# projects

application_id: 9542454
project_number: 1R13EB026314-01
project_title: IEEE International Symposium on Biomedical Imaging (ISBI) 2018
administering_ic: NIBIB
award_notice_date: 2018-04-02
opportunity_number: PA-16-294
application_type: 1
activity_code: R13
ic: EB
serial_number: 026314
program_official: WEITZ, ANDREW CHARLES
project_start_date: 2018-04-02
project_end_date: 2019-03-31
study_section: Special Emphasis Panel[ZEB1 OSR-E (J2)]
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:
IEEE International Symposium on Biomedical Imaging (ISBI) 2018The project provides NIH Student travel support to graduate students and Ph.D. candidates incomputational bioimaging or closely related areas to attend and participate in the ISBI 2018 conferenceorganized jointly by the IEEE Signal Processing Society (SPS) and Engineering in Medicine and BiologySociety (EMBS) in Washington D.C. April 4-7 2018. ISBI participants  on the order of 600-700 fromacross the world are involved in biomedical imaging research and development - in academic institutionsgovernment laboratories or R&D departments of private companiesThe Objective of ISBI is to bring together both established and young researchers with interests in themathematical and computational aspects of biomedical imaging with a focus on addressing problems ofsignificance to the development and application of imaging systems across the spatial scales frommicroscopy to whole-body imaging. The forum aims to have an educational component on topics ofsignificant interest to the community in the form of tutorials and plenary talks as well as oral and posterpresentations from full paper peer-reviewed submissions competitively selected. In addition a set ofresearch challenges are also organized and announced which have become very popular over the years.The participating groups in these challenges work on common data sets which can be downloaded fromthe challenge website and results are reported in special challenge sessions organized prior to start of theconference. The research methods typically presented at the meeting include physical biological andstatistical modeling image formation and reconstruction computational image analysis statistical imageanalysis visualization and image quality assessment. ISBI like other IEEE SPS and EMBS conferencesrequires submission and review of 4-page papers which are peer-reviewed much like journal articles peerreviews handled by a 50 member editorial board (area editors) who are leading experts in the communitywho in turn assign papers to reviewers through an electronic paper handling system. The area editorsrecommend acceptance/rejection of papers with the final decision made by program chairs.We anticipate that the primary impact of this R13 grant program will be increased student and postdoctoralfellow attendance to both the main conference and the tutorials. By offering to cover a portion of attendeestravel expenses we allow students to propose to her/his mentors or departmental administration that thecost-to-benefit ratio for attending ISBI will be extremely favorable. The benefits can largely besummarized as exposure and education. ISBI provides the opportunity for students to be exposed tomany more areas of computational imaging research than those to which one is generally exposed to inher/his home institution and concurrently it provides the opportunity for the students to hear and interactwith the world leaders in the field through tutorials plenary oral and poster presentations lunches withleaders and individual discussions. Through submission and presentation of a research paper a younginvestigator will gain the experience of presenting her/his research to others for critical evaluation anddissemination. But it is also informal interactions during the breaks where detailed discussions take placeand life-long friendships are formed.

project_terms:
Address;Anatomy;Area;Autoradiography;Biological;Biological Models;Biology;Brain Mapping;Cellular biology;Clinical;Communities;Computational algorithm;Computer Simulation;Data Set;Development;Discipline of Nuclear Medicine;District of Columbia;Doctor of Philosophy;Drug Delivery Systems;Education;Electroencephalography;Electrons;Engineering;Ensure;Evaluation;Exposure to;Faculty;Fertilization;Friendships;Functional Magnetic Resonance Imaging;Funding;Gene Chips;Gene Expression;Goals;Government;Grant;Growth;Hearing;Home environment;Image;Image Analysis;Imagery;In Situ Hybridization;Individual;Institution;International;Laboratories;Life;Location;Magnetic Resonance Imaging;Mathematics;Medical Imaging;Medicine;Mentors;Microscopy;Modality;Modeling;Molecular;National Institute of Biomedical Imaging and Bioengineering;Neuroanatomy;Oral;Organ;Paper;Participant;Peer Review;Postdoctoral Fellow;Privatization;Public Health;Reporting;Research;Research Methodology;Research Personnel;Schedule;Series;Site;Small Animal Imaging Systems;Societies;Statistical Models;Students;System;Time;Travel;Ultrasonography;United States National Institutes of Health;Washington;Work;X-Ray Computed Tomography;X-Ray Tomography;age effect;base;bioimaging;biological systems;cancer imaging;career;collaborative environment;cost;drug discovery;editorial;experience;fluorescence imaging;graduate student;heart imaging;imaging modality;imaging system;interest;journal article;meetings;member;microscopic imaging;molecular imaging;multi-photon;nano;optical imaging;physical model;posters;programs;reconstruction;research and development;signal processing;spectroscopic imaging;student participation;suburb;success;symposium;trend;web site;whole body imaging

public_health_relevance:
Public Health StatementThe ISBI Conference is unique among biomedical imaging meetings in its aim tofacilitate cross-fertilization across different imaging modalities and scales withapplications ranging from the nano molecular and cellular levels via microscopythrough macroscopic and whole-body clinical systems such as nuclear medicineUltrasound MRI CT and optical imaging.


application_id: 9542391
project_number: 5R01NR012967-05
administering_ic: NINR
award_notice_date: 2018-07-18
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NR
serial_number: 012967
program_official: HUSS, KAREN
project_start_date: 2014-09-26
project_end_date: 2020-07-31
study_section: Behavioral Medicine, Interventions and Outcomes Study Section[BMIO]
contact_pi_person_id: 8446344
contact_pi: CHUNG, MISOOK LEE
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-08-01
project_title:
Effects of Family Sodium Watchers Program on Outcomes in Heart Failure Patient-Family Caregiver Dyads

project_abstract:
DESCRIPTION (provided by applicant): Heart failure (HF) emerged as a significant public health threat in the 1990s and has now reached epidemic proportions. Despite advances in the medical treatment of HF patients with HF face frequent hospitalizations for acute exacerbations. Inadequate self-care strategies in particular non-adherence to a sodium restricted diet (SRD) are a main cause of these hospitalizations. Prior interventions to increase adherence have focused on increasing knowledge about restricting sodium in the diet have met with limited success. Unaddressed by these interventions are the major barriers of measuring and tracking daily sodium intake family members who continue to eat high sodium diets and a preference for salty foods-particularly in the elderly who have a decreased sense of taste. It is possible to retrain the taste buds to enjoy low salt foods by gradually reducing the amount of sodium in foods over the course of 16 weeks. This retraining works best with direct involvement and support from family members. The Family Sodium Watcher Program (Family Swap) proposed in this study incorporates the use of a unique electronic salt monitoring device that easily measures salt content in food-the major source of sodium. The intervention is designed to improve adherence to a SRDby both patients and family caregivers through education and strategies for gradual taste adaptation to low salt foods. The purpose of this 2-group randomized controlled repeated measures (baseline 4-month and 12-month) study is to examine effects of Family Swap on adherence (24-hour urine sodium excretion) to a SRD; knowledge attitudes and barriers about SRD; perceived control and perceived social support (in patient- caregiver dyads); caregiving burden (in caregivers only); and symptom distress and hospitalizations (in patients only). We will enroll a total of 220 patient-caregiver dyads. Dyads will be stratified as adherent and non-adherent using baseline patients' 24-hour urine sodium excretion (cut point = 3000 mg) and then randomly assigned to Family Swap intervention group or a usual care control group. The Family Swap intervention (6 weekly 45-minute sessions followed by 5 bi-weekly booster sessions) will be delivered remotely using a video- conferencing program on an iPad tablet. Patient-caregiver dyads will complete questionnaires (knowledge attitudes and barriers about diet; symptoms distress; perceived control; perceived social support; caregiving burden; and quality of life) and collect a 24-hour urine for sodium excretion at each assessment. Data will be analyzed using repeated measures ANOVA Cox regression and an innovative actor-partner interdependence model dyadic analysis for longitudinal data. This dyadic intervention study will provide rich data on the complex interpersonal relationships within patient-caregiver dyads that affect adherence and health outcomes in patients with HF and family caregivers. Given the recommendation that all individuals should consume a sodium restricted diet the intervention has the potential for expanded application beyond patients who need to follow a sodium restricted diet for cardiovascular reasons to everyone consuming a diet high in sodium.

project_terms:
Acute;Address;Adherence;Adult;Affect;Age;Analysis of Variance;Attitude;Behavior;Cardiovascular system;Caregivers;Chronic Care;Chronic Disease;Chronically Ill;Complex;Compliance behavior;Control Groups;Data;Desire for food;Diet;Dietary Intervention;Dietary Sodium;Distress;Eating;Education;Educational Intervention;Educational process of instructing;Elderly;Enrollment;Epidemic;Excretory function;Face;Family;Family Caregiver;Family member;Feeling;Food;Food Labeling;Food Preferences;Goals;Health;Health Care Costs;Health Status;Heart failure;Hospitalization;Hour;Individual;Intake;Interpersonal Relations;Intervention;Intervention Studies;Knowledge;Lead;Measures;Medical;Modeling;Monitor;Outcome;Patient Care;Patient-Focused Outcomes;Patients;Perception;Physiological;Play;Prevalence;Public Health;Quality of life;Questionnaires;Randomized;Randomized Controlled Trials;Recommendation;Research;Research Personnel;Resources;Role;Self Care;Self Management;Sensory;Social support;Sodium;Sodium Chloride;Sodium-Restricted Diet;Source;Symptoms;Tablets;Taste Buds;Taste Perception;Testing;Time;Urine;Videoconferencing;Wit;Work;base;care giving burden;caregiving;design;family support;follow-up;group intervention;hedonic;high salt diet;improved;improved outcome;innovation;longitudinal analysis;member;monitoring device;outcome forecast;preference;prevent;programs;public health relevance;reduce symptoms;skills;success;treatment as usual;urinary;usual care arm

public_health_relevance:
PUBLIC HEALTH RELEVANCE: With the rising costs of health care family members are playing a greater role in the care of chronically ill patients. This family-based intervention addresses the public health goal of improving the health status and quality of life of patients wit heart failure and their family caregivers through an innovative educational program focused on the self-care of sodium restricted diet.


application_id: 9539974
project_number: 5R01CA194030-04
project_title: An Integrative Approach to Identify Causal Epigenetic Markers for Breast Cancer
administering_ic: NCI
award_notice_date: 2018-06-15
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 194030
program_official: VERMA, MUKESH
project_start_date: 2017-07-05
project_end_date: 2019-06-30
study_section: Cancer Biomarkers Study Section[CBSS]
contact_pi_person_id: 9152491
contact_pi: HE, CHUNYAN
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 objective of this proposal is to identify potentially causal DNA methylation markers that driver breast cancer development. Aberrant DNA methylation plays an important role in breast cancer initiation and progression via inactivation oftumor suppressor genes and activation of oncogenes. Identifying causal epigenetic markers that drive breast cancer development remains a major challenge. Conventional approaches comparing DNA methylation profiles in tumor and adjacent non-tumorous tissue have shown that changes in DNA methylation contribute to deregulation of gene expression in breast cancer. However such approaches are unable to distinguish causal DNA methylation alterations which drive tumorigenesis from reactive ones that are influenced by the tumor. In addition important cancer-related methylation changes may have been missed when a suboptimal baseline control (adjacent non-tumorous tissue) was used in previous studies. We hypothesize that an individual's genetic susceptibility and environmental risk factors (e.g. diet lifestyle) contribut to alterations in causal DNA methylation for breast cancer development and that such causal changes have already taken place in normal breast tissue before tumor occurrence. To test this hypothesis normal breast tissue from healthy women is required to prospectively assess the effects of these risk factors on DNA methylation. We propose an integrative genomic and epidemiological approach that combines the regulation of DNA methylation in normal breast tissue and differential DNA methylation profiling in tumor and normal breast tissue. Specifically we will generate and integrate multiple layers of data on environmental exposures and genome-wide genomic variations (germline and tissue-specific DNA methylation variations). We will examine the impact of genetic and environmental regulation on DNA methylation in normal breast tissue and determine the association of these epigenetic changes with breast cancer development and occurrence. Normal breast tissue from healthy women will be used as the most desirable baseline control in comparison with tumor as well as the most desirable target tissue to identify changes in potentially causal DNA methylation markers before tumor occurrence. We are uniquely positioned to conduct the proposed research as we have ready access to unique normal breast tissue through the Susan G. Komen Tissue Bank at Indiana University Simon Cancer Center. This resource represents the only biorepository in the world for large numbers of epidemiologically annotated optimally prepared normal breast tissue specimens (>3200) from healthy women in a wide range of ages and environmental exposures. This project will contribute significantly to our understanding of the key early biological processes during breast cancer development in particular the complex mechanisms among genetic variation environmental and lifestyle risk factors and epigenetic changes. It will lead t breakthroughs for breast cancer management in developing novel more effective prevention and treatment strategies that specifically target causal DNA methylation markers.

project_terms:
Aberrant DNA Methylation;Age;Age at Menarche;Biological Process;Body mass index;Breast Cancer Risk Factor;Cancer Biology;Cancer Center;Cancer Etiology;Complex;DNA Methylation;DNA Methylation Regulation;Data;Development;Diet;Environmental Exposure;Environmental Risk Factor;Epidemiology;Epigenetic Process;Epithelial Cells;Gene Expression;Gene Expression Regulation;Genetic;Genetic Predisposition to Disease;Genetic Risk;Genetic Variation;Genomics;Hormone use;Indiana;Individual;Lead;Life Style;Malignant Neoplasms;Mammary Gland Parenchyma;Mammary Neoplasms;Menopause;Methylation;Modification;Molecular Profiling;Normal tissue morphology;Oncogene Activation;Oncogene Deregulation;Play;Positioning Attribute;Prevention strategy;Quantitative Trait Loci;Regulation;Research;Resources;Risk Factors;Role;Site;Specimen;Testing;Time;Tissue Banks;Tissues;Tumor Tissue;Tumor-Suppressor Gene Inactivation;Universities;Variant;Woman;anticancer research;biobank;cancer initiation;cell type;epigenetic marker;epigenome-wide association studies;genetic variant;genome wide methylation;genome-wide;genomic variation;malignant breast neoplasm;methylation biomarker;non-genetic;novel;novel strategies;parity;prospective;public health relevance;treatment strategy;tumor;tumor progression;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Current approaches in breast cancer research are unable to distinguish causal DNA methylation alterations which drive tumorigenesis from reactive ones that are influenced by the tumor. This project is aimed at identifying potentially causal DNA methylation markers for breast cancer development through an integrative genomic and epidemiological approach that combines the regulation of DNA methylation in normal breast tissue and differential DNA methylation profiling in normal and tumor breast tissue. This information is critical not only for understanding breast cancer biology but also for developing novel more effective prevention and treatment strategies that target causal DNA methylation.


application_id: 9538825
project_number: 5U01HL133359-02
project_title: Multiscale modeling of inherited cardiomyopathies and therapeutic interventions
administering_ic: NHLBI
award_notice_date: 2018-07-13
opportunity_number: PAR-15-085
application_type: 5
activity_code: U01
ic: HL
serial_number: 133359
program_official: ADHIKARI, BISHOW B
project_start_date: 2017-08-03
project_end_date: 2022-07-31
study_section: ZEB1-OSR-C(M1)S
contact_pi_person_id: 8356696
contact_pi: CAMPBELL, KENNETH S
other_pis: WENK, JONATHAN F
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Affect;Algorithms;American;Biological Assay;Biology;Cardiac;Cardiac Death;Cardiomyopathies;Cardiovascular Diseases;Cells;Chronic;Computer Simulation;Computer software;Congenital cardiomyopathy;Coupled;DNA Sequence Alteration;Data;Data Analyses;Depressed mood;Development;Drug usage;Elements;Engineering;Fiber;Future;Genetic;Geometry;Goals;Growth;Heart;Heart Abnormalities;Heart Diseases;Heart Hypertrophy;Heart failure;Histology;Hypertrophy;Inherited;Intervention;Kinetics;Laws;Magnetic Resonance Imaging;Mathematics;Measurement;Measures;Modeling;Molecular;Motor;Mutation;Myocardial;Myosin ATPase;Myosin Regulatory Light Chains;Organ;Patients;Pattern;Performance;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacotherapy;Proteins;Records;Research;Research Personnel;Sarcomeres;Scientist;Structure;Techniques;Testing;Therapeutic Intervention;Time;Tissues;Transgenic Animals;Transgenic Mice;Treatment Failure;Validation;Ventricular;Ventricular Remodeling;Wild Type Mouse;Work;cell motility;drug testing;experience;experimental study;genetic regulatory protein;heart function;improved;innovation;interest;mathematical model;model development;molecular scale;multi-scale modeling;novel therapeutics;personalized medicine;predictive modeling;response;simulation;skills;software development;treatment optimization;treatment planning


application_id: 9538776
project_number: 5P30GM110788-05
project_title: OHPP Oral Health Pilot Program
administering_ic: NIGMS
award_notice_date: 2018-07-20
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110788
project_end_date: 2021-07-31
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: 2018-08-01
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;Research;Research Personnel;Resources;Science;Site;Systemic disease;Systems Development;Time;United States National Institutes of Health;base;college;design;improved;programs;recruit;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: 9538773
project_number: 5P30GM110788-05
project_title: CTDL Laboratory Core
administering_ic: NIGMS
award_notice_date: 2018-07-20
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110788
project_end_date: 2021-07-31
study_section: ZGM1-TWD-C
subproject_number: 8149
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: 2018-08-01
project_abstract:
The CTDL was designed to provide a centralized service to support investigators in the College of Dentistry who required biologic measures fortheir clinical translational and basic science projects. The core support services in the Phase III center operations include: (1) an array of measures of host responses in a range of biologic fluids (eg. serum saliva cervico-vaginal fluids cell culture supernatants tissue homogenates etc.); (2) microbiological/virological assays for oral bacteria and bacteria from other mucosal sites and viruses related to oral diseases. This includes cultivation molecular analysis and preparation of batches of organisms for in vitro studies; (3) genetics/genomics analysis which include preparation of DNA and RNA from various samples analytic approaches for GWAS SNP miRNA and epigenetic variations related to specific project needs; and (4) mineralized tissue analysis including both histomorphometric microCT and cellular studies of bone biology.

project_terms:
Basic Science;Biological Assay;Biology;Cell Culture Techniques;Clinical Sciences;Communities;DNA;Dentistry;Genetic;Genomics;Immune response;In Vitro;Knowledge;Laboratories;Liquid substance;Measures;MicroRNAs;Microbiology;Minerals;Molecular Analysis;Mouth Diseases;Oral;Oral health;Organism;Outcome;Phase;Population;Preparation;RNA;Research Personnel;Saliva;Sampling;Serum;Services;Specimen;Systemic disease;Tissues;Translational Research;Virus;base;bone;cervicovaginal;college;design;epigenetic variation;genome wide association study;improved;microCT;mucosal site;operation;oral bacteria;virology

public_health_relevance:
While the CTDL is primarily designed to support UK investigators for a range of analytic services specimens evaluated in this core could also be derived from populations derived from community-based partners. In either case these outcomes will help create new knowledge of the biology of oral-systemic disease relationships to improve oral health in the population.


application_id: 9538772
project_number: 5P30GM110788-05
project_title: DDKCRC Clinical Core
administering_ic: NIGMS
award_notice_date: 2018-07-20
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110788
project_end_date: 2021-07-31
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: 2018-08-01
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;Reporting;Research Personnel;Research Project Grants;Services;Systemic disease;Time;Translational Research;clinical implementation;college;improved;operation;recruit;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: 9538771
project_number: 5P30GM110788-05
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2018-07-20
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110788
project_end_date: 2021-07-31
study_section: ZGM1-TWD-C
subproject_number: 8147
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-08-01
project_abstract:
The Administrative/Educational Core (AEC) ofthe Phase III COBRE is designed to provide oversight to the center organizational structure to support management of the cores and support for the solicitation and awarding of pilot grants. This core includes a center director and administrator to provide the interface to the other activities in the center. Additionally the AEC houses biostatistical/bioinformatics liaison support for linking investigators to thpse resources existing at UK and a training education and outreach activity that will cultivate participation of dental faculty and students in clinical and translational sciences research as well as working through the Dental Public Health outreach program and the UK Health Services Research Center to move the COBRE research accomplishments towards technology transfer and community adoption of new evidence in practice.

project_terms:
Administrator;Adoption;Award;Bioinformatics;Biometry;Centers of Research Excellence;Clinical Sciences;Communities;Dental;Dental Faculty;Dental Students;Education and Outreach;Grant;Health;Health Services Research;Kentucky;Knowledge;Link;Oral;Oral health;Phase;Play;Population;Public Health;Research;Research Personnel;Resources;Role;Systemic disease;Technology Transfer;Training and Education;Translational Research;Work;design;improved;organizational structure;outreach program

public_health_relevance:
The AEC plays multiple roles in overseeing the progress ofthe COBRE; however these can be stratified into internal and external effects. Internally it will oversee the use of key resources and investigators to develop new knowledge to improve oral health. Externally it will work with community partners in Kentucky to identify opportunities with this new knowledge will be put into action to change oral and systemic health metrics for the population.


application_id: 9538737
project_number: 5P30GM110788-05
project_title: Center for the Biologic Basis of Oral/Systemic Diseases (Phase III)
administering_ic: NIGMS
award_notice_date: 2018-07-20
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: 2021-07-31
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;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;recruit;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: 9537695
project_number: 5R01NS097722-02
project_title: Neurovascular astrocyte dysfunction in VCID
administering_ic: NINDS
award_notice_date: 2018-05-22
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 097722
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
arra_indicator: N
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 pathology;foot;human tissue;large-conductance calcium-activated potassium channels;mouse model;neuroinflammation;neurovascular;protein expression;vascular cognitive impairment and dementia


application_id: 9537687
project_number: 5U01NS090408-06
project_title: The Center for SUDEP Research (CSR) Informatics and Data Analytics Core (IDAC)
administering_ic: NINDS
award_notice_date: 2018-08-22
opportunity_number: RFA-NS-14-004
application_type: 5
activity_code: U01
ic: NS
serial_number: 090408
program_official: LEENDERS, MIRIAM
project_start_date: 2016-02-27
project_end_date: 2020-07-31
study_section: ZNS1-SRB-B(40)
contact_pi_person_id: 7938505
contact_pi: ZHANG, GUO-QIANG
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): Project Summary The goal of SUTRA (SUDEP Translational Research Alliance) Center Without Walls is to better understand the brainstem mechanisms responsible for SUDEP and elucidate the role of cortical influences thereon using a data-driven systems-biology-based approach. This understanding requires a strategy that shares research resources and infrastructure to make good and efficient use of a spectrum of prospectively collected data encompassing clinical electrophysiological biochemical genetic and neuropathological domains. A critical aspect of SUTRA is the process and infrastructure facilitating the sharing of clinical and research data across centers. In our NINDS-funded center- planning award Prevention and Risk Identification of SUDEP Mortality (PRISM; 1P20- NS076965) a team of world-class epileptologists computer scientists biomedical informaticians and data analytics experts has developed an informatics infrastructure for sharing research data using the Multi-Modality Epilepsy Data Capture and Integration System (MEDCIS). The main goal of this Informatics and Data Analytics U01 Core (IDAC) is to build on the paradigm-changing progress already achieved through PRISM's MEDICS infrastructure and expand and broaden the sharing and utilization of research resources among SUTRA partners. With access to biospecimen materials and alliances with stakeholder organizations including Dup15q the North American SUDEP Registry Courtagen GW Pharma and CURE SUTRA will continuously boost materials and data collection. IDAC will promote and facilitate SUDEP research by expanding an integrated clinical and translation data resource for epilepsy; providing coordinated services and support for SUTRA members; empowering investigator with web-based cohort search interface for data mining and hypothesis generation; data analytics and statistical support for in-depth analyses of multi-modal data collected in the shared and expanding SUTRA Data Repository.

project_terms:
Address;Algorithmic Analysis;Algorithms;American;Animals;Award;Big Data;Biochemical Genetics;Biological;Blood Pressure;Brain;Brain Stem;Clinical;Clinical Research;Cloud Computing;Collection;Computers;Consultations;Coupling;Custom;Data;Data Analytics;Data Collection;Data Set;Development;Electrocardiogram;Electroencephalography;Electrophysiology (science);Enrollment;Epilepsy;Event;Feedback;Formalin;Freezing;Funding;Galvanic Skin Response;Generations;Goals;Imagery;Informatics;Institution;Intervention;Modality;Motion;National Institute of Neurological Disorders and Stroke;Online Systems;Ontology;Oxygen;Patients;Performance;Phenotype;Prevention;Prevention Measures;Process;Registries;Research;Research Design;Research Infrastructure;Research Personnel;Resources;Respiration;Rest;Risk;Role;Scientist;Seizures;Services;Signal Transduction;Sleep;Statistical Data Interpretation;Structure;Surveys;System;Systems Biology;Systems Integration;Technology;Terminology;Translational Research;Visual;Work;base;clinical translation;cohort;computerized tools;crosslink;data management;data mining;data resource;data warehouse;demographics;design;empowered;evidence base;genetic resource;improved;informatics infrastructure;member;mortality;neuropathology;open source;phenotypic data;prospective;public health relevance;quality assurance;satisfaction;signal processing;sudden unexpected death in epilepsy;tool;user-friendly;webinar

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Project Narrative The main goal of this Informatics and Data Analytics Core a part of the SUDEP Translational Research Alliance is to expand and broaden the sharing and utilization of research resources across centers to accelerate the understanding of biological mechanisms responsible for SUDEP and to develop intervention and prevention measures to reduce SUDEP mortality.


application_id: 9537568
project_number: 5R01EY028188-02
project_title: Understanding signal processing in retinal bipolar cell pathways
administering_ic: NEI
award_notice_date: 2018-06-05
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: EY
serial_number: 028188
program_official: GREENWELL, THOMAS
project_start_date: 2017-09-01
project_end_date: 2022-05-31
study_section: Neurotransporters, Receptors, and Calcium Signaling Study Section[NTRC]
contact_pi_person_id: 11294714
contact_pi: BORGHUIS, BART GERARD
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Aging;Amacrine Cells;Area;Axon;Biosensor;Brain;Calcium;Cell physiology;Cells;Electrophysiology (science);Equilibrium;Feedback;Glutamate Receptor;Glutamates;Glycine;Goals;Image;Individual;Kainic Acid Receptors;Kinetics;Knowledge;Light;Light Adaptations;Lighting;Maps;Measures;Methods;Molecular;Natural regeneration;Neurons;Optic Nerve;Output;Pathway interactions;Photic Stimulation;Photoreceptors;Preparation;Process;Property;Retina;Retinal;Retinal Diseases;Retinal Ganglion Cells;Role;Route;Series;Shapes;Signal Pathway;Signal Transduction;Slice;Stimulus;Stratification;Structure;Synapses;Testing;Transgenic Mice;Vision;Visual;Visual system structure;Whole-Cell Recordings;base;cell type;developmental disease;experimental study;extrastriate visual cortex;fluorescence imaging;gamma-Aminobutyric Acid;ganglion cell;information processing;innovation;live cell imaging;loss of function mutation;luminance;mouse model;nervous system disorder;neural circuit;neuromechanism;parallel processing;postsynaptic;prevent;receptive field;receptor;response;retinal rods;signal processing;spatiotemporal;transmission process;two-photon;visual information;visual processing;voltage;voltage gated channel


application_id: 9537135
project_number: 3R01HL124015-02S1
project_title: Latexin function in the maintenance and regeneration of the hematopoietic system
administering_ic: NHLBI
award_notice_date: 2017-08-11
opportunity_number: PA-17-078
application_type: 3
activity_code: R01
ic: HL
serial_number: 124015
suffix: S1
program_official: BAI, C BRIAN
project_start_date: 2016-01-01
project_end_date: 2020-12-31
study_section: Molecular and Cellular Hematology Study Section[MCH]
contact_pi_person_id: 9839693
contact_pi: LIANG, YING
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY The long-term goal of this study is to develop new strategies to mitigate and protect radiation-inducedhematopoietic injury by delineating the molecular mechanisms responsible for enhancing hematopoietic stemcells (HSC) self-renewal and survival. Radiation therapy commonly results in not only acute hematopoieticsuppression but also long-term bone marrow (BM) injury. To date no effective treatment has been developedto prevent or treat these pathological consequences. Enhancing HSC survival and maintaining their genomicintegrity upon radiation are crucial for preservation of HSC self-renewal function and for protection againstradiation-induced BM injury. However the molecular mechanisms for regulating HSC survival and self-renewalare not well defined. HSC number and function demonstrate natural variations and underlying genetic diversityis an important yet largely unknown mechanism involved in the regulation of HSC function. Latexin (Lxn) waspreviously identified as the first stem cell regulatory gene whose natural variation negatively contributes to theHSC population size in different mouse strains. In preliminary studies constitutive gene ablation approacheswere developed to define the role of Lxn in HSCs and hematopoiesis in normal and radiation stress conditions.Results showed that Lxn inactivation protects HSCs and hematopoietic progenitor cells (HPCs) from radiation-induced cell death thus mitigating acute hematopoietic suppression and conferring a survival advantage.Moreover Lxn knockout mice do not develop hematological malignancies following single or fractionateddosages of radiation. Mechanistically Lxn inactivation in vivo increases HSC self-renewal and survival. At themolecular level our published and preliminary work showed that ribosomal protein subunit 3 (Rps3) is a novelLxn-binding protein and Lxn overexpression inhibits Rps3 activity thus enhancing radiation sensitivity andtoxicity. In addition the number of human HSCs/HPCs negatively correlates with Lxn expression levelindicating the potential role of Lxn in regulating human hematopoiesis. These findings lead to the hypothesisthat Lxn maintains homeostatic HSC and hematopoiesis and inhibition of Lxn function protects againstradiation-induced hematopoietic injury via Rps3-dependent prosurvival pathways. Specific aims are to: 1)determine the cellular mechanisms by which Lxn inactivation enhances HSC survival and self-renewal andconfers radioprotection 2) identify the molecular mechanisms by which Lxn inactivation enhances Lxn-Rps3-NF-kB prosurvival pathway and 3) determine the role of Lxn in mitigating human hematopoietic cell toxicityfrom radiation injury. This research will advance understanding of a critical but understudied mechanisminvolved in the natural regulator of HSC function and self-renewal. By using mouse and human model systemsand state-of-the-art molecular and genomic techniques findings from the proposed study may facilitate to thedevelopment of novel mechanism-based therapeutic strategy to protect against radiation-induced BM injurywhich could be beneficial for the patients receiving cancer therapy and BM transplantation.

project_terms:
Ablation;Acute;Apoptosis;Attenuated;Binding;Binding Proteins;Biological Models;Biological Preservation;Blood;Bone Marrow;Bone Marrow Cells;Bone Marrow Transplantation;CD34 gene;Cancer Patient;Cell Count;Cell Death;Cell Survival;Cell model;Cell physiology;Cells;Complex;DNA Damage;Development;Exposure to;Genes;Genetic;Genetic Transcription;Genetic Variation;Genomics;Goals;Hematologic Neoplasms;Hematopoiesis;Hematopoietic;Hematopoietic Stem Cell Transplantation;Hematopoietic System;Hematopoietic stem cells;Human;In Vitro;Injury;Knockout Mice;Late Effects;Lead;Liquid substance;Maintenance;Mediating;Modeling;Molecular;Mouse Strains;Mus;Myelosuppression;NF-kappa B;Natural regeneration;Nuclear Translocation;PC3.1 antigen;Pathologic;Pathway interactions;Patients;Pharmacology;Population Sizes;Process;Protein Subunits;Publishing;Quality of life;Radiation;Radiation Dosage;Radiation Injuries;Radiation Tolerance;Radiation Toxicity;Radiation therapy;Radioprotection;Reactive Oxygen Species;Recruitment Activity;Regulation;Regulator Genes;Reporting;Research;Ribosomal Proteins;Role;Second Primary Cancers;Signal Transduction;Solid;Stem cells;Stress;Techniques;Therapeutic;Variant;Work;Xenograft procedure;base;cancer therapy;cell injury;cell transformation;chemotherapy;effective therapy;functional decline;genome integrity;in vivo;knock-down;mortality;mouse model;novel;overexpression;p65;preconditioning;prevent;promoter;radiation response;radiation-induced injury;response;self-renewal;senescence;small hairpin RNA;tumor

public_health_relevance:
PROJECT NARRATIVEMitigation and protection of bone marrow cells particularly hematopoietic (blood forming) stem cells fromradiotherapy-induced acute and permanent injury is critical for the quality of life of cancer patients receivingradiotherapy and bone marrow transplantation. This study will investigate the radiomitigation andradioprotection of inhibition of a novel HSC regulatory gene latexin and will have great therapeutic value forpatients receiving radiation chemotherapy and bone marrow transplantation.


application_id: 9536745
project_number: 5UH3DA041115-04
project_title: Development of Long-acting Cocaine Hydrolase as a Treatment for Cocaine Abuse
administering_ic: NIDA
award_notice_date: 2018-08-01
opportunity_number: RFA-DA-15-017
application_type: 5
activity_code: UH3
ic: DA
serial_number: 041115
program_official: KLINE, RICHARD
project_start_date: 2015-09-15
project_end_date: 2020-07-31
study_section: ZDA1-JXR-D(12)R
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
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): Cocaine abuse is a major public health problem that directly or indirectly affects most communities and families. There is still no FDA-approved medication specific for cocaine addiction or overdose. Disastrous medical and social consequences of cocaine abuse have made the development of an anti-cocaine medication a high priority. Accelerating cocaine metabolism that produces biologically inactive metabolites via a route similar to the principal cocaine-metabolizing pathway-cocaine hydrolysis catalyzed by human butyrylcholinesterase (BChE) in plasma-is recognized as the most efficient treatment strategy for cocaine overdose and addiction. Since the catalytic efficiency (kcat/KM) of wild-type BChE against the naturally occurring (-)-cocaine is low (kcat = 4.1 min and KM = 4.5 M) we have recently designed and discovered a set of BChE -1 mutants known as cocaine hydrolases (CocHs) with at least 1000-fold improved catalytic efficiency against (- )-cocaine compared to wild-type BChE. In vivo and clinical data for the first one of our discovered and patented CocHs demonstrate the promise of enzyme therapy for cocaine abuse. In addition to improved efficacy our recently designed discovered and patented new CocH entities have not only significantly higher catalytic efficiency against (-)-cocaine but also possess much longer biological half-lives Built on our success in rational design and discovery of the highly efficient CocHs and their long-acting forms (LAFs or CocH-LAFs) this investigation will focus on further optimization manufacturing process development formulation development and preclinical testing of the most promising CocH-LAF as a novel therapeutic candidate for cocaine addiction treatment. The specific aims are: (1) to optimize a promising CocH-LAF which has not only a high catalytic efficiency against (-)-cocaine but also a long biological half-life; (2) to test feasibility of lage- scale expression of promising CocH-LAF entities; (3) to develop large-scale manufacturing processes for the most promising CocH-LAF selected in Aim 2; (4) to characterize the detailed pharmacology and toxicology profiles of the most promising CocH-LAF in animal models with the CocH-LAF material produced in Aim 3. The most promising CocH-LAF entity developed in this investigation is expected to be highly effective and safe as a novel exogenous enzyme suitable for a monthly dosing schedule for treatment of cocaine addiction in humans. This investigation will make the best possible CocH-LAF entity ready for the cGMP (current Good Manufacturing Practices) protein manufacturing Investigational New Drug (IND)-enabling studies and subsequent clinical trials. Thus this investigation will move a promising therapeuticcandidate closer toward FDA approval for cocaine addiction treatment.

project_terms:
Affect;Albumins;Animal Model;Animals;Antibodies;Binding;Binding Sites;Biological;Biological Assay;Butyrylcholinesterase;Cell Line;Clinical Data;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependence;Communities;Computer Simulation;Data;Development;Dose;Drug Kinetics;Enzymes;Evaluation;FDA approved;Family;Formulation;Half-Life;Human;Hydrolase;Hydrolysis;Immunoglobulins;In Vitro;Injections;Investigation;Investigational Drugs;Legal patent;Medical;Metabolic;Metabolism;Monkeys;Monoclonal Antibodies;Neuraxis;Neurons;Pathway interactions;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology and Toxicology;Plasma;Preclinical Testing;Process;Production;Proteins;Public Health;Rattus;Route;Self Administration;Self-Administered;Serum Albumin;Technology;Testing;Toxic effect;Treatment Protocols;Vaccines;Work;base;cell bank;clinical development;cocaine overdose;design;drug of abuse;enzyme therapy;expression cloning;immunogenicity;improved;in vivo;innovation;manufacturing process;manufacturing process development;mutant;novel;novel therapeutics;public health relevance;small molecule;social;success;therapeutic candidate;treatment strategy

public_health_relevance:
PUBLIC HEALTH RELEVANCE The long-acting cocaine hydrolase developed in this project will be a promising candidate for therapeutic treatment of cocaine addiction.


application_id: 9536128
project_number: 5R01HL138488-02
project_title: Lysophosphatidic Acid Mediates Cardiac Inflammation After Acute Infarction
administering_ic: NHLBI
award_notice_date: 2018-07-31
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 138488
program_official: SOPKO, GEORGE
project_start_date: 2017-08-01
project_end_date: 2022-07-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 11330155
contact_pi: ABDEL LATIF, AHMED
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Acute myocardial infarction;Address;Adhesions;Affect;Animal Model;Atherosclerosis;Blood;Blood Vessels;Bone Marrow;Bone Marrow Cells;Cardiac;Cardiac Myocytes;Cells;Cessation of life;Chemotactic Factors;Clinical;Complement;Coupled;DNA Sequence Alteration;Data;Development;Endothelial Cells;Enzymes;Frequencies;GTP-Binding Proteins;Gap Junctions;Genetic;Goals;Healthcare;Heart;Heart failure;Heritability;Homing;Human;Impairment;Infarction;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Injury;Knowledge;Link;Lipids;Lysophosphatidic Acid Receptors;Lysophospholipids;Mass Spectrum Analysis;Mediating;Metabolism;Mission;Modeling;Molecular;Monocytosis;Morbidity - disease rate;Mus;Myelopoiesis;Myocardial;Myocardial Ischemia;Myocarditis;Outcome;Pathologic;Pathway interactions;Patients;Pharmacology;Phosphoric Monoester Hydrolases;Plasma;Play;Population;Process;Production;Proteins;Public Health;Recovery;Research;Role;Sampling;Signal Pathway;Signal Transduction;Site;Source;Spleen;System;Testing;Therapeutic;Tissues;Tracer;United States National Institutes of Health;Variant;base;cardiogenesis;chemokine;cytokine;experience;genetic manipulation;genetic variant;gustin;healing;improved;inhibitor/antagonist;innovation;lysophosphatidic acid;monocyte;mortality;mouse model;novel strategies;peripheral blood;progenitor;receptor;receptor expression;repaired;response;role model;stable isotope


application_id: 9536085
project_number: 5R01HD080205-05
administering_ic: NICHD
award_notice_date: 2018-06-25
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: 2020-08-04
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: 2018-07-01
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;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: 9535968
project_number: 5R01CA208343-02
project_title: Altered Lipid Metabolism as a Novel Target for Colon Cancer Treatment
administering_ic: NCI
award_notice_date: 2018-07-18
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 208343
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
arra_indicator: N
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;Non-Small-Cell Lung Carcinoma;Oncogenic;Oral;Ovarian;Oxidative Stress;Palmitates;Patients;Pharmacodynamics;Pharmacologic Substance;Phospholipids;Placebos;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;cell growth;cell transformation;chemotherapy;colon cancer patients;colon cancer treatment;colorectal cancer metastasis;colorectal cancer progression;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;secondary endpoint;small molecule inhibitor;stable isotope;treatment strategy;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor metabolism;tumorigenesis


application_id: 9534710
project_number: 5R01HG008988-03
project_title: Addressing Ethical Challenges in Networked Biorepositories
administering_ic: NHGRI
award_notice_date: 2018-07-26
opportunity_number: PA-14-276
application_type: 5
activity_code: R01
ic: HG
serial_number: 008988
program_official: LOCKHART, NICOLE C
project_start_date: 2016-09-28
project_end_date: 2020-07-31
study_section: Special Emphasis Panel[ZRG1-SEIR-R(01)Q]
contact_pi_person_id: 10692185
contact_pi: BROTHERS, KYLE BERTRAM
other_pis: GOLDENBERG, AARON J
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:
PROJECT SUMMARY/ABSTRACTIndividual institutions across the country have worked to support research in a wide variety of areas includingprecision medicine research by developing large biorepositories comprised of biospecimens and health datacollected from local patients and controls. However these local cohorts rarely provide the diversity and sizeneeded to identify and study subsets of patients who share biological mechanisms for their disease and arethus more likely to respond to the same targeted therapies. To address this need researchers have begun topromote the networking of multiple repositories within or across multiple institutions. This networkedbiorepository approach makes it possible for researchers to access larger more diverse sets of data andbiospecimens in a way that leverages the research relationships that local institutions have built with their owncommunities of donors. In order for this approach to be successful networked biorepositories need to addressimportant ethical legal and social challenges. Networked biorepositories are comprised of diverse sets ofspecimens and data from different institutions each with their own governance structures and donor needs.For these reasons they encounter complex issues related to consent and donor permission privacy and datasecurity and data access. These novel challenges have not previously been examined in detail and bestpractices for addressing these issues through governance and oversight processes are lacking. This study willaddress these important needs through a rigorous mixed-methods study of the perspectives and experiencesof stakeholders currently engaged in designing operating and governing networked biorepositories. It will alsoaim to develop approaches to consent and donor permission privacy and data security data accessgovernance and oversight that are most appropriate and effective for a variety of networked biorepositoryconfigurations.

project_terms:
Address;American;Area;Authorization documentation;Biological;Collection;Communities;Complex;Consent;Country;Data;Data Security;Data Set;Development;Disease;Elements;Ethics;Focus Groups;Future;Genetic Variation;Genomics;Health;Human Resources;Individual;Institution;Interview;Knowledge;Link;Literature;Medical;Methods;National Human Genome Research Institute;Participant;Patients;Persons;Policies;Precision Medicine Initiative;Privacy;Problem Solving;Process;Rare Diseases;Recommendation;Research;Research Personnel;Research Support;Resources;Sampling;Specimen;Structure;Time;Work;biobank;cohort;data access;design;ethical legal social implication;experience;health data;informant;interest;meetings;network models;novel;patient subsets;personalized health care;precision medicine;prospective;repository;sharing data;symposium;targeted treatment;tool

public_health_relevance:
PROJECT NARRATIVENetworked biorepositories make it possible for investigators in a wide variety of research domains to accesslarge diverse collections of biospecimens and health data across multiple institutions. At the same time theyalso raise complex issues related to consent and donor permission privacy and data security and dataaccess. Developing a detailed account of these challenges and identifying appropriate solutions includingeffective governance and oversight processes will enable new and developing networked biorepositories tosupport important health research while at the same time meeting the needs of donors and protecting theinterests of contributing institutions.


application_id: 9533631
project_number: 5R35GM124977-02
project_title: Probing cellular intracellular calcium signaling and sensing through computation
administering_ic: NIGMS
award_notice_date: 2018-07-06
opportunity_number: RFA-GM-17-004
application_type: 5
activity_code: R35
ic: GM
serial_number: 124977
program_official: RESAT, HALUK
project_start_date: 2017-08-01
project_end_date: 2019-07-31
study_section: Special Emphasis Panel[ZRG1-CB-M(50)R]
contact_pi_person_id: 10445272
contact_pi: KEKENES-HUSKEY, PETER MICHAEL
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:
2+Intracellular Ca signaling Kekenes-Huskey PM. University of KentuckyProbing cellular intracellular calcium signaling and sensing throughcomputation Calcium signaling regulates biological function across a broad range of tissue types and species2+but several factors known to control Ca -dependent signaling efciency have challenged both compu-tational and experimental inquiry. There are signicant gaps in our understanding of how nuances inprotein structure and dynamics as well as their intracellular distribution affect fundamentally important2+processes including how 1) Ca accumulates within localized intracellular regions 2) proteins bind2+ 2+Ca with high afnity 3) Ca 'sensor' proteins regulate signaling cascades. Detailed knowledge aboutthese topics and their inter-dependencies would yield new paradigms in how we view biology physiologyand health. Computer simulations are attractive in this regard both for describing phenomena that aredifcult to directly resolve experimentally as well as forming integrative conceptual models spanningthese underlying topics. However several prominent hurdles render such transformative simulationscost-prohibitive. Among these reducing the intractable computational expense involved with model-ing ne detail processes like transport governed by sub-nanometer to micron scales atomistic-scalethermodynamic factors shaping ion/protein binding and long-range forces that promote protein/proteinsignaling pathways is likely the foremost challenge in biophysics today. In this proposal we outline sev-eral multi-scale algorithmic advances that will ease this challenge while providing insight into important2+Ca -driven processes that orchestrate life: Theme 1 Tuning Ca2+ sensing and response at the molecular level. In this theme we will develop new paradigms for understanding nature's tricks for controlling specicity and kinetics in2+ Ca sensing functions. Theme 2 Automated detection of disease-associated morphological changes in cardiac2+ cells and their inuence on Ca homeostasis. In this theme our lab will leverage troves of underutilized microscopy data to answer questions regarding the role of intracellular organization2+ in shaping Ca signaling. Theme 3 Molecular mechanisms of cellular-scale control via the P2X4 receptor. In thistheme we will establish strong links between molecular scale protein structure/function and theircontrol of cellular-scale signaling outcomes.1

project_terms:
Affect;Affinity;Algorithms;Binding Proteins;Biological Process;Biology;Biophysics;Calcium Signaling;Cardiac;Cell physiology;Cells;Computer Simulation;Data;Dependence;Detection;Disease;Functional disorder;Health;Homeostasis;Immune response;Ions;Kentucky;Kinetics;Knowledge;Lead;Life;Link;Malignant Neoplasms;Microscopy;Modeling;Molecular;Morphology;Motivation;Muscle Contraction;Nature;Nervous System Physiology;Outcome;Physiology;Process;Protein Dynamics;Proteins;Role;Shapes;Signal Pathway;Signal Transduction;Signaling Protein;Specificity;Thermodynamics;Tissues;Universities;combat;computerized tools;cost;hormone regulation;human disease;innovation;insight;molecular scale;nanometer;novel;novel strategies;protein structure;protein structure function;receptor;response;sensor;simulation

public_health_relevance:
2+Intracellular Ca signaling Kekenes-Huskey PM. University of KentuckyThe key innovation in this proposal are novel computational tools to integrate molecular details of2+Ca handling into whole-cell cellular physiology as well as specic hypotheses examining aspects2+of molecular through cellular control of Ca -dependent function. These innovations are directly2+relevant to human disease given the pervasive role of Ca in orchestrating cellular physiology andpathophysiology including muscle contraction neurological function immune responses hormoneregulation and cancer. Successful completion of these studies would lead to new insight into how2+Ca signaling is modulated at the subcellular level which affords new insight and motivation to novelstrategies to combat human disease.2


application_id: 9533570
project_number: 5R01EY023561-05
project_title: Mid-level mechanisms of surface and binocular perception
administering_ic: NEI
award_notice_date: 2018-08-20
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: EY
serial_number: 023561
program_official: WIGGS, CHERI
project_start_date: 2014-08-01
project_end_date: 2020-07-31
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 1965646
contact_pi: HE, ZIJIANG
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Retinal images are inherently fragmentary and ambiguous because images of separate entities overlap. But the early visual mechanisms are not equipped to parse the overlapping 2-D retinal images into distinct 3-D entities. The job of parsing these images falls on the mid-level mechanisms whose main role is to represent the distinct entities as separate surfaces. The represented surface information then serves as inputs to the WHAT and WHERE systems that underlie our 3-D perception of objects and space respectively. As such the mid-level mechanisms are not just simple "conduits" of information between early and late level visual mechanisms but play a crucial role in determining the quality and reliability of the visual information conveyed. Compared to other aspects of visual processing less is known about the mid-level mechanisms. One of the biggest challenges is to discover how the often fragmentary and ambiguous retinal information is transformed into reliable surface representations presumably through a spreading-in operation. At times when an image belonging to the same entity is broken into parts due to occlusion a surface interpolation operation is required to integrate the parts into a global surface. Moreover inputs from the two eyes that contribute to these operations can be disparate in content and location. In the face of the myriad complexities of the visual inputs it is further proposed that the mid-level mechanisms must rely on internal assumptions (perceptual rules) and feedbacks from the higher visual levels for guidance in representing surfaces. But how these operations are accomplished is still unclear. Remedying it this proposal uses the human psychophysical approach to investigate the above issues by focusing on three specific aims. Aim 1 investigates how the spreading-in operation represents surfaces with texture patterns which is more complex than representing texture-free surfaces. It is proposed the principle of reducing coding redundancy that governs the spreading-in operation causes the global surface representation operation to be efficient but prone to poor resolution. The latter could be one basis of the well-known "crowding effect" phenomenon. Aim 2 investigates the texture-surface interpolation operation. Cognizant of the roles of attention and object knowledge the research investigates how these top-down factors influence surface integration. Aim 3 investigates the long-term plasticity of the mid-level mechanisms. Perceptual learning experiments will be conducted to reveal how extensive training modifies the perceptual rules implemented at the mid-level. The long-term goal of this proposal is to advance our knowledge of how visual information is processed and represented by the mid-level mechanisms. This knowledge helps us better understand how humans perceive the visual world and provides a clinical basis for behavioral diagnoses and treatments of visual dysfunctions related to amblyopia strabismus and aging.

project_terms:
3-Dimensional;Affect;Aging;Amblyopia;Attention;Behavioral;Clinical;Code;Color;Complex;Crowding;Diagnosis;Ensure;Environment;Eye;Feedback;Frequencies;Functional disorder;Goals;Grant;Human;Image;Knowledge;Link;Location;Measurement;Motion;Occupations;Ownership;Pattern;Perception;Perceptual learning;Play;Process;Property;Protocols documentation;Psychophysics;Research;Resolution;Retinal;Role;Space Perception;Strabismus;Surface;System;Testing;Texture;Time;Training;Visual;Visual Perception;Visual system structure;detector;experimental study;falls;feeding;imaging properties;improved;luminance;neurophysiology;noninvasive diagnosis;object perception;object shape;operation;public health relevance;retinal imaging;visual information;visual processing;visual stimulus

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Early level visual information is often fragmentary and ambiguous because images of distinct entities overlap. A role of the mid-level mechanisms is to "make sense" of this information by representing the distinct entities as separate surfaces. Discovering how this is achieved leads to better scientific understanding of how humans perceive the visual world and provides a clinical basis for non-invasive diagnoses and treatments of visual dysfunctions related to amblyopia and strabismus.


application_id: 9533466
project_number: 5R01AR071398-02
project_title: Mechanistic assessment of blood flow restricted training for an ACL injury
administering_ic: NIAMS
award_notice_date: 2018-07-03
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AR
serial_number: 071398
program_official: WASHABAUGH, CHARLES H
project_start_date: 2017-07-22
project_end_date: 2022-06-30
study_section: Musculoskeletal Rehabilitation Sciences Study Section[MRS]
contact_pi_person_id: 10137938
contact_pi: NOEHREN, BRIAN
other_pis: Not Applicable
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_terms:
Address;Anterior Cruciate Ligament;Architecture;Area;Attenuated;Biomechanics;Biopsy;Blood flow;Clinical;Data;Degenerative polyarthritis;Development;Effectiveness;Electric Stimulation;Evidence based intervention;Extensor;Extracellular Matrix;Fatty acid glycerol esters;Fiber;Fibrosis;Frequencies;Generations;Goals;Imaging Techniques;Individual;Infiltration;Injury;Knee;Lead;Limb structure;Link;Magnetic Resonance Imaging;Measurement;Measures;Mechanics;Mediating;Microscopic;Morphology;Multi-Institutional Clinical Trial;Muscle;Muscle Fibers;Muscle Weakness;Muscle satellite cell;Outcome;Patient Care;Patients;Phenotype;Physical therapy;Physiological;Physiological Adaptation;Population;Positioning Attribute;Procedures;Property;Quality of life;Randomized;Reconstructive Surgical Procedures;Recovery;Rehabilitation therapy;Resistance;Risk;Stem cells;Techniques;Testing;Thigh structure;Time;Training;Work;alternative treatment;anterior cruciate ligament reconstruction;anterior cruciate ligament rupture;base;functional outcomes;improved;injured;knee mechanics;ligament injury;muscle strength;novel;novel strategies;premature;prevent;progenitor;quadriceps muscle;reconstruction;rehabilitation strategy;satellite cell;stem;strength training;treatment as usual;treatment strategy;vastus lateralis


application_id: 9533458
project_number: 5R21AI129522-02
project_title: Pathogenesis of Borrelia mayonii infection
administering_ic: NIAID
award_notice_date: 2018-07-09
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: AI
serial_number: 129522
program_official: ILIAS, MALIHA R
project_start_date: 2017-07-24
project_end_date: 2020-06-30
study_section: Special Emphasis Panel[ZRG1-IDM-R(02)M]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTBorrelia mayonii is the causative agent of a newly-recognized tick-borne disease. First reported in the upperMidwest during February 2016 the geographic range of this emerging public health threat is not yet known.Although B. mayonii is related to the classic Lyme disease agent Borrelia burgdorferi the two species exhibitsubstantial genetic differences. We hypothesize that those differences are responsible for the distinct featuresof B. mayonii infection. A striking difference between the two diseases is the high spirochetemia that has beenobserved only in patients infected with B. mayonii. Other symptoms of B. mayonii infection include macularrashes across the body myalgia and neurological signs with some patients requiring hospitalization. Threecritical questions about B. mayonii and its associated disease are being addressed by our studies: (1) Whatare the extents of spirochetemia tissue pathology and other infectious qualities in untreated mammalian B.mayonii infection? (2) What is responsible for the high-level spirochetemia that occurs during B. mayoniiinfection but not during B. burgdorferi infection? and (3) What antigenic proteins are produced during B.mayonii infection but not during B. burgdorferi infection that can be used for diagnosis of this emergingdisease? Results from our studies will provide valuable insight on the pathogenic properties of B. mayonii andlay important groundwork for diagnosis and treatment.

project_terms:
Address;Affinity;Amino Acids;Antigens;Bacteremia;Bacterial Adhesins;Blood Vessels;Borrelia;Borrelia burgdorferi;Borrelia mayonii;Chromosomes Human 4-5;Clinical;Complement;Development;Diagnosis;Diffuse;Disease;Event;Exanthema;Exhibits;Genes;Genetic;Geography;Goals;Hospitalization;Human;Inbred Mouse;Infection;Lyme Disease;Membrane Proteins;Midwestern United States;Modeling;Molecular;Mus;Myalgia;Neurologic Signs;Orthologous Gene;OspC protein;Pathogenesis;Pathogenicity;Pathologic;Pathology;Patients;Property;Proteins;Proteomics;Public Health;Reporting;Surface Antigens;Symptoms;Tick-Borne Diseases;Ticks;Tissues;Virulence Factors;insight;macula;mouse model;novel;outer surface lipoprotein;pathogen;tool

public_health_relevance:
PROJECT NARRATIVEBorrelia mayonii is a newly-identified tick-borne pathogen of humans in the USA. Symptoms of B. mayoniiinfection include high-level bacteremia and diffuse macular rashes which are distinct from those of its relativeBorrelia burgdorferi the Lyme disease agent. The proposed studies focus on elucidating the molecularmechanisms responsible for the unique pathogenic properties of B. mayonii.


application_id: 9533054
project_number: 1R21AI135345-01A1
project_title: HDAC6 regulation of beta-catenin and endothelial adherens junctions in sepsis
administering_ic: NIAID
award_notice_date: 2018-04-25
opportunity_number: PA-16-161
application_type: 1
activity_code: R21
ic: AI
serial_number: 135345
suffix: A1
program_official: MINNICOZZI, MICHAEL
project_start_date: 2018-05-01
project_end_date: 2020-04-30
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 8693493
contact_pi: FU, JIAN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project SummarySepsis a systemic inflammatory response syndrome is a life-threatening disease with highmorbidity and mortality. Sepsis is often triggered by bacterial infection. Excessive inflammatoryresponses lead to vascular injury in sepsis including increased vascular permeability and edema.Identifying novel therapeutic targets that can help control sepsis-induced vascular injury iscrucial to treat this devastating disease. Endothelial barrier dysfunction contributes to thepathogenesis of multi-organ failure in sepsis. Acetylation and deacetylation of cell-cell junctionand cytoskeleton proteins may serve as an important mechanism to control the dynamics ofendothelial barrier integrity. HDAC6 a deacetylase primarily localized in the cytoplasm hasbeen reported to modulate non-nuclear protein function through deacetylation. -catenin is anendogenous substrate for HDAC6. -catenin is a key component of adherens junction complex.-catenin interacts with VE-Cadherin at cell-cell junctions to maintain endothelial barrier integrity.In this project we will investigate HDAC6 regulation of -catenin and endothelial adherensjunctions in sepsis. In our preliminary studies we demonstrated that HDAC6 knockdown orselective HDAC6 inhibition prevented TNF- induced endothelial cell barrier disruption andincreased -catenin acetylation in endothelial cells which was associated with increasedmembrane localization of -catenin and stabilization of adherens junctions. Furthermore in amouse model of polymicrobial sepsis HDAC6 inhibition was able to prevent sepsis-induceddeacetylation of -catenin in lung tissues which was associated with the protection of adherensjunctions and reduced pulmonary edema. In the proposed studies we will investigate molecularmechanisms of HDAC6 regulation of endothelial adherens junctions in sepsis using inducibleendothelial-specific HDAC6 knockout mice. We will also assess the therapeutic potential ofnovel HDAC6 inhibitors in the protection of endothelial adherens junctions during sepsis.

project_terms:
Acetylation;Adherens Junction;Bacterial Infections;Blood Vessels;Cells;Cessation of life;Clinical Research;Clinical Trials;Complex;Cytoplasm;Cytoskeleton;Data;Deacetylase;Deacetylation;Disease;Edema;Endothelial Cells;Failure;Functional disorder;Future;HDAC6 gene;Human;Inflammatory;Inflammatory Response;Injury;Intercellular Junctions;Knockout Mice;Lead;Life;Lung;Mediating;Membrane;Molecular;Morbidity - disease rate;Mus;Operative Surgical Procedures;Pathogenesis;Proteins;Pulmonary Edema;Regulation;Reporting;Role;Sepsis;Structure of parenchyma of lung;Systemic Inflammatory Response Syndrome;TNF gene;Testing;Therapeutic;Therapeutic Effect;Vascular Permeabilities;beta catenin;cadherin 5;experimental study;inhibitor/antagonist;knock-down;mortality;mouse model;new therapeutic target;novel;novel therapeutics;polymicrobial sepsis;prevent;protective effect;protein function

public_health_relevance:
Project NarrativeSuccessful completion of the proposed studies will reveal a novel role of HDAC6 in sepsis-inducedendothelial adherens junction dysfunction. We will also validate the therapeutic potential of HDAC6inhibition against vascular injury in sepsis. The proposed studies will provide important information forfuture clinical studies.


application_id: 9532588
project_number: 5R01GM107586-05
project_title: Light-responsive ruthenium compounds for applications in disease
administering_ic: NIGMS
award_notice_date: 2018-07-26
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: 2021-07-31
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;anticancer treatment;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;preclinical 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: 9532319
project_number: 261201300013I-0-26100012-1
project_title: IGF::OT::IGF PATTERNS OF CARE/QUALITY OF CARE STUDY: DIAGNOSIS YEAR 2016 POP 7/31/2017-7/30/2018
administering_ic: NCI
project_start_date: 2017-07-31
project_end_date: 2018-07-30
contact_pi_person_id: 15138368
contact_pi: NEE, JACLYN
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
funding_mechanism: R and D Contracts
project_abstract:
SEER Patterns of Care Studies describe characterize and compare practice patterns and treatments provided for cancer in different geographic areas of the United States. SEER Patterns of Care/Quality of Care Studies (POC/QOC) are conducted to satisfy a Congressional directive (under Public Law 100-607 Sec. 413 (a) (2) (C) adopted November 4 1988) to the National Cancer Institute (NCI) to assess the incorporation of state-of-the-art cancer treatments into clinical practice and the extent to which cancer patients receive such treatments and include the results of such assessment in the biennial reports. To select the cancers to satisfy this directive the Division of Cancer Control and Population Sciences has been working closely with the Division of Cancer Treatment. This years Patterns of Care (POC) Study shall investigate state-of-the-art therapies for patients with cancers of sites: corpus uteri head and neck and pancreas.

project_terms:
Adjuvant Therapy;Adopted;Age;Beds;Biological Markers;Body of uterus;Cancer Patient;Characteristics;Clinical Trials;Communities;Community Practice;Community of Practice;Comorbidity;Data;Diagnosis;Diagnostic tests;Division of Cancer Control and Population Sciences;Educational process of instructing;Ethnic Origin;Geographic Locations;Head and neck structure;Hospitals;Immunoglobulin Variable Region;Immunotherapy;Insurance Coverage;Laws;Link;Malignant Neoplasms;Medicare;National Cancer Institute;Operative Surgical Procedures;Outcome;Pancreas;Patients;Pattern;Patterns of Care;Physicians;Quality of Care;Race;Radiation therapy;Reporting;Time;United States;cancer site;cancer therapy;chemotherapy;clinical practice;hormone therapy;sex


application_id: 9532310
project_number: 5R01NS091582-04
project_title: The role of macrophage phenotype and age in spinal cord injury
administering_ic: NINDS
award_notice_date: 2018-06-22
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 091582
program_official: BAMBRICK, LINDA LOUISE
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;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;Immunomodulators;Impairment;In Vitro;Incidence;Individual;Inflammatory;Inflammatory Response;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;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;immunomodulatory therapies;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: 9532141
project_number: 5R33DA038817-04
project_title: Single molecule determination of nAChR structural assembly for therapeutic targeting
administering_ic: NIDA
award_notice_date: 2018-07-02
opportunity_number: PAR-13-350
application_type: 5
activity_code: R33
ic: DA
serial_number: 038817
program_official: HILLERY, PAUL
project_start_date: 2017-08-01
project_end_date: 2021-06-30
study_section: NSS
contact_pi_person_id: 8957529
contact_pi: RICHARDS, CHRISTOPHER I
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): The consumption of tobacco products leads to the elevation of several health risks. Smokers have a higher likelihood of developing cardiovascular disease respiratory disease and several types of cancer. As a result approximately 20% of all deaths in the United States are associated with tobacco products. Despite the clear hazards it is estimated that more than 40 million adults in the United States are smokers. One of the primary barriers to decreasing the number of smokers is that nicotine a component of tobacco is highly addictive. We propose a novel approach to elucidate the mechanism of nicotine addiction and to identify target nAChR assemblies and phenotypes for nicotine cessation therapeutics. In the R21 phase we will focus on the development of a novel approach to monitor the assembly and trafficking of nicotinic receptors at the single molecule level. Nicotinicreceptors cannot be purified outside of the cellular environment making them inaccessible to common single molecule techniques that require the purification and reconstitution of proteins. We will utilize receptors isolated in cell derived vesicles. Isolation of vesicles from different organelles will allow us to determine nicotine and therapeutic ligands affect the assembly and trafficking of nAChRs. Identification of the specific structural assemblies targeted by existing therapeutics will allow us to identify specific targets for cessation therapeutics. In the R33 phase we will extend studies to receptors generated in live animals by isolating vesicles from different regions of the brain of nicotinic receptor GFP knock-mice. These will be the first singlemolecule studies of nicotinic receptors generated in live animals. We will be able to correlate theassembly of different receptor subtypes to specific brain regions. These studies will for the firsttime allow us to perform single molecule fluorescence studies on brain derived nAChRs. Understanding how existing therapeutics alter structural assembly in specific brain regions will provide an understanding of which nAChRs to target and the structural assembly they should induce. This will provide insight into the mechanism of nicotine addiction and on the receptor phenotypes optimally induced by cessation therapeutics.

project_terms:
Adult;Affect;Animals;Brain;Brain imaging;Brain region;Cardiovascular Diseases;Cell membrane;Cells;Cessation of life;Development;Environment;Exposure to;Fluorescence;Goals;Golgi Apparatus;Health;Knock-in Mouse;Label;Ligands;Lung diseases;Measures;Mediating;Membrane;Molecular Chaperones;Monitor;Mus;Nicotine;Nicotine Dependence;Nicotinic Receptors;Organelles;Pharmacology;Phase;Phenotype;Play;Risk;Role;Series;Smoker;Structure;Synapses;Synaptosomes;Techniques;Testing;Therapeutic;Therapeutic Effect;Time;Tobacco;Tobacco use;United States;Vesicle;addiction;cancer type;experimental study;fluorescence imaging;hazard;in vivo;innovation;insight;molecular imaging;nicotine cessation;nicotine exposure;novel;novel strategies;novel therapeutics;presynaptic;protein reconstitution;public health relevance;receptor;single molecule;stoichiometry;targeted treatment;therapeutic target;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The consumption of tobacco products leads to a higher likelihood of developing cardiovascular disease respiratory disease and several types of cancer. Despite the clear hazards it is estimated that more than 40 million adults in the United States are smokers. The proposed studies will help to elucidate the underlying mechanism of nicotine addiction and will identify specific structural targets for therapeutic targeting.


application_id: 9532109
project_number: 5R01CA180986-05
project_title: Prevention of Breast Cancer Development by Epidermal Fatty Acid Binding Protein (
administering_ic: NCI
award_notice_date: 2018-07-23
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: 2020-07-31
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;Expression Profiling;Hematopoietic;Human;ITGAM gene;ITGAX gene;Impairment;Incidence;Infiltration;Inflammatory;Interferon Type II;Lipids;Malignant Neoplasms;Mammary Neoplasms;Mammary Tumorigenesis;Mediating;Metabolic;Metastatic Neoplasm to the Lung;Molecular;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;Tumor-associated macrophages;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;protective factors;protein expression;public health relevance;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: 9531436
project_number: 5R01HL135000-02
project_title: Role of myocyte Na+ dysregulation in diabetic heart disease
administering_ic: NHLBI
award_notice_date: 2018-07-13
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 135000
program_official: BUXTON, DENIS B
project_start_date: 2017-08-01
project_end_date: 2021-07-31
study_section: Electrical Signaling, Ion Transport, and Arrhythmias Study Section[ESTA]
contact_pi_person_id: 9983033
contact_pi: DESPA, SANDA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTType-2 diabetes (T2D) heightens the risk of heart failure arrhythmias and sudden cardiac death even in theabsence of vascular complications. However the underlying mechanisms are poorly understood. We proposethat a critical contributor to diabetic heart disease involves myocyte Na+ dysregulation. Maintenance of cardiacNa+ homeostasis is vital for preserving heart function. Elevated myocyte Na+ concentration ([Na+]i) causesoxidative stress and augments the sarcoplasmic reticulum (SR) Ca2+ leak thus amplifying the risk forarrhythmias and promoting heart dysfunction. Using a rat model of late-onset T2D (the HIP rat) that displaysmyocardial dysfunction and arrhythmias we recently found that [Na+]i is increased in T2D hearts.Unexpectedly higher [Na+]i seems to be caused by enhanced Na+ entry through the Na+-glucose cotransporterisoform 1 (SGLT1) a previously ignored player in cellular Na+ homeostasis. Furthermore we found higherSGLT1 expression in hearts from patients with T2D compared to lean non-diabetic individuals and in heartsfrom diabetic HIP rats vs. control rats. Cardiac-specific SGLT1 overexpression was recently shown to causehypertrophy and left-ventricular dysfunction while SGLT1 activation has been linked to the cardiomyopathycaused by mutations in the gene encoding the 2 subunit of AMP-activated protein kinase. Thus the evidencethat enhanced SGLT1 activity damages the heart is mounting but little is known about the underlyingmechanisms and its role in diabetic cardiomyopathy. Based on these findings we hypothesize that SGLT1upregulation contributes to the multifactorial mechanism driving cardiac remodeling in T2D by perturbingmyocyte Na+ dyshomeostasis. To test this overall hypothesis we will i) assess the role of SGLT1 activation inthe myocyte [Na+]i rise and consequent oxidative stress larger SR Ca2+ leak and spontaneousafterdepolarizations in T2D ii) test whether SGLT1 upregulation is a maladaptation of the myocardium toimpaired insulin-dependent glucose uptake and iii) assess whether SGLT1 and [Na+]i are elevated in heartsfrom humans with T2D. Experiments will combine fluorescence imaging electrophysiology biochemistry invivo assessment of heart function pharmacological tools T2D and transgenic animal models and humanstudies. By integrating physiological and pharmacological analyses in rat and human hearts this project willestablish whether SGLT1 activation and Na+ overload are key events in the pathology of diabetic heart diseaseand will identify SGLT1 as a new therapeutic target for cardiac complications in T2D patients.

project_terms:
5'-AMP-activated protein kinase;Animal Model;Animals;Arrhythmia;Automobile Driving;Biochemistry;Blood Vessels;Cardiac;Cardiomyopathies;Diabetes Mellitus;Electric Stimulation;Electrophysiology (science);Event;Genes;Glucose;Heart;Heart Diseases;Heart failure;Homeostasis;Human;Hyperglycemia;Hypertrophy;Impairment;Individual;Insulin;Insulin Resistance;Kidney;Left Ventricular Dysfunction;Link;Maintenance;Mediating;Messenger RNA;Mitochondria;Modeling;Mus;Muscle Cells;Mutation;Myocardial;Myocardial dysfunction;Myocardium;Na(+)-K(+)-Exchanging ATPase;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oxidative Stress;Pathology;Patients;Pharmacology;Phase;Physiological;Prediabetes syndrome;Protein Isoforms;Proteins;Rattus;Regulation;Rest;Risk;Role;Sarcoplasmic Reticulum;Structure;Testing;Thinness;Tissues;Transgenic Animals;Transgenic Mice;Translating;Up-Regulation;Work;base;cardioprotection;db/db mouse;diabetic;diabetic cardiomyopathy;experimental study;fluorescence imaging;glucose uptake;heart damage;heart function;improved;in vivo;injured;insulin sensitizing drugs;insulin signaling;new therapeutic target;non-diabetic;overexpression;prevent;sudden cardiac death;tool

public_health_relevance:
NARRATIVEType-2 diabetes heightens the risk of heart failure arrhythmias and sudden cardiac death but the underlyingmechanisms are poorly understood and there is no specific treatment for heart disease in patients withdiabetes. Proposed work seeks to test the hypothesis that enhanced activity of the Na+-glucose cotransporter 1and myocyte Na+ dysregulation are critical contributors to diabetic cardiomyopathy. Thus this work mayidentify novel therapeutic targets for cardioprotection that are specifically tailored to patients with type-2diabetes.


application_id: 9531322
project_number: 5R01DE014605-16
project_title: Inter-kingdom signaling by A. actinomycetemcomitans
administering_ic: NIDCR
award_notice_date: 2018-07-23
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DE
serial_number: 014605
program_official: MCNEALY, TAMARA L
project_start_date: 2002-04-01
project_end_date: 2022-10-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 8652094
contact_pi: URIARTE, SILVIA M
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Periodontitis  is  a  widespread  and  costly  disease  that  is  primarily  manifest  in  the  oral  cavity  but  is  also  associated  with  systemic  dieases  such  as  atherosclerosis  and  rheumatoid  arthritis.    Although  several  organisms  have  been identified  as  periodontal  pathogens  A. actinomycetemcomitans has  been  strongly  associated with aggressive forms of periodontitis.  Our prior work showed that quorum sensing is essential for A.  actinomycetemcomitans  virulence  and  we  identified  the  QseBC  two  component  system  as  a  critical  component  of  the  quorum  sensing  pathway.    Our  new  results  suggest  that  QseBC  may  interact  with  catecholamine hormones produced by the host and thus QseBC may mediate both cell density dependent  signaling and inter-kingdom signaling.  This application focuses on the mechanisms of interaction of the two  component  system  with  catecholamine  hormones  and  is  potential  role  in  regulating  iron  uptake  by  A. actinomycetemcomitans.  Aim 1 will determine if catecholamine hormones and iron represent signals that activate QseBC and identify functional motifs of the QseC sensor that are required for binding.  The genes  that  are  regulated  upon  activation  of  QseBC  will  also  be  identifed  using  genomic  microarrays.  Aim 2 will study an operon encoding a putative enterobactin receptor and transporter and determine if this receptor interacts with catecholamine-iron complexes.    The  contribution  of  the  enterobactin  receptor  to  virulence  will  also be examined  using  a  mouse  model  of  periodontitis.    We have also shown that QseBC may be coupled to the cell stress response through the activity of two iron responsive toxin-antitoxin (TA) systems. This regulatory  network  will  be  studied  in  Aim  3  to  determine  if  the  expression  of  stress  proteases  is  induced under iron limiting conditions and whether these proteases activate the TA toxins by degrading the  labile  antitoxin.    The  effect  of  TA  toxin activation  on  the  expression  of  QseBC  and  virulence  of  A. actinomycetemcomitans will also be determined.  The overall goal of this study is to better understand the functional outcomes of activation of the essential QseBC two component system and how signaling through QseBC contributes to virulence.

project_terms:
ATP-Binding Cassette Transporters;Actinobacillus actinomycetemcomitans;Address;Adult;Antitoxins;Atherosclerosis;Bacterial Proteins;Binding;Binding Proteins;Bordetella;Catecholamines;Cell Density;Cells;Cellular Stress;Cellular Stress Response;Complex;Cost of Illness;Coupled;Data;Disease;Enterobactin;Environment;Expenditure;Family;Funding;Genes;Genome;Genomics;Gingival Pocket;Goals;Growth;Heart Diseases;Hormones;Infection;Inflammatory;Iron;Lactoferrin;Ligands;Mediating;Microbial Biofilms;Mouth Diseases;Operon;Oral cavity;Organism;Orphan;Pathway interactions;Peptide Hydrolases;Periodontitis;Phagocytes;Phenotype;Population;Prevention;Production;Proteins;Regulation;Regulon;Rheumatoid Arthritis;Role;Siderophores;Signal Transduction;Stimulus;Stress;System;Testing;Toxin;Transferrin;United States;Virulence;Work;biological adaptation to stress;deprivation;functional outcomes;macrophage;mouse model;mutant;neutrophil;pathogen;periplasm;prevent;public health relevance;quorum sensing;receptor;response;sensor;solute;targeted treatment;therapeutic target;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Periodontitis  is  a  common  oral  disease  that  is  present  in  up  to  40%  of  the  adult  population  in  the  United  States. Annual expenditures for treatmentand prevention of periodontitis exceed $15 billion.  Although periodontitis is primarily manifest i the oral cavity it is also  associated  with  systemic illnesses  such as heart disease and rheumatoid  arthritis. Our recent studies suggest that the periodontal pathogen A. actinomycetemcomitans  interacts  with  host  hormones  and  iron  and  that  this  interaction  contributes  to  its  virulence.  This study will characterize the bacterial proteins that are invoved in this interaction in order to understand their role in disease.  These proteins represent new potential targets for therapies that may control or prevent periodontitis and the systemic illnesses associated with this disease.


application_id: 9531275
project_number: 5R01CA185972-05
project_title: Chemoprevention of metastatic colorectal cancer
administering_ic: NCI
award_notice_date: 2018-07-23
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: 2020-07-31
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;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;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;colon cancer metastasis;colon cancer prevention;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: 9529933
project_number: 1R21NS093440-01A1
project_title: Elucidating the pathological consequences of tau-ribosome interactions
administering_ic: NINDS
award_notice_date: 2018-07-10
opportunity_number: PA-16-161
application_type: 1
activity_code: R21
ic: NS
serial_number: 093440
suffix: A1
program_official: CORRIVEAU, RODERICK A
project_start_date: 2018-07-15
project_end_date: 2018-07-16
study_section: Special Emphasis Panel[ZRG1 MDCN-P (03)]
contact_pi_person_id: 10569691
contact_pi: ABISAMBRA, JOSE FRANCISCO
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
There is a fundamental gap in understanding why tau causes memory impairment in 20 known tauopathies.One pathological mechanism involves the association of aberrant tau with ribosomes. However theconsequences of this interaction are unknown. The long-term goal of this work is to better understand the linkbetween tau abnormalities and memory impairment. The overall objective of this proposal is to determine theimpact of pathological tau on ribosomal function. We will use in vitro and in vivo models that encompassstudies of ribosomes in isolation RNA translation and protein synthesis in cells and protein production in micebrains. Our preliminary results substantiate that the tau-ribosome association reduces protein synthesis.Therefore the central hypothesis is that pathological tau inhibits ribosomal function. The rationale for theproposed research is that understanding the tau-mediated mechanism of ribosomal dysfunction will aid in thedesign of therapeutic targets for tauopathies which currently afflict a vast majority of the aging population. Ourstrong preliminary data serves as support for our hypothesis which will be tested in the following specific aims:1) Determine the extent to which endogenous pathological tau reduces ribosomal efficiency in vivo; and 2)Measure the effect of exogenous tauopathic brain-derived tau seeds on ribosomal efficiency. Aim 1 is tomeasure the effects of endogenous pathological tau on ribosomes using rTg4510 tau transgenic mice. In thismodel tau expression can be regulated with doxycycline. Tau expression will be manipulated in these miceand protein synthesis will be measured in the brain using SUnSET in vivo which has not been previously done.The anticipated results are that pathological tau levels will be inversely proportional with protein synthesis. Aim2 is to investigate the impact of exogenous pathological tau on ribosomal function. We will isolate the mosttoxic tau variants from human tauopathic brains. In addition we will isolate tau from brains at different stagesof Alzheimer's disease and related tauopathies. The toxic tau species will be incubated with ribosomes in acell-free environment (2.1) cell-based assays (immortalized and primary neurons) that measure proteinsynthesis: photoconversion-based method and non-radioactive pulse assay (SUnSET). These aims have thepotential of extrinsic merit to be used as screening tools for modulators of ribosomal function. Our approach isinnovative because it incorporates novel assays which offer excellent sensitivity that is not achievable by moretraditional approaches. This work is significant because it departs from the status quo by testing a newmechanism in which ribosomal function mediates tauopathic symptoms. This work is expected to advance thefield by filling the gap in understanding of tau-mediated brain dysfunction. This knowledge will serve to bettercharacterize the link between tau and memory impairment in order to develop novel therapeutic strategies.

project_terms:
Alzheimer's Disease;Attenuated;Biological Assay;Biology;Brain;Brain Diseases;Cells;Cognitive;Data;Disease;Doxycycline;Environment;Foundations;Functional disorder;Future;Goals;Human;Image;In Vitro;Incubated;Interruption;Knowledge;Link;Measures;Mediating;Memory;Memory Loss;Memory impairment;Messenger RNA;Methods;Mission;Modeling;Molecular;Mouse Protein;Mus;Neurofibrillary Tangles;Neurons;Operon;Outcome;Paralysed;Pathogenicity;Pathologic;Pathology;Physiologic pulse;Play;Production;Protein Biosynthesis;Proteins;Public Health;Puromycin;RNA;Regulation;Research;Ribosomal Interaction;Ribosomes;Role;Screening procedure;Seeds;Symptoms;Tauopathies;Temporal Lobe;Testing;Tetracyclines;Therapeutic;Transgenic Mice;Translating;Translations;United States National Institutes of Health;Variant;Wild Type Mouse;Work;age related;aging population;base;brain dysfunction;clinically relevant;common symptom;design;in vitro Model;in vivo;in vivo Model;innovation;non-demented;novel;novel therapeutics;tau Proteins;tau aggregation;tau expression;tau mutation;therapeutic target;virtual

public_health_relevance:
The proposed research is relevant to public health because it aims to clarify a pathological relationshipbetween clinically relevant tau and ribosomal function. The anticipated results from this study will serve as thefoundation for future efforts to clarify the impact of the tau-ribosome relationship on memory decline acommon symptom of virtually all tauopathies. Therefore the proposed research is relevant to the NIH'smission that pertains to contributing fundamental knowledge of the disease and establishing innovativeresearch strategies.


application_id: 9529361
project_number: 5R01DK074720-11
project_title: Novel mechanisms involving complement cascade in stem cell trafficking
administering_ic: NIDDK
award_notice_date: 2018-07-25
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DK
serial_number: 074720
program_official: ROY, CINDY
project_start_date: 2007-03-01
project_end_date: 2021-06-30
study_section: Molecular and Cellular Hematology Study Section[MCH]
contact_pi_person_id: 2265592
contact_pi: RATAJCZAK, MARIUSZ Z
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Modified Project Summary/Abstract SectionThe main hypothesis of this competing renewal is based on new exciting data that further supports the pivotalrole of the complement cascade (ComC) and other elements of innate immunity in the mobilization ofhematopoietic stem/progenitor cells (HSPCs). The ComC is activated by the i) classical ii) mannan-bindinglectin (Mbl) and iii) alternative pathways and as we already reported mice that lack the common distalcomponent of the ComC (C5/ mice) are poor mobilizers. To our surprise however we found that mice thatdo not activate the classical ComC (C1q/ mice) are normal mobilizers. This discrepancy is now explained byour latest results that show the pivotal involvement of the Mbl-dependent ComC pathway and not the classicalpathway in mobilization. We also recently found that two stress-induced enzymes heme oxygenase 1 (HO-1)and inducible nitric oxide synthetase (iNOS) are negative regulators of cell migration. Based on these findingswe have assembled a proposal that in a comprehensive way addresses the involvement of elements of innateimmunity (ComC Gr-1+ granulocytes/monocytes naturally occurring antibodies) in the mobilization of HSPCs.In three interrelated specific aims we address the crucial: i) inititation ii) amplification and execution phases ofmobilization. Specific Aim 1. The initiation phase of mobilization is explained by Mbl-mediated ComCactivation. We have maintained that the classical ComC activation pathway plays a crucial role in triggeringmobilization. However as we discovered recently it is not the classical but the Mbl pathway that is crucial inthis process. The main target cells for mobilizing agents are Gr-1+ cells which in addition to proteolytic andlipolytic enzymes also secrete ROS and danger-associated molecular pattern molecules (DAMPs). Whileproteolyic and lipolytic enzymes perturb the retention of HSPCs in bone marrow (BM) niches ROS-exposedneoepitope antigens bound by naturally occurring IgM antibodies and DAMPs released from Gr-1+ cells arerecognized by the circulating pattern recognition receptor (PRR) Mbl which via mannan-binding lectin serineproteases (MASPs) activates the ComC and coagulation cascade (CoaC). Specific Aim 2. The amplificationphase of mobilization - the generation of C5 convertase. Since C5 cleavage is crucial for egress of HSPCsfrom BM the main function of this phase is generation of C5 convertase activity. This enzyme is generated asa result of C3 cleavage which provides elements of classical C5 convertase and additionally by thrombinwhich has C5 convertase-like activity. The amplification phase is also modulated by a spontaneousamplification loop of C3 activation and by possible involvement of an alternative pathway of ComC activationand will be studied in detail in this aim. Specific Aim 3. Execution phase of ComC-mediated mobilization.Our recent results show that egress of HSPCs from BM is negatively controlled by HO-1 and iNOS which arenegative regulators of cell migration. We will focus on the molecular mechanisms of this phenomenon. It isexpected that these results will be translated into the development of better mobilization protocols.1

project_terms:
Address;Alternative Complement Pathway;Animal Model;Antibodies;Blood Circulation;Blood Vessels;Bone Marrow;Bone Marrow Transplantation;CXCR4 Receptors;CXCR4 gene;Cell Adhesion Molecules;Cell physiology;Cells;Chemotactic Factors;Circadian Rhythms;Coagulation Process;Complement;Complement 1q;Complement 3 Convertase;Complement Activation;Complement Factor H;Data;Defect;Development;Distal;Elements;Engraftment;Enzymes;Generations;Growth Factor;Hematopoiesis;Hematopoietic;Hematopoietic Stem Cell Mobilization;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Homing;Immunoglobulin M;Integrin alpha4beta1;Integrins;Ligands;Mannose Binding Lectin;Mediating;Molecular;Mus;Natural Immunity;Nitric Oxide;Nitric Oxide Synthase;Pathway interactions;Patients;Pattern;Pattern recognition receptor;Pharmacology;Phase;Physiological;Play;Process;Properdin;Protocols documentation;Reporting;Research;Role;Stem cells;Stress;Testing;Thrombin;Translating;Transplantation;Vascular Cell Adhesion Molecule-1;antigen binding;base;cell motility;conditioning;granulocyte;heme oxygenase-1;leukemia;mannose-binding protein-associated serine proteases;monocyte;neoantigens;novel;novel therapeutics;peripheral blood;pre-clinical;public health relevance;reconstitution;small molecule inhibitor;trafficking

public_health_relevance:
Modified Public Health Relevance SectionIn this proposal we will focus on the role of a major component of innate immunity namely the complementcascade in the trafficking of hematopoietic stem/progenitor cells. This application will allow us to betterunderstand this process and will lead to the development of novel therapeutic strategies to treat patients withleukemia and inborn defects of hematopoiesis by employing hematopoietic stem cell transplants.2


application_id: 9528690
project_number: 5P01NS097197-03
project_title: Genome editing mRNA suppression and chain termintion as therapy for Lafora Epilepsy
administering_ic: NINDS
award_notice_date: 2018-06-20
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: 8556
contact_pi_person_id: 11654552
contact_pi: MINASSIAN, BERGE 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: 2018-07-01
budget_end_date: 2019-06-30
project_abstract:
Lafora disease (LD) is a catastrophic epilepsy with onset in teenage years in otherwise normal adolescents. Its causes are known its pathogenesis in advanced understanding in major part through the research of members of this proposed program project. The disease genes EPM2A and EPM2B encode the laforin glycogen phosphatase and the malin ubiquitin E3 ligase which regulate glycogen synthesis in particular glycogen structure. Mutations of either gene lead to formation of malstructured glycogen (polyglucosan) which precipitates aggregates and accumulates into Lafora bodies (LB). These overtake neuronal somatodendritic cytoplasm and initiate a progressive soon-intractable epilepsy that aggressively escalates and leads to death after 10 years of essentially constant seizing. Our groups have shown in the LD mouse models that reducing glycogen synthesis by 50-100% through knockouts of the glycogen synthase (GS) gene or the GS activator PTG gene are safe and fully rescue murine LD. Here we propose to translate these findings from gene knockout experiments to therapeutic interventions in mouse as a step towards human therapy. In Aim 1 we target the GS and Ptg genes at the DNA level through CRISPR/Cas9 genome editing in collaboration with F Zhang co- discoverer of the CRISPR system. We deliver CRISPR/Cas9 using the AAV9 virus in collaboration with B Kaspar an AAV9 field leader. We utilize a new Cas9 enzyme recently developed in the Zhang lab with a size that for the first time allows packaging in AAV9. In Aim 2 we target the GS and Ptg genes at the mRNA level using antisense oligonucleotides with unique brain-specific chemistries. Here we already preliminarily show rescue. In Aim 3 we target glycogen itself. We utilize an innovative chain-termination approach which introduces glucose derivatives into the growing chains of polyglucosans to block extension and thus prevent their formation and prevent LB and LD. Finally in Aim 4 we utilize the ketogenic diet under which the brain utilizes ketones for energy in lieu of glucose and determine whether this can prevent LB formation. The aims of this and our other projects of this CWOW are a comprehensive intervention on the pathogenic pathway in LD. We expect that one though more likely a combination of these aims will succeed in our murine models and later translate to eliminating LD from the roster of intractable epilepsies.

project_terms:
Adolescent;Antiepileptic Agents;Antisense Oligonucleotide Therapy;Antisense Oligonucleotides;Base Pairing;Blood - brain barrier anatomy;Brain;CRISPR/Cas technology;Cessation of life;Chemistry;Child;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Cytoplasm;DNA;Dendrites;Dependovirus;Disease;Disease Progression;Enzymes;Epilepsy;GYS1 gene;Gene Targeting;Genes;Genetic;Genome;Glucose;Glycogen;Glycogen (Starch) Synthase;Homologous Gene;Hospitals;Human;Institutes;Intervention;Intractable Epilepsy;Ketones;Knock-out;Lafora Disease;Lead;Mediating;Messenger RNA;Mus;Mutation;Names;Nerve Degeneration;Neuraxis;Neurons;Oligonucleotides;Pathogenesis;Pathogenicity;Pathway interactions;Patients;Phosphoric Monoester Hydrolases;Plasmids;Positioning Attribute;Production;Property;Protein Isoforms;Proteins;RNA;Refractory;Regulation;Research;Solubility;Staphylococcus aureus;Starch;Structure;Symptoms;System;Teenagers;Therapeutic Intervention;Time;Translating;Universities;Virus;effective therapy;experimental study;gene therapy;genome editing;hydroxyl group;innovation;ketogenic diet;knockout gene;member;mouse model;nervous system disorder;nuclease;polyglucosan;prevent;programs;receptor;small molecule;ubiquitin-protein ligase;vector


application_id: 9528689
project_number: 5P01NS097197-03
project_title: Personalized diagnosis - defining how glycogen metabolism and proteostasis impact LD
administering_ic: NINDS
award_notice_date: 2018-06-20
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: 2018-07-01
budget_end_date: 2019-06-30
project_abstract:
Lafora disease (LD) is a fatal recessive neurodegenerative disorder that presents as an epileptic event in the 2nd decade of life. A hallmark of LD is the accumulation of cytoplasmic hyperphosphorylated water- insoluble glycogen-like particles called Lafora bodies (LBs). LD results from mutations in either of the genes encoding laforin a glycogen phosphatase or malin an E3 ubiquitin ligase and mutations in either gene results in development of LD. LBs cause disease from acute neurotoxicity due to the sensitivity of neurons to energy perturbations. Associated with LB formation cells display multiple markers indicating perturbations in critical cellular pathways including increased endoplasmic reticulum stress autophagy ROS production and others.  The overall focus of this Program Project Grant is to facilitate the Lafora Epilepsy Cure Initiative (LECI): which is an international collaboration devoted to the Diagnosis Treatment and Cure of LD. The goals of this project are to define the clinical biochemistry of LD mutations to provide a personalized diagnosis and establish therapeutic options. To achieve these goals we will define the molecular basis of LD utilizing structural biochemistry cellular biology and mouse models and translate our insights into mutation-specific diagnoses and novel therapeutic approaches to ameliorate LD induced epilepsy and cure LD.  We will first utilize integrated structural and functional tools to define the physical and cellular perturbations caused by LD mutations in both laforin and malin. These approaches will allow us to define the basis of neuronal-specific toxicity leading to disease. We will then develop personalized approaches to diagnosis and treat LD patients. We will define the role of neurotransmitter transporters affected in LD. Further we will determine how laforin and malin affect transporter homeostasis and how LD mouse models respond to treatment of symptoms with antiepileptic drugs. Lastly we will establish the beneficial effect of pharmacological intervention novel compounds that promote read-through of premature termination codons. Embedded in these approaches is the development of a novel bioassay will allow patient-specific diagnosis and definition of molecular sub-types of the disease key to each of the LECI Center projects. Further these results have significant broader implications since LD is one of five major progressive myoclonic epilepsies and the connection between metabolic dysfunction and epilepsy is an emerging theme.  Cumulatively these results will allow personalized therapeutic options that are developed to promote recovery of molecular and cellular function as a means of treating and curing LD.

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 dysfunction;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;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: 9528686
project_number: 5P01NS097197-03
project_title: Administrative Core
administering_ic: NINDS
award_notice_date: 2018-06-20
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: 2018-07-01
budget_end_date: 2019-06-30
project_abstract:
The Lafora Epilepsy Cure Initiative (LECI) Center exists to develop innovative and effectiveDiagnoses Treatments and Cures for Lafora Disease (LD). The LECI Center was initiatedduring a LD workshop held in San Diego in June 2014. The gathering of patient's familiesphysicians and scientists identified key progress that could be made when working togethertowards a cure for LD. We identified fundamental research questions and therapeutic strategiesto make this dream a reality. This Center will be a key aspect of our collaborative endeavor. The Administrative Core will be housed at the Center for Molecular Medicine within theUniversity of Kentucky College of Medicine and directed by Dr. Matthew Gentry. The LECIAdministrative Core will coordinate all of the activities of the Center. The Administrative Core isresponsible for implementing the goals of the Program overseeing the operations of thescientific and resources cores and ensuring open lines of communication within and betweenall projects as well as with NINDS. The Administrative Core will also coordinate activitiesinvolving the Executive Committee and the Advisory Board. The Administrative Core willcommunicate decisions by the Executive Committee concerning appropriate implementation ofthe LECI Charter and policies related to publications data sharing protocols and the website. This will be accomplished by: 1) Providing clear and transparent leadership; 2) Reportingcenter activities and accomplishments to all center members NINDS members of the oversightcommittees and members of the public; 3) Providing logistical support for communication withinthe project and with the community; 4) Coordinating research effort by overseeing all facets ofcollaborations both within and between the Center's four scientific projects and two scientificCores as well as with the broader scientific community to ensure the needs of the project PIsare being met.

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;Reporting;Research;Research Personnel;Resource Sharing;Resources;Scientist;Screening procedure;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;recruit;sharing data;skills;web site


application_id: 9527748
project_number: 5R21AI134323-02
project_title: Effector molecules for IFN-gamma-mediated prevention of Toxoplasma proliferation in the brain
administering_ic: NIAID
award_notice_date: 2018-06-29
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: AI
serial_number: 134323
program_official: PESCE, JOHN T
project_start_date: 2017-07-15
project_end_date: 2020-06-30
study_section: AIDS-associated Opportunistic Infections and Cancer Study Section[AOIC]
contact_pi_person_id: 1882071
contact_pi: SUZUKI, YASUHIRO
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:
Reactivation of chronic infection with Toxoplasma gondii results in the development of life-threateningtoxoplasmic encephalitis (TE) in AIDS and other immunocompromised patients. To improve prevention andmanagement of TE it is critical to gain a better understanding of the immunopathogenesis of the disease. IFN- is required for preventing cerebral tachyzoite proliferation and TE. However the effector mechanisms bywhich the IFN--mediated immunity prevents tachyzoite growth within brain-resident cells are poorlyunderstood. Whereas in vitro studies previously showed an importance of inducible nitric oxide synthase andimmunity-related GTPase m3 in inhibition of tachyzoite growth within murine microglia and astrocytesrespectively more recent in vivo studies using bone marrow (BM) chimeric mice demonstrated that their rolesto control T. gondii within brain-resident cells (irradiation-resistant non-hematopoietic population in the brainsof the BM chimeras) are negligible or subordinate. Thus it is essential to employ in vivo models fordetermining IFN--mediated effector mechanisms to prevent tachyzoite growth within brain-resident cells anddevelopment of TE. Our recent study using a murine model revealed that an inhibition of cerebral tachyzoitegrowth by the IFN--dependent protective immunity is associated with marked increases in expression ofguanylate binding protein 1 (Gbp1) and indoleamine-2 3-dioxygenase 1 (IDO1) but not IDO2 in the brain. Invitro studies by others previously showed inhibitory activities of Gbp1 and IDO against intracellular T. gondiigrowth in multiple types of host cells activated by IFN-. However it is unknown whether Gbp1 preventstachyzoite growth in vivo. The role of IDO against cerebral tachyzoite growth also remains to be determined.Thus in order to elucidate the effector mechanisms required for prevention of TE it is important to examine theroles of Gbp1 and IDO especially IDO1 in inhibiting cerebral tachyzoite growth in vivo. Thus the goal of thisproject is to determine the roles of Gpb1 and IDO1 in IFN--mediated prevention of tachyzoite proliferationwithin the major glial cell populations in the brain microglia and astrocytes during reactivation of T. gondiiinfection using murine models. Whereas viral infections induce Gbp1 expression in both murine and humanmicroglia the induction of Gbp1 by infections in astrocytes has not been reported. In contrast both mouse andhuman primary astrocytes express IDO1. Thus we will determine the roles of Gpb1 in microglia (Aim 1) andthe roles of IDO1 in astrocytes (Aim 2) in their IFN--mediated protective activities to prevent intracellulartachyzoite proliferation and development of TE in vivo using murine models. We will employ a novel in vivomodel using BM chimeric mice deficient in Gbp1 or IDO1 only in brain-resident cells in the brain and infectingthe mice with a double reporter strain of T. gondii expressing red fluorescent protein in tachyzoites and greenfluorescent protein in bradyzoites. We will utilize an advanced system of purifying microglia from the brainsand flow cytometry to quantitatively visualize tachyzoite growth within the glial cell population.

project_terms:
Acquired Immunodeficiency Syndrome;Astrocytes;Binding Proteins;Bone Marrow;Brain;CD4 Positive T Lymphocytes;Cell Count;Cell physiology;Cells;Cerebrum;Chimera organism;Cyst;Development;Dioxygenases;Disease;Exhibits;Flow Cytometry;Goals;Green Fluorescent Proteins;Growth;Growth and Development function;Guanosine Triphosphate Phosphohydrolases;Human;Immunity;Immunocompromised Host;In Vitro;Individual;Infection;Interferon Type II;Knock-out;Knockout Mice;Lead;Life;Mediating;Methods;Microglia;Modeling;Mus;NOS2A gene;Neuroglia;Nitric Oxide;Nitric Oxide Synthase;Organ;Parasites;Patients;Play;Population;Prevention;Production;Reporter;Reporting;Resistance;Role;Rupture;T-Lymphocyte;Tissues;Toxoplasma;Toxoplasma gondii;Toxoplasmosis;Tumor stage;Virus Diseases;advanced system;base;brain parenchyma;chronic infection;guanylate;improved;in vivo;in vivo Model;indoleamine;inhibitor/antagonist;instrument;interest;irradiation;macrophage;mortality;mouse model;novel;pathogen;prevent;red fluorescent protein;toxoplasmic encephalitis

public_health_relevance:
Reactivation of chronic infection with Toxoplasma gondii in the brain causes life-threatening toxoplasmic encephalitis (TE) in immunocompromised individuals. Theproposed studies are aimed to determine the effector molecules required for preventionof the pathogen growth within brain-resident cell populations. These studies will providethe information crucial for developing a novel method(s) to improve preventiontreatment and management of TE by directly amplifying the capability of the brain-resident cells to inhibit the pathogen growth.


application_id: 9526982
project_number: 5R01AG057187-02
project_title: Novel pathogenetic mechanism for hippocampal sclerosis a common Alzheimers mimic
administering_ic: NIA
award_notice_date: 2018-04-13
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 057187
program_official: OPANASHUK, LISA A
project_start_date: 2017-07-15
project_end_date: 2022-03-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: 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:
ABCC9 gene;Affect;Age;Aging;Agonist;Alzheimer's Disease;American;Area;Astrocytes;Autopsy;Behavior;Biological Markers;Biometry;Blood specimen;Brain;Brain Diseases;Brain Pathology;Cell Culture Techniques;Cells;Clinical;Cognitive;DNA;Data;Databases;Dementia;Development;Diagnosis;Disease;Elderly;Exhibits;Functional disorder;Future;Gene Expression;Genes;Genetic;Genotype;Glimepiride;Goals;Hippocampus (Brain);Hormone Responsive;Human;Impaired cognition;Individual;Infarction;Interdisciplinary Study;Kentucky;Knockout Mice;Knowledge;Life;Link;Metformin;Methods;Modeling;Morbidity - disease rate;Mus;Mutation;Neurofibrillary Tangles;Oral;Pathogenesis;Pathologic;Pathology;Patient Self-Report;Persons;Pharmaceutical Preparations;Pharmacology;Phenotype;Regulator Genes;Research;Research Personnel;Risk;Sampling;Severities;Spinal Puncture;Testing;Therapeutic;Thyroid Gland;Thyroid Hormones;Thyroxine;Transcript;Triiodothyronine;Universities;Widespread Disease;aged;base;biobank;cell transformation;clinical biomarkers;cohort;digital;experimental study;genetic variant;genomic biomarker;hippocampal sclerosis;human embryonic stem cell;human genomics;in vivo;neurobehavior;neuropathology;novel;novel marker;prevent;programs;protein TDP-43;risk variant;synucleinopathy;therapeutic target


application_id: 9526967
project_number: 5P30AG028383-13
project_title: Core E: Outreach and Recruitment Core
administering_ic: NIA
award_notice_date: 2018-08-06
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1-ZIJ-G
subproject_number: 6812
contact_pi_person_id: 9662252
contact_pi: SCHMITT, FREDERICK
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: 2018-07-01
budget_end_date: 2019-06-30
project_abstract:
Project Summary/Abstract: Outreach and Recruitment CoreThe Outreach and Recruitment (OR) Core functions as a key link between the UK-ADC and the local and statecommunities. OR Core programs and activities have created and will maintain an educated local communityeager to receive updated information on AD and to participate in our Centers research. Through OR Coreefforts the UK-ADC will continue to work with both the Commonwealth of Kentucky and UK partners indirecting state and institutional responses to meeting dementia health care needs and increasing healthliteracy in the elderly. Over the past five years the OR Core has taken the lead in developing innovativepartnerships and products to support research participation by African Americans the largest minority group inKentucky. We will continue to emphasize recruitment and retention of research participants at the earlieststages of the cognitive continuum (Cognitively Normal and MCI). These efforts involve engaging theseparticipants in the ADC longitudinal cohort as well as agreement to brain donation in support of theNeuropathology Core willingness to engage in clinical studies and therapeutic trials that support the ClinicalCore and donation of antemortem biospecimens (plasma DNA CSF and neuroimaging) that support allCores. In the next cycle we will maintain and further build on these efforts and partnerships through thefollowing specific aims:Aim 1. Recruit and retain individuals into our longitudinal cohort ADC-affiliated research studies and nationalinitiatives with a special focus on recruitment and retention of African Americans.Aim 2. Increase community awareness of AD and related disorders through the promotion of health literacythat further enhances recruitment and retention of minority participants in research.Aim 3. Evaluate the effectiveness of our outreach recruitment and educational activities with both qualitativeand quantitative metrics of success.Aim 4. Support and collaborate with the other Cores to reach UK-ADC goals.The OR Core plays a critical role in the UK-ADC and works closely with the other Cores to support recruitmentand retention activities for research protocols clinical trials and national initiatives; increase communityawareness of AD and maintain a strong presence in the African-American community; support educationalinitiatives for the lay community in collaboration with key partners. These functions are vital to the UK-ADCmission to catalyze outstanding and innovative research outreach education and clinical programs.

project_terms:
Address;African American;Aging;Agreement;Alzheimer's Disease;Alzheimer's Disease Core Center;Area;Autopsy;Awareness;Biological Markers;Brain;Catchment Area;Clergy;Clinical;Clinical Research;Clinical Trials;Cognitive;Collaborations;Communication;Communities;Community Actions;Consent;DNA;Data Collection;Databases;Dementia;Development;Disease;Education;Educational Activities;Effectiveness;Elderly;Enrollment;Event;Extramural Activities;Failure;Fostering;Future;Goals;Health Promotion;Healthcare;Individual;Intervention Trial;Kentucky;Lead;Link;Longitudinal cohort;Minority;Minority Groups;Minority Participation;Mission;Outcome Measure;Participant;Plasma;Play;Poa plant;Program Development;Protocols documentation;Recording of previous events;Recruitment Activity;Reporting;Research;Research Activity;Research Support;Resources;Risk Factors;Role;System;Therapeutic Trials;Time;Translational Research;Translations;Universities;Update;Work;cohort;dementia care;demographics;design;education research;health literacy;healthcare community;innovation;meetings;member;minority communities;neuroimaging;neuropathology;outreach;parity;participant retention;programs;recruit;research study;response;success;volunteer;willingness


application_id: 9526966
project_number: 5P30AG028383-13
project_title: Core D: Neuropathology Core
administering_ic: NIA
award_notice_date: 2018-08-06
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1-ZIJ-G
subproject_number: 6811
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
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: 2018-07-01
budget_end_date: 2019-06-30
project_abstract:
Project Summary/Abstract: Neuropathology CoreThe overall objective of the Neuropathology Core of the University of Kentucky Alzheimers Disease Center(UK-ADC) is to support research on normal brain aging presymptomatic Alzheimers disease (pAD) mildcognitive impairment (MCI) early and late AD mixed dementia syndromes and other dementing disorders.Autopsies will be performed by our Rapid Autopsy Team on longitudinally followed subjects from our ClinicalCore. We will perform short post-mortem interval autopsies in relation to our clinical cohort and we willmaintain a high autopsy rate. This Core is optimally tailored to help address important research questions.The Core will provide brain tissue specimens CSF and synaptosomes for investigators at UK other ADCsand outside investigators. The Core will also provide consensus conference determined diagnosesquantitation of neurofibrillary tangles (NFT) neuritic plaques and diffuse plaques from 8 brain regions A 1-40and 1-42 quantitation Braak staging CERAD and NIA-Reagan Institute staging on all autopsied cases toinvestigators. This brain bank has been operating continuously for over three decades with a strong trackrecord so special care will be taken to ensure diagnostic excellence consistency and continuity. The Corewill maintain a tissue bank of the above specimens and frozen serum plasma buffy coats and CSF from livingpatients. Special emphasis will be placed on defining the neuropathological findings in the brains of the oldestold (>85 years) and providing investigators with specimens from cognitively intact control subjects with no Adeposition and sparse tau pathology (successful cerebral aging) and also cognitively intact subjects withabundant plaques and neurofibrillary tangles. Providing these samples will contribute to clinical-pathologicalcorrelation studies and cutting-edge research that include sponsored studies related to AD genomics oxidativestress hippocampal sclerosis dementia with Lewy bodies amyloid precursor protein processing Downsyndrome and neuroinflammation. Frequent consensus conferences will be held with the Clinical Core andBiostatistics Core to help define clinical-pathological diagnoses on all autopsied subjects. This Core is stronglyintegrated with other Cores of the UK-ADC and exploits unique opportunities to conduct clinical-pathologicalcorrelative studies on longitudinally followed subjects. Through these methods we will better understandnormal brain aging and the transition to dementia with the focused goal of contributing to therapeutic orpreventive measures. The Neuropathology Core complements the other Cores of the UK-ADC to provide extremely essentialdiagnoses and tissue samples that are required for many cutting-edge researchers at the University ofKentucky and elsewhere. We will build on our track record of excellence using innovative tools related to brainautopsies neuropathological diagnoses tissue banking and state-of-the-art clinical-pathological correlation.

project_terms:
Address;Aged 80 and over;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Amyloid beta-Protein;Area;Autopsy;Biological;Biological Markers;Biometry;Biostatistics Core;Brain;Brain Diseases;Brain imaging;Brain region;Caring;Catalogs;Cerebrospinal Fluid;Cerebrum;Clinical;Clinical Trials;Cognition Disorders;Cognitive;Collaborations;Complement;Consensus;Correlation Studies;Correlative Study;DNA;Data;Databases;Dementia;Diagnosis;Diagnostic;Disease;Down Syndrome;Ensure;Freezing;Frontotemporal Lobar Degenerations;Genetic study;Genomics;Goals;Impaired cognition;Individual;Institutes;Investigation;Kentucky;Laboratory Research;Lesion;Lewy Body Dementia;Medical Genetics;Memory;Methodology;Methods;Mission;Nerve Degeneration;Neurofibrillary Tangles;Oxidative Stress;Pathologic;Pathology;Patients;Plasma;Preparation;Preventive measure;Protocols documentation;Publishing;Religion and Spirituality;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Running;Sampling;Senile Plaques;Serum;Services;Specimen;Staging;Standardization;Synaptosomes;Syndrome;Tauopathies;Therapeutic;Thinness;Time;Tissue Banks;Tissue Sample;Tissues;Universities;Work;abeta deposition;age related;age related neurodegeneration;aging brain;amyloid precursor protein processing;blood product;brain tissue;cerebrovascular pathology;cohort;data management;digital;experience;genome wide association study;hippocampal sclerosis;innovation;meetings;mild cognitive impairment;mixed dementia;neuroinflammation;neuropathology;normal aging;novel;pre-clinical;protein TDP-43;repository;symposium;synucleinopathy;tau Proteins;tool


application_id: 9526965
project_number: 5P30AG028383-13
project_title: Core C: Data Management and Statistical Core
administering_ic: NIA
award_notice_date: 2018-08-06
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1-ZIJ-G
subproject_number: 6810
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD 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: 2018-07-01
budget_end_date: 2019-06-30
project_abstract:
Program Summary/Abstract: Data Management and Statistical CoreThe Data Management and Statistical (DMS) Core can be conceptualized as the lynchpin for integration of theADC Cores and is vital to the success of the UK-ADC. Its critical roles include managing a large centralizeddatabase consulting with ADC-affiliated researchers and working to develop and apply innovative statisticalmethodology for data analysis. Data management efforts focus on collecting and storing high quality data.This focus begins with the leadership and vision and attention to detail provided by the DMS Core. This corehas an enviable track record of timely and accurate reporting of a high volume of data to NACC. Furtherweekly Core meetings are popular with UK-ADC investigators who find that the expert advice provided by ourseasoned investigators improves their success in pilot studies grant applications and publications. The Corealso participates as a full partner to the research mission of the UK-ADC emphasizing transitions andtranslations. One such partnership with the Clinical and Neuropathology Cores relates to clinico-pathologicalmodels of mixed dementias. A key element of this DMS Core is the well-established track record of developingnovel methodology to analyze data collected at the UK-ADC and from other cohorts with a focus on elderlysubjects transitions to MCI and eventually dementia. The Core also provides training for students enrolled inthe graduate programs in Gerontology Public Health Epidemiology and Biostatistics Psychology andStatistics. It is committed to developing younger faculty to become productive ADC investigators. In keepingwith the mission of the UK-ADC faculty in this Core also contribute to the dementia research community atlarge through service on external advisory committees study sections manuscript reviews and data safetymonitoring boards. The DMS Core will continue these critical responsibilities through the following specificaims.1: Create and maintain a web-based integrated data warehouse for ADC Cores and projects.2: Provide expertise on experimental design and statistical analysis.3: Support the clinical neuropathological and educational/outreach missions of the ADC.4: Contribute to the activities of the dementia community at large through service and research.

project_terms:
Adopted;Advisory Committees;Alzheimer's Disease;Alzheimer's Disease Core Center;Applications Grants;Area;Attention;Biological Markers;Biometry;Cerebrospinal Fluid;Clinical;Clinical Trials;Clinical Trials Data Monitoring Committees;Cognitive;Collaborations;Communities;Consult;Data;Data Analyses;Data Collection;Data Element;Data Quality;Databases;Dementia;Elderly;Enrollment;Epidemiology;Evaluation;Event;Experimental Designs;Extramural Activities;Faculty;Funding;Future;Generations;Genetic;Gerontology;Growth;Health Services Research;Image;Kentucky;Leadership;Literature;Manuscripts;Mentors;Methodology;Methods;Mission;Modeling;Neuroepidemiology;Online Systems;Paper;Participant;Pathologic;Pathology;Phase;Pilot Projects;Psychology;Public Health;Publications;Records;Reporting;Research;Research Design;Research Personnel;Research Support;Risk Factors;Role;Scanning;Seasons;Secure;Services;Statistical Data Interpretation;Study Section;System;Tablets;Time;Training;Translational trial;Translations;Universities;Ursidae Family;Vision;cohort;data management;data warehouse;direct application;doctoral student;improved;innovation;interest;meetings;member;mixed dementia;neuropathology;novel;outreach;programs;recruit;statistics;student training;success


application_id: 9526964
project_number: 5P30AG028383-13
project_title: Core B: Clinical Core
administering_ic: NIA
award_notice_date: 2018-08-06
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1-ZIJ-G
subproject_number: 6809
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY 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: 2018-07-01
budget_end_date: 2019-06-30
project_abstract:
Project Summary/Abstract: Clinical CoreThe Clinical Core of the UK-ADC maintains a well-characterized community-based cohort focused onnormal aging and early transitional disease states and follows individuals longitudinally until brain autopsy.We maintain a mandatory autopsy requirement for all subjects (with the exception of our Minority GatewayClinic where autopsy is promoted but not required) allowing major contributions in the area of clinical-pathological correlative studies definition of early preclinical and pre-dementia disease state pathologyand basic translational research. The UK-ADC Clinical Core emphasizes: 1) collection of demographicclinical genetic and autopsy data from large numbers of subjects readily available as potential researchsubjects for current and future research needs 2) provision of non-autopsy biospecimens includingantemortem imaging and CSF biomarkers in a sub-cohort of subjects and 3) efforts to further advance thediscovery and development of novel therapeutics for AD. We are major contributors to nationalcollaborative initiatives such as NACC ADCS ADNI NCRAD and ADGC. Our research cohort is stronglymotivated to participate in research as evidenced by 304 unique active (living) subjects who haveparticipated in clinical studies over the report period. The Clinical Core has supported 40 grants and affiliatedprojects focused on specific research questions beyond standard UK-ADC data collections culminating in 64direct and 18 indirect publications supported by Core activities. Antemortem biomarker collections over thecurrent funding cycle include 361 clinical and 267 standardized research MRI scans 229 CSF collections and90 A-PET scans in order to more fully characterize our normal control and early transitional (MCI) cohort.Another major strength of our center lies in our robust minority outreach and engagement. Our efforts inconjunction with the OR Core have led to above-par for local and regional area minority engagement in ADCand affiliated studies. We have effectively engaged minority subjects in perceived invasive and therapeuticresearch efforts at a level of participation that has previously been considered untenable by most ADCs andnon-NIA funded centers nationally (37.6% unique minority subjects engaged in interventional trials). Theseefforts and successes will continue in the next five years under the harmonized and integrated Clinical Coreefforts that have proven successful at the UK-ADC. We will continue to play a leading role in clinicaltranslational research and development of potential novel therapeutic strategies to prevent or modifypathogenesis of AD and related disorders. Overall the Clinical Core will continue to provide an infrastructureand environment that will continue to contribute to our success in advancing multidisciplinary innovative ADresearch supporting our center theme of Transitions & Translation.

project_terms:
Alzheimer's Disease;Alzheimer's Disease Core Center;Amyloid beta-Protein;Area;Autopsy;Basic Science;Biological Markers;Blood;Brain;Cessation of life;Clinic;Clinical;Clinical Research;Clinical Trials;Cognitive;Collaborations;Collection;Communities;Correlative Study;Data;Data Collection;Data Set;Dementia;Development;Disease;Education and Outreach;Environment;Extramural Activities;Foundations;Funding;Genetic Markers;Grant;Heart;Image;Impairment;Individual;Industry;Intervention Trial;Kentucky;Leadership;Longitudinal cohort;MRI Scans;Magnetic Resonance Imaging;Medical Genetics;Minority;Minority Participation;Mission;Pathogenesis;Pathologic;Pathology;Pharmaceutical Preparations;Phase;Play;Population;Positron-Emission Tomography;Publications;Reporting;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Subjects;Research Support;Role;Schedule;Specimen;Standardization;Therapeutic Human Experimentation;Tissues;Translational Research;Translations;United States National Institutes of Health;Universities;Work;active lifestyle;base;cohort;data management;innovation;meetings;minority communities;minority subjects;multidisciplinary;normal aging;novel therapeutics;operation;outreach;pre-clinical;prevent;programs;research and development;success;therapeutic development


application_id: 9526960
project_number: 5P30AG028383-13
project_title: Core A: Administrative Core
administering_ic: NIA
award_notice_date: 2018-08-06
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1-ZIJ-G
subproject_number: 6808
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-07-01
budget_end_date: 2019-06-30
project_abstract:
Project Summary/Abstract: Administrative CoreThe ultimate goal of the UK-ADC is to catalyze innovative and outstanding AD research while ensuring a morerapid rate of progress toward new therapies to delay or prevent AD so that our human volunteers patients andcaregivers become the beneficiaries of our advances in knowledge. The Administrative Core provides thefoundation infrastructure leadership overall direction strategic planning and integration of all ADCcomponents to more rapidly achieve this goal. We support and facilitate research aimed at elucidating thepathogenic mechanisms underlying the transitions from normal cognitive aging to the development ofcognitive impairment with a long-term goal of enabling more effective translation of this mechanisticknowledge to intervention strategies. The UK-ADC functions in a multidisciplinary integrated collaborative andsupportive environment that catalyzes high-quality AD research within the UK community region nation andbeyond. Our major emphases continue to support our traditional strengths in neuropathologic discoveries andprovision of normal and MCI autopsy tissue to support basic translational research as well as our maturingprogram in antemortem biomarker assessment of predementia-stage subjects. The UK-ADC also enhanceseducation and outreach within UK and in the community. We have developed a trusting partnership with theAfrican-American community that has resulted in successful outreach programs and educational products aswell as increasing minority participation in research studies. We have innovative programs focused on qualityof care and support for people with dementia and their caregivers. We offer multi-faceted educational andtraining programs to healthcare professionals and researchers that are aimed at enhancing the training of aworkforce to meet the nations biomedical behavioral and clinical needs in AD-related research. Oursuccessful Pilot Project program leveraged support from university partners to be able to fund 6 additional pilotprojects beyond the 10 funded by the ADC grant. The UK-ADC also reaches beyond Kentucky to enhance ADresearch education and clinical practice on a national level through its interactions with other ADCs as wellas other regional and national institutions including the Alzheimers Association NIA and industry. TheAdministrative Core will continue to support the ability of our UK-ADC to serve as a vital resource for theuniversity community state region and nation through the following specific aims.Aim 1: Provide leadership and an organizational framework for management and coordination of all ADCactivities to ensure optimal resource utilization to meet the overall goals of the ADC.Aim 2: Promote our translational mission and enhance research education and scientific interactions.Aim 3: Contribute to and interact with other ADCs and other national collaborative activities and increasevisibility in the local and national community.

project_terms:
Advisory Committees;African American;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Area;Autopsy;Behavioral;Biological Markers;Caregivers;Clinical;Clinical Trials;Cognitive aging;Collaborations;Communication;Communities;Dementia;Education;Education and Outreach;Ensure;Ethics;Evaluation;Faculty Recruitment;Fostering;Foundations;Funding;Future;Goals;Grant;Growth;Health Professional;Human Volunteers;Impaired cognition;Industry;Institution;Intervention;Kentucky;Knowledge;Leadership;Medical;Minority Participation;Mission;Pathogenicity;Patients;Pilot Projects;Policies;Productivity;Quality of Care;Research;Research Activity;Research Infrastructure;Research Personnel;Resources;Strategic Planning;Tissues;Training;Training Programs;Translational Research;Translations;Trust;Universities;University resources;beneficiary;career;caregiver education;clinical practice;cognitive development;collaborative environment;innovation;multidisciplinary;novel therapeutics;outreach;outreach program;prevent;programs;research study;training opportunity;translational scientist


application_id: 9526955
project_number: 5P30AG028383-13
project_title: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2018-08-06
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
program_official: SILVERBERG, NINA B
project_start_date: 2006-07-15
project_end_date: 2021-06-30
study_section: ZAG1-ZIJ-G(M1)
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract: OverallThis application seeks to renew the University of Kentucky Alzheimers Disease Core Center (UK-ADC) anexperienced and collaborative ADC originally funded in 1985. Our principal mission is to serve as the focalpoint for all AD-related activities at UK and this region of the United States by providing an environment andcore resources that catalyze innovative research outreach education and clinical programs. Our signatureresources include: 1) a cognitively normal group of ~500 subjects followed longitudinally with all committed tobrain autopsy upon death; 2) a strong program in clinical-neuropathological correlations and short postmorteminterval autopsies; 3) a maturing program studying the early preclinical biological emergence of pathology thatmay lead to dementia states with an increasing focus on antemortem imaging and CSF biomarker collection;4) an integrated centralized database and innovative biostatistical expertise to characterize clinical andbiological transitions; and 5) a successful and close partnership with the African-American community andincreased participation of underrepresented individuals in our longitudinal cohort and ADC-affiliated researchstudies and clinical trials. The overall scientific emphasis of the UK-ADC continues to be on our interrelatedthemes: Transitions & Translation. Our well-characterized longitudinal cohort and historically strongneuropathology program focused on normal aging preclinical disease states and early cognitive transitionshave been central to our success in defining early pathogenic mechanisms underlying the transitions fromnormal cognitive aging to impairment. The depth of expertise and collaborative nature of our investigators havealso resulted in substantial progress on translation of that knowledge into new targets and novel therapeuticstrategies. The UK-ADC will continue to provide the infrastructure and resources to focus on these integratedthemes and advance innovative AD research through the pursuit of four overarching specific aims.Aim 1. Facilitate and enhance basic translational and clinical research in AD and related dementias.Aim 2. Provide the necessary resources and interactive environment to support and create new opportunitiesfor innovative research.Aim 3. Maintain and grow educational opportunities and community partnerships to promote awarenessincrease participation in research and provide an innovative and interdisciplinary training environment.Aim 4. Contribute to the national efforts to advance AD research education and care.The UK-ADC provides an infrastructure and environment that focuses on these integrated themes andadvances AD research education outreach and clinical programs through six highly interactive and effectivecomponents: Administrative Core Clinical Core Data Management and Statistics Core Neuropathology CoreOutreach and Recruitment Core and Research Education Component.

project_terms:
African American;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Area;Autopsy;Awareness;Basic Science;Biological;Biological Markers;Biometry;Brain;Caring;Cessation of life;Clinical;Clinical Research;Clinical Trials;Cognitive;Cognitive aging;Collaborations;Collection;Communities;Community Outreach;Comorbidity;Databases;Dementia;Disease;Education;Education and Outreach;Environment;Funding;Goals;Health Professional;Image;Impaired cognition;Impairment;Individual;Industry;Intervention;Kentucky;Lead;Longitudinal cohort;Mission;Nature;Neurodegenerative Disorders;Outcome;Pathogenicity;Pathology;Pilot Projects;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Risk;Training;Translating;Translational Research;Translations;United States;Universities;Work;aging brain;biomarker development;clinical practice;cognitive development;cohesion;collaborative environment;community partnership;data management;education research;experience;healthcare community;innovation;knowledge translation;neuropathology;new therapeutic target;next generation;normal aging;novel therapeutics;outreach;pre-clinical;prevent;programs;recruit;research study;statistics;success

public_health_relevance:
NARRATIVE: OVERALLThe University of Kentucky Alzheimers Disease Center facilitates and supports research efforts to identify theearly manifestations of disease and the pathogenic mechanisms underlying the transitions from normal agingto the development of cognitive impairment with an overall goal of more rapid translation of that knowledgeinto new therapies to delay or prevent AD. We are also dedicated to training the next generation ofresearchers and to educating the lay and healthcare community to increase awareness of AD and relateddisorders and the importance of research and research participation.


application_id: 9526461
project_number: 5R01DA040694-04
administering_ic: NIDA
award_notice_date: 2018-07-26
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DA
serial_number: 040694
program_official: WALTON, KEVIN
project_start_date: 2015-09-15
project_end_date: 2020-07-31
study_section: Pregnancy and Neonatology Study Section[PN]
contact_pi_person_id: 9641889
contact_pi: ASHFORD, KRISTIN H.
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-08-01
project_title:
The impact of electronic cigarettes (e-cigs) on perinatal immune responsiveness and birth outcomes in Appalachia

project_abstract:
DESCRIPTION (provided by applicant): The United States has the largest and fastest growing market for electronic cigarettes (e-cigs) and adult women of childbearing age are the most common users. However no data exist regarding the health effects of e-cigs on pregnant women or their babies. It is well known that tobacco use during pregnancy is the most modifiable risk associated with adverse birth outcome yet nearly one in four women in Kentucky continue to use tobacco products during pregnancy. E-cigs also contain varied (unregulated) concentrations of nicotine despite nicotine being classified as a pregnancy class-D drug (exhibiting teratogenic effects on the fetus). The addictive nature of nicotine may explain continued use during this vulnerable time. E-cigs have been the center of recent controversy regarding novel smoking cessation or harm reduction products. There is also concern that marketing strategies promoting harm reduction may increase the appeal and obfuscate the known adverse effects of nicotine on fetal development. In addition to the adverse effects of prenatal nicotine maternal tobacco use alters immune response during pregnancy placing women at increased risk for preterm birth. We plan to build on previous work to determine the impact (better same or worse) that e-cigs and dual use (conventional + e-cig) have on prenatal immune response and birth outcomes compared to conventional use and dual use. Our overall goal is to determine the effects of e-cigs (and dual use) on perinatal biomarkers and birth outcomes. Three hundred and sixty pregnant women will be recruited. Participants will complete a survey to measure tobacco related behaviors and provide perinatal biomarkers at four time points (each trimester and postpartum). Data analysis will include a series of repeated ANCOVAs to determine the association of perinatal cigarette smoking (conventional e-cigarettes-only and dual use) with perinatal biomarkers. A one- way ANCOVA will be used to determine the association with birth outcomes. Primary biomarker measures include: expired air carbon monoxide urine and serum cotinine serum immune markers and urinary NNAL. Gestational age at birth and birth weight are the primary birth outcomes. Until more data about the effects of e-cigs and dual use on perinatal immune response and birth outcomes are available promotion of e-cigs during pregnancy would be premature. There is an urgent need to investigate the impact of e-cigs and dual use on perinatal biomarkers and birth outcomes. The lack of research may unnecessarily place women-and their babies -at risk for lifelong adverse health outcomes.

project_terms:
1-Butanol;Adult;Adverse effects;Air;Analysis of Covariance;Appalachian Region;Awareness;Behavior;Biological;Biological Markers;Birth;Birth Weight;Bone Density;Butanones;Carbon Monoxide;Cigarette;Cotinine;Data;Data Analyses;Electronic cigarette;Exhibits;Female of child bearing age;Fetal Development;Fetus;Gestational Age;Goals;Harm Reduction;Health;Heart Diseases;Immune;Immune Sera;Immune response;Immunologic Markers;Immunologics;Infant;Interleukin-1 beta;Interleukin-10;Interleukin-6;Interleukin-8;Interleukins;Kentucky;Liquid substance;Literature;Malignant neoplasm of lung;Marketing;Measures;Methods;National Institute of Drug Abuse;Nature;Neutrophil Collagenase;Nicotine;Nitrosamines;Outcome;Participant;Perception;Perinatal;Pharmaceutical Preparations;Postpartum Period;Postpartum Women;Pregnancy;Pregnant Women;Premature Birth;Relapse;Research;Risk;Safety;Series;Serum;Serum Immunologic;Smoke;Smoking;Smoking Behavior;Smoking Status;Spontaneous abortion;Surveys;TNF gene;Teratogenic effects;Time;Tobacco;Tobacco use;United States;United States Food and Drug Administration;Urine;Vulnerable Populations;Woman;Work;adverse pregnancy outcome;authority;burden of illness;carcinogenicity;cigarette smoking;cytokine;design;electronic cigarette use;experience;maternal tobacco use;modifiable risk;mortality;novel;perinatal period;premature;prenatal;prospective;public health relevance;recruit;smoking cessation;smoking during pregnancy;tobacco use in pregnancy;urinary;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE: There has been a dramatic escalation of electronic cigarette (e-cig) use among women of childbearing age including pregnant women. Our overall goal is to determine the effects of e-cigs on prenatal biomarkers and birth outcomes. It is imperative that more data about these effects be available to better inform this vulnerable population. We believe our goals will generate the necessary data to guide regulatory authorities.


application_id: 9526110
project_number: 3R01DA033862-05S1
project_title: Effect of structural interventions on substance use and HIV/HCV risk among rural PWUD
administering_ic: NIDA
award_notice_date: 2017-09-13
opportunity_number: PA-16-287
application_type: 3
activity_code: R01
ic: DA
serial_number: 033862
suffix: S1
program_official: DUFFY, SARAH Q
project_start_date: 2017-08-01
project_end_date: 2021-11-30
contact_pi_person_id: 7018622
contact_pi: HAVENS, JENNIFER R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overarching goal of this renewal application (R01DA033862) is to determine the influence of structural interventions on engagement in risk reduction and health promotion activities among rural Appalachian drug users. Results from the three-year R01 that the investigators seek to continue reveal an ever-changing landscape of prescription drug abuse; an epidemic that is still in its infancy. Unlike many rural and suburban areas there is little evidence for the transition to heroin abuse. In this cohort there has been  marked shift from abuse of OxyContin(r) (extended-release oxycodone) to immediate release oxycodone to more recently buprenorphine and gabapentin-containing products. In addition rates of HCV prevalence and incidence are high especially given the population density of rural Appalachia. Given the syndemic of opioid abuse and infectious disease transmission two structural interventions are particularly relevant to this population of rural people who use drugs(PWUD). Medicaid (MC) expansion (under the Affordable Care Act [ACA]) and syringe access programs (SAP) are two structural interventions that may allow for increased engagement in health promotion among PWUD but are likely heavily influenced by individual network and community-level factors. Utilizing Latkin's Dynamic Social Systems model and leveraging the extant highly successful cohort of rural PWUD the aims include: 1) examining how dynamic factors of these structural interventions influence longitudinal trends in illicit and prescriptiondrug abuse; 2) determining the influence of these structural interventions on HIV/HCV incidence and engagement in risk reduction; and 3) assessing the influence of these structural interventions on uptake of substance abuse treatment. This study is highly significant given that understanding the mechanisms by which these specific structural interventions influence health promotion is key to improving public health in rural Appalachia. Substance abuse and HCV are two of the most important if not the most important health issues facing this region already plagued with marked health disparities. Using innovative measures of network and geospatial risk as well as conjoint analysis and multilevel longitudinal statistical models results will notonly inform development of interventions that optimize uptake and utilization of risk reduction services such as SAP and substance abuse treatment but may inform policies surrounding further implementation of health promotion programs in the rural U.S.

project_terms:
Accounting;Address;Affordable Care Act;Alcohol or Other Drugs use;Appalachian Region;Area;Behavior;Biological Models;Buprenorphine;Communicable Diseases;Communities;Complement;County;Data;Data Collection;Development;Disease Outbreaks;Disease Outcome;Drug abuse;Drug usage;Drug user;Effectiveness;Enrollment;Epidemic;Frequencies;Goals;HIV;HIV/HCV;Health;Health Promotion;Hepatitis C;Hepatitis C Incidence;Hepatitis C Prevalence;Hepatitis C Transmission;Heroin Abuse;Illicit Drugs;Indiana;Individual;Injecting drug user;Injection of therapeutic agent;Insurance Coverage;Intervention;Kentucky;Laws;Literature;Longitudinal trends;Measures;Medicaid;Modeling;Natural experiment;Nature;Needle Sharing;Outcome;Oxycodone;Participant;Personal Communication;Pharmacoepidemiology;Policies;Population;Population Density;Prevalence;Public Health;Research;Research Personnel;Resources;Risk;Risk Behaviors;Risk Reduction;Rural;Rural Population;Services;Shares syringes;Statistical Models;Sterility;Substance Use Disorder;Substance abuse problem;Syringes;System;Time;Treatment outcome;Uninsured;cohort;disease transmission;drug of abuse;follow-up;gabapentin;health disparity;improved;infancy;innovation;opioid abuse;prescription drug abuse;prescription opioid;programs;public health relevance;response;rural area;social;substance abuse treatment;suburb;success;therapy design;therapy development;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Both MC expansion and SAPs have great potential to improve substance abuse and infectious disease outcomes among rural PWUD/PWID; however first we must understand the mechanisms by which these SIs are influencing outcomes. Therefore results may inform ways in which to optimize uptake and utilization of structural interventions as well as to inform policies surrounding further implementation of SIs that will improve public health outcomes in rural Appalachia.


application_id: 9525936
project_number: 5R01DA040637-04
project_title: NK-1 Receptor Antagonism: A Role in Opioid Use Disorders
administering_ic: NIDA
award_notice_date: 2018-07-16
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: 2020-07-31
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;Nociception;Opiate Addiction;Opioid;Opioid Antagonist;Opioid Receptor;Opioid abuser;Opioid agonist;Oral;Outcome;Oxycodone;Pain;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Pharmacology;Pharmacotherapy;Phase;Physical Dependence;Physiological;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;heroin use;improved;laboratory experiment;mortality;mu opioid receptors;novel;opioid misuse;opioid use;opioid use disorder;opioid withdrawal;overdose death;prescription opioid;prescription opioid misuse;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: 9525584
project_number: 5R01AR060701-09
project_title: Novel Roles for Satellite Cells in Adult Skeletal Muscle Adaptation
administering_ic: NIAMS
award_notice_date: 2018-08-13
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;Expression Profiling;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;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;Untranslated Regions;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: 9524379
project_number: 1R01EY028206-01A1
project_title: The Role of Histone Deacetylases in Age-related Macular Degeneration
administering_ic: NEI
award_notice_date: 2018-03-27
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: EY
serial_number: 028206
suffix: A1
program_official: SHEN, GRACE L
project_start_date: 2018-04-01
project_end_date: 2018-05-31
study_section: Diseases and Pathophysiology of the Visual System Study Section[DPVS]
contact_pi_person_id: 8784086
contact_pi: KLEINMAN, MARK E
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project Summary:Most scientific understanding of epigenetic biology is in the field of development and cancer. In my early careerperiod I have been investigating various pathways of pro-inflammatory signaling in the retina and have recentlydiscovered a powerful ability for biochemical modification of histones a protein that complexes with DNA toform the nucleosome to regulate the expression of specific inflammatory factors found in AMD. The strikingchanges in pro-inflammatory gene signatures that can be induced by inhibiting deacetylation of histonessuggest that this pathway may be involved in the pathogenesis of AMD. Preliminary data demonstrateddecreased expression of critical enzymes involved in these pathways in advanced dry AMD eyes and inexperimental models of oxidative stress. Inhibition of histone deacetylation resulted in significant cytotoxiceffects on the retinal pigment epithelium. In this project I plan to rigorously dissect the role of histonedeacetylase expression and function in the pathogenesis of dry AMD and RPE cell death using a novel mousemodel and correlate in vitro studies. The proposed work will directly address a fundamental lack of knowledgeon the role of histone deacetylases in the regulation of retinal inflammation and cell death making the workunderway critically important in our search for effective targeted therapeutics for dry AMD.

project_terms:
Acetylation;Address;Affect;Age;Age related macular degeneration;Animals;Apoptosis;Apoptotic;Atrophic;Biochemical;Bioinformatics;Biology;Biology of Aging;Cell Culture Techniques;Cell Death;Cells;Cessation of life;Chemicals;Choroidal Neovascularization;Chromatin;Clinical;Clinical Research;Communities;Complex;DNA;DNA Structure;DNA sequencing;Data;Development;Disease;Down-Regulation;Engineering;Enzymes;Epigenetic Process;Experimental Models;Expression Profiling;Eye;Foundations;Functional disorder;Gene Expression;Gene Expression Regulation;Gene Silencing;Gene Targeting;Genes;Genetic Transcription;Histone Acetylation;Histone Deacetylase;Histone Deacetylation;Histones;Human;Immunofluorescence Immunologic;In Situ Hybridization;In Vitro;Individual;Inflammation;Inflammatory;Investigation;Knowledge;Lysine;Malignant Neoplasms;Mass Spectrum Analysis;Measures;Methylation;Microglia;Modality;Modeling;Modification;Molecular;Nerve Degeneration;Nucleosomes;Oxidative Stress;Pathogenesis;Pathway interactions;Pattern;Pharmacology;Phosphorylation;Photoreceptors;Pigment Epithelium of Eye;Post-Translational Protein Processing;Post-Translational Regulation;Process;Proteomics;Regulation;Reporting;Research;Retina;Retinal;Retinitis Pigmentosa;Role;Scientific Advances and Accomplishments;Secondary to;Signal Pathway;Signal Transduction;Stable Isotope Labeling;Structure of retinal pigment epithelium;Techniques;Therapeutic;Ubiquitination;Valproic Acid;Western Blotting;Work;Yeasts;Zinc;cancer cell;career;cell type;chemokine;chromatin immunoprecipitation;chromatin remodeling;combinatorial;cytotoxic;cytotoxicity;effective therapy;genetic signature;genome-wide;histone modification;improved;in vivo;in vivo Model;inhibitor/antagonist;insight;interest;methyl group;molecular array;mouse model;novel;protein complex;response;retinal apoptosis;small molecule;targeted treatment;therapeutic target;transcriptome;transcriptome sequencing;web site

public_health_relevance:
Project Narrative:We are just beginning to gain scientific insight into the power of epigenetic modifications on genome-widetranscription. In this proposal a highly significant role for histone deacetylase function in retinal pigmentepithelial cell gene expression profiles and cell death in dry age-related macular degeneration will be studied.These data will provide important molecular insights to enhance our knowledge of the complex intersection ofaging biology epigenetics and inflammation.


application_id: 9524130
project_number: 1R01NS102920-01A1
project_title: Transformation of Paraplegic Paralysis to Overground Stepping in Humans
administering_ic: NINDS
award_notice_date: 2019-09-25
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: NS
serial_number: 102920
suffix: A1
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2019-09-30
project_end_date: 2024-08-31
study_section: Bioengineering of Neuroscience, Vision and Low Vision Technologies Study Section[BNVT]
contact_pi_person_id: 10737162
contact_pi: GERASIMENKO, YURY
other_pis: EDGERTON, REGGIE
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:
Agonist;Ankle;Awareness;Body Weight;Buspirone;Chronic;Clinic;Communities;Cutaneous;Development;Devices;Diagnosis;Effectiveness;Electrodes;Family Caregiver;Force of Gravity;Generations;Goals;Health;Health Care Costs;Hip region structure;Human;Individual;Injury;Intervention;Knee;Lead;Lesion;Locomotion;Lower Extremity;Mediating;Motion;Motor;Motor Activity;Movement;Mus;Musculoskeletal Equilibrium;Neurostimulation procedures of spinal cord tissue;Outcome;Painless;Paralysed;Paraplegia;Performance;Pharmacology;Probability;Property;Quality of life;Rattus;Recovery;Recovery of Function;Sensory;Series;Site;Speed;Spinal;Spinal Cord;Spinal Injuries;Spinal cord injury;Spinal cord injury patients;Step training;Technology;Training;Volition;Walkers;Weight-Bearing state;connectome;cost;exoskeleton;experience;experimental study;improved;insight;limb movement;motor control;motor function improvement;motor function recovery;neuroregulation;novel;relative effectiveness;robot assistance;robotic device;technology development;tool;treadmill


application_id: 9523354
project_number: 5R01DK112136-02
project_title: Community to Clinic Navigation to Improve Diabetes Outcomes
administering_ic: NIDDK
award_notice_date: 2018-07-25
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DK
serial_number: 112136
program_official: THORNTON, PAMELA L
project_start_date: 2017-08-01
project_end_date: 2022-07-31
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Affect;American;Appalachian Region;Biometry;Blood Pressure;Church;Clinic;Clinical;Communities;Community Health Aides;Complications of Diabetes Mellitus;Data;Diabetes Mellitus;Diagnosis;Education;Environment;Epidemic;Evidence based intervention;Focus Groups;Future;Glycosylated hemoglobin A;Goals;Health;Health care facility;Healthcare;Individual;Influentials;Intervention;Interview;Kentucky;Lipids;Low income;Mediator of activation protein;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Participant;Patients;Persons;Pilot Projects;Population;Positioning Attribute;Prediabetes syndrome;Protocols documentation;Randomized;Randomized Controlled Trials;Recruitment Activity;Research;Research Activity;Rural;Rural Population;Self Management;Social support;Talents;Testing;Training;Vulnerable Populations;Work;adverse outcome;arm;base;behavioral outcome;clinical care;community center;community setting;cost effectiveness;design;diabetes control;evidence base;glycemic control;health care quality;health care service organization;health disparity;health professional shortage areas;improved;improved outcome;innovation;low socioeconomic status;meetings;member;outreach;primary outcome;programs;randomized trial;recruit;relative cost;satisfaction;self-management program;social;theories;waist circumference


application_id: 9523182
project_number: 5R01AA023681-05
project_title: Mechanisms for alcohol induced gut barrier dysfunction in ALD
administering_ic: NIAAA
award_notice_date: 2018-07-02
application_type: 5
activity_code: R01
ic: AA
serial_number: 023681
program_official: GAO, PETER
project_start_date: 2014-07-05
project_end_date: 2020-06-30
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: 2018-07-01
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 Membrane;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;gut microbiota;intestinal epithelium;liver injury;loss of function;mouse model;novel therapeutics;probiotic supplementation;probiotic therapy;protective effect;protective factors;protein degradation;protein expression;repaired;response;treatment effect;trefoil factor


application_id: 9522425
project_number: 3R44EY021940-02A1S1
project_title: Implantable Optical Intraocular Pressure Sensor for Improved Glaucoma Treatment
administering_ic: NEI
award_notice_date: 2017-08-14
opportunity_number: PA-15-269
application_type: 3
activity_code: R44
ic: EY
serial_number: 021940
suffix: A1S1
program_official: WUJEK, JEROME R
project_start_date: 2012-04-01
project_end_date: 2018-07-31
study_section: Special Emphasis Panel[ZRG1-ETTN-G(12)B]
contact_pi_person_id: 8625040
contact_pi: HASTINGS, JEFFREY TODD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 964829142
primary_uei: ZJUUV8RMN287
duns_number: 964829142
uei: ZJUUV8RMN287
fips: US
organization_id: 10027679
organization_name: BROCKMAN-HASTINGS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY/ABSTRACTBrockman-Hastings LLC seeks to reduce vision loss for glaucoma sufferers by creating a simpleaccurate and clinically acceptable system for monitoring intraocular pressure (IOP). Trends indicatethat by 2020 approximately 80 million people worldwide will have glaucoma 11 million of whom willbecome blind. Elevated IOP remains the key risk factor and treated symptom for glaucoma andophthalmologists routinely measure IOP during office visits. However infrequent single pointmeasurements are often insufficient to fully manage glaucoma and infrequent measurements make itdifficult to assess the effectiveness of pharmaceutical or surgical treatments. To address this problemseveral research groups have developed implantable intraocular pressure sensors; however thesedevices have thus far proven too large complex inaccurate and/or high risk for rapid clinical adoption.In contrast Brockman-Hastings sensor does not include any implanted microelectronic circuitry orexternal or internal power sources. Instead the system relies on the reflection of light from the sensorsactive region (smaller than one square millimeter) and a hand held or eye-glass-mounted readout unitcaptures an infrared image to measure IOP. The simplicity of our sensor minimizes its physical sizeproviding for an aesthetic implant and allowing a simple lower-risk implantation procedure.In Phase I we established feasibility of the technology by achieving both specific aims: (1) sub-1 mmHgsensing accuracy in a simulated physiological environment and (2) sub 2-mmHg precision and onemonth tolerability in the rabbit eye. Our phase II hypothesis is that the optical IOP monitoring systembased around a refined anterior chamber implant will provide measurements sufficiently accurate forglaucoma management and will satisfy preclinical requirements for an investigational device exemption.To establish this we propose two specific aims: (1) Demonstrate that the optical IOP monitoring systemmeets preclinical performance requirements (1 mmHg accuracy) under real-time accelerated agingand in-vivo (rabbit eye) conditions and (2) Demonstrate that the optical IOP monitoring system satisfiespreclinical (mechanical dimensional biocompatibility and sterility) safety requirements. Successfulcommercialization of this device could ultimately benefit millions of glaucoma patients especially thosethat could immediately combine the sensor implantation with another eye surgery. Even this narrowermarket encompasses ~100000 glaucoma patients per year in the U.S. alone. Ultimately the systemwill reduce the human and financial cost of glaucoma-related vision loss by providing physicians withaccurate long-term IOP data on which to base treatment decisions and assess treatment effectiveness.

project_terms:
Address;Adoption;Aging;Algorithms;Biocompatible Materials;Blindness;Cataract Extraction;Clinical;Clinical Trials;Complex;Compliance behavior;Data;Devices;Diagnosis;Dimensions;Effectiveness;Electronics;Elements;Ensure;Environment;Esthetics;Event;Eye;Failure;Feedback;Financial cost;Glass;Glaucoma;Goals;Hand;Human;Image;Implant;Implantation procedure;In Vitro;Intraocular lens implant device;Investigation;Investments;Knowledge;Light;Marketing;Measurement;Measures;Mechanics;Monitor;Office Visits;Operative Surgical Procedures;Ophthalmologic Surgical Procedures;Ophthalmologist;Optics;Oryctolagus cuniculus;Outcome;Patients;Performance;Pharmacologic Substance;Phase;Physicians;Physiologic Intraocular Pressure;Physiological;Power Sources;Preclinical Testing;Privatization;Recovery;Research;Research Design;Risk;Risk Factors;Safety;Small Business Innovation Research Grant;Software Design;Specialist;Sterility;System;Systems Analysis;Technology;Testing;Third-Party Payer;Time;Treatment Effectiveness;Visual impairment;anterior chamber;base;biomaterial compatibility;blind;clinically relevant;commercial application;commercialization;cost;experience;eye chamber;high intraocular pressure;high risk;image processing;implantation;implanted sensor;improved;in vivo;millimeter;optical sensor;performance tests;pre-clinical;preclinical safety;prototype;public health relevance;sensor;success;symptom treatment;trend

public_health_relevance:
PUBLIC HEALTH RELEVANCETrends indicate that by 2020 there will be 80 million people worldwide with glaucoma 11 million ofwhom will become blind. Vision loss could be reduced if more frequent and longer term intraocularpressure monitoring were available to glaucoma patients and their physicians. In this SBIR Phase IIeffort Brockman-Hastings LLC will demonstrate the performance and safety of an intraocular pressuremonitoring system based on a simple implantable optical sensor.


application_id: 9522077
project_number: 5R21AI128206-02
project_title: Intestinal epithelial cells-derived exosomal miRNAs regulate liver inflammation in obesity
administering_ic: NIAID
award_notice_date: 2018-06-20
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: AI
serial_number: 128206
program_official: ROTHERMEL, ANNETTE L
project_start_date: 2017-07-14
project_end_date: 2021-06-30
study_section: Gastrointestinal Mucosal Pathobiology Study Section[GMPB]
contact_pi_person_id: 11629370
contact_pi: DENG, ZHONG-BIN
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:
The overarching theme of this project is to explore the mechanisms that lead to liver inflammation/injury in obesity.We will focus on extracellular miRNAs of intestinal epithelial cells (IECs) and macrophages. Specifically we willexamine how polyunsaturated fatty acids mediated-intestinal inflammation stimulates the production ofextracellular miRNAs from IECs and the consequences of these events. Novel in vitro and in vivo approacheswill be used to address mechanisms of action with the goal of identifying new targets for intervention. Wepropose that dietary n-6 polyunsaturated fatty acids (n-6 PUFAs) promote liver inflammation and injuryvia IEC-derived exosomes. We specifically propose that Stat3-activated extracellular miRNAs are the keyto the accumulation/polarization of macrophages in liver in obese mice. Based on our published work andother preliminary data this proposal will test the hypothesis that the n-6 PUFAs regulate the production ofextracellular miRNAs from intestinal epithelial cells through Stat3 signaling which initiates a crosstalk amongmacrophages NK cells and hepatocytes in liver. Moreover we will determine whether diet fat-associatednanoparticles carrying miR-155 inhibitor have potential therapeutic implications in obesity. These hypotheseswill be tested in the following Specific Aims: Aim 1: Determine whether IEC-derived extracellular miRNAsregulated by the n-6 PUFAs/Stat3 pathway are specific mediators of NFALD development andprogression. Aim 2: Determine whether alteration of IEC miRNAs via STAT3 modulation affects theseverity of HFD-induced liver inflammation and injury in obesity. Following the successful completion of theabove Specific Aims our novel studies will (i) validate Stat3-activated extracellular miRNAs is directly relevantto the accumulation/polarization of hepatic macrophages in obesity and (ii) provide a foundation for futuremechanistic investigation of the regulation of diet fat and extracellular miRNA in obesity therapy.

project_terms:
Address;Affect;Automobile Driving;Cell physiology;Cells;Chronic;Colitis;Colon Carcinoma;Consumption;Data;Development;Diet;Dietary Supplementation;Distant;Eicosapentaenoic Acid;Encapsulated;Epithelial;Epithelial Cells;Event;Fatty acid glycerol esters;Foundations;Future;Goals;Hepatic;Hepatocyte;High Fat Diet;Hypoxia;Immune;Immune signaling;Impairment;In Vitro;Individual;Infiltration;Inflammation;Inflammatory;Inflammatory disease of the intestine;Injury;Intervention;Intestinal permeability;Intestines;Investigation;Lead;Link;Linoleic Acids;Liver;Mediating;Mediator of activation protein;MicroRNAs;Modeling;Molecular;Mucins;Mucous Membrane;N-3 polyunsaturated fatty acid;Natural Killer Cells;Nonesterified Fatty Acids;Obese Mice;Obesity;Pathogenicity;Pathway interactions;Patients;Play;Polyunsaturated Fatty Acids;Production;Property;Proteins;Publishing;Regulation;Role;STAT3 gene;Severities;Signal Transduction;Testing;Therapeutic;Therapeutic Intervention;Tumor Angiogenesis;Ulcerative Colitis;Up-Regulation;Work;antimicrobial;base;exosome;extracellular;gastrointestinal epithelium;gut-liver axis;in vivo;inhibitor/antagonist;interest;liver development;liver inflammation;liver injury;macrophage;migration;nanoparticle;nanovesicle;non-alcoholic fatty liver disease;novel;nutrition;octadecadienoic acid;overexpression;prevent;recruit;translational study

public_health_relevance:
Project NarrativeThis proposal underscores the importance of investigating Stat3-activated extracellular miRNAs as a criticalIECs-derived factor for the development of nonalcoholic fatty liver diseases by regulating the function of hepaticmacrophages. We anticipate that we can abrogate their local and/or distant activities by targeting gutextracellular miRNAs.


application_id: 9521929
project_number: 7R01CA194030-03
project_title: An Integrative Approach to Identify Causal Epigenetic Markers for Breast Cancer
administering_ic: NCI
award_notice_date: 2017-08-07
opportunity_number: PA-16-285
application_type: 7
activity_code: R01
ic: CA
serial_number: 194030
program_official: VERMA, MUKESH
project_start_date: 2017-07-05
project_end_date: 2019-06-30
study_section: Cancer Biomarkers Study Section[CBSS]
contact_pi_person_id: 9152491
contact_pi: HE, CHUNYAN
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 objective of this proposal is to identify potentially causal DNA methylation markers that driver breast cancer development. Aberrant DNA methylation plays an important role in breast cancer initiation and progression via inactivation oftumor suppressor genes and activation of oncogenes. Identifying causal epigenetic markers that drive breast cancer development remains a major challenge. Conventional approaches comparing DNA methylation profiles in tumor and adjacent non-tumorous tissue have shown that changes in DNA methylation contribute to deregulation of gene expression in breast cancer. However such approaches are unable to distinguish causal DNA methylation alterations which drive tumorigenesis from reactive ones that are influenced by the tumor. In addition important cancer-related methylation changes may have been missed when a suboptimal baseline control (adjacent non-tumorous tissue) was used in previous studies. We hypothesize that an individual's genetic susceptibility and environmental risk factors (e.g. diet lifestyle) contribut to alterations in causal DNA methylation for breast cancer development and that such causal changes have already taken place in normal breast tissue before tumor occurrence. To test this hypothesis normal breast tissue from healthy women is required to prospectively assess the effects of these risk factors on DNA methylation. We propose an integrative genomic and epidemiological approach that combines the regulation of DNA methylation in normal breast tissue and differential DNA methylation profiling in tumor and normal breast tissue. Specifically we will generate and integrate multiple layers of data on environmental exposures and genome-wide genomic variations (germline and tissue-specific DNA methylation variations). We will examine the impact of genetic and environmental regulation on DNA methylation in normal breast tissue and determine the association of these epigenetic changes with breast cancer development and occurrence. Normal breast tissue from healthy women will be used as the most desirable baseline control in comparison with tumor as well as the most desirable target tissue to identify changes in potentially causal DNA methylation markers before tumor occurrence. We are uniquely positioned to conduct the proposed research as we have ready access to unique normal breast tissue through the Susan G. Komen Tissue Bank at Indiana University Simon Cancer Center. This resource represents the only biorepository in the world for large numbers of epidemiologically annotated optimally prepared normal breast tissue specimens (>3200) from healthy women in a wide range of ages and environmental exposures. This project will contribute significantly to our understanding of the key early biological processes during breast cancer development in particular the complex mechanisms among genetic variation environmental and lifestyle risk factors and epigenetic changes. It will lead t breakthroughs for breast cancer management in developing novel more effective prevention and treatment strategies that specifically target causal DNA methylation markers.

project_terms:
Aberrant DNA Methylation;Age;Age at Menarche;Biological Process;Body mass index;Breast Cancer Risk Factor;Cancer Biology;Cancer Center;Cancer Etiology;Complex;DNA Methylation;DNA Methylation Regulation;Data;Development;Diet;Environmental Exposure;Environmental Risk Factor;Epidemiology;Epigenetic Process;Epithelial Cells;Gene Expression;Gene Expression Regulation;Genetic;Genetic Predisposition to Disease;Genetic Risk;Genetic Variation;Genomics;Hormone use;Indiana;Individual;Lead;Life Style;Malignant Neoplasms;Mammary Gland Parenchyma;Mammary Neoplasms;Menopause;Methylation;Modification;Molecular Profiling;Normal tissue morphology;Oncogene Activation;Oncogene Deregulation;Play;Positioning Attribute;Prevention strategy;Quantitative Trait Loci;Regulation;Research;Resources;Risk Factors;Role;Site;Specimen;Testing;Time;Tissue Banks;Tissues;Tumor Tissue;Tumor-Suppressor Gene Inactivation;Universities;Variant;Woman;anticancer research;biobank;cancer initiation;cancer risk;cell type;epigenetic marker;epigenome-wide association studies;genetic variant;genome wide methylation;genome-wide;genomic variation;malignant breast neoplasm;methylation biomarker;non-genetic;novel;novel strategies;parity;prospective;public health relevance;treatment strategy;tumor;tumor progression;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Current approaches in breast cancer research are unable to distinguish causal DNA methylation alterations which drive tumorigenesis from reactive ones that are influenced by the tumor. This project is aimed at identifying potentially causal DNA methylation markers for breast cancer development through an integrative genomic and epidemiological approach that combines the regulation of DNA methylation in normal breast tissue and differential DNA methylation profiling in normal and tumor breast tissue. This information is critical not only for understanding breast cancer biology but also for developing novel more effective prevention and treatment strategies that target causal DNA methylation.


application_id: 9521817
project_number: 1R01NS102196-01A1
project_title: RIT1-mediated Protection following Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2018-02-06
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: NS
serial_number: 102196
suffix: A1
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2018-02-15
project_end_date: 2023-01-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 7875195
contact_pi: ANDRES, DOUGLAS ALLEN
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Acute;Affect;Area;Attenuated;Behavioral;Biochemical;Bioinformatics;Biological Assay;Brain Contusions;Brain Injuries;CREB1 gene;Cause of Death;Cell Death;Cells;Cessation of life;Chronic;Clinical;Collection;Contusions;Cortical Contusions;Data;Development;Economics;Electrophysiology (science);Emotional;Experimental Models;Functional disorder;Gene Expression;Genetic Transcription;Guanosine Triphosphate Phosphohydrolases;Hippocampus (Brain);Hour;Impaired cognition;Individual;Injury;Knock-in Mouse;Language;Learning;Leg;Link;Mediating;Memory impairment;Modeling;Molecular;Multiple Trauma;Nerve Degeneration;Nerve Regeneration;Neuronal Dysfunction;Neuronal Injury;Neuronal Plasticity;Neurons;Pathway interactions;Play;Proteins;Recovery;Recovery of Function;Role;Signal Transduction;Speech;Suggestion;Survivors;Synapses;Testing;Therapeutic;Therapeutic Intervention;Thinking;Tissues;Transgenic Mice;Traumatic Brain Injury;United States;adult neurogenesis;arm;brain repair;clinically relevant;dentate gyrus;disability;experience;experimental study;implementation strategy;in vivo;injured;insight;loss of function;mouse model;network dysfunction;neurogenesis;neuronal survival;neuroprotection;programs;relating to nervous system;response to injury;social;synaptic function;targeted treatment;tool;transcriptome sequencing


application_id: 9521059
project_number: 2R01DE012505-21
project_title: Molecular Aspects of Oral Plaque Formation
administering_ic: NIDCR
award_notice_date: 2018-03-07
opportunity_number: PA-16-160
application_type: 2
activity_code: R01
ic: DE
serial_number: 012505
program_official: LUNSFORD, DWAYNE
project_start_date: 1998-09-01
project_end_date: 2023-04-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adhesions;Adopted;Alveolar Bone Loss;Animal Model;Bacteria;Bacterial Adhesins;Communication;Communities;Complex;Cues;Data;Detection;Development;Disease;Event;Exhibits;Fimbrial Adhesins;Genes;Genetic Transcription;Goals;Grant;Human;In Vitro;Individual;Infection;Inflammatory;Investigation;Measures;Mediating;Membrane Proteins;Metabolic;Modeling;Molecular;Mono-S;Mus;Mutation;Organism;Oxidative Stress;Pathogenesis;Pathogenicity;Periodontal Diseases;Phosphoric Monoester Hydrolases;Phosphorylation;Porphyromonas gingivalis;Process;Production;Protein Tyrosine Kinase;Protein Tyrosine Phosphatase;Proteome;Regulation;Regulon;Resistance;Role;Shapes;Signal Transduction;Streptococcus gordonii;System;Therapeutic;Translating;Tyrosine;Tyrosine Phosphorylation;Up-Regulation;Virulence;base;bone loss;design;in vivo;insight;microbial community;multimodality;neutrophil;novel;oral infection;oral plaque;pathogen;polymicrobial disease;prevent;response;small molecule;synergism;transcriptome


application_id: 9519632
project_number: 5R01AG046920-05
project_title: Novel Actions of Metformin to Augment Resistance Training Adaptations in Older Ad
administering_ic: NIA
award_notice_date: 2018-05-11
opportunity_number: PA-12-271
application_type: 5
activity_code: R01
ic: AG
serial_number: 046920
program_official: DUTTA, CHHANDA
project_start_date: 2014-09-30
project_end_date: 2020-05-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: BAMMAN, MARCAS M;KERN, PHILIP A
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The loss of skeletal muscle mass and strength with advancing age reduces quality of life and is a major factor limiting an elderly person's chance of living independently. Progressive resistance exercise training (PRT) is the most effective intervention identified to increase muscular strength and combat muscle atrophy of aging; however overall the muscle response to PRT is blunted and highly variable in the elderly. Our research team has determined that the abundance of anti-inflammatory alternatively activated M2 macrophages in muscle predicts response to PRT in the elderly; those with the highest number of M2 macrophages and lowest inflammatory gene expression prior to the start of training gained the most mass. Further reexamination of muscle biopsies obtained in a study on insulin resistance showed that metformin treatment increased M2 macrophage abundance and decreased inflammatory cytokine gene expression. These provocative findings have led us to our central hypothesis that adjuvant metformin may improve the responses to PRT in the elderly by altering the muscle tissue inflammatory environment thereby enhancing mechanisms that drive PRT-induced myofiber hypertrophy. In Aim 1 we will determine if metformin treatment augments skeletal muscle size and strength gains in conjunction with PRT in older functionally limited adults. Participants will be recruited and randomized to receive either placebo or metformin for 2 weeks followed by a 14 week PRT program with continued drug/placebo treatment. Gains in muscle size and strength will be quantified. In Aim 2 we will identify cellula and molecular responses in muscle to metformin which are associated with improved response to PRT. Muscle macrophages inflammatory gene expression and anabolic and inflammatory signaling pathways will be examined in muscle biopsies. Finally mechanisms underlying metformin effects on muscle response to training using a human muscle cell culture system modeling exercise and the muscle microenvironment will be explored in Aim 3. Prospective identification of individuals likely to be refractory to routine exercise programs and determiningthe effectiveness of metformin in improving muscle growth response to PRT may contribute to the development of an affordable personalized approach to maintain or restore skeletal muscle mass and strength thereby promoting longer healthspan.

project_terms:
Adjuvant;Adult;Aging;Anti-inflammatory;Area;Biological Models;Biopsy;Blinded;Cell Culture System;Clinical Research;Coculture Techniques;Cytokine Gene;Development;Disabled Persons;Effectiveness;Elderly;Exercise;Gene Expression;Goals;Growth;Health;Human;Hypertrophy;In Vitro;Independent Living;Individual;Inflammatory;Insulin;Insulin Resistance;Intervention;Mediating;Metabolic;Metformin;Molecular;Muscle;Muscle Cells;Muscle Fibers;Muscular Atrophy;Myoblasts;Nuclear;Organ;Participant;Persons;Pharmaceutical Preparations;Phenotype;Physiological;Placebos;Positioning Attribute;Quality of life;Randomized;Refractory;Regulation;Research;Risk;Signal Pathway;Skeletal Muscle;Stretching;System;Testing;Time;Training;Training Programs;age related;cell type;combat;cost;effective intervention;exercise program;exercise regimen;exercise training;frailty;glucose uptake;healthspan;improved;improved functioning;in vivo;inflammatory milieu;insulin sensitivity;macrophage;monocyte;muscle form;muscle hypertrophy;muscle strength;novel;personalized approach;physical inactivity;predicting response;prevent;prospective;public health relevance;recruit;resistance exercise;response;sarcopenia;satellite cell;secondary analysis;skeletal muscle wasting;strength training;vastus lateralis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Resistance exercise training is the most effective intervention identified to combat loss of skeletal muscle mass and strength with advancing age; however the response to exercise is blunted and highly variable in the elderly. Prospective identification of individuals likely to be refractory to routine exercise programs and determining the effectiveness of metformin in improving the muscle growth response may contribute to the development of a low cost personalized approach to prevent frailty in the elderly.


application_id: 9519107
project_number: 3R01AG049806-02S1
project_title: The effects of exercise on satellite cell dynamics during aging
administering_ic: NIA
award_notice_date: 2017-08-29
opportunity_number: PA-16-287
application_type: 3
activity_code: R01
ic: AG
serial_number: 049806
suffix: S1
program_official: WILLIAMS, JOHN
project_start_date: 2017-09-01
project_end_date: 2018-11-30
contact_pi_person_id: 1873134
contact_pi: MCCARTHY, JOHN JOSEPH
other_pis: PETERSON, CHARLOTTE A.
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractA key determinant of geriatric frailty is sarcopenia the age-associated loss of skeletal muscle mass andstrength. Although the etiology of sarcopenia remains to be determined studies in humans and rodents havereported a strong correlation between the loss and/or dysfunction of satellite cells and sarcopenia. Despite thecorrelation between declining satellite cell-dependent regenerative capacity and age no studies to date havedirectly tested this relationship to determine if the loss of satellite cells causes sarcopenia. To test this idea wedepleted (>85%) satellite cells in five month old mice to a level dramatically lower than that observed withnormal aging. A detailed analysis of multiple muscles through 24 months of age revealed that despitesignificantly reduced regenerative capacity the life-long depletion of satellite cells did not accelerate norexacerbate sarcopenia; however the depletion of satellite cells at a young age was associated with asignificant increase in fibrosis in old mice. These highly provocative findings together with our data on thefiber-type specific role of satellite cells in response to exercise reveal our limited understanding of how agingaffects the function of satellite cells in skeletal muscle maintenance the development of fibrosis and inresponse to a growth stimulus; addressing these fundamental gaps in our knowledge clearly requires newtools. Towards this end we will utilize a novel mouse strain (Pax7-H2B-GFP) that will allow us to track satellitecell dynamics for the first time in adult skeletal muscle aging. To better understand how aging and exerciseaffects satellite cell dynamics and the regulation of fibrosis the following aims will be pursued: 1) determinehow age and life-long exercise affects satellite cell dynamics in the maintenance of skeletal muscle 2)determine how age and life-long exercise affects satellite cell regulation of fibrosis and 3) determine how ageaffects satellite cell dynamics in response to a growth stimulus. The approaches described herein usepowerful new genetic tools to determine how aging and life-long exercise alters the function of satellite cells inskeletal muscle homeostasis regulation of fibrosis and adaptability. The development of the Pax7-H2B-GFPmouse represents a long sought-after method for tracking satellite cells especially following fusion into themyofiber. This novel mouse strain will allow us to address formally intractable questions regarding how satellitecell dynamics are affected by age and life-long exercise. Such fundamental knowledge is necessary to criticallyevaluate the therapeutic value of satellite cells for the treatment of muscle mass loss and function associatedwith aging.

project_terms:
Ablation;Address;Adult;Affect;Age;Age-Months;Aging;Biological Assay;CD34 gene;Cell Nucleus;Cell physiology;Cells;Coculture Techniques;Collagen;Data;Development;Disease;Elderly;Environment;Etiology;Exercise;Fiber;Fibroblasts;Fibrosis;Functional disorder;Gastrocnemius Muscle;Gene Targeting;Genetic;Goals;Growth;Homeostasis;Human;Hypertrophy;Immunohistochemistry;Individual;Integrins;Intervention;Knock-out;Knowledge;Label;Life;Longevity;MAPK14 gene;Maintenance;Measures;Mediating;Methods;MicroRNAs;Modeling;Molecular Profiling;Mouse Strains;Mus;Muscle;Muscle Fibers;Nucleosomes;Outcome;Phase;Phenotype;Physical activity;Production;Proteins;Publishing;Quality of life;Regulation;Reporter;Reporting;Research;Rodent;Role;Running;Skeletal Muscle;Skeletal Muscle Satellite Cells;Stem cells;Stimulus;Testing;Therapeutic;Time;base;exosome;experimental study;extracellular;falls;frailty;improved;loss of function;muscle aging;muscle form;muscle hypertrophy;muscle strength;normal aging;novel;progenitor;regenerative;response;sarcopenia;satellite cell;sedentary;senescence;skeletal muscle growth;skeletal muscle wasting;tool

public_health_relevance:
RelevanceA hallmark of aging in humans is the progressive loss of skeletal muscle mass and strength which is known tohave a negative impact on an individual's quality of life by robbing them of their daily independence as well asincreasing the occurrence of falls and other diseases. The primary goal of the proposed research is tounderstand how stem cell dynamics change with age how stems cells influence the muscle environment andthe impact of exercise on satellite cell function during aging. This knowledge is required to evaluate thetherapeutic potential of these cells to treat the loss of skeletal muscle mass and fucntion duirng aging.


application_id: 9519066
project_number: 5F30NS096876-03
project_title: Multi-mechanistic protection of mitochondria following traumatic brain injury
administering_ic: NINDS
award_notice_date: 2018-12-19
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;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;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: 9518791
project_number: 5T32DA016176-15
project_title: Training in Drug Abuse Related Research
project_terms: Drug abuse;Research;Training
administering_ic: NIDA
award_notice_date: 2018-05-16
opportunity_number: PA-11-184
application_type: 5
activity_code: T32
ic: DA
serial_number: 016176
program_official: BABECKI, BETH
project_start_date: 2004-07-01
project_end_date: 2021-06-30
study_section: ZDA1-EXL-T(02)S
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This application requests a second renewal of five years of support for a successful interdisciplinary and translational training program in broad-based contemporary aspects of drug abuse research. Training the next generation of drug abuse researchers is critical to current and future public health challenges associated with drug addiction. The goal is to prepare trainees for productive and successful careers in drug abuse research. This program proposes to support 4 predoctoral and 2 postdoctoral trainees. We will vigorously recruit individuals from underrepresented minorities disadvantaged backgrounds and individuals with disabilities to increase diversity. This program provides a highly collaborative environment of interdisciplinary and translational training in drug abuse research. The 17 training faculty represent 7 academic units have excellent training records and will provide a rich interdisciplinary training environment. The program fosters the development of essential experimental and critical thinking skills and provides the opportunity to gain an in depth understanding of and expertise in the interrelationships of the molecular/cellular aspects of receptors and signaling mechanisms involved in the neural and behavioral response to drugs of abuse and to become immersed in drug discovery and development in the pursuit of novel treatments for drug abuse. The overarching theme of the program is that drug addiction alters fundamental cellular and macromolecular processes resulting in long term changes in neural plasticity and behavior which can be treated using pharmacotherapeutic intervention. The curriculum provides knowledge from physicochemical properties of molecules to structural biology neurophysiology neurochemistry to animal and human behavior with numerous opportunities for in depth study of focused areas of drug abuse research. The breadth of drug abuse research opportunities is enhanced by strong links to the University of Kentucky's (UK's) Center on Drug and Alcohol Research the Center for Drug and Alcohol Research Translation the Center for Clinical and Translational Science the Center for Pharmaceutical Research and Innovation the Laboratory on Human Behavioral Pharmacology and the Residential Research Facility. This program provides "value added" by serving as a linchpin to networking interactions and collaborations with other trainees and training faculty focused on human behavioral and clinical aspects of drug abuse research and supported by a second T32 program directed by Dr. Craig Rush at UK. All positions in both T32 programs have been filled completely during the last funding period indicative of the large number of promising trainees in drug abuse research at UK. UK provides solid infrastructure and institutional support optimizing the training environment. The majority of program graduates continue to actively pursue drug abuse research and advance towards independent investigator status. In the upcoming funding period we propose to continue our record of success and develop responsible and ethical drug abuse researchers who will move the field of drug abuse forward.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The goal of this training program is to prepare promising predoctoral and postdoctoral trainees for productive and successful careers in drug abuse research a critical endeavor for current and future public health challenges associated with drug addiction. The program fosters the development of essential experimental and critical thinking skills and focused expertise on the interrelationships of cellular and molecular aspects of receptors and signaling mechanisms involved in the response to drugs of abuse within the context of drug discovery and development of novel treatments for drug abuse. Our program provides a highly collaborative environment of interdisciplinary and translational training in drugabuse research coupled with opportunities for networking and collaboration to advance our trainees towards independent investigator status in drug abuse research.


application_id: 9518010
project_number: 5R01NR016824-03
project_title: Rural Intervention for Caregivers' Heart Health (RICHH)
administering_ic: NINR
award_notice_date: 2018-06-29
opportunity_number: RFA-NR-16-003
application_type: 5
activity_code: R01
ic: NR
serial_number: 016824
program_official: HUSS, KAREN
project_start_date: 2016-09-26
project_end_date: 2021-06-30
study_section: ZNR1-REV-M(25)
contact_pi_person_id: 1906318
contact_pi: MOSER, DEBRA KAY
other_pis: CHUNG, MISOOK LEE
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT In the patient-family caregiver dyad emphasis traditionally has been on the patient or on helping thecaregiver take care of the patient. This approach ignores the health of the caregiver. Family caregivers ofpatients with chronic disease are at uniquely high risk for development of cardiovascular disease (CVD).Because of the environment they share with the patient lack of time for personal care due to caregivingdemands and persistent psychological distress caregivers of patients with chronic illness have substantiallyhigher risk for CVD than non-caregivers. To reduce this risk cardiovascular health interventions aimed at (1)CVD risk reduction (2) improving adherence to self-management of CVD risk reducing behaviors and (3)preventing and managing depressive symptoms are required. Rural caregivers are particularly at risk for poorhealth. Most rural areas are characterized by marked health disparities including elevated CVD risk persistentpoverty and lack of social and healthcare resources. As such innovative intervention programs are needed toimprove cardiovascular health among rural caregivers while overcoming personal and environmental barriersto achieving this goal. The Rural Intervention for Caregivers Heart Health (RICHH) program proposed in this study willaddress the important components of CVD risk reduction for rural caregivers of patients with chronic illness most notably improved self-management of CVD risk reduction efforts including prevention and managementof depressive symptoms. We propose an innovative delivery modality designed to overcome environmentalbarriers in socioeconomically austere rural areas. The purpose of the proposed 2-group (RICHH vs control)randomized clinical trial is to examine short- and long-term effects of the RICHH intervention on CVD risk (i.e.lipid profile body mass index and blood pressure) self-care behaviors (i.e. diet quality physical activity levelself-reported adherence to health behaviors) and depressive symptoms compared to usual care control inrural caregivers of persons with chronic disease. A total of 280 caregivers of patients with chronic illness will beenrolled. Rural caregivers will be randomly assigned to either the RICHH intervention group or a usual carecontrol group. We will stratify caregivers by gender in order to examine the moderating effect of gender onintervention outcomes given the many differences between male and female caregivers. The RICHHintervention (6 interactive modules) will be delivered for 12 weekly sessions (30- to 45 minutes per session). Inorder to enhance maintenance of behaviors we will also deliver 8 biweekly (every other week) boostersessions (20-30 minutes per sessions) for 2 months and then 6 monthly sessions. All sessions are deliveredindividually using a video-conferencing program on a multimedia digital device (i.e. mini iPad). Data onoutcomes will be collected at baseline 4 months and 12 months.

project_terms:
Address;Adherence;Adult;American;Behavior;Blood Pressure;Body mass index;Cardiac health;Cardiovascular Diseases;Caregivers;Caring;Cessation of life;Chronic Disease;Chronically Ill;Communication;Computer software;Data;Development;Devices;Diagnostic;Diet;Distress;Economically Deprived Population;Enrollment;Environment;Epidemic;Family;Family Caregiver;Family member;Female;Fibrinogen;Gender;Goals;Health;Health Personnel;Health Policy;Health Promotion;Health Resources;Health behavior;Healthcare;Heart Diseases;High Prevalence;Individual;Intervention;Kentucky;Light;Lipids;Long-Term Effects;Maintenance;Major Depressive Disorder;Mental Depression;Mental Health;Methods;Modality;Multimedia;Outcome;Patient Care;Patient Self-Report;Patients;Personal Satisfaction;Persons;Physical activity;Physically Handicapped;Policy Maker;Population;Poverty;Prevention;Psyche structure;Quality of life;Randomized;Randomized Clinical Trials;Randomized Controlled Trials;Reporting;Research;Resources;Risk;Risk Factors;Risk Reduction;Rural;Rural Health;Self Care;Self Management;Skilled Nursing Facilities;Symptoms;Tablets;Technology;Testing;Time;United States Health Resources and Services Administration;Videoconferencing;Work;associated symptom;cardiogenesis;cardiovascular disorder risk;cardiovascular health;caregiver interventions;caregiving;clinically significant;depressive symptoms;design;digital;efficacy testing;evidence base;group intervention;health care availability;health disparity;high risk;improved;informal caregiver;innovation;intervention effect;intervention program;male;mortality;physical conditioning;prevent;primary caregiver;primary outcome;programs;psychological distress;rural America;rural area;rural environment;rural setting;self-management program;social;socioeconomics;treatment as usual;usual care arm

public_health_relevance:
PROJECT NARRATIVE Rural caregivers of individuals with chronic illness are at uniquely high risk for development of heartdisease. We propose to test the Rural Intervention for Caregivers Heart Health program an innovative self-management program designed to lower heart disease and depression risk and overcome environmental andpersonal barriers to self-management. This innovative intervention program will improve physical andpsychological health for rural caregivers of chronically ill patients in rural Kentucky.


application_id: 9515833
project_number: 5R01AI127970-02
project_title: Mechanisms of successful vaccine adjuvants
administering_ic: NIAID
award_notice_date: 2018-05-04
opportunity_number: PAS-15-055
application_type: 5
activity_code: R01
ic: AI
serial_number: 127970
program_official: LAPHAM, CHERYL K
project_start_date: 2017-06-26
project_end_date: 2022-05-31
study_section: Special Emphasis Panel[ZRG1-IMM-U(90)S]
contact_pi_person_id: 1941645
contact_pi: MITCHELL, THOMAS C.
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_terms:
Adjuvant;Agonist;CD8-Positive T-Lymphocytes;Cell Culture Techniques;Cells;Cervarix;Chemicals;Clinical;Clinical Trials;Communicable Diseases;Dendritic Cells;Development;Dose;Epitopes;Goals;HLA A*0201 antigen;Human;Immune;Immune response;Immune system;Immunization;Individual;Inflammatory;Knowledge;Learning;Lipid A;Malaria;Modeling;Mus;Oryctolagus cuniculus;Outcome;Pathway interactions;Pattern;Peripheral Blood Mononuclear Cell;Persons;Preparation;Property;Public Health;Research;Research Personnel;Safety;Signal Pathway;Signal Transduction;Squalene;Structure;Subunit Vaccines;System;T cell response;TLR4 gene;Testing;Therapeutic;Tissues;Tonsil;Toxic effect;Transgenic Organisms;Vaccinated;Vaccine Adjuvant;Vaccine Design;Vaccines;Work;aluminum sulfate;analog;clinical development;cytokine;immunoregulation;improved;inhibitor/antagonist;mimetics;neutrophil;next generation;novel;novel vaccines;pathogen;peripheral blood;preclinical study;predictive modeling;prevent;prophylactic;research study;response;success;vaccine safety


application_id: 9515146
project_number: 1R15GM128050-01
project_title: Identification of Novel Human tRNA Modification Genes
administering_ic: NIGMS
award_notice_date: 2018-04-23
opportunity_number: PA-16-200
application_type: 1
activity_code: R15
ic: GM
serial_number: 128050
program_official: ADKINS, RONALD
project_start_date: 2018-05-01
project_end_date: 2022-04-30
study_section: Molecular Genetics B Study Section[MGB]
contact_pi_person_id: 14341647
contact_pi: GUY, MICHAEL P.
other_pis: Not Applicable
congressional_district: 04
department: CHEMISTRY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTTranslation is the cellular process that converts DNA into proteins and defects in this process are linked tomany human diseases. A key component in translation is transfer RNA (tRNA) which must be extensivelychemically modified by numerous cellular enzymes to function properly. Many of these enzymes and the tRNAmodifications that they form are conserved in eukaryotic organisms ranging from single-celled budding yeast tomulti-cellular organisms such as humans thus making yeast a powerful model organism for studying the rolesof modifications in the cell. However some modifications found on human tRNAs are not found in yeast andmuch less is known about human tRNA modifications in general. Because defects in tRNA modifications arestrongly linked to several human diseases this NIH R15 AREA proposal seeks to expose undergraduatestudents to modern biomedical research by advancing the field of human tRNA modification research in threeways. First we propose to study the yeast and human proteins required to form two related conserved tRNAmodifications. Defects in these modifications cause intellectual disability and are linked to type 2 diabetes andpolycystic ovary syndrome. Thus in Aim 1 of the proposal students will identify regions in the tRNA modifyingproteins Trm7 Trm732 and Trm734 required for function and intramolecular interactions. These proteins arerequired for the addition of a 2-O-methyl group on positions 32 and 34 in the critical anticodon loop region ofyeast tRNAs. Students will use bioinformatics along with genetic molecular biological and biochemicalapproaches to identify these regions. Second we propose to determine if the corresponding human Trm7Trm732 and Trm734 proteins are required for methylation of 32 and 34 on human and animal tRNA. Thisresearch will follow up on our intriguing preliminary data suggesting that these methylations are formed by twodifferent mechanisms on human tRNAs. Thus in Aim 2 of our proposal students will quantify the levels ofthese modifications on tRNAs purified from human and fruit fly cell lines lacking the predicted Trm7 Trm732and Trm734 genes. Third we propose to identify the gene required to form a human tRNA anticodon loopmodification that is not found in yeast. Thus in Aim 3 we propose to identify the enzyme that adds a 2-O-methyl group to position 39 of certain human and animal tRNAs. Students will use bioinformatics to identifycandidate genes that could be required for this modification and then determine if the genes are responsibleusing a rapid gene knockdown technique in cultured fruit fly cells. Once identified in fruit flies we willdetermine if the corresponding human gene is required for the modification activity on human tRNA. Theresearch proposed herein meets the criteria of the NIH R15 AREA award because it gives undergraduatestudents the opportunity to participate in a holistic modern research approach that will increase knowledge ofthe underlying molecular causes of disease. Undergraduates will be trained in genetic molecular biologicalbiochemical and bioinformatics techniques helping prepare a new generation of biomedical researchers.

project_terms:
Animal Model;Animals;Anticodon;Applications Grants;Archaea;Attention;Award;Binding;Biochemical;Biochemistry;Bioinformatics;Biological;Biomedical Research;CRISPR/Cas technology;Candidate Disease Gene;Cell Line;Cell physiology;Cells;Chemicals;DNA;Data;Defect;Disease;Double-Stranded RNA;Drosophila genus;Enzymes;Eukaryota;Exposure to;Funding;Gene-Modified;Generations;Genes;Genetic;Health;Human;Institution;Intellectual functioning disability;Kentucky;Knock-out;Knowledge;Learning;Link;Maps;Measures;Medical;Methylation;Methyltransferase;Modernization;Modification;Molecular;Molecular Biology;Mutagenesis;Mutation;Non-Insulin-Dependent Diabetes Mellitus;Organism;Pathway interactions;Plants;Polycystic Ovary Syndrome;Positioning Attribute;Process;Protein Region;Proteins;Research;Research Personnel;Role;Saccharomycetales;Science;Sequence Alignment;Site-Directed Mutagenesis;Students;Techniques;Testing;Training;Transfer RNA;Translations;United States National Institutes of Health;Universities;Variant;Work;X-linked mental retardation 9;Yeasts;cancer type;career;cell growth;design;fly;follow-up;human disease;insight;knock-down;methyl group;nervous system disorder;novel;protein protein interaction;tRNA Methyltransferases;undergraduate student

public_health_relevance:
PROJECT NARRATIVEPosttranscriptional modification of transfer RNA (tRNA) is crucial for proper protein translation and cell growthand defects in modifications have been linked to several human diseases. Because the majority of research inthe tRNA modification field has been done in yeast the study of tRNA modifications in humans and otheranimals represents a gap in our understanding. This proposal will engage undergraduate students in a holisticmodern research approach that employs bioinformatics molecular biology genetics and biochemistry tocharacterize and identify the proteins that form modifications in a critical region of human and animal tRNAs.


application_id: 9515030
project_number: 5R01HL138179-02
project_title: Platelet Endocytosis in Innate Immunity
administering_ic: NHLBI
award_notice_date: 2018-04-04
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 138179
program_official: YANG, YU-CHUNG
project_start_date: 2017-07-01
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
arra_indicator: N
project_abstract:
Surprisingly platelets are capable of many cellular processes (i.e. RNA splicing translationglycosylation endocytosis); however their effects on platelet function are often unclear. Ascirculating sentries platelets sample the vasculature via endocytosis. Some of theendocytosed cargo (i.e. fibrinogen) traffics to granules; however other material initiatesplatelet responses. In this proposal we show that pathogen endocytosis induces immuno-activation of platelets. This likely contributes to the increased cardiovascular risks associatedwith persistent infections (as seen in HIV-1/AIDS patients). In this application we build onour novel findings hypothesizing that platelet endocytosis is critical for innate immuneresponse to viral infections. To test this hypothesis we focus on how platelet endocytosisfacilitates Toll-like Receptor (TLR)-based signaling in an animal model that mimics chronicHIV-1/AIDS. Using novel genetically-altered mice (Arf6-/- VAMP-3-/- and Syntaxin-2/4-/-)which are defective at different endocytic steps we will address the roles routes andmechanisms of platelet endocytosis with specific focus on how platelets interact with HIV-1virus. We propose two specific aims: Aim 1. Determine the effects of defective plateletendocytosis on innate immune responses in a model of viremia. Aim 2. Determine themechanisms and routes of the platelet endocytosis system. Our proposal advances plateletsas active monitors of the vasculature continuously interacting with and interpreting theirenvironment while circulating. In this scenario platelets use endocytosis to continuouslysample their microenvironment and through endocytic trafficking process and evaluate cuesthat initiate responses to what the platelets have endocytosed. Our work will yield insights intoplatelet function during systemic infections thus reshaping the uses of anti-thrombotictherapies. Finally understanding platelet endocytosis will uncover novel strategies to increasethe efficiency of loading platelets with therapeutics that can be used to treat CVD.

project_terms:
AIDS/HIV problem;Acquired Immunodeficiency Syndrome;Address;Affect;Agonist;Albumins;Animal Model;Area;Binding;Biogenesis;Blood - brain barrier anatomy;Blood Platelets;Blood Tests;Blood-Borne Pathogens;Cardiovascular Diseases;Cell physiology;Cells;Cellular biology;Chronic;Clot retraction;Communicable Diseases;Cues;Cytoplasmic Granules;DNA;Data;Dextrans;Endocytosis;Environment;Fibrinogen;Goals;HIV-1;Hemorrhage;Hemostatic function;Image;Immune;Immune response;Immune system;Injections;Innate Immune Response;Innate Immune System;Integrins;Kinetics;Knockout Mice;LAMP-1;Label;Leukocytes;MPL gene;Maps;Measurement;Measures;Mediating;Modeling;Molecular;Monitor;Mus;Natural Immunity;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Phase;Physiological;Platelet Activation;Positioning Attribute;Preparation;Process;Proteins;Public Health;RNA Splicing;Recycling;Role;Route;Sampling;Sepsis;Signal Transduction;Stream;Surface;Surveys;System;Systemic infection;Testing;Therapeutic;Thrombocytopenia;Thrombosis;Thrombus;Toll-like receptors;Transgenic Mice;Translations;Viral;Viremia;Virion;Virus;Virus Diseases;Work;antiretroviral therapy;base;cardiovascular disorder risk;cardiovascular risk factor;chronic infection;detector;emergency service/first responder;experimental study;glycosylation;in vivo Model;insight;novel;novel strategies;particle;pathogen;receptor;response;syntaxin-2;trafficking;uptake

public_health_relevance:
NarrativeRelevance of the Project to Public Health:Cardiovascular disease (CVD) is the #1 killer in the US and the risk for CVD increases by 50% inHIV/AIDS patients. Platelets are circulating sentries that detect and respond to vessel damage and topathogens (e.g. viruses). This proposal seeks to understand how platelets actively test the bloodstream to determine how their sentry duty contributes to CVD during persistent viral infections.


application_id: 9514524
project_number: 1R15MH113045-01A1
project_title: Dimensions of emotion regulation in nonsuicidal self-injury and suicide in adolescents
administering_ic: NIMH
award_notice_date: 2018-06-06
opportunity_number: PA-16-200
application_type: 1
activity_code: R15
ic: MH
serial_number: 113045
suffix: A1
program_official: MURPHY, ERIC ROUSSEAU
project_start_date: 2018-08-01
project_end_date: 2022-07-31
study_section: Child Psychopathology and Developmental Disabilities Study Section[CPDD]
contact_pi_person_id: 12499648
contact_pi: BRAUSCH, AMY MARIE
other_pis: Not Applicable
congressional_district: 02
department: PSYCHOLOGY
primary_duns: 077876258
primary_uei: U5GMACGETKJ1
duns_number: 077876258
uei: U5GMACGETKJ1
fips: US
organization_id: 9186501
organization_name: WESTERN KENTUCKY UNIVERSITY
organization_city: BOWLING GREEN
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 421011001
organization_country: UNITED STATES
project_abstract:
Dimensions of emotion regulation in nonsuicidal self-injury and suicide in adolescents. Deaths from suicidecontinue to be a major public health concern particularly among youth for whom suicide ranks as the secondleading cause of death. Despite growing research on suicide knowledge about the proximal behavioral andpsychosocial mechanisms that facilitate the development of suicidal thinking is limited. Nonsuicidal self-injury(NSSI) is the intentional destruction of body tissue without suicidal intent typically cutting or burning the skinand has been identified as a particularly robust risk factor for suicide. Studies find that more than 20% ofadolescents report engaging in NSSI placing many at elevated risk for suicide. Remarkably little is knownabout the temporal course of NSSI and suicide ideation or about how and why NSSI confers its risk forsuicide. Emotion regulation deficits are associated with both NSSI and suicide ideation/behaviors but haverarely been studied in the temporal relationship between NSSI and suicide. Furthermore it is not known whichemotion regulation deficits are more salient for NSSI and identifying specific deficits will aid prevention andintervention efforts. The proposed study aims to fill these knowledge gaps through a 12-month longitudinalstudy of 650 non-clinical unselected adolescents between the ages of 14 and 17. The current study proposesthat specific emotion regulation deficits will strongly associate with NSSI; specifically lack of emotional claritylack of access to emotion regulation strategies and poor cognitive reappraisal as measured by self-report anddecreased cognitive control for emotions as measured by a behavioral task. Additionally the proposed studyexpects that NSSI behavior will associate with emotion regulation deficits to predict severity of suicide ideationmeasured both explicitly with self-report and explicitly with a behavioral task at follow-up points. Adolescentsin 9th-11th grades will be recruited to complete a research protocol of self-report and behavioral measures attheir home schools at baseline 6- and 12-months post baseline. Tests of the difference between twodependent correlations coupled with effect size estimates will be used to determine which emotion regulationdeficits most strongly associate with NSSI. SEM will be used to estimate cross-lagged panel models toexamine how NSSI behavior associates with emotion regulation deficits over time and to examine how NSSIand emotion regulation interact to predict severity of suicide ideation over time. The results will provideessential information to the field of suicide prevention; there is potential to significantly impact clinical practiceby identifying specific dimensions of emotion regulation that may be a marker of suicide risk that can betranslated into assessment and intervention techniques.

project_terms:
15 year old;16 year old;17 year old;18 year old;AIDS prevention;Adolescence;Adolescent;Adult;Age;Alcohol or Other Drugs use;Anxiety;Assessment tool;Behavior;Behavioral;Cause of Death;Centers for Disease Control and Prevention (U.S.);Collection;Common Data Element;Communities;Coupled;Data Collection;Development;Dimensions;Early Intervention;Emotional;Emotions;Expressed Sequence Tags;Feeling hopeless;Feeling suicidal;Female;Future;Goals;Health;Home environment;Individual;Intervention;Interview;Knowledge;Lead;Link;Longitudinal Studies;Measures;Mental Depression;Mental Health;Modeling;National Institute of Mental Health;Office for Human Research Protections;Patient Self-Report;Pilot Projects;Prevalence;Prevention;Preventive Intervention;Procedures;Protocols documentation;Public Health;Questionnaires;Recording of previous events;Regulation;Reporting;Research;Research Personnel;Risk;Risk Behaviors;Risk Factors;Safety;Sampling;Schools;Self-Administered;Self-Injurious Behavior;Severities;Skin;Students;Suicide;Suicide attempt;Suicide prevention;Techniques;Testing;Thinking;Time;Tissues;Translating;Visit;Youth;adolescent suicide;age group;aged;behavior measurement;clinical practice;cognitive control;cognitive reappraisal;design;eleventh grade;emotion regulation;follow up assessment;follow-up;improved;innovation;medical specialties;programs;prospective;psychosocial;public health priorities;recruit;screening;sleep quality;suicidal;suicidal behavior;suicidal morbidity;suicidal risk;tool

public_health_relevance:
Suicide is the second leading cause of death for adolescents and engaging in nonsuicidal self-injury behavior(NSSI) is a strong risk factor for future suicide. Deficits in the ability to effectively manage negative emotionsare strongly linked to NSSI but less is known about how these deficits impact the development of suicidalthoughts and how these deficits may change over time. Identifying early signs of specific deficits that mayindicate increased risk for NSSI and suicide will help professionals know when to intervene and what to target.


application_id: 9514121
project_number: 5R01DK048498-23
project_title: Mechanistic Impact of PI3K/mTOR Signaling on Intestinal Homeostasis
administering_ic: NIDDK
award_notice_date: 2018-05-22
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;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: 9513102
project_number: 3U01AA021901-05S1
project_title: Novel therapies in alcoholic hepatitis University of Louisville
administering_ic: NIAAA
award_notice_date: 2017-07-26
opportunity_number: RFA-AA-12-007
application_type: 3
activity_code: U01
ic: AA
serial_number: 021901
suffix: S1
program_official: WANG, JOE
project_start_date: 2012-09-15
project_end_date: 2018-06-30
study_section: ZAA1-JJ(07)R
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
project_abstract:
DESCRIPTION (provided by applicant): This application is the translational component of an overall UO1 application entitled "Novel therapies in alcoholic hepatitis - University of Louisvill." Alcoholic hepatitis (AH) has a high morbidity and mortality. In VA Cooperative Studies in which liver biopsies were performed only 35% of patients with AH and underlying cirrhosis and 60% of those with AH alone (no cirrhosis) were alive at the end of four years with most deaths occurring early in the study. There is no FDA-approved therapy for any stage of alcoholic liver disease (ALD). The most widely-used (off-label) drug therapies for AH are glucocorticoids and pentoxifylline. Both agents have anti-inflammatory activities and downregulate proinflammatory cytokines such as tumor necrosis factor (TNF). Unfortunately an important subset of AH patients treated with glucocorticoids have "steroid resistance" and some patients have contraindications to steroid therapy. Studies on pentoxifylline in AH are limited and efficacy appears highest in preventing/treating the hepatorenal syndrome. Thus new therapies as well as a better understanding of mechanisms/biomarkers for severity of disease and response to therapy are necessary. Our research team has been a leader in defining mechanisms of alcohol-induced liver injury using in vitro and animal models of ALD and in translating basic findings into the clinical setting. Our group is the first to describe dysregulated cytokine metabolism in AH. We have a long-standing interest in mechanisms of inflammation and liver injury. We also have extensive experience in the gut-liver axis and AH as well as in the development of novel therapies for AH.!!Building on the above translational research strengths of our program which focus on the gut-liver axis and inflammation in ALD we propose three highly translational Specific Aims which all relate to and utilize samples from our proposed UO1 clinical trial. Aim 1 will evaluate novel mechanisms for alcohol-induced alterations in gut integriy leading to endotoxemia and AH. We will study the therapeutic efficacy of both live probiotics and probiotic supernatants. Aim 2 will study the role of specific PDE4 inhibition in AH using animal models and our AH clinical patient population. There are recent data in the pulmonary literature showing that specific PDE4 inhibitors are effective in steroid resistant patients which may translate to AH. Lastly Aim 3 evaluates mechanisms for steroid resistance using both specimens from patients in our clinical trial and in vitro data. All three of our specific aims utiize specimens obtained from our U01 clinical trial and our protocol interacts with the two other translational protocols in our U01 consortium. Our goal is not only to better understand mechanisms for AH but also to develop new therapies (including those already available for other diseases) for AH either immediately transforming clinical practice or providing novel therapies for our clinical trial consortium.

project_terms:
Acute Alcoholic Hepatitis;Adenylate Cyclase;Alcohol consumption;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Amino Acids;Anabolic steroids;Animal Model;Anti-Bacterial Agents;Anti-Inflammatory Agents;Anti-inflammatory;Attenuated;Bacteria;Biological Assay;Biological Markers;Cessation of life;Cirrhosis;Clinical;Clinical Trials;Cyclic AMP;Data;Development;Dinoprostone;Disease;Effectiveness;Endotoxemia;Endotoxins;FDA approved;Glucocorticoids;Goals;Hepatorenal Syndrome;Human;Hypoxia;Hypoxia Inducible Factor;Impairment;In Vitro;Inflammation;Interleukin-1;Interleukin-10;Intestines;Label;Laboratories;Literature;Liver;Lung;Metabolism;Misoprostol;Morbidity - disease rate;Mucins;Mucous body substance;Nutritional Support;Patients;Pentoxifylline;Peptides;Permeability;Pharmacotherapy;Phosphodiesterase Inhibitors;Placebos;Positioning Attribute;Prednisone;Probiotics;Production;Prognostic Marker;Protocols documentation;Research;Research Personnel;Resistance;Role;Sampling;Severities;Severity of illness;Signal Transduction;Site;Specimen;Steroid Resistance;Steroid therapy;Steroids;Stimulus;Supplementation;TNF gene;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Therapeutic Studies;Translating;Translational Research;Treatment Efficacy;Universities;Zinc supplementation;analog;clinical practice;cooperative study;cytokine;experience;improved;inhibitor/antagonist;interest;liver biopsy;liver injury;monocyte;mortality;novel;novel strategies;novel therapeutics;patient population;peripheral blood;phosphoric diester hydrolase;prevent;probiotic therapy;programs;response;response biomarker;trefoil factor

public_health_relevance:
This is a translational application portion of an overall UO1 application. Our goal is not only to better understand mechanisms for AH but also to develop new therapies (including those already available for other diseases) for AH.


application_id: 9513077
project_number: 5R24OD010435-18
project_title: Research Resources for Model Amphibians
administering_ic: OD
award_notice_date: 2018-06-18
opportunity_number: PAR-13-253
application_type: 5
activity_code: R24
ic: OD
serial_number: 010435
program_official: CONTRERAS, MIGUEL A
project_start_date: 2001-10-01
project_end_date: 2020-06-30
study_section: Special Emphasis Panel[ZRG1-BBBP-Y(45)R]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThis application proposes to develop fundamental genomic and bioinformatic resources that willbetter enable studies of a model amphibian the Mexican axolotl (Ambystoma mexicanum). Theaxolotl is used in several areas of biomedical research including regenerative medicine and stem cellbiology. Axolotls show a remarkable ability to regenerate damaged body parts including whole limbsspinal cord and brain. Understanding how axolotls regenerate complex tissues may revealmechanisms to achieve endogenous regeneration in humans. Specific Aim 1 will continue efforts tosequence the large axolotl genome which is 10x larger than the human genome. An innovativechromatin capture approach (Hi-C) will be used to develop DNA libraries that contain information forscaffolding unordered genomic fragments. Accomplishment of this aim will yield a highly contiguousand annotated genome assembly an essential resource for any model organism. Specific Aim 2 willperform the first epigenetic studies of the axolotl genome. These studies will characterize changes inhistone modifications whole genome methylation patterns and local chromatin interactions duringlimb regeneration leveraging an existing transcriptional dataset that provides robust temporalresolution of gene expression. These studies will identify chromatin modifications and interactions thatarise or are remodeled during critical phases of limb regeneration. Specific Aim 3 will developgenomic sequence for a second salamander model the red-spotted newt (Notophthalamusviridescens). The newt is a logical choice for sequencing because it too serves as a model organismin tissue regeneration research and its phylogenetic distance from axolotl is ideal for identifyingconserved and lineage-specific non-coding sequences that may function to regulate transcriptionduring regeneration. Thus the proposed newt genomic sequence will broaden the salamander toolkitincreasing the likelihood for future clinical applications in biomedicine. Broad impact will be achievedby sharing genomic and epigenetic data from all three Specific Aims through an existing publicwebsite (Sal-Site). Overall the project will greatly enhance salamander models for biomedicalresearch.

project_terms:
Ambystoma;Ambystoma mexicanum;Amphibia;Animal Model;Area;Biomedical Research;Body part;Brain;ChIP-seq;Chromatin;Chromosomes;Complex;DNA;DNA Library;DNA Methylation;DNA Sequence;Data;Data Set;Distal;Enhancers;Epigenetic Process;Erythroblasts;Funding;Future;Gene Expression;Gene Structure;Genetic;Genetic Transcription;Genome;Genomics;Human;Human Genome;Libraries;Limb structure;Location;Maps;Meiosis;Methods;Modeling;Molecular;Natural regeneration;Newts;Nucleic Acid Regulatory Sequences;Partner in relationship;Phase;Phylogenetic Analysis;Red-Spotted Newts;Regenerative Medicine;Regulatory Element;Research;Research Personnel;Resources;Salamander;Sampling;Site;Spinal Cord;Testing;Tissues;Transcript;Untranslated RNA;Vision;Work;bioinformatics resource;chromatin modification;clinical application;design;epigenetic variation;histone modification;improved;innovation;limb amputation;limb regeneration;methylation pattern;promoter;scaffold;stem cell biology;temporal measurement;tissue regeneration;transcriptome;transcriptome sequencing;web site;whole genome

public_health_relevance:
The project will develop critical genomic resources to enhance research efforts using the Mexicanaxolotl. Studies using the axolotl may reveal strategies to achieve endogenous tissue regeneration inhumans.


application_id: 9512733
project_number: 5U01AI132817-02
administering_ic: NIAID
award_notice_date: 2018-05-25
opportunity_number: RFA-AI-16-042
application_type: 5
activity_code: U01
ic: AI
serial_number: 132817
program_official: KULKARNI, SHILPA S
project_start_date: 2017-06-20
project_end_date: 2022-05-31
study_section: ZAI1-TC-I(M1)
contact_pi_person_id: 1894295
contact_pi: SHIRWAN, HAVAL
other_pis: GARCIA, ANDRES J;YOLCU, ESMA S
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: 2018-06-01
project_title:
Targeted delivery of immunomodulatory biologics for induction of immune privilege to allogeneic pancreatic islet grafts

project_abstract:
PROJECT SUMMARY Type 1 diabetes (T1D) is a chronic autoimmune disorder that affects ~1% of population worldwide.Exogenous insulin treatment is the standard of care for T1D but often negatively affects the quality of life andis ineffective in preventing recurrent hyperglycemia episodes and chronic complications. Recent studies showthat human islet allografts can restore long-term normoglycemia and insulin independence protect from severehypoglycemia and slow progression of microvascular lesions in immunosuppressed T1D patients. Howeverimmune rejection and continuous use of immunosuppression to control rejection are two major limitationsof clinical islet transplantation. Standard immunosuppression is ineffective in achieving long-term graft survivaland also has significant adverse effects on the graft and graft recipients. Therefore the development of novelapproaches to prevent rejection of islet grafts without chronic immunosuppression is a significant goal. Allogeneic islets are subject to rejection by both alloreactive and autoreactive T effector (Teff) cells. Animbalance in the frequency of pathogenic Teff and protective T regulatory (Treg) cells is the underlying causeof T1D and allogeneic islet graft rejection. Restoring the physiological Teff and Treg balance has significanttherapeutic potential. Approaches attempting to tilt the balance in favor of Treg cells have so far targeted eitherTeff or Treg cells individually for modulation with limited success. The primary goal of this application is totarget both cell types simultaneously for modulation for an outcome in favor of Treg cell expansion. This willbe achieved using innovative polyethylene glycol hydrogel particle platforms for graft-targeted deliveryand controlled presentation of two novel biologics serving as agonists of Fas and IL-2R receptors. Teffcells activated by antigens express Fas receptor and become sensitive to FasL-mediated apoptosis. IL-2Rsignaling preferentially sensitizes Teff cells to Fas-induced apoptosis and is also required for Treg cells(CD4+CD25+FoxP3+) generation expansion and survival. Therefore we hypothesize that the combined useof agonists of Fas and IL-2R will preferentially eliminate Teff cells and generate/expand Treg cells withinthe graft microenvironment resulting in induced-immune privilege and sustained survival and function of isletallograft in the absence of any immunosuppression. A set of preliminary data support this hypothesis andprovide strong scientific premise and feasibility for this application. This concept will be tested in threedifferent allogeneic islet transplantation settings for efficacy and mechanisms; chemically diabetic BALB/c-to-C57BL/6 mice spontaneously diabetic C57BL/6-to-NOD mice and human islets into humanized mice. Thesemodels will generate critical data relevant to the human setting. Furthermore proof-of-efficacy and theelucidation of the immune mechanisms regulating effective outcomes will expedite further refinement of thisimmunomodulatory concept and its eventual translation to nonhuman primates as a prelude to clinical trials forthe treatment of type 1 diabetes.

project_terms:
Acute;Adverse effects;Affect;Agonist;Allogenic;Antigens;Apoptosis;Apoptotic;Autoantigens;Autoimmune Diseases;Binding;Biocompatible Materials;Biological Process;Biological Response Modifiers;C57BL/6 Mouse;CD8B1 gene;CD95 Antigens;Cell Death;Cell membrane;Cells;Chemicals;Chronic;Clinical;Clinical Treatment;Clinical Trials;Cloning;Complex;Data;Development;Engineering;Equilibrium;Eragrostis;FOXP3 gene;Failure;Formulation;Frequencies;Generations;Goals;Graft Rejection;Graft Survival;Homeostasis;Human;Hydrogels;Hyperglycemia;Hypoglycemia;IL2 gene;IL2RA gene;Immune;Immune response;Immunosuppression;Immunosuppressive Agents;Inbred BALB C Mice;Inbred NOD Mice;Individual;Insulin;Insulin-Dependent Diabetes Mellitus;Interleukin-2;Islets of Langerhans;Islets of Langerhans Transplantation;Lead;Lesion;Life;Mediating;Membrane;Memory;Metabolic Control;Modeling;Outcome;Pathogenicity;Pathway interactions;Patients;Peripheral;Pharmaceutical Preparations;Physiological;Play;Polyethylene Glycols;Population;Pre-Clinical Model;Prevention Protocols;Protocols documentation;Quality of life;Rattus;Recurrence;Regulatory T-Lymphocyte;Research;Rodent;Signal Pathway;Signal Transduction;Skin;Streptavidin;Surface;T memory cell;T-Lymphocyte;Testing;Therapeutic;Time;Translations;Tumor Necrosis Factor Ligand Superfamily Member 6;Work;alternative treatment;autoreactivity;base;cell type;chronic autoimmune disease;controlled release;design;diabetic;effective therapy;efficacy testing;extracellular;graft function;humanized mouse;immunoregulation;immunosuppressed;improved;innovation;islet;islet allograft;mouse model;negative affect;nonhuman primate;novel;novel strategies;particle;prevent;receptor;response;standard of care;success;synergism;targeted delivery;therapeutic target;translation to humans

public_health_relevance:
PROJECT NARRATIVEType 1 diabetes (T1D) is a chronic autoimmune disorder that affects more than 1% of the populationworldwide. Transplantation of pancreatic islets producing insulin has been shown to be an effective treatment.However graft recipients are required to take immunosuppressive drugs which has significant adverse effectsduring their life to control rejection. The primary objective of this proposal is to establish and test a graft-targeted immunomodulatory protocol delivered using advanced biomaterials that sustains long-term islet graftsurvival and function in the absence of any immunosuppression in various relevant pre-clinical modelsincluding a humanized mouse model. If effective this approach will have immediate and important implicationsfor the use of allogeneic islets for the treatment of T1D in humans.


application_id: 9512635
project_number: 5R01AG053999-03
project_title: Role of Systemic Amylin Dyshomeostasis in Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2018-06-08
opportunity_number: PAR-15-358
application_type: 5
activity_code: R01
ic: AG
serial_number: 053999
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2016-09-15
project_end_date: 2021-05-31
study_section: Special Emphasis Panel[ZRG1-MDCN-C(56)R]
contact_pi_person_id: 9696701
contact_pi: DESPA, FLORIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractWe propose that an early and possibly treatable contributor to the multifactorial etiology of Alzheimer's disease(AD) involves dyshomeostasis of amylin a pancreatic hormone that crosses the blood brain barrier and hasamyloidogenic properties similar to those of the -amyloid (A) peptide. This hypothesis is supported byrecent work from our lab and others showing large amylin deposits in brains of AD patients. Moreover wefound >4-fold higher brain amylin level in ApoE4 carriers particularly in patients with type-2 diabetessuggesting a link of the accumulation of amylin in the brain with ApoE and metabolic risk factors. Using ratsexpressing human amylin in the pancreas and amylin knockout we found that the brain amylin accumulation islikely promoted by elevated blood levels of oligomerized amylin via the interaction with plasma low densitylipoproteins and causes neuroinflammation and neurologic deficits. Here we propose to test these ideas.Planned studies will determine physiological and functional changes in the brain using a rat modelexpressing human amylin in the pancreas and appropriate controls (Aim 1). We will specificallyidentify therapeutic targets to reduce amylin-induced cytotoxicity in the brain. Pharmaceuticalinterventions will reinforce mechanistic insights while also informing on mechanisms that underlie thebrain amylin accumulation and potential functional effects in humans. Human studies will elucidateamylin-APOE and amylin-A interactions contributing to AD pathology (Aim 2). Here we collaboratewith the University of Kentucky AD Center which has a large repository of brain plasma andcerebrospinal fluid specimens from clinically well-characterized subjects. We also collaborate with theQueen Square Brain Bank for Neurological Disorders of the University College of London andMedical Research Council of King's College London which provided for this project brain specimensfrom early onset familial AD patients (PSEN1 and APP mutation carriers). These brain specimens willbe used to elucidate a potential relationship between the brain amylin accumulation and AD-type ofplaque i.e. early onset familial AD (associated with increased A oligomerization) vs. late onset AD(attributed to the impaired A clearance). To further elucidate the pathobiology of amylin-Ainteraction we crossed the human amylin expressing rat with the TgF344-19 rat model of AD. Thesuccessful completion of this project offers the potential to refining diagnosis and tailoring specifictherapies to modify/ delay/ prevent brain injury and cognitive decline in aging and metabolic disorders.

project_terms:
4 hydroxynonenal;Abeta clearance;Aging;Alleles;Alzheimer's Disease;Alzheimer's disease model;Amyloid;Amyloid beta-Protein;Animal Model;Apolipoprotein E;Biological Markers;Blood;Blood - brain barrier anatomy;Blood Vessels;Brain;Brain Diseases;Brain Injuries;CREB1 gene;Carnosine;Cell Culture Techniques;Cell model;Cerebrospinal Fluid;Cerebrovascular Circulation;Clinical;Clinical Data;Cognitive;Data;Dementia;Deposition;Diagnosis;Disease Progression;Early Onset Familial Alzheimer's Disease;Eicosanoids;Etiology;Genotype;Goals;Hormones;Human;Hypertrophy;Impaired cognition;Impairment;Injections;Injury;Interleukin-1 beta;Intervention;Kentucky;Knock-out;Knowledge;Late Onset Alzheimer Disease;Lead;Link;Lipid Peroxidation;London;Low-Density Lipoproteins;Malondialdehyde;Measures;Mediating;Medical Research;Membrane;Metabolic;Metabolic Diseases;Modeling;Neurologic Deficit;Non-Insulin-Dependent Diabetes Mellitus;Pancreas;Pancreatic Hormones;Pathologic;Pathology;Pathway interactions;Patients;Peptides;Peroxides;Pharmacologic Substance;Physiological;Plasma;Prevention strategy;Property;Protein Isoforms;Rattus;Research Project Grants;Rest;Risk Factors;Role;Signal Transduction;Smooth Muscle Myocytes;Specimen;Testing;Toxic effect;Transgenic Animals;Universities;Vascular Diseases;Work;apolipoprotein E-4;brain tissue;cerebrovascular;clinically relevant;college;cytotoxicity;data modeling;diabetic;diabetic rat;experimental study;human data;human disease;human tissue;inflammatory milieu;inhibitor/antagonist;insight;islet amyloid polypeptide;lipid peroxidation inhibitor;mutation carrier;nervous system disorder;neuroinflammation;neurotoxicity;neurovascular unit;novel;presenilin-1;prevent;repository;therapeutic evaluation;therapeutic target

public_health_relevance:
NarrativeWe have recently discovered that in addition to plaques laden with -amyloid brains of Alzheimer's diseasepatients contain large deposits of amylin an amyloidogenic hormone secreted from the pancreas. In thisresearch project we propose to use human tissue clinical data transgenic animals and cell models to 1)decipher mechanisms of brain amylin pathology in humans 2) determine the impact of amylin deposition onthe neurovascular unit and 3) test clinically relevant therapies to modify/ reduce/ prevent amylin-mediateddeleterious effects in the brain. The successful completion of this project offers the potential to refiningdiagnosis and tailoring specific therapies to modify/ delay/ prevent cerebrovascular injury and cognitive declinein aging and metabolic disorders.


application_id: 9511939
project_number: 5TL1TR001997-03
project_title: NRSA Training Core
administering_ic: NCATS
award_notice_date: 2018-06-05
opportunity_number: PAR-15-304
application_type: 5
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_abstract:
PROJECTSUMMARYTheUniversityofKentucky(UK)CenterforClinicalandTranslationalScience(CCTS)TrainingPrograminClinicalandTranslationalScience(UKTL1program)willprepareprofessionalandpredoctoralstudentstoassumeleadershiprolestodirectteamscienceacrosstheclinicalandtranslationalresearch(CTR)spectrum.OverthelastfiveyearstheUKTL1programhasleveragedUKsCTRstrengthstoprovideamultidisciplinaryandtransdirectionaltrainingprogramthatintegratestraineesacrossdiversefieldstoprovidearigorousandsolidresearcheducationinCTR.Withthisapproachwehaveachievedourgoalofincreasingthenumberofinvestigatorswhobridgethegapbetweenbasicscienceadvancesandtheirapplicationtoclinicalmedicine.Thishasbeenaccomplishedbyprovidingahighlycollaborativetrainingenvironmentthatincubatesscholarsandmentorswithaninnovativeandnurturingstructuretodevelopresearchcompetenciesinateam-basedenvironment.ThesuccessoftraineesinthefirstfundingcycleandthedevelopmentofaninnovativetrainingprocesstoengageevengreaternumbersofstudentsinCTRarethefoundationforthefollowingSpecificAims:1)toincreasethepipelineofinvestigatorsengagedinCTR;2)totrainacrossthespectrumofCTR;and3)topreparescholarstoparticipateeffectivelyinteamscience.TomeetouraimsweproposetoincreasethenumberofpredoctoralTL1studentssupportedeachyearandtoincludeanew12-monthintensiveCTRexperiencetomeetanidentifiedneedamongprofessionalstudentsandmedicalprofessionalsinresidency.WewillcontinuetosolicitapplicationsbroadlyacrosscampusoffernewexperientialtrainingincommunityresearchinruralpopulationsinCentralAppalachiaanddevelopdoctoral-leveltraininginbiomedicalinformaticstakingadvantageoftherecentinfluxofleadershipandexpertiseinthisareaatUK.Finallywewillprovidetraineeswiththelatestskillsetstoparticipateeffectivelyininterdisciplinaryandcollaborativeteamscience.Theseinitiativeswillacceleratethecareerdevelopmentoffutureleadersofthebiomedicalresearchworkforcewhocanaddresstodayscomplexresearchchallengesandspearheadadvancesinhumanhealth.

project_terms:
Address;Appalachian Region;Area;Basic Science;Biomedical Research;Certification;Clinical Medicine;Clinical Research;Clinical Sciences;Collaborations;Communication;Communities;Competence;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;Medicine;Mentors;Monitor;National Research Service Awards;Oral;Outcome;Pathway Analysis;Pharmacy facility;Population;Positioning Attribute;Preparation;Process;Productivity;Psychology;Public Health;Publications;Research;Research Infrastructure;Research Personnel;Research Training;Residencies;Role;Rural Population;Science;Social Work;Solid;Structure;Students;TNFSF15 gene;Talents;Time Management;Training;Training Programs;Translational Research;Universities;Writing;antiretroviral therapy;base;biomedical informatics;career;career development;cohort;college;education research;experience;graduate student;innovation;instructor;multidisciplinary;patient oriented;posters;pre-doctoral;professor;programs;skills;success;training opportunity


application_id: 9511521
project_number: 5U01DE025383-04
project_title: Roles for lymphocyte RANKL in periodontal complications of type 2 diabetes
administering_ic: NIDCR
award_notice_date: 2018-08-20
opportunity_number: PAR-15-192
application_type: 5
activity_code: U01
ic: DE
serial_number: 025383
program_official: CHANDER, PREETHI
project_start_date: 2016-07-01
project_end_date: 2021-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-S(02)S]
contact_pi_person_id: 6409370
contact_pi: NIKOLAJCZYK, BARBARA
other_pis: VAN DYKE, THOMAS ELLIOTT
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute Periodontitis;Address;Alveolar Bone Loss;Animal Model;B-Lymphocytes;Cell physiology;Cells;Chronic;Chronic Phase;Clinical;Complement;Complications of Diabetes Mellitus;Coupled;Data;Development;Disease;Drug Targeting;Etiology;FDA approved;Future;Gingiva;Goals;Hematopoietic;High Fat Diet;Human;Hyperglycemia;Immunologics;Infection;Inflammation;Inflammatory;Interleukin-1 beta;Interleukin-10;Interleukin-6;Knowledge;Lesion;Link;Lymphocyte;Mediator of activation protein;Metabolic;Methods;Modeling;Morbidity - disease rate;Mus;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathogenesis;Pathogenicity;Periodontal Diseases;Periodontal Infection;Periodontitis;Play;Positioning Attribute;Production;Receptors Antigen B-Cell;Refractory;Regulation;Role;Source;Supporting Cell;T-Cell Receptor;T-Lymphocyte;TNF gene;TRANCE protein;Testing;Thinness;Time;Work;base;clinical application;clinical practice;cytokine;gain of function;glycemic control;high standard;human model;human subject;immunomodulatory drugs;insight;mouse model;osteoclastogenesis;pathogen;standard care


application_id: 9510661
project_number: 1R34DA046005-01
administering_ic: NIDA
award_notice_date: 2018-06-26
opportunity_number: PA-15-250
application_type: 1
activity_code: R34
ic: DA
serial_number: 046005
program_official: SIROCCO, KAREN
project_start_date: 2018-07-01
project_end_date: 2021-05-31
study_section: Special Emphasis Panel[ZRG1 NRCS-V (08)]
contact_pi_person_id: 9641889
contact_pi: ASHFORD, KRISTIN H.
other_pis: FALLIN-BENNETT, AMANDA
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 NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-07-01
project_title:
Behavioral and Enhanced Perinatal Intervention for Cessation (B-EPIC): Reducing Tobacco use among Opioid Addicted Women

project_abstract:
ABSTRACT:Each year 225000 infants in the United States are exposed prenatally to illicit drugs. Women with substance usedisorders particularly those with opioid dependence are highly vulnerable to cigarette smoking during the perinatalperiod. Pregnant opioid dependent patients seeking medication-assisted treatment (MAT) have high rates of smokingranging from 88% to 95%. Smoking during pregnancy is an independent risk factor (outside of illicit drug use) for severaladverse outcomes including ectopic pregnancy premature birth orofacial clefts and sudden infant death syndrome. Illicitopioid use magnifies these risks; among women who use opioids during pregnancy there is a 6-fold greater risk forintrauterine growth restriction third trimester vaginal bleeding preterm delivery and a majority also will experienceneonatal abstinence syndrome (NAS). Prenatal tobacco use significantly increases the severity and duration of NAS yet isnot commonly treated among opioid dependent pregnant women receiving MAT. On average the healthcare cost perdischarged infant with NAS ranges from $39400 to $53400; and 77.6% is paid for by Medicaid. MAT has been shown todecrease the severity of NAS compared to no treatment; yet most opioid dependent women in MAT still continue tosmoke cigarettes throughout pregnancy clearly suggesting that there is a significant need for a comprehensive evidence-based tobacco treatment intervention. To date there is no specific pharmacologic or non-pharmacologic tobacco-treatment standard for opioid dependent pregnant women in MAT. More research is needed to develop and test tailoredtobacco treatment interventions for pregnant opioid dependent women. The purpose of this trial is to test a novelintervention for tobacco cessation Behavioral and Enhanced Perinatal Intervention for Cessation (B-EPIC) in anestablished community MAT clinic. B-EPIC is designed to reduce tobacco-associated morbidity (e.g. preterm birthNAS) and healthcare expenditures in pregnant women who are tobacco users receiving buprenorphine for opioiddependence. This two-group randomized and controlled clinical trial (n =100) will provide critical preliminary data to testlarger-scale trials. As nearly all B-EPIC services are billable services via public and private insurers; there is highlikelihood for sustainability.

project_terms:
Accident and Emergency department;Address;Adoption;Behavior;Behavioral;Birth;Buprenorphine;Child;Childhood;Cigarette;Clinic;Communities;Control Groups;Cotinine;Counseling;DSM-IV;Data;Diagnosis;Ectopic Pregnancy;Emergency department visit;Epidemic;Expenditure;Feedback;Fetal Growth Retardation;Frequencies;Gestational Age;Goals;Health;Health Care Costs;Health Expenditures;Hemorrhage;Hospital Readmission;Hospitalization;Illicit Drugs;Infant;Insurance Carriers;Intervention;Length;Length of Stay;Medicaid;Medical;Medical Records;Morbidity - disease rate;Morphine;Neonatal Abstinence Syndrome;Neonatal Intensive Care Units;Opiate Addiction;Opioid;Outcome;Outpatients;Participant;Patients;Perinatal;Pharmacology;Pharmacotherapy;Postpartum Women;Pregnancy;Pregnant Women;Premature Birth;Privatization;Randomized Controlled Clinical Trials;Readiness;Research;Respiratory Tract Infections;Risk;Risk Factors;Services;Severities;Smoke;Smoking;Substance Use Disorder;Sudden infant death syndrome;Surveys;Testing;Third Pregnancy Trimester;Time;Tobacco;Tobacco Dependence;Tobacco use;United States;Urine;Vagina;Visit;Woman;adverse outcome;biomarker validation;cigarette smoke;cigarette smoking;cost;cost-effectiveness ratio;design;ear infection;effectiveness research;evidence base;experience;health care service utilization;illicit drug use;illicit opioid;incremental cost-effectiveness;infant outcome;maternal tobacco use;medication-assisted treatment;novel;opioid use;opioid use in pregnancy;orofacial cleft;perinatal intervention;perinatal period;pregnant;prenatal;prenatal exposure;reduce tobacco use;smoking cessation;smoking during pregnancy;standard care;tobacco cessation intervention;tobacco user;treatment as usual

public_health_relevance:
PROJECT NARRATIVEEach year 225000 infants in the United States are exposed prenatally to illicit drugs. The proposed study uses abehavioral and enhanced perinatal intervention for cessation (B-EPIC) to address this epidemic and will provide thenecessary data to develop and prepare larger scale trials with the ultimate goal of reducing tobacco-associated morbidityand health care expenditures in pregnant and postpartum women with substance use disorders.


application_id: 9510375
project_number: 1R03HD095098-01
project_title: The Function of Progesterone Receptor in Human Ovulatory Follicles
administering_ic: NICHD
award_notice_date: 2018-05-22
opportunity_number: PA-16-162
application_type: 1
activity_code: R03
ic: HD
serial_number: 095098
program_official: TAYMANS, SUSAN
project_start_date: 2018-05-22
project_end_date: 2020-04-30
study_section: Reproduction, Andrology, and Gynecology Study Section[CHHD-R]
contact_pi_person_id: 8244639
contact_pi: JO, MISUNG
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:
Abstract We seek to understand the mechanisms underlying ovulation and luteal formation in the human bydetermining the function of key ovulatory mediators progesterone (P4) and progesterone receptor (PGR) inhuman periovulatory follicles. The understanding of P4/PGR-mediated cellular events underlying ovulation andluteal formation has strong translational potential because P4 and its antagonists have been used ascontraceptives and the modulation of P4 levels is one of most common practices to aid or prevent femalefertility. The increase in P4 production and PGR expression in periovulatory follicles after the LH surge hasbeen found to be crucial for successful ovulation in many species. For instance Pgr knockout mice fail toovulate. The inhibition of P4 synthesis and PGR action blocked ovulation and/or luteal function in studies usingrodents sheep and non-human primates. However there are very few reports of PGR expression in thehuman ovary and virtually no experimental data on the mechanism(s) of P4/PGR's action in humanperiovulatory follicles. In the present proposal we hypothesize that PGR induced by the LH surge inperiovulatory follicles plays a crucial role in ovulation and/or luteal formation by regulating the expression ofkey ovulatory and/or luteal genes in women. To test this hypothesis we will utilize a unique in vivo model thatallows the collection of timed human periovulatory follicles from normally cycling women and a primary humangranulosa cell culture model in which the LH-induced increase in the expression of PGR and other keyovulatory genes in vivo can be mimicked in vitro. We proposed first to unveil potential downstream targetgenes of P4/PGR using a primary human granulosa cell culture model (Specific Aim #1). Secondly we willdetermine the expression pattern of PGR-downstream target genes in preovulatory follicles obtained before theLH surge periovulatory follicles obtained at defined hours after hCG administration and post-ovulatory folliclesfrom normally cycling women (Specific Aim #2). This study will be the first to document the comprehensiveexpression pattern of key and novel ovulatory genes in human periovulatory follicles during the ovulatoryperiod in vivo and identify P4/PGR-target genes to delineate the mechanisms by which P4/PGR mediates theovulatory process in humans.

project_terms:
AREG gene;Amphiregulin;Cell Culture Techniques;Cell model;Collection;Complex;Contraceptive Agents;Data;Development;Epiregulin;Event;Expression Profiling;Failure;Fertility;Gene Targeting;Genes;Gonadotropins;Hormones;Hour;Human;Human Chorionic Gonadotropin;Immunohistochemistry;In Situ Hybridization;In Vitro;Knockout Mice;Laboratories;Luteinization;Mediating;Mediator of activation protein;Mifepristone;Modeling;Ovarian;Ovary;Ovulation;PTGS2 gene;Pathologic;Pathway interactions;Pattern;Physiology;Play;Process;Production;Progesterone;Progesterone Receptors;Prostaglandin-Endoperoxide Synthase;Prostaglandins;RNA;Rattus;Reporting;Reproductive Health;Rodent;Role;Sheep;Small Interfering RNA;Testing;Time;Woman;corpus luteum;design;emergency contraception;female fertility;granulosa cell;in vitro Model;in vivo;in vivo Model;insight;next generation sequencing;nonhuman primate;novel;prevent;receptor;receptor expression;transcriptome sequencing;virtual

public_health_relevance:
NARRATIVE Successful ovulation and subsequent corpus luteum formation and development areessential for female fertility and the failure of these processes results in pathological conditionsin women. In the present proposal we will characterize for the first time the expression profile ofkey ovulatory genes in timed human periovulatory follicles and explore the mechanisms bywhich PGR coordinates the ovulatory process in women. Information derived from the presentproposal will provide novel insights into the mechanisms involved in ovulation and lutealformation in humans and can be applied for promoting and inhibiting the critical facet of ovarianphysiology thereby allowing us to better manage fertility in women.


application_id: 9509879
project_number: 1R34DA045856-01
project_title: Re-entry XR-NTX for rural opioid dependent women
administering_ic: NIDA
award_notice_date: 2018-09-14
opportunity_number: PA-15-250
application_type: 1
activity_code: R34
ic: DA
serial_number: 045856
program_official: MULFORD, CARRIE FRIED
project_start_date: 2018-09-15
project_end_date: 2021-06-30
study_section: Interventions to Prevent and Treat Addictions Study Section[IPTA]
contact_pi_person_id: 14909213
contact_pi: STATON, MICHELE
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: 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 overall aim of this R34 proposal is to examine the feasibility acceptability and short-term outcomesassociated with an innovative service delivery model to increase adherence to extended-release naltrexone (XR-NTX) during the transition from jail to the community for rural women with opioid use disorder (OUD). Thesignificance of this study is grounded in the public health crisis associated with the opioid epidemic in ruralAppalachia the increased vulnerability of rural women with OUD and the dearth of available and accessibleevidence-based treatment in the region. This R34 has potential to make a significant contribution to the OUDtreatment field by advancing knowledge on innovative service delivery models to increase access to evidence-based treatment to reduce high-risk opioid use and related health disparities among hard-to-reach high-riskunderserved populations. The study will be accomplished through two specific aims: (1) Adapt XR-NTX servicesfor use in community supervision (P&P) offices to increase adherence during re-entry from jail for rural womenwith OUD. (2) Examine feasibility acceptability and short-term outcomes of XR-NTX adherence and relapse toopioid use through a small pilot trial with 60 rural women with OUD. The pilot trial will include OUD screeningmedical evaluation XR-NTX initiation prior to jail release and random assignment to one of two community re-entry treatment models to receive on-going XR-NTX injections in the community after release in either: (1) Alocal rural P&P office (n=30) or (2) Services as Usual (n=30 referral to a community clinic). If this studyestablishes feasibility of this innovative community-based treatment model for XR-NTX in a rural underservedarea findings will be used to develop an R01 application to test the approach in a larger RCT during communityre-entry from jail among high-risk rural women with OUD in Appalachia. The long-term goal of this research is toincrease access to evidence-based treatment for OUD among high-risk underserved populations.

project_terms:
Adherence;Alcohol or Other Drugs use;American College of Obstetricians and Gynecologists;Appalachian Region;Area;Attitude;Cessation of life;Client;Clinic;Clinical;Communities;Consent;Country;Coupling;Criminal Justice;Dependence;Dose;Drug user;Economics;Education;Evaluation;Evidence based treatment;Goals;HIV Infections;Health Service Area;Health Services Accessibility;Healthcare;Hepatitis C;Hepatitis C virus;Impairment;Imprisonment;Injections;Jail;Kentucky;Knowledge;Life;Link;Location;Medical;Modeling;Morbidity - disease rate;Naltrexone;Needle Sharing;Opiate Addiction;Opioid;Outcome;Participant;Pharmaceutical Preparations;Poverty;Prevalence;Prisons;Procedures;Protocols documentation;Provider;Public Health;Quality of life;Randomized;Randomized Clinical Trials;Recording of previous events;Relapse;Research;Rural;Rural Community;Safety;Savings;Service delivery model;Services;Severities;Standardization;Supervision;System;Testing;Time;Transportation;Underserved Population;Vulnerable Populations;Woman;community based treatment;community reentry;disability;disease transmission;evidence base;follow-up;health disparity;high risk;high risk behavior;innovation;meetings;men;opioid epidemic;opioid injection;opioid use;opioid use disorder;parole;pilot trial;prescription opioid;primary outcome;probation;recruit;rural area;rural underserved;screening;service delivery;sex;standard care

public_health_relevance:
PROJECT NARRATIVE The overall aim of this R34 proposal is to examine the feasibility acceptability and short-term outcomesassociated with an innovative service delivery model to increase adherence to extended-release naltrexone (XR-NTX) during the transition from jail to the community for rural women with opioid use disorder (OUD). Thesignificance of this study is grounded in the public health crisis associated with the opioid epidemic in ruralAppalachia the increased vulnerability of rural women with OUD and the dearth of available and accessibleevidence-based treatment in the region. This study has potential to make a significant contribution to the OUDtreatment field by advancing knowledge on innovative service delivery models to increase access to evidence-based treatment to reduce the prevalence of opioid use disorders and related health disparities among hard-to-reach high-risk underserved populations.


application_id: 9509856
project_number: 272201000033I-0-27200006-1
administering_ic: NIAID
project_start_date: 2017-03-21
project_end_date: 2018-11-20
contact_pi_person_id: 14973661
contact_pi: WARAWA, JONATHAN
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 A111: 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;Antimicrobial Resistance;Contracts;Development;Infection;Lung;Multi-Drug Resistance;Pseudomonas aeruginosa;Standardization;Therapeutic;animal model development;efficacy testing;infectious disease model;mouse model;therapeutic evaluation


application_id: 9509590
project_number: 5KL2TR001996-03
project_title: Institutional Career Development Core
administering_ic: NCATS
award_notice_date: 2018-06-05
opportunity_number: PAR-15-304
application_type: 5
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_abstract:
PROJECT SUMMARYThe University of Kentucky (UK) Center for Clinical and Translational Science (CCTS) proposes to establish aCareer Development Core to build upon the current KL2 program which is in its fifth year of NIH support. Thecurrent program provides two to three years of release time (75% effort) and research funding support formentored career development designed to accelerate academic growth of the next generation of clinical andtranslational scholars. This program has garnered strong institutional support with notable scholar productivity;in five years two NIH-supported training slots have been expanded to six slots. All eight program graduateshave each made important contributions to science through research and have successfully competed forextramural funding seven as PIs. The current KL2 cohort consists of six scholars. The scholar programsupports career development across the full spectrum of clinical and translational science includingtranslational clinical community/policy studies and novel methodology development (e.g. biomedicalinformatics) focusing on a broad array of health topics. Scholars and mentors represent a wide range ofcolleges and disciplines including Medicine Nursing Health Sciences Public Health Education Engineeringand Arts & Sciences (Health Psychology). To build on these achievements this new program requests NIHsupport for four KL2 scholars. The training of three additional institutionally sponsored early-career scholarswill be integrated with these NIH-supported scholars to establish a cohort of seven scholars. The foundation ofthe proposed program will continue to be practical research experiences within interdisciplinary teams guidedby experienced mentors. In addition to prepare future leaders of the evolving academic discipline of Clinicaland Translational Research (CTR) new efforts designed to promote program excellence are proposed. Theyinclude: 1) new Faculty Oversight and Workforce Integration Committee structures; 2) use of educationaltechnology to develop vigorous yet efficient new competency programs designed to strengthen thefoundational training for future leaders in CTR; and 3) developing a new institutionally sponsored ClinicalScientist Pipeline Program targeting residents fellows and early career clinical faculty to provide a strongerlinking of our successful undergraduate and early faculty career training programs. These initiatives aredesigned to accelerate the career development of future leaders of the biomedical research workforce who willbe prepared to address today's complex research challenges and spearhead advances in human health.

project_terms:
Academia;Achievement;Address;Aptitude;Arts;Behavioral;Biomedical Research;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Communication;Communities;Competence;Complement;Complex;Dentistry;Development;Discipline;Discipline of Nursing;Doctor of Philosophy;Economics;Education;Educational Curriculum;Educational Technology;Engineering;Enhancement Technology;Ensure;Environment;Evaluation;Extramural Activities;Faculty;Foundations;Funding;Future;Good Clinical Practice;Growth;Health;Health Occupations;Health Psychology;Health Sciences;Healthcare;Human;Incubated;Industry;Instruction;Kentucky;Leadership;Link;Location;Medicine;Mentors;Methodology;NCI Scholars Program;Nursing Faculty;Outcome;Pharmacy facility;Policies;Population;Process;Productivity;Program Development;Psychology;Public Health;Public Health Education;Research;Research Training;Resource Development;Resources;Role;Scholarship;Science;Scientist;Self Efficacy;Social Work;Structure;Students;Talents;Teacher Professional Development;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 development;clinical practice;cohort;college;design;early-career faculty;evidence base;experience;improved;interest;member;next generation;novel;programs;recruit;skills;training opportunity;translational medicine;undergraduate student;workforce needs


application_id: 9508076
project_number: 1R03AG059107-01
project_title: Dementia and Physical Disablement Processes among Aging Latinos
administering_ic: NIA
award_notice_date: 2018-05-14
opportunity_number: PA-16-162
application_type: 1
activity_code: R03
ic: AG
serial_number: 059107
program_official: PATMIOS, GEORGEANNE E
project_start_date: 2018-06-01
project_end_date: 2020-05-31
study_section: Social Sciences and Population Studies A Study Section[SSPA]
contact_pi_person_id: 11167033
contact_pi: ROTE, SUNSHINE MARIE
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 SOCIAL WELFARE/WORK
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Dementia and Physical Disablement Processes among Aging LatinosProject SummaryThe Latino population is rapidly aging and by 2050 will represent over 20% of the older adult population in theU.S. At the same time the burden of dementia in the older Latino population is expected to increase from around200000 cases in 2000 to as many as 1.3 million cases in 2050 with many more suffering from milder degreesof cognitive impairment. A further stress on the Latino and specifically Mexican-origin population is high povertyrates. Close to 27% of older Mexican Americans in the U.S. live below the poverty line which is over double therate for older adults in general (Administration for Community Living 2014). Disparities in dementia raise seriouspublic health concerns; yet there have been surprisingly few longitudinal studies on the role of dementia andcognitive impairment for physical disablement processes in the Mexican-origin population. Understanding howdementia shapes physical disablement pathways and identifying factors that slow down or speed up disablementwill lead to a better understanding at which point geriatric public health intervention is most needed. We proposeto employ a longitudinal cohort study of 3050 older Mexican-origin individuals the 1993/94-2016/17 HispanicEstablished Populations for the Epidemiologic Studies of the Elderly (H-EPESE). First we will use nine wavesof survey data to 1) describe the long-term patterns of dementia and cognitive impairment for a prospectivecohort of older Mexican Americans. Growth Mixture Modeling (GMM) is used for this part of the analysis. Thenwe will 2) estimate the role of dementia and cognitive impairment for changes in physical disablement processesover twenty years of study data. Finally we will 3) assess differences in dementia-related physical disablementwithin the group by gender socioeconomic status and sociocultural factors. The proposed research will lead toa better understanding of long-term health change for Mexican Americans in late life and an estimation of howmany Mexican Americans with dementia need support in late life. Ultimately our objective is to develop andevaluate a new empirical model to describe long-term patterns of dementia for physical disablement processesthat can be replicated with other segments of the aging population to determine the extent of need for specializedlong-term support services.

project_terms:
Acculturation;Activities of Daily Living;Affect;Age;Aging;Alzheimer's Disease;Area;Bathing;Caregivers;Cohort Studies;Communities;Cultural Backgrounds;Data;Dementia;Diagnosis;Eating;Elderly;Family;Gender;Gills;Growth;Health;Heterogeneity;Hispanics;Household;Immigration;Impaired cognition;Impairment;Individual;Intervention;Interview;Knowledge;Latino;Life Cycle Stages;Life Expectancy;Long-Term Care;Longitudinal Studies;Longitudinal cohort study;Maintenance;Mexican;Mexican Americans;Modeling;Nature;Pathway interactions;Patient Self-Report;Patients;Pattern;Performance;Physical shape;Physically Handicapped;Policies;Population;Population Intervention;Poverty;Prevalence;Process;Prospective cohort;Public Health;Recording of previous events;Research;Research Design;Risk;Role;Self Care;Services;Socioeconomic Status;Source;Speed;Sterile coverings;Stress;Subgroup;Surveys;Symptoms;Theoretical model;Time;Transportation;aging population;base;care costs;care systems;cognitive ability;cognitive disability;community living;dementia care;disability;epidemiology study;ethnic disparity;experience;high risk;human old age (65+);innovation;instrumental activity of daily living;mental state;middle age;migration;novel;programs;public health intervention;socioeconomics

public_health_relevance:
Project NarrativeCurrently little is known about the nature of dementia-specific physical disablement processes for the rapidlygrowing and rapidly aging Mexican American population. We propose to utilize data from a cohort study ofMexican Americans and develop an innovative research design to examine heterogeneity in physicaldisablement processes and the role of dementia as these disablement processes unfold. The proposed studywill advance knowledge of dementia-related physical disablement in the aging Latino population in the U.S. andhighlight segments of this population that would greatly benefit from effective policy and program initiatives.


application_id: 9506728
project_number: 5R01DE026727-02
project_title: SGK1 and the control of periodontal inflammation
administering_ic: NIDCR
award_notice_date: 2018-05-30
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DE
serial_number: 026727
program_official: CHANDER, PREETHI
project_start_date: 2017-07-01
project_end_date: 2019-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-S(02)M]
contact_pi_person_id: 16064057
contact_pi: WANG, HUIZHI
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractHost inflammatory immune responses to oral microbiota are tightly regulated by multiple pro-inflammatory andanti-inflammatory mechanisms. The balance of there two activities ensures a state of immune homeostasiswhich is critical for protecting against microbial invasion and avoiding subsequent collateral tissue damages.To limit the ferocity of inflammation a number of established pathways exist that dampen the innate immuneresponse. Our recent publication has demonstrated a novel role for serum- and glucocorticoid- induciblekinase 1 (SGK1) a serine/threonine kinase associated with the PI3K pathway in restraining the production ofE. coil LPS-mediated pro-inflammatory cytokine production in human monocytes. Preliminary data for thisapplication show for the first time that SGK1 is phospho-activated in human monocytes in response tochallenge with multiple oral bacteria. In addition using P. gingivalis a well-established model oral organismfor the investigation of host-pathogen interactions in the periodontium we show that inhibition of SGK1 robustlyenhances the production of pro-inflammatory cytokines (TNF IL-12 IL-6 IL-1 IL-8) and reduces IL-10 levelsa result also confirmed by using Cre-loxP-mediated SGK1 knockout mice. Moreover the anti-inflammatoryrole for SGK1 was validated by our preliminary in vivo evidence showing that systemic administration of theSGK1 inhibitor EMD638683 elevated infiltration of neutrophils and macrophages into the gingival tissues andaggravated the severity of alveolar bone resorption in mice orally infected with P. gingivalis. Thus we haveidentified a novel role for SGK1 as a negative regulator of inflammation and propose that stimulation of thisendogenous anti-inflammatory pathway in the host will help limit or prevent P. gingivalis-induced tissuedestruction. The specific hypothesis to be tested in this application is that in the context of P. gingivalischallenge SGK1 constrains the production of pro-inflammatory cytokines; down-regulates recruitmentof inflammatory cells to the periodontium; and in turn protects against alveolar bone loss throughdownstream modification of inflammatory signaling molecules including Nedd4-2 MKP-1 and TAK1which ultimately converge on NF-B. We will challenge this hypothesis with three specific Aims: (i) Tocharacterize SGK1 as an innate immune suppressor of inflammatory responses in vitro; (ii) To elucidate thesignaling mechanisms by which SGK1 controls host inflammatory responses; and (iii) To establish the in vivorelevance of SGK1 in the control of host inflammation using mouse subcutaneous chamber and alveolar boneloss models. Successful completion of these studies will characterize for the first time the anti-inflammatoryfunction of SGK1 in host inflammatory responses to P. gingivalis and elucidate the novel anti-inflammatorysignaling network mediated by the SGK1-MKP1 module in the control of the inflammation progression. In thelong term this work could pave the way for the development of novel anti-inflammatory agents targeting SGK1or MKP-1 to ameliorate or prevent not only P. gingivalis-induced tissue destruction but other inflammatorydisorders. Such an approach has relevance both for periodontal disease and for chronic inflammatoryconditions in general.

project_terms:
Acute;Adopted;Agonist;Alveolar Bone Loss;Anti-Inflammatory Agents;Anti-inflammatory;Autocrine Communication;Bacteria;Biological Response Modifiers;Bone Resorption;Cells;Chronic;Communities;Coronary Arteriosclerosis;Data;Development;Disease;Ensure;Equilibrium;Gingiva;Glucocorticoids;Goals;Gram-Negative Bacteria;Homeostasis;Human;IL8 gene;Immune;Immune response;In Vitro;Infection;Infiltration;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Innate Immune Response;Interleukin-1 beta;Interleukin-10;Interleukin-12;Interleukin-6;Investigation;Knockout Mice;MAP3K7 gene;MAPK phosphatase;Mediating;Modeling;Modification;Molecular;Mus;Natural Immunity;Neutrophil Infiltration;Oral;Oral cavity;Organism;Pathway interactions;Periodontal Diseases;Periodontitis;Periodontium;Phosphorylation;Phosphotransferases;Porphyromonas gingivalis;Predisposition;Production;Protein-Serine-Threonine Kinases;Publications;Role;Serum;Severities;Signal Pathway;Signal Transduction;Signaling Molecule;TNF gene;Testing;Time;Tissues;Work;alveolar bone;bone loss;cytokine;design;dysbiosis;immunomodulatory drugs;in vivo;inhibitor/antagonist;insight;macrophage;microbial;microbial community;monocyte;novel;novel therapeutic intervention;oral bacteria;oral infection;oral microbial community;oral pathogen;oral tissue;p65;pathogen;prevent;recruit;response;subcutaneous;targeted agent;therapeutic target

public_health_relevance:
PROJECT NARRATIVEAn uncontrolled host inflammatory immune response to a dysbiotic plaque community is the principal reasonfor the initiation and progression of multiple inflammatory diseases including periodontal diseases such aschronic periodontitis. Thus identification of the intracellular immune regulators that control the host responseand elucidation of their related signaling networks are critical to redirect the dysregulated host inflammatoryresponses and develop the novel immunomodulatory therapeutic targets. We have identified a potentsuppressor of the innate immune response to the classic bacterial agonist LPS called SGK1. In this studywe will characterize the role of SGK1 in the immune response to a representative oral pathogen with theultimate goal of designing means to stimulate this molecule in order to constrain inflammatory destruction ingum disease.


application_id: 9506724
project_number: 5R01DA036550-04
project_title: Human Laboratory Screening of Pregabalin and Tiagabine for Cannabis Dependence
administering_ic: NIDA
award_notice_date: 2018-06-18
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DA
serial_number: 036550
program_official: HAMPSON, AIDAN
project_start_date: 2014-09-01
project_end_date: 2020-06-30
study_section: Special Emphasis Panel[ZRG1-RPIA-N(09)F]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cannabis use disorders are a significant public health concern and the absence of effective medications is a critical barrier to overcome. This application is founded on promising results from our laboratory suggesting that drugs that act at a2d-1 subunit containing voltage-dependent calcium channels (VDCCs) and/or elevate g- aminobutyric acid (i.e. GABA) will be effective medications for cannabis-use disorders. Our laboratory results are supported by a recent pilot clinical trial showing that gabapentin which isa VDCC ligand and elevates GABA reduced cannabis use in dependent treatment-seeking adults. The goal of the present proposal is to build upon these promising laboratory and clinical findings by determining the ability of outpatient maintenance on pregabalin a "next generation" VDCC ligand and tiagabine a GABA reuptake inhibitor to attenuate the reinforcing effects of cannabis. Pregabalin will be tested because although their mechanism of action is the same the pharmacokinetic profile of pregabalin is improved compared to gabapentin and clinical results suggest that this translates into greater pharmacotherapeutic effectiveness. Tiagabine will be tested because its effects overlap with gabapentin and pregabalin GABA elevation is a possible mechanism for gabapentin's effects on cannabis use and our recent data demonstrated that tiagabine produced a profile of effects that was comparable to gabapentin when tested in combination with D9-THC. Outpatient maintenance dosing will be tested because it more closely resembles the clinical treatment situation. Cannabis self-administration using a concurrent progressive-ratio drug-money choice procedure will be the primary outcome because drug seeking and drug taking behaviors and the choice to use drugs to the exclusion of other behaviors are defining characteristics of drug dependence and drug self-administration procedures are predictive of therapeutic efficacy. Cannabis use in the natural environment will also be monitored during drug maintenance as a secondary outcome to optimize resource management and quicken the pace of intervention development. Our preliminary data with the proposed procedures support the feasibility of the project the assembled research team is highly qualified and the environment will significantly contribute to the success of the research. The proposed project is innovative because it employs a novel hybrid procedure to study the impact of medication maintenance on direct cannabis effects in the laboratory as well as cannabis use in the natural environment the effects of pregabalin and tiagabine on cannabis self-administration have not been tested previously and a novel real-time medication maintenance compliance technology will be implemented. Positive findings will exert an immediate and sustained impact by rapidly advancing currently available medications for the treatment of cannabis-use disorders promoting novel pharmacological targets for further medications development and providing valuable basic science information about the mechanisms underlying cannabis reinforcement.

project_terms:
Abstinence;Acute;Admission activity;Adult;Adverse effects;Attenuated;Award;Basic Science;Behavior;Behavior Therapy;Calcium Channel;Cannabis;Characteristics;Clinical;Clinical Treatment;Clinical Trials;Cost Savings;Data;Dependence;Development;Dose;Double-Blind Method;Drug Addiction;Drug Kinetics;Drug usage;Effectiveness;Environment;Exclusion;Goals;Human;Hybrids;Illicit Drugs;Incentives;Independent Scientist Award;Information Sciences;Intervention;Laboratories;Ligands;Maintenance;Marijuana Dependence;Measures;Methods;Modeling;Monitor;Motivation;Outpatients;Patients;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacology;Pharmacotherapy;Placebos;Principal Investigator;Procedures;Process;Psychological reinforcement;Public Health;Randomized;Relapse;Research;Resources;Role;Schedule;Self Administration;Statistical Data Interpretation;Statistical Models;Study Subject;Techniques;Technology;Testing;Therapeutic Effect;Time;Translating;Treatment Efficacy;United States;career development;cost effectiveness;drug maintenance;experience;gabapentin;gamma-Aminobutyric Acid;illicit drug use;improved;inhibitor/antagonist;innovation;marijuana use;marijuana use disorder;marijuana user;next generation;novel;pregabalin;primary outcome;public health relevance;reinforcer;response;reuptake;screening;secondary outcome;success;therapy development;tiagabine;treatment response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cannabis is the most commonly used illicit drug in the United States and its use is associated with rates of development of abuse and dependence treatment admission and relapse that are comparable to other illicit drugs that are often perceived as more harmful. Currently there are no effective pharmacological treatments for cannabis-use disorders. This project will evaluate pregabalin and tiagabine for cannabis-use disorders using state-of-the-art human laboratory methods.


application_id: 9506575
project_number: 5R01DC007176-14
project_title: Neurotrophin receptor regulation of adult taste bud innervation and function
administering_ic: NIDCD
award_notice_date: 2018-06-21
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_abstract:
Project Summary/Abstract: Taste receptor cells detect chemicals in our food and communicate this information to thenerve fibers innervating them. Our goal is to understand the structural and functionalrelationship between taste receptor cells and innervating neurons. Because taste receptor cellsundergo continuous renewal and must constantly attract and connect to nerve fibers even in theadult some mechanism exists to control this process. Since the neurotrophin BDNF controlsinitial innervation of taste buds and is present in adult taste receptor cells it may have this role.BDNF also can function as a neuromodulator regulating function so it is certainly possible thatBDNF can regulate both innervation and/or function of adult taste buds. Here we are testing thehypothesis that BDNF signaling through its receptor TrkB regulates both the structural andfunctional connections between taste receptor cells and ganglion neurons. The proposedstudies combine sparse cell genetic labeling with 3-dimensional analysis of the taste bud andelectrophysiology in mice where TrkB-signaling can be blocked using a combination ofchemical and genetic approaches to: 1) determine the identity and connectivity of BDNFexpressing taste receptor cells 2) determine the role of BDNF-TrkB-signaling in maintaining thisconnectivity and 3) determine if BDNF-TrkB signaling regulates taste function. Together theseexperiments will determine how specific taste receptor cells (BDNF-expressing) becomeinnervated by a subset of taste ganglion neurons (TrkB-expressing) during taste cell renewaland will determine if BDNF-TrkB-signaling is an important gustatory system neuromodulator ofthis pathway.

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;receptor;relating to nervous system;response;sensory system;small molecule;taste system

public_health_relevance:
Project NarrativeTaste disorders can have detrimental effects on a person's health and quality of life. Theunderlying mechanisms of these disorders are not understood but could result from disruptionof the connections between taste buds and the neurons carrying taste information to the brain.Here we are looking at the role of neurotrophins in maintaining these connections andevaluating the effects of potentially therapeutic neurotrophin agonists and antagonists on tastefunction with an eye toward basic research applicable to the larger clinical question of nerveregeneration in adulthood.


application_id: 9505014
project_number: 1R21CA216447-01A1
project_title: Investigation of a lectibody targeting tumor-associated oligomannose glycans
administering_ic: NCI
award_notice_date: 2018-02-08
opportunity_number: PAR-16-176
application_type: 1
activity_code: R21
ic: CA
serial_number: 216447
suffix: A1
program_official: WELCH, ANTHONY R
project_start_date: 2018-02-08
project_end_date: 2020-01-31
study_section: Special Emphasis Panel[ZCA1 RTRB-U (J1)]
contact_pi_person_id: 8640855
contact_pi: MATOBA, NOBUYUKI
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY/ABSTRACTThe major goal of this NCI Clinical and Translational R21 application is to reveal the cancer therapeutic anddiagnostic potentials of a novel antibody-like chimeric fusion protein Avaren-Fc lectibody (AvFc) in mousetumor models. AvFc consists of the high mannose glycan (HMG)-specific lectin Avaren and the fragmentcrystallizable (Fc) region of human immunoglobulin (Ig)G1. Recent studies have revealed that HMGs areelevated on the cell surface glycome of various tumors. In normal cells these glycans are processed into morecomplex forms in the endomembrane system and therefore rarely found on cell surface. Hence HMGs mayprovide a new target for cancer therapy and/or diagnosis. However there is currently no agent selectivelytargeting tumor-associated HMGs.Our preliminary data showed that AvFc is capable of binding to a broad spectrum of cancer cell lines includingleukemia melanoma and lung breast colon and cervical cancers but not to noncancerous human cells.Additionally AvFc exhibited strong antibody-dependent cell-mediated cytotoxicity activity against variouscancer cells tested. AvFc showed good safety profiles in mice upon repeated systemic administration. LastlyAvFc is efficiently bioproduced in tobacco plants using a plant virus vector. Given these promisingdevelopability profile we hypothesize that AvFc could be developed as a first-in-class cancer therapeuticand/or diagnostic agent targeting tumor-associated HMGs.To prove this hypothesis we propose two specific aims in this application. In Aim 1 we will investigate AvFc'santi-tumor activity in murine tumor challenge models. We will use well-established syngeneic and human tumorxenograft models to determine the effectiveness of AvFc. In Aim 2 we will employ dynamic positron emissiontomography scan and radiolabeled AvFc to determine their in vivo biodistribution and tumor specificity in mice.Additionally we will attempt to isolate and identify tumor cell-surface glycoproteins targeted by AvFc using aproteomics approach. Results generated in this project will provide a compelling preclinical data package forthe development of AvFc as a novel therapeutic and/or diagnostic agent targeting tumor-associated HMGs.Additionally our data will provide a new basis and a unique tool to investigate the as-yet-unknown roles andmechanisms of elevated HMGs in tumors.

project_terms:
Affinity;Affinity Chromatography;Antibodies;Antibody -dependent cell cytotoxicity;Binding;Biochemical;Biodistribution;Biological Assay;Biological Markers;Cancer Detection;Cancer cell line;Carbohydrates;Cell surface;Cells;Chimeric Proteins;Clinical;Colon Carcinoma;Complement 1q;Complex;Data;Development;Diagnosis;Diagnostic;Effectiveness;Emission-Computed Tomography;Exhibits;Glycocalyx;Glycoproteins;Goals;Human;ITGAM gene;IgG1;Immunoglobulins;In Vitro;Investigation;Label;Laboratories;Lectin;Lesion;Link;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Mannose;Mass Spectrum Analysis;Mediating;Melanoma Cell;Membrane Glycoproteins;Modeling;Molecular;Mus;Mutation;Normal Cell;Oligosaccharides;Pattern;Plant Viruses;Plants;Polysaccharides;Positron-Emission Tomography;Process;Proteomics;Radiolabeled;Recombinant Proteins;Research;Role;SCID Mice;Safety;Series;System;Techniques;Testing;Therapeutic;Therapeutic Effect;Tobacco;Toxic effect;Transplantation;Tumor Burden;Tumor-Associated Carbohydrate Antigens;Variant;Wild Type Mouse;X-Ray Computed Tomography;Xenograft Model;anti-cancer;anti-cancer therapeutic;anticancer activity;base;bioimaging;cancer cell;glycosylation;imaging potential;imaging probe;in vivo;leukemia;malignant breast neoplasm;manufacturability;melanoma;microPET;mouse model;mutant;nanomolar;neoplastic cell;novel;novel therapeutics;pre-clinical;targeted agent;targeted cancer therapy;tool;tumor;tumor specificity;tumor xenograft;vector

public_health_relevance:
NARRATIVEThe goal of this project is to investigate the therapeutic and diagnostic potential of a novel recombinant proteinAvaren-Fc which targets a unique carbohydrate biomarker found on a broad spectrum of cancer cells. We willemploy preclinical mouse tumor challnege models in vivo bioimaging techniques and biochemical assays toreveal Avaren-Fc's anti-cancer activity and tumor specificity.


application_id: 9504589
project_number: 5R01AA024102-03
project_title: The role of dietary unsaturated fat and inflammasome in alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2018-06-29
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_abstract:
DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) is a major cause of morbidity and mortality in the world. It affects millions of patients worldwide each year. Althoughsubstantial progress has been made in ALD pathogenesis the specific mechanisms responsible for ALD development and progression remain poorly understood. Importantly there is no FDA approved therapy for any stage of ALD. Recent studies from our laboratory and others have demonstrated that dietary unsaturated fat rich in linoleic acid (LA) exacerbated alcohol- mediated intestinal permeability and liver injury as compared with dietary saturated fat in an experimental animal model of ALD. In addition our preliminary data show elevated levels of circulating oxidized LA metabolites (OXLAMs) specifically 9- and 13-hydroxy-octadecadienoic acids (9- and 13-HODEs) concomitant with the up-regulation of hepatic 12/15 lipoxygenase (12/15-LO) the key enzyme involved in the oxidation of LA. These findings provide initial evidence that OXLAMs which are natural ligands to the transient receptor potential vanilloid 1 (TRPV1 subfamily V member 1) contribute to the pathogenesis of ALD. TRPV1 is a ligand-gated non-selective cation channel with high permeability for Ca2+. A number of recent studies have shown a critical role for intracellular Ca2+ in inflammasome activation. NLRP3 Inflammasome activation with release of highly pro-inflammatory cytokines interleukin-1 (IL-1) and interleukin-18 (IL-18) is an important pro-inflammatory response in ALD. However the molecular mechanisms contributing to the inflammasome priming and activation in ALD are not fully identified.  Our central hypothesis is that dietary unsaturated fat (linoleic acid enriched) exacerbates alcohol-mediated liver inflammation and injury via oxidized linoleic acid metabolites that facilitate hepatic inflammasome activation. We propose that the OXLAM/TRPV1/Ca2+ signaling pathway is an upstream mechanism of inflammasome activation. To address our hypothesis we propose the following specific aims. Aim 1. Determine the role of oxidized linoleic acid metabolites (OXLAMs) and the 12/15-LO-mediated pathway of linoleic acid oxidation in the development and/or progression of ALD.  Aim 2. Assess whether hepatic inflammasome activation is mediated by an OXLAM-TRPV1-Ca2+ pathway in an animal model of ALD.  Aim 3. Determine the potential role of 12/15-LO TRPV1 and OXLAMs in inflammasome activation in human Alcoholic Hepatitis. The proposal will provide a better understanding of alcohol-diet interactions and molecular mechanisms contributing to the pathogenesis of alcohol-induced liver inflammation and injury. The study will lead to identification of new therapeutic targets and potential dietary interventions for treating ALD andprovide a dietary mechanism to explain why only some heavy drinkers develop clinically important ALD.  A combination of in vitro in-vivo animal (gain and loss of function) and human studies will be employed.

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;Intestinal permeability;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

public_health_relevance:
PUBLIC HEALTH RELEVANCE: My RO1 application investigates the role of dietary fat in the development of alcoholic liver disease. Specifically the project directly examines how dietary linoleic fatty acid and its oxidized products promote alcohol-mediated liver injury.


application_id: 9504366
project_number: 1K22HL141299-01
administering_ic: NHLBI
award_notice_date: 2018-08-16
opportunity_number: PAR-16-267
application_type: 1
activity_code: K22
ic: HL
serial_number: 141299
program_official: HUANG, LI-SHIN
project_start_date: 2018-08-20
project_end_date: 2021-07-30
study_section: NHLBI Mentored Transition to Independence Study Section[MTI (JA)]
contact_pi_person_id: 14386534
contact_pi: GORDON, SCOTT M
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-08-20
project_title:
The Role of High Density Lipoprotein Associated Protease Inhibitor Activity in Protection Against Atherosclerosis.

project_abstract:
Project Summary and AbstractHigh density lipoproteins (HDL) have a well-established inverse correlation with the occurrence ofcardiovascular disease. However the functional activities of HDL which mediate this protection arenot well understood. HDL are micellar complexes composed of lipids and an array of differentproteins which are likely to confer specific functions to the HDL particles that carry them. Of morethan 85 identified HDL associated proteins over 20% have known functions related to proteaseinhibition the majority of these are members of the Serine Protease Inhibitor (SERPIN) family ofproteins. This proposal will examine the structural interaction between the most abundant HDL-boundSERPIN alpha-1-antitrypsin (A1AT) and HDL particles and also the functional consequences of thisinteraction. Dr. Gordon will use individual particle electron tomography a novel molecular imagingtechnique to determine the structural details of the interaction between A1AT and HDL and to identifythe region of the A1AT protein involved in binding. Using reconstituted HDL enriched with A1AT Dr.Gordon will investigate the capacity of these particles to reduce vascular protease activity andsubsequent atherosclerosis development in a mouse model. Additionally a novel HDL targeting smallpeptide mimetic of A1AT will be developed and evaluated for its capacity to prevent atherosclerosisdevelopment and to stabilize existing plaque in an effort to prevent thrombus formation andsubsequent cardiovascular events such as heart attack stroke or pulmonary embolism. This work has been proposed by Dr. Scott Gordon a postdoctoral fellow of the National HeartLung and Blood Institute at the National Institutes of Health as part of an NHLBI K22 CareerTransition Award. Dr. Gordon performed his graduate studies on the composition and function of HDLand has extended his previous work in the current proposal. A team of experienced mentors with avariety of skills related to aspects of this proposal has been assembled by Dr. Gordon to assist in thesuccessful completion of the proposed research as well as the successful transition of Dr. Gordoninto an independent tenure track academic faculty position at a major research university in theUnited States.

project_terms:
ATP binding cassette transporter 1;Active Biological Transport;Acute;Acute-Phase Reaction;Anti-inflammatory;Apolipoprotein E;Arterial Fatty Streak;Arteries;Atherosclerosis;Binding;Biological Assay;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Career Transition Award;Cause of Death;Cell Culture Techniques;Cholesterol;Complex;Coronary Angiography;Coronary Artery Bypass;Data;Developed Countries;Developing Countries;Development;Dimensions;Elastases;Event;Faculty;High Density Lipoprotein Cholesterol;High Density Lipoproteins;Histologic;Human;Imaging Techniques;In Vitro;Individual;Inflammation;Inflammatory Response;Infusion procedures;LDL Cholesterol Lipoproteins;Label;Leukocyte Elastase;Lipids;Lipoprotein Binding;Maps;Mass Spectrum Analysis;Measures;Mediating;Mentors;Methionine;Methods;Morphology;Mus;Myocardial Infarction;National Heart Lung and Blood Institute;Oxides;Peptide Hydrolases;Peptides;Pharmaceutical Preparations;Plasma;Plasma Proteins;Population;Positioning Attribute;Postdoctoral Fellow;Production;Property;Protease Inhibitor;Protein Family;Proteins;Pulmonary Embolism;Reporting;Research;Residual state;Risk;Role;Rupture;Serine Proteinase Inhibitors;Site;Site-Directed Mutagenesis;Small Interfering RNA;Stroke;Testing;Therapeutic;Thrombus;Tissues;Transference;United States;United States National Institutes of Health;Universities;Untranslated RNA;Up-Regulation;Variant;Vascular Endothelium;Work;alpha 1-Antitrypsin;base;cardiovascular risk factor;crosslink;cytokine;elastase inhibitor;electron tomography;experience;experimental study;genetic variant;human subject;in vivo;knock-down;macrophage;member;men;molecular imaging;mouse model;neglect;neutrophil;novel;overexpression;oxidation;particle;peptidomimetics;preservation;prevent;protein degradation;protein function;public health relevance;reconstitution;research clinical testing;skills;study population;tenure track;tool;transcytosis;uptake

public_health_relevance:
Public Health Relevance StatementCardiovascular disease is the leading cause of death in developed countries and atherosclerosis orhardening of the arteries is responsible for the occurrence of the majority of cardiovascular eventssuch as heart attack and stroke. High density lipoproteins (HDL) also known as the goodcholesterol have an established correlation with reduced risk of cardiovascular events. This proposalfocuses on a specific sub-population of HDL and its protective potential against atherosclerosis.


