variant;stroke;syntaxin 11;target SNARE proteins;targeted treatment;therapeutic target;vesicle-associated membrane protein;vesicular SNARE proteins

public_health_relevance:
NarrativeRelevance of the Project to Public Health:Worldwide thrombotic events e.g. strokes and heart attacks account for 1 of 4 deaths not caused bycommunicable diseases. Platelet secretion is essential for clot formation and thus is a target forcontrolling thrombosis; however we need to know more about the process before we can manipulate it.This proposal will yield the knowledge necessary to understand the process of platelet secretion andwill identify strategies to control it.


application_id: 9309164
project_number: 1R01AG053585-01A1
project_title: Reversing Microvascular Dysfunction in Advancing Age
administering_ic: NIA
award_notice_date: 2017-02-27
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: AG
serial_number: 053585
suffix: A1
program_official: KERR, CANDACE L
project_start_date: 2017-03-01
project_end_date: 2022-02-28
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 8957618
contact_pi: LEBLANC, AMANDA JO
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
project_terms:
Address;Adipocytes;Adipose tissue;Age;Aging;Animals;Arteries;Autologous;Blood Pressure;Blood Vessels;Blood flow;Cardiac;Cardiovascular Diseases;Catheters;Cell Fraction;Cell Therapy;Cell physiology;Cells;Clinical;Coronary;Coronary Arteriosclerosis;Coronary Vessels;Coronary artery;Coronary heart disease;Deterioration;Disease;Elderly;Endothelial Cells;Evaluation;Exhibits;Female;Functional disorder;Gender;Heart;Homeostasis;Human;Hydrogen Peroxide;ITGAM gene;Impairment;Individual;Injectable;Injection of therapeutic agent;Intravenous;Ischemia;Mediating;Mediator of activation protein;Methods;Microspheres;Microvascular Dysfunction;Modeling;Molecular;Monitor;Mus;Muscle Tonus;Myocardial Infarction;Myocardial Ischemia;Oxidative Stress;Pathway interactions;Patient-Focused Outcomes;Perfusion;Peripheral;Persons;Pharmaceutical Preparations;Pharmacology;Population;Postmenopause;Publishing;Rattus;Reactive Oxygen Species;Regulation;Relaxation;Reporter;Rest;Role;Safety;Signal Transduction;Skin;Stromal Cells;Surface;Symptoms;Telemetry;Testing;Therapeutic;Therapeutic Uses;Time;Tissues;Transgenic Organisms;Trees;Tunica Adventitia;Ultrasonography;Vascular Diseases;Vascular Smooth Muscle;Woman;Workload;age related;aged;arteriole;base;cardiovascular disorder risk;cell type;density;design;effective therapy;experimental study;improved;improved outcome;in vivo;insight;intravital microscopy;juvenile animal;macrophage;macrovascular disease;men;molecular drug target;older men;older women;pressure;regenerative;repaired;response;senescence;targeted treatment;therapy design


application_id: 9309157
project_number: 1R01CA207538-01A1
project_title: Addressing ELSI Issues in Unregulated Health Research Using Mobile Devices
administering_ic: NCI
award_notice_date: 2017-05-04
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: CA
serial_number: 207538
suffix: A1
program_official: CAGA-ANAN, EMILIE CHARLISSE F
project_start_date: 2017-05-04
project_end_date: 2020-04-30
study_section: Societal and Ethical Issues in Research Study Section[SEIR]
contact_pi_person_id: 6098284
contact_pi: ROTHSTEIN, MARK A
other_pis: WILBANKS, JOHN
congressional_district: 03
department: SOCIAL SCIENCES
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:
PROJECT SUMMARYHealth research using mobile devices such as smartphones and tablets is becoming more common. Newhardware and software can transform a mobile device into a sophisticated data collection and analyticalplatform. These technologies are fundamentally changing health research because the recruitment datacollection and data sharing are conducted online without any face-to-face interaction between researchers andresearch participants.Increasingly this research also is being conducted by researchers who do not receive any federal funding andare not subject to the Common Rule the FDA research regulations and the HIPAA Privacy Rule. Yetunregulated health research using mobile devices raises numerous important ethical issues including externalreview recruitment inclusion and exclusion criteria informed consent privacy and security incidental findingsand data sharing.This project has the following three aims:Aim 1: Conduct in-depth qualitative interviews to elicit thought leaders' perspectives on the risks andappropriate protections for participants in unregulated health research using mobile devices.Aim 2: Develop a detailed analysis of the ELSI issues through a series of 4 meetings by a diverseexpert working group and use a consensus-building methodology to develop recommendations.Aim 3: Devise and implement educational programs and translation of the consensusrecommendations. Sub-aim 3-1: Because app developers play a key role in mobile health innovations we will hold 2 workshops exclusively for app developers on ethical issues in designing mobile health apps with video highlights posted on the internet. Sub-aim 3-2: We will hold a conference in Washington DC on policy issues of interest to the NIH FDA OHRP FTC Congressional staffs state governments professional organizations researchers IRBs patient groups and other stakeholders. Sub-aim 3-3: Members of the working group will draft 20 articles containing consensus policy recommendations for publication in a special symposium issue of the Journal of Law Medicine &Ethics. Sub-aim 3-4: We will present our findings and recommendations at meetings of consumers professionals and policy makers.

project_terms:
Address;Categories;Cellular Phone;Child;Computer software;Consensus;Data;Data Analytics;Data Collection;Educational workshop;Ensure;Ethical Issues;Ethics;Exclusion Criteria;Funding;Government Agencies;Grant;Health;Health Insurance Portability and Accountability Act;Health Technology;Incidental Findings;Informed Consent;Institutional Review Boards;Internet;Interview;Journals;Laws;Measures;Medicine;Methodology;Nonprofit Organizations;Participant;Patients;Play;Policies;Policy Maker;Precision Medicine Initiative;Privacy;Professional Organizations;Publications;Recommendation;Recruitment Activity;Regulation;Research;Research Ethics;Research Personnel;Risk;Security;Series;Social Welfare;State Government;Tablets;Technology;Translations;United States National Institutes of Health;Washington;cancer care;citizen science;common rule;design;handheld mobile device;inclusion criteria;innovation;interest;mHealth;meetings;member;novel;patient advocacy group;programs;sharing data;symposium;working group

public_health_relevance:
PROJECT NARRATIVEHealth research using mobile devices such as smartphones and tablets is becoming increasingly common.Because some of this research is not subject to the federal research regulations it raises novel ethical andpolicy issues such as independent review informed consent and privacy. The proposed study will developand disseminate recommendations for the ethical conduct of this emerging research.


application_id: 9309110
project_number: 5P01NS097197-02
project_title: Defining the therapeutic window for the treatment of Lafora Epilepsy
administering_ic: NINDS
award_notice_date: 2017-07-14
opportunity_number: PAR-14-183
application_type: 5
activity_code: P01
ic: NS
serial_number: 097197
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8558
contact_pi_person_id: 12485842
contact_pi: GUINOVART, JOAN 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: 2017-07-01
budget_end_date: 2018-06-30
project_terms:
Adolescence;Alleles;Applications Grants;Behavioral;Biochemical;Birth;Brain;Child;Clinical;Complementary DNA;Deposition;Development;Disease;Disease Progression;Electrophysiology (science);Enzyme Inhibition;Enzymes;Epilepsy;Excision;Future;GYS1 gene;Gene Expression;Generations;Genes;Genetic;Glycogen;Glycogen (Starch) Synthase;Heart Abnormalities;Histologic;Human;Killings;Knock-out;Knockout Mice;Knowledge;Lafora Disease;Lead;Mus;Muscle;Nerve Degeneration;Neurons;Newly Diagnosed;Onset of illness;Pathogenesis;Pathogenicity;Pathology;Patients;Phase;Phenotype;Phosphoric Monoester Hydrolases;Physiological;Process;Protein Isoforms;Seizures;Specific qualifier value;Structure;Symptoms;Teenagers;Therapeutic;Therapeutic Intervention;Time;Tissues;Torture;disease phenotype;experimental study;genome editing;mouse model;neuronal cell body;polyglucosan;prevent;small molecule;ubiquitin-protein ligase


application_id: 9309109
project_number: 5P01NS097197-02
administering_ic: NINDS
award_notice_date: 2017-07-14
opportunity_number: PAR-14-183
application_type: 5
activity_code: P01
ic: NS
serial_number: 097197
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8557
contact_pi_person_id: 1888145
contact_pi: ROACH, PETER 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: 2017-07-01
budget_end_date: 2018-06-30
funding_mechanism: Non-SBIR/STTR
project_terms:
Active Sites;Age-Months;Allosteric Site;Alpha Cell;Animals;Biochemical;Biological;Biological Assay;Blood - brain barrier anatomy;Brain;Cell Line;Cells;Chemicals;Childhood;Core Facility;Data;Deposition;Development;Disease;Dose;Drug Kinetics;Enzyme Kinetics;Epilepsy;Evaluation;Genes;Genetic;Genomics;Glucose-6-Phosphate;Glycogen;Glycogen (Starch) Synthase;Histologic;Human Cell Line;Impairment;In Vitro;Investigation;Laboratories;Lafora Disease;Lead;Libraries;Long-Term Effects;Measurement;Monitor;Mus;Mutation;National Institute of Neurological Disorders and Stroke;Nerve Degeneration;Nervous System Physiology;Neurologic Symptoms;Neurons;Pathology;Pattern;Penetration;Pharmaceutical Chemistry;Prevention;Program Development;Property;Protocols documentation;Radioactive;Series;Structure;Structure-Activity Relationship;Testing;Therapeutic;Thinking;Tissues;Toxic effect;Toxicology;Validation;Weaning;analog;base;behavioral impairment;cohort;drug development;effective therapy;high throughput screening;human disease;in vitro activity;inhibitor/antagonist;mouse model;novel;novel strategies;phosphatase inhibitor;polyglucosan;preclinical development;response;small molecule;small molecule inhibitor


application_id: 9309107
project_number: 5P01NS097197-02
project_title: Personalized diagnosis - defining how glycogen metabolism and proteostasis impact LD
administering_ic: NINDS
award_notice_date: 2017-07-14
opportunity_number: PAR-14-183
application_type: 5
activity_code: P01
ic: NS
serial_number: 097197
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8555
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
budget_end_date: 2018-06-30
project_terms:
Acute;Address;Affect;Antiepileptic Agents;Apoptosis;Area;Astrocytes;Autophagocytosis;Biochemical;Biochemistry;Biochemistry and Cellular Biology;Biological Assay;Brain;Cell Culture Techniques;Cell physiology;Cells;Cessation of life;Clinical;Collaborations;Cystic Fibrosis;Data;Defect;Development;Diagnosis;Disease;Disease Progression;Energy Metabolism;Epilepsy;Event;Family;Functional disorder;Genes;Glucans;Glycogen;Goals;Homeostasis;International;Intervention;Ion Channel;Knowledge;Lafora Disease;Life;Metabolic;Modeling;Molecular;Mutation;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Neurotransmitters;Outcome;Oxidative Stress;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacology;Phosphoric Monoester Hydrolases;Production;Program Research Project Grants;Progressive Myoclonic Epilepsies;Proteins;Recovery;Research;Role;Sampling;Stress;Structural Biochemistry;Structure;Symptoms;Terminator Codon;Testing;Therapeutic;Toxic effect;Translating;Translations;Water;clinical application;design;disease-causing mutation;disorder subtype;drug efficacy;endoplasmic reticulum stress;glycogen metabolism;in vitro Model;induced pluripotent stem cell;insight;member;misfolded protein;molecular subtypes;mouse model;neuron apoptosis;neurotoxicity;new therapeutic target;novel;novel therapeutic intervention;overexpression;particle;personalized approach;personalized diagnostics;personalized therapeutic;potency testing;premature;protein degradation;protein expression;proteostasis;receptor;restoration;small molecule;symptom treatment;tool;trafficking;ubiquitin-protein ligase


application_id: 9309106
project_number: 5P01NS097197-02
project_title: Biological Core
administering_ic: NINDS
award_notice_date: 2017-07-14
opportunity_number: PAR-14-183
application_type: 5
activity_code: P01
ic: NS
serial_number: 097197
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8554
contact_pi_person_id: 9487963
contact_pi: WORBY, CAROLYN ANN
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: 2017-07-01
budget_end_date: 2018-06-30
project_terms:
Aftercare;Antisense Oligonucleotides;Ataxia;Basic Science;Behavior;Biochemical;Biological;CRISPR/Cas technology;Cell Culture Techniques;Cell Line;Cell model;Cells;Cessation of life;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Communities;Consensus;Cytoplasm;Deterioration;Development;Diagnosis;Disease;Disease Progression;Disease model;Educational workshop;Electroencephalography;Ensure;Epilepsy;Funding;Genes;Glycogen;Goals;Grant;Hormonal;Human;Impaired cognition;Incidence;Intractable Epilepsy;Knock-in Mouse;Lafora Disease;Lead;Missense Mutation;Modeling;Molecular;Mutation;Myoclonic Epilepsies;Neurologic;Neurons;Nonsense Codon;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphoric Monoester Hydrolases;Plants;Preclinical Drug Evaluation;Program Research Project Grants;Progressive Myoclonic Epilepsies;Reagent;Research;Research Personnel;Side;Starch;Stimulus;Structure;Techniques;Teenagers;Therapeutic;TimeLine;Transgenic Mice;Transgenic Organisms;United States National Institutes of Health;Work;behavioral study;drug testing;epileptic encephalopathies;genome editing;high throughput screening;induced pluripotent stem cell;innovation;meetings;member;mouse model;multidisciplinary;nervous system disorder;patient advocacy group;personalized diagnostics;personalized medicine;polyglucosan;prevent;small molecule;success;ubiquitin-protein ligase


application_id: 9309104
project_number: 5P01NS097197-02
project_title: Administrative Core
administering_ic: NINDS
award_notice_date: 2017-07-14
opportunity_number: PAR-14-183
application_type: 5
activity_code: P01
ic: NS
serial_number: 097197
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8552
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
budget_end_date: 2018-06-30
project_terms:
Administrative Personnel;Biological;Biological Markers;Clinical;Clinical Trials;Collaborations;Committee Members;Communication;Communities;Diagnosis;Disease;Dreams;Educational workshop;Electronic Mail;Ensure;Epilepsy;Event;Family Physicians;Flowcharts;Goals;Grant;Innovative Therapy;Institution;Intellectual Property;Kentucky;Knowledge;Lafora Disease;Lead;Leadership;Logistics;Medicine;Methods;Mission;Molecular Medicine;Myoclonus;National Institute of Neurological Disorders and Stroke;Neurons;Neurosciences;Newborn Infant;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phase;Policies;Property Rights;Protocols documentation;Publications;Reagent;Recruitment Activity;Reporting;Research;Research Personnel;Resource Sharing;Resources;Scientist;Severities;Teleconferences;Therapeutic;United States National Institutes of Health;Universities;Work;career development;college;community planning;fundamental research;glycogen metabolism;innovation;meetings;member;operation;patient population;programs;sharing data;skills;tool;web site


application_id: 9309102
project_number: 5P01NS097197-02
project_title: Lafora Epilepsy - Basic mechanisms to therapy
administering_ic: NINDS
award_notice_date: 2017-07-14
opportunity_number: PAR-14-183
application_type: 5
activity_code: P01
ic: NS
serial_number: 097197
program_official: LEENDERS, MIRIAM
project_start_date: 2016-07-01
project_end_date: 2021-06-30
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adolescence;Antiepileptic Agents;Antisense Oligonucleotides;Bioenergetics;Biological;Biological Assay;Biological Models;Biological Products;Biology;Brain;Carbohydrates;Cessation of life;Chemistry;Child;Clinic;Clinical Research;Clinical Trials;Collaborations;Communities;Convulsions;Core Facility;Coupled;Cytoplasm;Data;Defect;Dementia;Dendrites;Development;Diagnosis;Diagnostic;Disease;Dreams;Employee Strikes;Enzymes;Epilepsy;Frequencies;Gene Expression;Generations;Genes;Genetic;Glycogen;Grant;Headache;Hormones;International;Intractable Epilepsy;Knowledge;Lafora Disease;Life;Medicine;Messenger RNA;Methods;Modality;Modeling;Molecular;Molecular Target;Mutation;Myoclonic Epilepsies;Myoclonus;National Institute of Neurological Disorders and Stroke;Neurodegenerative Disorders;Neurons;Neurosciences;Outcome;Pathogenicity;Pathology;Pathway interactions;Patients;Persons;Pharmaceutical Chemistry;Pharmacology;Phase;Phosphoric Monoester Hydrolases;Physicians;Plants;Positioning Attribute;Process;Production;Program Research Project Grants;Pulmonary Inflammation;RNA;Reagent;Refractory;Research;Research Personnel;Scientist;Seizures;Shapes;Starch;Status Epilepticus;Structural Biochemistry;Techniques;Technology;Teenagers;Testing;Therapeutic;Time;Training;Translating;United States National Institutes of Health;Vision;Work;base;brain cell;career;clinical application;cognitive function;genome editing;glycogen metabolism;induced pluripotent stem cell;innovation;insight;interdisciplinary approach;member;mouse model;novel;personalized diagnostics;proteostasis;response;sex;small molecule;small molecule inhibitor;spelling;success;sugar;therapeutic evaluation;ubiquitin-protein ligase


application_id: 9308696
project_number: 5R01ES023470-05
project_title: Endocrine disruptor mediated activation of PXR causes dyslipidemia
administering_ic: NIEHS
award_notice_date: 2017-06-30
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: ES
serial_number: 023470
program_official: SCHUG, THADDEUS
project_start_date: 2013-09-26
project_end_date: 2020-06-30
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)S]
contact_pi_person_id: 8880095
contact_pi: ZHOU, CHANGCHENG
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): The goal of this project is to investigate a novel mechanism linking exposure to endocrine disrupting chemicals (EDCs) with dyslipidemia and cardiovascular disease. The pregnane X receptor (PXR) is a nuclear receptor activated by numerous drugs xenobiotic and dietary chemicals. Many EDCs activate PXR including organochlorine and organophosphate pesticides alkylphenols phthalates polychlorinated biphenyls bisphenol A and its analogs. However the role of PXR in mediating the pathophysiological effects of EDCs in humans and animals remains elusive. Mounting evidence implicates EDC exposure in the development of chronic human diseases but the contribution of these EDCs to the etiology of cardiovascular disease (CVD) obesity and diabetes is poorly understood. We have recently revealed the pro-atherogenic effects of PXR in animal models and demonstrated that chronic PXR activation induces hyperlipidemia in wild-type mice and increases atherosclerosis in atherosclerosis-prone apolipoprotein E deficient (ApoE-/-) mice. Our central hypothesis is that EDCs which activate PXR will lead to hyperlipidemia and accelerated atherosclerosis in mice thereby increasing the risk of CVD in exposed individuals. We propose the following specific aims to test this hypothesis: 1) What are the molecular mechanisms through which intestinal PXR activation induces hyperlipidemia? 2) How does exposure to FDA-approved phthalate substitute plasticizers elevate plasma lipid levels in mice? 3) Is EDC-mediated PXR activation necessary and sufficient to increase atherosclerosis development in ApoE-/- mice? Our research will establish the role of PXR in linking exposure to EDCs with hyperlipidemia and CVD and will provide novel mechanistic links explaining how EDC exposure causes atherogenic effects. These studies are broadly translational and will provide strong evidence to inform future risk assessment for EDCs.

project_terms:
Acute;Adverse effects;Affect;Agonist;Animal Model;Animals;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;CD36 Antigens;Cardiovascular Diseases;Cause of Death;Cells;Chemical Exposure;Chemicals;Chlorinated Hydrocarbons;Cholesterol;Chronic;Citrates;Cosmetics;Development;Diabetes Mellitus;Diet;Disease;Dose;Dyslipidemias;Endocrine Disruptors;Environment;Environmental Risk Factor;Etiology;Exposure to;FDA approved;Food Packaging;Future;Gene Expression;Genetic;Genetic Transcription;Genetic Variation;Goals;Health;Homeostasis;Human;Hyperlipidemia;In Vitro;Individual;Intestines;Knowledge;LDL-Receptor Related Protein 1;Link;Lipids;Liver;Mediating;Medical Device;Modeling;Molecular;Morbidity - disease rate;Mus;Nuclear Receptors;Obesity;Organophosphates;Pesticides;Pharmaceutical Preparations;Pharmacologic Substance;Pilot Projects;Plasma;Plasticizers;Play;Polychlorinated Biphenyls;Receptor Activation;Regulation;Research;Risk Assessment;Role;Testing;Wild Type Mouse;Xenobiotic Metabolism;Xenobiotics;absorption;analog;bisphenol A;cardiovascular disorder risk;cholesterol transporters;disorder risk;environmental chemical;experimental study;gene environment interaction;human disease;humanized mouse;in vivo;interest;mortality;mouse model;novel;packaging material;phthalates;pregnane X receptor;public health relevance;receptor function;sensor;tool;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the leading cause of death worldwide and can be caused by genetic and environmental factors. The proposed studies will investigate the mechanisms through which exposure to certain environmental chemicals leads to hyperlipidemia and cardiovascular disease. These studies will provide important new information about underlying causes of cardiovascular disease and strong evidence to inform future risk assessment for environmental chemicals.


application_id: 9308675
project_number: 5R01CA180986-04
project_title: Prevention of Breast Cancer Development by Epidermal Fatty Acid Binding Protein (
administering_ic: NCI
award_notice_date: 2017-07-20
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 180986
program_official: EMENAKER, NANCY J
project_start_date: 2015-08-01
project_end_date: 2019-07-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 9620088
contact_pi: LI, BING
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The increasing incidence of breast cancer poses a major threat to women's health in the USA and worldwide. How to prevent breast tumorigenesis and to identify new protective factors for the control of breast cancer represents a great challenge in this field. The objectives of this proposal are to unravel a protective role of epidermal fatty acid binding protein (E-FABP) in preventing breast cancer development and to determine the molecular mechanisms by which E-FABP regulates IFN production and signaling in a specific subset of tumor associated macrophages for antitumor responses. E-FABP abundantly expressed in macrophages has been recognized as an important regulator to coordinate cell metabolic and inflammatory pathways. Our preliminary studies demonstrate that E-FABP deficient mice exhibit significant increases in mammary tumor growth and lung metastasis compared to wild type mice suggesting a protective role of host expression of E-FABP in mammary tumor prevention. Further analysis of E-FABP expression profile indicates that E-FABP is specifically expressed in the subset of F4/80+CD11b+MHCII+CD11c+ cells. Microarray and qPCR experiments show that tumor-induced IFN production and signaling in macrophages are significantly impaired by E-FABP deficiency. Interestingly IFN stimulation specifically induces E-FABP upregulation in the process of M1 polarization. Moreover -3 fatty acids can greatly enhance E-FABP expression in macrophages. Thus we hypothesize that E-FABP may regulate macrophage function by promoting IFN production signaling and M1-like phenotype switch through enhancing cell lipid metabolism. E-FABP as a new cancer protective factor can prevent breast carcinogenesis through promoting macrophage anti-tumor responses. Therefore modulating E-FABP activity will represent a novel strategy for breast cancer prevention. Specific Aim 1 will determine how E-FABP regulates IFN production in macrophages. We hypothesize that E-FABP is an unidentified host-derived factor to regulate tumor-induced IFN production through impacting lipid-mediated signals in specific subsets of macrophages. Specific Aim 2 will determine how E-FABP regulates IFN signaling to promote anti-tumor responses. We will test the hypothesis that E-FABP-regulated IFN signaling promotes tumor specific T lymphocyte infiltration and IFN production which further upregulates E-FABP expression to facilitate macrophage M1 polarization for antitumor immunity. Specific Aim 3 will address whether host-derived E-FABP protects against breast cancer development in clinically relevant animal models and in humans. We will verify E-FABP as a host-derived protective factor in breast cancer prevention and establish an effective strategy for the control o breast cancer via dietary upregulation of E-FABP. In conclusion successful completion of this project will reveal E-FABP as a new protective factor in control of breast cancer development and help us develop an effective strategy to prevent breast cancer via targeting E- FABP.

project_terms:
Address;Animal Model;Antitumor Response;Basic Science;Breast Cancer Model;Breast Cancer Prevention;Breast Carcinogenesis;Cells;Clinical;Data;Development;Diet;Diet Modification;Exhibits;Hematopoietic;Human;ITGAM gene;ITGAX gene;Impairment;Incidence;Infiltration;Inflammatory;Interferon Type II;Killings;Lipids;Malignant Neoplasms;Mammary Neoplasms;Mammary Tumorigenesis;Mediating;Metabolic;Metastatic Neoplasm to the Lung;Molecular;Molecular Profiling;Mouse Mammary Tumor Virus;Mus;Omega-3 Fatty Acids;Pathway interactions;Phenotype;Population;Prevention;Preventive;Process;Production;Protein Deficiency;Role;Signal Transduction;T-Lymphocyte;Testing;Tissues;Transforming Growth Factor alpha;Tumor Immunity;Up-Regulation;Wild Type Mouse;Women's Health;breast tumorigenesis;clinically relevant;design;experimental study;fatty acid-binding proteins;in vivo;lipid metabolism;macrophage;malignant breast neoplasm;novel strategies;prevent;protein expression;public health relevance;response;tumor;tumor growth

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


application_id: 9307118
project_number: 1R01AI123486-01A1
project_title: Role of the gut microbiota in shaping severity of malaria
administering_ic: NIAID
award_notice_date: 2017-01-11
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: AI
serial_number: 123486
suffix: A1
program_official: PESCE, JOHN T
project_start_date: 2017-01-11
project_end_date: 2021-12-31
study_section: Pathogenic Eukaryotes Study Section[PTHE]
contact_pi_person_id: 11178918
contact_pi: SCHMIDT, NATHAN
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Infections by parasites of the genus Plasmodium cause more than 200 million cases of malaria and kill morethan 400000 people annually the majority of whom are Plasmodium falciparum-infected children in sub-Saharan Africa. Most Plasmodium infections are either asymptomatic or cause only mild malaria. A smallproportion of infections progress to severe malaria that can be life threatening. To date the host factors thatpredispose patients to developing severe malaria are not known and it has not been possible to identify riskfactors that predict progression from asymptomatic infection to severe malaria. These knowledge gaps hinderdiscovery of new strategies for the prevention of severe malaria. Using multiple Plasmodium species andmouse strains we have recently published the novel observation that mice with distinct gut bacterialcommunities exhibit differences in the severity of malaria and humoral immune response following infectionwith Plasmodium. Mice resistant to severe malaria exhibit elevated T follicular helper (Tfh) and germinal center(GC) B cell numbers and accelerated antibody class switching following Plasmodium yoelii infection comparedto susceptible mice. When mice predicated to develop mild malaria were treated with antibodies that disruptTfh-GC B cell communication they developed high parasite burdens similar to mice that develop severemalaria. These new observations support the scientific premise of this application and suggest that gutmicrobiome-mediated modulation of the GC reaction may be a critical mechanism underlying the developmentof severe malaria. The objective of this proposal is to determine the immunological mechanisms by which thegut microbiome determines susceptibility to severe malaria and identify the specific microbes and metabolitesresponsible for this outcome. These studies will move the field of malaria pathogenesis forward in newdirections and may lead to new translational approaches to control severe malaria which could in turn savethe hundreds of thousands of lives lost to severe malaria each year. The central hypothesis of this proposalis that specific microbes and their metabolites modulate GC reactions to determine susceptibility to severemalaria. Our hypothesis will be tested through the following specific aims: Aim 1. Determine the dynamics ofgut microbiota-mediated modulation of the GC reaction in mice. Aim 2. Determine the Tfh cell- and GC B cell-intrinsic pathways modulated by the gut microbiota in mice. Aim 3. Identify the specific gut bacteria and theirmetabolites that determine resistance or susceptibility to severe malaria in mice.

project_terms:
Adoptive Transfer;Affect;Africa South of the Sahara;Anemia;Antibodies;B-Lymphocytes;Bacteria;Biological Models;CD4 Positive T Lymphocytes;Cause of Death;Cell Communication;Cell Count;Cell physiology;Cerebral Malaria;Cessation of life;Child;Clinical;Communicable Diseases;Communities;Data;Development;Disease;Evolution;Exhibits;Foundations;Future;Germ-Free;Health;Helper-Inducer T-Lymphocyte;Human;Immune response;Immunity;Immunoglobulin Class Switching;Immunologics;Immunology;Inbreeding;Individual;Infection;Integration Host Factors;Killings;Knowledge;Lead;Life;Malaria;Mediating;Metabolic;Microbe;Molecular;Morbidity - disease rate;Mouse Strains;Mus;Outcome;Parasite Control;Parasites;Pathogenesis;Pathology;Pathway interactions;Patients;Physiology;Plasmodium;Plasmodium falciparum;Plasmodium yoelii;Population;Predictive Factor;Predisposing Factor;Predisposition;Prevention strategy;Process;Publishing;Reaction;Resistance;Risk Factors;Rodent;Role;Severities;Shapes;Structure of germinal center of lymph node;Syndrome;Testing;Virus;Wild Type Mouse;fungus;gut microbiome;gut microbiota;imprint;microbial community;microbiota;mortality;mouse model;novel;novel therapeutics;prevent;programs;translational approach;translational study;ward

public_health_relevance:
Recent studies have shown that the trillions of microbes living on and within us profoundly influence multipleaspects of human physiology. Malaria remains a significant infectious disease causing the death of about400000 people annually. Completion of this proposal will both determine how gut microbes modulate hostimmunity to the parasite that causes malaria and identify the specific bacteria and their metabolic products thatdetermine susceptibility to severe malaria which will be important in the identification of novel therapeutics tomitigate morbidity and mortality caused by malaria.


application_id: 9306779
project_number: 5R01CA091901-15
project_title: Novel aureolic acid type antitumor agents
administering_ic: NCI
award_notice_date: 2017-06-20
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 091901
program_official: FU, YALI
project_start_date: 2001-06-01
project_end_date: 2020-06-30
study_section: Special Emphasis Panel[ZRG1-BCMB-B(02)M]
contact_pi_person_id: 2257319
contact_pi: ROHR, JURGEN T
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Aureolic acid-type anticancer agents such as mithramycin (MTM) chromomycin (CMM) and durhamycin (DHM) are potent anticancer and anti-HIV drugs with a unique mode-of-action. They inhibit the growth of cancer cells by cross-linking GC-rich DNA thereby shutting down specificity-protein (Sp)-dependent pathways toward various proto-oncogenes including c-myc and c-src the latter being associated with the unique hypocalcemic activity found for these drugs. Particularly MTM is important and has become a popular biochemical tool to study Sp-dependent signal transduction pathways but -due to its toxic side effects- is rarely used as anticancer agent except for the treatment of tumor hypercalcemia refractory to other chemotherapy. However MTM was identified in 2011 by the NCI as the only lead from a screen of 50000 compounds that inhibits the EWS-FLI1 transcription factor responsible for the highly malignant phenotype of Ewing sarcomas which often affect children and were untreatable for the past 40 years. In addition another NCI group found in June 2012 that MTM represses cigarette smoke induced ABCG2 efflux pumps responsible for the drug resistance of lung and esophageal cancers and inhibited multiple stem-cell related pathways relevant for tumorigenicity and proliferation of such cancers. A few years ago MTM was identified as a potential lead drug against neurological diseases arthritis and for the treatment of hematologic disorders. All these new applications require only very small less toxic concentrations of the drug although the mode-of-action in these contexts remains obscure particularly the mode affecting the EWS-FLI1 transcription factor. MTM's biosynthesis has been studied intensely during the previous funding periods of this research project and consequently pursued combinatorial biosynthetic efforts revealed various biosynthetic intermediates and many new MTM-analogues which allowed deducing important structure-activity-relationships. Two regions are of special interest: First a modification of the 3-side chain first exemplified in the superior analogues MTM SK and MTM SDK led to much better anticancer activity profiles with a greatly improved therapeutic index compared to MTM itself. Second exchange of the D-mycarose sugar in E-position of MTM's trisaccharide chain by D-digitoxose led to superior analogues with greatly reduced toxic side effects. This now allows for new strategies to further concentrate on these regions of the molecule for further drug optimization.  During the previous biosynthetic studies biosynthetic intriguing and interesting keyenzymes were discovered which need to be further investigated particularly the co-dependent enzymes MtmGIV/MtmC (bifunctional glycosyltransferase/methyltransferase-ketoreductase) MtmOIV/MtmW (C-C-bond cleaving oxygenase/ketoreductase) which play key roles for the 3-side chain and the trisaccharide chain formation. Furthermore the PKS release remains unclear and it is hypothesized that another co-dependent enzyme pair namely oxygenase MtmOII and cyclase MtmX play an important role for this process. The goal here is to gain a deeper understanding of the biosynthetic roles mechanisms and interactions of these key enzymes of the MTM pathway to pave the way for the optimization and re-engineering of these enzymes that are crucial for novel further improved MTM derivatives. It is planned to (a) further investigate unclear biosynthetic steps and mechanisms of the MTM and other aureolic acid pathways (b) to further develop strategies for the selective generation of new improved MTM analogues including selective 3-side chain and sugar exchange/glycorandomization strategies (c) to analyze intriguing enzymes particularly recently discovered co- dependent enzyme pairs. New resulting MTM analogues will be submitted to the NCI DTP (developmental therapeutics program) for further mechanistic investigations.

project_terms:
ABCG2 gene;Address;Adverse effects;Affect;Anabolism;Anti-HIV Agents;Antineoplastic Agents;Arthritis;Biochemical;Cancer Cell Growth;Child;Cleaved cell;DNA;Developmental Therapeutics Program;Drug resistance;EWS-FLI1 fusion protein;Engineering;Enzymatic Biochemistry;Enzymes;Ewings sarcoma;FLI1 Transcription Factor;Funding;Generations;Goals;Hematological Disease;Hypercalcemia;Investigation;Lead;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of lung;Methods;Methyltransferase;Modification;Natural Products;Oxygenases;Pathway interactions;Pattern;Pharmaceutical Preparations;Play;Plicamycin;Positioning Attribute;Process;Production;Proteins;Proto-Oncogenes;Reaction;Refractory;Research;Research Project Grants;Role;SRC gene;Side;Signal Transduction Pathway;Specificity;Stem cells;Structure-Activity Relationship;Techniques;Therapeutic;Therapeutic Index;Toxic effect;Trisaccharides;Tumorigenicity;Work;analog;anticancer activity;antitumor agent;base;biochemical tools;c-myc Genes;chemotherapy;chromomycin;cigarette smoke-induced;combinatorial;crosslink;design;digitoxose;drug modification;efflux pump;glycosylation;glycosyltransferase;improved;interest;malignant phenotype;mycarose;nervous system disorder;novel;protein structure;public health relevance;sugar;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed work aims to develop and refine a new generation of aureolic acid type natural product analogues with significantly diminished toxicity that will be useful as anticancer drugs and/or as drugs to treat neurological diseases arthritis and hematologic disorders. To enable the production of these fine-tuned drugs through combinatorial biosynthesis or chemo-enzymatic engineering in-depth research of the biosynthetic machinery of three aureolic acid pathways will be explored including key enzymes followed by enzyme re- engineering. In addition based on so far achieved structure-activity-relationship studies chemoenzymatic approaches for drug derivatization glycosylation exchange methods and chemoenzymatic glycorandomization techniques will be applied to selectively alter crucial structural features.


application_id: 9306482
project_number: 1R21CA216090-01
administering_ic: NCI
award_notice_date: 2017-04-12
opportunity_number: RFA-CA-15-009
application_type: 1
activity_code: R21
ic: CA
serial_number: 216090
program_official: KONDAPAKA, SUDHIR B
project_start_date: 2017-04-12
project_end_date: 2019-03-31
study_section: Special Emphasis Panel[ZCA1 SRB-8 (J2)]
contact_pi_person_id: 9246960
contact_pi: JALA, VENKATAKRISHNA RAO
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-04-12
project_title:
PQ-10: Microbial metabolite Urolithin A is  a potent immunomodulator and chemosensitizing adjuvant in treating colon cancer.

project_abstract:
Abstract Colon cancer is the third leading cause of cancer related deaths in United States of America.Chemoresistance (drug resistance) of tumors is the primary reason for the failure of chemotherapy and the majorcause of mortality in colon cancer. The molecular mechanisms involved in chemoresistance or approaches toresensitize cancer cells to chemotherapy remain elusive. Recent studies suggest that gut microbiota andmicrobial metabolites play a crucial role in the development and progression of colon cancer but their role inchemoresistance remains unknown. Towards this goal we investigated the influence of commensal microbialmetabolite Urolithin A (UroA) on cancer chemotherapy. UroA is a microbial metabolite derived from ellagic acidand ellagitannins which are major components of berries and pomegranate. Our preliminary data showed thatUroA significantly reduced bacteria induced inflammation in macrophages and protected from lipopolysaccharideinduced barrier dysfunction by upregulating junctional proteins in colon epithelial cells. More importantly UroAsignificantly increased the chemosensitization of colon cancer cells to 5florouracil (5FU) by down regulating drugtransporters and modulating epithelial-mesenchymal transition (EMT) pathways. The combination therapysignificantly reduced colony formation of colon cancer cells as well as blocked cancer cell migration. By screeningseveral novel structural analogues of UroA we have identified a potent compound UAS03 which displayedincreased chemosensitizing activities compared to UroA. Based on these observations we hypothesize thatUroA and UAS03 act as chemosensitizing adjuvants in 5-FU therapies through regulation of drugtransporters and cancer stemness. The goal of the proposal is to determine the effects of microbial derivedmetabolites (UroA and its analogue UAS03) on colon cancer chemotherapy especially 5FU resistant cancers.In aim1 we propose to identify the molecular target of UroA using bioactive biotinylated UroA; to determine themolecular mechanisms of UroA and UAS03 mediated chemosensitization of 5FU-resistance (5FUR) coloncancer cells. In aim 2 we will evaluate the therapeutic efficacies of UroA or UAS03 in combination with 5 FU inpreclinical colon cancer models. We will utilize both implantable (tumors generated by 5FUR colon cancer cells)and azoxymethane-DSS models. The successful completion of these studies will delineate regulatorymechanisms of microbial metabolite (UroA) mediated chemosensitization and offer better therapeutic options forcolon cancer.

project_terms:
ABCG2 gene;Address;Adjuvant;Adopted;Affect;Americas;Anti-Inflammatory Agents;Anti-inflammatory;Area;Azoxymethane;Bacteria;Berry;Cancer Etiology;Cancer Model;Cell Survival;Cessation of life;Chemosensitization;Chemotherapy-Oncologic Procedure;Colitis;Colon;Colon Carcinoma;Combined Modality Therapy;Custom;Data;Development;Diet;Drug Efflux;Drug Regulations;Drug resistance;E-Cadherin;Ellagi-Tannins;Ellagic Acid;Epithelial;Epithelial Cells;Failure;Fluorouracil;Functional disorder;Genes;Goals;High-Throughput Nucleotide Sequencing;Immunomodulators;Inflammation;Inflammatory disease of the intestine;Interleukin-6;Knowledge;Lipopolysaccharides;Malignant Neoplasms;Mediating;Mesenchymal;Methods;Modeling;Molecular;Molecular Target;Mus;Oral Administration;P-Glycoprotein;Pathway interactions;Pharmaceutical Preparations;Play;Pomegranate;Population;Pre-Clinical Model;Proteins;Resistance;Role;Sodium Dextran Sulfate;Symbiosis;TLR4 gene;TNF gene;Therapeutic;Therapeutic Effect;Treatment Efficacy;United States;Xenograft Model;Xenograft procedure;analog;base;cancer cell;cancer therapy;carcinogenicity;cell motility;chemosensitizing agent;chemotherapy;clinically relevant;colon cancer cell line;colon cancer patients;colon tumorigenesis;gut microbiota;immunoregulation;improved;indexing;innovation;iron metabolism;macrophage;microbial;microbiota;mortality;mouse model;neoplastic cell;novel;occludin;pre-clinical;response;screening;stemness;synergism;three dimensional cell culture;translational impact;tumor

public_health_relevance:
Project NarrativeChemoresistance of tumors is a major cause of mortality in colon cancer patients. Mechanisms responsible forchemoresistance and factors to improve the chemosensitization are not completely understood. Here weidentified microbial metabolite urolithin A (UroA) and its novel structural analogue (UAS03) significantlychemosensitized the colon cancer cells to 5florouracil (5FU). Current proposal investigates effects of microbialmetabolite UroA on colon cancer chemotherapy by utilizing cellular and preclinical colon cancer mouse models.Successful completion of these studies will have tremendous translational impact on utilization of microbialmetabolites along with existing chemotherapeutic drugs in colon cancer.


application_id: 9306465
project_number: 1R01NS097722-01A1
project_title: Neurovascular astrocyte dysfunction in VCID
administering_ic: NINDS
award_notice_date: 2017-08-01
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: NS
serial_number: 097722
suffix: A1
program_official: CORRIVEAU, RODERICK A
project_start_date: 2017-08-01
project_end_date: 2022-05-31
study_section: Clinical Neuroimmunology and Brain Tumors Study Section[CNBT]
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Alzheimer's Disease;Astrocytes;Autopsy;Basal lamina;Biochemical;Blood flow;Brain;Cerebral Amyloid Angiopathy;Cerebrovascular Circulation;Cerebrovascular Disorders;Cerebrovascular system;Characteristics;Comorbidity;Data;Dementia;Diagnosis;Dystroglycans;Electrophysiology (science);Environment;Enzymes;Extracellular Matrix;Family;Functional disorder;Gene Expression;Glial Fibrillary Acidic Protein;Histologic;Homeostasis;Human;Hyperhomocysteinemia;Impaired cognition;Impairment;Inhibition of Matrix Metalloproteinases Pathway;Interleukin-1 beta;Knockout Mice;MMP9 gene;Matrix Metalloproteinase Inhibitor;Matrix Metalloproteinases;Measures;Mediator of activation protein;Methods;Modeling;Molecular;Morphology;Mus;Neuroglia;Neuronal Dysfunction;Neurons;Pathologic;Pathologic Processes;Pathology;Patients;Pharmacology;Pilot Projects;Potassium;Prevalence;Proteins;Research Proposals;Role;TNF gene;Testing;Time;Tissues;aquaporin 4;behavioral outcome;cerebrovascular;foot;human tissue;large-conductance calcium-activated potassium channels;mouse model;neuroinflammation;neurovascular;protein expression;vascular cognitive impairment and dementia


application_id: 9306088
project_number: 5R01DK080770-07
project_title: Renal Osteodystrophy: A Fresh Approach
administering_ic: NIDDK
award_notice_date: 2017-07-17
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 080770
program_official: CHAN, KEVIN E
project_start_date: 2009-03-01
project_end_date: 2020-06-30
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 7875292
contact_pi: MALLUCHE, HARTMUT H
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): Renal osteodystrophy (ROD) represents the bone histologic abnormalities resulting from loss of renal function. It starts early during the loss of kidney function and is seen in virtually all chronic end stage kidney disease patients on dialysis (CKD-5D). A major component of ROD is bone loss leading to CKD-associated osteoporosis. Debilitating hip fractures occur in patients with CKD at a rate 4.4 times higher than in the general population with associated high costs morbidity and an annual mortality of 64%. CKD osteoporosis is distinctly different from post-menopausal osteoporosis. Presently no uniformly accepted CKD osteoporosis treatment protocol exists because of challenges related to racially specific bone turnover states. Therefore most physicians are reluctant to treat this disorder despite the profound impact on health and quality of life and its association with vascular calcifications. These vascular calcifications confer an increased risk for cardiovascular events which are the major cause of the over 20% annual mortality rate in CKD-5D patients. The goal of the proposed controlled randomized study is to test the concept that CKD osteoporosis can be successfully treated when treatment is individualized by patients' turnover status. The study will demonstrate that reversal of bone loss can be achieved by increasing bone formation in low turnover patients and by reducing bone resorption in normal or high turnover patients. A second aim of this study is to provide new information whether these treatments will also retard progression of vascular calcifications. Blood tests measuring FGF23 indicators of Wnt pathway activity bone resorption and formation will be followed to understand potential mechanisms and to evaluate their usefulness for prediction of changes in bone mass and vascular calcifications. CKD-5D patients with established osteoporosis will be enrolled into one of two treatment arms based on bone turnover status. Each arm will be adaptively randomized by race age and gender into treatment or control groups. In the low turnover arm teriparatide combined with cinacalcet will be given and in the normal or high turnover arm alendronate will be administered. Bone mineral density will be measured at baseline and after one year of treatment by quantitative computed tomography. Calcifications of the coronaries aorta and heart valves will also be measured at the same times by multi-detector computed tomography. If this proof-of-concept study is successful it will offer a heretofore unavailable treatment for osteoporosis i CKD-5D patients thus changing the prevailing clinical practice paradigm. This will provide immediate benefit to CKD patients by reducing fracture risk bone pain and cardiovascular risk while greatly improving their quality of life. These improvements will also convey major socioeconomic benefits by decreasing the high associated treatment costs. The proposed study is highly relevant to the NIDDK's mission of disseminating science-based information to improve the health and quality of life for patients with endocrine metabolic and kidney diseases.

project_terms:
Address;Affect;Age;Alendronate;Alkaline Phosphatase;Aorta;Biochemical;Blood;Blood Tests;Bone Density;Bone Diseases;Bone Pain;Bone Resorption;Calcified;Categories;Chronic;Chronic Kidney Failure;Clinical;Control Groups;Coronary;Data;Dialysis procedure;Disease;End stage renal failure;Endocrine System Diseases;Enrollment;Event;FDA approved;Forteo;Funding;Gender;General Population;Goals;Health;Heart Arrest;Heart Valves;Hip Fractures;Histologic;Individual;Kidney Diseases;Link;Malignant Neoplasms;Measures;Metabolic Diseases;Minerals;Mission;Monitor;Morbidity - disease rate;Myocardial Infarction;N-terminal;National Institute of Diabetes and Digestive and Kidney Diseases;Operative Surgical Procedures;Osteogenesis;Osteoporosis;PTH gene;Pathway interactions;Patients;Physicians;Postmenopausal Osteoporosis;Procollagen;Quality of life;Race;Randomized;Randomized Controlled Trials;Renal Osteodystrophy;Renal function;Research;Safety;Science;Serum;Severities;Telephone;Testing;Therapeutic;Time;Treatment Cost;Treatment Protocols;United States;United States National Institutes of Health;Vascular calcification;Visit;X-Ray Computed Tomography;arm;base;bone;bone loss;bone mass;bone turnover;calcification;cardiovascular risk factor;cinacalcet;clinical practice;coronary artery calcification;cost;detector;fibroblast growth factor 23;fracture risk;improved;individualized medicine;mortality;novel;public health relevance;response;socioeconomics;stroke;tartrate-resistant acid phosphatase;treatment group;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE: More than 30 million people in the United States have chronic kidney disease and this research will provide proof of concept for a novel osteoporosis treatment regimen for patients with late-stage chronic kidney disease. There is currently no established treatment regimen for chronic kidney disease associated osteoporosis even though it is associated with early and frequent debilitating hip fractures which require costly surgery result in reduced quality of life high mortality and impose an enormous socioeconomic burden. The study will also provide information whether this novel treatment will reduce the relentless progression of vascular calcifications in these patients which have been linked to heart attack cardiac arrest and stroke resulting in an annual mortality that exceeds many cancers.


application_id: 9305772
project_number: 5F30NS096876-02
project_title: Multi-mechanistic protection of mitochondria following traumatic brain injury
administering_ic: NINDS
award_notice_date: 2017-06-29
opportunity_number: PA-14-150
application_type: 5
activity_code: F30
ic: NS
serial_number: 096876
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2016-07-01
project_end_date: 2020-12-31
study_section: NST-2 Study Section [NST-2]
contact_pi_person_id: 12672057
contact_pi: KULBE, JACQUELINE RENEE
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Over five million people currently live with a disability resulting from a traumatic brain injury (TBI) with an associated economic burden of 60 billion dollars annually. Clinically there are limited treatment options for TBI and single mechanism agents are unlikely to prevent its devastating neurologic consequences. Therefore multi-mechanistic combinational therapies must be developed. Synaptic and non-synaptic mitochondrial dysfunction and lipid peroxidation (LP) induced oxidative damage are key contributors to the downstream pathology associated with TBI including cytoskeletal degradation neurodegeneration and behavioral impairments. Following injury increased Ca++ is sequestered by mitochondria resulting in formation of the mitochondrial permeability transition pore (mPTP) and increased formation of reactive oxygen and nitrogen species. These reactive species initiate LP leading to formation of the neurotoxic LP-breakdown products 4- HNE and acrolein which covalently bind mitochondrial proteins causing oxidative damage further enhancing mitochondrial respiratory dysfunction generation of reactive species and enhancing formation of mPTP with synaptic mitochondria being particularly susceptible. Upon mPTP formation the mitochondria stop producing ATP and lose their Ca++ buffering capacity. Ca++ is released back into the cytosol where it activates the protease calpain causing cytoskeletal degradation. Ultimately synaptic dysregulation neurodegeneration and neurologic impairment ensue. Individually the aldehyde scavenger phenelzine (PZ) and the mPTP inhibitor cyclosporine A (CsA) partially attenuate mitochondrial dysfunction and neuronal damage following controlled cortical impact injury (CCI) in rats. Therefore our overall hypothesis is that LP-induced neurotoxic aldehyde scavenging and inhibition of mPTP are complimentary and that combining these two mechanisms will additively or synergistically attenuate synaptic and non-synaptic mitochondrial respiratory dysfunction and LP- induced oxidative damage following severe controlled cortical impact (CCI) in rats leading to decreased cytoskeletal degradation decreased neurodegeneration and improved motor and cognitive function. Aim 1 a dose response tests the hypothesis that early administration (15min.) of the combination PZ & CsA additively or synergistically attenuates synaptic and non-synaptic mitochondrial respiratory dysfunction and LP-induced oxidative damage as well as neuronal cytoskeletal degradation following severe CCI. Aim 2 tests the hypothesis that the combination PZ & CsA improves the therapeutic window for neuroprotection following severe CCI. Aim 3 tests the hypothesis that the combination PZ & CsA additively or synergistically decreases neurodegeneration and improves motor and cognitive function over the first 28 days following severe CCI. This study will identify differential responses of synaptic and non-synaptic mitochondria to drug therapy following injury. It re-purposes two FDA approved drugs which use complimentary neuroprotective mechanisms to ultimately identify a more neuroprotective combinational therapy that can successfully translate to human TBI.

project_terms:
Acrolein;Affect;Aldehydes;Antidepressive Agents;Attenuated;Back;Binding;Buffers;Calcium;Calpain;Clinical;Clinical Treatment;Combined Modality Therapy;Cyclosporine;Cytosol;Dose;Economic Burden;FDA approved;Functional disorder;Generations;Health;Homeostasis;Hour;Human;Immunosuppressive Agents;Impairment;Individual;Injury;Learning;Lipid Peroxidation;Lipid Peroxides;Lipids;Memory;Mitochondria;Mitochondrial Proteins;Motor;Nerve Degeneration;Neurologic;Neurons;Nitrogen;Outcome Measure;Oxygen;Pathology;Peptide Hydrolases;Peroxonitrite;Pharmaceutical Preparations;Pharmacotherapy;Phenelzine;Process;Rattus;Respiratory physiology;Role;Silver Staining;Spectrin;Staining method;Stains;Stress;Synapses;Testing;Therapeutic;Translating;Traumatic Brain Injury;Western Blotting;behavioral impairment;cognitive function;controlled cortical impact;disability;improved;improved outcome;inhibitor/antagonist;mitochondrial dysfunction;mitochondrial permeability transition pore;morris water maze;neuroprotection;neurotoxic;novel;object recognition;oxidative damage;perhydroxyl radical;prevent;respiratory;response;uptake

public_health_relevance:
Traumatic brain injury (TBI) represents a significant health crisis and affects millions of people worldwide. Currently there are no approved pharmacotherapies for the clinical treatment of TBI. This project combines two FDA approved drugs phenelzine and cyclosporine A to protect synaptic and non-synaptic mitochondria prevent neuronal damage and improve motor and cognitive function following experimental TBI.


application_id: 9305106
project_number: 5R01HD080205-04
administering_ic: NICHD
award_notice_date: 2017-07-28
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HD
serial_number: 080205
program_official: NITKIN, RALPH M
project_start_date: 2014-09-23
project_end_date: 2019-06-30
study_section: Urologic and Genitourinary Physiology and Pathology[UGPP]
contact_pi_person_id: 6490947
contact_pi: HUBSCHER, CHARLES H.
other_pis: HARKEMA, SUSAN J
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
project_abstract:
DESCRIPTION (provided by applicant): Spinal cord injury (SCI) results in impairments of locomotor sensory and autonomic functions severely affecting overall health and quality of life. Recent discoveries related to activity-dependent plasticity in humans have led to a widely implemented rehabilitation intervention Locomotor Training which includes stepping using body weight support on a treadmill with manual facilitation. Evidence suggests that this particular typeof task specific training optimizes the lumbosacral spinal circuitry. We have intriguing evidence from four SCI individuals who are unable to stand or walk showing improved bladder and sexual function after undergoing Locomotor Training. These changes in urogenital function may be due to activity-dependent plasticity of lumbosacral circuitry that mediates micturition and erectile functions.  Proper bladder management post-SCI is necessary to decrease the risk of upper urinary tract disease a major source of morbidity. The life-long urologic care is required for SCIindividuals yet most efforts treat symptoms but do not improve intrinsic function. In addition paraplegics rank sexual function as the function post-injury that should be given the highest priority in order to enhance quality of life. This proposal focuses on the mechanisms involved in the reorganization of spinal cord circuits for bladder and sexual function in response to activity-dependent plasticity induced by step training after SCI with and without epidural stimulation. Stand training and/or arm crank exercise serve as controls. Of potential mechanistic importance is that neurotrophins have been implicated in modulating bladder function. It is therefore hypothesized that weight bearing task specific training for locomotion post-SCI induces plasticity of neural networks that mediate not just walking but bladder and sexual function as well and may do so for bladder function by reducing specific neurotrophins that are elevated post-SCI.  Our unique approach will utilize the expertise of each investigator to 1) To determine whether the effect of weight-bearing task-specific training for locomotion on voiding frequency and urodynamic parameters is due to an interaction between locomotor and urinary bladder circuitry after traumatic incomplete upper motor neuron SCI in humans (versus standing or general exercise); 2) To assess the effect of LT on urine (biomarkers) and bladder (biopsy tissue) NGF and BDNF levels after severe incomplete SCI; 3) To determine the effect of weight-bearing task-specific training for locomotion on erectile function and sexual satisfaction after traumatic incomplete upper motor neuron SCI in humans; and 4) To assess the effect of epidural stimulation in combination with LT on voiding frequency urodynamic parameters erectile function and bladder/urine NGF and BDNF levels after complete and motor complete/sensory incomplete upper motor neuron SCI in humans. Our innovative multi-disciplinary study may lead to the translation of a combination approach of weight bearing step training epidural stimulationand neurotrophic factor manipulation to promote functional recovery for multiple systems following SCI.

project_terms:
Affect;Animals;Ataxia;Awareness;Biological Markers;Biological Neural Networks;Biopsy;Bladder;Bladder Dysfunction;Bladder Tissue;Body Weight;Brain-Derived Neurotrophic Factor;Caring;Case Study;Catheterization;Chemicals;Clinical;Contusions;Country;Data;Disease;Ejaculation;Electric Stimulation;Esthesia;Evaluation;Exercise;Extensor;Female;Fertility;Flexor;Foundations;Frequencies;Genitourinary system;Hardness;Health;Hospitalization;Human;Hyperreflexia;Impairment;Individual;Infection;Injury;International;Intervention;Interview;Knowledge;Lead;Learning;Life;Locomotion;Locomotor training;Lower Extremity;Manuals;Mediating;Morbidity - disease rate;Motor;Motor Neurons;Neuronal Plasticity;Operative Surgical Procedures;Oral;Outcome Measure;Paralysed;Paraplegia;Patient Self-Report;Patients;Pharmaceutical Preparations;Pharmacology;Quality of life;Questionnaires;Rattus;Recovery;Recovery of Function;Rehabilitation therapy;Reporting;Research Personnel;Residual volume;Rest;Risk;Seminal fluid;Sensory;Sex Functioning;Sexual Dysfunction;Source;Sphincter;Spinal;Spinal Cord;Spinal cord injury;Stents;Step training;System;Testing;Therapeutic;Tissues;Training;Translations;United States;Urethra;Urination;Urine;Urodynamics;Urologic Diseases;Viagra;Walking;Weight-Bearing state;arm;base;erection;improved;improved functioning;indexing;inhibitor/antagonist;innovation;life time cost;male;multidisciplinary;neurotrophic factor;neurotropin;novel;phosphodiesterase V;pressure;prevent;public health relevance;response;satisfaction;symptom treatment;treadmill;urologic

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Spinal cord injury (SCI) results in devastating effects on overall health and quality of life. The Christopher and Dana Reeve Foundation has recently estimated that 1275000 people are living with paralysis from SCI in the United States alone. This country could save an estimated $400 billion on direct and indirect lifetime costs if we can find ways to treat and prevent SCI. Bladder and sexual dysfunction affects daily life reduces quality of life and results in numerous life-long health complications. Improvements in bladder and sexual function have been reported in some people with incomplete SCI while they are undergoing a new rehabilitation intervention Locomotor Training. In addition four individuals with motor complete SCI who have received epidural stimulation in combination with Locomotor Training have also reported significant improvements in bladder and sexual function. We propose unique experimental human studies to understand whether spinal cord circuits responsible for walking are also important for bladder and sexual functions and reorganize in response to Locomotor Training and/or epidural stimulation after SCI to improve these functions and alter important chemicals in the body. The knowledge gained from our innovative multi-disciplinary study may lead to the translation of non-invasive approaches that will improve bladder and sexual function in people with SCI. Because we study humans with SCI directly what we learn will be immediately applicable to patients and provide immense improvements in quality of life.


application_id: 9304883
project_number: 5R21AR070620-02
project_title: Effects of Sodium-dependent Glucose Co-transporter 2 Inhibition on Bone.
administering_ic: NIAMS
award_notice_date: 2017-07-13
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: AR
serial_number: 070620
program_official: NICKS, KRISTY
project_start_date: 2016-07-01
project_end_date: 2019-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-V(02)M]
contact_pi_person_id: 1919059
contact_pi: THRAILKILL, KATHRYN M
other_pis: NYMAN, JEFFRY STEPHEN
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryPersons with type 1 and type 2 diabetes (T1D T2D) both have increased fracture risk attributedto specific deficits in the microarchitecture material properties and strength of diabetic bone.Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors are a new class of FDA-approved glucose-regulating agents for use in persons with T2D. These drugs (canagliflozindapagliflozin and empagliflozin are FDA-approved in the USA and Europe) increase urinaryglucose excretion by inhibiting glucose reabsorption in the renal proximal tubule and therebyimprove glycemic control in persons with type 2 diabetes. They are likely to play a prominentrole in the future treatment of T2D because of this unique mechanism of action and becausethey provide concurrent beneficial reductions in body weight and blood pressure. Howeverearly clinical studies have demonstrated a possible ~30% increase in bone fractures in patientsreceiving these medications with fractures occurring as early as 12 weeks of therapy. Atpresent very little is known about the effects of SGLT2 inhibition on bone mineral homeostasisbone turnover or bone microarchitecture or how these drugs specifically impact diabetic bonedisease. Therefore the objective of this proposal is to utilize several relevant rodent models(slc5a2-functional mutants STZ-induced diabetes TallyHo) to investigate potential mechanismscontributing to the adverse effects of SGLT2-inhibitor therapy on the skeleton. Furthermore wewill investigate the efficacy of co-therapy with anti-calciuric thiazide diuretic drugs to potentiallymitigate the negative effects of SGLT2-inhibitor therapy on the skeleton. Recognizing that alifelong increased risk for fragility fracture is now an established comorbidity of diabetes a betterunderstanding of the effects of SGLT2 inhibitors on bone health is both timely and highlyrelevant to the future of diabetes treatment.

project_terms:
Adverse effects;Affect;Age;Attenuated;Blood Glucose;Blood Pressure;Body Weight;Bone Density;Bone Diseases;Bone Resorption;Caring;Clinical;Clinical Research;Clinical Trials;Communication;Comorbidity;Diabetes Mellitus;Diabetic mouse;Disease;Europe;Excretory function;Exhibits;FDA approved;Fracture;Functional disorder;Future;Genes;Glucose;Homeostasis;Human;Hydrochlorothiazide;Incidence;Insulin-Dependent Diabetes Mellitus;Kidney;Laboratories;Link;Measures;Mediating;Minerals;Modeling;Mus;Mutate;Mutation;Non-Insulin-Dependent Diabetes Mellitus;Nonsense Mutation;Obesity;Patients;Persons;Pharmaceutical Preparations;Phenotype;Physiology;Play;Population;Positioning Attribute;Pre-Clinical Model;Prevention;Property;Proximal Kidney Tubules;Reporting;Resistance;Risk;Rodent;Rodent Model;Role;Safety;Skeleton;Sodium;Streptozocin;Structure;Testing;Thiazide Diuretics;Time;Urine;blood glucose regulation;bone;bone health;bone turnover;clinically relevant;diabetic;diabetic patient;early onset;experience;fracture risk;fragility fracture;glycemic control;hypercalciuria;improved;inhibitor/antagonist;innovation;mouse model;mutant;non-diabetic;preclinical study;prevent;skeletal;substantia spongiosa;symporter;urinary

public_health_relevance:
Project NarrativePersons with either Type 1 or Type 2 diabetes (T1D T2D) have an increased risk for bonefracture which is not predicted by bone mineral density testing alone; rather diabetic boneappears to be more brittle owing to diabetes-related changes in the microarchitecture andstrength of the skeleton. The SGLT2 inhibitor class of drugs is a new class of glucose-regulatingagents which improves glucose control in persons with diabetes by allowing the excess glucoseto be excreted in the urine. However these drugs appear to also further increase the risk offractures in diabetic patients; therefore the objectives of this proposal are to study themechanisms contributing to the increased fracture risk in persons receiving these medications.


application_id: 9304400
project_number: 2R15HD072713-02
project_title: Accents Focus and Syntactic Attachment
administering_ic: NICHD
award_notice_date: 2017-06-26
opportunity_number: PA-16-200
application_type: 2
activity_code: R15
ic: HD
serial_number: 072713
program_official: MILLER, BRETT
project_start_date: 2013-07-01
project_end_date: 2021-06-30
study_section: Language and Communication Study Section[LCOM]
contact_pi_person_id: 2219344
contact_pi: CARLSON, KATHRYN A
other_pis: Not Applicable
congressional_district: 05
department: MISCELLANEOUS
primary_duns: 041957010
primary_uei: MRGUP99ZAZ59
duns_number: 041957010
uei: MRGUP99ZAZ59
fips: US
organization_id: 569601
organization_name: MOREHEAD STATE UNIVERSITY
organization_city: MOREHEAD
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 403511684
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The ultimate goal of this research is to help understand sentence comprehension in spokenlanguage. Prosody or the way a sentence is spoken is important to sentence understanding andcan be affected by aphasia autism and hearing difficulties. Detailed linguistic research isnecessary to show how unimpaired adults use both types of prosodic units (accents for emphasisand prosodic phrasing for grouping) in their processing so as to better understand and treatdisorders in processing. This project specifically explores the effects of pitch accents and focus on syntacticallyambiguous sentences. It is well-known that prosodic boundaries one of the two major prosodicunits in English can affect the attachment of ambiguous phrases. Pitch accents on the otherhand were usually thought to influence only semantic and discourse representations of asentence by marking given new and contrastive information. This research follows up on thefinding that pitch accents can also attract attachment and traces the effect to the focus conveyedby accents: focused elements are important to the main assertion of a sentence and thus draw theattachment of optional modifiers. A series of auditory experiments will explore how accentsinteract with other focus markers (such as only) in attachment structures and how particularprosodic renditions of disambiguated attachment sentences are perceived in context. Additionalexperiments will explore three new attachment structures which have shown sensitivity toprosodic boundaries in order to find out whether accents also affect attachment withinpossessive structures and wh-questions.

project_terms:
Accent;Address;Adult;Affect;Affective;Aphasia;Auditory;Autistic Disorder;Cochlear Implants;Comprehension;Deafness;Diagnosis;Disease;Elements;Emotional;Funding;Goals;Grant;Grouping;Head;Health;Hearing;Hearing problem;Individual;Kentucky;Language;Language Disorders;Left;Linguistics;Patients;Pattern;Positioning Attribute;Process;Psychology;Recruitment Activity;Research;Research Project Grants;Resolution;Role;Semantics;Series;Site;Structure;Students;Testing;Universities;design;experience;experimental study;language comprehension;particle;phrases;programs;right hemisphere brain damage;syntax;undergraduate research;undergraduate student

public_health_relevance:
This project will contribute to a fuller understanding of how prosody or the tune and rhythm oflanguage affects sentence processing. It explores how pitch accents an aspect of linguisticprosody (rather than affective or emotional prosody) can modify the syntactic structure andmeaning of a sentence interacting with focus particles and context. The better we understand theuse of all types of linguistic prosody in language comprehension for unimpaired adults the betterwe will be able to analyze prosodic deficits in patients with aphasia autism or hearingdifficulties and the better we can plan to treat these problems.


application_id: 9304075
project_number: 5P30CA177558-05
project_title: PROJECT 12. Protocal Review
administering_ic: NCI
award_notice_date: 2017-06-23
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8636
contact_pi_person_id: 9360703
contact_pi: HAYSLIP, JOHN
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
The Markey Cancer Center (MCC) Protocol Review and Monitoring System (PRMS) provides thorough review of clinical trials for scientific validity feasibility and prioritization within the clinical trials portfolio and monitoring of scientific progress. The PRMS must approve all interventional cancer research prior to study initiation and has the authority to recommend closure of trials for lack of scientific progress or patient accrual. The PRMS provides a framework which aims to balance appropriate resource utilization while maximizing the opportunities for current and future patients with cancer in this region to participate in clinical trials including the underserved area of Appalachian Kentucky. The development of novel MCC investigator-initiated clinical trials and participation in high-priority national trials provide a robust portfolio of therapeutic research studies available to MCC patients.

project_terms:
Appalachian Region;Area;Basic Science;Behavioral Sciences;Cancer Center;Cancer Center Support Grant;Cancer Intervention;Charge;Clinical;Clinical Data;Clinical Research;Clinical Sciences;Clinical Trials;Colorectal Cancer;Development;Documentation;England;Ensure;Equilibrium;Future;Incidence;Instruction;Kentucky;Lead;Malignant Neoplasms;Malignant neoplasm of lung;Medical center;Monitor;Patient Care;Patients;Population Heterogeneity;Population Sciences;Poverty;Process;Protocols documentation;Research Personnel;Resource Sharing;Resources;Risk Behaviors;Services;Smoking;System;Therapeutic Human Experimentation;Translational trial;United States;Universities;anticancer research;authority;cancer survival;clinical translation;data management;health disparity;novel;operation;patient oriented;research study;screening

public_health_relevance:
RELEVANCE (See instructions): The patients of the MCC represent a diverse population with the highest incidence rates of lung and colorectal cancers in the United States high rates of poverty and increased rates of important risk behaviors (i.e. smoking and low screening rates for some cancers). These challenges require a well-developed PRMS to facilitate effective clinical and translational trials to overcome the health disparities of this region and lead to improvement in cancer survival.


application_id: 9304074
project_number: 5P30CA177558-05
project_title: PROJECT 11. Clinical Research and Data
administering_ic: NCI
award_notice_date: 2017-06-23
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8635
contact_pi_person_id: 9360703
contact_pi: HAYSLIP, JOHN
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
: The Markey Cancer Center (MCC ) Clinical l Research and Data a Management Shared Resource Facility (CRD M SRF ) coordinates and facilitates clinical cancer trials at the MCC . The major goals of the shared resource are to provide support of the clinical trial process  including implementing and regulating trials provide a centralized clinical trial l database  and integrate with the following: investigational pharmacy support  financial accounting  data safety monitoring  and quality assurance . This shared resource also assist s physician investigators in the design and subsequent conduct of clinical l trials through its support of the Investigator Initiated Trial Protocol Development Unit . It performs all regulatory reporting and quality assurance needed to comply with Good Clinical Practice in the performance of clinical trials . The CRDM SRF has Standard Operating Procedures for all its activities including training of all new faculty an d staff . From Ma y 2011 through April 2012  254 2 new patient s with cancer were seen at the MCC . Of these  145 1 were from Appalachian Kentucky . During the s time period  the CRDM SRF administrated therapeutic cancer clinical l trials that engage d 25 3 (10% ) participants in therapeutic intent clinical trials . Importantly  14 1 Appalachian patient s were engage d in therapeutic intent clinical research  a 10 % accrual rate from these disadvantaged and unique.

project_terms:
Accounting;Appalachian Region;Area;Cancer Center;Cancer Center Support Grant;Clinical;Clinical Cancer Center;Clinical Data;Clinical Nursing Research;Clinical Research;Clinical Research Associate;Clinical Trials;Conduct Clinical Trials;Data;Databases;Development;Disadvantaged;Education;Ensure;Faculty;Goals;Good Clinical Practice;Industry;Investigation;Kentucky;Location;Maintenance;Malignant Neoplasms;Mission;Monitor;NCI Center for Cancer Research;Nurses;Participant;Patients;Performance;Pharmacy facility;Phase;Physicians;Procedures;Process;Protocols documentation;Quality Control;Reporting;Research;Research Activity;Research Infrastructure;Research Personnel;Research Priority;Resource Development;Resource Sharing;Resources;Risk;Safety;Services;Therapeutic;Time;Training;Translational Research;Universities;Update;anticancer research;base;cancer clinical trial;data management;design;digital;experience;protocol development;quality assurance;support tools

public_health_relevance:
The CRD M SR F provides central management an d oversight fo r coordinating  facilitating  and reporting on MCC cancer clinical trials . Th e CRDM SR F provides a central location for digital an d hard copy cancer protocols  a central database o f protocol-specific data  an update d lis t of active protocol s for investigators  an d protocol status reports . The CRDM SR F support s quality control functions  including education an d training service s for data managers and nurses and data auditing in support of the audit committee .


application_id: 9304073
project_number: 5P30CA177558-05
project_title: PROJECT 10. Cancer Reserch SRF
administering_ic: NCI
award_notice_date: 2017-06-23
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8634
contact_pi_person_id: 9276771
contact_pi: DURBIN, ERIC B.
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
The Markey Cancer Center (MCC) Cancer Research Informatics (CRI) Shared Resource Facility facilitates collaborative research among members of the MCC through the optimal application of informatics technologies and methods that maximize the accessibility and usability of data information and knowledge for cancer research. The primary goal of CRI is to provide comprehensive and centralized data acquisition and informatics support that is readily available to cancer center members.  The Specific Aims of the CRI are to:  1. Develop and support innovative technologies for funded research studies that facilitate  accurate timely and secure data acquisition and dissemination. 2. Maintain and support a comprehensive patient-centered data warehouse offering unique  opportunities for MCC investigators to utilize integrated data sets from diverse sources ranging from genetic biomarkers to population-based surveillance data. 3. Facilitate rapid and efficient recruitment of patients to investigator-initiated trials and other  research studies. 4. Facilitate investigator access to data biospecimens and patients from Kentucky's Appalachian population. 5. Ensure the interoperability of informatics systems in compliance with evolving data standards. 6. Collaborate with the University of Kentucky (UK) Division of Biomedical Informatics to provide novel and state-of-the-art informatics solutions that increase the efficiency and accuracy of information and knowledge derived from diverse data sources.

project_terms:
Appalachian Region;Cancer Center;Cancer Center Support Grant;Clinical Research;Data;Data Set;Data Sources;Ensure;Funding;Funding Agency;Genetic Markers;Goals;Informatics;Kentucky;Knowledge;Malignant Neoplasms;Methods;Mission;NCI Center for Cancer Research;Participant;Patient Recruitments;Patients;Population;Publications;Recruitment Activity;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Secure;Services;Source;System;Technology;Time;Universities;Work;anticancer research;biomedical informatics;data acquisition;informatics shared resource;innovative technologies;interoperability;member;novel;patient oriented;population based;research study;surveillance data;usability

public_health_relevance:
The CRI is a critical resource supporting the acquisition storage management and utilization of data information and knowledge. The CRI integrates data from population clinical and research sources to identify and recruit study participants annotate biospecimens and derive unique research datasets for MCC investigators. This shared resource provides value-added service to MCC members which has led to numerous publications and research grants from the NCI and other funding agencies.


application_id: 9304072
project_number: 5P30CA177558-05
project_title: PROJECT 9. Biostatistics SRF
administering_ic: NCI
award_notice_date: 2017-06-23
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8633
contact_pi_person_id: 7719959
contact_pi: WEISS, HEIDI 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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
The Biostatistics Shared Resource Facility (BSRF) is a Markey Cancer Center (MCC)-managed resource providing comprehensive and centralized support that is readily accessible to cancer center investigators. The specific aims of the BSRF encompass support during study planning and study conduct and at the final stage of each project. In order to achieve these aims our services are categorized broadly into: 1) study planning power and sample size calculations for grant applications clinical trials population-based studies and preclinical experiments; 2) statistical analyses including interim and final analysis for the entire spectrum of cancer research studies; 3) statistical programming for data quality control and data processing; and 4) mentoring teaching and general consultation to MCC investigators. We also collaborate closely with MCC's Clinical Research and Data Management SRF Cancer Research Informatics SRF and other MCC shared facilities. The shared resource personnel include six faculty statisticians two master's-level statisticians and a faculty bioinformatician. Collectively they have extensive cancer-specific experience expertise and ongoing collaborations with investigators involved in studies ranging from laboratory in vitro in vivo studies in mouse models of cancer translational and bioinformatics studies in clinical samples clinical trials and population-based intervention studies. BSRF personnel are highly integrated with investigators across all research programs and interact closely with other SRFs at MCC to ensure comprehensive and seamless support. With personnel who are well-versed in all aspects of the biostatistical needs of MCC investigators the dedicated BSRF team adds significant value to the conduct of research at the MCC.

project_terms:
Address;Animals;Applications Grants;Bioinformatics;Biometry;Biostatistics Shared Resource;Cancer Center;Cancer Center Support Grant;Cancer Model;Clinical;Clinical Cancer Center;Clinical Data;Clinical Research;Clinical Trials;Collaborations;Complex;Consultations;Data;Data Analyses;Data Collection;Data Quality;Databases;Development;Educational process of instructing;Ensure;Faculty;Goals;Human Resources;In Vitro;Informatics;Intervention Studies;Kentucky;Laboratories;Malignant Neoplasms;Manuscripts;Mentors;Methodology;Mission;Monitor;Phase;Play;Population Study;Preparation;Quality Control;Reporting;Research;Research Design;Research Infrastructure;Research Personnel;Research Support;Resource Sharing;Resources;Role;Safety;Sample Size;Sampling;Science;Secure;Services;Statistical Data Interpretation;Time;Toxic effect;Training;Universities;analytical method;anticancer research;computerized data processing;data management;design;experience;experimental study;in vivo;member;mouse model;neoplasm registry;population based;pre-clinical;programs;research study

public_health_relevance:
The Biostatistics Shared Resource Facility (BSRF) plays a key collaborative role in providing scientific and statistical input across the entire spectrum of cancer research being performed at the MCC. This SRF has demonstrated significant impact in the conduct of science at MCC as evidenced by participating as co-investigators in grant applications providing critical input in clinical trial development and trial conduct and co-authoring with investigators in all research programs of the MCC.


application_id: 9304071
project_number: 5P30CA177558-05
project_title: PROJECT 8. Biospecimen
administering_ic: NCI
award_notice_date: 2017-06-23
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8632
contact_pi_person_id: 8828637
contact_pi: CIBULL, MICHAEL
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
The Biospecimen and Tissue Procurement Shared Resource Facility (BSTP SRF) procures and distributes biospecimens and provides expertise and support to the University of Kentucky (IJK) Markey Cancer Center (MCC) researchers to perform specialized histopathologic immunohistochemical and molecular analyses. The use of both neoplastic and non-neoplastic human and animal tissues is a key component of translational population-based and basic science cancer research. The goals of the facility are to provide formalin-fixed paraffin-embedded (FFPE) tissues frozen tissue blood and other specimens and histopathological and immunohistochemistry expertise for the studies related to the aims of Markey Cancer Center (MCC)-supported research projects. To meet these goals the following Specific Aims are proposed: 1) to provide quality-controlled human tissue biospecimens necessary for all research studies including both frozen and FFPE tissues annotated with clinical follow-up and outcomes; 2) to provide expert pathological review for all clinical specimens utilized in the projects and to provide specific histopathological technical services as necessary for analysis of all clinical and animal tissues; and 3) to coordinate and facilitate acquisition and quality control of tissue samples from the MCC affiliate hospitals required for the studies. The BSTP SRF will leverage the existing resources within the MCC the UK Department of Pathology and Laboratory Medicine the MCC Clinical Research and Data Management Shared Resource Facility and the Kentucky Cancer Registry thus assuring that this core benefits from previous efforts and techniques and that funds are used efficiently without reproducing existing facilities.

project_terms:
Appalachian Region;Basic Science;Blood;Cancer Center;Cancer Center Support Grant;Cancer Research Project;Clinical;Clinical Cancer Center;Clinical Data;Clinical Research;Collaborations;Colorectal Cancer;Formalin;Freezing;Funding;Goals;Hospitals;Human;Immunohistochemistry;Incidence;Individual;Kentucky;Laboratories;Leadership;Malignant Neoplasms;Malignant neoplasm of lung;Medicine;Molecular Analysis;Outcome;Paraffin Embedding;Pathologic;Pathology;Population Study;Positioning Attribute;Production;Quality Control;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Sampling;Services;Specimen;Structure of nail of toe;Surgical Pathology;Techniques;Time;Tissue Embedding;Tissue Microarray;Tissue Procurements;Tissue Sample;Tissues;Translational Research;Underserved Population;Universities;Urine;animal tissue;anticancer research;biobank;data management;digital imaging;follow-up;human tissue;neoplasm registry;neoplastic;novel;population based;repository;research clinical testing;research study;translational cancer research

public_health_relevance:
A central biospecimen repository processing and analysis facility specifically for cancer provides for productive and efficient use of resources to achieve the specific aims of cancer research projects in a timely fashion. A particularly novel aspect of our facility is the large sample repository (tissue blood urine toenails) from individuals in Appalachia an underserved population with a disproportionate incidence of lung and colorectal cancer. This repository has facilitated population-based studies in this region.


application_id: 9304070
project_number: 5P30CA177558-05
project_title: PROJECT 7. Free Radical
administering_ic: NCI
award_notice_date: 2017-06-23
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8631
contact_pi_person_id: 8329002
contact_pi: BUTTERFIELD, D. ALLAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
There is increasing evidence that oxidative damage and free radicals with sequelae of altered cellular energetics and protein alterations are important in the initiation promotion invasion metastasis and treatment of cancers. Moreover oxidative damage and free radicals also are implicated in the side effects of normal tissue injury following cancer therapy including chemotherapy radiafion and biological modifiers. The Free Radical Biology in Cancer Shared Resource Facility (FRBC SRF) was established to provide expertise in and analyses of free radicals cellular energetics and reactive species as well as proteomics in cancer and cancer biology for Markey Cancer Center (MCC) investigators who perform basic pre-clinical and clinical research. The four basic services provided by the FRBC SRF are: 1) Analysis of markers of oxidative and nitrosative stress; 2) Molecular biological manipulation of biological systems with which to investigate redox signals including measurements of mitochondrial function by Seahorse technology; 3) Proteomics identification of differentially expressed differentially oxidized or differentially covalently modified proteins in various cancer-related systems; 4) Electron paramagnetic resonance (EPR) detection of free radicals. Development of new applications and methodology for better understanding of the roles of free radicals in cancer and cancer chemotherapy and technical assistance with grant and manuscript preparation by MCC investigators will also be provided. Included in these functions of the considerable expertise of the FRBC SRF Technical Advisory Committee to educate MCC investigators on proper sample handling and preparation methods so that reliable precise and artifact-free assay results are obtained. Multiple investigators from all four research programs of the MCC (Redox Injury and Repair [RR]; Cancer Cell Biology and Signaling [CS]; Cancer Prevention and Control [CP]; and Drug Discovery Delivery and Translational Therapeutics [DT]) have used one or more services of the FRBC SRF. Indeed even as a relatively new shared resource the FRBC SRF still had usage by 26% of MCC investigators.

project_terms:
Address;Adverse effects;Advisory Committees;Appalachian Region;Area;Bioenergetics;Biological;Biological Assay;Biological Sciences;Biology;Buffers;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Etiology;Cellular biology;Chemotherapy-Oncologic Procedure;Clinical Research;Clinical Trials;Detection;Development;Electron Spin Resonance Spectroscopy;Etiology;Evaluation;Free Radicals;Freezing;Genus Hippocampus;Grant;Injury;Investigation;Ions;Kentucky;Lipids;Malignant Neoplasms;Manuscripts;Measurement;Measures;Mediating;Membrane;Metabolism;Metals;Methodology;Methods;Mitochondria;Modeling;Modification;Molecular;Morphologic artifacts;Neoplasm Metastasis;Normal tissue morphology;Nucleic Acids;Oxidation-Reduction;Oxidative Stress;Oxides;Preparation;Proteins;Proteomics;Reagent;Research;Research Personnel;Resource Sharing;Resources;Role;Sampling;Services;Signal Transduction;Strategic Planning;System;Techniques;Technology;Therapeutic;Training;Universities;biological systems;cancer cell;cancer prevention;cancer therapy;carcinogenesis;cell injury;chemotherapy;differential expression;drug discovery;injury and repair;insight;instrumentation;interest;member;mitochondrial dysfunction;nitrosative stress;organizational structure;oxidative damage;pre-clinical;programs;sample fixation;tumor progression

public_health_relevance:
Damaging free radicals are produced by cancers and with various cancer treatments. When cells are damaged evidence of free radical-induced oxidative or nitrosative stress becomes apparent. The Free Radical Biology in Cancer Shared Resource Facility addresses these issues for members of the MCC by determining markers of oxidative stress measuring oxidative stress-mediated mitochondrial dysfunction using Seahorse technology and identifying aberrant cellular proteins using proteomics.


application_id: 9304069
project_number: 5P30CA177558-05
project_title: PROJECT 6. Flow Cytometry
administering_ic: NCI
award_notice_date: 2017-06-23
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8630
contact_pi_person_id: 1878476
contact_pi: COHEN, DONALD A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
The Markey Cancer Center (MCC) Flow Cytometry and Cell Sorting Shared Resource Facility (FCCS SRF) provides University of Kentucky (UK) cancer researchers with comprehensive state-of-the-art analytical flow cytometry and cell sorting services to support both human and animal studies. The goals of the FCCS SRF are to provide: 1) multiparameter cell phenotyping; 2) analysis of DNA content and cell cycle; 3) analysis of cellular apoptosis and necrosis; 4) quantification of cell cytotoxicity; 5) intracellular cytokine analysis; 6) measurement of cell activation parameters; 7) high speed cell sorting of live human and animal cells under biocontainment conditions; and 8) single cell cloning of sorted cells. Another important function of the shared resource is to assist researchers in data analysis of flow cytometric studies and to help investigators in the development of new flow cytometric assays or approaches as needed for their research efforts. Finally FCCS SRF addresses the future needs of investigators by adding new and updated instrumentation to the facility that will expand the number of techniques and approaches available to cancer researchers at the university.

project_terms:
Address;Animals;Apoptosis;Basic Science;Biological Assay;Cancer Center;Cancer Center Support Grant;Cancerous;Cell Cycle;Cell Separation;Cells;Characteristics;Clinical Research;Clone Cells;DNA analysis;Data Analyses;Data Quality;Development;Faculty;Flow Cytometry;Funding Agency;Future;Goals;Human;Institutes;Kentucky;Malignant Neoplasms;Measurement;NCI Center for Cancer Research;Necrosis;Output;Phenotype;Ploidies;Publications;Research;Research Personnel;Research Project Grants;Resource Sharing;Sampling;Services;Signal Transduction;Sorting - Cell Movement;Speed;Techniques;Tissues;Training;Translational Research;United States National Institutes of Health;Universities;Update;anticancer research;cytokine;cytotoxicity;instrument;instrumentation;member;operation;programs

public_health_relevance:
Thirty-three cancer researchers from the four MCC research programs use FCCS SRF services for analysis and sorting of basic clinical or translational research samples. FCCS SRF services offer cancer investigators the ability to assay phenotypic and functional characteristics of cells from normal and cancerous tissues. Value-added service from FCCS SRF has led to numerous publications and research grants from the NCI other NIH institutes and additional funding agencies.


application_id: 9304068
project_number: 5P30CA177558-05
project_title: PROJECT 5. Program Leaders
administering_ic: NCI
award_notice_date: 2017-06-23
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8629
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
The Program Leaders for the Markey Cancer Center (MCC) provide cohesive leadership for promoting the research activities within and among the program areas. They assure continued interchange program planning and evaluation and educational exchange within their program. The Program Leaders identify areas of need within their research program and work with leadership of the cancer center to establish priorities and pursue recruitment in their respective areas. They are involved in identifying the shared resource needs of their program members and encourage collaborations between programs by communicating with leaders of other programs on possible areas of interactions and collaborations. They inform the appropriate Associate Director and the MCC Director on program activities and serve on the MCC's Scientific Advisory Panel and the Program and Shared Resource Leaders Committee. The four research programs of the MCC) are: Program 1: Cancer Cell Biology and Signaling Program 2: Cancer Prevention and Control Program 3: Drug Discovery Delivery and Translational Therapeutics Program 4: Redox Injury and Repair

project_terms:
Area;Cancer Center;Cancer Center Support Grant;Cancer Control;Cellular biology;Collaborations;Evaluation;Kentucky;Knowledge;Leadership;NCI Center for Cancer Research;Oxidation-Reduction;Recruitment Activity;Research;Research Activity;Resource Sharing;Signal Transduction;Therapeutic;Universities;Work;cancer cell;cancer prevention;cancer research center director;cohesion;drug discovery;injury and repair;innovation;member;programs;research study

public_health_relevance:
The four Markey Cancer Center research programs provide an exchange of scientific knowledge with their program members and with members of the other research programs by collaborating on innovative research studies.


application_id: 9304067
project_number: 5P30CA177558-05
project_title: PROJECT 4. Admin
administering_ic: NCI
award_notice_date: 2017-06-23
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8628
contact_pi_person_id: 9098327
contact_pi: GOSKY, DAVID M
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
The Markey Cancer Center (MCC) Administration has as its primary focus the provision of efficient and effective managerial planning and financial leadership and by doing so adding value to all MCC research programs shared resource facilities and all other services. Within that role MCC Administration provides important administrative support services to facilitate and enhance scientific productivity and collaboration among its 108 faculty research members who are organized into four research programs and who utilize MCC-supported shared resources. Administrative services include:   Coordination and participation in center-wide strategic planning and evaluation efforts.  Stimulation and support of inter- and intra-programmatic activities including grant development consultation and direct service support meeting organization and documentation and retreat/seminar/symposia coordination.  Administrative oversight and support for MCC-supported shared resources including the establishment of user fees provision of billing and auditing services coordination of and participation in oversight committees and evaluations.  Oversight of all center-related development/fundraising activities.  Fiscal management of university and Markey Cancer Foundation accounts related to the center.  Facilities management and management of all other assigned MCC space and equipment  Coordination of new faculty recruitment in collaboration with other university departments.  Human resource management of center staff.  Management of MCC membership including new application processes and annual reviews.  Administration of pilot project and other internal research award processes.  Computer networking and design of research management databases.  Coordination of internal communications and public relations for all center members.  From 2009 to the present MCC Administration has expanded staffing levels from 11.5 FTE to 19.5 FTE and in that process further developed key areas of administrative support in research communications shared resource facility development and financial management. This unit also oversaw a dramatic 40% expansion of MCC-controlled space including new construction.

project_terms:
Accountability;Applications Grants;Area;Award;Cancer Care Facilities;Cancer Center;Cancer Center Support Grant;Clinic;Collaborations;Communication;Communication Research;Consultations;Data Base Management;Development;Documentation;Electronic Mail;Ensure;Equipment;Evaluation;Event;Expenditure;Faculty Recruitment;Fees;Floor;Foundations;Goals;Grant;Grant Review;Human Resources;Information Technology;Kentucky;Leadership;Maintenance;Malignant Neoplasms;Mission;NCI Center for Cancer Research;Newsletter;Occupational activity of managing finances;Pilot Projects;Policies;Process;Productivity;Public Relations;Reporting;Request for Applications;Research;Research Activity;Research Design;Research Support;Resource Sharing;Resources;Retreatment;Role;Series;Services;Strategic Planning;Training;United States National Institutes of Health;Universities;Vision;base;cancer research center director;career development;computer design;computer network;cost effective;data management;equipment acquisition;experience;faculty research;meetings;member;multidisciplinary;operation;peer;programs;support network;symposium;web site

public_health_relevance:
The Markey Cancer Center Administration is an essential component of the center's overall efforts in that it provides key services - fiscal management meeting/project/program coordination facilities management and communication - to ensure that the center is able to meet its mission vision and strategic goals.


application_id: 9304066
project_number: 5P30CA177558-05
project_title: PROJECT 3. Dev Funds
administering_ic: NCI
award_notice_date: 2017-06-23
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8627
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
The Markey Cancer Center (MCC) will utilize developmental funds leveraged with institutional and philanthropic funds to support pilot grants and strategic new faculty recruitments. Pilot grant funding ($125000) from the CCSG will support collaborative and interdisciplinary cancer research focusing on MCC priority areas; funded projects will be carried out by interactions between MCC members in our four research programs and supported by our six shared resource facilities. Pilot funds will stimulate high return on investment research that makes a significant impact in the field of basic clinical population or translational cancer research. New faculty recruitment priorities have been established based on the MCC Strategic Plan in consultation with Senior and Program Leaders and include recruitment of: 1) a senior level molecular epidemiologist in years 1-3 ($50000 each year); and 2) a drug discovery scientist in years 4-5 ($50000 each year).

project_terms:
American Cancer Society;Area;Award;Cancer Center;Cancer Center Support Grant;Cancer Research Project;Clinical;Collaborations;Consultations;Data;Development;Epidemiologist;Extramural Activities;Faculty;Faculty Recruitment;Fostering;Funding;Funding Agency;Generations;Goals;Grant;Interdisciplinary Study;Investments;Kentucky;Malignant Neoplasms;Malignant neoplasm of lung;Modeling;Molecular;Peer Review;Philanthropic Fund;Population;Process;Publications;Recruitment Activity;Request for Applications;Research;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Scientist;Strategic Planning;Translational Research;United States National Institutes of Health;Universities;anticancer research;base;drug discovery;member;programs;success;translational cancer research

public_health_relevance:
Developmental funds will allow the MCC to invest in those areas of cancer research that present the greatest opportunity and are vital to the continued success of the MCC. The MCC requests Developmental Funds from the CCSG to fund pilot research projects and to recruit new faculty; both endeavors will support the goal of translational research.


application_id: 9304065
project_number: 5P30CA177558-05
project_title: PROJECT 2. Planning and Evaluation
administering_ic: NCI
award_notice_date: 2017-06-23
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8626
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
Continual planning and evaluation have been key to the development and sustained excellence of the research infrastructure at the Markey Cancer Center (MCC). Planning and evaluation activities are accomplished through the internal and external advisory boards councils and committees that provide the Director and Senior Leadership ongoing guidance and support. The MCC External Advisory Board (EAB) is the primary external mechanism for review and advice on the MCC's progress in basic and translational research and community research. Internal mechanisms include the advice and support of MCC's Senior Leaders who formally comprise the MCC Director's Council; the MCC Scientific Advisory Panel; and an Internal Advisory Board (lAB) comprised of deans center directors and department chairs at the University of Kentucky. Other planning and evaluation efforts occur at the program and shared resource levels. Shortly after joining the MCC in 2009 Dr. Evers and the Senior Leadership developed a strategic plan for the MCC which has served as a road map to guide the development of scientific research programs and initiatives the reorganization of shared resources required to facilitate and achieve the scientific goals and strategic recruitments of basic and translational scientists who will synergize and further strengthen ongoing research efforts over a five-year period. The strategic plan outlines directions for research to be developed the need for expanded services within existing shared resources and organizational strategies to improve collaboration and interdisciplinary interactions. This strategic plan is regularly reviewed for progress and revised. The most recent review and revision process was conducted in 2012 to reflect the tremendous progress that has occurred over three years and to redefine the strategic goals for the next five years based on the stronger foundations that are now in place.

project_terms:
Address;Advertisements;Appalachian Region;Area;Award;Basic Science;Behavioral;Biological Markers;Cancer Burden;Cancer Center;Cancer Center Support Grant;Clinical;Clinical Research;Clinical Trials;Collaborations;Collection;Colorectal Cancer;Communities;Department chair;Department of Defense;Development;Diagnosis;Ecology;Enrollment;Environmental Exposure;Epigenetic Process;Evaluation;Faculty;Foundations;Future;Genetic;Goals;Growth;Health;Incidence;Interdisciplinary Study;Kentucky;Laboratories;Lead;Leadership;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of lung;Maps;Marketing;Measurable;Mentors;Molecular Epidemiology;Multimedia;Oncologist;Organ;Outcome;Patients;Policies;Population;Prevention;Process;Publications;Recruitment Activity;Regulation;Research;Research Infrastructure;Research Personnel;Resource Sharing;Rural;Scientist;Services;Site;Site Visit;Strategic Planning;Therapeutic;TimeLine;Tobacco;Translational Research;Universities;Update;Validation;Wages;West Virginia;Woman;assay development;base;cancer clinical trial;cancer health disparity;cancer research center director;cancer therapy;career;improved;lung carcinogenesis;malignant breast neoplasm;member;novel;population based;pre-clinical;programs;repository;research study;sarcoma;social;success;survivorship;translational scientist

public_health_relevance:
The MCC has set up an ongoing and continual planning and evaluation process which has been instrumental in the dramatic growth in translational and interdisciplinary research collaborative publications and interactions and enrollment in clinical trials.


application_id: 9304064
project_number: 5P30CA177558-05
project_title: PROJECT 1 Senior Leadership
administering_ic: NCI
award_notice_date: 2017-06-23
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8625
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
The Markey Cancer Center (MCC) is directed by B. Mark Evers MD with the assistance of nationally recognized leaders in cancer research prevention and clinical care. Senior Leadership of the MCC includes: Susanne M. Arnold MD (Associate Director for Clinical Translation); David M. Gosky MA MBA (Associate Director for Administration); Daret St. Clair PhD (Associate Director for Basic Research) and Thomas Tucker PhD MPH (Associate Director for Cancer Prevention and Control). This highly experienced Senior Leadership team works together to ensure consistency in the shared vision and goals of the MCC; to develop synergistic and highly collaborative interactions among the basic translational and clinical components of the Center; to plan proactive approaches to the development of the research base and resources; to effectively leverage all available resources at the University of Kentucky and at the state and national levels; to engage in community outreach and philanthropy; and to oversee all activities of the MCC.  This Senior Leadership team meets several times a month in some capacity (i.e. in the context of various MCC Board/Committee/Council meetings one-on-one with the Director and bi-weekly as a Director's Council). They provide critical advice and recommendations to the Director based on those interactions. All final authority for decisions on behalf of the MCC resides with the Director.

project_terms:
Basic Science;Cancer Center;Cancer Center Support Grant;Cancer Control;Clinical;Community Outreach;Doctor of Philosophy;Ensure;Evaluation;Goals;Kentucky;Leadership;Prevention;Recommendation;Resources;Strategic Planning;Time;Universities;Vision;Work;anticancer research;authority;base;cancer prevention;clinical care;clinical translation;experience;meetings;member;research and development

public_health_relevance:
Support is requested for several members of the MCC Senior Leadership team who provide advice and recommendations to the Director regarding the strategic planning and evaluation of the Center's efforts.


application_id: 9304061
project_number: 5P30CA177558-05
project_title: University of Kentucky Markey Cancer Center - Cancer Center Support Grant
administering_ic: NCI
award_notice_date: 2017-06-23
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
program_official: ROBERSON, SONYA
project_start_date: 2013-07-08
project_end_date: 2018-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The Markey Cancer Center (MCC) a dedicated matrix cancer center established as an integral part of the University of Kentucky (UK) and the UK Healthcare enterprise has undergone dramatic expansion in recent years under the leadership of MCC Director Dr. B. Mark Evers. At this point in the center's development the MCC seeks support through the National Cancer Institute (NCI) Cancer Center Support Grant to capitalize on this momentum and to drive a measurable reduction in cancer mortality in Kentucky particularly Appalachian Kentucky through a comprehensive program of cancer research prevention and patient care. The need for NCI Cancer Center designation is particularly acute in a state that leads the nation across numerous cancer indicators including the highest rate of cancer deaths in the nation. Situated on a campus with all six health professions colleges in proximity to each other the MCC offers a history of rich transdisciplinary
collaboration an outstanding program of cancer prevention and control that has produced seminal work in Appalachian Kentucky nationally acclaimed basic research programs in cancer biology and DNA repair and oxidative stress and a translational therapeutics program complemented by a top five College of Pharmacy.    
   
These strengths have coalesced in MCC's four thematic research programs:  Cancer Cell Biology and Signaling; Cancer Prevention and Control; Drug Discovery Delivery and Translational Therapeutics; and Redox Injury and Repair. Currently the MCC's 108 Research and Associate Research members hold appointments in 24 departments in 7 colleges across the university (25 new faculty were recruited in the last 3 years). MCC members hold grants for 144 research projects funded in the annual composite (direct + indirect) amount of more than $30.5 million of which over $11.3 million (37%) comes from the NCI. Accrual to therapeutic clinical trials has increased over 130% in three years and MCC assignable space has increased 40% including a doubling of state-of-the-art research space. In addition six shared resources facilitate cutting-edge research by providing a robust infrastructure for specialized expertise and advanced methods. They include:  Biospecimen and Tissue Procurement; Biostatistics; Cancer Research Informatics; Clinical Research and Data Management; Flow Cytometry and Cell Sorting; and Free Radical Biology in Cancer. The MCC is currently well positioned to take on new challenges and to continue to evolve in key strategic directions that take maximum advantage of these strengths.


application_id: 9303474
project_number: 5R01NS083405-05
project_title: Multi-Mechanism Inhibition of Lipid Peroxidation in TBI
administering_ic: NINDS
award_notice_date: 2017-06-29
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: NS
serial_number: 083405
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2013-07-01
project_end_date: 2018-12-31
study_section: Special Emphasis Panel[ZRG1-BDCN-L(02)M]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): We have previously documented that generation of the potent reactive nitrogen species (RNS) peroxynitrite (PN) is responsible for oxidative damage by lipid peroxidation (LP) and protein modification (carbonylation and tyrosine nitration) to mitochondrial and other cellular elements during the first 72 hrs after traumatic brain injury (TBI). The PN-mediated oxidative damage leads to brain mitochondrial dysfunction and ultimately failure. As a consequence of oxidative compromise of mitochondrial function including calcium (Ca++) buffering) posttraumatic intracellular Ca++ overload is exacerbated leading to calpain-mediated cytoskeletal degradation neurodegeneration and neurological impairment. We have preliminarily shown that treatment with the potent LP inhibitor U-83836E with the LP-derived lipid aldehyde 4-hydroxynonenal (4-HNE) scavenger phenelzine or with the mitochondrial permeability transition inhibitor cyclosporine (CsA) can partially attenuate posttraumatic brain LP damage mitochondrial dysfunction and calpain-mediated cytoskeletal damage in a mouse TBI model. Most importantly the window for this effect is at least 12 hrs post-injury. However our preliminary results show only a partial attenuation of post-injury LP-related neural damage' even when any of these antioxidant compounds is individually administered after injury. This partial neuroprotective effect strongly points to the logic of an antioxidant neuroprotective strategy that combines either two or all three of these mechanistically complimentary antioxidant compounds to achieve a greater degree of neuroprotection. Therefore the overall goal of the proposed experiments is to explore the hypothesis that interrupting post-traumatic secondary LP oxidative damage at multiple points will produce a quantitatively greater neuroprotective effect with less variability that will have agreater chance of translational success in future TBI clinical trials. The combination approach should not only increase the maximal neuroprotective effect but may also prolong the therapeutic window for inhibition of secondary brain injury after TBI.

project_terms:
3-nitrotyrosine;4 hydroxynonenal;Aldehydes;Antioxidants;Attenuated;Brain;Brain Injuries;Buffers;Calcium;Calpain;Clinical;Clinical Trials;Complex;Cyclosporine;Dose;Effectiveness;Elements;Extravasation;Failure;Free Radicals;Functional disorder;Future;Generations;Goals;Human;Impairment;Individual;Injury;Interruption;Intervention;Lesion;Lipid Peroxidation;Lipid Peroxides;Lipids;Logic;Mediating;Membrane Lipids;Mitochondria;Modeling;Molecular;Motor;Mus;Nerve Degeneration;Nervous System Trauma;Neurologic;Neurons;Nitrates;Patients;Permeability;Peroxonitrite;Pharmaceutical Preparations;Pharmacology;Phase III Clinical Trials;Phenelzine;Post-Translational Protein Processing;Production;Rattus;Reactive Nitrogen Species;Reactive Oxygen Species;Recovery of Function;Regimen;Reporting;Testing;Therapeutic;Tissues;Translating;Traumatic Brain Injury;Traumatic Subarachnoid Hemorrhage;Treatment Efficacy;Treatment Protocols;Tyrosine;attenuation;base;cognitive function;controlled cortical impact;design;experimental study;improved;inhibitor/antagonist;lipid peroxidation inhibitor;mitochondrial dysfunction;mortality;neuroprotection;neurotoxic;nitration;oxidative damage;protective effect;public health relevance;relating to nervous system;respiratory;response;success;treatment strategy

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This project will examine the potentially greater benefits that might be obtained in the rat controlled cortical impact traumatic brain injury model when multiple neuroprotective compounds that target oxidative secondary injury mechanisms are administered together. Specifically we will test a combination multi-mechanistic antioxidant treatment strategy combining two or three of the following mechanistically complimentary antioxidant compounds: 1) the lipid peroxidation-inhibiting drug U-83836E 2) the commercially available compound phenelzine that scavenges the neurotoxic lipid peroxidation-derived lipid aldehyde 4- hydroxynonenal (4-HNE) and 3) the extensively demonstrated mitochondrial protective compound cyclosporine A(CsA) which reduces post-TBI mitochondrial permeability transition and free radical leakage. After determining the best neuroprotective dose optimal treatment regimen and therapeutic efficacy window of each compound pharmacologically-optimized dosing regimens of each of the compounds will be compared in a single experiment. This will be followed by the testing of the combination effectiveness of two (U-83836E + phenelzine U-83836E + CsA phenelzine + CsA) or all three (U-83836E + phenelzine + CsA).


application_id: 9303423
project_number: 5R01GM109195-03
project_title: Reconciling Nanoceria's Jekyll and Hyde Reputation Toward Safer Nanotherapy
administering_ic: NIGMS
award_notice_date: 2017-06-06
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: GM
serial_number: 109195
program_official: FABIAN, MILES
project_start_date: 2015-06-01
project_end_date: 2019-05-31
study_section: Nanotechnology Study Section[NANO]
contact_pi_person_id: 7876821
contact_pi: YOKEL, ROBERT ALLEN
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): The technological development of nanomaterials has been underway for decades. Only in the past decade has serious attention been paid to their potential unwanted health and environmental effects. Many nanomaterials do not readily dissolve or disintegrate in biological and environmental milieu. As a result they can persist where they are sequestered (in mammals mostly in mononuclear phagocyte system organs such as the liver spleen and bone marrow) for months possibly years often associated with inflammatory/oxidative stress responses including granuloma. These unwanted effects have been seen with nanoceria (nanoscale cerium dioxide). On the other hand nanoceria has been shown to be an effective anti-inflammatory/antioxidant in numerous cellular cell and whole animal models of inflammation/oxidative stress. Nanoceria's pro- and antioxidant effects result from its auto-catalytic redox behavior (oxidation from Ce (III) to Ce (IV) and reduction back to Ce(III)). The first specific aim of this project will determine if nanoceria can produce inflammatory/pro- oxidant effects in the absence of elevated inflammation/oxidative stress and anti-inflammatory/antioxidant effects when inflammation/oxidative stress is elevated and determine the lowest observed adverse dose and lowest observed beneficial dose. Four nanoceria will be studied: a 5 and a 30 nm nanoceria extensively studied for their distribution persistence and effects in the rat (preliminary findings) and a third that others have demonstrated produces beneficial inflammatory/pro-oxidant effects. These three will be synthesized and extensively characterized in-house. The fourth will be NM-212 a commercial nanoceria that is being extensively studied by the inhalation route by others. Due to the very low oral and pulmonary absorption of nanomaterials nanoceria will be delivered by intravenous injection to establish sufficient levels in multiple organs to study its biodistribution persistene biotransformation and effects. Preliminary findings indicate that nanoceria undergoes some bioprocessing in mammalian cells over months to a more stable form. This appears to occur via dissolution and formation of very small nanoceria particles. These very small nanoceria particles have a greater enrichment of Ce (III) on their surface; therefore they are expected to have enhanced anti-inflammatory/antioxidant properties. This biotransformation suggests enhanced benefit over time associated with nanoceria's persistence and bioprocessing. The second specific aim will test the hypothesis that the distribution form and effects of nanoceria change over time due to its bioprocessing in the liver to smaller more antioxidant forms. The third specific aim will identify factors that contribute to nanoceria dissolution and precipitation and mediate its bioprocessing and precipitation in the liver. The proposed studies will identify nanoceria doses that maximize its efficacy relative to its unwanted effects elucidate nanoceria's long term fate in a model mammal the rat and provide the insight into its biotransformation that may enable safer by design nanoceria for use as a therapeutic agent with prolonged anti-inflammatory/antioxidant activity.

project_terms:
3-Dimensional;Address;Adverse effects;Affect;Animal Model;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Area;Attention;Back;Behavior;Biodistribution;Biological;Biological Availability;Bone Marrow;Breathing;Buffers;Cells;Characteristics;Chemicals;Coculture Techniques;Development;Diesel Fuels;Dose;Employee Strikes;Family;Future;Goals;Granuloma;Health;Industrialization;Inflammasome;Inflammation;Inflammatory;Lipopolysaccharides;Liver;Lung;Mammalian Cell;Mammals;Measures;Mechanics;Mediating;Medical;Metabolic Biotransformation;Modeling;Mononuclear;Morphology;Oral;Organ;Oxidation-Reduction;Oxidative Stress;Phagocytes;Physiological;Pilot Projects;Polishes;Precipitation;Property;Rattus;Reactive Oxygen Species;Recycling;Reporting;Research;Research Personnel;Route;Safety;Spleen;Stress;Surface;System;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;absorption;base;biological adaptation to stress;biological systems;bioprocess;body system;catalyst;ceric oxide;design;insight;interest;intravenous injection;metal oxide;nanomaterials;nanoscale;nanotherapy;novel;oxidation;particle;public health relevance;response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cerium dioxide nanomaterials (nanoceria) have many current commercial uses including as a diesel fuel additive to catalyze combustion and in chemical-mechanical polishing to manufacture integrated circuits with future applications expected in fuel cells and batteries. Nanocerias have been shown to produce adverse effects as well as beneficial antioxidant/anti-inflammatory effects the latter suggesting potential medical applications. The proposed research will determine the influence of dose and biotransformation on long-term nanoceria effects with the goal of minimizing its adverse and maximizing its beneficial effects supporting its design for safe use for its many potential applications.


application_id: 9302876
project_number: 1R21CA210202-01A1
project_title: Targeting melanoma hypoxia with lactic acid bacterium L. lactis
administering_ic: NCI
award_notice_date: 2017-03-09
opportunity_number: PAR-15-053
application_type: 1
activity_code: R21
ic: CA
serial_number: 210202
suffix: A1
program_official: SCHWARTZ, ELENA IVAN
project_start_date: 2017-03-09
project_end_date: 2019-02-28
study_section: Special Emphasis Panel[ZRG1 OBT-A (55)]
contact_pi_person_id: 10284580
contact_pi: GOMEZ-GUTIERREZ, JORGE G
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Project SummaryMelanoma is the most aggressive form of skin cancer and if disseminated through the dermis has a poorprognosis with a high mortality rate. Hypoxia is a component of the tumor microenvironment which reducesefficacy of both immuno- and chemo-therapies resulting in poor clinical outcome. Therefore we will exploit thehypoxic microenvironment as a target for gene therapy utilizing commensal facultative anaerobic bacteria. Theoverall goal of this proposal is to develop an effective and safe delivery system for cancer gene therapy bytargeting the hypoxic tumor microenvironment with food-grade lactic acid bacteria (LAB) Lactococcus lactis (L.lactis). The use of LAB as opposed to other bacteria represents a much more desirable strategy to delivertherapeutic genes than attenuated pathogenic strains as there is no risk of reversion or potential to instigatehost reactions in immunocompromised patients. Because identification of tumor-specific accumulation andbiodistribution of gene delivery vehicles in vivo is essential for translation of these agents to the clinic we willutilize a newly emerging technology multispectral optoacoustic tomography (MSOT). MSOT is a hybridmodality that detects sound waves generated by the absorption of electromagnetic energy thus enabling thecapability for 3D high-resolution at depth and in real time. Our preliminary data indicates that L. lactisexpresses high levels of -galactosidase (LacZ) and in combination with 5-bromo-4-chloro-3-indolyl--D-galactopyranoside (X-gal) produces a strong blue color to facilitate detection of L. lactis using MSOT. Giventhese findings we hypothesize that L. lactis will preferentially colonize the hypoxic areas of the tumormicroenvironment to deliver therapeutic genes in a safe tumor-specific and effective manner. We propose twoaims: (1) Evaluate the efficacy of L. lactis as a gene delivery vehicle in melanoma cells in vitro and (2)determine the biodistribution and tumor-specific accumulation of L. lactis in metastatic melanoma-bearingmice. The successful completion of this proposal will substantially influence the field of gene therapyspecifically utilization of facultative bacteria as delivery agents for tumor-specific targeting of melanoma.

project_terms:
Affect;Anaerobic Bacteria;Antibiotic Therapy;Area;Attenuated;BRAF gene;Bacteremia;Bacteria;Biodistribution;Blood;Cells;Characteristics;Clinic;Clinical;Clostridium;Color;Communicable Diseases;Consumption;Data;Dermis;Detection;Dose;Dyes;Electromagnetic Energy;Emerging Technologies;Food;Galactose;Galactosidase;Gastrointestinal Diseases;Gene Delivery;Gene Mutation;Gene Targeting;Gene Transfer;Genes;Goals;Home environment;Hybrids;Hypersensitivity;Hypoxia;Image;Immunocompromised Host;Implant;In Vitro;Indocyanine Green;Invaded;Killings;LacZ Genes;Lactococcus lactis;Ligands;Light;Listeria;Liver;Malignant Neoplasms;Melanoma Cell;Metastatic Melanoma;Methods;Mind;Modality;Molecular Probes;Mus;Oncogenes;Optics;Organ;Organism;Outcome;Oxygen;Pathogenicity;Patients;Penetration;Pharmacotherapy;Photons;Production;Progression-Free Survivals;Proliferating;Reaction;Relapse;Reporter Genes;Resolution;Risk;Salmonella;Sentinel Lymph Node;Signal Transduction;Skin Cancer;Staining method;Stains;Surface;Symbiosis;System;Therapeutic;Time;Tissue Stains;Tissues;Toxicity due to chemotherapy;Translations;Ultrasonics;Virulent;Zinc;absorption;attenuation;base;beta-Galactosidase;bioluminescence imaging;clinical application;design;experimental study;fluorescence imaging;fluorophore;gene therapy;genetic manipulation;imaging system;improved;in vivo;inhibitor/antagonist;lactic acid bacteria;melanoma;mortality;optoacoustic tomography;outcome forecast;photoacoustic imaging;promoter;routine Bacterial stain;sound;subcutaneous;targeted treatment;therapeutic gene;treatment response;tumor;tumor microenvironment;tumor specificity;tumor-specific gene delivery;uptake

public_health_relevance:
Project NarrativeSome bacteria selectively grow in areas of low oxygen. We will evaluate the ability of L. lactis as a genedelivery vehicle to target areas of low oxygen within melanoma tumors implanted in the liver. Thebiodistribution and tumor accumulation of L. lactis will be evaluated using multispectral optoacoustictomography. The efficacy of L. lactis as a gene delivery vehicle into melanoma cells will also be evaluated.


application_id: 9302620
project_number: 5R01AA023681-04
project_title: Mechanisms for alcohol induced gut barrier dysfunction in ALD
administering_ic: NIAAA
award_notice_date: 2017-07-04
application_type: 5
activity_code: R01
ic: AA
serial_number: 023681
program_official: GAO, PETER
project_start_date: 2014-07-05
project_end_date: 2019-06-30
study_section: ZAA1-GG(50)P
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
project_abstract:
It is increasingly recognized that gut flora and gut barrier function play a pivotal role in thepathogenesis of several forms of liver disease including ALD. Gut-derived endotoxins normally penetrate thegut epithelium in only trace amounts due to tightly regulated intestinal barrier function. However endotoxinleakiness is increased under pathological conditions including alcohol abuse. The barrier function ofintestinal epithelium Is provided in part by paracellular apical junction complexes including tight andadherens junctions and by a mucus layer. In our initial systems biology approach to ALD we found that intestinal trefoil factor (ITF) was by far themost altered (~50-fold down regulated) protein in the liver following chronic alcohol feeding in rats andsubsequent studies also showed marked down regulation of ITF mRNA and protein in the intestines ofalcohol fed mice. ITF plays a critical role in the formation and stabilization of intestinal mucus barrier andenhancement of rapid intestinal repair "restitution". Formation and restitution of the barrier is also dependenton uninterrupted mucosal blood flow. Intestinal epithelial cells are positioned between an anaerobic lumenand a highly metabolic lamina propria forming a steep physiologic oxygen gradient. Increased hypoxia-inducible factor (HIF) signaling represents a major adaptive response to hypoxic stress by upregulating avariety of gene products such as ITF and mucins to form an integrated epithelial barrier. Our preliminarystudies demonstrated that chronic alcohol administration decreases intestinal HIF-2 ITF and tight junctionprotein expression resulting in increased endotoxemia and ultimately liver injury. Moreover supplementationwith a probiotic strain Lactobacillus rhamnosus GG (LGG) increased intestinal HIF-2 and ITF expressiondecreased endotoxemia and attenuated alcohol induced liver injury. We hypothesize that alcohol exposurecauses detrimental metabolic changes favoring intestinal oxidative stress inflammation and alterations ofHIF responsive signaling with decreased ITF leading to intestinal barrier dysfunction blood endotoxemiaand ALD. We postulate that probiotic supplementation will attenuate alcohol-induced intestine and liverinjury in part by increasing HIF-mediated expression of mucus protective factors such as ITF in the intestine.We test our hypothesis with 4 specific aims using in vitro animal and human studies approaches. Ourultimate goal is the development of new therapies for ALD.RELEVANCE (See instructions):Alcohol overuse/abuse induces organ injury in multiple organs. This translational research project willexamine the mechanisms of the beneficial effects of probiotics on the intestine and the liver in anexperimental mouse model of alcoholic liver disease (ALD) and in mild human alcoholic hepatitis (AH).

project_terms:
Adherens Junction;Alcohol abuse;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Anaerobic Bacteria;Animal Model;Animals;Apical;Attenuated;Bacteria;Blood;Blood flow;Cells;Chronic;Complex;Defect;Development;Down-Regulation;Endotoxemia;Endotoxins;Epithelial;Epithelial Cells;Functional disorder;Goals;Human;Hypoxia;Hypoxia Inducible Factor;Immune response;In Vitro;Inflammation;Injury;Instruction;Intestines;Knockout Mice;Lactobacillus casei rhamnosus;Lamina Propria;Liver;Liver diseases;Mediating;Messenger RNA;Metabolic;Metabolic Pathway;Mucins;Mucous body substance;Mus;Organ;Oxidative Stress;Oxygen;Pathogenesis;Pathologic;Patients;Physiological;Play;Positioning Attribute;Probiotics;Process;Procollagen-Proline Dioxygenase;Proteins;Rattus;Recombinants;Research Project Grants;Role;Sampling;Signal Transduction;Stress;Supplementation;Systems Biology;Testing;Tight Junctions;Translational Research;alcohol effect;alcohol exposure;alcohol response;comparative efficacy;feeding;gain of function;gastrointestinal epithelium;gene product;intestinal epithelium;liver injury;loss of function;mouse model;novel therapeutics;probiotic supplementation;probiotic therapy;protective effect;protein degradation;protein expression;repaired;response;treatment effect;trefoil factor


application_id: 9302597
project_number: 5R01AA021434-05
project_title: Role of microRNAs in Ethanol-induced Apoptosis and Teratogenesis
administering_ic: NIAAA
award_notice_date: 2017-07-03
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AA
serial_number: 021434
program_official: HERELD, DALE
project_start_date: 2013-07-20
project_end_date: 2021-06-30
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 7035096
contact_pi: CHEN, SHAO-YU
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): Prenatal ethanol exposure is the leading known cause of mental retardation. Growing evidence suggests that excessive cell death is a major component of the pathogenesis of ethanol-induced birth defects. However there is a fundamental gap in understanding how ethanol leads to apoptotic cell death in embryos. MicroRNAs (miRNAs) are a recently discovered class of small 18-23 nucleotide non-coding RNA that have been implicated in the regulation of genes involved in apoptosis. We have recently discovered that miR-34a a pro-apoptotic miRNA and miR-125b an anti-apoptotic miRNA are involved in ethanol-induced apoptosis in neural crest cells (NCCs). Our long-term goal is directed toward the development of effective strategies against ethanol's teratogenesis; strategies based on prevention of ethanol-induced apoptosis through targeting specific pathways involved in apoptosis. The overall objective of this particular proposal is to establish miRNA as a feasible target for the prevention of ethanol-induced apoptosis and teratogenesis. The central hypothesis to be tested is that miR-34a and miR-125b modulate ethanol-induced apoptosis in NCCs by the regulation of p53 and Bcl2 signaling pathways and that the inhibition of miR-34a or overexpression of miR-125b can prevent ethanol-induced teratogenesis. Our hypothesis has been formulated on the basis of strong preliminary data produced in our laboratory. To test our hypothesis the following specific aims will be addressed: Aim1: To characterize the role of miR-34a and miR-125b in ethanol-induced apoptosis in NCCs. We will determine the effects of ethanol on miR-34a and miR-125b expression in NCCs and in mouse embryos and the involvement of miR-34a and miR-125b in ethanol-induced apoptosis. Aim2: To test the hypothesis that miR-34a and miR- 125b modulate ethanol-induced apoptosis in NCCs by the regulation of p53 and Bcl2 pathways. This will be accomplished by determining the role of miR-34a in ethanol-induced activation of p53 and suppression of Bcl2 signaling and the effects of down-regulation of miR-125b by ethanol on p53 and Bcl2 signaling in ethanol- exposed NCCs. Aim3: To test the hypothesis that modulation of miR-34a and miR-125b represents a novel therapeutic strategy for preventing ethanol-induced teratogenesis. We will determine whether knockdown of miR-34a or overexpression of miR-125b diminishes ethanol-induced malformations in mouse embryos. The proposed work is innovative because it focuses on a novel approach targeting miRNAs involved in apoptosis to preventing ethanol-induced teratogenesis. The theoretical concept described in this application is also highly innovative because this is the first study attempting to prevent ethanol-induced apoptosis and teratogenesis specifically through the newly recognized actions of miR-34a and miR-125b in apoptosis. The results from this study will be significant because the insights gained by the accomplishment of these aims will help in elucidating the role of miRNAs in modulating ethanol-induced teratogenesis. They are also expected to yield strategies for preventing ethanol's teratogenesis and to fundamentally advance the field of FASD research.

project_terms:
Address;Alcohol consumption;Alcohols;Antioxidants;Apoptosis;Apoptotic;Brain;Brain region;Cell Death;Cell Line;Cells;Cessation of life;Congenital Abnormality;Data;Development;Down-Regulation;Embryo;Ethanol;Fetal Alcohol Exposure;Fetal Alcohol Spectrum Disorder;Gene Expression Regulation;Genes;Goals;Human;Knockout Mice;Knowledge;Laboratories;Life;Mental Retardation;MicroRNAs;Mission;Molecular;Molecular Target;Mus;National Institute on Alcohol Abuse and Alcoholism;Neural Crest Cell;Neurons;Nucleotides;Pathogenesis;Pathway interactions;Population;Pregnancy;Prevention;Prevention strategy;Preventive Intervention;Public Health;Regulation;Research;Role;Signal Pathway;Signal Transduction;Site;TP53 gene;Testing;Therapeutic;Therapeutic Intervention;Third Pregnancy Trimester;Time;Untranslated RNA;Up-Regulation;Work;alcohol effect;alcohol exposure;base;effective intervention;embryo culture;fetal;in vivo;innovation;insight;knock-down;malformation;mouse model;non-genetic;novel strategies;novel therapeutics;overexpression;prevent;public health relevance

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the insights gained by the accomplishments of the proposed studies will help in elucidating the mechanisms underlying ethanol-induced cell death and validating possible molecular targets for the development of novel therapeutics for the prevention of human Fetal Alcohol Spectrum Disorders (FASD). Thus the proposed research is relevant to the NIAAA's mission that pertains to using knowledge gained in uncovering target sites for alcohol's action on the embryonic and fetal stages of life to begin developing potential therapeutic or preventative interventions.


application_id: 9302396
project_number: 5R01DK048498-22
project_title: Mechanistic Impact of PI3K/mTOR Signaling on Intestinal Homeostasis
administering_ic: NIDDK
award_notice_date: 2017-06-22
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 048498
program_official: SERRANO, JOSE
project_start_date: 1996-03-15
project_end_date: 2020-05-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The mammalian intestinal mucosa undergoes a process of continual renewal characterized by active proliferation of stem cells localized near the base of the crypts; progression of these cells up the crypt-villus axis with cessation of proliferation; and subsequent differentiation into one of the four primary cell types (i.e. enterocytes goblet cells Paneth cells and enteroendocrine cells). An imbalance in this highly-regimented and orderly process within the crypts is associated with a number of common intestinal pathologies (e.g. colorectal cancer and inflammatory bowel disease [IBD]) which are associated with significant morbidity and mortality. Delineating the molecular factors regulating intestinal proliferation and differentiation is crucial to our understanding of not only normal gutdevelopment and adaptation but also aberrant gut growth. With the support of this grant we have shown the importance of the PI3K/Akt/mTOR pathway in the regulation of intestinal cell proliferation and differentiation. In addition we have shown the differential effects of various NFAT isoforms which integrate and cooperate with the PI3K/mTOR pathway to maintain intestinal homeostasis. As an extension to our published results our recent findings have demonstrated a novel metabolomic profile associated with intestinal cell differentiation and found that the ketogenic enzyme hydroxymethylglutaryl CoA synthase 2 (HMGCS2) and its product -hydroxybutyrate (HB) an endogenous inhibitor of histone deacetylases (HDACs) are increased with differentiation. In addition inhibition of mTOR Complex 1 (mTORC1) increases HMGCS2 expression in vitro and in vivo and moreover HB induces intestinal cell differentiation. Finally we have shown that HB increases the expression of the sirtuin proteins that contribute to intestinal cell differentiation; mTOR interacts with and regulates the expressio and deacetylase activity of the sirtuin proteins. Based on our recently published and preliminary findings we have further refined our central hypothesis to state that intestinal cell proliferatio and differentiation are regulated by PI3K/Akt/mTOR signaling pathway acting on critical downstream proteins (e.g. HMGCS2 and sirtuin proteins); a novel interaction between these pathways may exist that further adds to the intricate but highly regimented regulation of intestinal homeostasis. To examine our central hypothesis we have planned experiments with the following Specific Aims: 1) to delineate mTOR-mediated metabolic reprogramming in intestinal cell proliferation and differentiation; 2) to define the role of HMGCS2/HB in mediatin the effects of mTOR in the intestine; 3) to determine whether sirtuin proteins act cooperatively with HMGCS2/HB to maintain intestinal homeostasis. The studies in the current proposal represent direct extensions of our previous findings and are designed to define in a systematic fashion the molecular mechanisms and signaling events regulating the processes of intestinal proliferation differentiation and adaptation.

project_terms:
3-hydroxy-3-methylglutaryl-coenzyme A;Atrophic;Biochemistry;Biometry;Cell Differentiation process;Cell Proliferation;Cell model;Cells;Colorectal Cancer;Complex;Deacetylase;Development;Enterocytes;Enteroendocrine Cell;Enzymes;Event;Excision;FRAP1 gene;Glycolysis;Goals;Goblet Cells;Grant;Growth;Histone Deacetylase Inhibitor;Human;In Vitro;Inflammatory Bowel Diseases;Intestinal Mucosa;Intestines;Ketone Bodies;Lead;Maintenance;Mediating;Metabolic;Metabolism;Molecular;Morbidity - disease rate;Mus;Operative Surgical Procedures;Organoids;Paneth Cells;Pathology;Pathway interactions;Phenotype;Play;Process;Protein Isoforms;Proteins;Publishing;Regulation;Role;Signal Pathway;Signal Transduction;Sirtuins;Stem cells;Stress;System;Testing;Time;Transgenic Mice;Tuberous sclerosis protein complex;Villus;base;beta-Hydroxybutyrate;cell type;clinically relevant;design;experimental study;in vivo;insight;intestinal homeostasis;ketogenesis;ketogentic;mTOR Signaling Pathway;mTOR inhibition;metabolomics;migration;mortality;mouse model;multidisciplinary;novel;novel therapeutic intervention;nuclear factors of activated T-cells;protein E;public health relevance;stable isotope

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The intestinal mucosa is in a constant state of growth and renewal; the molecular pathways contributing to this critical function are poorly understood. Our recent findings have identified novel roles for components of the mTOR/HMGCS2 and sirtuin signaling pathways in intestinal homeostasis. Delineating the cellular factors and signaling pathways regulating these processes is crucial to our understanding of not only normal gut development and maturation but also the effects of surgical resection and stress on intestinal adaptation and survival and the aberrant gut growth that can occur with deregulation of these normal processes.


application_id: 9301333
project_number: 5R01AR060701-08
project_title: Novel Roles for Satellite Cells in Adult Skeletal Muscle Adaptation
administering_ic: NIAMS
award_notice_date: 2017-07-07
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AR
serial_number: 060701
program_official: BOYCE, AMANDA T
project_start_date: 2010-09-17
project_end_date: 2020-06-30
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1873134
contact_pi: MCCARTHY, JOHN JOSEPH
other_pis: PETERSON, CHARLOTTE A.
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Under the current award we have acquired exciting new evidence that satellite cells are necessary for the proper remodeling of the extracellular matrix during hypertrophy. We reported that in muscle depleted of satellite cells there was a significant increase in fibrosis that was associated with a blunted long-term hypertrophic response. Our preliminary data show that activated satellite cells/myogenic progenitor cells (MPCs) are capable of repressing the synthesis of extracellular matrix components by fibroblasts through exosomal delivery of microRNAs. We hypothesize that the loss of satellite cells removes this "brake" leading to the over-production of collagen and fibrosis ultimately limiting long-term hypertrophic growth. We further hypothesize that fibrosis as a result of loss ofsatellite cells preferentially limits growth in fast muscle fibers whereas growth of slow fibers i limited by myonuclear domain size. Thus fast fibers display a relatively flexible myonuclear domain whereas slow fibers may have a more stringent requirement for satellite cells for growth. The objectives of this proposal are to use genetic mouse models and in vitro cell culture to investigate these novel roles for satellite cells in skeletal muscle adaptation by pursuing the following aims. Aim 1 will determine the mechanisms underlying satellite cell regulation of extracellular matrix remodeling during skeletal muscle hypertrophy. Aim 2 will determine if fibrosis attenuates long-term hypertrophy in satellite cell-depleted muscle and the influence of fiber type composition. Aim 3 will determine if there is a fiber type-specific requirement for satellite cell fusion during skeletal muscle hypertrophy. Our published work and new preliminary data clearly show that our understanding of satellite cell function in adult skeletal muscle adaptation remains incomplete. The studies described in this proposal address this fundamental gap in our knowledge and are expected to provide critical information necessary to more effectively evaluate the use of satellite cells as a therapeutic agent to prevent or restore the los of skeletal muscle mass associated with dystrophies cancer age and rehabilitation following disuse.

project_terms:
Ablation;Acquired Immunodeficiency Syndrome;Address;Adult;Affect;Age;Aging;Area;Atrophic;Attenuated;Award;Biological Assay;Cell Culture Techniques;Cell Therapy;Cell fusion;Cell physiology;Chronic;Clinical;Coculture Techniques;Collagen;Data;Deterioration;Environment;Extracellular Matrix;Fiber;Fibroblasts;Fibronectins;Fibrosis;Foundations;Gene Expression;Gene Targeting;Genes;Genetic;Grant;Growth;HIV;Heart failure;Hypertrophy;Immobilization;In Vitro;Individual;Knockout Mice;Knowledge;Limb structure;Maintenance;Malignant Neoplasms;Mediating;MicroRNAs;Molecular;Molecular Profiling;Morbidity - disease rate;Mouse Strains;Mus;Muscle;Muscle Fibers;Muscle function;Operative Surgical Procedures;Phenotype;Plantaris muscle;Process;Production;Publishing;Quality of life;Regulation;Rehabilitation therapy;Reporter;Reporting;Rheumatoid Arthritis;Role;Sepsis;Series;Skeletal Muscle;Skeletal Muscle Satellite Cells;Soleus Muscle;Stem cells;Systemic disease;Tamoxifen;Testing;Therapeutic Agents;Therapeutic Uses;Time;Wasps;Weight;Work;base;cell growth;exosome;experimental study;extracellular;flexibility;in vivo;loss of function;mortality;mouse model;muscle form;muscle hypertrophy;novel;patient population;physical inactivity;prevent;public health relevance;response;sarcopenia;satellite cell;skeletal muscle plasticity;skeletal muscle wasting;stem

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  A decrease in 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. The purpose of this grant is to better understand the role of skeletal muscle stems (satellite cells) in muscle growth thereby providing a foundation for their therapeutic use to prevent or restore losses in skeletal muscle mass.


application_id: 9300987
project_number: 5P20GM103492-10
project_title: Project 5 - Metabolomic Analysis of Atherothrombosis
administering_ic: NIGMS
award_notice_date: 2017-07-12
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5010
contact_pi_person_id: 9847182
contact_pi: DEFILIPPIS, ANDREW
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
Cardiovascular disease (CVD) is the leading cause of death in individuals with diabetes with rates of acute coronary syndrome (ACS) and total mortality several fold higher in younger adults with versus without type 2 diabetes (T2D). Nevertheless the mechanisms that impart greater CVD risk in T2D are not well understood and no diabetes-specific CVD treatment regimens have been developed. ACS occurs when intracoronary thrombus obstructs coronary flow to produce myocardial ischemia and is responsible for the majority of irreversible myocardial damage in T2D. Although great advances have been made in diagnosing ACS all of the current ACS biomarkers measure the result myocardial necrosis and not the cause and therapeufic target -atherothrombosis. The ability to identify atherothrombotic-MI at the start of the event prior to irreversible myocardial necrosis and quickly disfinguish atherothrombotic from non-atherothrombofic ACS would materially increase the safety and effectiveness of ACS treatment in T2D patients. The long-term goal of this project is to develop a biomarker which differentiates atherothrombotic from non-atherothrombotic Ml in patients with T2D. Such an approach will not only improve diagnostic accuracy but could also potentially identify events at the start of coronary thrombosis prior to "inevitable" myocardial necrosis allowing for more prompt and targeted interventions. Hence using both targeted and unbiased metabolomic approaches we plan to identify specific biomarkers of atherothrombosis. Our central hypothesis is atherothrombotic events are associated with increased production of metabolites derived from oxidized lipids in the culprit lesion or generated by the atherothrombotic event itself and that measurement of these metabolites will allow for eariy and accurate diagnosis of atherothrombotic Ml is T2D patients.

project_terms:
Biological Markers;Cardiovascular Diseases;Cause of Death;Clinical Management;Coronary;Coronary Thrombosis;Development;Diabetes Mellitus;Diagnosis;Diagnostic;Diagnostic tests;Effectiveness;Event;Goals;Individual;Intervention;Lead;Lesion;Measurement;Measures;Myocardial;Myocardial Ischemia;Necrosis;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Patients;Production;Research;Safety;Thrombus;Treatment Protocols;accurate diagnosis;acute coronary syndrome;atherothrombosis;cardiovascular disorder risk;cohort;diagnostic accuracy;improved;metabolomics;mortality;myocardial damage;oxidized lipid;specific biomarkers;young adult

public_health_relevance:
Successful complefion of this project will result in the development of a well-characterized cohort of T2D and non-T2D pafients with and without atherothrombofic Ml. The findings ofthis study could lead to the identificafion of unique metabolite(s) associated with atherothrombosis leading to the development of diagnostic test for overcoming the major diagnostic and treatment shortcomings associated with clinical management of T2D patients with ACS


application_id: 9300986
project_number: 5P20GM103492-10
project_title: Project 4 - Cardiac Stem Cell Dysfunction in Diabetes
administering_ic: NIGMS
award_notice_date: 2017-07-12
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5009
contact_pi_person_id: 11675369
contact_pi: HONG, KYUNG UK
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
Type II diabetes (T2D) is a growing pandemic and one ofthe most serious health threats of our time. In addition to the well-characterized central endocrine defects some T2D patients present with distinct manifestation of cardiomyopathy termed diabetic cardiomyopathy. Diabetic cardiomyopathy occurs in the presence of neither clinically identifiable coronary artery disease nor hypertension suggesting that independent of its vascular effects T2D has direct impact on the myocardium. Although its etiology is complex hyperglycemia and dyslipidemla leading to increased oxidative stress may play a central role in the pathogenesis of diabetic cardiomyopathy. Recent studies have proposed that stem cell dysfunction may be responsible for complications related to T2D. The mammalian heart contains a cardiac stem cell (CSC) population with the capacity to maintain and regenerate myocardium. However little is known about CSCs function in the diabetic heart or their involvement in pathogenesis of diabetic cardiomyopathy. Our preliminary data indicate that the growth and differentiation characteristics of CSCs are impaired in diabetes. We hypothesize that T2D alters CSC growth and differentiation and these changes in stem cell function contribute to structural abnormalities and contractile dysfunction in the diabetic heart. To test this hypothesis we will: 1) Identify central defects in CSC biology in the diabetic heart in vivo; 2) Elucidate the cellular defects provoked by diabetes and nutrient excess in CSCs in vitro; and 3) Rescue the CSCs' functional defects in the diabetic heart in vivo. The studies proposed here will 1) Establish correlation between CSC dysfunction and cardiac abnormalities in the diabetic heart; 2) Explore mechanisms by which diabetes and nutrient excess affect function of CSCs; and 3) Decipher whether or not CSC dysfunction significantly contributes to the pathogenesis of diabetic cardiomyopathy using an innovative transgenic mouse model. Results of this study will lead to a better understanding of how diabetes affects CSC competence and function and how these abnormalities contribute to diabetic cardiomyopathy. Successful completion of these studies could illuminate new avenues for preventing or treating T2D.

project_terms:
Adult;Affect;Antigens;Apoptotic;Attenuated;Blood Vessels;Cardiac;Cardiac Myocytes;Cardiomyopathies;Cardiovascular Diseases;Cell Count;Cell Differentiation process;Cell physiology;Cells;Characteristics;Clinical;Competence;Complex;Coronary Arteriosclerosis;Data;Defect;Development;Diabetes Mellitus;Diabetic mouse;Differentiation and Growth;Endocrine;Enterobacteria phage P1 Cre recombinase;Etiology;Fatty Acids;Functional disorder;Gene Expression;Genes;Glucose;Growth;Health;Heart;Heart Abnormalities;Heart failure;Hyperglycemia;Hypertension;Impairment;In Situ;In Vitro;Individual;Lead;Left;Left Ventricular Dysfunction;Measurement;Measures;Mediating;Mus;Myocardial;Myocardial dysfunction;Myocardium;Natural regeneration;Non-Insulin-Dependent Diabetes Mellitus;Nutrient;Obesity;Oxidative Stress;Pathogenesis;Patients;Play;Proto-Oncogene Protein c-kit;Research;Risk;Role;Stem cells;Structural defect;Structure;Supporting Cell;System;Techniques;Testing;Time;Transgenic Mice;Vascular Diseases;Ventricular;atherogenesis;attenuation;cardiac repair;cardiogenesis;cardiovascular disorder risk;cardiovascular risk factor;cell growth;diabetic;diabetic cardiomyopathy;epidemiology study;genetic element;heart preservation;hemodynamics;innovation;insight;insulin sensitivity;interest;mouse model;non-diabetic;novel;novel therapeutic intervention;pandemic disease;prevent;progenitor;repaired;senescence;stem cell biology;stem cell population

public_health_relevance:
Type II diabetes is a growing pandemic. Independent of its vascular effects diabetes directly affects the heart. In this study we will investigate the influence of diabetes on cardiac stem cells. Successful completion of these studies could lead to development of novel therapeutic approaches targeting cardiac stem cells for preventing or treating cardiac dysfunction in patients with diabetes.


application_id: 9300985
project_number: 5P20GM103492-10
project_title: Project 3 - Regulation of Metabolism by Nitric Oxide
administering_ic: NIGMS
award_notice_date: 2017-07-12
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5008
contact_pi_person_id: 9543696
contact_pi: HILL, BRADFORD GUY
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
Obesity and type 2 diabetes (T2D) are epidemics in the U.S. and abroad. A better understanding ofthe mechanisms that promote obesity and induce T2D is urgently needed to stem the tide of these epidemics and to control their cardiovascular complications. We suggest that endothelial dysfunction induced by nutrient excess is the primary cause that leads to metabolic changes resulting in an increase in adiposity and whole-body insulin resistance. Our studies show that overexpression of eNOS in mice prevents diet-induced obesity. These changes are accompanied by systemic and adipose tissue-specific changes in metabolism. Our metabolomic analyses indicate that eNOS over expression increases the abundance of circulating bile acids which have been shown to be potent effectors of metabolism and regulators of adipose tissue phenotype. Nevertheless we do not know how NO regulates bile acid production or which metabolic pathways triggered by bile acids are responsible for the lean phenotype of eNOS-TG mice. Therefore we will test the hypothesis that NO exerts an anti-obesogenic effect by regulating bile acid metabolism which promotes the development of adipocytes into a novel "lean" phenotype characterized by high mitochondrial content and fat burning capacity. To test this hypothesis we will: (1) Examine the effects of NO on diet induced obesity; (2) Determine how NO regulates metabolism; and (3) Elucidate the mechanisms regulating adipocyte phenotype. The experimental approaches in these aims will test whether NO directly regulates obesity and whether the anti-obesity effects of NO are mediated through the ability of eNOS to increase bile acid production and to regulate adipose tissue phenotype. The results of these studies will develop a strong platform for constructing a competitive ROI application and will lead to a new understanding of the role of NO in regulating the metabolic changes that contribute to diabetes and obesity. These studies could lay the groundwork for the development of novel therapeutic interventions to prevent manage or reverse obesity and insulin resistance.

project_terms:
Adipocytes;Adipose tissue;Adult;Affect;Bile Acid Biosynthesis Pathway;Bile Acids;Biogenesis;Body fat;Branched-Chain Amino Acids;Cardiovascular system;Cell Differentiation process;Centers for Disease Control and Prevention (U.S.);Cyclic GMP;Development;Diabetes Mellitus;Diet;Endothelium;Epidemic;Europe;High Fat Diet;Human;In Vitro;Individual;Insulin;Insulin Resistance;Link;Lipids;Measures;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Mus;NOS3 gene;Nitric Oxide;Nitric Oxide Donors;Nitric Oxide Synthase;Non-Insulin-Dependent Diabetes Mellitus;Nutrient;Obesity;Overweight;Pharmacology;Phenotype;Population;Predisposition;Production;Regulation;Reporting;Research;Resistance;Risk;Risk Factors;Role;Secondary to;Signal Transduction;Stem cells;Testing;Thinness;Tissues;Transplantation;Weight Gain;absorption;adipocyte differentiation;cofactor;diabetic;endothelial dysfunction;enzyme activity;fat burning;in vivo;metabolomics;novel;novel therapeutic intervention;obesogenic;overexpression;prevent;stem

public_health_relevance:
Obesity and diabetes are emerging epidemics in the US and Europe. In this project we will examine the mechanisms by which nitric oxide regulates metabolism obesity and susceptibility to diet-induced diabetes. These studies could lay the groundwork for the development of novel therapeutic interventions to prevent manage or reverse obesity and diabetes.


application_id: 9300984
project_number: 5P20GM103492-10
project_title: Project 2 - Effects of Particulate Matter on Insulin Resistance and Endothelial
administering_ic: NIGMS
award_notice_date: 2017-07-12
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5007
contact_pi_person_id: 11375489
contact_pi: HABERZETTL, PETRA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
Inhalation of fine particulate matter air (PM) pollution (<2.5pm) is associated with an increased risk for cardiovascular disease (CVD) and Type 2 diabetes (T2D). Short-term exposure of mice to concentrated ambient air particulate matter (CAP) decreases vascular insulin sensivity and circulating endothelial progenitor cells (EPCs). EPCs are thought to be involved in endothelial maintenance thus we propose that CAP-induced suppression of circulating and tissue-resident EPCs leads to endothelial injury and insulin resistance which provokes systemic insulin resistance ultimatively increasing the risk for T2D and CVD. CAP exposure affects vascular health by triggering low-grade inflammation via Inflammasome activation. To elucidate both mechanism(s) and causal relationship of endothelial injury EPC depletion and vascular insulin resistance we will examine in the aim 1:1) whether CAP-exposure alone is sufficient to induce systemic insulin resistance or whether it only exacerbates the effects of obesity and 2) the physico-chemical composition and body deposition of CAP to establish a more precise dosimetry and to find potential particle properties responsible for the biological effects. In our second aim we will investigate whether alterations in circulating/tissue resident EPCs and endothelial health are causative for the development of vascular insulin resistance. Finally to find the mechanisms of CAP-induced vascular insulin resistance we will examine in aim 3 a possible role ofthe activation ofthe inflammasome. We will utilize a mouse model of diet-induced obesity (DIO) to investigate effects of HFD-feeding and use mice deficient in NLRP3 and Casp-1 to test the contribution of Inflammasome activation in the development of vascular insulin resistance. Completion of these studies will provide novel insights into the mechanism(s) by which inhaled ambient particles increase the risk for T2D and CVD and as such will provide unique and detailed information of particle dose composition and deposition and their correlation with biological responses which could lead to the development of novel biomarkers and strategies for the regulation of environmental pollutants and the prevention and management of insulin resistance obesity T2D and CVD.

project_terms:
Aerosols;Affect;Air;Air Pollution;Arrhythmia;Biological;Blood Vessels;Breathing;Cardiovascular Diseases;Centers of Research Excellence;Cessation of life;Chronic;Data;Deposition;Developing Countries;Development;Diabetes Mellitus;Diet;Dose;Environmental Pollutants;Environmental Risk Factor;Epidemic;Epidemiology;Exposure to;Fatty acid glycerol esters;Funding;Future;Health;High Fat Diet;Human;IL18 gene;Incidence;Inflammasome;Inflammation;Inflammatory;Injury;Insulin;Insulin Resistance;Interruption;Intervention;Knockout Mice;Lead;Link;Longevity;Maintenance;Measures;Mediating;Metabolic Diseases;Metabolic syndrome;Modeling;Molecular;Mus;Myocardial Infarction;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Organ;Particulate Matter;Pathway interactions;Patients;Policies;Prevalence;Prevention;Process;Property;Prospective Studies;Regulation;Research;Risk;Risk Factors;Role;Stem cells;System;Testing;Tissues;Vascular Diseases;Vascular Endothelium;air filter;ambient air pollution;ambient particle;cardiovascular disorder risk;chemical property;diabetes risk;dosimetry;endothelial dysfunction;epidemiology study;experimental study;feeding;fine particles;high efficiency particulate air filter;improved;indexing;insight;insulin sensitivity;laboratory experiment;mortality;mouse model;novel;novel marker;novel strategies;particle;physical inactivity;physical property;prevent;repaired;response;stroke

public_health_relevance:
Environmental factors seem to enhance the rapid evolving epidemic of diabetes and obesity. In this project we will investigate a potential link between diabetes and air pollution by determine the role of inhaled PM on the development of vascular and systemic insulin resistance. This project will provide unparalleled findings that PM may cause diabetes and could be the basis for future regulations pre- and intervention strategies.


application_id: 9300983
project_number: 5P20GM103492-10
project_title: Project 1 - Carnosine Metabolism in Diet-Induced Obesity
administering_ic: NIGMS
award_notice_date: 2017-07-12
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5006
contact_pi_person_id: 11110260
contact_pi: BABA, SHAHID P
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
Obesity is a highly prevalent condition and is associated with an increased risk for the development of type 2 diabetes (T2D) and cardiovascular disease. As such an understanding of how obesity develops and the identification of novel therapeutics aimed at controling obesity and its metabolic consequences are of utmost importance. Recent studies demonstrate that the dipeptide carnosine is depleted in the skeletal muscle of patients with T2D and that carnosine feeding decreases diet-induced obesity. Carnosine (ala-his) is a dipeptide present in skeletal muscle brain and heart. It buffers protons during glycolysis and it is a strong antioxidant. Carnosine is synthesized by the enzyme carnosine synthetase and is hydrolysed back to alanine and histidine by carnosinase.The homeostatic balance of carnosine is also maintained by the peptide transporter Pept2 . Although obesity and T2D in humans is associated with a decrease in carnosine levels in the skeletal muscle the mechanisms underiying carnosine depletion and its protective effects against obesity are not entirely known. Our intial studies show that high fat feeding in mice decreases carnosine levels and that restoration of these levels by carnosine supplementation restricts weight gain increases energy expenditure insulin senstivity and glucose tolerance. Based on these observations we propose that chronic carnosine deficiency decreases energy expenditure and antioxidant capacity ofthe muscle resulting in insulin resistance and oxidative stress. To test this hypothesis we will: (1) elucidate the mechanism of carnosine depletion in obesity; 2) test whether carnosine supplementation prevents or reverses obesity and its metabolic consequences; and (3) investigate the mechanism by which carnosine regulates adiposity and insulin sensitivity. To evaluate the clinical relevance of our findings we will also measure carnosine and carnosinase activity in obese and non-obese children. The findings of this project could lead to the development of a novel and validated anti-obesity strategy that could also prevent or reverse diet-induced insulin resistance. Successful completion ofthis project would lay the foundaton and form the rationale for testing the anti-obesogenic and anti-diabetic effects of carnosine in humans.

project_terms:
Alanine;Antioxidants;Back;Brain;Buffers;Cardiovascular Diseases;Carnosine;Chronic;Development;Diabetes Mellitus;Diet;Dipeptides;Energy Metabolism;Enzymes;Equilibrium;Fatty acid glycerol esters;Glycolysis;Heart;Histidine;Human;Insulin;Insulin Resistance;Lead;Ligase;Measures;Metabolic;Metabolism;Mus;Muscle;Non obese;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oxidative Stress;Patients;Peptides;Protons;Research;Risk;Role;Skeletal Muscle;Supplementation;Testing;Weight Gain;base;clinically relevant;diabetic;feeding;glucose tolerance;insulin sensitivity;mouse model;novel;novel therapeutics;obesogenic;prevent;protective effect;restoration

public_health_relevance:
Few options are available to prevent or reverse obesity and its metabolic consequences. In this project we will test the role of the naturally occuring dipeptide carnosine in regulating adiposity and insulin resistance in a mouse model of diet-induced obesity. Results of these studies could lead to the identification of a safe and effective anti-obesity strategy that could be tested in humans.


