# projects

application_id: 9300982
project_number: 5P20GM103492-10
project_title: Core E - Imaging and Physiology Core
administering_ic: NIGMS
award_notice_date: 2017-07-12
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5005
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
The Imaging and Physiology Core (Core E) will play a key role in nurturing the growth ofthe Center and developing the Projects by promoting scientific excellence in investigations of cardiometabolic disease. Core E will provide investigators with access to state-of-the-art instrumentation and expert instruction related to confocal imaging assessment of cardiac function and performance of surgery in mice. The Core will promote education on the theory as well as sound technical comprehension related to the various instruments and approaches available. This group will also work closely with the Center members particulariy junior investigators to develop new tailored procedures to answer their experimental questions. The Director will provide guidance not only for the techniques provided by Core E but also mentorship to the junior faculty members in the Center. Dr. Steven Jones (Director Core E) brings approximately ten years of experience in confocal/fluorscent microscopic imaging and mitochondrial function assessment to Core E. The Core will enable Project leaders to use fluorescence microscopy to evaluate either fixed tissue (from Core C) or live cultured cells (from individual Projects). In addition. Dr. Jones' expertise in cardiovascular physiology will allow careful assessment of or surgery on mice generated by Core D. Furthermore the spatial resolution of confocal microscopy complements to high throughput techniques offered by Core B. Given the scope of approaches used in Core E Dr. Jones is perfectly suited to lead this Core. In addition to meeting the needs of the proposed Projects the Core has established a viable plan for a transition to financial independence during Phase II ofthe COBRE. The COBRE University Center and Members have all contributed to extensively to the expansive list of instrumentation in Core E. Such investments reflect the important role of Core E in the progress of the Center. Once the needs of the Projects and Center members are addressed the Director will continue developing new protocols acquiring additional instrumentation and initiating additional collaborations with other investigators in the UofL community. Core E will play a pivotal role in bringing this Center to national prominence in cardiometabolic research.

project_terms:
Address;Biochemical;Cardiac;Cardiovascular Physiology;Cells;Centers of Research Excellence;Collaborations;Communities;Complement;Comprehension;Confocal Microscopy;Cultured Cells;Diabetes Mellitus;Disease;Education;Experimental Designs;Faculty;Fluorescence Microscopy;Growth;Image;Individual;Instruction;Investigation;Investments;Lead;Mentorship;Mitochondria;Modeling;Mus;Obesity;Operative Surgical Procedures;Organ;Organism;Performance;Phase;Physiology;Play;Procedures;Protocols documentation;Research;Research Personnel;Resolution;Role;Techniques;Tissues;Universities;Work;cardiovascular imaging;data acquisition;experience;insight;instrument;instrumentation;meetings;member;microscopic imaging;sound;theories

public_health_relevance:
Core E serves the Imaging and Physiology needs of the Projects and others in the Center. This Core enables the integration of biochemical insights at the level of intact cells organs and intact organisms. Core E leverages its expertise in cardiovascular physiology and imaging to provide the Projects and other Center members with insights into model choice experimental design data acquisition and interpretation of results.


application_id: 9300981
project_number: 5P20GM103492-10
project_title: Core D - Animal Models and Phenotyping Core
administering_ic: NIGMS
award_notice_date: 2017-07-12
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5004
contact_pi_person_id: 8767000
contact_pi: CONKLIN, DANIEL JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
The Animal Models and Phenotyping Core (Core D) has four major goals. 1) Its primary function is to support the research projects of COBRE-supported Junior Investigators by providing state-of-the-art facilities and intellectual capability for the development and characterization of new and existing animal models used in diabetes and obesity research. Other goals are: 2) to provide training and education to Diabetes and Obesity Center junior investigators and members; 3) to develop new models techniques and protocols to further diabetes and obesity research; and 4) to become a self-sustaining entity that supports the Diabetes and Obesity Center. While the Animal Core will preferentially address the needs of the COBRE-supported junior investigators it will also assist in the development of new protocols maintenance of unique mouse lines and creation of new models for other Diabetes and Obesity Center investigators. It will provide a comprehensive assessment of animal adiposity glucose insulin and pyruvate tolerance physical activity body temperature food and water intake oxygen consumption and carbon dioxide production in order to evaluate the overall metabolic condition ofthe model animal under environmental challenges including high fat diet. Training and educating investigators is an integral function of the Animal Core and it will continue to provide education to Center junior investigators and members. The Animal Core has trained personnel who in turn educate individual junior investigators on how to perform metabolic phenotyping tests correctly. The Animal Core has and will continue to develop new models of interest to investigators for specific mechanistic purposes. It will expand its operations to support future needs by adding infrastructure equipment and by developing state-of-the-art animal models and by establishing new methods refining assays and using statistical modeling approaches useful in metabolic phenotyping. The Animal Core intends to become a selfsustaining entity that will promote the long-term stability of the Center by providing essential services and developing new and unique capabilities for individual and multi-PI projects.

project_terms:
Address;Animal Model;Animals;Biological Assay;Body Temperature;Carbon Dioxide;Centers of Research Excellence;Development;Diabetes Mellitus;Eating;Education;Equipment;Future;Glucose;Goals;High Fat Diet;Human Resources;Individual;Insulin;Maintenance;Metabolic;Methods;Modeling;Mus;Obesity;Oxygen Consumption;Phenotype;Physical activity;Production;Protocols documentation;Pyruvate;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Services;Statistical Models;Techniques;Testing;Training;Training and Education;Water consumption;interest;member;metabolic phenotype;operation

public_health_relevance:
The metabolic phenotyping of animal models used in diabetes and obesity research is an integral component of all COBRE-supported Junior Investigator-initated projects and for members ofthe Diabetes and Obesity Center. As such Core D provides the infrastructure animal models techniques and oversight to support the in-depth and state-of-the-art characterization of metabolic phenotypes in models of obesity and diabetes.


application_id: 9300979
project_number: 5P20GM103492-10
project_title: Core C - Pathology and Bio-analytics Core
administering_ic: NIGMS
award_notice_date: 2017-07-12
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5003
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
Overarching goal of the Center is to understand the mechanisms of pathophysiology of diabetes and obesity and their cardiovascular complications. The Pathology and Bio-analytics Core is an integral part ofthe Center and will play a key role in the evolution of COBRE-funded projects. The Core will render services for rigorous and comprehensive pathological analysis of diabetic specimens. It will provide intellectual input with experimental design and state-of-the-art technical expertise to address the needs of investigators. The Core consists of a group of outstanding scientists with expertise in cardiovascular physiology pathology and analytical biochemistry. Director ofthe Core Dr. Sanjay Srivastava more than twenty years of research experience in analytical biochemistry and pathology and vascular inflammation atherosclerosis and diabetes. He will oversee all the Core operations and will work closely with junior investigators to teach them principles of histology chromatography and mass spectrometry. Dr Srivastava will also help the COBRE investigators with quantification and characterization of atherosclerotic lesions. Dr. Michael Merchant coinvestigator in the Core has extensive experience in analytical biochemistry and will assist the COBRE investigators with proteomics analyses. Drs. Srivastava and Merchant will provide hands on training to junior investigators for various histology and bio-analytical assays. The training acquired at the Core will facilitate them to grow as scientists and expand their repertoire of technical skills. The Core is equipped with state-ofthe- art pathology and analytical biochemistry equipment and is located in the Delia Baxter Building. In addition to address the current requirements of the COBRE projects the Core will continue to expand its knowledgebase and technical expertise to satisfy the future needs of the Center. Long term goal of the Core is to become a fiscally independent entity capable of providing cutting-edge pathology and bio-analytical services to researchers interested in diabetes and cardiovascular pathophysiology. Continued excellence in pathological analyses will foster collaborations which will not only help the Core financially but will also advance the field in combatting diabetic complications.

project_terms:
Address;Analytical Biochemistry;Arterial Fatty Streak;Arts;Atherosclerosis;Biochemical;Biological Assay;Cardiovascular Physiology;Cardiovascular system;Centers of Research Excellence;Chromatography;Collaborations;Complications of Diabetes Mellitus;Diabetes Mellitus;Equipment;Evolution;Experimental Designs;Fostering;Functional disorder;Funding;Future;Goals;Histologic;Histology;Mass Spectrum Analysis;Obesity;Pathologic;Pathology;Play;Proteomics;Research;Research Personnel;Scientist;Services;Specimen;Technical Expertise;Tissues;Training;Work;combat;diabetic;experience;interest;knowledge base;operation;vascular inflammation

public_health_relevance:
The Pathology and Bio-analytics Core of the Center will provide technical expertise in the pathological examination and quantification of various analytes in diabetic tissues. The Core will train junior investigators with histological assessment and biochemical analyses of diabetic tissues and tease out the biochemical mechanisms associated with the onset of diabetes and obesity and their cardiovascular complications.


application_id: 9300978
project_number: 5P20GM103492-10
project_title: Core B - Flow Cytometry Core
administering_ic: NIGMS
award_notice_date: 2017-07-12
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5002
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
The Flow Cytometry Core (Core B) has three major goals. Its primary function is to offer Center Investigators the ability to utilize complex and technically-challenging flow cytometric approaches to characterize cells and their functional and signaling properties. Thus the Core will provide access to state ofthe art equipment for flow cytometric analysis of cellular antigen expression metabolism and signaling and cell sorting capability to support cardiovascular research in diabetes and obesity at the University of Louisville. Core B personnel are highly-experienced investigators who have worked for several years on flow cytometry using various tissues and cells from multiple species and have extensive expertise in rare event sorting and analysis. The complementary nature of their backgrounds and areas of expertise coupled with their collegial nature provides a strong foundation for productive synergy within this Core and its productive interactions with other investigators associated with the Diabetes and Obesity Center. Secondly the Core is committed to an educational goal. Not only will Center members be trained on the operation of instruments it is the intent that all users completely understand cytometric theory application and data analysis. It is hoped that all Project investigators in their transition to independence will be able to competently incorporate flow cytometry as an analytical tool in future studies. The Core is also committed to developing its scope and operation to support multidimensional flow cytometry needs in the future. It will continue to upgrade its equipment and analytical repertoire. Finally this Core has the ultimate goal of developing into a self-supporting and large-scale flow cytometry operation that will cater not only to the specific needs of the Center but to other University investigators interested in diabetes and obesity research. A fully developed Flow Cytometry Core will be a significant asset in developing future multi-investigator projects and for helping researchers conduct multifaceted basic and clinical investigations aimed at the amelioration of health hazards caused by diabetes and obesity.

project_terms:
Antigens;Area;Arts;Cardiovascular system;Cell Separation;Cells;Centers of Research Excellence;Complex;Coupled;Data Analyses;Development;Diabetes Mellitus;Equipment;Evaluation;Event;Felis catus;Flow Cytometry;Foundations;Future;Goals;Health Hazards;Human Resources;Metabolism;Nature;Obesity;Population;Property;Research;Research Infrastructure;Research Personnel;Services;Signal Transduction;Sorting - Cell Movement;Tissues;Training;Universities;Work;analytical tool;clinical investigation;experience;improved;instrument;interest;member;operation;synergism;theories

public_health_relevance:
The isolation characterization and functional evaluation of distinct cell populations or tissues is an essential component of all Projects in the COBRE and studies by several Center members. Core B will provide flow cytometric capability as a facile means to meet these needs. Successful operation of Core B will enhance the scientifc development of junioir investigators provide essential services to Center members and improve the research infrastructure at the University of Louisville.


application_id: 9300977
project_number: 5P20GM103492-10
project_title: Core A - Administrative Core
administering_ic: NIGMS
award_notice_date: 2017-07-12
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5001
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
Core A will continue to provide scientific fiscal administrative and logistic oversight to all aspects of the Center. As before. Core personnel will facilitate communication among investigators and the sharing of reagents tools specimens and data to ensure appropriate allocation and effective use of Center funds. The Core will also continue to: provide clerical support; coordinate interactions between facility cores and research projects; organize regular investigator meetings and; provide biostatistical support. In addition to these functions the Core will develop and implement a clear path for transition to and attainment of independent status and for the continued career development of early career investigators . The Core will provide leadership and administrative support needed to maintain the thematic focus of the Center and to achieve Center goal. It will provide mentorshp to early-career investigaotrs by expanding curernt mentoring activitis while continued to provide personalized mentoring. Core personnel will encourage the exploratoin of new research avenues and phase out unpromising resarch and maximize the intellectual environment of the Center. The Core will also provide statistical support to assist in study design and analysis and help in developing grant proposals. It will monitor evaluate overall Center progress in achieving specific milestones. Core personel will prepare annual scientific reports and financial statements and plan and organize symposia seminars and regulary-scheduled meetings. They will invite prominent scientists to present seminars and interact with Center members and communiate with University and NIH officials to report progress and discuss Center related issues. In consultation with the external and internal advisory committee the Program Director will recruit new faculty to replace graduating COBRE investigators and if required increase the critical mass of investiagtors working in the Center. If required Core A will adopt remedial measures for Principal Investigators who fail to satisfactory review by the External Advisory Committee. The Core will also maintain a Center Website and faciliate the dissemination of information about Center activities as well as diabetes and obesity.

project_terms:
Adopted;Advisory Committees;Applications Grants;Area;Biometry;Centers of Research Excellence;Communication;Consultations;Core Facility;Data;Development;Diabetes Mellitus;Ensure;Environment;Faculty;Funding;Goals;Human Resources;Information Dissemination;Leadership;Logistics;Measures;Mentors;Monitor;Obesity;Phase;Prevention strategy;Principal Investigator;Progress Reports;Reagent;Recruitment Activity;Reporting;Research;Research Design;Research Personnel;Research Project Grants;Schedule;Scientist;Specimen;Training;United States National Institutes of Health;Universities;career;career development;meetings;member;next generation;programs;symposium;tool;web site

public_health_relevance:
The Core will provide administrative support to the Diabetes and Obesity Center at the University of Louisville and therefore contribute to the development of new and effective strategies for prevention and treatment of diabetes and obesity research by facilitating research in this area and by providing mentoring and training to the next generation of scientists.


application_id: 9300972
project_number: 5P20GM103492-10
project_title: Center for Excellence in Diabetes and Obesity Research
administering_ic: NIGMS
award_notice_date: 2017-07-12
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
program_official: CALDWELL, SHEILA
project_start_date: 2008-09-26
project_end_date: 2018-06-30
study_section: ZGM1-TWD-Y(C2)
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal is for continued support for the multi-disciplinary Diabetes and Obesity Center at the University of Louisville. The central focus of the Center is to enable promote and support research on the cardiovascular causes and consequences of diabetes and obesity. The second major aim of the program is to continue to provide mentoring and guidance to junior investigators in the Center. Specific objectives of the program are to: (1) Enhance and expand a thematic multi-disciplinary research center focused on diabetes and obesity; (2) Foster the research careers of junior investigators leading to their development as independent principal investigators; (3) Develop a nationally-competitive program that will attract the best clinical and post-doctoral fellows graduate students and faculty; (4) Expand and bridge on-going research within the Center and further integrate current expertise into a thematically coherent program; (5) Promote collaborative interactions to build additional complementary research projects both individual and multi-investigator; (6) Build upon existing research capabilities and core facilities to provide state-of-the-art infrastructure support; (7) Develop basic and clinical understanding of the molecular mechanisms of diabetes and obesity and how they contribute to the burden of cardiovascular disease; (8) Discover new and effective means for preventing and treating diabetes and obesity; and (9) Develop and implement a plan for the transition from COBRE support to independent funding. The five related projects of the junior investigators will: (1) Examine the effects of dietary carnosine on diabetes and obesity; (2) Assess the impact of particulate air pollution on insulin resistance; (3)
Elucidate the role of eNOS in obesity; (4) Assess stem cell dysfunction in diabetes; and (5) Develop biomarkers for detecting atherothrombotic events in patients with type 2 diabetes. These investigations will be supported by state-of-the-art core facilities in flow cytometry pathology and bioanalytical chemistry imaging and physiology and animal model development and phenotyping. Continued support to the Center will strengthen the infrastructure of biomedical research at the University of Louisville and will positively impact the field of diabete and obesity research worldwide.

project_terms:
Address;Air Pollution;Biological Markers;Biomedical Research;Cardiology;Cardiovascular Diseases;Cardiovascular system;Carnosine;Centers of Research Excellence;Chemistry;Clinical;Core Facility;Data;Development;Diabetes Mellitus;Diet;Disease;Event;Faculty;Flow Cytometry;Fostering;Foundations;Functional disorder;Funding;Goals;Health;Image;Individual;Insulin Resistance;Interdisciplinary Study;Investigation;Knowledge;Mentors;Modality;Molecular;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Particulate;Pathology;Patients;Phase;Phenotype;Physiology;Postdoctoral Fellow;Prevention;Principal Investigator;Reagent;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Role;Stem cells;Universities;animal model development;career;clinical investigation;cohesion;design;epidemiology study;graduate student;multidisciplinary;novel;prevent;programs;public health relevance

public_health_relevance:
Research supported by the Diabetes and Obesity Center at the University of Louisville will address two of the most significant health concerns in the nation An established independent Diabetes and Obesity Center at the University of Louisville with a well-supported cadre of new and established investigators would create new knowledge and develop novel treatment and prevention modalities for these diseases.


application_id: 9298613
project_number: 5R21CA209045-02
project_title: Systemic delivery of miR-29 for basal-like breast cancer treatment
administering_ic: NCI
award_notice_date: 2017-08-28
opportunity_number: PAR-15-340
application_type: 5
activity_code: R21
ic: CA
serial_number: 209045
program_official: O'HAYRE, MORGAN
project_start_date: 2016-09-01
project_end_date: 2020-08-31
study_section: ZCA1-TCRB-Q(M3)
contact_pi_person_id: 10533977
contact_pi: XU, REN
other_pis: SHU, DAN
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:
ABSTACT Basal-like breast cancer is estrogen receptor (ER) progesterone receptor (PR) and Her2 negative; it isnot responsive to hormone therapy and drugs that target the HER2 protein. Therefore it is urgent to developnovel therapeutic strategies for basal-like breast cancer. Basal-like breast cancer is rich in tumor-initiating cells.Tumor initiating cells are drivers of cancer metastasis and relapses; thus targeting tumor-initiating cells iscritical for basal-like breast cancer treatment. Our recent study shows that 3WJ RNA nanoparticlesincorporated with EGFR aptamer successfully bind and enter into the basal-like breast cancer cell line MDA-MB 231 in culture and in the orthotopic mouse mammary tumor model. RNA aptamers targeting the tumorinitiating cell marker CD44 have been identified and characterized which offers a potential strategy fordelivering the 3-way junction (3WJ) RNA nanoparticles into tumor initiating cells. We and others recentlydemonstrate that miR-29b is a potent tumor suppressor for basal-like breast cancer. Expression of exogenousmiR-29b in basal-like breast cancer cell lines significantly inhibits cancer metastasis in orthotopic mammarytumor models and repressed malignant phenotypes in 3D culture. MiR-29 also demonstrate potent inhibitoryactivity on tumor-initiating cells. Therefore we predict that therapeutic delivery of miR-29b will inhibit basal-likebreast cancer progression and metastasis. The overall objective of this proposal is to develop a novelapproach to therapeutically deliver tumor suppressor miRNA into basal-like breast cancer. In combining withRNA aptamers to target cell surface markers of basal-like breast cancer and 2F modification to enhancemiRNA stability the RNA nanoparticle provides a powerful tool to therapeutically deliver miR-29 to basal-likebreast cancer. The central hypothesis of this proposal is that tumor suppressor miR-29b can betherapeutically delivered to basal-like breast cancer tissue using 3WJ RNA nanoparticles and subsequentlyrepresses cancer progression and metastasis. To test our central hypothesis and achieve the objective of thisproposal we have designed experiments with the following specific aims. Aim 1. Construct RNAnanoparticles harboring therapeutic miR-29b that will target basal-like breast cancer cells. Aim 2.Examine the biologic activity of multifunctional therapeutic RNA nanoparticles in the orthotopic mousemammary tumor model. Development of RNA nanoparticles that deliver miR-29b to basal-like breast cancertissue and tumor-initiating cells will overcome the current hurdle in utilizing miRNA for cancer therapy.Examining the potential of exogenous miR-29b in inhibiting progression and metastasis of basal-like breastcancer may identify a potential therapeutic strategy for this deadly disease.

project_terms:
Binding;Biodistribution;Biological;Biology;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Treatment;Breast Cancer cell line;Breast Cancer therapy;CD44 gene;Cancer Biology;Cancer Relapse;Cell surface;Cells;Clinical;Data;Development;Disease;Drug Kinetics;Drug Targeting;ERBB2 gene;Epidermal Growth Factor Receptor;Estrogen Receptors;In Vitro;Incidence;Injection of therapeutic agent;MDA MB 231;Malignant Neoplasms;Mammary gland;MicroRNAs;Modeling;Modification;Mus;Nanotechnology;Neoplasm Metastasis;Organ;Physiological;Population;Positioning Attribute;Progesterone Receptors;Proteins;Publications;RNA;Recurrent disease;Research;System;Testing;Therapeutic;Tissues;Treatment Efficacy;Tumor Initiators;Tumor Suppressor Proteins;anticancer research;aptamer;cancer therapy;design;experimental study;functional restoration;hormone therapy;in vivo;malignant breast neoplasm;malignant phenotype;mouse model;multidisciplinary;nanoparticle;novel;novel strategies;novel therapeutics;targeted treatment;therapeutic RNA;therapeutic miRNA;therapeutic target;three dimensional cell culture;tool;tumor;tumor progression

public_health_relevance:
Development RNA nanoparticles to specifically deliver miR-29b to basal-like breast cancer tissue and tumor-initiating cells will help to overcome the current hurdle for utilizing microRNA as a therapeutic target. Examiningthe potential of exogenous miR-29b in inhibiting progression and metastasis of basal-like breast cancer mayidentify a novel therapeutic strategy for this deadly disease.


application_id: 9298598
project_number: 5K01CA197073-03
project_title: Intestinal phosphatidylcholine exposure and breast cancer risk
administering_ic: NCI
award_notice_date: 2017-06-20
opportunity_number: PAR-12-050
application_type: 5
activity_code: K01
ic: CA
serial_number: 197073
program_official: SOYOMBO-SHOOLA, ABIGAIL ADEBISI
project_start_date: 2015-07-01
project_end_date: 2020-06-30
study_section: Transition to Independence Study Section (I)[NCI-I]
contact_pi_person_id: 10392720
contact_pi: ONONO, FREDRICK ONYANGO
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): Diet-dependent obesity is a risk factor for many cancers including postmenopausal breast cancer. Obesity is also associated with more aggressive breast cancer subtypes and poorer clinical outcomes in breast cancer patients. The increasing prevalence of overweight and obese postmenopausal breast cancer patients makes it critical to identify the mechanisms that underlie this link between obesity and breast cancer risk and prognosis. A better understanding of the link between diet obesity and breast cancer risk might then lead to improvements in healthful nutrition for obese or overweight patients or identify markers for breast cancer risk assessment or targets for pharmacological intervention to mitigate breast cancer risk associated with obesity. The aim of this K01 application is to support mentored training in advanced mass spectrometry/metabolomics and preclinical models that will enable me to become an independent investigator working at the interface of obesity and cancer research. A broad hypothesis to explain the link between obesity and cancer risk is that consumption of a high fat diet and/or increased synthesis and storage of fats is associated with the production of bioactive lipids or lipid-derived molecules that themselves promote disease. I propose to investigate the possibility that intestinal exposure to the phospholipid phosphatidylcholine (PC) constitutes a link between diet and breast cancer risk by promoting the synthesis of a PC derived bioactive lipid lysophosphatidic acid (LPA). Breast cancer cells are acutely responsive to LPA which stimulates their migration growth and survival in vitro. Genetic and pharmacological targeting of LPA synthesis and signaling attenuate breast cancer tumor growth and metastasis in mouse models. We propose that dietary consumption of foods rich in PC or secretion of PC into the stomach as bile in response to a fatty meal results in uptake of this lipid as its lyso derivative lysoPC (LPC) that is transported in the blood as a component of intestinally derived lipoproteins where is serves as a substrate for production of LPA by the secreted lysophospholipase D autotaxin. In support of this idea we show that plasma LPA levels in mice and humans are acutely sensitive to fasting and re-feeding and that in mice dietary PC can be converted to LPA in the blood. To address our hypothesis we will use mass spectrometry to monitor metabolism of dietary PC in mice and develop mouse diets with defined PC composition that we propose will lead to alterations in plasma LPA levels. The information in this aim will then be exploited to determine the impact of manipulations of dietary PC and pharmacological inhibition of the LPA generating enzyme autotaxin on breast cancer metastasis in mouse models. Completion of these studies will provide important new information about how a specific dietary constituent could contribute to breast cancer metastasis in humans and might also provide an impetus for future translational studies exploring the possibility that pharmacological inhibition of LPA synthesis and signaling could be a viable strategy to mitigate human breast cancer risk particularly in obese subjects.

project_terms:
Acute;Address;Adipose tissue;Animals;Attenuated;Award;Bile fluid;Bioavailable;Blood;Blood Circulation;Breast;Breast Cancer Cell;Breast Cancer Patient;Breast cancer metastasis;Calories;Cancer Patient;Cancer Prognosis;Chylomicrons;Clinical;Consumption;Data;Diet;Dietary Fats;Disease;Enterocytes;Enzymes;Exposure to;Fasting;Fatty acid glycerol esters;Food;Funding;Future;Genetic;Growth;High Fat Diet;Human;Hydrolysis;In Vitro;Incidence;Individual;Intervention;Intestinal Absorption;Intestines;Lead;Lecithin;Link;Lipids;Lipoproteins;Low-Density Lipoproteins;Lymphatic System;Lysophospholipase;Lysophospholipids;Malignant Neoplasms;Mass Spectrum Analysis;Mediator of activation protein;Mentors;Metabolic;Metabolism;Metastatic Neoplasm to the Bone;Modernization;Monitor;Mus;Neoplasm Metastasis;Nonesterified Fatty Acids;Obesity;Oral;Outcome;Overweight;Pathway interactions;Patients;Pharmacology;Phospholipase A2;Phospholipase D;Phospholipids;Plants;Plasma;Postmenopause;Pre-Clinical Model;Prevalence;Process;Production;Reaction;Request for Proposals;Research;Research Personnel;Research Support;Research Training;Risk Assessment;Risk Factors;Signal Transduction;Stomach;Testing;Tracer;Training;Underrepresented Minority;United States;United States National Institutes of Health;Weight;Woman;Work;anticancer research;cancer risk;cancer subtypes;career development;diet and cancer;dietary constituent;dietary manipulation;disorder risk;experience;feeding;food consumption;inhibitor/antagonist;lysophosphatidic acid;malignant breast neoplasm;metabolomics;migration;minority scientist;mouse model;nutrition;obesity risk;particle;public health relevance;response;sedentary lifestyle;skills;stable isotope;translational study;tumor growth;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Being obese or overweight dramatically increases cancer risk particularly in women and obese or overweight cancer patients often experience worse clinical outcomes than normal weight individuals. However the basis for this association of obesity with cancer risk and prognosis is not well understood. This proposal requests funds to support research training and career development for a promising underrepresented minority scientist who proposes to investigate a potential mechanism linking obesity to cancer risk and clinical outcomes.


application_id: 9297214
project_number: 5R21AI126883-02
project_title: Borrelia miyamotoi: mechanisms of tick colonization and transmission
administering_ic: NIAID
award_notice_date: 2017-06-28
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: AI
serial_number: 126883
program_official: ILIAS, MALIHA R
project_start_date: 2016-07-01
project_end_date: 2019-12-31
study_section: Vector Biology Study Section[VB]
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:
ABSTRACTHuman infection by the spirochete Borrelia miyamotoi is a newly-recognized public health threat in the US andother parts of the world. Borrelia miyamotoi infection may require hospitalization with symptoms that includehigh fever joint and muscle pain and meningoencephalitis. B. miyamotoi is spread by the bites of infectedIxodes spp. ticks but almost nothing is known about how or where the bacterium colonizes its vector or thedynamics of transmission. This proposal brings together an expert team of Borrelia and tick researchers whowill conduct a series of synergistic studies that will greatly expand understanding of B. miyamotoi transmissionand infection mechanisms.

project_terms:
Acute;Address;Adult;Anaplasma phagocytophilum;Area;Argasidae;Arthralgia;Babesia;Bacteria;Biology;Bite;Black-legged Tick;Borrelia;Borrelia burgdorferi;Borrelia miyamotoi;Climate;Diagnosis;Ehrlichia;Emerging Communicable Diseases;Exhibits;Exposure to;Fever;Geographic Locations;Health;Horizontal Disease Transmission;Hospitalization;Hour;Human;Immunocompromised Host;Incidence;Infection;Institute of Medicine (U.S.);Invaded;Ixodes;Ixodidae;Laboratories;Larva;Location;Lyme Disease;Maintenance;Meningoencephalitis;Midwestern United States;Myalgia;New England;Nymph;Ohio;Order Spirochaetales;Ornithodoros;Population;Prevalence;Proteins;Public Health;Publishing;Relapsing Fever;Reporting;Research Personnel;Risk;Rivers;Sampling;Seminal;Series;Seroprevalences;Site;Spirochaetales Infections;Symptoms;Tick-Borne Diseases;Tick-Borne Encephalitis Virus;Tick-Borne Encephalitis Viruses;Tick-Borne Infections;Ticks;Vertical Disease Transmission;Widespread Disease;differential expression;disorder prevention;experimental analysis;exposed human population;feeding;field study;laboratory experiment;land use;pathogen;transmission process;vector

public_health_relevance:
PROJECT NARRATIVEHuman infection by the tick-borne bacterium Borrelia miyamotoi has recently been recognized as a threat tohuman health. Currently very little is currently known about how B. miyamotoi is transmitted by its tick vector.This proposal brings together three experts in tick and Borrelia biology who will conduct a series of studiesthat will reveal mechanisms by which B. miyamotoi colonizes its tick vector and is transmitted to mammalianhosts.


application_id: 9296127
project_number: 5R03DK107851-02
project_title: Estrogen Regulation of Daily Metabolic Rhythms
administering_ic: NIDDK
award_notice_date: 2017-06-30
opportunity_number: PAR-15-343
application_type: 5
activity_code: R03
ic: DK
serial_number: 107851
program_official: SPAIN, LISA M
project_start_date: 2016-07-01
project_end_date: 2019-06-30
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 7003021
contact_pi: PENDERGAST, JULIE S
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 SummaryObesity-related disorders account for 2.8 million deaths per year. The loss of circulating estrogen aftermenopause increases the prevalence of obesity and the risk of life-threatening obesity-related disorders suchas cardiovascular disease and stroke in women. Shift work and night-eating also increase the risk of obesityand metabolic syndrome suggesting that disruption of circadian rhythms causes metabolic dysfunction. Thisproject will determine how estrogen interacts with the circadian system to protect females from obesity andrelated disorders. In our previous studies we demonstrated a link between disruption of circadian rhythmsconsumption of high-fat diet and obesity in male mice. Male mice develop profound diet-induced obesity. Wefound that after only one week of high-fat diet consumption the daily rhythm of eating behavior wasimmediately altered and the timing of the circadian clock in the liver was robustly advanced in male mice. Incontrast female mice are resistant to diet-induced obesity. In our preliminary studies we found high-fat dietdoes not alter the daily rhythm of eating behavior or the liver clock in females. Thus we hypothesize thatretention of normal daily metabolic rhythms during high-fat diet consumption confers protection from diet-induced obesity in females. The goal of this proposal is to elucidate the molecular and behavioral mechanismsthat protect daily rhythms from high-fat diet in females. Our specific aims are (1) to determine if estrogenregulates the effects of high-fat diet on daily rhythms in female mice; and (2) to determine if estrogen regulationof the daily rhythm of eating behavior protects females from diet-induced obesity. The completion of this projectwill reveal mechanisms whereby females are protected from diet-induced obesity and inform the developmentof novel therapeutics for obesity in women.

project_terms:
Adult;Behavior;Behavioral Mechanisms;Brain;Cardiovascular Diseases;Cessation of life;Circadian Rhythms;Consumption;Development;Diet;Disease;Eating;Eating Behavior;Epidemic;Estrogen Receptor alpha;Estrogens;Excision;Fatty acid glycerol esters;Female;Functional disorder;Goals;High Fat Diet;Knock-out;Knockout Mice;Lead;Life;Link;Liver;Measures;Menopause;Metabolic;Metabolic syndrome;Metabolism;Modeling;Molecular;Mus;Neurons;Obesity;Ovariectomy;Peripheral;Phase;Physiology;Postmenopause;Prevalence;Regulation;Reporter;Resistance;Risk;Signal Transduction;Synapsins;System;Tissues;Weight;Weight Gain;Woman;circadian pacemaker;epidemiology study;experience;feeding;glucose metabolism;male;novel therapeutics;obesity risk;phase change;prevent;shift work;stroke

public_health_relevance:
Obesity prevalence increases sharply in women after menopause demonstrating that estrogen has potent anti-obesity effects. Circadian disruption caused by shift-work and night-eating also increases the risk of obesity.This project will determine how estrogen interacts with the circadian system to inhibit obesity in females.


application_id: 9296108
project_number: 5T32DA035200-20
project_title: Research Training in Drug Abuse Behavior
project_terms: Behavior;Drug abuse;Research Training
administering_ic: NIDA
award_notice_date: 2017-06-26
opportunity_number: PA-11-184
application_type: 5
activity_code: T32
ic: DA
serial_number: 035200
program_official: KAUTZ, MARY A
project_start_date: 1998-08-01
project_end_date: 2018-06-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This continuation application proposes to support three pre-doctoral and three post-doctoral trainees with a faculty of 28 drawn from seven academic and research units of the University of Kentucky. The environment is rich with opportunities for bio-behavioral research in facilities such as the: 1) Center on Drug and Alcohol Research; 2) Center for Drug and Alcohol Research Translation; 3) Center for Clinical and Translational Science; 4) Laboratory of Human Behavioral Pharmacology; 5) Residential Research Facility; and 6) Straus Behavioral Research Building. During the most recent five-year funding period we trained seven pre-doctoral students and eight post-doctoral fellows. Fourteen of these trainees remain involved in research or academics. Additional pre-doctoral trainees (2) and post-doctoral fellows (1) will be added during the final year of the current funding period. Individuals from under-represented racial and ethnic groups filled 17 percent of the available training slots. These trainees authored 129 publications and presented 90 papers at national or international conferences. The program is designed to prepare trainees to assume research responsibilities in academic and other scientific organizations concerned with bio-behavioral aspects of drug abuse. Post-doctoral fellows will either have a doctorate in a behavioral science discipline and will be preparing for a research role in the drug abuse field or they will be healt professionals who are seeking a behavioral science research orientation in drug abuse. Pre-doctoral trainees will concentrate in behavioral aspects of drug abuse as part of a doctoral program in a behavioral science discipline (e.g. psychology sociology). Basic elements of the program include: (1) training in the basic building blocks of research (e.g. experimental design data analysis) and independent research competence; (2) an interdisciplinary orientation which takes students beyond their basic discipline and provides exposure to key theoretical concepts and methodological issues of the related behavioral sciences along with a bio-behavioral conceptualization; (3) a program of enculturation and orientation to drug abuse health and mental health settings; (4) exploration of drug abuse topics from a medical behavioral perspective through courses offered by training faculty; and (5) opportunities for research around relevant questions in drug abuse behavior constituting significant learning experiences for post-doctoral fellows and a dissertation project for pre-doctoral trainees. The post-doctoral program is individually geared to the objectives of the fellows and will build on their previous knowledge and experience while drawing on these five core elements. We feel the need for a translational and interdisciplinary program such as the one proposed is greater today than ever before and fills a unique niche in substance abuse research.

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  The purpose of this application is to continue a highly successful 15-year training program in translational and interdisciplinary drug-abuse research. The program offers translational and interdisciplinary research training on bio-behavioral factors in drug abuse at the pre-doctoral and post-doctoral levels. Graduates of this program are actively involved in research teaching publishing articles and becoming independent drug abuse researchers. We aim to continue this record of success in the next funding period because the need for a translational or interdisciplinary program is greater today than ever before and the proposed training program fills a unique niche in drug abuse research.


application_id: 9295972
project_number: 5R03AI126252-02
project_title: Functions of T. pallidum and L. interrogans PUR proteins
administering_ic: NIAID
award_notice_date: 2017-06-02
opportunity_number: PA-13-304
application_type: 5
activity_code: R03
ic: AI
serial_number: 126252
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2016-06-15
project_end_date: 2019-05-31
study_section: Special Emphasis Panel[ZRG1-IDM-B(81)S]
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:
ABSTRACTThe pathogenic spirochetes Treponema pallidum (syphilis) and Leptospira interrogans (leptospirosis) changetheir protein compositions during infection processes evidently as means to adapt to different niches. Despitethe significance of these two diseases essentially nothing is known about how either bacterium regulates geneexpression. Complicating matters there are no methods to genetically manipulate T. pallidum and the genetictoolbox for L. interrogans is largely limited to random mutagenesis. In our studies of a related spirocheteBorrelia burgdorferi (Lyme disease) we discovered a differentially expressed DNA- and RNA-binding proteinnamed BpuR which in turn controls expression of numerous genes and proteins. Mutant B. burgdorferi thatare unable to control BpuR levels are severely attenuated for mammalian infection. The protein's name derivesfrom its PUR-domain a motif also found in crucial regulatory proteins of humans and all other highereukaryotes as well as many pathogenic bacterial species. T. pallidum and L. interrogans each encode a singlePUR-domain protein which we named TpuR and LpuR respectively. We hypothesize that TpuR and LpuRwill bind specific sequences in their respective DNA and RNA as does every other known PUR-domainprotein. In silico analyses will then be applied to identify potential PUR protein-binding sites within eachspecies' genome and a subset of putative binding sites will be experimentally validated. We furtherhypothesize that T. pallidum and L. interrogans control production of their PUR proteins and that PURprotein levels correlate with differential expression of genes that contain PUR protein-binding sitesadjacent to their promoters. We predict that this combination of computational biochemical and in vivoanalyses will provide insight into regulatory mechanisms employed by these two pathogens important stepstoward understanding the bacteria's infectious properties and development of therapies that specifically blockadaptation to their human hosts.

project_terms:
Affect;Affinity;Attenuated;Bacteria;Bacterial Genes;Binding;Binding Proteins;Binding Sites;Biochemical;Biological;Birth;Borrelia;Borrelia burgdorferi;Cessation of life;Computer Simulation;Consensus;DNA;Data;Defect;Development;Disease;Engineering;Enzymes;Eukaryota;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Gene Proteins;Genes;Genetic;Genetic Transcription;Genome;Homologous Protein;Human;In Vitro;Infection;Infectious Agent;Insecta;Leptospira interrogans;Leptospirosis;Lyme Disease;Metabolic;Methods;Molecular;Mus;Mutagenesis;Names;Nucleic Acid Binding;Order Spirochaetales;Organism;Pathogenicity;Plants;Process;Production;Property;Proteins;RNA;RNA-Binding Proteins;Recombinants;Regulatory Pathway;Rest;Reverse Transcriptase Polymerase Chain Reaction;Sexually Transmitted Diseases;Syphilis;Techniques;Tertiary Protein Structure;Therapeutic;Ticks;Tissue-Specific Gene Expression;Transcript;Treponema pallidum;Virulence Factors;differential expression;genetic regulatory protein;human disease;improved;in vivo;insight;mutant;nervous system development;novel strategies;nucleic acid binding protein;pathogen;promoter;therapy development;transcriptome sequencing;transcriptomics;vector

public_health_relevance:
PROJECT NARRATIVEThe spirochetes that cause syphilis and leptospirosis regulate expression of different genes during mammalianinfection but very little is known about the regulatory mechanisms of either pathogen. We found that eachproduces a protein with a PUR-domain a structural motif that binds to DNA and which is found in importantregulatory proteins of the Lyme disease spirochete and in human insects plants and many other organisms.We propose that the treponemal and leptospiral PUR-domain proteins serve similar functions which we willexplore through a combination of biochemical computational and molecular biological techniques.


application_id: 9295353
project_number: 1R21AI130437-01
project_title: Exploring neurotropism in a food borne model of listeriosis
administering_ic: NIAID
award_notice_date: 2017-01-25
opportunity_number: PA-16-161
application_type: 1
activity_code: R21
ic: AI
serial_number: 130437
program_official: MILLS, MELODY
project_start_date: 2017-01-25
project_end_date: 2018-12-31
study_section: Special Emphasis Panel[ZRG1 IDM-B (80)]
contact_pi_person_id: 2545336
contact_pi: D'ORAZIO, SARAH E. F.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary:Systemic listeriosis is one of the most deadly foodborne bacterial diseases in North America as evidencedby recent outbreaks caused by contaminated cantaloupes (2011; 21% mortality) and cold cuts (2008; 39%mortality). After Listeria monocytogenes (Lm) spread to the brain it is difficult to eradicate the infectionand many patients die even while receiving aggressive antibiotic treatment. Two different types of braininfections are observed in humans: a diffuse meningitis/meningoencephalitis typically seen in the elderlyand other immune-compromised individuals; and a more focal infection localized in the brainstem(rhombencephalitis) that occurs in otherwise healthy adults. The central hypothesis of this proposal is thatmeningitis occurs via hematogenous spread primarily due to a failure of the immune system to limitoverwhelming growth of Lm in peripheral tissues while rhombencephalitis occurs when neurotropic strainsof Lm invade cranial nerves and spread to the brain by axonal migration. Progress in understanding braininfections has been limited by the lack of an appropriate small animal model to study the two proposedroutes of dissemination and by the technical limitation that very few bacteria are needed to causesymptomatic disease in the brain. In Aim 1 of this proposal bacterial colonization patterns in the brain(focal vs. diffuse) will be identified in mice given food contaminated with either neurotropic Lm (humanrhombencephalitis and sheep brain isolates) or non-neurotropic Lm (veterinary strains isolated from theliver). In Aim 2 an innovative approach will define the pathway used by neurovirulent Lm to disseminate tothe brain. Lm will be engineered to secrete Cre recombinase during intracellular growth and then used toinfect mice with a floxed GFP gene allowing for permanent identification of all cells in the body thatharbored intracellular Lm during any point of the infection. A key strength of this proposal is theinterdisciplinary approach resulting from a collaboration between microbiologists in the DOrazio lab withextensive expertise in manipulating Lm and studying host responses to infection and neuroscientists inthe Gensel lab who have the expertise to perform high resolution imaging of the nerves and brainstems ofmice. Working together this group will advance the field by revealing how Lm disseminate to the brainfollowing natural foodborne transmission and will develop a set of tools that may be used in future studiesto identify the features of neurotropic Lm strains that promote brain infection.

project_terms:
Adult;Affect;Animal Model;Antibiotic Therapy;Axon;Bacteremia;Bacteria;Bacterial Infections;Biological Models;Blood;Blood - brain barrier anatomy;Brain;Brain Stem;Breathing;Cantaloupes;Cells;Cerebellum;Cerebrum;Cheese;Clinical;Collaborations;Cranial Nerves;Cytosol;Data;Diffuse;Disease;Disease Outbreaks;Eating;Elderly;Engineering;Enterobacteria phage P1 Cre recombinase;Facial nerve structure;Failure;Fatality rate;Focal Infection;Food;Food Contamination;Future;Gastrointestinal tract structure;Genes;Goals;Growth;Hematogenous Spread;Human;Immune;Immune response;Immune system;Immunodeficient Mouse;Incidence;Individual;Infant;Infection;Inflammation;Inflammatory;Ingestion;Injection of therapeutic agent;Intestines;Invaded;Left;Listeria monocytogenes;Listeriosis;Liver;LoxP-flanked allele;Meat;Meninges;Meningitis;Meningoencephalitis;Modeling;Morbidity - disease rate;Mus;Nerve;Neurologic Deficit;Neurons;Neurotropism;North America;Oral cavity;Pathway interactions;Patients;Pattern;Peripheral;Phagocytes;Process;Recombinants;Route;Ruminants;Sheep;Source;Spleen;Time;Tissues;Treatment Efficacy;Virulence Factors;Work;base;cell type;foodborne;foodborne pathogen;high resolution imaging;high risk population;innovation;interdisciplinary approach;migration;mortality;mouse model;neurotropic;neurovirulence;novel;sciatic nerve;therapeutic target;tool;transmission process;virtual

public_health_relevance:
Project Narrative:Ingestion of ready-to-eat foods (such as deli meat cheeses and produce) that are contaminated withListeria monocytogenes can cause serious infections of the brain that result in lingering neurologicaldeficits in otherwise healthy people and a high fatality rate (20-30%) in high risk groups such as infantsand the elderly. The goal of this proposal is to understand the pathways used by the bacteria to spreadfrom the intestinal tract to the brain with a long-term goal of developing an effective therapeutic that mightblock this process.


application_id: 9293427
project_number: 3P42ES007380-19S2
project_title: Nutrition and Superfund Chemical Toxicity
administering_ic: NIEHS
award_notice_date: 2016-06-21
opportunity_number: RFA-ES-13-001
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S2
program_official: HENRY, HEATHER F
project_start_date: 1997-04-07
project_end_date: 2019-03-31
study_section: ZES1-LKB-K(S)
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Adipose tissue;Affinity;Atherosclerosis;Binding;Biological;Biological Markers;Biology;Biomedical Research;Biomimetics;Blood Vessels;Chemicals;Collaborations;Communities;Coupled;Detection;Diabetes Mellitus;Diet;Diffusion;Disease;Drug Metabolic Detoxication;Ecology;Education;Environment;Environmental Health;Exercise;Exposure to;Health;Human;In Vitro;Inflammation;Inflammatory;Insulin Resistance;Iron;Kentucky;Lead;Learning;Life Style;Longevity;Mass Spectrum Analysis;Mediator of activation protein;Membrane;Mentorship;Methods;Modeling;Monitor;Nanostructures;National Institute of Environmental Health Sciences;Nutritional;Nutritional Toxin;Obesity;Outcome;Oxidation-Reduction;Oxidative Stress;Pigments;Plants;Policies;Policy Developments;Polychlorinated Biphenyls;Polymers;Population;Populations at Risk;Prevention strategy;Primary Prevention;Process;Production;Public Health;Recommendation;Research;Research Design;Research Project Grants;Research Support;Research Training;Risk;Risk Assessment;Risk Management;Role;Rotation;Scientist;Site;Statutes and Laws;Students;Superfund;System;Techniques;Technology;Technology Transfer;Tissues;Toxic effect;Training;Translational Research;Translations;Trichloroethylene;United States Environmental Protection Agency;Universities;Work;base;biomedical scientist;chemical stability;computer infrastructure;cytokine;data management;dechlorination;development policy;evidence base;experience;fetal;global environment;improved;in vivo Model;innovative technologies;insight;lifestyle intervention;manufacturing process;nanomaterials;nanostructured;novel;nutrition;organic contaminant;particle;pollutant;programs;public health relevance;remediation;science education;sensor;superfund chemical;superfund site;technology development;tool;toxicant;translational engagement


application_id: 9293344
project_number: 5P20GM113226-02
project_title: Effects of Dietary Fat on the Hepatotoxicity of Environmental Arsenic
administering_ic: NIGMS
award_notice_date: 2017-03-31
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6176
contact_pi_person_id: 1902836
contact_pi: WATSON, WALTER H
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-04-01
budget_end_date: 2018-03-31
project_abstract:
One of every three American adults is obese and is afflicted with some form of non-alcoholic fatty liver disease(NAFLD). The majority of obese individuals will have steatosis (fatty liver) but only about 20% will have themore serious condition of steatohepatitis (fatty liver with inflammation and liver injury). There is still no FDA-approved therapy for any stage of NAFLD. Therefore it is critical that we understand the multiple factors thatpromote progression from steatosis to steatohepatitis in NAFLD. Our previous studies have shown thatconsumption of arsenic-contaminated drinking water is an important risk factor for progression of NAFLD.Preliminary proteomic analysis demonstrated that the abundance of a number of proteins that are controlled atthe transcriptional level by HNF-4a was decreased in the livers of mice with arsenic-enhanced NAFLD.Mechanistic studies showed that the expression of this zinc finger transcription factor was not altered but thatits DNA binding activity was inhibited at the post-translational level. HNF-4a is known to be regulated by post-translational modifications (PTMs) and arsenic has the potential to affect zinc binding cysteine oxidationarginine methylation and lysine acetylation. Very little is known about how PTMs of HNF-4a are regulated orhow disruption of these regulatory processes contributes to liver disease. To follow up on these importantfindings the objective of the current proposal is to delineate the mechanisms by which environmental arsenicexposure promotes the progression from steatosis to steatohepatitis in mice fed a Western-style diet that ishigh in saturated fat. The central hypothesis to be tested is that alterations in HNF-4a-mediated geneexpression induced by arsenic play a critical role in the progression of NAFLD from steatosis to steatohepatitisin this model. This hypothesis will be tested in three Specific Aims. First we will define the specific molecularinteractions of arsenic with the zinc finger domain of HNF-4a. Second we will analyze the mechanisms bywhich arsenic affects PTMs of HNF-4a and how these changes translate into altered DNA binding activity andtransactivation potential. Third we will define the post-translational modifications of hepatic HNF-4a in mice feda high fat diet and exposed to arsenic-contaminated drinking water and relate these changes to the occupancyof HNF-4a-response elements in genes involved in lipid metabolism and inflammation. This model ofinflammatory liver injury is relevant to the United States population where high fat diets are common andarsenic exposure levels are typically below the threshold for overt hepatotoxicity. The new information obtainedfrom these studies will delineate pathways that are altered by arsenic and that are important in the etiology ofNAFLD.

project_terms:
Acetylation;Adult;Affect;American;Animal Model;Arginine;Arsenic;Arsenites;Benign;Binding;Cells;Centers of Research Excellence;ChIP-seq;Chemicals;Cirrhosis;Clinical;Consumption;Cysteine;DNA;DNA Binding;DNA Binding Domain;Diet;Dietary Fats;Disease;Disease Progression;Disease model;Environment;Etiology;FDA approved;Fatty Liver;Fatty acid glycerol esters;Fibrosis;Gene Expression;Genes;Genetic;Genetic Transcription;Hepatic;Hepatotoxicity;High Fat Diet;In Vitro;Incubated;Individual;Inflammation;Inflammatory;Injury;Knowledge;Liver;Liver diseases;Lysine;Mediating;Methylation;Modeling;Modification;Mus;Obesity;Pathway interactions;Pharmacology;Play;Population;Post-Translational Protein Processing;Process;Proteins;Proteomics;Response Elements;Risk Factors;Role;Signal Pathway;Steatohepatitis;Techniques;Testing;Tissues;Toxic effect;Toxicology;Transactivation;Translating;United States;Zinc;Zinc Fingers;cell injury;contaminated drinking water;drinking water;experimental study;follow-up;genetic regulatory protein;innovation;lipid metabolism;liver injury;non-alcoholic fatty liver;novel;oxidation;promoter;response;saturated fat;transcription factor;transcriptome sequencing


application_id: 9293343
project_number: 5P20GM113226-02
project_title: Mechanisms of Probiotics in Alcoholic Liver Disease
administering_ic: NIGMS
award_notice_date: 2017-03-31
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6175
contact_pi_person_id: 8029790
contact_pi: FENG, WENKE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-04-01
budget_end_date: 2018-03-31
project_abstract:
Severe alcoholic liver disease (ALD) has a high morbidity and mortality. Recent studies demonstrated thatprobiotics reversed alcohol-induced hepatic steatosis and inflammation and improved liver enzymes in animalmodels and in patients. Our laboratory showed that administration of a probiotic strain Lactobacillus rhamnosusGorbach-Goldin (LGG) significantly improved liver enzymes and histology in alcohol treated mice. These micealso had reduced intestinal permeability and plasma endotoxin levels. Gut-derived endotoxins normallypenetrate the gut epithelium only in trace amounts due to tightly regulated intestinal barrier function. Howeverendotoxin leakiness is increased under pathological conditions including alcohol abuse. We recently reportedthat chronic alcohol intake in mice caused a marked reduction in the intestinal expression of the mastertranscription factor hypoxia inducible factor (HIF) and two HIF related proteins cathelin-related antimicrobialpeptide (CRAMP) and intestinal trefoil factor (ITF) in the intestine. ITF plays a critical role in the formation andstabilization of the intestinal mucus barrier enhancement of rapid intestinal repair (restitution) and modulationof mucosal differentiation processes and immune responses while CRAMP is important in blocking intestinalbacterial overgrowth/dysbiosis. In addition our preliminary data demonstrate a significant decrease of shortchain fatty acids (SCFAs) in particular butyric acid in the intestinal lumen following alcohol exposure inrodents. Our hypothesis is that alcohol consumption causes decreased intestinal CRAMP and ITF expressionand intestinal lumen butyric acid concentration resulting in bacterial overgrowth/dysbiosis and disruptedgut-barrier function; LGG supplementation attenuates these deleterious effects and protects the liver fromalcohol-induced injury. To test this hypothesis we will have 3 specific aims. Specific aim 1 will determine therole of CRAMP and the beneficial effects of LGG on CRAMP in alcohol-mediated changes in gut microbiotahomeostasis. The experiments will be performed using a metagenomic approach in CRAMP knockout mice.Specific aim 2 will determine the role of LGG in promoting ITF expression and will evaluate whether ITFpositively modulates intestinal tight junctions as a mechanism for improved intestinal barrier integrity. We willuse goblet and intestinal epithelial cell culture and recombinant ITF to delineate the effect of ITF. Specific aim 3will determine the role and mechanisms of butyric acid in the beneficial effects of LGG on intestinal tightjunctions using a butyric transporter knockout mouse model. This study will have a major impact on thedevelopment of probiotic-based new therapeutic strategy for the prevention and treatment of ALD.

project_terms:
Acute;Alcohol abuse;Alcohol consumption;Alcohol-Induced Disorders;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Model;Attenuated;Bacteria;Bacterial Translocation;Biological Assay;Butyrates;Butyric Acids;Carbohydrates;Cell Culture Techniques;Cell Line;Centers of Research Excellence;Chronic;Cirrhosis;Data;Development;Disease Progression;Endotoxins;Enzymes;Epithelial;Epithelial Cells;Etiology;Experimental Models;Fatty Liver;Functional disorder;Future;Goals;Goblet Cells;Health;Histology;Histone Deacetylase;Homeostasis;Human;Hypoxia Inducible Factor;Immune response;Impairment;Inflammation;Injury;Intervention;Intestinal Diseases;Intestines;Knockout Mice;Laboratories;Lactobacillus casei rhamnosus;Link;Liver;Liver diseases;Mediating;Metagenomics;Morbidity - disease rate;Mucous body substance;Mus;Oral Administration;Pathologic;Patients;Permeability;Pilot Projects;Plasma;Play;Prevention strategy;Probiotics;Process;Production;Proteins;Proteomics;Recombinants;Regulation;Reporting;Rodent;Role;Sampling;Supplementation;Testing;Therapeutic;Tight Junctions;Toxicology;Volatile Fatty Acids;alcohol exposure;bacterial metabolism;base;cathelicidin antimicrobial peptide;comparative efficacy;experimental study;gastrointestinal epithelium;gut microbiota;improved;in vivo;lipid metabolism;liver inflammation;liver injury;metabolomics;mortality;mouse model;novel therapeutic intervention;occludin;prevent;protective effect;repaired;transcription factor;trefoil factor


application_id: 9293342
project_number: 5P20GM113226-02
project_title: High fat diet induced hepatocyte exosomes-promoted hepatic inflammation and tumorigenesis
administering_ic: NIGMS
award_notice_date: 2017-03-31
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6174
contact_pi_person_id: 11629370
contact_pi: DENG, ZHONG-BIN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-04-01
budget_end_date: 2018-03-31
project_abstract:
ABSTRACTThe overall goal of this proposal is to study the role of hepatocyte exosomes in high fat diet mediatedpromotion of liver cancer development. Further we will determine whether using novel edible fruit exosomesas a delivery vehicle for targetable delivery of an anti-inflammatory agent to tumor cells for treatment of livercancer. Our preliminary data has indicated that hepatocyte exosomes are present in the peripheral blood ofobese mice and obese individuals and the hepatocyte exosomes from mice fed a high-fat diet (HFD-exosomes) promote inflammatory responses and the growth of liver cancer in mouse model. These dataimplicate the production of hepatocyte exosomes in the inflammatory responses associated with liver cancer.Our preliminary data indicate that the HFD-exosomes carry high levels of sumoylated CSN5 (sumo-CSN5) andthat the delivery of the sumo-CSN5 to immature myeloid promotes the degradation of Jak3 a process that isessential for differentiation of the myeloid cells. This pinpointed the production of the sumo-CSN5 as a criticalpathogenic step in exosomes mediated Induction of inflammation cytokines. In hepatocyte cells ErK1/2 kinaseis activated by a soluble factor(s) from the supernatant of liver extracts of high fat-fed mice and causes thedisassociation of Senp1 which acts as a suppressor of sumoylation of CSN5 thereby promoting the productionof sumo-CSN5. This process is inhibited by curcumin which is known to inhibit ErK1/2 activation. Thereforewe hypothesize that a high-fat diet promotes the production of exosomes with high levels of sumo-CSN5 byhepatocyte cells; that these exosomes are taken up by immature myeloid cells resulting in sumo-CSN5-mediated immunosuppression by enhancing degradation of Jak3 and thus the promotion of tumor growth. Wefurther hypothesize that curcumin treatment leads to the inhibition of processing of sumoylation of CSN5 in thehepatocyte cells from mice fed a high-fat diet by inhibition of ErK1/2. These hypotheses will be tested in vitroand in vivo to determine whether: (1) Sumoylated CSN5 in high-fat hepatocyte exosomes is essential foraccumulation of activated iMCs and promotion of liver tumor progression; (2) The ErK1/2 signaling pathwaydetermines the balance of desumoylation vs. sumoylation of CSN5 in hepatocyte cells and is promoted by ahigh-fat diet; and (3) the high-fat diet-induced hepatocyte exosome-mediated promotion of liver tumor growth isreversible by using novel edible fruit exosomes as a delivery vehicle for targetable delivery of an anti-inflammatory agent to inflammatory cells for treatment of cancer. Clinical Relevance. The data generatedshould identify a novel mechanism that links a high-fat diet to inflammatory and immunosuppressive responsesassociated with tumor development and thereby identify molecular targets for chemotherapy orchemoprevention. Demonstration of the safety of fruit exosomes-based delivery of curcumin and its targeting toinflammatory cells would be a significant step forward in the treatment of this debilitating disease.

project_terms:
Acceleration;Address;Anti-Inflammatory Agents;Binding Sites;C57BL/6 Mouse;COPS5 gene;Cells;Centers of Research Excellence;Chemoprevention;Chronic;Clinical Treatment;Curcumin;Data;Development;Diet;Diethylnitrosamine;Disease;Elements;Enzymes;Equilibrium;Fatty acid glycerol esters;Fruit;Goals;Growth;Hepatic;Hepatocyte;High Fat Diet;Human;ITGAM gene;Immunosuppressive Agents;In Vitro;Individual;Inflammation;Inflammatory;Inflammatory Response;Lead;Link;Liver;Liver Extract;Liver neoplasms;MAPK3 gene;Malignant Neoplasms;Malignant neoplasm of liver;Mediating;Membrane;Modeling;Molecular Target;Mus;Mutation;Myelogenous;Myeloid Cells;Natural Killer Cells;Natural immunosuppression;Obese Mice;Obesity;Pathogenicity;Pathway interactions;Phosphorylation Site;Phosphotransferases;Play;Prevention;Process;Production;Property;Role;Safety;Signal Pathway;Signal Transduction;Site;Small Interfering RNA;T-Lymphocyte;Technology;Testing;Toxicology;Tumor Promotion;Vesicle;base;cancer therapy;cell growth;chemotherapy;cytokine;exosome;in vitro testing;in vivo;knock-down;liver development;macrophage;mouse model;nanoparticle;neoplastic cell;novel;peripheral blood;prevent;response;targeted delivery;tumor;tumor growth;tumor progression;tumorigenesis


application_id: 9293341
project_number: 5P20GM113226-02
project_title: Pathogenic role of PDE4 in hepatic stellate cell activation and TGF signaling
administering_ic: NIGMS
award_notice_date: 2017-03-31
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6173
contact_pi_person_id: 11058066
contact_pi: GOBEJISHVILI, LEILA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-04-01
budget_end_date: 2018-03-31
project_terms:
Address;Attenuated;Centers of Research Excellence;Cirrhosis;Collagen;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;DNA Modification Process;Development;Enzymes;Epigenetic Process;Etiology;FDA approved;Family;Fibrosis;Funding;Genes;Genetic Transcription;Hepatic Stellate Cell;Hepatocyte;In Vitro;Inflammation;Injury;Knockout Mice;Liver Fibrosis;Mass Spectrum Analysis;Mediating;Modeling;Modification;Morphology;Myofibroblast;PDE4B;Pathogenicity;Peroxisome Proliferator-Activated Receptors;Phenotype;Phosphorylation;Play;Post-Translational Protein Processing;Prevention strategy;Primary carcinoma of the liver cells;Process;Promoter Regions;Protein Isoforms;Proteins;Proteomics;Rattus;Regulation;Role;Rolipram;Second Messenger Systems;Signal Transduction;Therapeutic;Toxicology;Transcriptional Activation;Wound Healing;base;cell transformation;cytokine;experimental analysis;histone modification;in vivo;inhibitor/antagonist;liver injury;member;phosphodiesterase IV;promoter;translational study


application_id: 9293339
project_number: 5P20GM113226-02
project_title: Role of oxidized linoleic acid metabolites in the pathogenesis of alcoholic liver disease
administering_ic: NIGMS
award_notice_date: 2017-03-31
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6172
contact_pi_person_id: 10484237
contact_pi: KIRPICH, IRINA A.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-04-01
budget_end_date: 2018-03-31
project_abstract:
Alcoholic liver disease (ALD) ranks among the major causes of morbidity and mortality in the world andaffects millions of patients worldwide each year. Despite the progress made on ALD pathogenesis the specificmechanism(s) responsible for ALD development and progression remain poorly understood. Importantly thereis no FDA approved therapy for any stage of ALD. Recent studies from our laboratory and others havedemonstrated that dietary unsaturated fat specifically rich in linoleic acid (LA) exacerbated alcohol-mediatedliver and intestinal injury in an experimental animal model of ALD. Our preliminary data show elevated levels ofcirculating oxidized LA metabolites specifically 9- and 13-hydroxy-octadecadienoic acids (9-and 13-HODEs) inparallel with the up-regulation of hepatic 12/15 lipoxygenase (12/15-LO) a key enzyme involved in theoxidation of LA. These findings have led us to postulate that specific oxidized LA metabolites (OXLAMs) mayplay a significant role in ALD. OXLAMs are natural ligands to the transient receptor potential vanilloid 1(TRPV1) a ligand-gated non-selective cation channel with high permeability for Ca2+. Recent studiesdemonstrate a critical role for Ca2+ release in inflammasome activation which are key signaling platforms forstressor-induced pathogenesis and which upon activation trigger the release of highly pro-inflammatorycytokines interleukin-1 (IL-1) and interleukin-18 (IL-18). IL-1 release is thought to be a critical mediator ofinflammation and thus serves as a potential therapeutic target for treating hepatic inflammation in ALD. Basedon our own and other published findings our CENTRAL HYPOTHESIS is that OXLAMs play a significantrole in the development and progression of ALD. We hypothesize that OXLAMs contribute to the EtOH-induced hepatic inflammation and injury via two mechanisms: 1) OXLAMs-mediated mitochondrialdysfunction and hepatocyte death; and 2) OXLAM/TRPV1/Ca2+-mediated inflammasome activation andIL-1 release. The proposed studies will lead to better understanding of molecular mechanisms contributing tothe pathogenesis of alcohol-induced liver inflammation and injury. These studies will also help us to betterunderstand alcohol-diet interactions which may lead to identification of new therapeutic targets and potentialdietary interventions for treating ALD as well as help to explain why only some people who drink heavilydevelop clinically important ALD. A combination of in vitro in-vivo animal (knockouts and chimeric mousemodels) and human studies will be employed.

project_terms:
Affect;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Model;Animals;Arachidonate 15-Lipoxygenase;Attenuated;Cations;Centers of Research Excellence;Cessation of life;Chronic;Clinical;Data;Development;Diet;Dietary Intervention;Enzymes;Experimental Animal Model;FDA approved;Fatty Liver;Heavy Drinking;Hepatic;Hepatocyte;Human;In Vitro;Inflammasome;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury;Interleukin-1;Interleukin-18;Intestines;Knock-out;Knockout Mice;Kupffer Cells;Laboratories;Lead;Ligands;Linoleic Acids;Liver;Mediating;Molecular;Morbidity - disease rate;Mus;Oxides;Pathogenesis;Pathway interactions;Patients;Permeability;Pharmacology;Plasma;Play;Production;Publishing;Role;Signal Pathway;Signal Transduction;Testing;Toxicology;Translating;Unsaturated Fats;Up-Regulation;Vanilloid;Whole Blood;base;cytokine;human study;in vitro testing;in vivo;liver inflammation;liver injury;macrophage;mitochondrial dysfunction;monocyte;mortality;mouse model;new therapeutic target;octadecadienoic acid;oxidation;peripheral blood;receptor;stressor;therapeutic target


application_id: 9293336
project_number: 5P20GM113226-02
project_title: OMICS CORE
administering_ic: NIGMS
award_notice_date: 2017-03-31
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6169
contact_pi_person_id: 8487327
contact_pi: ZHANG, XIANG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-04-01
budget_end_date: 2018-03-31
project_terms:
Ablation;Acetylation;Affinity;Alcohols;Arsenic;Binding;Bioinformatics;Biological;Blood;Centers of Research Excellence;Chemicals;Complex Mixtures;Curcumin;Cysteine;DNA Binding Domain;Diet;Dimensions;Drug Interactions;Environment;Ethanol;Event;Feces;Gas Chromatography;Gel;Goals;Hepatic;Hepatic Stellate Cell;High Fat Diet;Immunoprecipitation;Inductively Coupled Plasma Mass Spectrometry;Inflammation;Injury;Intestines;Iodoacetamide;Iodoacetic Acid;Ions;Label;Lactobacillus casei rhamnosus;Large Intestine;Lasers;Linoleic Acids;Liquid Chromatography;Liver;Mass Spectrum Analysis;Measurement;Measures;Mediating;Metals;Methods;Methylation;Mus;Oxides;Pathology;Phenotype;Phosphopeptides;Phosphorylation;Plasma;Post-Translational Protein Processing;Production;Protein Fragment;Protein Isoforms;Proteins;Proteomics;Recombinant Proteins;Regulation;Research;Resolution;Role;Sampling;Science;Site;Small Intestines;Stable Isotope Labeling;Steatohepatitis;Techniques;Technology;Time;Tissue Sample;Tissues;Toxicology;Toxin;Tumor Promotion;Unsaturated Fatty Acids;Urine;Volatile Fatty Acids;Zinc;exosome;experimental study;feeding;liquid chromatography mass spectrometry;liver inflammation;liver injury;mass spectrometer;metabolomics;non-alcoholic fatty liver;novel;nutrition;oxidation;phosphodiesterase IV;protein complex;recombinant peptide;response;transcription factor;tumor growth;two-dimensional;zinc-binding protein


application_id: 9293335
project_number: 5P20GM113226-02
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2017-03-31
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6168
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-04-01
budget_end_date: 2018-03-31
project_terms:
Adult;Affect;Alcoholic Liver Diseases;Alcohols;Area;Basic Science;Bioinformatics;Biometry;Budgets;Centers of Research Excellence;Child;Cirrhosis;Clinical;Clinical Trials;Communities;Community Outreach;Complex;Conflict (Psychology);Country;Development;Diabetes Mellitus;Disease;Doctor of Philosophy;Drug Delivery Systems;Drug Interactions;Ensure;Environment;Environmental Health;Extramural Activities;Faculty;Funding;Grant;Health;Healthcare;Hepatitis B;Hepatitis C;Hepatology;Individual;Industry;Intellectual Property;Kansas;Kentucky;Leadership;Link;Liver;Liver Failure;Liver diseases;Malignant Neoplasms;Malignant neoplasm of liver;Mentors;Metabolic syndrome;Metabolism;Names;National Institute of Environmental Health Sciences;National Institute on Alcohol Abuse and Alcoholism;Nuclear Receptors;Obesity;Organ;Overweight;Pharmaceutical Preparations;Pharmacology and Toxicology;Population;Positioning Attribute;Primary carcinoma of the liver cells;Process;Public Health;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Research Training;Retirement;Rural;Structure;Superfund;Teacher Professional Development;Toxic Environmental Substances;Toxicology;Training;United States National Institutes of Health;Universities;Work;cancer transplantation;cohesion;drug development;drug metabolism;faculty mentor;improved;liver injury;liver metabolism;liver transplantation;multidisciplinary;non-alcoholic fatty liver;nonalcoholic steatohepatitis;novel therapeutics;personalized medicine;problem drinker;programs;ranpirnase;senior faculty;toxicant


application_id: 9293332
project_number: 5P20GM113226-02
project_title: Hepatobiology and Toxicology COBRE
administering_ic: NIGMS
award_notice_date: 2017-03-31
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
program_official: GOROSPE, RAFAEL
project_start_date: 2016-06-10
project_end_date: 2021-03-31
study_section: ZGM1-TWD-A(C1)
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
project_abstract:
DESCRIPTION (provided by applicant): The University of Louisville (UofL) Hepatobiology and Toxicology COBRE is a unique thematic research center. The UofL COBRE scientists comprise a multidisciplinary group senior mentors and junior investigators focusing on the mechanisms and therapy for liver injury nutrition and gut:liver interactions and liver:environment/toxin/dru interactions. The liver is the largest internal organ in the body and is possibly the most complex
organ in terms of metabolism. Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) is the most common liver disease affecting about 1/3 of adults and over 10% of children in the US. NAFLD arises most commonly among overweight/obese individuals and is highly linked to the Metabolic Syndrome. Alcoholic Liver Disease (ALD) remains a common problem among those who drink. Environmental Toxicant Induced Liver Injury is an increasingly recognized problem and Louisville has been a leader in this area. Hepatitis B and C remain important causes of cirrhosis and hepatocellular carcinoma (HCC) worldwide. Personalized Medicine is an increasingly important factor in medication efficacy. Drug-Induced Liver Injury (DILI) is the most common reason drugs are removed from the market and an important cause of liver failure. This COBRE brings together experienced senior mentors and promising junior investigators from across UofL in collaboration with scientists across the U.S./World to perform cross-cutting research on the unique topics of Hepatobiology and Toxicology. The Specific Aims of the Hepatobiology and Toxicology COBRE are to: 1. Develop a thematically-focused program in Hepatobiology and Toxicology that strengthens the overall research infrastructure at UofL. 2. Create a multidisciplinary program in research education mentoring and career development in Hepatobiology and Toxicology. 3. Provide the necessary research resources and translational science/basic technologies to support and sustain state-of-the-art research in Hepatobiology and Toxicology. 4. Discover new mechanisms/molecular targets and effective means for preventing and/or treating liver diseases/toxicant exposures and communicate our findings to the public.

project_terms:
Acute Liver Failure;Address;Adult;Affect;Alcohol-Induced Disorders;Alcoholic Liver Diseases;Alcohols;American;Area;Back;Basic Science;Blood Circulation;Carbohydrates;Centers of Research Excellence;Child;Cirrhosis;Collaborations;Communities;Complex;Core Facility;County;Data Analyses;Development;Diabetes Mellitus;Drug Interactions;Endotoxins;Environment;Enzymes;Evaluation;FDA approved;Fatty acid glycerol esters;Fostering;Goals;Government;Health;Hepatitis B;Hepatitis C;Hepatotoxicity;Home environment;Immune Tolerance;Individual;Industrialization;Industry;Kentucky;Link;Liver;Liver Failure;Liver diseases;Medical History;Mentors;Metabolic syndrome;Metabolism;Micronutrients;Molecular Target;Monitor;National Institute on Alcohol Abuse and Alcoholism;Neighborhoods;Obesity;Organ;Overweight;Patients;Pharmaceutical Preparations;Pharmacotherapy;Play;Prevention;Primary carcinoma of the liver cells;Process;Production;Proteins;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Role;Scientist;Site;Specimen;Strategic Planning;Structure;Technology;Toxic Environmental Substances;Toxicant exposure;Toxicology;Toxin;Translational Research;United States National Institutes of Health;Universities;biobank;career development;education research;experience;liver injury;liver transplantation;medical complication;multidisciplinary;non-alcoholic fatty liver;nonalcoholic steatohepatitis;novel;novel therapeutics;nutrition;personalized medicine;prevent;programs;public health relevance;toxicant


application_id: 9293315
project_number: 5R01GM079684-09
project_title: The Regulation of Smoothened in Hedgehog Signaling
administering_ic: NIGMS
award_notice_date: 2017-06-08
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: GM
serial_number: 079684
program_official: MELILLO, AMANDA A
project_start_date: 2008-07-01
project_end_date: 2018-09-06
study_section: Development - 1 Study Section[DEV1]
contact_pi_person_id: 8575677
contact_pi: JIA, JIANHANG
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Hedgehog (Hh) proteins function as morphogens and play critical roles in pattern formation and cell growth control. Dysregulation and dysfunction of the Hh signaling pathway induces diverse types of cancers. The seven-pass transmembrane protein Smoothened (Smo) is required in both insects and mammals for transduction of the Hh signal. Our strategy is to use Drosophila as a simple and genetically tractable model system to explore the mechanisms of Hh signal transduction by the receptor complex. The long-term goal of our research is to elucidate how Hh signals are sensed and transmitted to control downstream biological events that ultimately govern cell growth and patterning. Although many components in the Hh pathway have been identified how the Hh signal is transduced through Patched (Ptc) to Smo is still unclear. We have discovered that Smo activation requires phosphorylation by multiple kinases including protein kinase A (PKA) casein kinase 1 (CK1) casein kinase 2 (CK2) and G protein-coupled receptor kinase 2 (Gprk2) and that phosphorylation leads to increased Smo cell surface levels and signaling activity. We show that Smo transduces Hh signals by directly recruiting a downstream Fused-Costal2 (Fu-Cos2) complex and that Fus- Cos2 protein complex promotes hyperphosphorylation of Smo uncovering a feedback mechanism essential for optimal Hh pathway activation. Furthermore we have identified protein phosphatase PP4 as a negative regulator of Smo. Results from our studies have suggested that the cell surface accumulation and intracellular trafficking of Smo play critical roles in regulating Hh-induced Smo activation. However many questions persist regarding the mechanism controlling Smo localization and trafficking. To begin address these questions we have recently discovered that the deubiquitinase USP8 promotes Smo signaling activity by preventing Smo ubiquitination and regulating Smo subcellular localization. Combined with the preliminary studies in the project our findings provide new tools and hypotheses for investigating the mechanisms of Smo signaling. In this project our central hypothesis is that Smo activation downstream of Hh is tightly controlled by its subcellular localization in which a novel kinase and small molecules promotes Hh signaling by enhancing the cell surface accumulation of Smo whereas ubiquitin inactivates Smo by promoting Smo endocytosis and degradation. We will use a combination of genetic and biochemical approaches in three Specific Aims: 1) To determine how a newly identified kinase regulates Smo phosphorylation and basolateral membrane localization; 2) to investigate the molecular mechanisms by which small molecules activate Smo in response to Hh stimulation; 3) to determine how Hh regulates the ubiquitin-mediated endosomal sorting of Smo via a novel E3 ligase of Smo.

project_terms:
Address;Basal cell carcinoma;Binding;Biochemical;Biological;Biological Models;Cancer Etiology;Cell surface;Cells;Complex;Congenital Abnormality;Cyclic AMP-Dependent Protein Kinases;Development;Diagnostic;Dimerization;Drosophila genus;Embryonic Development;Endocytosis;Erinaceidae;Event;Family member;Feedback;Functional disorder;G protein coupled receptor kinase;G-Protein-Coupled Receptors;Genetic;Goals;High Pressure Liquid Chromatography;Homologous Gene;Insecta;Integral Membrane Protein;Investigation;Malignant Neoplasms;Mammals;Mass Spectrum Analysis;Mediating;Molecular;Molecular Conformation;PARD6A gene;Pathway interactions;Pattern;Pattern Formation;Phospholipids;Phosphorylation;Phosphotransferases;Physiological;Play;Preventive;Process;Protein Tyrosine Kinase;Protein phosphatase;Proteins;Publishing;RNA interference screen;Recruitment Activity;Regulation;Research;Role;Signal Transduction;Signaling Molecule;Sorting - Cell Movement;Technology;Tertiary Protein Structure;Testing;Therapeutic;USP8 gene;Ubiquitin;Ubiquitination;Wing;base;basolateral membrane;cancer therapy;cancer type;casein kinase I;casein kinase II;cell growth;design;dimer;fly;hedgehog signal transduction;insight;medulloblastoma;morphogens;novel;phosphatidylinositol 4-phosphate;prevent;protein complex;protein function;public health relevance;receptor;response;small molecule;smoothened signaling pathway;tool;trafficking;ubiquitin-protein ligase

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Hedgehog (Hh) signaling is known for its role in directing processes such as cell growth proliferation and differentiation during embryogenesis. Abnormal activation of Smo an atypical GPCR in the receptor complex results cancers such as basal cell carcinoma (BCC) and medulloblastoma. Investigation of the Smo signaling mechanisms the goal of this project will provide both insights into fundamental developmental problems and new strategies to design preventive and curative tools and treatments for cancers caused by deregulated Hh signaling.


application_id: 9293140
project_number: 5R01OH010666-04
project_title: Farm Theater: A Novel Safety Strategy Approach for Agricultural Communities
administering_ic: NIOSH
award_notice_date: 2017-04-27
opportunity_number: PAR-13-129
application_type: 5
activity_code: R01
ic: OH
serial_number: 010666
program_official: CHIOU, SHARON
project_start_date: 2014-09-01
project_end_date: 2018-08-31
study_section: Safety and Occupational Health Study Section[SOH-1]
contact_pi_person_id: 8431098
contact_pi: REED, DEBORAH BAKER
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Excessive worker injury rates continue in agriculture. Adult and senior farmers in the Southern U.S. region experience the highest occurrence of agricultural occupational injury and mortality in the nation. In this community-based translationa intervention effectiveness research study we will work with established farm community organizations in Kentucky Tennessee and Mississippi to develop and test a novel intervention: didactic reader's theater with 450 adult and senior farmers and their family members to positively change farm work culture and safety behavior. A comparison group (n=450) will allow rigorous analysis of the effect of the intervention. In the final year we will pilot test the intervention's effect with younger farmers (n=80) plus a comparison group (n=80). Together with the farm organizations we will establish mechanisms to sustain the intervention in farm communities. We expect given our pilot data that this intervention will have a substantial impact on decreasing injury risk in the target states and other southern states with generalizability to multiple rural areas in the United States. This proposal addresses HP 2020 Occupational Safety and Health through the NORA Agriculture Forestry and Fishing (AgFF) Sector Council's Strategic Goal #2 - Vulnerable workers (subset older farmers) Action step 2.43: "Facilitate the development and evaluation of high quality and appropriate materials where gaps exist"; Goal #3: "Move proven health and safety strategies into agricultural forestry and fishing workplaces through the development of partnerships and collaborative efforts"; Goal #4: "Reduce the number rate and severity of traumatic injuries and deaths involving hazards of production agriculture and support activities" and Goal #5: "Improve the health and well-being of agricultural workers by reducing occupational causes or contributing factors to acute and chronic illness and disease". It also addresses the cross sectors of work organization health disparities traumatic injury and stress-related disorders. The specific aims are to: 1. Develop and deliver in cooperation with the farm community a translational intervention didactic readers  theater to reduce injury and enhance the health of adult and senior farmers and their families; 2. Test the efficacy of the agricultural health/safety didactic readers theater in changig farm work behavior of  adult and senior farmers and their families; 3. Strengthen the local capacity of agricultural communities and organizations to develop and deliver effective  health and safety interventions through theater and other approaches over time (sustainability).

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Agriculture has excessive worker injury rates. Senior farmers and adult farmers in the South experience some of the highest occupational injury and mortality in the nation. In this community-based intervention project we will work with established farm community organizations to develop and test a didactic reader's theater intervention to positively change farm work culture and safety behavior. Together with the farm organizations we will establish mechanisms to sustain the intervention in farm communities. We expect given our pilot data that this intervention will have a substantial impact on decreasing farmers' injury ris in Southern states with generalizability to multiple rural areas in the United States.


application_id: 9292274
project_number: 5U01DA036158-05
project_title: Kentucky TRIALS Research Center
administering_ic: NIDA
award_notice_date: 2017-06-02
opportunity_number: RFA-DA-13-009
application_type: 5
activity_code: U01
ic: DA
serial_number: 036158
program_official: MULFORD, CARRIE FRIED
project_start_date: 2013-07-01
project_end_date: 2019-06-30
study_section: ZDA1-EXL-T(11)S
contact_pi_person_id: 1873108
contact_pi: LEUKEFELD, CARL G
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This cooperative agreement Center application the Kentucky TRIALS Substance Abuse and HIV Research Center (KY-TRIALS) is submitted by the University of Kentucky in cooperation with the Kentucky Department of Juvenile Justice community substance abuse service organizations and HIV service providers to respond to RFA-DA-13-009 "Translational Research on Interventions for Adolescents in the Legal System: TRIALS". This project focuses on filling the need for implementation studies to enhance continuity of care for juvenile justice Involved adolescents. Kentucky provides an ideal setting to study the implementation of evidence-based practices because of our longstanding Juvenile Justice and university relationship. KY-TRIALS is well-positioned to conduct rigorous research on implementing evidence-based practices. The Overall Aim of the KY-TRIALS Substance Abuse and HIV Research Center is to collaborate in developing and testing implementation strategies and associated measures to improve the continuum of substance abuse and HIV prevention and treatment services for youth under juvenile justice supervision. The KY-TRIALS approach Incorporates theoretical frameworks of implementation science (Proctor et. al. 2009; Aarons et al. 2011) and organizational change to examine how evidence-based practices are implemented into practice in organizational settings. Our conceptual approach draws upon our experience in implementation science and previous cooperative studies to carry out the KY-TRIALS research center vision and research. This application presents 4 proven and partner-rich Center Committees: 1) Design and Measures 2) Study Implementation 3) Data Management and Analysis and 4) Publications for achieving success in the aims of TRIALS in concert with our KY-TRIALS Center Steering Committee the national TRIALS Steering Committee and the National Institute on Drug Abuse. Letters of commitment include our state's Juvenile Justice Commissioner; Acting Director of the Division of Behavioral Health; Executive Director of the Kentucky Office of Drug Control Policy; juvenile justice officials; and community substance abuse and HIV service providers to support our innovative vision.

project_terms:
AIDS prevention;Address;Adolescence;Adolescent;Adoption;Area;Clinical Research;Communities;Community Services;Continuity of Patient Care;Criminal Justice;Data;Data Analyses;Disease;Drug Controls;Drug abuse;Environmental Risk Factor;Evidence based intervention;Evidence based practice;Federal Hospitals;HIV;Intervention;Justice;Kentucky;Knowledge;Legal system;Letters;Measures;National Institute of Drug Abuse;Organizational Change;Outcome;Pharmaceutical Preparations;Policies;Positioning Attribute;Provider;Publications;Research;Research Personnel;Research Project Grants;Services;Site;Substance abuse problem;Supervision;Testing;Translational Research;U-Series Cooperative Agreements;United States Public Health Service;Universities;Vision;Youth;adolescent substance abuse;alcohol research;base;behavioral health;cooperative study;data management;design;experience;implementation research;implementation science;improved;innovation;juvenile justice system;prevention service;response;success;theories

public_health_relevance:
The Overall Aim of the KY-TRIALS Substance Abuse and HIV Research Center is to collaborate in developing and testing implementation strategies and associated measures to Improve the continuum of substance abuse and HIV prevention and treatment services delivered to youth under juvenile justice supervision. The KY-TRIALS Center has the potential to make a significant contribution to an understudied area by providing knowledge on adolescent assessment for substance abuse disorders and HIV community implementation science and theory juvenile justice and evidence-based practices. Successful completion of the KY-TRIALS cooperative agreement will provide essential information to add significant new and groundbreaking knowledge about implementation science and to improve the continuity of care for adolescents involved in juvenile justice.


application_id: 9290374
project_number: 1R01DA043519-01
administering_ic: NIDA
award_notice_date: 2017-04-04
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: DA
serial_number: 043519
program_official: NOURSI, SAMIA
project_start_date: 2017-05-01
project_end_date: 2022-02-28
study_section: Child Psychopathology and Developmental Disabilities Study Section[CPDD]
contact_pi_person_id: 3100162
contact_pi: BADA, HENRIETTA S.
other_pis: LEGGAS, MARKOS
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-05-01
project_abstract:
ABSTRACTThe number of newborns that develop the constellation of drug withdrawal symptoms or Neonatal AbstinenceSyndrome (NAS) in the US has increased to epidemic proportions. The pharmacologic treatment of NAS withmorphine or methadone is highly concerning as it corresponds with a timeframe of rapid postnatal brain devel-opment. The negative effects of opioids on the developing brain include decreased neurogenesis synaptogen-esis and corticogenesis decreased brain size and decreased brain volumes in older children with prenatalopiate exposure. Furthermore response of neonates to treatment is highly variable and limited pharmaco-genetic and metabolic activity data which can be used to optimize therapy in this population pose additionalchallenges in using any drug to treat NAS. Collectively these issues present a critical need to evaluate andoptimize the use of a non-opioid drug for treatment of NAS. The long term goals of our research is to establishthe best pharmacological treatment for NAS and determine how pharmacologic treatment of NAS affects long-term developmental outcomes. The objective of this application is to evaluate the effectiveness of clonidine an2 adrenergic receptor agonist as a treatment for neonates with NAS in a randomized clinical trial. Our cen-tral hypothesis is that clonidine will effectively treat drug withdrawal manifestations in neonates. Preliminaryclinical evidence supports this hypothesis. Clonidine has previously been reported by us and others as a singledrug therapy for NAS in small number of infants with relief of withdrawal symptoms and as an effective adjunc-tive treatment when giving chloral hydrate or morphine. The rationale for the proposed research is that oncewe understand how clonidine can be used optimally in the clinic to treat NAS a safe medication will be availa-ble and it could potentially minimize complications associated increased length-of-stay in the hospitalhealthcare costs and the deleterious opiate assaults on the developing brain that continue with postnatal opiateadministration. To test our central hypothesis and accomplish the objective of this application we plan to pur-sue the following three specific aims: 1) To determine whether the treatment of NAS with a non-opiate medica-tion clonidine will be more effective than morphine. 2) To determine whether treatment of NAS with clonidinewill result in better early childhood outcomes than those treated with morphine. 3) To determine how infantswith NAS metabolize morphine and clonidine. With respect to expected outcomes this proposal will provideprospective evidence: a) regarding the potential of clonidine treatment to treat NAS; b) regarding how opioidand non-opioid exposure affect early childhood development; c) regarding factors that influence response totreatment. These results are expected to have an important positive impact because they have the potential toprovide fundamental information regarding the metabolic ontogeny of infants exposed to opioid drugs andmost importantly to improve the long-term outcomes of children born to addicted mothers.

project_terms:
Abstinence;Adrenergic Agonists;Affect;Aftercare;Age;Analgesics;Brain;Cells;Child;Child Behavior Checklist;Chloral Hydrate;Chronic;Clinic;Clinical;Clonidine;Cognitive;Collaborations;Data;Development;Drug Kinetics;Drug Withdrawal Symptoms;Effectiveness;Epidemic;Exposure to;Genetic;Goals;Growth;Health;Health Care Costs;Heroin;Hospitals;Individual;Infant;Informal Social Control;Injury;Laboratory Study;Language;Length of Stay;Life;Metabolic;Methadone;Mission;Modeling;Morphine;Mothers;Motor;Narcotics;Neonatal;Neonatal Abstinence Syndrome;Neurons;Newborn Infant;Norepinephrine;Opiates;Opioid;Opioid Receptor;Outcome;Performance;Pharmaceutical Preparations;Pharmacogenetics;Pharmacological Treatment;Pharmacology;Pharmacotherapy;Pilot Projects;Population;Pregnancy;Problem behavior;Property;Public Health;Randomized Clinical Trials;Reflex action;Reporting;Research;Stress;Testing;Time;United States National Institutes of Health;Withdrawal;Withdrawal Symptom;assault;brain size;brain volume;cost;drug withdrawal;early childhood;fetal opiate exposure;improved;neonate;neurobehavioral;neurogenesis;noradrenergic;pharmacodynamic model;postnatal;prevent;prospective;response;standard of care;synaptogenesis;treatment duration;treatment response


application_id: 9289167
project_number: 1R01ES027881-01
project_title: Air Pollution Circadian Rhythm Disruption and Cardiometabolic Disease
administering_ic: NIEHS
award_notice_date: 2017-04-26
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: ES
serial_number: 027881
program_official: SCHUG, THADDEUS
project_start_date: 2017-05-01
project_end_date: 2022-04-30
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 11375489
contact_pi: HABERZETTL, PETRA
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
ARNTL gene;Aerosols;Affect;Air;Air Pollution;Animal Model;Aorta;Attenuated;Behavior;Biochemical Process;Biological;Biological Availability;Blood Pressure;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Characteristics;Circadian Rhythms;Darkness;Data;Deposition;Development;Diet;Disease;Eating;Exposure to;Gene Expression;Genes;Goals;Health;Human;Individual;Industrialization;Injury;Insulin Resistance;Knockout Mice;Laboratories;Lead;Life Style;Light;Link;Lung;Mediating;Metabolism;Modeling;Modernization;Mus;Nitric Oxide Synthase;Non-Insulin-Dependent Diabetes Mellitus;Oxidation-Reduction;Oxidative Stress;Particulate;Periodicity;Peripheral;Phase;Physiological Processes;Policies;Pollution;Post-Translational Protein Processing;Predisposition;Prevention strategy;Research;Sleep;Sleep Deprivation;System;Testing;Toxic effect;Transcriptional Regulation;Urbanization;Work;air filter;ambient air pollution;atherogenesis;base;cardiometabolic risk;cardiovascular disorder risk;chemical property;diabetes risk;disorder risk;epidemiologic data;evidence based guidelines;mortality;mouse model;novel;overexpression;particle;physical property;pollutant;premature;prevent;response


application_id: 9288741
project_number: 1R01NS101105-01
project_title: Promoting and understanding recovery of breathing after chronic spinal cord injury
administering_ic: NINDS
award_notice_date: 2017-03-14
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: NS
serial_number: 101105
program_official: JAKEMAN, LYN B
project_start_date: 2017-03-15
project_end_date: 2022-02-28
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 8838438
contact_pi: ALILAIN, WARREN JOSEPH
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_terms:
Acute;Adverse effects;Americas;Anatomy;Animals;Applications Grants;Behavior;Breathing;Cervical;Cervical spinal cord injury;Cervical spinal cord structure;Chondroitin ABC Lyase;Chondroitin Sulfate Proteoglycan;Chondroitinases;Chronic;Communities;Equilibrium;Excision;Extracellular Matrix;Health Care Costs;Healthcare;Hypersensitivity;Hypoxia;Injury;Intervention;Investigation;Knowledge;Lead;Learning;Length;Measures;Mechanical Ventilators;Mediating;Modeling;Motor;Motor Activity;Motor Neurons;Natural regeneration;Paralysed;Patients;Pattern;Periodicity;Play;Population;Positioning Attribute;Process;Production;Quality of life;Recovery;Recovery of Function;Regimen;Rehabilitation therapy;Research;Respiratory Diaphragm;Role;Saline;Serotonin;Spinal Cord;Spinal cord injury;Subgroup;Testing;Therapeutic Intervention;Time;Training;Translating;United States;Work;effective intervention;experimental study;functional outcomes;improved;inhibitor/antagonist;injured;insight;motor recovery;motor rehabilitation;neurotransmission;novel therapeutics;prevent;receptor;respiratory;response;response to injury;restoration;serotonin receptor;success


application_id: 9288139
project_number: 5R01CA187273-03
project_title: Suppression of Prostate Tumor Growth and Metastasis by Inhibition of Vimentin
administering_ic: NCI
award_notice_date: 2017-06-20
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 187273
program_official: CHEN, WEIWEI
project_start_date: 2015-07-01
project_end_date: 2020-06-30
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1883986
contact_pi: RANGNEKAR, VIVEK M
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Advanced prostate tumors that often metastasize to the lung bone and other vital tissues are resistant to conventional therapy. Prostate apoptosis response-4 (Par-4) is a tumor suppressor that causes apoptosis in therapy-resistant prostate cancer cells. Although baseline levels of Par-4 secreted by cells are inadequate to induce apoptosis normal cells can be induced to produce robust secretion of Par-4 protein that targets cancer cells in a paracrine manner. Accordingly secreted Par-4 is systemically available in vivo and binds to its cell surface receptor GRP78 in cancer cells to trigger apoptosis in primary and metastatic tumors. Importantly secreted Par-4 induces cancer-specific apoptosis but it does not induce apoptosis in normal cells as GRP78 is expressed only on the surface of cancer cells not on normal cells. "Small-molecule" drugs that efficiently and selectively induce Par-4 secretion without killing the normal cells would therefore represent an important therapeutic advance. In preliminary studies we synthesized and screened newly developed 3-arylquinolines as well as related quinolones and quinothiolones for the secretion of Par-4 protein from normal mouse and human fibroblast and epithelial cells. This screening led to the identification of 2-amino-7-(NN-dimethylamino)-3-(2'-fluorophenyl)quinoline (called "Arylquin-1") as a member of a new class of agents that trigger robust secretion of Par-4 from normal cells at nanomolar non-toxic concentrations. As expected Par-4 secreted from these normal cells induced paracrine apoptosis in diverse prostate and lung cancer cell cultures but not in normal cell cultures. Usinga biotinylated biologically active version of Arylquin-1 we identified vimentin a protein linkedto motility invasion EMT and metastasis as the molecular target of Arylquin-1 that in turn produces Par-4 secretion. In this study we will determine the effect of Arylquin-1 on Par-4 secretion from normal cells and apoptosis in prostate cancer cell culture and in vivo on tumor growth in prostate cancer models. Computational dynamics revealed that Arylquin-1 forms a stable interaction with a hydrophobic pocket on vimentin. We will therefore determine the domains of Par-4 and vimentin that bind to each other to elucidate the mechanism underlying inhibition of Par-4 secretion by vimentin and its release by Arylquin-1. Consistent with the interaction of Arylquin-1 with vimentin our preliminary studies also indicated that Arylquin-1 inhibits motility and invasion in prostate cancer cells by an apoptosis-independent mechanism. We will therefore study whether Arylquin-1 inhibits motility invasion and EMT in cell culture and metastasis in mouse models of prostate cancer via vimentin-dependent mechanisms. Developing agents that selectively promote Par-4 secretion from normal cells induce apoptosis in cancer cells and halt metastatic processes in prostate cancer would be of extraordinary academic and therapeutic value.

project_terms:
Apoptosis;Apoptotic;Binding;Biological;Biology;Cancer Etiology;Cell Culture Techniques;Cell Surface Receptors;Cells;Cessation of life;Chemicals;Conditioned Culture Media;Development;Epithelial;Epithelial Cells;Family;Fibroblasts;GRP78 gene;Growth;Human;Hydrophobicity;Impaired wound healing;Killings;Knockout Mice;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Mesenchymal;Metastatic Neoplasm to the Lung;Modeling;Molecular Target;Mus;Neoplasm Metastasis;Normal Cell;Organ;PAWR protein;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Phenotype;Primary Neoplasm;Prostate;Prostate Cancer therapy;Prostatic Neoplasms;Proteins;Quinolones;Resectable;Resistance;Role;Structure-Activity Relationship;Surface;Testing;Therapeutic;Tissues;Toxic effect;Tumor Suppressor Proteins;Vimentin;analog;androgen deprivation therapy;bone;cancer cell;cell motility;conventional therapy;extracellular;in vivo;insight;member;men;metastatic process;mouse model;nanomolar;novel;paracrine;prostate cancer cell;prostate cancer model;public health relevance;quinoline;receptor;response;screening;small molecule;therapy resistant;tumor;tumor growth;tumor xenograft

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed studies will examine the role of vimentin in intracellular sequestration of the tumor suppressor Par-4 and the ability of a novel small molecule 3-arylquinoline called Arylquin-1 which targets vimentin in releasing Par-4 from vimentin for secretion and paracrine apoptosis of prostate cancer cells. Moreover owing to its vimentin-targeting ability Arylquin-1 will be also studied for inhibition of prostate cancer cell motility invasion EMT and tumor metastasis that are promoted by vimentin function. Both cell culture and mouse models of prostate cancer will be used to determine the effect of Arylquin-1 on Par-4 secretion apoptosis and inhibition of EMT and metastasis.


application_id: 9287928
project_number: 5R01HL133723-02
project_title: Adventitial-medial interactions in thoracic aortic diseases
administering_ic: NHLBI
award_notice_date: 2017-05-30
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 133723
program_official: MCDONALD, CHERYL
project_start_date: 2016-06-01
project_end_date: 2020-05-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8378256
contact_pi: DAUGHERTY, ALAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Aneurysm;Angiotensin II;Angiotensin II Type 1 Receptor Blockers;Aorta;Aortic Aneurysm;Aortic Diseases;Area;Attenuated;Blood Vessels;Cardiac;Chest;Communication;Complex;Data;Development;Disease;Dissection;Distributional Activity;Drug Targeting;Embryo;Employee Strikes;Expert Opinion;FBN1;Fibroblasts;Genetic;Guidelines;Heart;Hematoma;Human;Individual;Infusion procedures;Knowledge;Lead;Level of Evidence;Literature;Losartan;LoxP-flanked allele;Medial;Mediating;Medical;Modeling;Mus;Neural Crest;Pathologic;Pathologic Processes;Pathology;Patients;Pericytes;Phenotype;Plant Roots;Play;Process;Proteins;Recommendation;Reporting;Role;Severities;Signal Transduction;Site;Smooth Muscle Myocytes;Testing;Thoracic Aortic Aneurysm;Thoracic aorta;Transforming Growth Factor beta;Tunica Adventitia;ascending aorta;base;bicuspid aortic valve;cell dedifferentiation;clinical investigation;constriction;experimental study;fibulin-4;in vivo;insight;interest;migration;mouse model;mutant;receptor;response;therapy development;transdifferentiation


application_id: 9287319
project_number: 1R01CA215095-01
project_title: Roles of RORalpha in breast cancer development and progression
administering_ic: NCI
award_notice_date: 2017-03-02
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: CA
serial_number: 215095
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2017-07-01
project_end_date: 2022-06-30
study_section: Tumor Microenvironment Study Section[TME]
contact_pi_person_id: 10533977
contact_pi: XU, REN
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Agonist;Biological Assay;Biology;Breast;Breast Cancer Cell;Breast Cancer Model;Breast Epithelial Cells;Cell Polarity;Cellular Metabolic Process;Chronic;Coculture Techniques;Complex;Development;Down-Regulation;Epithelial Cells;Gene Expression;Gene Expression Profiling;Generations;Glutathione Disulfide;Goals;Human;Hydrogen Peroxide;Immunocompetent;Infiltration;Inflammation;Knockout Mice;Knowledge;Lead;Link;Malignant Neoplasms;Mammary gland;Measurement;Mediating;Metabolic;Metformin;Mitochondria;Modeling;Molecular;Molecular Profiling;Mus;NADP;Nature;Neoplasm Metastasis;Nuclear Orphan Receptor;Oxidation-Reduction;Pathway interactions;Positioning Attribute;Production;Reactive Oxygen Species;Research;Role;Scheme;Source;Structure;Superoxides;System;TP53 gene;Testing;Tissue Microarray;Tissues;Tumor Suppressor Proteins;base;cancer cell;cancer prevention;cancer therapy;cytokine;healing;improved;inhibitor/antagonist;insight;knock-down;loss of function;macrophage;malignant breast neoplasm;metabolomics;monocyte;multidisciplinary;novel;novel strategies;stable isotope;tumor;tumor microenvironment;tumor progression


application_id: 9285875
project_number: 5R24OD010435-17
project_title: Research Resources for Model Amphibians
administering_ic: OD
award_notice_date: 2017-06-20
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;Bioinformatics;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;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: 9284281
project_number: 5R01HD070792-06
project_title: Indomethacin and delayed umbilical cord clamp for preterm infant IVH
administering_ic: NICHD
award_notice_date: 2017-03-24
opportunity_number: PAR-11-246
application_type: 5
activity_code: R01
ic: HD
serial_number: 070792
program_official: REN, ZHAOXIA
project_start_date: 2013-04-01
project_end_date: 2020-03-31
study_section: Special Emphasis Panel[ZRG1-EMNR-R(55)R]
contact_pi_person_id: 6654912
contact_pi: GIANNONE, PETER J
other_pis: BAUER, JOHN ANTHONY
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) are brain lesions that commonly occur in preterm infants and are well-recognized major contributors to long-term brain injury and related disabilities later in life. Despite its prevalence long term consequences and enormous medical and social costs mechanisms of IVH and optimal strategies to prevent or treat its occurrence are poorly defined especially for extremely premature infants. Only one medical therapy prophylactic indomethacin during the first 3 days of life has been shown to prevent or decrease the severity of IVH in preterm infants but its use is limited by toxic side effects and debatable effects on long-term outcomes. Several small studies and case reports suggest that delayed umbilical cord-clamping (DCC) may also decrease the incidence of IVH in premature infants but thus far these trials have indomethacin treatment mixed within their cord clamping protocols. We will therefore conduct a randomized blinded investigation of 4 treatment groups: 1) Control (no intervention); 2) DCC alone; 3) Prophylactic indomethacin alone; 4) Combination of DCC/indomethacin with respect to survival IVH or PVL incidence and severity neurodevelopmental outcomes and relevant mechanistic effects. Our Specific Aims are: Aim 1) Compare efficacy and safety of prophylactic indomethacin DCC and their combination in affecting the incidence and severity of IVH/PVL in infants <28wks gestational age (primary outcome measure of 'fraction of survivors with no severe IVH or PVL' among the 4 groups) and longer term neurocognitive function; Aim 2) Investigate mechanistic effects of prophylactic indomethacin DCC and their combination in infants less than 28wks gestational age (blood volume/circulatory status inflammatory stress progenitor cells); and Aim 3) Determine relationships between clinical outcomes and mechanistic measurements among treatment groups (n=400 total cases). With the steady rise in extreme prematurity births and clear links of IVH to long-term disabilities there is a need to improve care for these patients. This multi-disciplinary project addresses an important medical problem for an understudied patient population where the current practice has clear limitations.

project_terms:
Address;Adverse effects;Affect;Apoptotic;Biological Markers;Birth Weight;Blinded;Blood;Blood Vessels;Blood Volume;Brain;Brain Injuries;Brain imaging;Caring;Case Study;Cerebral Palsy;Child;Clinical;Closure by clamp;Cognitive;Communities;Costs and Benefits;Data;Developmental Delay Disorders;Developmental Disabilities;Disabled Persons;Effectiveness;Evaluation;FDA approved;Frequencies;Gestational Age;Goals;Head;Health Care Costs;Hemorrhage;Incidence;Indomethacin;Infant;Inflammation;Inflammatory;Intervention;Intestinal Perforation;Investigation;Kidney;Lesion;Life;Link;Magnetic Resonance Imaging;Measurement;Medical;Medical center;Mental Retardation;Mothers;Neonatology;Neurocognitive;Neurologic;Neurons;Newborn Infant;Organ failure;Outcome;Outcome Measure;Patient Care;Patients;Pediatric Hospitals;Performance;Periventricular Leukomalacia;Phenotype;Pregnancy;Premature Birth;Premature Infant;Prevalence;Prevention;Prevention therapy;Protocols documentation;Randomized;Research;Risk;Safety;Severities;Site;Stem cells;Stress;Surveys;Survivors;Testing;Toxic effect;Ultrasonography;Umbilical cord structure;biomedical referral center;clinical care;comparative efficacy;cost;design;disability;extreme prematurity;follow-up;hemodynamics;high risk;improved;intraventricular hemorrhage;multidisciplinary;patient population;prevent;primary outcome;prophylactic;public health relevance;social;treatment group

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This project is designed to improve the medical care of extremely premature infants and to determine improved strategies to prevent intracranial bleeding that often occurs in the first few days of life. Intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) are brain lesions that commonly occur in preterm infants and are well-recognized major contributors to long-term brain injury and related neurological disabilities later in life. We will conduct a randomized blinded investigation of 4 treatment groups: 1) Control (no intervention); 2) delayed umbilical cord clamp (DCC) alone; 3) Prophylactic indomethacin alone; 4) Combination of DCC/indomethacin with respect to survival IVH or PVL incidence and severity neurodevelopmental outcomes and relevant mechanistic effects (n=400 total cases). With the steady rise in extreme prematurity births and clear links of IVH to long-term disabilities there is a need to improve care for these patients. This multi-disciplinary project addresses an important medical problem for an understudied patient population where current medical practice has clear limitations.


application_id: 9284184
project_number: 3R43ES025446-01S1
project_title: Electronic Platform for the Delivery of Site Specific Health and Safety Training
administering_ic: NIEHS
award_notice_date: 2016-06-03
opportunity_number: RFA-ES-14-003
application_type: 3
activity_code: R43
ic: ES
serial_number: 025446
suffix: S1
program_official: AHLMARK, KATHY
project_start_date: 2015-05-07
project_end_date: 2016-07-31
study_section: ZES1-JAB-D(EL)1
contact_pi_person_id: 10166727
contact_pi: NICOLALDE, ROBERTO JAVIER
other_pis: SHAPOREV, ALEKSEY
congressional_district: 06
department: Unavailable
primary_duns: 963949107
primary_uei: VKSAV1S1KC77
duns_number: 963949107
uei: VKSAV1S1KC77
fips: US
organization_id: 10027501
organization_name: NICOLALDE R AND D, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40509
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The Emergency Responder Health Monitoring and Surveillance (ERHMS) Technical Assistance Document (TAD) aimed at National Response Teams highlights the need for a technology platform for collecting data before during and after disasters to assess the effect training has on response-related illness and injury for emergency responders. This SBIR grant application is aimed at developing a software platform that will not only provide the means to efficiently collect data for the assessment of training impact; but also will provide the means to efficiently deliver pre-deployment and site specific training (SST) against which the assessment of training impact on responders' illness and injury can be evaluated. If successfully implemented the software platform will be a useful tool both for delivering just-in-time training and for supporting environmental health research relating to responders' exposure to potentially harmful environmental contaminants during and after disaster events. This research project proposes an innovative system for generation and distribution of incident-related knowledge (including manuals general and site-specific trainings)with integrated monitoring and reporting functionality to address the needs described above. The system will allow the incident command official to generate training materials and data collection tools by simple and straightforward import from existing materials as well as to customize previously generated tools to better-fit the current situation. All the materials will bedelivered to emergency responders in the form of instantly generated smartphone (iOS Android) and web applications which will significantly reduce costs of logistics and latency of materials delivery. Materials encapsulation into mobile apps will address the prevalence of mobile devices (smartphones tablets) at the scene and will ensure that emergency responders can access the content of any situation and circumstances anywhere in the field in the most convenient form independently of what kind of device they have. Phase I will concentrate on assessing validating and prioritizing the most demanded tools together with a representative set of key stakeholders; developing a system prototype for digitization and modularization of training and data collection tools and instant distribution via rapidly created mobile application; prototyping specific interfaces for emergency responders and incident command personnel; testing and finally evaluating the first prototype. Phase II will concentrate on capabilities of electronic collection and distribution of health status and surveillance data on integration with an external IT system for two-way communication of hazard data outside incident command and on generation and delivery of additional materials in response to changed environmental conditions.

project_terms:
Address;Android;Applications Grants;Cellular Phone;Collaborations;Collection;Communication;Communication Methods;Computer software;Data;Data Analytics;Data Collection;Databases;Development;Devices;Disasters;Electronics;Emergency Situation;Emergency response;Ensure;Environmental Health;Environmental Pollution;Event;Exposure to;Fire - disasters;Generations;Goals;Health;Health Status;Human Resources;Information Systems;Injury;Institution;International;Knowledge;Language;Lead;Logistics;Manuals;Medical;Medical Staff;Monitor;New Hampshire;Phase;Police;Prevalence;Provider;Publishing;Questionnaires;Reaction;Reporting;Research;Research Project Grants;Resources;Safety;Sampling;Services;Site;Small Business Innovation Research Grant;Statistical Data Interpretation;Surveys;System;Tablets;Technology;Testing;Time;Training;Training Activity;Training Support;Validity and Reliability;analytical tool;base;cloud based;cost;emergency service/first responder;environmental change;handheld mobile device;hazard;health training;innovation;learning community;mobile application;operation;prototype;research and development;resilience;response;screening;support tools;surveillance data;tool;user-friendly;volunteer;web app

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed research and development will advance the field of emergency response health and safety by providing new and innovative means for incident command communications with field personnel and nonprofessional responders. The proposed research project will lead to significantly more efficient use of resources during emergencies better safety of emergency responders and more rapid reaction to incidents through the development of robust scalable and reusable tools for generation and distribution of incident-related knowledge as well as tools for real-time health monitoring and control.


application_id: 9284008
project_number: 1R01DE026727-01
project_title: SGK1 and the control of periodontal inflammation
administering_ic: NIDCR
award_notice_date: 2017-06-14
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: DE
serial_number: 026727
program_official: CHANDER, PREETHI
project_start_date: 2017-07-01
project_end_date: 2022-06-30
study_section: Special Emphasis Panel[ZRG1 MOSS-S (02)]
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;Recruitment Activity;Role;Serum;Severities;Signal Pathway;Signal Transduction;Signaling Molecule;TNF gene;Testing;Time;Tissues;Work;alveolar bone;bone loss;cytokine;design;immunoregulation;in vivo;inhibitor/antagonist;insight;macrophage;microbial;microbial community;microbiota;monocyte;novel;novel therapeutic intervention;oral bacteria;oral infection;oral pathogen;oral tissue;p65;pathogen;prevent;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: 9283319
project_number: 5R01CA175003-05
project_title: Activating Bax as a therapeutic strategy for lung cancer
administering_ic: NCI
award_notice_date: 2017-05-22
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 175003
program_official: SALNIKOW, KONSTANTIN
project_start_date: 2013-08-01
project_end_date: 2019-05-31
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 6950638
contact_pi: LI, CHI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Most human cancer cells are resistant to apoptosis. Among the major regulators of apoptosis are the Bcl-2 family of proteins. An emerging cancer therapeutic strategy is directly activating the apoptotic pathways by inhibiting the activity of ani-apoptotic Bcl-2 proteins or promoting the function of pro-apoptotic Bcl-2 proteins. However many of these strategies target the interaction among various Bcl-2 proteins particularly the interaction between pro- apoptotic and anti-apoptotic Bcl-2 proteins. Due to functional redundancy among Bcl-2 proteins these approaches are likely effective only on limited tumor types or display non-specific killing activities. As an important pro-apoptotic Bcl-2 protein Bax s involved in the development of tumors and Bax activation has been linked to apoptosis in lung tumors. Given that Bax alone is sufficient to initiate apoptosis in almost all apoptotic paradigmsdirect activation of Bax by small molecule compounds could induce death of Bax-expressing tumor cells. Our preliminary studies using in silico screening of large chemical libraries identifid a small molecule predicted to bind to the Bax hydrophobic groove. This compound is able to activate Bax leading to Bax-dependent tumor cell apoptosis and inhibition of mouse tumor growth. The following specific aims are proposed: 1) Examine the mechanisms by which the Bax activator inhibits tumor growth in mice. We will test the ability of the Bax activator to inhibt the growth of transplanted human tumors in mice as well as spontaneous mouse lung tumors. Furthermore we will investigate whether the active compound acts synergistically with other therapeutic drugs to inhibit the growth of tumors. 2) Improve the ability of Bax activators to activate Bax induce apoptosis and inhibit tumor growth. Ligand-based analyses will be used to identify potential compounds with greater biological activities and the compounds will be experimentally examined. 3) Investigate the mechanism of Bax activation on biological membranes by the Bax activators. We will use a novel patch-clamp technique combined with biochemical and cell biology approaches to investigate how the Bax activators induce Bax permeation channels on native biological membranes in vitro. We will also study how Bax permeation pore formation is regulated by the anti-apoptotic Bcl-2 protein Bcl-XL. As dysregulation of Bax expression has been implicated in lung tumor development inducing apoptosis in tumor cells by directly activating Bax holds promise as a novel therapeutic strategy to treat lung cancer patients.

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

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This project is designed to address the question of whether inducing apoptosis by direct activation of the pro- apoptotic protein Bax will be an effective chemotherapeutic treatment for cancer. By carrying out the experiments proposed in this study we hope to develop agents for the selective activation of Bax as a novel anti-neoplastic strategy.


application_id: 9282762
project_number: 5R01AG042475-05
project_title: CELLULAR CHANGES ALTERING SYNAPTIC CONNECTIVITY IN PRECLINICAL AD
administering_ic: NIA
award_notice_date: 2017-06-20
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AG
serial_number: 042475
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2013-06-01
project_end_date: 2019-05-31
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: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alzheimer's disease (AD) manifests severe pathological changes in the CNS including increased levels of amyloid hyperphosphorylated tau and synaptic loss. Synaptic dysfunction is a hallmark of the disease that associates with the cognitive ability and level of dementia during the progression of AD. It is unclear why synaptic numbers are reduced in the early stages of AD and how it is linked to other features of the pathology. We believe that oxidative damage and microtubule/actin changes are early events in the progression of AD and underlie synaptic dysfunction. Increasing evidence suggests that the medial temporal lobe (MTL) is the earliest regions of the brain affected and may provide important clues to the progression of the disease. Our hypothesis is that multiple different cellular changes occur in the MTL initiating the loss of synaptic plasticity resulting in a declinein cognition and the onset of clinical AD. The proposed experiments will evaluate changes in this brain region in regards to synaptic proteins oxidative stress and structural proteins. Studies ar carried out on short post mortem samples from longitudinally followed individuals with detailed cognitive testing. Individuals with amnestic mild cognitive impairment (aMCI) will be compared to individuals that clinically show no cognitive impairment (NCI). The NCI group is further classified as individuals with very low pathology (LP- NCI) or high (AD levels) of histopathology (HP-NCI). Current literature suggests that HP-NCI represents individuals with preclinical AD. Aim one assess the direct relationship between different key synaptic proteins and oxidative stress in the MTL. Aim two probes whether or not NADPH-oxidase (NOX) activity and its subunits change during the disease progression and how it associates with changes in synaptic proteins and soluble A beta. The NOX enzyme is normally expressed throughout the central nervous system and is a key non-mitochondrial source of free radicals. The third aim explores whether or not key cytoskeletal proteins such as the actin binding protein cofilin and tau increase in the MTL and alters different levels of key synaptic proteins. Successful completion of the proposed studies will reveal new insights into the mechanisms underlying the very early stages in the progression of AD and contribute to the development of rational therapies.

project_terms:
Actin-Binding Protein;Actins;Adult;Affect;Alzheimer's Disease;Amyloid;Anatomy;Antioxidants;Area;Binding;Biochemical;Brain region;Clinical;Cognition;Cognitive;Cytoskeletal Proteins;Data;Dementia;Development;Disease;Disease Progression;Enzymes;Etiology;Event;Free Radicals;Functional disorder;Heat shock proteins;Hippocampal Formation;Hippocampus (Brain);Histopathology;Impaired cognition;Individual;Lead;Link;Literature;Maintenance;Medial;Microtubules;Mission;Mitochondria;Molecular;NADPH Oxidase;Nerve Degeneration;Neuraxis;Neurofibrillary Tangles;Neuronal Dysfunction;Neurons;Oxidants;Oxidative Stress;Pathologic;Pathology;Play;Principal Investigator;Process;Production;Proteins;Reactive Oxygen Species;Research Support;Role;Sampling;Seminal;Source;Structural Protein;Subcellular Fractions;Symptoms;Synapses;Synaptic plasticity;System;Temporal Lobe;Testing;amnestic mild cognitive impairment;cofilin;cognitive ability;cognitive function;cognitive testing;cohort;dentate gyrus;design;differential expression;early detection biomarkers;entorhinal cortex;experimental study;frontal lobe;human tissue;hyperphosphorylated tau;insight;mental state;neurofibrillary tangle formation;novel marker;novel therapeutics;oxidative damage;pre-clinical;prevent;programs;public health relevance;synaptic failure;tau Proteins;tau aggregation

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Understanding cellular changes that occur in the early progression of AD will help to develop novel biomarkers for early detection. In addition it will help in designing specific novel therapies to slow or perhaps prevent the progression when detected early. The proposed studies are directly relevant to the mission of the NIA to support research aimed at understanding the cellular and clinical processes of dementia.


application_id: 9281896
project_number: 5R01HL131647-02
project_title: Regulation of Metabolic Genes in the Heart
administering_ic: NHLBI
award_notice_date: 2017-05-17
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 131647
program_official: WONG, RENEE P
project_start_date: 2016-06-01
project_end_date: 2020-05-31
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
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:
Project AbstractProfound derangements in pathophysiology occur during heart failure including alterations in thecardiomyocyte's ability to coordinate metabolic cues. Glucose represents the quintessential substrate formetabolism. Yet not all glucose is dedicated to the production of ATP; a fraction of intracellular glucose isshunted into several accessory pathways such as the Hexosamine Biosynthetic Pathway which forms themonosaccharide donor for the post-translational modification known as O-linked--N-acetylglucosamine (O-GlcNAc). The PI's laboratory has identified O-GlcNAcylation as an important event in the failing heart and O-GlcNAcase (OGA) is a key regulator of O-GlcNAc removal from targets. Despite significant insights related tothe phenomenology of O-GlcNAc in acute myocardial ischemia and heart failure almost nothing is knownabout the regulation of the O-GlcNAc enzymes (OGA and OGT) in the heart or other tissues. The presentproposal will reduce significantly this critical gap in knowledge. To this end the present proposal will: i) Identifytranscriptional and post-transcriptional regulators of OGA expression; again nothing is known currentlyregarding such regulation in the cardiomyocyte. In addition to in vivo studies experiments will be performed inisolated cells and cell lines using common molecular biology techniques (e.g. promoter mutations transcriptionfactor binding transduction). ii) Using a loss-of-function approach the project will determine the impact ofOGA suppression during heart failure. Studies will incorporate tissue-specific inducible cre-lox-mediateddeletion of the OGA gene in cardiomyocytes. The PI will use genetically modified surgically operated micecoupled with state-of-the-art physiologic assessment of cardiac function. iii) Mechanistic inquiries will focus onmitochondria to understand how OGA suppression attenuates the severity of heart failure. The PI will performvarious analyses of mitochondrial function including bioenergetics assays along with protein chemistry todetermine how suppression of OGA improves mitochondrial function. The overarching hypothesis holds thatthat OGA suppression attenuates heart failure through preservation of mitochondrial respiratory integrity.Although not the direct near-time goal of this project the results could eventually contribute to new potentialtreatment options for heart failure and because of the potential involvement of O-GlcNAcylation in severaldiseases will contribute to new directions in studies of diabetes Alzheimer's aging and vascular diseases.

project_terms:
Ablation;Accounting;Acute;Address;Aging;Alzheimer's Disease;Area;Attenuated;Binding;Bioenergetics;Biological;Biological Assay;Biological Preservation;Biology;Cardiac;Cardiac Myocytes;Cell Line;Cell physiology;Cells;Collaborations;Coupled;Cues;Diabetes Mellitus;Disease;Elements;Enzymes;Event;Excision;Functional disorder;Gene Expression Regulation;Genes;Genetic Transcription;Glucose;Goals;Heart;Heart failure;Hexosamines;Hypertrophy;Infarction;Knowledge;Laboratories;Life;Link;Mediating;Metabolic;Metabolism;MicroRNAs;Mitochondria;Molecular;Molecular Biology Techniques;Monosaccharides;Mus;Mutation;Myocardial Ischemia;Myocardium;Neurodegenerative Disorders;O-GlcNAc transferase;Operative Surgical Procedures;Outcome;Pathway interactions;Physiological;Positioning Attribute;Post-Translational Protein Processing;Production;Protein Chemistry;Proteins;Recording of previous events;Regulation;Research Personnel;Respiratory physiology;Role;Severities;Signal Transduction;Stress;System;Testing;Therapeutic;Time;Tissues;Vascular Diseases;Ventricular Function;Work;authority;experience;experimental study;human disease;improved;in vivo;innovation;insight;interest;loss of function;novel;peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase;phenomenological models;promoter;respiratory;response;synergism;tool;transcription factor;vector;virtual

public_health_relevance:
Project NarrativeThis project will determine the role of a unique metabolism-related signal in the failing heart. This project willalso provide new insights into the molecular regulation of genes also involved in neurodegenerative diseasesdiabetes and other diseases. This project will produce broadly applicable basic biological insights.


application_id: 9280048
project_number: 1T35EY026509-01A1
project_title: Summer Vision Sciences Training Program
administering_ic: NEI
award_notice_date: 2017-05-25
opportunity_number: PA-16-151
application_type: 1
activity_code: T35
ic: EY
serial_number: 026509
suffix: A1
program_official: CLAYTON, EDWIN C
project_start_date: 2017-07-01
project_end_date: 2022-04-30
study_section: Special Emphasis Panel[ZEY1 VSN (03)]
contact_pi_person_id: 1925445
contact_pi: CERESA, BRIAN P.
other_pis: KAPLAN, HENRY JERROLD
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_terms:
Authorship;Basic Science;Biology;Clinical;Clinical Research;Conflict of Interest;Data;Environment;Faculty;Foundations;Funding;Goals;Homeostasis;Hour;Institutional Review Boards;Interview;Laboratories;Laboratory Research;Medical Students;Mentors;Mentorship;Ophthalmology;Physicians;Plagiarism;Publications;Research;Research Personnel;Research Project Grants;Research Training;Retinal Degeneration;Scientist;Series;Structure;Student recruitment;Students;Systems Development;Time;Training;Training Programs;Translational Research;Universities;Uveitis;Vision;Vision research;Visual;Work;animal care;base;career;corneal epithelium;design;ethnic disadvantage;ethnic minority population;experience;human subject;medical schools;peer;peer coaching;posters;programs;responsible research conduct;skills;vision development;vision science


application_id: 9280014
project_number: 2R25CA134283-06A1
project_title: University of Louisville Cancer Education Program
administering_ic: NCI
award_notice_date: 2017-03-23
opportunity_number: PAR-15-152
application_type: 2
activity_code: R25
ic: CA
serial_number: 134283
suffix: A1
program_official: RADAEV, SERGEY
project_start_date: 2011-09-14
project_end_date: 2022-03-31
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 1924912
contact_pi: HEIN, DAVID W
other_pis: KIDD, LA CREIS RENEE
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_terms:
Benchmarking;Cancer Center;Cancer Research Project;Country;Development;Enrollment;Faculty;Goals;Health Professional;Health Sciences;Incidence;Kentucky;Malignant Neoplasms;Mentorship;Morbidity - disease rate;Outcome;Recruitment Activity;Research;Schools;Student recruitment;Students;Training;Training Activity;Underrepresented Groups;Universities;anticancer research;cancer education;career;college;meetings;member;mortality;programs;research and development;satisfaction;science teacher;student participation;symposium;undergraduate student;university student


application_id: 9278488
project_number: 1R25CA203637-01A1
project_title: Training in Interprofessional Education for Palliative Care in Oncology
administering_ic: NCI
award_notice_date: 2017-03-14
opportunity_number: PAR-15-151
application_type: 1
activity_code: R25
ic: CA
serial_number: 203637
suffix: A1
program_official: RADAEV, SERGEY
project_start_date: 2017-03-14
project_end_date: 2022-02-28
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 8126973
contact_pi: PFEIFER, MARK P
other_pis: HEAD, BARBARA A
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_terms:
Accreditation;Address;Cancer Patient;Caring;Collaborations;Communication;Complex;Crowding;Development;Diagnosis;Discipline;Discipline of Nursing;Education;Educational Activities;Educational Curriculum;Educational workshop;Faculty;Future;Goals;Health Sciences;Institution;Knowledge;Lead;Learning Skill;Length;Logistics;Malignant Neoplasms;Medicine;Mentors;Modeling;Nature;Nurses;Outcome;Palliative Care;Patient Care;Patient-Centered Care;Patients;Physicians;Pre-Post Tests;Program Sustainability;Quality of life;Research Infrastructure;Resources;Role;Site;Social Work;Social Workers;Students;Teacher Professional Development;Time;Trainers Training;Training;Training Programs;Work;base;cancer care;cancer diagnosis;cancer education;cancer palliative treatment;design;experience;health care service utilization;improved;instrument;interest;method development;oncology;outcome forecast;palliative;patient oriented;pedagogy;programs;science teacher;skills;student training;success;symposium;webinar


application_id: 9278387
project_number: 3R01ES024478-02S1
administering_ic: NIEHS
award_notice_date: 2016-11-22
opportunity_number: PA-15-322
application_type: 3
activity_code: R01
ic: ES
serial_number: 024478
suffix: S1
program_official: TYSON, FREDERICK L
project_start_date: 2016-12-01
project_end_date: 2020-01-31
contact_pi_person_id: 10313148
contact_pi: FONDUFE-MITTENDORF, YVONNE NSOKIKA
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
budget_start_date: 2016-12-01
project_title:
Diversity Supplement: The Role of Chromatin Structural and Epigenetic Changes in Arsenic-Induced Gene Expression Supplement

project_abstract:
DESCRIPTION (provided by applicant): Establishing the influence of pollutants on genome function is essential in defining their impact on human health. Arsenic is a ubiquitous environmental toxic metalloid that leads to carcinogenesis. The World Health Organization estimates that over 100 million people worldwide are at risk to drinking arsenic contaminated water. Recent studies indicate that arsenic alters gene expression leading to tumorigenesis. Proper gene regulation is essential for normal growth development and etiology of diseases such as cancer. Eukaryotic DNA stored as chromatin whose basic repeating unit is the nucleosome plays an integral role in gene regulation. Previously we (and others) showed that nucleosome locations within promoters play critical roles in chromatin accessibility thus controlling gene activity. Consequently chromatin accessibility is an essential component in gene regulation yet is not fully understood. Chromatin accessibility appears to be modulated by several key epigenetic factors: histone post-translational modifications (PTMs) DNA methylation nucleosome position/occupancy transcription factors and chromatin architectural proteins (CAPs). Recent studies now indicate that changes in DNA methylation and histone PTMs influence gene expression in response to arsenic: Thus it is critically important to understand how these key epigenetic modulators integrate and interrelate to regulate the chromatin state and gene expression during arsenic exposure. This project will determine the functional changes in gene regulation chromatin composition structure and dynamics genome-wide due to arsenic in normal and iAs- transformed cells. We hypothesize that iAs-induced alterations in nucleosome position and occupancy histone PTMs and CAP occupancy all combine to dynamically restructure chromatin resulting in differential expression of key genes resulting in a failure to ensure proper gene regulation and cancer. We propose in this application the following Specific Aims: (1) determine the effect of iAs on in vivo nucleosome positioning and/occupancy during iAs-induced transformation. (2) Determine the impact of iAs- triggered modulation of CAPs-chromatin structure to impact gene expression. (3) Determine the mechanisms whereby iAs-provoked changes in chromatin composition structure and dynamics control TF occupancy. Our interdisciplinary broad approach will establish unique comprehensive functional and mechanistic data that will provide a detailed understanding of the interplay between arsenic-induced epigenetic changes and chromatin in the mammalian cell. We have developed novel systems that will provide an unprecedented and unique opportunity to discover the functional and mechanistic roles of the epigenome in toxin-induced diseases.

project_terms:
Adhesions;Affect;Architecture;Arsenic;Binding;Biochemical;Bioinformatics;Biophysics;Cell Adhesion;ChIP-seq;Chromatin;Chromatin Structure;Cues;DNA;DNA Binding;DNA Methylation;DNA Sequence;Data;Development;Diagnostic;Disease;Ensure;Epigenetic Process;Etiology;Eukaryotic Cell;Exposure to;Failure;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Gene Structure;Generations;Genes;Genetic Transcription;Genome;Goals;Growth and Development function;Health;Heavy Metals;Histones;Human;ITGB4 gene;In Vitro;Integrins;Lead;Location;Malignant Neoplasms;Malignant neoplasm of lung;Mammalian Cell;Mediating;Modification;Molecular Profiling;Molecular Target;NCAM1 gene;Neoplasm Metastasis;Nucleosomes;Organism;Outcome;Pathogenesis;Play;Positioning Attribute;Post-Translational Protein Processing;Prevention;Process;Proteins;Reactive Oxygen Species;Research;Risk;Role;Site;Specific qualifier value;Stimulus;Structure;System;To specify;Toxin;Transcriptional Regulation;World Health Organization;Zinc Fingers;base;carcinogenesis;carcinogenicity;cell transformation;chromatin protein;chromatin remodeling;clinical biomarkers;clinical development;contaminated water;differential expression;drinking;epigenome;epigenomics;epithelial to mesenchymal transition;genome-wide;in vivo;insight;metaplastic cell transformation;novel;novel diagnostics;novel therapeutic intervention;novel therapeutics;pollutant;promoter;public health relevance;response;single-molecule FRET;targeted treatment;tool;transcription factor;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Proper regulation of gene expression is essential to the development and health of all organisms. The DNA in each eukaryotic cell found as chromatin plays an integral part in this gene regulation. Indeed where nucleosomes are located is important in our understanding of gene regulation. Furthermore knowing how chromatin structure responds to particular stimuli to control the on and off state of genes would be helpful in the development of new diagnostic and therapeutic tools.


application_id: 9277578
project_number: 5R01HL130174-02
project_title: Metabolic optimization of cell therapy
administering_ic: NHLBI
award_notice_date: 2017-05-29
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 130174
program_official: SCHWARTZ, LISA
project_start_date: 2016-06-01
project_end_date: 2021-05-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 9543696
contact_pi: HILL, BRADFORD GUY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
6-Phosphofructo-2-kinase;Affect;Attenuated;Biochemical;Carbon;Cardiac;Cause of Death;Cell Proliferation;Cell Survival;Cell Therapy;Cell Transplants;Cell physiology;Cells;Cicatrix;Clinical Treatment;Competence;Defect;Development;Diabetes Mellitus;Diabetic mouse;Enzymes;Equilibrium;Exhibits;Fatty acid glycerol esters;Fibrosis;Fructose-26-bisphosphatase;Functional disorder;Future;Glucose;Glycolysis;Heart;Heart failure;Hexosamines;Impairment;In Vitro;Inflammation;Injury;Insulin;Intervention;Measurement;Mediating;Metabolic;Metabolic Pathway;Modeling;Mus;Myocardial;Myocardial Infarction;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Oxidation-Reduction;Pathway interactions;Patients;Pentosephosphate Pathway;Pentosephosphates;Pharmacology;Phosphoric Monoester Hydrolases;Phosphotransferases;Property;Protein Isoforms;Protocols documentation;Radiolabeled;Reaction;Recovery;Resistance;Risk Factors;Role;Stem cells;Stress;Testing;Tissues;Tracer;Transplantation;aerobic glycolysis;cardiogenesis;cell growth;cellular transduction;db/db mouse;diabetic;diabetic patient;extracellular;glucose metabolism;impaired capacity;improved;inhibitor/antagonist;metabolomics;mortality;non-diabetic;novel therapeutic intervention;repaired;stable isotope;stem


application_id: 9276647
project_number: 5K02DA035116-05
project_title: Social Networks and HIV Risk Behaviors of Special Populations of Drug Users
administering_ic: NIDA
award_notice_date: 2017-06-02
opportunity_number: PA-11-191
application_type: 5
activity_code: K02
ic: DA
serial_number: 035116
program_official: HARTSOCK, PETER
project_start_date: 2013-07-01
project_end_date: 2018-06-30
study_section: Behavioral and Social Consequences of HIV/AIDS Study Section[BSCH]
contact_pi_person_id: 6264981
contact_pi: OSER, CARRIE BETH
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The primary goal of this resubmitted K02 application is to further develop Dr. Carrie Oser's productive independent research career and to augment her research focus on HIV substance abuse treatment crime and health disparities by gaining new training on social networks and HIV intervention development. The K02 builds upon her focus on special populations including both rural drug users and African American drug users. The proposed training goals will provide new instruction in social networks HIV intervention development and the responsible conduct of research. The specific aims are: (1) to identify HIV and HCV risk and longitudinal changes in risk in the social networks of 503 rural out-of-treatment drug using women as compared to men; and (2) to examine the effect of social networks including structure (e.g. size density) function (e.g. emotional and instrument support) and content (e.g. attitudes towards physicians) on HIV and HCV risk behaviors and health services utilization among African American drug using women as compared to men across criminal justice status. This significant and innovative study will have strong public healt impacts and will support NIDA's Health Disparities Initiative because of its potential to contribut to our understanding of the cultural and social network correlates of health disparities among both rural and African American drug users. In addition this study improves upon the methodological limitations of previous research findings by examining various social networks (e.g. egocentric dyadic and sociocentric) and using longitudinal data in multilevel models. Thisproposed project will allow for a practical application of the substantive knowledge and analytical skills acquired from the K02 training activities and will ultimately culminate in the development of forthcoming investigator initiated NIDA grant applications. Specifically these findings will be used as a foundation for future HIV social networks based intervention to increase special populations' use of preventative health care and subsequently reduce the need for expensive medical services as well as to decrease HIV risk behaviors including drug use unprotected sex and recidivism.

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

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This study is significant to the public health field because of its potential to understand the individual cultural and social network factors associated with HI and HCV risk behaviors among two special populations - rural drug users and African American drug users. These findings will be used as a foundation for developing social network based HIV interventions to increase special populations' use of preventative health care and subsequently reduce the need for expensive medical services as well as to decrease HIV risk behaviors including drug use unprotected sex and recidivism.


application_id: 9276592
project_number: 3U19AI113182-03S1
project_title: Project 2: PREVENT Preclinical safety and efficacy studies
administering_ic: NIAID
award_notice_date: 2016-06-10
opportunity_number: RFA-AI-13-023
application_type: 3
activity_code: U19
ic: AI
serial_number: 113182
suffix: S1
program_official: TURPIN, JIM A
project_start_date: 2016-07-01
project_end_date: 2019-06-30
study_section: ZAI1-BP-A
subproject_number: 6666
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
project_abstract:
The antiviral lectin Griffithsin (GRFT) has broad spectrum activity against human immunodeficiency viruses (HIV) types 1 and 2 herpes simplex virus type 2 (HSV-2) and hepatitis C virus (HCV) (1-4). Griffithsin-based topical microbicide formulations offer the potential for use as a multipurpose non- antiretroviral based method to prevent HIV-1 and epidemiologically linked infections. The Project 2 objective is to show that GRFT containing rectal microbicide products are safe and effective in the Rhesus macaque model of rectal HIV transmission. These studies are designed to be complementary to the human clinical studies proposed in Project 3. We have three specific aims: Aim 1 is to evaluate the safety pharmacokinetics and pharmacodynamics (PK/PD) of GRFT carbopol gel. We will conduct a three stage placebo controlled PK/PD study in adult male Rhesus macaques with the GRFT rectal gel formulation and matched placebo gel supplied by Core B. The proposed macaque study is designed to address specific translational questions concerning immunotoxicity and health of the mucosal environment after GRFT exposure. Favorable stage 1 outcomes include detection of active HIV-1 inhibitory concentrations of GRFT in rectal fluids and acceptable clinical safety metrics which allows progression to the efficacy Stage 2. Using a cohort of GRFT treatment experienced animals will allow us to determine whether pre-existing immunity to GRFT affects product efficacy. Stage 3 will test the GRFT and placebo products in SHIV infected animals where we will compare amounts of virus shed in experimental versus control animals providing an additional safety metric. Aim 2 is to assess the impact of GRFT treatment on the mucosal immune environment. We will use multiplexed immunoassays and gene expression arrays to measure markers of inflammatory immune responses. The highly sensitive immunohistochemistry (IHC) techniques refined in Prof. Kristina Broliden's laboratory will be applied to compare the number distribution and activation state of HIV target cells and expression of HIV receptor targets CD4 CCR5 DC-SIGN and Langerin plus markers of epithelial integrity in rectal biopsies from animals treated with GRFT active drug or matched placebo. Flow cytometry analyses will also enumerate and phenotype lymphocytes in biopsy tissues. Aim 3 is to assess the impact of GRFT treatment on the mucosal environment in the rectum using a systems biology approach that utilizes modern mass spectrometry proteomics assays to compare tissues and rectal secretions from animals that receive active drug versus placebo and to evaluate the effect of GRFT treatment on the rectal microbiota of treated animals.

project_terms:
Address;Adult;Affect;Affinity;Anal Sex;Animals;Anti-Retroviral Agents;Antiviral Agents;Anus;Attention;Awareness;Binding;Biological Assay;Biopsy;CCR5 gene;CD209 gene;Carbopol;Cell surface;Cells;Clinical;Clinical Research;Clinical Trials;Colorectal;Communities;Community Health;Control Animal;Data;Data Set;Detection;Development;Dose;Drug Kinetics;Effectiveness;Environment;Enzyme-Linked Immunosorbent Assay;Epithelial;Epithelial Cells;Exposure to;Female;Flow Cytometry;Formulation;Gel;Gene Chips;Gene Expression;Goals;HIV;HIV-1;Health;Hepatitis C virus;Heterosexuals;Human;Human Herpesvirus 2;Human Volunteers;Immune;Immune response;Immunity;Immunoassay;Immunohistochemistry;Incidence;Infection;Laboratories;Lectin;Link;Liquid substance;Local Microbicides;Lymphocyte;Macaca;Macaca mulatta;Mass Spectrum Analysis;Measures;Metagenomics;Methods;Modeling;Mucous Membrane;Mus;Outcome;Pharmaceutical Preparations;Pharmacodynamics;Phenotype;Placebo Control;Placebos;Polysaccharides;Population;Prevention;Proteins;Proteomics;Rectum;Reporting;Research Design;Safety;Sexual Transmission;Staging;Structure;Surface;Systems Biology;Techniques;Testing;Tissues;Trauma;Vagina;Viral;Virus Diseases;Virus Receptors;Virus Shedding;Woman;base;cohort;crosslink;design;experience;immunotoxicity;in vivo;inflammatory marker;langerin;male;men who have sex with men;microbial community;microbicide;microbiome;microbiota;novel;placebo controlled study;preclinical efficacy;preclinical safety;prevent;product development;protective efficacy;rRNA Genes;rectal;rectal microbicide;research clinical testing;response;safety testing;simian human immunodeficiency virus;transcriptomics;transmission process;trial design;viral transmission

public_health_relevance:
The global incidence of HIV-1 infection is declining but not in populations that practice unprotected anal intercourse (URAI) highlighting urgent need for attention to the preventative health needs in communities where men who have sex with men are especially stigmatized. Our rectal gel formulations have potential to prevent HIV-1 transmission via URAI but must first be tested for safety and effectiveness in animals. Our studies aim to provide a comprehensive set of data in support of further product development and clinical testing of the griffithsin gel product in the PREVENT clinical trial.


application_id: 9276584
project_number: 5U19AI113182-04
project_title: Project 3: PREVENT: A first-in-human clinical trial of Griffithsin an HIV entry
administering_ic: NIAID
award_notice_date: 2017-05-26
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
study_section: ZAI1-BP-A
subproject_number: 6667
contact_pi_person_id: 7904401
contact_pi: MCGOWAN, IAN MICHAEL
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
The overarching goal of the PREVENT Program is to develop a Griffithsin (GRFT) rectal gel that could be used prior to receptive anal intercourse (RAI) to reduce the risk of HIV infection by men who have sex with men (MSM). Project 3 will conduct a randomized placebo-controlled pre-Phase 1 human study to measure GRFT safety pharmacokinetics (PK) and pharmacodynamics (PD). We will recruit 18 healthy men to participate in a prospective trial to evaluate GRFT carbopol gel versus a matched placebo in a 2:1 randomization design. The study will address traditional product safety and PK parameters but we will also evaluate the effect of the product on adaptive immunity to GRFT by conducting a three stage study. The first stage will involve a single drug exposure. In Stages 2 and 3 men will receive 5 doses of gel product on consecutive days separated by a two week washout period. Rectal biopsies and other samples taken at baseline and during Stages 1-3 will be used to characterize mucosal responses to GRFT including enumeration of HIV target cells and detection of representative HIV receptors and epithelial junction proteins in the rectumby immunohistochemistry and flow cytometry. The biopsies will also be used for a PD assessment by ex vivo challenge of the tissue with HIV-1. Additionally we will employ a systems biology approach including transcriptomics proteomics and microbiome analysis to analyze the global impact of GRFT treatment on the mucosal environment in the rectum.

project_terms:
AIDS prevention;Address;Affinity;Animals;Antigens;Antiviral Agents;Anus;Awareness;Binding;Biopsy;Carbopol;Cell surface;Cells;Clinical Trials;Community Health;Data;Data Set;Detection;Dimensions;Dose;Drug Exposure;Drug Kinetics;Environment;Epithelial;Epithelial Cells;Exposure to;Flow Cytometry;Formulation;Gel;Gene Expression;Goals;HIV;HIV Entry Inhibitors;HIV Infections;HIV Receptors;HIV-1;HIV-2;Health;Hepatitis C;Human;Human Development;Immune;Immune response;Immunohistochemistry;In Vitro;Incidence;Inflammatory;Laboratories;Laboratory Animals;Lectin;Link;Lymphocyte;Measures;Metagenomics;Mucous Membrane;Mus;Natural Immunity;Oryctolagus cuniculus;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Phase;Phase I Clinical Trials;Placebo Control;Placebos;Plants;Polysaccharides;Prevention;Proteins;Proteomics;Randomized;Recruitment Activity;Rectum;Risk;Safety;Sampling;Simplexvirus;Structure;Surface;Systems Biology;T-Lymphocyte;Techniques;Tissues;Toxic effect;Vagina;Viral;adaptive immune response;adaptive immunity;base;crosslink;cytokine;design;healthy volunteer;human study;immunotoxicity;inhibitor/antagonist;men;men who have sex with men;microbial community;microbicide;microbiome;microbiota;novel;preclinical safety;prevent;programs;prospective;rRNA Genes;rectal;rectal microbicide;response;transcriptomics;transmission process;trial design;volunteer

public_health_relevance:
There is now evidence that rectal microbicides based on entry inhibitors can successfully block HIV transmission in high incidence settings and provide an invaluable addition to HIV prevention packages. This project describes the initial human development of a new anti-HIV rectal microbicide griffithsin (GRFT). If GRFT were shown to be effective it would have significant advantages over current microbicides.


application_id: 9276583
project_number: 5U19AI113182-04
project_title: Project 2: PREVENT Preclinical safety and efficacy studies
administering_ic: NIAID
award_notice_date: 2017-05-26
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
study_section: ZAI1-BP-A
subproject_number: 6666
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
The antiviral lectin Griffithsin (GRFT) has broad spectrum activity against human immunodeficiency viruses (HIV) types 1 and 2 herpes simplex virus type 2 (HSV-2) and hepatitis C virus (HCV) (1-4). Griffithsin-based topical microbicide formulations offer the potential for use as a multipurpose non- antiretroviral based method to prevent HIV-1 and epidemiologically linked infections. The Project 2 objective is to show that GRFT containing rectal microbicide products are safe and effective in the Rhesus macaque model of rectal HIV transmission. These studies are designed to be complementary to the human clinical studies proposed in Project 3. We have three specific aims: Aim 1 is to evaluate the safety pharmacokinetics and pharmacodynamics (PK/PD) of GRFT carbopol gel. We will conduct a three stage placebo controlled PK/PD study in adult male Rhesus macaques with the GRFT rectal gel formulation and matched placebo gel supplied by Core B. The proposed macaque study is designed to address specific translational questions concerning immunotoxicity and health of the mucosal environment after GRFT exposure. Favorable stage 1 outcomes include detection of active HIV-1 inhibitory concentrations of GRFT in rectal fluids and acceptable clinical safety metrics which allows progression to the efficacy Stage 2. Using a cohort of GRFT treatment experienced animals will allow us to determine whether pre-existing immunity to GRFT affects product efficacy. Stage 3 will test the GRFT and placebo products in SHIV infected animals where we will compare amounts of virus shed in experimental versus control animals providing an additional safety metric. Aim 2 is to assess the impact of GRFT treatment on the mucosal immune environment. We will use multiplexed immunoassays and gene expression arrays to measure markers of inflammatory immune responses. The highly sensitive immunohistochemistry (IHC) techniques refined in Prof. Kristina Broliden's laboratory will be applied to compare the number distribution and activation state of HIV target cells and expression of HIV receptor targets CD4 CCR5 DC-SIGN and Langerin plus markers of epithelial integrity in rectal biopsies from animals treated with GRFT active drug or matched placebo. Flow cytometry analyses will also enumerate and phenotype lymphocytes in biopsy tissues. Aim 3 is to assess the impact of GRFT treatment on the mucosal environment in the rectum using a systems biology approach that utilizes modern mass spectrometry proteomics assays to compare tissues and rectal secretions from animals that receive active drug versus placebo and to evaluate the effect of GRFT treatment on the rectal microbiota of treated animals.

project_terms:
Address;Adult;Affect;Affinity;Anal Sex;Animals;Antiviral Agents;Anus;Attention;Awareness;Binding;Biological Assay;Biopsy;CCR5 gene;CD209 gene;Carbopol;Cell surface;Cells;Clinical;Clinical Research;Clinical Trials;Colorectal;Communities;Community Health;Control Animal;Data;Data Set;Detection;Development;Dose;Drug Kinetics;Effectiveness;Environment;Enzyme-Linked Immunosorbent Assay;Epidemiology;Epithelial;Epithelial Cells;Exposure to;Female;Flow Cytometry;Formulation;Gel;Gene Chips;Gene Expression;Goals;HIV;HIV Receptors;HIV-1;Health;Hepatitis C;Heterosexuals;Human;Human Herpesvirus 2;Human Volunteers;Immune;Immune response;Immunity;Immunoassay;Immunohistochemistry;Immunologic Markers;Incidence;Infection;Laboratories;Lectin;Link;Liquid substance;Local Microbicides;Lymphocyte;Macaca;Macaca mulatta;Mass Spectrum Analysis;Measures;Metagenomics;Methods;Modeling;Modernization;Mucous Membrane;Mus;Outcome;Pharmaceutical Preparations;Pharmacodynamics;Phenotype;Placebo Control;Placebos;Polysaccharides;Population;Prevention;Proteins;Proteomics;Rectum;Reporting;Safety;Stigmatization;Structure;Surface;Symbiosis;Systems Biology;Techniques;Testing;Tissues;Trauma;Vagina;Viral;Virus Diseases;Virus Shedding;Woman;base;cohort;crosslink;design;efficacy study;experience;immunotoxicity;in vivo;inflammatory marker;langerin;male;men who have sex with men;microbial community;microbicide;microbiome;microbiota;novel;placebo controlled study;preclinical safety;prevent;product development;protective efficacy;rRNA Genes;rectal;rectal microbicide;research clinical testing;response;response biomarker;safety study;safety testing;sexual HIV transmission;simian human immunodeficiency virus;transcriptomics;transmission process;trial design

public_health_relevance:
The global incidence of HIV-1 infection is declining but not in populations that practice unprotected anal intercourse (URAI) highlighting urgent need for attention to the preventative health needs in communities where men who have sex with men are especially stigmatized. Our rectal gel formulations have potential to prevent HIV-1 transmission via URAI but must first be tested for safety and effectiveness in animals. Our studies aim to provide a comprehensive set of data in support of further product development and clinical testing of the griffithsin gel product in the PREVENT clinical trial.


application_id: 9276582
project_number: 5U19AI113182-04
project_title: Project 1: PREVENT Program Critical Path Project
administering_ic: NIAID
award_notice_date: 2017-05-26
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
study_section: ZAI1-BP-A
subproject_number: 6665
contact_pi_person_id: 8752851
contact_pi: TUSE, DANIEL
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
The overall goal of the Critical Path Project ("CPP"; Project 1) is to coordinate cGMP- compliant Drug Substance and Drug Product manufacture and release manage preclinical safety and efficacy studies and develop and integrate regulatory documents for submission of an Investigational New Drug (IND) application to US Food and Drug Administration (FDA) in support of an investigative clinical trial. Project 1 will establish the manufacturing methodology for the new product and help define an accelerated development path towards demonstration of clinical efficacy and product licensure. The novel active pharmaceutical ingredient (API) of our microbicide is Griffithsin (GRFT) a marine algal natural protein for which we have developed and scaled an efficient recombinant manufacturing process. GRFT is the most potent HIV-1 entry inhibitor known and also has high activity against other viruses that may be co-transmitted with HIV such as HSV-2. Through our collaborators in the PREVENT Program we have produced more than 200 g of GRFT for research use and developed effective and stable microbicide gel dosage forms. These prototype gels have been evaluated for initial safety in an ex vivo human explant system physicochemical stability and API release characteristics with very encouraging results. In Aim 1 of this Project we will apply methods we have successfully used to date to further optimize the API manufacturing process for maximum yield and recovery. The manufacturing process will be brought to compliance with FDA cGMP guidelines together with supporting documentation. Compliant API will be used to cGMP manufacture the rectal gel final dosage form optimized in Core B. In Aim 2 the safety and tolerability of the rectal gel product will be determined in regulation-compliant toxicology in 3 animal species with endpoints to include topical and systemic safety tolerability irritation sensitivity and immunotoxicity. Preliminary Chemistry Manufacturing and Controls (CMC) and safety information along with a draft clinical Protocol will be discussed with FDA in a pre-IND meeting. Agency feedback will assist us in finalizing an IND application activation of which by FDA will allow us to initiate a first-in-humans clinical trial of the GRFT microbicide in Project 3.

project_terms:
AIDS prevention;Animals;Biological Assay;Carbopol;Characteristics;Chemistry;Clinic;Clinical;Clinical Protocols;Clinical Research;Clinical Trials;Critical Pathways;Cyclic GMP;Development;Documentation;Dosage Forms;Ensure;Feedback;Formulation;Gel;Goals;Guidelines;HIV;HIV vaccine;HIV-1;Human;Human Herpesvirus 2;Investigational Drugs;Investigational New Drug Application;Licensure;Marines;Methodology;Methods;Mus;Nicotiana;Oryctolagus cuniculus;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology Study;Phase;Plants;Prevention;Production;Proteins;Published Comment;Rattus;Recombinants;Recovery;Regulation;Research;Risk;Rodent;Route;Safety;Skin;Suggestion;System;Toxicology;Training;United States Food and Drug Administration;Vagina;Viral;Virus;base;cGMP production;clinical efficacy;efficacy study;genotoxicity;immunotoxicity;in vivo;inhibitor/antagonist;irritation;manufacturing process;meetings;microbial;microbicide;novel;pre-clinical;preclinical safety;preclinical study;programs;prototype;rectal;rectal microbicide;safety study;transmission process

public_health_relevance:
Without a preventative HIV vaccine microbicides may offer a powerful option for the prevention of HIV transmission through the rectal and vaginal routes. This Project manages the key development tasks to bring to the clinic a novel microbicide candidate protein griffithsin which could be economically manufactured at a market-relevant scale using our plant-based production system.


application_id: 9276580
project_number: 5U19AI113182-04
project_title: Core C: PREVENT Program Pharmacokinetics and Pharmacodynamics Services Core
administering_ic: NIAID
award_notice_date: 2017-05-26
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
study_section: ZAI1-BP-A
subproject_number: 6663
contact_pi_person_id: 8640855
contact_pi: MATOBA, NOBUYUKI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
The objective of the Pharmacokinetics and Pharmacodynamics (PK/PD) Services Core will be to provide centralized support for the PK and key PD analyses common to preclinical macaque studies in Project 2 and human clinical studies in Project 3 thereby ensuring Program's research integrity and comparability between the preclinical and clinical studies proposed. To this end we will provide the following functions. (1) We will validate the quality of a griffithsin (GRFT) reference standard. A series of biochemical biophysical and virological assays will be used to validate the quality of GRFT. (2) We will develop an immunoassay to validate the potency of GLP/GMP-manufactured GRFT. Upon validation of the assay at OCRP its standard operating procedure will be transferred to Project 1 and Core B. (3) We will detect and quantify GRFT active pharmaceutical ingredient (API) and GRFT-binding antibodies in biological fluids to support PK/PD analysis in Projects 2 and 3. In addition to conventional methods based on enzyme-linked immunosorbent assays we will develop surface plasmon resonance-based analytical methods to detect low-affinity rapidly dissociating antibodies. As part of PK assessment we will use HIV-1 neutralization and cell-cell fusion assays to measure the anti-HIV-1 capacity of rectal fluid samples. (4) We will analyze the impact of GRFT gel treatment on the mucosal environment to support in vivo safety assessment. To this end we will employ a systems biology approach to comprehensively reveal the changes in the mucosal environment that may occur upon rectal administration of GRFT and GRFT combination gels. The induction of innate and adaptive immune responses in the mucosal and systemic immune compartments will be assessed using proteomic techniques. We will also use highly sensitive immunohistochemistry techniques to compare the number and location of HIV target cells and epithelial junction proteins in rectal tissue. Additionally the structure of rectal microbiota throughout the course of GRFT and combination gel treatment will be monitored by barcoded 16S rRNA genes sequencing to reveal the effect of microbicides formulation on the taxonomic structure of the rectal microbiota.

project_terms:
Adverse effects;Affinity;Alpha Cell;Anti-HIV Agents;Antibodies;Binding;Biochemical;Biological;Biological Assay;Biological Markers;Biophysics;Blood specimen;Body Fluids;Cell Line;Cell fusion;Cells;Clinical Research;Complement;Complex;Cyclic GMP;Detection;Development;Drug Kinetics;Ensure;Environment;Enzyme-Linked Immunosorbent Assay;Epithelial;Evaluation;Fluorescence;Formulation;Gel;Gene Expression Profiling;Giant Cells;Glycoproteins;HIV;HIV Envelope Protein gp120;HIV-1;Hela Cells;High Pressure Liquid Chromatography;Histopathology;Human;Human Herpesvirus 2;IgE;Immune;Immunoassay;Immunoblotting;Immunoglobulin A;Immunoglobulin G;Immunoglobulin M;Immunoglobulins;Immunohistochemistry;Lead;Liquid substance;Location;Macaca;Macaca mulatta;Measures;Methods;Molecular Sieve Chromatography;Monitor;Mucous Membrane;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Prevention;Procedures;Proteins;Proteomics;Quality Control;Reagent;Rectal Administration;Reference Standards;Reporter Genes;Research;Safety;Sampling;Series;Services;Standardization;Structure;Surface Plasmon Resonance;Systems Biology;Taxonomy;Techniques;Technology Transfer;Testing;Tissues;Toxicology;Validation;Viral;adaptive immune response;analytical method;base;immunogenicity;in vivo;microbicide;microbiota;pre-clinical;pre-clinical research;preclinical study;programs;rRNA Genes;rectal;rectal microbicide;virology

public_health_relevance:
Pharmacokinetics and Pharmacodynamics Services Core will facilitate preclinical and clinical research by developing and providing key assays and reagents to other components of the U19 PREVENT Program Project investigating the potent anti-HIV protein griffithsin as a candidate rectal microbicide.


application_id: 9276579
project_number: 5U19AI113182-04
project_title: Core B: PREVENT Product Development Core
administering_ic: NIAID
award_notice_date: 2017-05-26
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
study_section: ZAI1-BP-A
subproject_number: 6662
contact_pi_person_id: 6194125
contact_pi: ROHAN, LISA CENCIA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
Given the significant anatomical and physiological differences in the rectal and vaginal compartments it is essential to design rectal specific microbicide products to effectively inhibit rectal transmission of HIV. The overall goal of the Product Development Core (Core B) is in the provision of formulated Griffithsin (GRFT) gel products and quality physiochemical safety and efficacy assessments for these products. Specifically Core C will provide preformulation data formulation development efforts and formulation assessment evaluations in support of Projects 1 2 and 3 as well as Cores C and D. Formulation strategies within the scope of Core activities will be initiated utilizing knowledge obtained from previously developed rectal and vaginal GRFT gel products. Product attributes will be modified to obtain defined target specifications suitable for rectal application. The rectal specific GRFT product will be tested for safety and efficacy using an excised mucosal tissue explant model. A final formulation will be chosen based on successful achievement of defined target product profiles. Once the newly developed rectal GRFT formulation is obtained it will be scaled up and manufactured to support GLP animal safety testing studies and other preclinical assessments planned within Projects 1 and 2. Manufacture of GMP quality material will be achieved through a contract research organization within Project 1. Core B will be responsible for methods transfer provide assistance with development of batch records generated assist in protocol development for product assessment methods established for GMP product release and review stability results obtained. Additionally Core B will design a rectal specific GRFT combination product with enhanced potency as a second generation product. Efforts toward this end will be initiated through application of a screening algorithm to identify the most effective combination. Lead secondary antiretroviral candidates include tenofovir (TFV) and dapivirine(DPV). TFV and DPV are the lead ARV candidates currently being evaluated in the clinic. Quantitative assays to support formulation efforts have been developed in the laboratory for GRFT TFV and Dapivirine. This Core plays a critical role in the activities described within the PREVENT Program. The products and testing parameters developed within this core will be utilized by all projects and cores within the program.

project_terms:
Achievement;Algorithms;Anatomy;Animals;Anti-Retroviral Agents;Biological Assay;Carbopol;Characteristics;Chemicals;Chemistry;Clinic;Clinical Research;Clinical Trials;Critical Pathways;Cyclic GMP;Data;Development;Documentation;Dose;Drug Combinations;Drug Kinetics;Ensure;Evaluation;Formulation;Gel;Generations;Goals;HIV;Human;Investigational New Drug Application;Knowledge;Laboratories;Lead;Macaca;Methods;Modeling;Modification;Mucous Membrane;Pharmaceutical Preparations;Pharmacodynamics;Physiological;Placebos;Plasticizers;Play;Preparation;Prevention;Procedures;Production;Property;Proteins;Records;Rectal Administration;Regulation;Regulatory Affairs;Research Contracts;Role;Safety;Series;TMC120-R147681;Technology Transfer;Tenofovir;Testing;Toxic effect;Toxicology;Vagina;Vaginal Gel;Viral;analytical method;base;chemical stability;clinical development;condoms;design;dosage;efficacy study;immunogenicity;microbicide;oxidation;packaging material;pre-clinical;preclinical safety;preclinical study;product development;programs;protocol development;prototype;rectal;rectal microbicide;safety study;safety testing;scale up;screening;transmission process

public_health_relevance:
Product Development Core (Core B) will provide formulation development focused on the development of the anti-HIV protein griffithsin single entity and combination products. This Core will also conduct activities to ensure the safety of gels advancing to clinical trials.


application_id: 9276572
project_number: 5U19AI113182-04
project_title: Griffithsin-based Rectal Microbicides for PREvention of Viral ENTry (PREVENT)
administering_ic: NIAID
award_notice_date: 2017-05-26
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
program_official: TURPIN, JIM A
project_start_date: 2014-07-01
project_end_date: 2019-06-30
study_section: ZAI1-BP-A(M2)
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH E
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): PREVENT (Pre-exposure prevention of viral entry) is an Integrated Preclinical/Clinical Program with the overall goal to provide a comprehensive set of data to facilitate an informed decision on whether the antiviral lectin Griffithsin (GRFT) shoul progress in the topical microbicides pipeline. GRFT has broad-spectrum activity against human immunodeficiency viruses (HIV) types 1 and 2 herpes simplex virus type 2 (HSV-2) and hepatitis C virus (HCV). Our product target is a rectal microbicide gel containing GRFT as the primary Active Pharmaceutical Ingredient (API). People who practice unprotected receptive anal intercourse (URAI) represent the population most vulnerable to HIV-1 transmission due to the high preponderance of HIV target cells in the rectal mucosa and mucosal trauma commonly associated with RAI. As a small protein unlikely to be widely used in antiretroviral therapy the GRFT PREVENT program stands apart from pre-exposure prophylaxis (PREP) strategies that involve small molecule antiretrovirals (ARV) which bear the potential risk of selecting for viral resistance. Broad spectrum antiviral prophylaxis that is offered by lubricant gels containing GRFT offer a much needed option for HIV infected people who require effective PREP against superinfection with HIV as well as HSV-2 HCV and other enveloped viruses that are transmitted by URAI. Three Projects and four Cores will all contribute to the Specific Aims of the Overall Program. Aim 1: Provide a comprehensive set of safety and efficacy data to facilitate a Go/No-Go decision on progression of GRFT rectal microbicides into later stage clinical studies. Aim 2: Manage and integrate the PREVENT U19 Program with the goals and expectations of the NIH sponsor and future sponsors and investors in GRFT microbicide gel products.

project_terms:
Address;Affect;Animals;Anti-Retroviral Agents;Antiviral Agents;Anus;Cells;Characteristics;Chemistry;Clinical;Clinical Protocols;Clinical Research;Clinical Trials;Colorectal;Critical Pathways;Cyclic GMP;Data;Data Set;Development;Documentation;Dosage Forms;Dose;Drug Delivery Systems;Drug Kinetics;Ensure;Epidemic;Epithelium;Feedback;Formulation;Future;Gel;Goals;Guidelines;HIV;HIV-1;Hepatitis C;Human;Human Herpesvirus 2;Immune response;Immunoassay;Immunohistochemistry;Institution;Investigational Drugs;Investigational New Drug Application;Laboratories;Lead;Lectin;Licensure;Local Microbicides;Lubricants;Macaca mulatta;Manufacturer Name;Marines;Measures;Methodology;Methods;Modeling;Mucous Membrane;Nucleosides;Participant;Peptides;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Phase I Clinical Trials;Placebo Control;Placebos;Population;Practice Management;Pre-Clinical Model;Preclinical Testing;Prevention;Process;Prophylactic treatment;Proteins;Proteomics;Randomized;Recombinants;Recovery;Recruitment Activity;Regulation;Research;Reverse Transcriptase Inhibitors;Risk;Safety;Sampling;Services;Superinfection;System;TMC120-R147681;Techniques;Technology Transfer;Tenofovir;Topical application;Toxicology;Trauma;United States Food and Drug Administration;United States National Institutes of Health;Universities;Ursidae Family;Vagina;Viral;Virus;analytical method;antiretroviral therapy;base;clinical efficacy;condoms;design;efficacy study;efficacy testing;expectation;immunotoxicity;inhibitor/antagonist;innovation;irritation;manufacturing process;medical schools;meetings;microbicide;microbiome;next generation;non-nucleoside reverse transcriptase inhibitors;novel;novel therapeutics;pre-clinical;pre-exposure prophylaxis;preclinical safety;preclinical study;prevent;product development;programs;prototype;public health relevance;rectal;rectal microbicide;safety study;safety testing;small molecule;transcriptomics;transmission process;viral resistance;virus envelope;volunteer

public_health_relevance:
PUBLIC HEALTH RELEVANCE: PREVENT is an integrated preclinical/clinical project that aims to determine whether a gel based drug delivery system for a potent broad spectrum antiviral protein Griffithsin is safe in preclinical models and a pre-phase I clinical trial. Preclinical studies are also designed to predict whether the microbicide we develop might be effective against HIV-1 transmission. A safe and effective rectal microbicide gel would have significant impact on preventing expansion of the domestic and global HIV-1 epidemic.   
   
Project 1: PREVENT Program Critical Path Project   
Project Leader (PL): Tuse Daniel   
   
DESCRIPTION (as provided by applicant): The overall goal of the Critical Path Project ("CPP"; Project 1) is to coordinate cGMP-compliant Drug Substance and Drug Product manufacture and release manage preclinical safety and efficacy studies and develop and integrate regulatory documents for submission of an Investigational New Drug (IND) application to US Food and Drug Administration (FDA) in support of an investigative clinical trial. Project 1 will establish the manufacturing methodology for the new product and help define an accelerated development path towards demonstration of clinical efficacy and product licensure. The novel active pharmaceutical ingredient (API) of our microbicide is Griffithsin (GRFT) a marine algal natural protein for which we have developed and scaled an efficient recombinant manufacturing process. GRFT is the most potent HIV-1 entry inhibitor known and also has high activity against other viruses that may be co-transmitted with HIV such as HSV-2. Through our collaborators in the PREVENT Program we have produced more than 200 g of GRFT for research use and developed effective and stable microbicide gel dosage forms. These prototype gels have been evaluated for initial safety in an ex vivo human explant system physicochemical stability and API release characteristics with very encouraging results. In Aim 1 of this Project we will apply methods we have successfully used to date to further optimize the API manufacturing process for maximum yield and recovery. The manufacturing process will be brought to compliance with FDA cGMP guidelines together with supporting documentation. Compliant API will be used to cGMP manufacture the rectal gel final dosage form optimized in Core B. In Aim 2 the safety and tolerability of the rectal gel product will be determined in regulation-compliant toxicology in 3 animal species with endpoints to include topical and systemic safety tolerability irritation sensitivity and immunotoxicity. Preliminary Chemistry Manufacturing and Controls (CMC) and safety information along with a draft clinical Protocol will be discussed with FDA in a pre-IND meeting. Agency feedback will assist us in finalizing an IND application activation of which by FDA will allow us to initiate a first-in-humans clinical trial f the GRFT microbicide in Project 3.


application_id: 9276197
project_number: 3R01GM113087-02S2
project_title: Supplement: Deciphering the Molecular Mechanisms Underlying Active Scaffolding
administering_ic: NIGMS
award_notice_date: 2016-08-01
opportunity_number: PA-16-125
application_type: 3
activity_code: R01
ic: GM
serial_number: 113087
suffix: S2
program_official: DUNSMORE, SARAH
project_start_date: 2015-08-01
project_end_date: 2020-05-31
study_section: Molecular and Integrative Signal Transduction Study Section[MIST]
contact_pi_person_id: 8586925
contact_pi: GALPERIN, EMILIA
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:
Address;Affect;Apoptosis;Biochemical;Biological;Biological Markers;Biological Process;Blood;Cell Adhesion;Cell Culture System;Cell membrane;Cell model;Cell physiology;Cells;Cognitive deficits;Complex;Cultured Cells;Data;Defect;Development;Disease;Effectiveness;Embryo;Embryonic Development;Endocytosis;Endosomes;Ensure;Enzymes;Event;Face;Fluorescence Resonance Energy Transfer;Foundations;Genetic Models;Goals;Growth;Health;Heart Abnormalities;Hematopoiesis;Hematopoietic;Image;Lead;Link;MAP Kinase Gene;MEKs;Mediating;Microscopy;Mission;Mitogen-Activated Protein Kinases;Modeling;Molecular;Molecular Genetics;Mus;Mutation;Outcome;Pathology;Pathway interactions;Phosphoric Monoester Hydrolases;Phosphotransferases;Physiological;Play;Prevention;Prognostic Marker;Protein Biochemistry;Proteins;Proto-Oncogene Proteins c-raf;Ras/Raf;Regulation;Research;Role;Scaffolding Protein;Signal Pathway;Signal Transduction;Spatial Distribution;Specificity;Staging;Study models;System;Techniques;Testing;Ubiquitin;Ubiquitination;Work;Zebrafish;base;cell motility;cellular transduction;chromophore;developmental disease/disorder;disease diagnosis;in vivo;innovation;insight;novel;novel therapeutic intervention;novel therapeutics;scaffold;targeted treatment;therapeutic development;transmission process;tumor;tumor progression;ubiquitin-protein ligase


application_id: 9275838
project_number: 5R01CA166327-05
project_title: Regulation of Tumor Metabolism by Retinoblastoma Protein
administering_ic: NCI
award_notice_date: 2017-05-22
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 166327
program_official: SPALHOLZ, BARBARA A
project_start_date: 2013-06-01
project_end_date: 2019-05-31
study_section: Tumor Cell Biology Study Section[TCB]
contact_pi_person_id: 8077717
contact_pi: CLEM, BRIAN F
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): Tumorigenesis requires not only loss of proliferative control but also a metabolic shift towards increased glucose and glutamine consumption required for increased energy production and to drive the de novo biosynthesis of nucleotides amino acids and lipids essential for cell division. These processes are primarily driven through oncogenes or loss of tumor suppressors which act to circumvent normal regulatory pathways. The retinoblastoma (Rb) protein the first described tumor suppressor is extensively involved in cell cycle regulation and perturbations within the Rb pathway are found in most tumor types. Beyond cell cycle control Rb has been implicated in multiple additional biochemical pathways known to be involved in tumor progression such as metastasis and angiogenesis. However little is known about the role of Rb in regulating the unique changes in metabolism that have been observed in human cancers. Using stable 13C-glucose isotopomer NMR analyses we found that triple knock-out (TKO) of all three Rb family members in mouse embryonic fibroblasts (MEFs) resulted in increased glucose uptake and flux to lactate and simultaneously decreased glucose-derived carbon incorporation into TCA cycle intermediates relative to wild-type (WT) MEFs. This metabolic shift was mediated by changes in the expression of multiple glycolytic enzymes including increased Glut-1 HK2 PK-M2 levels and decreased HK1 ALT1 and PCB. To supplement this loss of glucose carbons for anaplerosis within the TCA cycle we speculated that the Rb TKO MEFs may increase glutamine uptake for both bioenergetic and anabolic precursors. We observed that loss of Rb caused increased 13C- glutamine uptake and flux into glutamate and TCA cycle intermediates via enhanced expression of the glutamine transporter ASCT2 and the activity of glutaminase 1 (GLS1). Further glutamine carbon is capable of facilitating oxygen consumption and glutamine withdrawal resulted in significant decrease in ATP levels in the TKO cells. Importantly this shift towards glutamine utilization was essential fo the survival of Rb TKO MEFs and not for the WT MEFs and addition of exogenous -ketoglutarate was able to rescue both ATP levels and cell viability in the Rb-depleted cells. Mechanistically E2F-1 -2 & -3 functionally alter both glucose and glutamine uptake and E2F-1 & -3 were observed to directly associate with the promoters of Glut-1 and ASCT2. Combined these studies suggest that the Rb/E2F cascade directly regulates two key metabolic pathways that are necessary for neoplastic growth. We hypothesize that inactivation of the Rb protein in human cancers leads to a global metabolic shift towards enhanced glycolysis and glutamine utilization which in turn is required for neoplastic immortalization and transformation. We will test this hypothesis by conducting the following Specific Aims: 1. To determine the precise metabolic transporters enzymes and pathways that are modulated by the loss of Rb and the relative requirements of these metabolic targets for the survival and growth of Rb-proficient and Rb-deficient MEFs human normal epithelial cells and human cancer cells. 2. To determine the effects of Rb1 deletion on glucose/glutamine metabolism and growth of lung adenocarcinomas in vivo. 3. To correlate the loss of Rb function with changes in the 13C-glucose utilization by human lung tumors in vivo.

project_terms:
ATP Synthesis Pathway;Affect;Alanine Transaminase;Amino Acids;Antineoplastic Agents;Biochemical Pathway;Bioenergetics;Biological Markers;Cancer Etiology;Carbon;Cell Cycle;Cell Cycle Progression;Cell Cycle Regulation;Cell Survival;Cell division;Cells;Characteristics;Citric Acid Cycle;Complex;Consumption;Data;Development;E2F transcription factors;E2F1 gene;Embryo;Enzymes;Epithelial Cells;Family member;Fibroblasts;Functional disorder;Gene Expression;Genes;Genomics;Glucose;Glutamates;Glutaminase;Glutamine;Glycolysis;Growth;HK2 gene;Histone Deacetylase;Human;Knock-out;Knockout Mice;Lipids;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolism;Molecular Target;Mus;Neoplasm Metastasis;Neoplasms;Neoplastic Cell Transformation;Normal Cell;Normal tissue morphology;Nucleotide Biosynthesis;Oncogenes;Oxygen Consumption;Pathway interactions;Positron-Emission Tomography;Process;Production;Promoter Regions;Proteins;Recruitment Activity;Regulation;Regulatory Pathway;Retinoblastoma;Retinoblastoma Protein;Role;TOCSY;Testing;Transcription Repressor/Corepressor;Tumor Markers;Tumor Suppressor Proteins;Wild Type Mouse;Withdrawal;alpha ketoglutarate;angiogenesis;base;bcr-abl Fusion Proteins;c-myc Genes;cancer cell;cell transformation;chromatin remodeling;enzyme pathway;glucose uptake;in vivo;macromolecule;metabolic phenotype;mitochondrial metabolism;neoplastic;neoplastic cell;potential biomarker;promoter;public health relevance;small molecule;tumor;tumor initiation;tumor metabolism;tumor progression;tumorigenesis;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: We anticipate that these studies will further expand our understanding of the role of the retinoblastoma protein (Rb) in tumor initiation and progression by detailing the precise regulatory mechanisms of Rb on tumor cell metabolism. These findings also may enable the identification of new molecular targets for development of anti-cancer agents as well as potential biomarkers for tumors that may be more responsive to anti-metabolic therapies.


application_id: 9275578
project_number: 3P30CA177558-04S5
project_title: University of Kentucky Markey Cancer Center - Cancer Center Support Grant
administering_ic: NCI
award_notice_date: 2016-08-31
opportunity_number: PAR-11-005
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S5
program_official: ROBERSON, SONYA
project_start_date: 2013-07-08
project_end_date: 2018-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  The Markey Cancer Center (MCC) a dedicated matrix cancer center established as an integral part of the University of Kentucky (UK) and the UK Healthcare enterprise has undergone dramatic expansion in recent years under the leadership of MCC Director Dr. B. Mark Evers. At this point in the center's development the MCC seeks support through the National Cancer Institute (NCI) Cancer Center Support Grant to capitalize on this momentum and to drive a measurable reduction in cancer mortality in Kentucky particularly Appalachian Kentucky through a comprehensive program of cancer research prevention and patient care. The need for NCI Cancer Center designation is particularly acute in a state that leads the nation across numerous cancer indicators including the highest rate of cancer deaths in the nation. Situated on a campus with all six health professions colleges in proximity to each other the MCC offers a history of rich transdisciplinary
collaboration an outstanding program of cancer prevention and control that has produced seminal work in Appalachian Kentucky nationally acclaimed basic research programs in cancer biology and DNA repair and oxidative stress and a translational therapeutics program complemented by a top five College of Pharmacy.    
   
These strengths have coalesced in MCC's four thematic research programs:  Cancer Cell Biology and Signaling; Cancer Prevention and Control; Drug Discovery Delivery and Translational Therapeutics; and Redox Injury and Repair. Currently the MCC's 108 Research and Associate Research members hold appointments in 24 departments in 7 colleges across the university (25 new faculty were recruited in the last 3 years). MCC members hold grants for 144 research projects funded in the annual composite (direct + indirect) amount of more than $30.5 million of which over $11.3 million (37%) comes from the NCI. Accrual to therapeutic clinical trials has increased over 130% in three years and MCC assignable space has increased 40% including a doubling of state-of-the-art research space. In addition six shared resources facilitate cutting-edge research by providing a robust infrastructure for specialized expertise and advanced methods. They include:  Biospecimen and Tissue Procurement; Biostatistics; Cancer Research Informatics; Clinical Research and Data Management; Flow Cytometry and Cell Sorting; and Free Radical Biology in Cancer. The MCC is currently well positioned to take on new challenges and to continue to evolve in key strategic directions that take maximum advantage of these strengths.

project_terms:
Acute;Appointment;Basic Science;Biology;Biometry;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Death Rates;Cancer Research Project;Cell Separation;Cellular biology;Clinical Data;Clinical Research;Complement;DNA Repair;Development;Faculty;Flow Cytometry;Free Radicals;Funding;Grant;Health;Health Occupations;Healthcare;Incidence;Informatics;Instruction;Kentucky;Leadership;Malignant Neoplasms;Measurable;Methods;National Cancer Institute;Outcome;Oxidation-Reduction;Oxidative Stress;Patient Care;Patients;Pharmacy facility;Positioning Attribute;Postdoctoral Fellow;Prevention;Recording of previous events;Recruitment Activity;Research;Research Infrastructure;Research Project Grants;Resource Sharing;Science;Seminal;Signal Transduction;Therapeutic;Therapeutic Clinical Trial;Tissue Procurements;United States;Universities;Work;anticancer research;bench to bedside;cancer cell;cancer prevention;cancer research center director;cancer site;college;data management;drug discovery;health disparity;injury and repair;interdisciplinary collaboration;member;mortality;programs


application_id: 9274596
project_number: 1S10OD023573-01
project_title: Essential Siemens Prisma Fit Upgrade for the University of Kentucky 3T Research Scanner
administering_ic: OD
award_notice_date: 2017-03-16
opportunity_number: PAR-16-053
application_type: 1
activity_code: S10
ic: OD
serial_number: 023573
program_official: WANG, GUANGHU
project_start_date: 2017-03-21
project_end_date: 2018-03-20
study_section: Special Emphasis Panel[ZRG1 SBIB-F (31)]
contact_pi_person_id: 8364843
contact_pi: SMITH, CHARLES DENNIS
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:
This is a multiuser equipment grant application for a Siemens Prisma Fit upgrade to theexisting Magnetom 3T TIM Trio MR scanner in the MRISC at the University of Kentucky.Funding to support this upgrade is being requested because of the significant advantages of thePrisma system for biomedical research particularly for a group of productive NIH-fundedinvestigators involved in neuroscience research. The Prisma system will be integral tomaintaining and expanding the research program of this group of investigators. Among the many advantages of the new instrument the most significant include theimproved magnetic field gradient system (higher amplitude and improved duty cycle) which willenable studies of white matter structure in a detail which is unavailable on the current Triosystem. The upgrade will include an improved radiofrequency (RF) system which includes adoubling of the number of RF receive channels. The resulting higher signal-to-noise and higherresolution images will enable newer insights into brain degeneration and remodeling. Theparallel transmit system on the Prisma will improve the homogeneity of excitation and enable 2Dselective excitation for reduced FOV imaging. A state-of-the-art computer system andprogramming environment also included in the upgrade will facilitate enhanced collaborationwith other biomedical researchers and a path to regular system modernization. The PI andmultiple co-PIs which form the Major Users Group on this application have funded programsranging from fundamental studies in neuroscience to clinical neuroscience research programs.Their research will significantly benefit from this advanced instrumentation which is not availableat the University or elsewhere in the State. Through the Universitys Magnetic ResonanceImaging and Spectroscopy Center which also manages a small animal high field MR imagerthe infrastructure (including space financial management routine maintenance technicalsupport and personnel) exists to rapidly bring the new scanner on line when funding becomesavailable and to continue to develop its capabilities to aid biomedical research.

project_terms:
Animals;Applications Grants;Biomedical Research;Brain;Clinical;Collaborations;Computer Systems;Computers and Advanced Instrumentation;Environment;Equipment;Funding;Human Resources;Image;Kentucky;Magnetic Resonance Imaging;Maintenance;Modernization;Neurosciences;Neurosciences Research;Noise;Occupational activity of managing finances;Research;Research Infrastructure;Research Personnel;Signal Transduction;Structure;System;United States National Institutes of Health;Universities;computer program;high resolution imaging;improved;insight;instrument;magnetic field;prisma;programs;radiofrequency;spectroscopic imaging;white matter

public_health_relevance:
NarrativeKentucky residents are unfortunately at unusually high risk for stroke and heart attack diabetes hypertensionobesity and vascular dementia and share the US trend for increasing population age and Alzheimersdisease. Human research in local at-risk populations is needed to combat these trends. This High-EndInstrumentation Grant will upgrade a multi-user MR imager to a state-of-the-art instrument for advancedneuroscience and other research at the University of Kentucky. The upgrade will add several essential newfeatures allowing researchers to better understand the structure and function of the brain heart and muscle inhealth and disease.


application_id: 9274555
project_number: 1S10OD021753-01A1
project_title: Triple Quadrupole Mass Spectrometer System
administering_ic: OD
award_notice_date: 2017-03-14
opportunity_number: PAR-16-054
application_type: 1
activity_code: S10
ic: OD
serial_number: 021753
suffix: A1
program_official: CHEN, YONG
project_start_date: 2017-03-15
project_end_date: 2018-03-14
study_section: Special Emphasis Panel[ZRG1 BCMB-T (31)]
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
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:
ABSTRACTThis revised application requests funds to purchase an ABSciex 5500 triple quadrupole mass spectrometer andHPLC system (Shimadzu UPLC with a multiwell plate handling/rack changing autosampler) and workstationcomputer. This instrument is needed to augment services currently provided by an ABSciex 4000 Q-TRAPsystem that was purchased in 2007 with funds provided by an NIH S10 award (S10 RR024598) and has beenin continuous service for the past 9 years as a mainstay of the University of Kentucky Small Molecule MassSpectrometry Core Laboratory (services provided to 42 unique investigators and data generated for 90 peerreviewed publications). The requested instrument offers moderate improvements in speed sensitivity androbustness over the 4000 series instrument and the UPLC system and rack changing/multiwell plate autosamplerprovide further improvements in sensitivity and sample throughput. This is an institution-wide facility core withpermanent technical staff and faculty and administrative oversight necessary to ensure productive and financiallysustainable operation. The core facility is directed by the PI of this application Dr Morris. During this time theinstrument has provided services to NIH funded researchers engaged in Cancer Cardiovascular MetabolicDisease Drug Discovery Nutrition and Environmental Toxicology research both at the University of Kentuckyand at several other regional and national institutions. The instrument has been used to generate data that werereported in 104 publications to provide services that were critical to successful applications for multiple personaland programmatic research awards and to provide training in biomedical applications of mass spectrometry tostudents and fellows. The requested instrument is required to maintain the overall research capacity of thefacility (~12000 services/year) which is currently dependent on use of a second ABSciex 4000 Q-Trap that waspurchased in 2009 with a supplement to one of Dr Morris's personal research grants. This instrument includesan ABSciex Flashquant vacuum MALDI source which enables its use for multiwell plate format enzyme assaysand its use in this configuration for personal research purposes limits its availability for core facility services. TheMajor Users conduct NIH sponsored research in Lipid Metabolism and Signaling Nutrition and EnvironmentalToxicology and Drug Discovery and Natural Products. Minor Users with relevant interests and qualifying supportare also included. The facility core employs two analytical chemists with broad experience in mass spectrometrythat will be responsible for day to day oversight upkeep and operation of the requested instrument. Dr Morrisand staff have extensive track record of success in the development and application of mass spectrometry-basedmethods for biomedical research and the facility core is overseen by an advisory committee staffed by individualswith appropriate and complementary expertise in analytical chemistry mass spectrometry data managementand facility core oversight. Financial operation of the core adheres to federal cost accounting standards with asustainable business plan underwritten by the College of Medicine and the Vice President for Research.

project_terms:
Accounting;Advisory Committees;Analytical Chemistry;Award;Biological Assay;Biomedical Research;Businesses;Cardiovascular system;Computer Workstations;Core Facility;Data;Development;Ensure;Enzymes;Faculty;Funding;High Pressure Liquid Chromatography;Individual;Institution;Kentucky;Laboratories;Malignant Neoplasms;Mass Spectrum Analysis;Medicine;Metabolic Diseases;Methods;Minor;Natural Products;Peer Review;Publications;Qualifying;Reporting;Request for Applications;Research;Research Personnel;Research Project Grants;Sampling;Series;Services;Signal Transduction;Source;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Speed;Students;System;Time;Training;United States National Institutes of Health;Universities;Vacuum;base;college;cost;data management;drug discovery;environmental toxicology;experience;instrument;interest;lipid metabolism;mass spectrometer;nutrition;operation;small molecule;success

public_health_relevance:
NARRATIVENatural and manmade molecules play critical roles in human disease processes. Detecting measuring andidentifying these molecules requires sophisticated instrumentation. The purpose of this application is torequest funds to purchase an instrument that will be used to identify and measure molecules that are importantfor research in human diseases (cancer cardiovascular disease and diabetes) toxic effects of environmentalpollutants and for the discovery and development of new drugs.


application_id: 9274260
project_number: 5R01CA188354-04
project_title: Non-peptide proteasome inhibitors as a novel anticancer agent
administering_ic: NCI
award_notice_date: 2017-05-22
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 188354
program_official: VERMA, SHARAD KUMAR
project_start_date: 2014-07-07
project_end_date: 2019-05-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 8152159
contact_pi: KIM, KYUNG BO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this project is to develop next-generation proteasome inhibitors that will serve as effective therapies 1) for multiple myeloma (MM) patients refractory to the existing proteasome-targeting drugs bortezomib and carfilzomib as well as 2) for patients with solid cancers. In the last decade the FDA has approved the proteasome-targeting drugs bortezomib (Velcade(R)) and carfilzomib (Kyprolis(R)) for the treatment of MM patients. These agents have greatly improved the prognosis of MM and firmly validated the proteasome as an important anticancer target. However many patients eventually develop resistance after prolonged proteasome inhibitor therapy and few effective treatment options exist for such patients. In addition the potential of proteasome-targeting drugs remain untapped for the treatment of solid cancers despite their promising anticancer activities in preclinical models of solid cancers. Thus it is critically important to develop novel proteasome inhibitors which can overcome the limitations of existing proteasome inhibitors and deliver the therapeutic benefits of proteasome inhibitor therapy to cancer patients of all types including solid cancers. We hypothesize that a new class of proteasome inhibitors with non-peptide scaffolds will provide new therapeutic options for MM patients refractory to bortezomib or carfilzomib and solid cancer patients. This is based on the drawbacks arising from the structural features shared among bortezomib carfilzomib and nearly all proteasome inhibitors in drug development pipelines. Specifically the structural features of peptide backbones and reactive pharmacophores contribute to a high susceptibility to chemical/metabolic inactivation and off-target interactions causing unwanted toxicities and an inability to achieve sufficient drug penetration within solid cancer sites. Using step-wise screening approaches combining virtual screen and in vitro enzyme kinetics we identified several promising hits with diverse non-peptide scaffolds and proteasome inhibitory potencies. G4-1 a 135-substitutive pyrazole derivative is our current lead candidate displaying its anticancer activity in multiple cancer cel lines including cell lines resistant to bortezomib or carfilzomib. In addition to having excellentmetabolic stability G4-1 displayed promising anticancer efficacy and safety profiles in vivo. Withthe goal of further improving the potency and other pharmacokinetic properties of G4-1 to be suitable for oral dosing we propose the following aims: 1) to extend our lead optimization effortsin developing more potent proteasome inhibitors with improved drug-like properties 2) to investigate the cytotoxic mechanism of action of optimized non-peptide proteasome inhibitors and 3) to evaluate the in vivo anticancer efficacy safety and pharmacokinetic profiles of selected lead non-peptide proteasome inhibitors. Successful completion of the proposed work will yield novel non-peptide proteasome inhibitors that can advance to next stages of drug development efforts and ultimately lead to effective therapies for patients with MM and solid cancers.

project_terms:
Active Sites;Bioavailable;Bortezomib;Cancer Patient;Cancer cell line;Cell Line;Chemicals;Clinic;Clinical;Clinical Trials;Data;Dose;Drug Kinetics;Drug Stability;Drug Targeting;Drug resistance;Effectiveness;Enzyme Kinetics;Evaluation;FDA approved;Goals;Hematologic Neoplasms;Human;In Vitro;Lead;Libraries;Malignant Neoplasms;Malignant neoplasm of lung;Metabolic;Mind;Molecular;Multiple Myeloma;Mus;Oral;Patients;Penetration;Peptides;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Pre-Clinical Model;Predisposition;Property;Proteasome Inhibitor;Pyrazoles;Refractory;Relapse;Research;Resistance;Resistance development;Safety;Solid;Specificity;Structure-Activity Relationship;Therapeutic;Toxic effect;Translating;Velcade;Vertebral column;Work;Xenograft procedure;anticancer activity;base;cancer cell;cancer site;cell killing;chymotrypsin;cytotoxic;design;drug candidate;drug development;effective therapy;improved;in vitro testing;in vivo;in vivo Model;inhibitor/antagonist;intraperitoneal;molecular dynamics;multicatalytic endopeptidase complex;next generation;novel;novel anticancer drug;novel therapeutics;outcome forecast;pharmacophore;pre-clinical;public health relevance;scaffold;screening;small molecule;small molecule libraries;success;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  With the remarkable success of the two proteasome inhibitor drugs bortezomib and carfilzomib in treating multiple myeloma patients extensive efforts have been under way to extend their therapeutic benefits to a larger number of patients with refractory multiple myeloma and those with solid cancers. However the effectiveness of the currently available proteasome inhibitors is limited by poor in vivo stability and unwanted toxicit arising from their structural features. In the proposed study we will develop proteasome inhibitors with novel structural scaffolds thus achieving improved stability efficacy and safety profiles against human multiple myeloma and solid cancers.


application_id: 9274042
project_number: 5R21LM012274-02
administering_ic: NLM
award_notice_date: 2017-06-01
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: LM
serial_number: 012274
program_official: VANBIERVLIET, ALAN
project_start_date: 2016-06-01
project_end_date: 2019-05-31
study_section: Biomedical Informatics, Library and Data Sciences Review Committee[BLR]
contact_pi_person_id: 11081240
contact_pi: KAVULURU, VENKATA NAGA RAMAKANTH
other_pis: Not Applicable
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-06-01
project_title:
From Syntactic Relations to Semantic Predications: Porting Open Information Extraction to Biomedicine

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

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

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


application_id: 9273599
project_number: 5R01HL123358-03
project_title: A novel mechanism for ART-associated dyslipidemia and atherosclerosis
administering_ic: NHLBI
award_notice_date: 2017-05-19
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 123358
program_official: FLEG, JEROME L
project_start_date: 2015-08-01
project_end_date: 2019-05-31
study_section: AIDS Discovery and Development of Therapeutics Study Section[ADDT]
contact_pi_person_id: 8880095
contact_pi: ZHOU, CHANGCHENG
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The rise in long-term HIV survivorship as a result of the introduction of effective antiretroviral therapy (ART) over the past decades has generated new awareness of the sequelae of both HIV infection and of the therapeutics used to treat HIV patients. Accumulating evidence of comorbidities associated with HIV infection and treatment with antiretroviral (ARV) drugs includes significant dyslipidemia and elevated risk of developing atherosclerotic cardiovascular disease (CVD). The goal of this project is to investigate a novel mechanism of ART-associated dyslipidemia and cardiovascular disease (CVD). Several ARV drugs have been identified as potent agonists for the pregnane X receptor (PXR) a nuclear receptor activated by numerous drugs xenobiotic and dietary chemicals. PXR functions as a xenobiotic sensor that induces expression of genes required for xenobiotic metabolism in the liver and intestine. In the past decade the function of PXR in the regulation of drug and xenobiotic metabolism has been extensively studied by many laboratories and the role of PXR as a xenobiotic sensor has been well established. We have recently revealed the pro-atherogenic effects of PXR in animal models and demonstrated that chronic PXR activation induces hyperlipidemia in wild-type mice and increases atherosclerosis in atherosclerosis-prone apolipoprotein E-deficient (ApoE-/-) mice. Preliminary studies demonstrated that HIV protease inhibitor amprenavir activates PXR and induces hyperlipidemia in wild- type mice but not in PXR-deficient mice; furthermore follow-up study of currently used first-line ARV drugs subsequently found that these drugs activated PXR and induced PXR-mediated gene expression. The goal of this project is to generate novel mechanistic insights into ART-associated dyslipidemia and risk of CVD. Our central hypothesis is that long-term treatment with ARV drugs that activate PXR will lead to aberrant lipid homeostasis and accelerated atherosclerosis. We propose the following specific aims to test this hypothesis: 1) Determine the contribution of PXR towards the adverse effects of currently recommended ARV drugs on lipid homeostasis; 2) Define the molecular mechanisms through which PXR agonistic ARV drugs induce hyperlipidemia; and 3) Determine the impact of ARV drug-mediated PXR activation on macrophage functions and atherosclerosis development. These studies will provide critical mechanistic insights and new understandings of ART-associated dyslipidemia and CVD risk and will have direct clinical consequences for patients undergoing long-term treatment with PXR agonistic drugs.

project_terms:
Adverse effects;Agonist;Amprenavir;Animal Model;Anti-Retroviral Agents;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Awareness;CD36 gene;Cardiovascular Diseases;Cells;Chemicals;Cholesterol;Chronic;Clinical;Comorbidity;Development;Diet;Disease;Dose;Drug Regulations;Dyslipidemias;Foam Cells;Follow-Up Studies;Gene Expression;Generations;Goals;HIV;HIV Infections;HIV Protease Inhibitors;HIV therapy;Health;Heart;Homeostasis;Hyperlipidemia;In Vitro;Individual;Infection;Inflammation;Intestines;Knockout Mice;Laboratories;Lipids;Liver;Long-Term Survivors;Longevity;Lopinavir;Mediating;Modeling;Molecular;Morbidity - disease rate;Mus;Nuclear Receptors;Pathway interactions;Patients;Pharmaceutical Preparations;Pilot Projects;Protease Inhibitor;Receptor Activation;Regulation;Risk;Ritonavir;Role;SXR receptor;Signal Pathway;Testing;Therapeutic Uses;Wild Type Mouse;Xenobiotic Metabolism;Xenobiotics;absorption;antiretroviral therapy;atherogenesis;base;cardiovascular disorder risk;cholesterol transporters;defined contribution;disorder risk;drug metabolism;efavirenz;experimental study;in vivo;insight;macrophage;mortality;mouse model;non-nucleoside reverse transcriptase inhibitors;novel;pregnane X receptor;public health relevance;receptor function;scavenger receptor;sensor;survivorship;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Infection with HIV is known to elevate the risk for serious heart and arterial disease. With the advent of new generations of drugs for HIV infection the number of long-term HIV-infected patients has brought new recognitions of drug-related side effects including altered lipid profiles and even more greatly increased risk for heart and arteril disease. This study will provide important new information about the impact of HIV therapy on cardiovascular disease in patients undergoing long-term treatment with these drugs.


application_id: 9273528
project_number: 5T35ES014559-12
project_title: Summer Environmental Health Sciences Training Program
administering_ic: NIEHS
award_notice_date: 2017-04-28
opportunity_number: PA-14-016
application_type: 5
activity_code: T35
ic: ES
serial_number: 014559
program_official: SHREFFLER, CAROL A
project_start_date: 2006-04-01
project_end_date: 2021-04-30
study_section: Environmental Health Sciences Review Committee[EHS(TK)]
contact_pi_person_id: 1886009
contact_pi: PROUGH, RUSSELL ALLEN
other_pis: CAVE, MATTHEW C;MCCLAIN, CRAIG J.;SRIVASTAVA, SANJAY
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Animal Experimentation;Appointment;Authorship;Cardiology;Clinical;Clinical Research;Conflict of Interest;Data;Dentistry;Diabetes Mellitus;Environment;Environmental Health;Funding;Future;Grant;Health;Laboratories;Lung diseases;Medical;Medical Students;Mentors;Mentorship;Metabolic Diseases;Metabolism;National Institute of Environmental Health Sciences;Obesity;Outcome;Peer Review;Physicians;Plagiarism;Positioning Attribute;Public Health;Publications;Research;Research Project Grants;Research Training;Residencies;Scientist;Specialist;Structure;Student recruitment;Students;Training;Training Programs;Training Support;Translational Research;Vertebrates;Work;base;design;ethnic disadvantage;ethnic minority population;experience;hormone regulation;human subject;interest;medical schools;non-alcoholic fatty liver;peer;peer coaching;posters;programs;responsible research conduct;skills;student training;symposium


application_id: 9273514
project_number: 5R01DK098176-04
project_title: Thrombospondin 1 in obesity associated inflammation and insulin resistance
administering_ic: NIDDK
award_notice_date: 2017-06-21
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 098176
program_official: ABRAHAM, KRISTIN M
project_start_date: 2014-08-20
project_end_date: 2021-05-31
study_section: Integrative Physiology of Obesity and Diabetes Study Section[IPOD]
contact_pi_person_id: 7837422
contact_pi: WANG, SHUXIA
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Increased accumulation of adipose tissue macrophages (ATMs) promotes obesity-associated chronic inflammation and insulin resistance. Although there have been some advances in the study of ATMs in obese condition the mechanisms underlying ATMs recruitment and activation remain to be determined. Thrombospondin 1 (TSP1) has been identified to be an adipokine and its expression levels correlate positively with human obesity adipose tissue inflammation and insulin resistance. By using TSP1 deficient mice preliminary studies revealed a novel role for TSP1 in stimulating macrophage recruitment and activation in adipose tissue that contributes to inflammation and insulin resistance resulting from high fat diet-induced obesity (DIO). Moreover TSP1 promoting macrophage migration and activation is through the N-terminal domain and the type 1 repeats to interact with receptors LRP1 and CD36 respectively. Blocking the interactions of TSP1/LRP1 and TSP1/CD36 inhibited TSP1 stimulation of macrophage function. Based on these data we hypothesize that blockade of the stimulatory effect of TSP1 on macrophage function prevents/ameliorates obesity-associated inflammation and insulin resistance. To test this hypothesis in Aim 1 tissue specific TSP1 knockout mice will be used to definitively answer the question of whether adipocyte-derived TSP1 serves as a primary chemokine to stimulate macrophage accumulation in adipose tissue and promotes the development of obesity-associated inflammation and insulin resistance. In Aim 2 utilizing the identified stimulatory domains on TSP1 as targets based on their available x-ray crystal structures new decoy peptides will be designed by structure-based computational design strategy. The inhibitory effect of decoy peptides on TSP1stimulation of macrophage function will be tested. In Aim 3 whether blocking of TSP1/CD36 interaction can prevent/ameliorate obesity-associated inflammation and insulin resistance in vivo will be tested. Together these proposed studies may lead to novel therapeutics for obesity-induced insulin resistance and metabolic complications and therefore have significant clinical relevance.

project_terms:
Address;Adipocytes;Adipose tissue;Binding;CD36 gene;Cardiovascular Diseases;Cells;Chemotactic Factors;Chronic;Crystallization;Data;Development;Diet;Disease;Fibrosis;Genotype;High Fat Diet;Human;Hypertension;In Vitro;Infiltration;Inflammation;Inflammatory;Injury;Insulin Resistance;Kidney;Kidney Diseases;Knockout Mice;Lead;Macrophage Activation;Mediating;Metabolic;Modeling;Molecular;Mus;N-terminal;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Obesity;Peptides;Phenotype;Play;Proteins;Recruitment Activity;Reporting;Resistance development;Rodent;Roentgen Rays;Role;Signal Transduction;Structure;TLR4 gene;Testing;Thrombospondin 1;Tissues;Visceral;Wild Type Mouse;adipokines;base;chemokine;clinically relevant;clinically significant;design;glucose tolerance;human subject;improved;in vivo;insulin mediators;insulin sensitivity;macrophage;migration;novel;novel therapeutics;obesity treatment;prevent;public health relevance;receptor;therapeutic target

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


application_id: 9273320
project_number: 5P50AA024337-02
project_title: Mechanisms of Alcohol-Induced Lung and Liver Injury
administering_ic: NIAAA
award_notice_date: 2017-05-01
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8305
contact_pi_person_id: 1876531
contact_pi: ROMAN, JESSE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-05-01
budget_end_date: 2018-04-30
project_terms:
Acute Lung Injury;Aging;Alcohol abuse;Alcohols;Alveolar;Animals;Antioxidants;Area;Cell surface;Cells;Chronic;Collagen;Complement Factor B;Cultured Cells;Defect;Deposition;Development;Dietary Intervention;Epigenetic Process;Epithelial Cells;Ethanol;Ethanol dependence;Extracellular Matrix;Fibroblasts;Fibronectins;Fibrosis;Functional disorder;Gene Expression;Genes;Glycoproteins;Growth Factor;Harvest;Immune;In Vitro;Income;Inflammation;Inflammatory;Injury;Interleukin-1 beta;Laboratories;Lead;Lung;Matrix Metalloproteinases;Modeling;Modification;Mus;Nicotinic Receptors;Organ;Organ Transplantation;Oxidation-Reduction;Oxidative Stress;Permeability;Phenotype;Play;Predisposition;Process;Production;Rodent;Role;Sepsis;Stress;Testing;Tissues;Transforming Growth Factors;Work;alcohol effect;cytokine;design;experience;histone modification;in vivo;indium-bleomycin;injury and repair;liver injury;lung injury;monocyte;monolayer;mortality;nutrition;problem drinker;programs;promoter;response to injury;sensor


application_id: 9273319
project_number: 5P50AA024337-02
project_title: Sulforaphane-mediated epigenetic modulation of ethanol-induced apoptosis and teratogenesis
administering_ic: NIAAA
award_notice_date: 2017-05-01
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8304
contact_pi_person_id: 7035096
contact_pi: CHEN, SHAO-YU
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-05-01
budget_end_date: 2018-04-30
project_terms:
Acetylation;Address;Alcohol consumption;Alcohols;Antioxidants;Apoptosis;Apoptotic;Attenuated;Broccoli - dietary;Cell Death;Cells;Chemicals;Congenital Abnormality;Consumption;CpG Islands;DNA Modification Methylases;Data;Development;Diet;Disease;Disease model;Embryo;Epigenetic Process;Ethanol;Fetal Alcohol Exposure;Fetal Alcohol Spectrum Disorder;Gene Expression;Gene Expression Regulation;Genes;Goals;Histone Deacetylase;Incidence;Injury;Intake;Laboratories;Lead;Malignant Neoplasms;Mediating;Mental Retardation;Methylation;Modification;Mus;Neural Crest Cell;Nutraceutical;Oral;Organ;Pathogenesis;Pathway interactions;Population;Prevention;Promoter Regions;Regimen;Role;Severities;Signal Transduction;Sulforaphane;Testing;Therapeutic;Transcriptional Activation;Vegetables;Work;alcohol exposure;antioxidant enzyme;base;effective intervention;epigenetic regulation;histone modification;in vivo;innovation;malformation;non-genetic;novel strategies;novel therapeutics;nutrition;prevent;programs;promoter;response


application_id: 9273318
project_number: 5P50AA024337-02
project_title: HDAC Mediated Epigenetic Mechanisms in Alcohol-Induced Abnormal Gut-Liver Axis
administering_ic: NIAAA
award_notice_date: 2017-05-01
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8303
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-05-01
budget_end_date: 2018-04-30
project_terms:
Acetylation;Affect;Alcoholic Liver Diseases;Alcohols;Attenuated;Automobile Driving;Bacteria;Butyrates;Carnitine O-Palmitoyltransferase;Chronic;Data;Development;Diet;Endotoxemia;Endotoxins;Enteral;Epigenetic Process;Ethanol;Fatty Acids;Fatty Liver;Functional disorder;Gene Expression;Genes;Goals;Gram-Negative Bacteria;HDAC1 gene;HDAC3 gene;Hepatic;Histone Deacetylase;Histone Deacetylase Inhibitor;Histone H3;Histones;Impairment;Inflammation;Injury;Intestines;Lactobacillus;Lactobacillus casei rhamnosus;Lead;Liver;Liver diseases;Mass Spectrum Analysis;Mediating;Modification;Molecular;Organ;Pathogenesis;Pathogenicity;Pathology;Permeability;Play;Prevention strategy;Probiotics;Prodrugs;Proteomics;Role;Testing;Therapeutic Intervention;Work;alcohol abuse therapy;alcohol effect;alcohol exposure;alcohol response;base;chronic alcohol ingestion;epigenetic regulation;feeding;histone modification;insight;interest;lipid metabolism;metabolomics;microbial;microbiome;microbiota;nutrition;probiotic supplementation;programs;promoter;therapeutic development;therapy development;translational study;treatment strategy;tributyrin


application_id: 9273317
project_number: 5P50AA024337-02
project_title: Role of Dietary Fat in Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2017-05-01
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8302
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-05-01
budget_end_date: 2018-04-30
project_terms:
Address;Affect;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Animal Model;Arachidonate 15-Lipoxygenase;Attenuated;Cations;Clinical;Data;Development;Diet;Dietary Fats;Dietary Intervention;Down-Regulation;Endotoxemia;Endotoxins;Enzymes;Experimental Animal Model;FDA approved;Genetic;Heavy Drinking;Hepatic;Human;Inflammasome;Inflammation;Inflammatory;Inflammatory Response;Inflammatory disease of the intestine;Injury;Interleukin-1 beta;Interleukin-18;Intestines;Kupffer Cells;Laboratories;Lead;Ligands;Linoleic Acids;Lipopolysaccharides;Mediating;Molecular;Morbidity - disease rate;Oral;Organ;Oxides;Pathogenesis;Pathogenicity;Pathway interactions;Patients;Permeability;Pharmacology;Play;Production;Proteins;Role;Severities;Signal Pathway;Supplementation;TRPV1 gene;Testing;Tight Junctions;Translating;Unsaturated Fats;Up-Regulation;Vanilloid;Whole Blood;base;cytokine;gut microbiome;human study;liver inflammation;liver injury;member;metabolome;monocyte;mortality;new therapeutic target;nutrition;octadecadienoic acid;overexpression;oxidation;peripheral blood;prevent;programs;receptor;saturated fat


application_id: 9273313
project_number: 5P50AA024337-02
project_title: Omics Core
administering_ic: NIAAA
award_notice_date: 2017-05-01
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8301
contact_pi_person_id: 8487327
contact_pi: ZHANG, XIANG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-05-01
budget_end_date: 2018-04-30
project_terms:
Acids;Acrolein;Affinity;Alcoholic Liver Diseases;Alcohols;Animals;Attention;Attenuated;Automobile Driving;Bioinformatics;Biological;Biotin;Blood;Blood specimen;Body Weight;Cell Line;Cells;Chronic;Complex Mixtures;Curcumin;Data;Data Collection;Data Reporting;Data Set;Development;Drug Interactions;Embryo;Endotoxemia;Ensure;Environment;Epigenetic Process;Extracellular Matrix;Feces;Fibroblasts;Gas Chromatography;Ginger;Goals;Grapefruit;Hepatic;High Pressure Liquid Chromatography;Histone Acetylation;Histones;Human Resources;Inflammation;Injury;Institution;Interleukin-2;Intestines;Lactobacillus casei rhamnosus;Liquid substance;Liver;Liver Dysfunction;Liver diseases;Lung;Lysine;Mass Spectrum Analysis;Measures;Mediating;Metabolic;Methodology;Methods;Molecular;Molecular Evolution;Mus;Neural Crest Cell;Oral;Organ;Pathogenicity;Pattern;Peptides;Performance;Post-Translational Protein Processing;Preparation;Protein Analysis;Protein Fragment;Proteins;Proteomics;Protocols documentation;Research;Research Infrastructure;Research Personnel;Resolution;Resources;Role;Sampling;Science;Services;Standardization;Sulforaphane;Techniques;Technology;Time;Tissue Sample;Tissues;Training and Education;Transcriptional Regulation;Unsaturated Fats;Urine;alcohol effect;design;exosome;histone methylation;histone modification;instrument;liquid chromatography mass spectrometry;liver injury;long chain fatty acid;male;member;metabolomics;method development;multiple reaction monitoring;nanoparticle;novel;nutrition;phosphoproteomics;programs;response;sample collection;saturated fat;sharing data;success;toxicant;tributyrin;two-dimensional


application_id: 9273311
project_number: 5P50AA024337-02
project_title: Pilot Project Core
administering_ic: NIAAA
award_notice_date: 2017-05-01
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8300
contact_pi_person_id: 2047731
contact_pi: ARTEEL, GAVIN E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-05-01
budget_end_date: 2018-04-30
project_terms:
Address;Advisory Committees;Alcohol Nutrition;Alcohol abuse;Alcohols;Awareness;Chronic Disease;Clinical;Clinical Research;Development;Educational Status;Environment;Evaluation;Extramural Activities;Funding;Goals;Health;Heart Diseases;Individual;Injury;Institution;Intervention;Kentucky;Lung diseases;Malignant Neoplasms;Mentors;Mission;Modeling;New Agents;Obesity;Organ;Patients;Peer Review;Pilot Projects;Prevention;Recruitment Activity;Research;Research Personnel;Resources;Role;Rural;Schools;Science;Secure;Study Section;Substance abuse problem;Translational Research;United States National Institutes of Health;Universities;alcohol abuse therapy;alcohol research;base;black lung;health disparity;improved;innovation;medically underserved;novel;nutrition;prevent;programs;stroke;translational scientist


application_id: 9273310
project_number: 5P50AA024337-02
project_title: Administrative Core
administering_ic: NIAAA
award_notice_date: 2017-05-01
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8308
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-05-01
budget_end_date: 2018-04-30
project_terms:
Advisory Committees;Alcohol Nutrition;Alcohol abuse;Alcohols;Archives;Area;Arts;Basic Science;Bioinformatics;Biometry;Budgets;Cancer Center;Clinical;Clinical Investigator;Collaborations;Communities;Conflict (Psychology);Consultations;Country;Development;Education;Engineering;Ensure;Epigenetic Process;Faculty;Functional disorder;Funding;Grant;Health;Health Sciences;Individual;Injury;International;Intervention;Intestines;Lead;Leadership;Letters;Medicine;Organ;Pilot Projects;Proteomics;Public Health Nurses;Public Health Nursing;Reporting;Research;Research Personnel;Research Proposals;Resources;Role;Schools;Science;Social Work;Specialized Center;Structure;Students;Therapeutic Intervention;Time;Tissue Sample;Tissues;Universities;alcohol research;body system;cohesion;high school;innovation;interest;medical schools;member;metabolomics;multidisciplinary;next generation;novel;nutrition;programs;training opportunity


application_id: 9273306
project_number: 5P50AA024337-02
project_title: The Role of Nutrition in the Development/Progression of Alcohol-Induced Organ Injury
administering_ic: NIAAA
award_notice_date: 2017-05-01
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
program_official: DUNTY, JR, WILLIAM
project_start_date: 2016-05-15
project_end_date: 2021-04-30
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
project_terms:
Acute Lung Injury;Alcohol Nutrition;Alcohol abuse;Alcohol consumption;Alcoholic Liver Diseases;Alcohols;Apoptosis;Area;Award;Biomedical Engineering;Carnosine;Cause of Death;Chronic;Clinical Research;Collaborations;Communities;Development;Diet;Dietary Intervention;Education;Epigenetic Process;Extracellular Matrix;FDA approved;Faculty;Functional disorder;Funding;Goals;Health;Health Care Costs;Histone Deacetylase;Histone Deacetylase Inhibitor;Immune system;Industry;Injury;Institution;Intervention;Intestines;Knowledge;Laboratories;Lead;Lipids;Liver;Mental Retardation;Morbidity - disease rate;National Institute on Alcohol Abuse and Alcoholism;New Agents;Nutraceutical;Nutritional;Organ;Pilot Projects;Predisposition;Prevention;Probiotics;Process;Proteomics;Research;Research Personnel;Research Training;Resources;Rewards;Role;S-Adenosylmethionine;Steatohepatitis;Structure of parenchyma of lung;Sulforaphane;Therapeutic Intervention;Training and Education;Translating;Translational Research;United States;United States National Institutes of Health;Universities;Unsaturated Fats;alcohol abuse therapy;alcohol intervention;alcohol research;base;cohesion;college;high school;improved;interdisciplinary approach;interest;metabolomics;mortality;multidisciplinary;new therapeutic target;next generation;novel;nutrition;offspring;prevent;programs;public health relevance;success;therapeutic target


application_id: 9272847
project_number: 5R01CA177679-04
project_title: The role of adipocyte/macrophage fatty acid binding protein in breast cancer deve
administering_ic: NCI
award_notice_date: 2017-05-22
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 177679
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2015-07-09
project_end_date: 2019-05-31
study_section: Tumor Microenvironment Study Section[TME]
contact_pi_person_id: 9620088
contact_pi: LI, BING
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Despite recent improvements in survival rates breast cancer still kills nearly half-a-million women worldwide annually. As the two most predominant populations in breast cancer stroma macrophages and adipocytes play central roles in breast tumorigenesis and progression. Thereby modifications in these cells can greatly influence tumor behavior. The objectives of this proposal are to determine the role of adipocyte/macrophage fatty acid binding protein (A-FABP) in promoting breast cancer development through simultaneously targeting both macrophages and adipocytes and to develop inhibitors to modulate A-FABP activity for breast cancer therapy. A-FABP abundantly expressed in macrophages and adipocytes has been identified as a central regulator of metabolic and inflammatory pathways in these cells. Our preliminary studies demonstrate that A- FABP is significantly upregulated in human and murine breast/mammary cancers. In response to tumor stimulation cytoplasmic A-FABP expression is markedly elevated in tumor associated macrophages (TAMs) whereas circulating A-FABP is mainly released by adipocytes. More importantly A-FABP deficiency alters macrophage phenotype and protects mice against mammary tumor growth and metastasis. While obesity is associated with poor prognosis and increased mortality in patients with breast cancer the mechanistic basis for this association remains unclear. We found that obesity increases A-FABP in both cytosol and the circulation and promotes breast cancer progression. It is likely that A-FABP links obesity and breast cancer via regulating macrophage and adipocyte functions. Thus we hypothesize that A-FABP as an unidentified link underlying the obesity-breast cancer association promotes the development of breast cancer through enhancing pro-tumor functions of macrophages and adipocytes. Therefore modulating A-FABP activity will represent a novel strategy for breast cancer therapy. Specific Aim 1 will answer how cytoplasmic A-FABP regulates macrophage functions for breast cancer progression. We hypothesize that upregulation of cytoplasmic A-FABP in TAMs reprograms the macrophages to promote a pro-tumor environment. Specific Aim 2 will delineate how circulating A-FABP released by adipocytes contributes to breast cancer invasion. Experiments will designed to test the hypothesis that circulating A-FABP released by adipocytes favors breast cancer progression by inducing oncogenic signaling in tumor cells to increase their aggressiveness. Specific Aim 3 will address whether obesity promotes breast cancer through increasing A-FABP expression. We propose that A-FABP represents an unidentified factor in obesity to promote breast cancer risk and inhibition of A-FABP with inhibitors may suppress breast cancer development and progression. In conclusion the data collected will help us unravel the critical role of A-FABP in breast cancer development and identify specific A- FABP inhibitors for potential breast cancer therapy.

project_terms:
Address;Adipocytes;Animal Model;Basic Science;Behavior;Biopsy;Blood Circulation;Breast;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Treatment;Breast Cancer therapy;Cells;Clinical;Cytosol;Data;Development;Environment;Human;Infiltration;Inflammatory;Killings;Link;Mammary Neoplasms;Mediating;Metabolic;Mitotic Cell Cycle;Modification;Molecular;Mus;Neoplasm Metastasis;Obesity;Oncogenic;Pathway interactions;Patients;Phenotype;Physiological;Play;Population;Protein Deficiency;Regulation;Role;Signal Transduction;Survival Rate;Testing;Tissues;Treatment Efficacy;Up-Regulation;Woman;Women's Health;anticancer research;breast tumorigenesis;cancer risk;design;experimental study;fatty acid-binding proteins;immunoregulation;in vivo;inhibitor/antagonist;link protein;macrophage;malignant breast neoplasm;mortality;mouse model;neoplastic cell;novel strategies;outcome forecast;protein expression;public health relevance;response;tumor;tumor growth;tumor progression;tumorigenesis

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


application_id: 9272473
project_number: 3U19AI113182-03S1
project_title: Griffithsin-based Rectal Microbicides for PREvention of Viral ENTry (PREVENT)
administering_ic: NIAID
award_notice_date: 2016-06-10
opportunity_number: RFA-AI-13-023
application_type: 3
activity_code: U19
ic: AI
serial_number: 113182
suffix: S1
program_official: TURPIN, JIM A
project_start_date: 2014-07-01
project_end_date: 2019-06-30
study_section: ZAI1-BP-A(M2)
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH E
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): PREVENT (Pre-exposure prevention of viral entry) is an Integrated Preclinical/Clinical Program with the overall goal to provide a comprehensive set of data to facilitate an informed decision on whether the antiviral lectin Griffithsin (GRFT) shoul progress in the topical microbicides pipeline. GRFT has broad-spectrum activity against human immunodeficiency viruses (HIV) types 1 and 2 herpes simplex virus type 2 (HSV-2) and hepatitis C virus (HCV). Our product target is a rectal microbicide gel containing GRFT as the primary Active Pharmaceutical Ingredient (API). People who practice unprotected receptive anal intercourse (URAI) represent the population most vulnerable to HIV-1 transmission due to the high preponderance of HIV target cells in the rectal mucosa and mucosal trauma commonly associated with RAI. As a small protein unlikely to be widely used in antiretroviral therapy the GRFT PREVENT program stands apart from pre-exposure prophylaxis (PREP) strategies that involve small molecule antiretrovirals (ARV) which bear the potential risk of selecting for viral resistance. Broad spectrum antiviral prophylaxis that is offered by lubricant gels containing GRFT offer a much needed option for HIV infected people who require effective PREP against superinfection with HIV as well as HSV-2 HCV and other enveloped viruses that are transmitted by URAI. Three Projects and four Cores will all contribute to the Specific Aims of the Overall Program. Aim 1: Provide a comprehensive set of safety and efficacy data to facilitate a Go/No-Go decision on progression of GRFT rectal microbicides into later stage clinical studies. Aim 2: Manage and integrate the PREVENT U19 Program with the goals and expectations of the NIH sponsor and future sponsors and investors in GRFT microbicide gel products.

project_terms:
Address;Affect;Animals;Antiviral Agents;Anus;Cells;Characteristics;Chemistry;Clinical;Clinical Protocols;Clinical Research;Clinical Trials;Colorectal;Critical Pathways;Cyclic GMP;Data;Data Set;Development;Documentation;Dosage Forms;Dose;Drug Delivery Systems;Drug Kinetics;Ensure;Epidemic;Epithelium;Feedback;Formulation;Future;Gel;Goals;Guidelines;HIV;HIV-1;Hepatitis C virus;Human;Human Herpesvirus 2;Immune response;Immunoassay;Immunohistochemistry;Institution;Investigational Drugs;Investigational New Drug Application;Laboratories;Lead;Lectin;Licensure;Local Microbicides;Lubricants;Macaca mulatta;Manufacturer Name;Marines;Measures;Methodology;Methods;Modeling;Mucous Membrane;Nucleosides;Participant;Peptides;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Phase I Clinical Trials;Placebo Control;Placebos;Population;Practice Management;Pre-Clinical Model;Preclinical Testing;Prevention;Process;Prophylactic treatment;Proteins;Proteomics;Randomized;Recombinants;Recovery;Recruitment Activity;Regulation;Research;Reverse Transcriptase Inhibitors;Risk;Safety;Sampling;Services;Staging;Superinfection;System;TMC120-R147681;Techniques;Technology Transfer;Tenofovir;Topical application;Toxicology;Trauma;United States Food and Drug Administration;United States National Institutes of Health;Universities;Ursidae Family;Vagina;Viral;Virus;Work;analytical method;antiretroviral therapy;base;clinical efficacy;condoms;design;efficacy testing;expectation;immunotoxicity;inhibitor/antagonist;innovation;irritation;manufacturing process;medical schools;meetings;microbicide;microbiome;next generation;non-nucleoside reverse transcriptase inhibitors;novel;novel therapeutics;pre-clinical;preclinical efficacy;preclinical safety;preclinical study;prevent;product development;programs;prototype;public health relevance;rectal;rectal microbicide;safety study;safety testing;small molecule;transcriptomics;transmission process;viral resistance;volunteer

public_health_relevance:
PUBLIC HEALTH RELEVANCE: PREVENT is an integrated preclinical/clinical project that aims to determine whether a gel based drug delivery system for a potent broad spectrum antiviral protein Griffithsin is safe in preclinical models and a pre-phase I clinical trial. Preclinical studies are also designed to predict whether the microbicide we develop might be effective against HIV-1 transmission. A safe and effective rectal microbicide gel would have significant impact on preventing expansion of the domestic and global HIV-1 epidemic.   
   
Project 1: PREVENT Program Critical Path Project   
Project Leader (PL): Tuse Daniel   
   
DESCRIPTION (as provided by applicant): The overall goal of the Critical Path Project ("CPP"; Project 1) is to coordinate cGMP-compliant Drug Substance and Drug Product manufacture and release manage preclinical safety and efficacy studies and develop and integrate regulatory documents for submission of an Investigational New Drug (IND) application to US Food and Drug Administration (FDA) in support of an investigative clinical trial. Project 1 will establish the manufacturing methodology for the new product and help define an accelerated development path towards demonstration of clinical efficacy and product licensure. The novel active pharmaceutical ingredient (API) of our microbicide is Griffithsin (GRFT) a marine algal natural protein for which we have developed and scaled an efficient recombinant manufacturing process. GRFT is the most potent HIV-1 entry inhibitor known and also has high activity against other viruses that may be co-transmitted with HIV such as HSV-2. Through our collaborators in the PREVENT Program we have produced more than 200 g of GRFT for research use and developed effective and stable microbicide gel dosage forms. These prototype gels have been evaluated for initial safety in an ex vivo human explant system physicochemical stability and API release characteristics with very encouraging results. In Aim 1 of this Project we will apply methods we have successfully used to date to further optimize the API manufacturing process for maximum yield and recovery. The manufacturing process will be brought to compliance with FDA cGMP guidelines together with supporting documentation. Compliant API will be used to cGMP manufacture the rectal gel final dosage form optimized in Core B. In Aim 2 the safety and tolerability of the rectal gel product will be determined in regulation-compliant toxicology in 3 animal species with endpoints to include topical and systemic safety tolerability irritation sensitivity and immunotoxicity. Preliminary Chemistry Manufacturing and Controls (CMC) and safety information along with a draft clinical Protocol will be discussed with FDA in a pre-IND meeting. Agency feedback will assist us in finalizing an IND application activation of which by FDA will allow us to initiate a first-in-humans clinical trial f the GRFT microbicide in Project 3.


application_id: 9272459
project_number: 5R24OD021479-02
project_title: Developing Regeneration Resources for a Model Amphibian
administering_ic: OD
award_notice_date: 2017-03-27
opportunity_number: PAR-13-252
application_type: 5
activity_code: R24
ic: OD
serial_number: 021479
program_official: MIROCHNITCHENKO, OLEG
project_start_date: 2016-06-01
project_end_date: 2020-03-31
study_section: Special Emphasis Panel[ZRG1-CB-J(55)R]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: THORSON, JON SCOTT
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This Multi-PD/PI application seeks to develop resources that will better enable studies of a highly regenerative amphibian the Mexican axolotl (Ambystoma mexicanum). There is need to probe axolotl regeneration more deeply with the same powerful approaches that have proven so effective in genetic model organisms. Specific Aim 1 will accomplish the first chemical genetic screen of axolotl regeneration using an embryo tail regeneration assay. Using pre-feeding axolotl embryos that are efficiently reared in micro-titer plates up to 10000 soluble chemicals from commercial clinical-stage and novel natural products libraries will be tested for impact on tail regeneration. Preliminary data show that the chemical screen and tail regeneration assay are likely to identify new molecules that impact regeneration. Positive hits from this screen including previously identified inhibitors of Wnt Tgf and Fgf signaling will be reported to the community and investigated further under Specific Aim 2 using cellular and transcriptional approaches. In particular assays will be developed to assess chemical effects on formation of the wound epidermis which acts as an early signaling center in the recruitment of progenitor/stem cells. Also assays will be developed to assess cellular proliferation and de- differentiation two processes that are associated with endogenous regeneration. Genes found to be expressed differently between control and chemically treated embryos will be prioritized for knock out using the CRISPR/Cas9 method. For each gene target two gRNA pairs will be designed and injected into single cell axolotl embryos. Embryos will be reared to assess viability and then administered tail amputations to confirm CRISPR gene editing and test for regeneration competence. Embryos associated with CRISPRs that block or cause abnormal regeneration will be prioritized for founding stable lines. Specific Aim 3 will generate fluorescent reporter lines to assay signaling activity through major pathways known to function in regeneration and will also compare efficacies of two methods for developing gene-specific reporter lines using as tester loci genes already known to mark cell populations critical for regenerative responses (neural stem cells glia muscle satellite cells). The chemical and genetic hits and biological information arising from this model will be shared through a community website (Sal-Site). The proposed transgenics will be distributed by the Ambystoma Genetic Stock Center. Overall this project integrates expertise across chemical screening pharmacology histology transcription transgenesis and vertebrate biology to discover reagents and develop tools that are needed to enhance the axolotl for stem cell and regenerative biology.

project_terms:
Accelerometer;Amaze;Ambystoma;Ambystoma mexicanum;Amphibia;Amputation;Animal Model;Biological;Biological Assay;Biological Process;Biology;CRISPR/Cas technology;Candidate Disease Gene;Cell Lineage;Cell Proliferation;Cells;Chemical Models;Chemicals;Chimeric Proteins;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Communities;Competence;Couples;Data;Development;Embryo;Event;FDA approved;Future;Gene Expression;Gene Targeting;Gene Transfer Techniques;Genes;Genetic;Genetic Models;Genetic Screening;Genetic Transcription;Guide RNA;Histology;Hormone use;Injectable;Insertional Mutagenesis;Investigation;Knock-out;Libraries;Mediating;Methods;Modeling;Molecular;Molecular Profiling;Monitor;Mosaicism;Muscle satellite cell;Mutagenesis;Mutation;Natural Products;Natural regeneration;Neuroglia;Organism;Pathway interactions;Pharmacology;Phenotype;Population;Process;Production;Reagent;Recruitment Activity;Regenerative Medicine;Regenerative response;Reporter;Reporting;Research;Research Infrastructure;Resources;Salamander;Signal Pathway;Signal Transduction;Site;Somatic Cell;Stem Cell Research;Stem cells;Tail;Testing;Thyroid Hormones;Time;Tissues;Transforming Growth Factor beta;Transgenic Organisms;Tretinoin;Vertebrate Biology;blastema;chemical genetics;comparative efficacy;design;dosage;feeding;in vivo;inhibitor/antagonist;mutant;nerve stem cell;network models;notch protein;novel;progenitor;promoter;public health relevance;regenerative;screening;stem cell biology;tool;web site;wound;wound epidermis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This application seeks to develop resources that will better enable the fundamental study and application of a highly regenerative amphibian the Mexican axolotl (Ambystoma mexicanum). Specifically this project integrates unique infrastructure and expertise to discover reagents and develop tools that are needed to enhance the axolotl for stem cell biology and regeneration.


application_id: 9272346
project_number: 5U01AG050636-03
project_title: Preclinical Development of a Selective Suppressor of Neuroinflammation for MCI/AD
administering_ic: NIA
award_notice_date: 2017-05-19
opportunity_number: PAR-12-015
application_type: 5
activity_code: U01
ic: AG
serial_number: 050636
program_official: PETANCESKA, SUZANA
project_start_date: 2015-09-01
project_end_date: 2019-04-30
study_section: ZAG1-ZIJ-6(M1)
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: WATTERSON, DANIEL MARTIN
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is one of the largest global public health crises facing us today and is predicted to increase dramatically over the next decades as the world population ages. There are no effective therapies available to prevent cure or slow the progression of disease and new therapeutic strategies are urgently needed. Our strategy is to target the abnormal glial activation and neuroinflammation that arises early in AD progression and that is becoming of increased interest as a therapeutic target. Dysregulated neuroinflammation responses such as proinflammatory cytokine overproduction from abnormally activated glia are seen early in AD and are thought to be a key contributor to downstream synaptic dysfunction and cognitive deficits. This raises the possibility that selective targeting of the dysregulated cytokine response may be a useful therapeutic approach. This application seeks three years of support to bring to IND status a novel experimental therapeutic (termed MW151) whose pharmacological mechanism of action is to attenuate disease- and injury-induced proinflammatory cytokine overproduction thereby reducing downstream synaptic and cognitive dysfunction in multiple animal models of CNS disorders. MW151 is a water-soluble orally bioavailable CNS-penetrant small molecule with outstanding chemical and metabolic stability. MW151 has been extensively de-risked through several non-GLP pharmacological and toxicology screens and a GMP compatible production scheme has been developed. However MW151 has not progressed into final GLP preclinical development. Our hypothesis is that MW151 will be a successful candidate for development as an oral formulation for the future treatment of individuals with mild cognitive impairment due to AD. With U01 funding we will pursue three aims that are milestone-driven with clear Go/No Go decision criteria. Aim 1: Perform preclinical pharmacokinetics and safety assessment of MW151. Aim 2: Produce GMP drug substance (API) and oral drug product. Aim 3: Obtain an IND for future first-in-human clinical investigations. This project will advance development of a promising drug candidate with the potential to prevent the transition to or slow the progression of AD. In addition successful development of MW151 could have broad clinical applications not only to AD but to a number of other CNS disorders where proinflammatory cytokine dysregulation is part of the pathophysiology progression mechanism.

project_terms:
Acute Brain Injuries;Address;Advanced Development;Adverse event;Age;Alzheimer's Disease;Animal Model;Attenuated;Bioavailable;Biological Availability;Brain;Canis familiaris;Central Nervous System Diseases;Cessation of life;Chemicals;Clinical;Clinical Data;Clinical Research;Cognitive deficits;Communication;Critical Care;Dementia;Development;Disease;Disease Progression;Dose;Drug Kinetics;Formulation;Functional disorder;Funding;Future;Guidelines;Head;Homeostasis;Human;Impaired cognition;Individual;Injury;Intellectual Property;Intervention;Intravenous;Investigation;Investigational Drugs;Investigational Therapies;Knock-in Mouse;Medicine;Metabolic;Modeling;Neurodegenerative Disorders;Neuroglia;Neurological outcome;Neurons;Oral;Oral Administration;Outcome;Parents;Pathology;Pathway interactions;Patients;Penetration;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Pharmacology and Toxicology;Phase;Phase I Clinical Trials;Physiological;Population;Production;Public Health;Publishing;Rattus;Reporting;Risk;Role;Route;Safety;Scheme;Stress;Study models;Synapses;Testing;Therapeutic;Time;TimeLine;Toxicogenetics;Toxicology;Traumatic Brain Injury;Water;Work;analog;attenuation;base;clinical application;clinical investigation;cytokine;drug candidate;effective therapy;experience;glial activation;healthy volunteer;humanized mouse;interest;mild cognitive impairment;neuroinflammation;novel;novel therapeutic intervention;phase 2 study;pre-clinical;preclinical development;prevent;progressive neurodegeneration;public health relevance;response;safety study;small molecule;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed preclinical campaign addresses the urgent and critical need to develop effective disease-modifying therapeutics to prevent delay and treat AD. We are proposing to develop a promising drug candidate that in animal models attenuates the overactive proinflammatory cytokine aspect of neuroinflammation and prevents the downstream neuron dysfunction and cognitive impairment that characterizes neurodegenerative disease progression. The aims are focused on FDA guidelines for investigational new drug status.


application_id: 9272159
project_number: 1UH2NS100606-01
project_title: Small vessel disease biomarkers in a longitudinally-followed "stroke-belt" cohort
administering_ic: NINDS
award_notice_date: 2016-09-23
opportunity_number: RFA-NS-16-020
application_type: 1
activity_code: UH2
ic: NS
serial_number: 100606
program_official: MCGAVERN, LINDA
project_start_date: 2016-09-30
project_end_date: 2018-07-31
study_section: Special Emphasis Panel[ZNS1 SRB-T (19)]
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
other_pis: JICHA, GREGORY A
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Affect;Alzheimer's Disease;Amyloid beta-Protein;Angiogenic Proteins;Applications Grants;Basic Science;Biological Markers;Brain;Brain Pathology;Cerebral small vessel disease;Cerebrovascular Disorders;Cerebrum;Clinical;Clinical Trials;Cognition;Cognitive;Comorbidity;Data;Dementia;Diagnosis;Diffusion;Disease;Disease Progression;Elderly;Ensure;Foundations;Functional disorder;Genetic Polymorphism;Genotype;Goals;Image;Impaired cognition;Individual;Inflammatory;Injury;Interleukin-12;Kentucky;Liquid substance;Longitudinal Studies;Magnetic Resonance Imaging;Measures;Microvascular Dysfunction;Monitor;Neurofilament-M;Participant;Pathology;Patients;Perfusion;Phase;Plasma;Population;Process;Proteins;Public Health;Recording of previous events;Research;Research Infrastructure;Research Personnel;Resource Sharing;Risk;Sampling;Severities;Spatial Distribution;Spin Labels;Subcategory;TNF gene;Therapeutic Intervention;Time;Translational Research;United States National Institutes of Health;Universities;Vascular Cognitive Impairment;Vascular Diseases;White Matter Hyperintensity;Work;abstracting;accurate diagnosis;biomarker development;candidate marker;cerebrovascular;cohort;effective intervention;experience;imaging biomarker;imaging modality;medical specialties;member;multidisciplinary;neuropsychological;pre-clinical;predictive marker;prognostic;response;sharing data;stroke;success;targeted treatment;tau Proteins;therapeutic development;vascular contributions


application_id: 9271948
project_number: 5R01DE023206-05
project_title: Structure-based design and synthesis of peptidominetics targeting P. gingivalis
administering_ic: NIDCR
award_notice_date: 2017-05-31
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: DE
serial_number: 023206
program_official: LUNSFORD, DWAYNE
project_start_date: 2013-07-23
project_end_date: 2019-05-31
study_section: Special Emphasis Panel[ZRG1-MOSS-F(02)M]
contact_pi_person_id: 1859425
contact_pi: DEMUTH, DONALD R
other_pis: LUZZIO, FREDERICK ANTHONY
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 diseases such as atherosclerosis and rheumatoid arthritis. Although several organisms have been identified as periodontal pathogens a recent study suggests that Porphyromonas gingivalis may be a "keystone" pathogen that disrupts host-microbe homeostasis by inducing populational changes in the biofilm that contribute to inflammation. Thus preventing P. gingivalis colonization of the oral cavity may not only limit periodontitis and have a positive impact on severe systemic diseases improving the health status of a significant portion of the adult population. The ideal niche for P. gingivalis is the subgingival pocket but prior to colonizing this niche P. gingivali associates with streptococci in the supragingival biofilm. This interaction is an ideal target for therapeutic intervention since it represents one of the first events that promotes colonization of the oral cavity by P. gingivalis. The basic science discoveries that form the foundation for this proposal arise from our previous work showing that the association of P. gingivalis with streptococci is driven by a protein-protein interaction. Our mechanistic characterization of this interaction led to the development of a peptide (designated BAR) that potently inhibits P. gingivalis colonization of the oral cavity. However peptides are not ideal therapeutic agents due to their high cost of production and susceptibility to degradation. This application addresses these shortcomings using a structure-based approach to design and synthesize non-peptide mimetics of BAR. The first Aim will apply our knowledge of the structure and mechanism of action of BAR to design and chemically synthesize inexpensive peptidomimetic inhibitors of P. gingivalis colonization using an innovative synthetic approach called click chemistry. The second Aim of this study will assess the biologic activity of the compounds to identify lead compounds that potently inhibit P. gingivalis adherence to streptococci and the formation of P. gingivalis biofilms. The most active lead compounds will subsequently be tested in Aim 3 for inhibition of P. gingivalis virulence using an animal model of periodontitis. Thus our prior mechanistic studies uniquely position us to design and develop new potential treatments for periodontitis and its systemic sequelae by specifically targeting P. gingivalis colonization of theoral cavity. The inherent stability and low toxicity of click chemistry products may also facilitat the rapid formulation of compounds in a mouth rinse varnish or toothpaste that will be suitable for clinical testing.

project_terms:
Address;Adherence;Adult;Alveolar Bone Loss;Animal Model;Antigens;Atherosclerosis;Back;Basic Science;Biochemical;Biological Assay;C-terminal;Chemicals;Chemistry;Cost of Illness;Coupled;Development;Disease;Enzyme-Linked Immunosorbent Assay;Event;Expenditure;Formulation;Foundations;Health;Health Status;Heart Diseases;Homeostasis;I-antigen;Infection;Inflammation;Knowledge;Lead;Measures;Mediating;Microbe;Microbial Biofilms;Minor;Modeling;Modification;Molecular Models;Mouth Diseases;Mus;Nuclear Receptors;Nuclear Structure;Oral cavity;Organism;Outcome;Peptide Hydrolases;Peptides;Periodontitis;Population;Porphyromonas gingivalis;Positioning Attribute;Predisposition;Prevention;Production;Protein Binding Domain;Proteins;Publishing;Rheumatoid Arthritis;Streptococcus;Streptococcus gordonii;Structural Models;Structural Protein;Structure;Systemic disease;Testing;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Tissues;Toothpaste;Toxic effect;United States;Variant;Varnish;Virulence;Work;base;cost;cycloaddition;design;feeding;flexibility;improved;inhibitor/antagonist;innovation;microbial;microbial host;molecular modeling;mouse model;multidisciplinary;oral biofilm;oral streptococci;pathogen;peptidomimetics;polypeptide;prevent;protein protein interaction;public health relevance;research clinical testing;scaffold;small molecule;subgingival biofilm;synthetic peptide;targeted treatment;three dimensional structure

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 treatment and prevention of periodontitis exceed $15 billion. Although periodontitis is primarily manifest in the oral cavity it is also associated with systemic illnesses such as heart disease and rheumatoid arthritis. An important recent study suggests that Porphyromonas gingivalis may be a "keystone" pathogen that induces populational changes in the oral biofilm that contribute to inflammation. Thus limiting P. gingivalis colonization of the oral cavity may have positive impact periodontal health and on other systemic illnesses associates with periodontitis. This multidisciplinary study will use molecular modeling and protein structural information to design and synthesize compounds that specifically target the periodontal pathogen P. gingivalis and block its colonization of the oral cavity. These compounds represent new potential therapies that may control or prevent periodontitis and the systemic illnesses associated with this disease.


application_id: 9271938
project_number: 5R01CA172379-05
project_title: Novel resveratrol analogs and colorectal cancer treatment
administering_ic: NCI
award_notice_date: 2017-05-22
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 172379
program_official: EMENAKER, NANCY J
project_start_date: 2013-08-06
project_end_date: 2020-05-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 7013090
contact_pi: LIU, CHUNMING
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States and accounts for more than 50000 deaths per year. CRC is initiated by mutations of adenomatous polyposis coli (APC) and b-catenin genes which result in abnormal activation of the Wnt signaling pathway. Inhibition Wnt signaling is essential for CRC prevention and treatment; however prior efforts along these lines were not successful because of the side effects displayed by these inhibitors. We hypothesize that natural products and their analogs are ideal therapeutic agents if they target key pathways in CRC and possess minimal toxicity. Recently we reported that resveratrol which is found in the skin of red grapes significantly inhibits Wnt signaling. Resveratrol is reported to have anti-cancer activity and not toxic at concentration (1 gram/day) effective for CRC treatment but resveratrol has a half-life in vivo that limits its utility as a therapeutic agent. Supported by anR21 grant (RCA139359) we designed and synthesized resveratrol analogs called FlDAS agents that are more potent than resveratrol in cell based assays and possess significantly greater half-lives than reservatrol. One particular compound FlDAS-4r inhibits growth of human CRC xenografts in nude mice and is well tolerated in mice. Using a biotinylated biologically active form of FIDAS-4r we identified methionine adenosyltransferase 2A (MAT2A) as the direct target for resveratrol analogs. Our central hypothesis is that resveratrol and its analogs inhibit MAT2A and regulate the levels and metabolism of S-adenosylmethionine (SAM) thus inhibiting Wnt signaling and the proliferation of CRC cells. To further define the molecular mechanism of these anti- cancer agents and to develop these agents for CRC treatment and chemoprevention we will pursue the following three Specific Aims: 1) To define the mechanisms regulating inhibition of MAT2A by FIDAS agents; 2) To delineate the mechanisms of how FIDAS agents inhibit CRC cell growth; and 3) To characterize novel FIDAS agents using in vivo mouse models.

project_terms:
APC gene;Adenomatous Polyposis Coli;Adverse effects;Affect;Anabolism;Animal Model;Antineoplastic Agents;Binding;Biological;Biological Assay;Biological Process;CTNNB1 gene;Cancer Cell Growth;Cancer Etiology;Cell Proliferation;Cell model;Cells;Cessation of life;Chemopreventive Agent;Colorectal Cancer;Development;Disclosure;Drug Targeting;Epigenetic Process;Event;Family;Funding;Future;Generations;Genes;Genetic Transcription;Genetically Engineered Mouse;Goals;Grant;Grapes;Growth;Half-Life;Human;Hypermethylation;In Vitro;Lead;Legal patent;Malignant Neoplasms;Malignant neoplasm of liver;Mediating;Metabolism;Modeling;Molecular;Molecular Target;Mus;Mutation;Natural Products;Neoplasms;Nude Mice;Oral;Organoids;Pathway interactions;Patients;Polyamines;Publications;Reporting;Resveratrol;Role;S-Adenosylmethionine;Skin;Testing;Therapeutic;Therapeutic Agents;Toxic effect;United States;WNT Signaling Pathway;Xenograft procedure;analog;base;beta catenin;cancer cell;cancer chemoprevention;cancer prevention;cancer therapy;colon carcinogenesis;colorectal cancer prevention;design;drug candidate;efficacy testing;experimental study;histone methylation;in vivo;inhibitor/antagonist;invention;methionine adenosyltransferase;mortality;mouse model;nanomolar;novel;promoter;public health relevance;small hairpin RNA;targeted treatment;tumor metabolism;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer death in the United States. Resveratrol and its novel analogs are promising agents for colorectal cancer prevention and treatment. This project will explore novel mechanisms of action of resveratrol analogs using cell and animal models of colorectal cancer in order to develop better chemopreventive and therapeutic agents in the future.


application_id: 9271178
project_number: 5R01DA037621-03
project_title: Long-term activation of spinal opioid analgesia after inflammation
administering_ic: NIDA
award_notice_date: 2017-05-31
opportunity_number: PA-13-118
application_type: 5
activity_code: R01
ic: DA
serial_number: 037621
program_official: LIN, YU
project_start_date: 2015-08-15
project_end_date: 2018-03-31
study_section: Special Emphasis Panel[ZRG1-IFCN-B(03)M]
contact_pi_person_id: 1879170
contact_pi: TAYLOR, BRADLEY K.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Severe tissue injury generates central sensitization (increased responsiveness of CNS nociceptive neurons to normal or sub-threshold afferent input) that contributes to hyperalgesia. Latent sensitization (LS) is a silent form of central sensitization that persists after tissue has healed and overt signs of hyperalgesia have resolved. LS can be revealed with opioid receptor antagonists or inverse agonists that "rekindle" or reinstate hyperalgesia. Thus pain remission during LS is likely maintained by tonic opioid receptor activity that masks the pronociceptive components of LS. LS is important because it primes nociceptive systems such that when inhibitory systems fail a pain episode ensues. A key first step in understanding LS is to demonstrate the translational significance and we now show that the opioid receptor inverse agonist naloxone can reinstate experimental pain when delivered 1 wk after the resolution of secondary hyperalgesia following first degree thermal injury. Specific Aim 1 tests the hypothesis that burn or surgery triggers LS and long-term opioid analgesia in humans. To further study the neurobiological mechanisms of LS we will also use a mouse model that is long-lasting powerful broad range repeatable and translates to human studies. We found that mu opioid receptor (MOR) inverse agonists reinstated behavioral and molecular signs of hyperalgesia even when administered months after tissue injury and this required NMDA receptor activation of adenylyl cyclase type 1 (AC1). Our results are important because they suggest that any event such as stress that interferes with MOR analgesia during LS will lead to relapse of hyperalgesia in chronic pain syndromes in humans. Specific Aim 2 tests the hypothesis that MOR constitutive activity (MORCA) and/or activation of MOR delta (DOR) or kappa (KOR) receptors by opioid peptides in the DH or rostroventromedial medulla maintains endogenous analgesia and thereby restricts LS to a state of pain remission. Specific Aim 3 determines the extent to which MORs inhibit spatially coordinated neural activity in the DH (using an innovative 64-channel field recording system) and synaptic strength in presynaptic terminals of primary afferent nociceptors or on DH neurons (using patch clamp electrophysiology) during LS. Specific Aim 4 then tests whether MORs specifically inhibit spinal NMDA receptor subunits (GluN2A or GluN2B) and/or Epac1 (exchange protein directly activated by cAMP recently found to contribute to peripheral pain senstization) to block pain during LS. Completion of this project will bring us closer to our long-term goal of alleviating chronic pain b either: a) facilitating endogenous opioid analgesia thus restricting LS within a state of remission; or b) extinguishing LS altogether for example with a selective AC1 or Epac1 inhibitor. Our general model and hypothesis shares similarities with the concept of allostasis: a pathologically-elevated balance between opposing processes (MOR and LS) that facilitate each other by mutual feedback. Our long-term vision is a new conceptual strategy for chronic pain therapy to restore homeostasis where there is neither central sensitization nor MOR compensatory responses.

project_terms:
Absence of pain sensation;Acute;Acute Pain;Address;Adenylate Cyclase;Affect;Affective;Agonist;American;Analgesics;Behavior;Behavioral;Binding;Brain;Burn injury;Chronic;Cutaneous;Cyclic AMP;Cyclic AMP Receptors;Cyclic AMP-Dependent Protein Kinases;Data;Development;Disease remission;Dynorphins;Electrophysiology (science);Endogenous Opiates;Enkephalins;Equilibrium;Event;Excitatory Postsynaptic Potentials;Failure;Feedback;Goals;Guanosine Triphosphate;Hernia;Homeostasis;Human;Hyperalgesia;Inflammation;Inguinal region;Injectable;Injury;Knockout Mice;Knowledge;Masks;Mediating;Messenger RNA;Modeling;Molecular;Mus;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;NR1 gene;Naloxone;Naltrexone;Nature;Neurons;Nociception;Nociceptors;Operative Surgical Procedures;Opioid;Opioid Analgesics;Opioid Peptide;Opioid Receptor;Pain;Pain management;Pathologic;Phase;Phosphorylation;Physical Function;Physiologic pulse;Posterior Horn Cells;Postoperative Pain;Presynaptic Terminals;Process;Productivity;Protein Isoforms;Proteins;Public Health;Publishing;Quality of life;Receptor Activation;Relapse;Resolution;Science;Secondary Hyperalgesias;Signal Transduction;Site;Slice;Spinal;Spinal Cord;Stress;Synapses;Synaptosomes;Syndrome;System;Testing;Tissues;Translating;Traumatic injury;Vision;Work;adenylyl cyclase 1;allostasis;central sensitization;chronic pain;cost;dorsal horn;healing;heat injury;inhibitor/antagonist;innovation;mental function;mouse model;mu opioid receptors;naltrexol;neurobiological mechanism;pain behavior;patch clamp;peripheral pain;prevent;public health relevance;receptor;relating to nervous system;repaired;response;spinal nerve posterior root;spontaneous pain;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Chronic pain is a public health problem which affects the physical and mental functioning quality of life and productivity of over 100 million Americans costing $600 billion dollars annually. Our recent work suggests that our body's own natural opioid pain killers exert an extremely powerful and very long-lasting ability to prevent chronic pain. This project seeks to elucidate the molecular mechanisms that create this pain relief system such as opioid systems being stuck in a constant "ON" state and to demonstrate its importance in humans after suffering from a traumatic injury.


application_id: 9270974
project_number: 1P30ES026529-01A1
project_title: Pilot Project Program
administering_ic: NIEHS
award_notice_date: 2017-05-01
opportunity_number: RFA-ES-16-001
application_type: 1
activity_code: P30
ic: ES
serial_number: 026529
suffix: A1
study_section: Environmental Health Sciences Review Committee[EHS (P3)]
subproject_number: 7095
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-05-01
project_terms:
Advertisements;Advertising;Appalachian Region;Area;Award;Budgets;Categories;Clinical Sciences;Collaborations;Communities;Data;Development;Dimensions;Discipline;Disease;Ecology;Electronic Mail;Emerging Technologies;Ensure;Environmental Exposure;Environmental Health;Environmental Medicine;Evaluation;Faculty;Fostering;Funding;Funding Opportunities;Generations;Goals;Grant;Human Biology;IACUC;Institutional Review Boards;Investigation;Kentucky;Leadership;Legal patent;Manuscripts;Mission;Monitor;National Institute of Environmental Health Sciences;Pilot Projects;Publishing;Research;Research Personnel;Research Support;Resources;Scientist;Supervision;System;Time;Translational Research;United States National Institutes of Health;Universities;Work;career;community organizations;design;early-career faculty;electronic data;experience;faculty support;high risk;improved;innovation;interest;meetings;new technology;next generation;novel;programs;research study;success;synergism;web site


application_id: 9270973
project_number: 1P30ES026529-01A1
project_title: Community Outreach and Engagement Core
administering_ic: NIEHS
award_notice_date: 2017-05-01
opportunity_number: RFA-ES-16-001
application_type: 1
activity_code: P30
ic: ES
serial_number: 026529
suffix: A1
study_section: Environmental Health Sciences Review Committee[EHS (P3)]
subproject_number: 7094
contact_pi_person_id: 1906116
contact_pi: HAHN, ELLEN J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-05-01
project_terms:
Academic Training;Acute;Address;Advocacy;Air;Appalachian Region;Area;Area Health Education Centers;Awareness;Basic Science;Cardiovascular Diseases;Chemicals;Child health care;Chronic Obstructive Airway Disease;Colorectal Cancer;Communication;Communities;Community Health;Community Outreach;Complex;Cor pulmonale;Decision Making;Development;Diabetes Mellitus;Disease;Ecology;Educational Background;Educational workshop;Employment;Enrollment;Ensure;Environmental Exposure;Environmental Health;Environmental Risk Factor;Event;Exposure to;Focus Groups;Goals;Healthcare;Heavy Metals;Interest Group;Kentucky;Knowledge;Laws;Lead;Link;Malignant Neoplasms;Malignant neoplasm of lung;Metabolic Diseases;Mining;Mission;Modality;Modeling;Nature;Obesity;Outcome;Particulate;Plague;Positioning Attribute;Poverty;Radon;Recording of previous events;Research;Research Personnel;Resources;Rivers;Rural;Science;Trust;Voice;Work;career development;dissemination research;early life exposure;health literacy;malignant breast neoplasm;member;operation;organizational structure;outreach;population health;programs;research data dissemination;self reliance;social media;success;water quality;web site;working group


application_id: 9270972
project_number: 1P30ES026529-01A1
project_title: Analytical Services Core
administering_ic: NIEHS
award_notice_date: 2017-05-01
opportunity_number: RFA-ES-16-001
application_type: 1
activity_code: P30
ic: ES
serial_number: 026529
suffix: A1
study_section: Environmental Health Sciences Review Committee[EHS (P3)]
subproject_number: 7093
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-05-01
project_terms:
Address;Analytical Chemistry;Appalachian Region;Area;Award;Big Data;Biological;Biological Assay;Biological Markers;Biometry;Complex;Consultations;Core Facility;Coupled;Data;Data Analyses;Data Analytics;Data Set;Detection;Diet;Disease;Ecology;Educational workshop;Ensure;Environmental Exposure;Environmental Pollutants;Evaluation;Exposure to;Feasibility Studies;Flame Retardants;Funding;Goals;Grant;Hand;Health;Individual;Informatics;Investments;Ions;Kentucky;Laboratories;Life Style;Mass Spectrum Analysis;Measurement;Measures;Metal exposure;Methods;Monitor;Outcome;Pesticides;Pharmacologic Substance;Pilot Projects;Plasticizers;Plastics;Polychlorinated Biphenyls;Polymers;Preparation;Property;Quality Control;Reproducibility;Research;Research Design;Research Infrastructure;Research Personnel;Resources;Sampling;Schedule;Services;Smoking;Statistical Data Interpretation;Statistical Methods;Technical Expertise;Technology;Training;Training and Education;United States National Institutes of Health;Universities;Use Effectiveness;analytical method;cost effectiveness;data archive;design;disorder risk;experience;improved;in vitro Model;instrument;instrumentation;member;metabolomics;method development;outreach;pollutant;programs;quality assurance;small molecule;stable isotope;statistics;validation studies


application_id: 9270971
project_number: 1P30ES026529-01A1
project_title: Integrative Health Sciences Facility Core
administering_ic: NIEHS
award_notice_date: 2017-05-01
opportunity_number: RFA-ES-16-001
application_type: 1
activity_code: P30
ic: ES
serial_number: 026529
suffix: A1
study_section: Environmental Health Sciences Review Committee[EHS (P3)]
subproject_number: 7092
contact_pi_person_id: 6457660
contact_pi: BAUER, JOHN ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-05-01
project_terms:
Address;Affect;Air;Analytical Chemistry;Animal Model;Animals;Appalachian Region;Area;Basic Science;Biological;Biological Models;Biometry;Cancer Center;Cell Culture Techniques;Cells;Clinical;Clinical Informatics;Clinical Research;Clinical Sciences;Coal;Communication;Communities;Complex;Cor pulmonale;Core Facility;Development;Disadvantaged;Disease;Ecology;Elements;Environmental Health;Environmental Risk Factor;Evaluation;Exposure to;Fostering;Funding;Gases;Geology;Goals;Health;Health Sciences;Heavy Metals;High Prevalence;Institution;Integrative Medicine;Interest Group;Intervention Studies;Kentucky;Life;Link;Malignant Neoplasms;Mass Spectrum Analysis;Metabolic Diseases;Mining;Modeling;Outcome;Particulate;Pediatric Hospitals;Pilot Projects;Poisons;Population;Population Research;Population Sciences;Population Study;Public Health;Public Health Practice;Radon;Recruitment Activity;Research;Research Activity;Research Design;Research Infrastructure;Research Personnel;Research Project Grants;Research Proposals;Resources;Rivers;Rural Health;Rural Population;Sampling;Scientist;Services;Specimen;Structure;Support System;Time;Tobacco smoke;Tobacco use;Toxicology;Translational Research;United States;Universities;Work;base;career;clinical practice;data management;design;early life exposure;epidemiology study;flexibility;hazard;health disparity;improved;instrumentation;interest;laboratory equipment;lung injury;member;patient oriented;pre-clinical research;programs;research and development;success;tobacco exposure;translational study


application_id: 9270970
project_number: 1P30ES026529-01A1
project_title: Administrative Core
administering_ic: NIEHS
award_notice_date: 2017-05-01
opportunity_number: RFA-ES-16-001
application_type: 1
activity_code: P30
ic: ES
serial_number: 026529
suffix: A1
study_section: Environmental Health Sciences Review Committee[EHS (P3)]
subproject_number: 7091
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-05-01
project_terms:
Affect;Appalachian Region;Applications Grants;Area;Award;Clinical;Collaborations;Communication;Communication Research;Communities;Community Outreach;Cor pulmonale;Core Facility;Data;Decision Making;Development;Disadvantaged;Disease;Ecology;Effectiveness;Employment;Ensure;Environment;Environmental Health;Environmental Impact;Environmental Risk Factor;Event;Goals;Group Meetings;Health;Health education;Individual;Interest Group;Journals;Kentucky;Leadership;Life;Malignant Neoplasms;Measures;Medicine;Metabolic Diseases;Mission;Monitor;Newsletter;Outcome;Pilot Projects;Play;Population;Process;Productivity;Program Development;Publications;Records;Research;Research Infrastructure;Research Personnel;Resource Sharing;Resources;Retreatment;Role;Rural Population;Science;Scientist;Series;Socioeconomic Status;Strategic Planning;Time;Training;Translations;Universities;career;career development;citizen science;college;design;innovation;interest;meetings;member;operation;programs;skills;success


application_id: 9270931
project_number: 3P50DA005312-26S1
project_title: CDART - Center for Drug Abuse Research Translation
administering_ic: NIDA
award_notice_date: 2016-05-26
opportunity_number: PAR-10-189
application_type: 3
activity_code: P50
ic: DA
serial_number: 005312
suffix: S1
program_official: LLOYD, JACQUELINE
project_start_date: 1992-09-30
project_end_date: 2018-06-30
study_section: ZDA1-EXL-T(02)P
contact_pi_person_id: 1884463
contact_pi: BARDO, MICHAEL T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Drug abuse is a significant health-related problem and novel preventive intervention strategies are needed to address this problem. The Center for Drug Abuse Translation (CDART) is a prevention center responding to the NIDA "Center of Excellence" (PA-10-189). CDART proposes to determine the biologically-based facets of personality that increase risk for drug abuse and to test different preventive interventions that target these multiple risk-related facets. The central theme of CDART is that: (1) sensation seeking involves the reward relevant dopamine system and is most closely related to initiation of use; (2) disinhibition involves the inhibition-relevant prefrontal cortex and is most closely relatd to escalation of use; and (3) urgency or mood-based rash action involves the stress-relevant amygdala and is most closely related to problem use. CDART hypothesizes that prevention interventions may be maximally effective if they are tailored specifically to these risk-related facets. Three integrated research projects are proposed; one will use laboratory rats and two will use college students transitioning from adolescence to young adulthood. Using neurochemical and electrophysiological techniques in rats as well as neuroimaging techniques in humans the basic neural mechanisms that mediate these different risk-related facets will be assessed. Humans varying in risk-related facets also will be tested for their response to drugs of abuse under controlled laboratory conditions. This basic research will be translated into the application of prevention in small-scale efficacy trials. An especially innovative aspect of the proposed work is that it will test the hypothesis that individuals high in urgency will be more responsive to an intervention that promotes emotional self-regulation (i.e. mindfulness training) relative to an intervention tailored to high sensation seekers. In addition to the specific researc proposed in the 3 research projects an administrative core a statistics/psychometrics core and a training/pilot program core will further synergize the projects. An outreach component also is proposed to enhance the bi-directional transfer of information between basic scientists and prevention practitioners. The long-range goal is to improve the design and implementation of targeted anti-drug preventive interventions.

project_terms:
Address;Adolescence;Advocate;Amygdaloid structure;Basic Science;Cessation of life;Characteristics;Communities;Development;Disease;Disinhibition;Drug abuse;Educational workshop;Electrophysiology (science);Emotional;Environment;Esthesia;Exanthema;Faculty;Funding;Goals;Health;Health Care Costs;Human;Human Resources;Impulsivity;Individual;Individual Differences;Informal Social Control;Information Dissemination;Institution;Intake;International;Intervention;Investigation;Laboratories;Laboratory Rat;Leadership;Life;Mediating;Mission;Moods;National Institute of Drug Abuse;Personality;Pharmaceutical Preparations;Positioning Attribute;Prefrontal Cortex;Prevention;Prevention Research;Preventive Intervention;Principal Investigator;Professional Organizations;Psychometrics;Public Health;Publications;Publishing;Rattus;Research;Research Institute;Research Personnel;Research Project Grants;Resources;Rewards;Risk;Science;Scientist;Series;Stress;Structure;Techniques;Testing;Training;Translating;Translational Research;Translations;Work;base;design;dopamine system;drug abuse prevention;drug of abuse;drug use vulnerability;efficacy trial;evidence base;improved;innovation;interdisciplinary collaboration;intervention program;mindfulness;neurobehavioral;neurochemistry;neuroimaging;neuromechanism;next generation;novel;outreach;programs;psychologic;psychosocial;public health relevance;relating to nervous system;response;social;statistics;substance use prevention;symposium;university student;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  This research is relevant to public health because drug abuse continues to be a major preventable disorder. Intervening early in life prior to the beginning of dysfunctional drug intake would have life-long positive health consequences thus reducing health costs and the likelihood of early death.    
   
CENTERS CHARACTERISTICS:


application_id: 9269679
project_number: 3U54OH007547-14S1
project_title: Southeast Center for Agricultural Health and Injury Prevention-Renewal
administering_ic: NIOSH
award_notice_date: 2016-05-07
opportunity_number: PAR-11-022
application_type: 3
activity_code: U54
ic: OH
serial_number: 007547
suffix: S1
program_official: DEARWENT, STEVE
project_start_date: 2001-09-30
project_end_date: 2016-09-29
study_section: ZOH1-EEO(51)R
contact_pi_person_id: 8216047
contact_pi: MANNINO, DAVID
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The Southeast Center for Agricultural Health and Injury Prevention at the University of Kentucky (UK) proposes to continue serving as a NIOSH Agricultural Center for 2011-2016. The Center founded in 1992 is one of seven Centers of excellence in the UK College of Public Health. Our location on a land-grant campus allows substantive trans-disciplinary collaboration within this renewal from disciplines including agriculture public health epidemiology engineering education social work communications economics nursing medicine and Cooperative Extension. We propose 9 projects: 3 are comprehensive R01 research; 2 are R18 prevention/intervention; 1 is an ROS education/translation project and 3 are R18 education/translation projects. The application includes an administrative/planning core and separate strategic plans for outreach pilot/feasibility studies and evaluation. The Center's theme "Trans-disciplinary approaches to agricultural safety and health in the Southeast" is further distinguished by our emphasis on serving limited resource and vulnerable farm populations while addressing persistent and emerging agricultural occupational safety concerns. The region served by the Center will continue to be the 10 southeastern states of AL FL GA KY MS NC SC TN VA and WV. With this renewal the Southeast Center expects to have a substantial impact on the following priorities: Hispanic farmworker safety and work organization; tractor overturns; cancer incidence in farmers/cancer surveillance; hazards in aquaculture; the personal operational and societal costs of injuries and the cost-effectiveness of prevention; safety communication in the logging industry; nurses' education service and clinical practice in farm safety and health; graduate education in agricultural occupational safety and health and Native American farm safety. While projects are based in our 10-state region each holds wider relevance as well as real potential for national impact. The Center benefits from a strong institutional commitment and support from 9 colleges within the University of Kentucky system at the Lexington campus. The Center also enjoys substantive collaboration with researchers at Auburn University Wake Forest University the Northeast Center for Agricultural & Occupational Health and diverse grassroots stakeholders.

public_health_relevance:
In concert with regional stakeholders and with trans-disciplinary teams of highly qualified investigators the Southeast Center for Agricultural Health and Injury Prevention has developed an integrated mutually reinforcing package of research prevention/intervention and education/translation projects aimed at achieving measurable improvements in agricultural occupational safety and health practice and outcomes.


application_id: 9268563
project_number: 5R01HL122581-04
project_title: Cardiac pathophysiology of histidyl dipeptides
administering_ic: NHLBI
award_notice_date: 2017-04-07
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: HL
serial_number: 122581
program_official: ADHIKARI, BISHOW B
project_start_date: 2014-06-01
project_end_date: 2019-04-30
study_section: Special Emphasis Panel[ZRG1-CVRS-Q(02)]
contact_pi_person_id: 11110260
contact_pi: BABA, SHAHID P
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): Myocardial ischemia and reperfusion (I/R) results in increased glycolysis changes in internal pH inflammation and elevated levels of reactive oxygen species (ROS) that contribute to I/R injury and its clinical outcomes. However a common biochemical feature of myocardial I/R is increased formation of reactive carbonyls which are generated in high abundance in the ischemic heart and their concentration is further increased upon reperfusion. Previous work has shown that increased enzymatic detoxification of these carbonyls decreases myocardial I/R injury. Nevertheless it remains unclear which carbonyls are generated during I/R and how they contribute to tissue injury. As a result the general contribution of carbonyls to myocardial I/R injury remains unclear and no specific carbonyl quenching interventions have been developed to limit I/R injury. The current project is designed to understand the role of endogenous histidyl dipeptides synthesized by the heart in preventing carbonyl toxicity during I/R. Histidyl dipeptides such as carnosine and anserine react avidly with structurally-diverse carbonyls we propose that these peptides represent a general carbonyl detoxification pathway. To test this hypothesis we will elucidate the role of histidyl dipeptides in myocardial I/R injury. Using both in situ and ex vivo models of myocardial I/R injury we will examine whether increasing myocardial levels of histidyl dipeptides either by overexpression of histidyl dipeptide synthase (HDS) in the heart or exogenous delivery will diminish tissue injury. To assess whether the cardioprotective effects of these peptides are due to increased carbonyl detoxification we will determine whether increased myocardial levels of these peptides are associated with increased carbonyl removal and excretion Our studies will also delineate the mechanism by which histidyl dipeptides affect myocardial I/R injury. Specifically we will examine whether histidyl dipeptides generated during I/R inhibit the proteasome and induce ER stress and that histidyl dipeptides decrease myocardial damage by preventing protein carbonylation and thereby attenuating proteasomal dysfunction and ER stress. Finally we will examine the relative efficacy of endogenous and synthetic histidyl dipeptides against myocardial I/R injury. For this we will compare the relative efficacy of differet endogenous histidyl dipeptides and their synthetic analogs against carbonyl toxicity and investigate whether enhanced carbonyl quenching properties of these peptides result in greater protection against myocardial I/R injury. Completion of this project will lead to the identificatio and assessment of a novel antioxidant system present in the heart and how components of this system (histidyl peptides HDS) prevent critical features of ischemia injury (carbonyl toxicity). We expect that these studies will lead to the identification of specific carbonyls that mediate I/Rinjury and how they contribute to myocardial damage. These findings might lead to the development of robust and effective interventions that could be used clinically to limit ischemic and oxidative injury in the heart as well as in other tissues.

project_terms:
Acrolein;Advanced Glycosylation End Products;Aerobic Exercise;Affect;Aldehyde Reductase;Amino Acids;Anserine;Antioxidants;Attenuated;Biochemical;Brain;Buffers;Cardiac;Cardiac Myocytes;Carnosine;Cause of Death;Clinical;Development;Dipeptides;Drug Metabolic Detoxication;Enzymes;Excision;Excretory function;Fructose;Functional disorder;Glutathione S-Transferase;Glyceraldehyde;Glycolysis;Heart;Heart Injuries;In Situ;Inflammation;Inflammatory;Injury;Intervention;Ischemia;Lead;Link;Lipids;Mediating;Mediator of activation protein;Membrane Lipids;Metabolic;Metals;Modeling;Mus;Myocardial;Myocardial Ischemia;Myocardial Reperfusion;Myocardial Reperfusion Injury;Outcome;Oxides;Pathway interactions;Peptides;Perfusion;Physiological;Process;Property;Proteins;Pyruvaldehyde;Reactive Oxygen Species;Recovery;Reperfusion Injury;Reperfusion Therapy;Role;Skeletal Muscle;Stress;System;Testing;Therapeutic;Tissues;Toxic effect;Work;adduct;aldehyde dehydrogenases;analog;base;chelation;crosslink;design;effective intervention;effective therapy;multicatalytic endopeptidase complex;myocardial damage;myocardial infarct sizing;novel;overexpression;oxidation;prevent;protein aggregation;public health relevance;sugar

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Myocardial ischemic heart disease remains leading causes of death worldwide; no effective therapy is available to attenuate ischemic injury. Histidyl dipeptides are endogenously present defense molecules that can modulate different mediators of ischemic injury and thus can act as therapeutics to prevent or treat ischemic heart injury.


application_id: 9268246
project_number: 7R01NS091146-02
project_title: Anti-Oxidant Promoting Cytokine LIF Enhances Neural Cell Survival During Ischemia
administering_ic: NINDS
award_notice_date: 2016-05-25
opportunity_number: PA-14-078
application_type: 7
activity_code: R01
ic: NS
serial_number: 091146
program_official: BOSETTI, FRANCESCA
project_start_date: 2016-05-01
project_end_date: 2019-12-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 1879898
contact_pi: PENNYPACKER, KEITH R
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): Leukemia inhibitory factor (LIF) is an anti-inflammatory cytokine that activates the expression of endogenous antioxidants in neural cells. Our laboratory has been examining the efficacy of LIF in the rodent stroke model of middle cerebral artery occlusion (MCAO) which reflects the most commonly occluded vessel in humans. We have found that LIF administered at 6 h after MCAO improves anatomical and functional outcomes in rats. Of interest this treatment reflects a 33% extension of the therapeutic window when extrapolated to the current clinical stroke window for therapy. LIF increased the expression of antioxidant proteins via Akt in cultured neurons and oligodendrocytes. Aim 1: Is the efficacy of LIF dependent on SOD? We have found total superoxide dismutase (SOD) levels are significantly elevated and protein levels of one isoform SOD3 are increased several-fold at 3 days following MCAO. In this Aim we will determine if specific SOD subtype(s) are responsible for the LIF-induced effects and determine cell-specific expression of these SOD isoforms. MCAO studies will first use knockout mice to examine the SOD subtypes and these results will then be confirmed in rats. Aim 2: Does this LIF dosing regimen translate into long-term behavioral recovery? This Aim will determine whether this treatment regimen has lasting effects. These data will be used to devise a treatment regimen to extend the short-term efficacy to long-term histological and functional recovery at 90 days post-MCAO in rats. Aim 3: Which signals are transduced following LIF activation? The efficacy of LIF is dependent on the protein kinase Akt. From analysis of antioxidant promoters the transcription factor MZF-1 is the putative transcription factor that activates their gene expression via Akt. We will use immunohistochemistry and gel shift assays to quantify their expression and promoter binding respectively in the infarct regions of rats treated with LIF after MCAO. siRNA techniques with neuronal cultures will be employed to knock down expression of this factor to validate previous findings. Aim 4: Will LIF administration be effective in elderly rats after MCAO?In this Aim we will treat elderly male and female rats in short-term studies. These studies will b used to determine if there are any age- or sex- dependent differences in LIF efficacy after MCAO. Both histological and functional recovery will be examined. This proposal is aimed to further elucidate the mechanism(s) of LIF treatment and optimize the treatment regimen for long-term efficacy. While treatment with exogenous antioxidants has failed we believe that the systemic activation of endogenous antioxidants is a better approach and could have substantial implications for treating clinical stroke.

project_terms:
Address;Age;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Behavioral;Binding;Cell Survival;Cells;Clinic;Clinical;Data;Dose;Elderly;Electrophoretic Mobility Shift Assay;Exploratory/Developmental Grant for Diagnostic Cancer Imaging;FDA approved;Female;Gene Expression;Health;Human;Immunohistochemistry;Infarction;Injury;Ischemia;Knockout Mice;LIF gene;Laboratories;Measures;Middle Cerebral Artery Occlusion;Modeling;Motor Skills;Neurologic;Neurons;Occlusion injury;Oligodendroglia;Performance;Protein Isoforms;Protein Kinase;Proteins;Public Health;Rattus;Records;Recovery;Recovery of Function;Regimen;Reperfusion Therapy;Rodent;Safety;Signal Transduction;Small Interfering RNA;Superoxide Dismutase;Techniques;Therapeutic;Tissues;Translating;Treatment Protocols;activating transcription factor;base;combat;cytokine;functional outcomes;gray matter;improved;individualized medicine;interest;knock-down;male;pre-clinical;promoter;research study;response;sex;stroke;transcription factor;treatment strategy;white matter

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Stroke is a major public health problem in the USA with only one FDA-approved treatment that has a limited treatment window. We have found that leukemia inhibitory factor (LIF) protects neural cells from stroke. The proposed experiments will identify how LIF increases the cells own antioxidants to protect it from stroke induced damage.


application_id: 9267674
project_number: 1R03DA043379-01
project_title: Epidemiology of HCV Treatment Knowledge and Utilization among Opioid Injectors in Rural Appalachia
administering_ic: NIDA
award_notice_date: 2016-09-06
opportunity_number: RFA-DA-16-015
application_type: 1
activity_code: R03
ic: DA
serial_number: 043379
program_official: DUFFY, SARAH Q
project_start_date: 2016-09-15
project_end_date: 2018-03-31
study_section: Special Emphasis Panel[ZDA1 HXO-H (14)]
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:
ABSTRACTThe overarching goal of this application submitted in response to RFA-DA-16-015 Services Planning Researchin the Appalachian Region to Address Adverse Health Consequences Associated with Increased Opioid InjectionDrug Use is to examine knowledge of new HCV pharmacotherapies and willingness to engage in HCVtreatment among rural HCV-positive people who inject drugs (PWID). In addition we propose to determine thecapacity of the current health care system to provide HCV treatment to PWID in Appalachian Kentucky. Theongoing HCV epidemic in the U.S. is largely driven by the increase in opioid injection (both prescription andheroin) in recent years. Kentucky has been particularly susceptible to the HCV/opioid abuse syndemic with HCVincidence rates that lead the nation concentrated in the rural Appalachian region. The Social Networks amongAppalachian People (SNAP) study is an ongoing NIDA-funded cohort of 675 rural Appalachian drug users forwhich vast epidemiologic data on substance use social networks and infectious disease outcomes have beencollected since 2008. It is clear that HCV is one of the most if not the most pressing issue facing rural PWIDand SNAP participants in particular. Although these increased HCV rates among PWID are highly concerningnewly approved HCV pharmacotherapies (direct-acting antivirals  DAAs) offer revolutionary advancement overprevious ribavirin/pegylated interferon--based treatment. The high rates of sustained virologic response amongthe newer DAA regimens may serve not only to cure the individual patient but may also prevent furthertransmission among PWID. However little is known about the knowledge of rural PWID around DAAs and moreimportantly whether they would even be willing to initiate treatment with these novel drugs. Further it is notknown what the capacity is to treat PWID with DAAs in rural Appalachian communities. Therefore the specificaims are: 1) To examine knowledge of the HCV clinical course and novel DAAs among HCV-positive PWID inAppalachian Kentucky; 2) To determine willingness to engage in DAA treatment among HCV-positive PWID;and 3) To establish the capacity of local health care providers to treat HCV-positive PWID with novel DAAs theresults of which will be shared via a Stakeholder Meeting. The SNAP study team is uniquely positioned to makea significant contribution to the knowledge around the potential for HCV treatment service delivery in resource-poor Appalachian Kentucky. Further it is highly likely these results will be generalizable to other areas inAppalachia (i.e. TN VA WV) with similar ongoing HCV opioid use syndemics. In addition to informing thepotential capacity for HCV service delivery in the community these data will also inform the optimal design oflocal HCV treatment programs that maximize DAA engagement rates among rural Appalachian PWID ultimatelyreducing HCV transmission rates and the overall burden of opioid injection in Appalachian Kentucky.

project_terms:
Address;Alcohol or Other Drugs use;Antiviral Agents;Appalachian Region;Area;Behavioral Model;Clinical;Communicable Diseases;Communities;Data;Data Collection;Disease Outcome;Drug user;Enrollment;Epidemic;Epidemiology;Funding;Future;Generations;Goals;Health;Health Personnel;Healthcare Systems;Hepatitis C Incidence;Hepatitis C Prevalence;Hepatitis C Transmission;Hepatitis C virus;Heroin;Individual;Injecting drug user;Injection of therapeutic agent;Insurance;Interferon-alpha;Interferons;Kentucky;Knowledge;Lead;Logistics;Morbidity - disease rate;National Institute of Drug Abuse;Needs Assessment;Opioid;Oral Administration;Outpatients;Participant;Patients;Pharmaceutical Preparations;Pharmacotherapy;Positioning Attribute;Primary Health Care;Public Health;Questionnaires;Regimen;Reporting;Research;Resources;Ribavirin;Risk;Rural;Series;Services;Social Network;Specialist;System;Time;Toxic effect;Transportation;age group;base;cohort;design;epidemiologic data;implementation research;individual patient;injection drug use;meetings;novel;novel therapeutics;opioid abuse;opioid use;peer;prevent;psychosocial;response;substance abuse treatment;success;transmission process;treatment duration;treatment program;viral transmission;willingness

public_health_relevance:
PROJECT NARRATIVETreatment with direct-acting antivirals (DAAs) has the potential to not only achieve sustained virologicresponse among HCV-positive PWID but can also curb transmission of the virus among drug injectors.However little is known about knowledge of DAA treatments among rural Appalachian PWID. The results ofthis study would inform the potential for treatment delivery as well as the circumstances around which PWIDwould be most likely to initiate treatment with DAAs in resource-poor areas.


application_id: 9267658
project_number: 1R03DA043377-01
project_title: Improving Outcomes after Prison for Appalachian PWIO: The Role of XR-NTX & Networks
administering_ic: NIDA
award_notice_date: 2016-08-29
opportunity_number: RFA-DA-16-015
application_type: 1
activity_code: R03
ic: DA
serial_number: 043377
program_official: DUFFY, SARAH Q
project_start_date: 2016-09-01
project_end_date: 2018-08-31
study_section: Special Emphasis Panel[ZDA1 HXO-H (14)]
contact_pi_person_id: 6264981
contact_pi: OSER, CARRIE BETH
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT The primary goal of this timely and significant services planning grant is to understand the facilitatingfactors and barriers in Appalachia associated with the continuum of care at re-entry for persons who injectopioids (PWIOs) who do and do not initiate extended-release injectable naltrexone (XR-NTX VivitrolAlkermes Inc.) while in prison. An ecological theoretical framework will be used to understand individualcharacteristics that predict treatment successes as well as contexts more distal to the individual includingsocial networks and institutional factors in the healthcare and justice systems. A mixed methods approach willbe used to carry out this natural history study. Building upon an existing dataset of intake assessments for allinmates participating in treatment in KY prisons this study will collect follow-up survey and personal networkdata 3-months post-release from 150 PWIOs who are returning to Appalachian counties. Qualitative datacollection includes open-ended questions in the follow-up interview for PWIOs who initiated XR-NTX in prisonand in-depth interviews with 13 social service clinicians. Specific aims include: (1) To identify the individual-level factors including XR-NTX initiation and personal (egocentric) network factors associated with continuityof care and adverse health outcomes among re-entering Appalachian PWIOs and (2) To describe individualnetwork and institutional gaps in the XR-NTX continuum of care among Appalachian PWIOs re-entering thecommunity after initiating XR-NTX in prison. This study is highly significant due to the opioid injectionepidemic high overdose rates in Appalachian Kentucky and limited available information on treatmentoutcomes during the vulnerable re-entry period when XR-NTX is implemented by a prison under naturalconditions. Innovation is high based on the lack of social network studies in Appalachian or justice-involvedpopulations the focus on networks social influence during the high-risk time after release and the Kentuckylegislative policy changes allowing prison-based XR-NTX initiation to improve offender post-releaseoutcomes. Findings will inform future process improvement efforts for the XR-NTX continuum of care inresource-limited Appalachian counties apply network science findings to improve the re-entry planningprocess and inform future R-level applications.

project_terms:
Adoption;Age;Appalachian Region;Applications Grants;Attitude;Back;Biological;Caring;Centers for Disease Control and Prevention (U.S.);Characteristics;Clinical;Communities;Continuity of Patient Care;County;Crime;Criminal Justice;Data;Data Collection;Data Set;Distal;Drug user;Economically Deprived Population;Economics;Effectiveness;Emotional;Epidemic;Equipment and supply inventories;Funding;Future;Goals;Grant;Health;Health Services Accessibility;Healthcare;Healthcare Systems;Hepatitis C;Hepatitis C Prevalence;Hepatitis C virus;Imprisonment;Individual;Injectable;Injection of therapeutic agent;Intake;Interview;Justice;Kentucky;Knowledge;Measures;Methods;Multivariate Analysis;Naltrexone;National Institute of Drug Abuse;Natural History;Opioid;Outcome;Outpatients;Overdose;Persons;Pharmaceutical Preparations;Policies;Population;Prisons;Process;Provider;Public Health;Publications;Recovery;Recruitment Activity;Relapse;Reporting;Request for Applications;Research;Research Design;Resources;Role;Rural;S-nitro-N-acetylpenicillamine;Safety;Science;Services;Social Network;Social Work;Social support;Structure;Support Groups;Surveys;System;Testing;Time;Treatment outcome;Work;addiction;adverse outcome;base;density;follow-up;high risk;implementation science;improved;improved outcome;injection drug use;innovation;medication-assisted treatment;offender;opioid use;opioid use disorder;psychosocial;recidivism;relapse risk;response;screening;success;treatment program

public_health_relevance:
PROJECT NARRATIVE This study capitalizes on a unique opportunity to examine the adoption of extended-release injectablenaltrexone (XR-NTX Vivitrol Alkermes Inc.) by one States Department of Corrections and its associatedoutcomes under real-world conditions in Appalachia an economically-deprived region with limited serviceavailability. This study will make significant contributions to public health as well as public safety in examiningif and how personal social network characteristics support or impede Appalachian offenders efforts to accesscontinuing care for opioid use disorders achieve stable recovery or desist from crime during the high-risk re-entry timeframe.


application_id: 9267404
project_number: 5R00AG044445-04
project_title: Involvement of myelin integrity in Alzheimer's disease pathogenesis
administering_ic: NIA
award_notice_date: 2017-05-12
opportunity_number: PA-11-197
application_type: 5
activity_code: R00
ic: AG
serial_number: 044445
program_official: OPANASHUK, LISA A
project_start_date: 2016-05-01
project_end_date: 2019-04-30
study_section: NSS
contact_pi_person_id: 10095513
contact_pi: BACHSTETTER, ADAM D
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This K99/R00 application provides career development training and a research plan to further the understanding of glial responses in white matter in the context of Alzheimer's disease (AD). The hypothesis to be tested is that a progressive loss of myelin integrity occurs in AD activating microglia towards a proinflammatory feed-forward loop which mediates hyperphosphorylation of the microtubule-associated protein tau and traditional AD pathology: neuritic plaques (NP) and neurofibrillary tangles (NFTs). Conventionally considered a disease of the CNS gray matter AD also has pronounced and progressive deterioration of cerebral white matter. Recent evidence suggests that changes in myelin integrity could be an early factor driving AD pathology through stimulation of inflammatory microglia activation and subsequent axonal damage. Extensive work has been done to understand the glial response in AD gray matter yet very little is known about microglia activation in AD white matter despite the fact that we and others have found a more robust activation of microglia and inflammatory response in AD white matter compared to gray matter. No studies have systematically and quantitatively examined myelin changes and inflammatory profiles as a function of disease progression. Our project will fill this gap by using human autopsy tissue and a mouse model that exhibits loss of myelin integrity to test our hypothesis. Our specific aims are: 1) Quantify the relationship between myelin integrity microglia activationproinflammatory cytokine levels and traditional measures of AD burden (NPs and NFTs) in the white matter of autopsy samples; 2) Determine if loss of myelin integrity induced by mutation in PLP in hTau mice will accelerate hyper-phosphorylated tau pathology and if this pathology can be rescued by suppressing the chronic neuroinflammation using a glia cytokine inhibitor. This project takes advantage of a strong scientific environment and extensive resources at the University of Kentucky including the Alzheimer's Disease Center clinically well-characterized autopsy cases that span the disease pathology continuum and renowned scientific expertise of an enthusiastic and committed mentoring team. A comprehensive training and career development plan has been developed for the K99 phase that includes further scientific training in oligodendrocyte/myelin biology and human neuropathology; formal coursework and participation in local national and international scientific meetings; evaluative meetings with th mentoring team; and activities designed to improve communication writing teaching and management skills. Overall there is an outstanding intellectual environment and access to relevant expertise in the applicant's project area multiple opportunities for career growth and substantial institutional commitment. This rich and supportive environment will enable a highly promising young scientist to further develop his research expertise pursue his structured training and career development plan and launch his career as an independent academic investigator.

project_terms:
Alzheimer's Disease;Amyloid beta-Protein Precursor;Animal Model;Area;Automobile Driving;Autopsy;Biochemistry;Biology;Brain;Brodmann's area;Central Nervous System Diseases;Cerebrum;Chronic;Clinical;Cognitive;Communication;Data;Deterioration;Development Plans;Diffusion Magnetic Resonance Imaging;Disease;Disease Progression;Educational process of instructing;Environment;Enzyme-Linked Immunosorbent Assay;Event;Exhibits;Genes;Genetic;Goals;Growth;Health;Human;Immunohistochemistry;Induced Mutation;Inflammation;Inflammatory;Inflammatory Response;Interleukin-1 beta;International;Kentucky;Late Onset Alzheimer Disease;MAPT gene;Measures;Medial;Mediating;Mental disorders;Mentors;Methods;Microglia;Mus;Mutation;Myelin;Myelin Proteins;Neocortex;Neuregulin 1;Neurodegenerative Disorders;Neurofibrillary Tangles;Neuroglia;Neurons;Oligodendroglia;Pathogenesis;Pathologic;Pathology;Pathway interactions;Phase;Research;Research Personnel;Research Project Grants;Resources;Role;Sampling;Scientist;Senile Plaques;Structure;Synapses;TNF gene;Temporal Lobe;Testing;Tissues;Training;Universities;White Matter Disease;Work;Writing;amnestic mild cognitive impairment;axon injury;beta-site APP cleaving enzyme 1;brain tissue;burden of illness;career;career development;collaborative environment;cytokine;design;digital;feeding;frontal lobe;genetic risk factor;gray matter;hTau Mice;human tissue;hyperphosphorylated tau;improved;inhibitor/antagonist;insight;lipid transport;meetings;mouse model;myelination;neuroinflammation;neuron loss;neuropathology;pre-clinical;public health relevance;response;skills;white matter;white matter change;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  This research project will provide fundamental insights regarding the role of microglia dysregulated neuroinflammation and white matter integrity in the temporal onset of Alzheimer's disease. Recent data suggest white matter involvement in a variety of neurodegenerative and psychiatric disease. Therefore the understanding of oligodendrocyte - microglia - neuron interaction in Alzheimer's disease could have a broad impact on our understanding of cognitive health and disease.


application_id: 9267120
project_number: 5R01AG046920-04
project_title: Novel Actions of Metformin to Augment Resistance Training Adaptations in Older Ad
administering_ic: NIA
award_notice_date: 2017-06-30
opportunity_number: PA-12-271
application_type: 5
activity_code: R01
ic: AG
serial_number: 046920
program_official: DUTTA, CHHANDA
project_start_date: 2014-09-30
project_end_date: 2019-05-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: BAMMAN, MARCAS M;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:
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 Agents;Anti-inflammatory;Area;Biological Models;Biopsy;Blinded;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;Placebo Control;Placebos;Positioning Attribute;Quality of life;Randomized;Recruitment Activity;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;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;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: 9266814
project_number: 5R00HL111215-05
project_title: Regulation of Airway Protective Behaviors
administering_ic: NHLBI
award_notice_date: 2017-03-30
opportunity_number: PA-11-197
application_type: 5
activity_code: R00
ic: HL
serial_number: 111215
program_official: TIGNO, XENIA
project_start_date: 2013-02-23
project_end_date: 2019-03-31
study_section: NSS
contact_pi_person_id: 10816268
contact_pi: PITTS, TERESA G
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The long-term goal of this project is to determine the role of tracheal and pharyngeal sensory feedback inthe regulation of cough and swallow. Our central hypothesis is that an aspiration event produces a series ofcoughs and swallows which are expressed in various behavioral interaction patterns and that there aredecipherable rules that regulate the various patterns of expression. Cough and swallow are airwayprotective behaviors. The pharyngeal phase of swallow prevents aspiration of oral material (saliva food andliquid) by epiglottal movement laryngeal adduction and clearing the mouth and pharynx. Cough is anaspiration-response behavior that clears material from the airway. Coordination of these behaviors is vital toprotect the airway from further aspiration-promoting events such as a swallow occurring during theinspiratory phase of cough. The peripheral inputs operational characteristics and primary strategies thatcoordinate cough and swallow are unknown. This lack of information impedes understanding of the deficitsin airway protection with co-occurrence of dystussia and dysphagia which occurs with diseases such asParkinson's disease and Alzheimer's disease. The Specific Aims of the project are: 1) Develop a predictivecomputational distributed network model of the central influence of tracheal sensory pathways on theexpression of cough and swallow; and 2) Identify the role of neurons in the reticular formation in processingtracheal and pharyngeal afferent feedback on cough and swallow. Our preliminary data demonstrates amodulatory effect of sensory feedback of the production of cough and swallow. Stimulation of trachealafferents by an aspiration stimulus increases the magnitude of swallows providing evidence of airwayfeedback-induced increased pharyngeal clearance. In aim 2 we will: 1) record from neurons in the reticularformation using a multi-electrode array to obtain multiple-spike train data during: a) the selective stimulationof the trachea or pharynx to elicit cough or swallow; 2) test an acute model of dystussia and dysphagiainduced by microinjection of the endogenous excitatory amino acid antagonist kynurenic acid into themedial reticular formation.

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

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


application_id: 9266681
project_number: 5R01HL127682-03
project_title: Specific Lysis for Large-Volume High-Purity Endothelial Progenitor Cell Isolates
administering_ic: NHLBI
award_notice_date: 2017-05-05
opportunity_number: PAR-13-137
application_type: 5
activity_code: R01
ic: HL
serial_number: 127682
program_official: LEE, ALBERT
project_start_date: 2015-07-15
project_end_date: 2019-04-30
study_section: Instrumentation and Systems Development Study Section[ISD]
contact_pi_person_id: 10218003
contact_pi: BERRON, BRADLEY JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: ENGINEERING (ALL TYPES)
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION:  Ischemic heart disease is the primary cause of death in both men and women globally. Ischemic heart conditions including angina and myocardial infarction are characterized by loss of blood flow to the heart tissue and reduced cardiac function both reducing quality of life and increasing mortality. Improved recovery of cardiac function following a myocardial infarction has been observed in several studies upon the injection of high concentrations of endothelial progenitor cells (EPCs) to the ischemic area. Multiple types of EPCs have been shown to play pivotal roles in the formation of new blood vessels and are promising candidates for accelerated and increased repair of ischemic tissues. Follow up studies indicate both high purity and quantity of EPCs are critical to recovery of function yet current technologies for sorting of EPCs are incapable of isolating these cells in the purity and speed required for widespread clinical use. This research grant will develop a novel technique for the isolation of EPCs which yields a high-purity isolate at high throughput. The developed technology Antigen Specific Lysis (ASL) is capable of being performed in a typical research lab setting where batches exceeding 200 mL (>1010 cells) are completed in under an hour. The proposed work will develop high speed selection modalities for the isolation of high purity functional EPCs. ASL uses targeted coatings to selectively protect EPCs while all other cells are lysed. Preliminary results demonstrate 1) antibody- initiator conjugates are capable of selectively forming a ~100 nm polymer coating on the exterior of only antigen expressing cells 2) these coatings stabilize cells in harsh environments (5% SDS) and 3) viable cells are released at high purity (>99% purity for antigen positive cells spiked into blood). This research grant drives new advances in wavelength specific polymerization and degradation for the selective protection of targeted cells and the subsequent release of cells with increased viabilityand proliferative capacity. Sequential selection for CD133+ and CD34+ cells is expected yielding a >99% pure population of EPCs. This system will also have the capability to process multiple smaller batches at one time using only standard disposable labware for cell- contacting materials. Finally the functional properties of clinically-relevant EPC populations isolated fluorescently or by ASL will be evaluated through in vitro and in vivo assays. ASL shows considerable promise as a powerful isolation technique that can be applied both clinically for the treatment of acute myocardial infarctions and in individual research settings for the analysis of rare cellular species in blood. This project is significant because in-lab isolation of large volums of cells will enable the widespread use of EPC therapy for improved cardiac function following acute myocardial infarctions. Future directions of this work include the use of ASL in the isolation of other rare cell populations (other progenitor cells circulating tumor cells) emergingin clinical research diagnostics prognostics and treatment.

project_terms:
Acute myocardial infarction;Antibodies;Antigens;Area;Automobile Driving;Biological;Biological Assay;Biological Preservation;Blood;Blood Vessels;Blood flow;CD34 gene;Capital;Cardiac;Cause of Death;Cell Separation;Cell Survival;Cell Therapy;Cells;Clinical;Clinical Research;Clinical Treatment;Cytolysis;Data;Deterioration;Diagnostic;Environment;Follow-Up Studies;Future;Goals;Growth;Heart;Hemorrhage;Home environment;Hour;In Vitro;Individual;Injection of therapeutic agent;Leukocytes;Life;Light;Magnetism;Medical;Methodology;Methods;Modality;Morbidity - disease rate;Mus;Myocardial Infarction;Myocardial Ischemia;Neoplasm Circulating Cells;Patient-Focused Outcomes;Patients;Perfusion;Play;Polymers;Polystyrenes;Population;Procedures;Process;Property;Quality of life;Recovery;Recovery of Function;Research;Research Project Grants;Risk;Role;Sampling;Science;Site;Sorting - Cell Movement;Source;Speed;Stem cells;Sterilization;System;T-Lymphocyte;Technical Expertise;Techniques;Technology;Time;Tissues;Training;Translations;Tube;Umbilical Cord Blood;Woman;Work;base;cell type;clinical application;clinically relevant;cost;hospital laboratories;improved;in vivo;irradiation;magnetic beads;matrigel;men;migration;mortality;new technology;novel;novel strategies;peripheral blood;polymerization;prognostic;prototype;public health relevance;repaired;scale up;subcutaneous;time use

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  This project develops a new approach to isolating a rare type of cell capable of repairing heart damage. This approach promises to deliver cells with fewer contaminants faster and at a lower cost than is possible today. This technology is also expected to both accelerate and reduce the cost of research across a broad spectrum of biological and medical sciences.


application_id: 9266500
project_number: 5U01MD010556-02
administering_ic: NIMHD
award_notice_date: 2017-01-19
opportunity_number: RFA-MD-15-010
application_type: 5
activity_code: U01
ic: MD
serial_number: 010556
program_official: ZHANG, XINZHI
project_start_date: 2016-04-26
project_end_date: 2020-12-31
study_section: ZMD1-DRI(03)
contact_pi_person_id: 8931964
contact_pi: SWANSON, MARK
other_pis: SCHOENBERG, NANCY E.
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-01-01
project_terms:
Administrator;Appalachian Region;Area;Behavior Therapy;Budgets;Child;Clinic;Communities;Community Health;Community Participation;Consumption;County;Diabetes Mellitus;Diet;Diet Habits;Dietary Intervention;Dietary intake;Disease;Eating;Educational workshop;Elements;Environment;Equilibrium;Evidence based program;Farming environment;Food;Food Services;Future;Health;Health Food;Health Priorities;Healthy Eating;Heart Diseases;Heart Rate;Home environment;Improve Access;Information Technology;Intake;Intervention;Kentucky;Lead;Life;Malignant Neoplasms;Marketing;Methods;Nutritional;Obesity;Outcome;Overweight;Parents;Pattern;Pilot Projects;Policies;Premature Mortality;Program Sustainability;Public Housing;Research;Research Personnel;Rural;Rural Health;Schools;Science;Services;Social Marketing;Specific qualifier value;Structure;Students;Teacher Professional Development;Techniques;Technology;Testing;To specify;Trainers Training;U-Series Cooperative Agreements;United States National Institutes of Health;Water;Youth;base;behavior change;community intervention;community organizations;cooking;design;disability;evidence base;experience;farmers markets;feeding;good diet;health disparity;health economics;improved;information gathering;innovation;innovative technologies;insight;meetings;member;multidisciplinary;next generation;novel;outreach;preference;prevent;programs;public health relevance;rural underserved;school district;skills;social;stem;stroke;sugar;sweetened beverage;teacher;theories;user-friendly


application_id: 9266345
project_number: 5R01AI087849-06
project_title: Biosynthesis of nucleoside antibiotics targeting bacterial translocase I
administering_ic: NIAID
award_notice_date: 2017-03-23
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AI
serial_number: 087849
program_official: XU, ZUOYU
project_start_date: 2011-06-15
project_end_date: 2021-04-30
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 9509796
contact_pi: VAN LANEN, STEVEN GARY
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
AIDS/HIV problem;Aldehydes;Amides;Anabolism;Anti-Bacterial Agents;Antibiotics;Bacteria;Cell Wall;Cessation of life;Chemicals;Clinic;Clinical;Data;Decarboxylation;Development;Dioxygenases;Disease;Drug resistance;Drug resistance in tuberculosis;Enzymes;Fatty Acids;Genetic Engineering;Genome;Genomics;Goals;Health;Hospitals;Human;In Vitro;Infection;Killings;Lead;Logic;Methodology;Mining;Modality;Molecular;Multi-Drug Resistance;Mus;Natural Product Drug;Nucleosides;Oxidoreductase;Pathway interactions;Peptides;Peptidoglycan;Pharmaceutical Preparations;Phosphotransferases;Process;Proteins;Public Health;Pyridoxal Phosphate;Research;S-Adenosylmethionine;Scanning;Side;Streptomyces;Structure;System;Time;Toxic effect;Transaldolase;Transketolase;Tuberculosis;United States;Uridine;Uridine Monophosphate;World Health Organization;analog;bacterial resistance;clinical application;community setting;drug discovery;enzyme pathway;expectation;improved;in vivo;in vivo Model;inhibitor/antagonist;member;methicillin resistant Staphylococcus aureus;multi-drug resistant pathogen;nanomolar;novel;nucleophilic substitution;pathogen;piperidine;prevent;scaffold;synthetic biology;tool;translocase


application_id: 9265881
project_number: 5P20GM103436-17
project_title: Genomics Core
administering_ic: NIGMS
award_notice_date: 2017-04-26
opportunity_number: PAR-12-205
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
study_section: ZGM1-TWD-7
subproject_number: 7045
contact_pi_person_id: 1969307
contact_pi: ZACHARIAS, WOLFGANG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-05-01
budget_end_date: 2018-04-30
project_abstract:
Over a decade ago the development of our bioinformatics infrastructure and capabilities was a new focus for the 2 major research institutions in KY because they had clearly recognizable needs associated with the blossoming of the 'omics' era in the life sciences. More recently health-related and biomedical informatics are seen as challenging necessities for clinical and translational research. The recognition of the importance of bioinformatics is being expressed now in the regional institutions because bioinformatics is seen to be an important requirement in the undergraduate science curriculum especially in biology and computer science classes. We will continue to encourage our KBRIN-affiliated regional institutions to integrate bioinformatics into their research and educational missions. In addition we propose to incorporate our KBRIN-outreach institutions into this 'movement' so that a larger proportion of the state's undergraduate student body can be engaged in our overall integrated genomics/bioinformatics research training/education mission.  Our operational model for bioinformatics (Table 10 above) shows that each of our 6 KBRIN primary networked institutions have resources committed to some aspect of bioinformatics whether it be in research training or education. For example Uofils committed to eliminating the bottlenecks in the data-analyses pipeline that currently hold up progress in research. UK similarly is developing a Clinical Translational Science Award (CTSA) supported bioinformatics center in support of translation/clinical research. A most impressive development in bioinformatics infrastructure among our network has to be the 50 member strong Bioinformatics and Information Science Center (BISC) at WKU. The integration of bioinformatics across departments into a Center-like organization at a regional institution has to be a first. Two faculty members associated with this center have participated for several years in the HHMI's SEA-PHAGE program a unique vehicle for introducing genomics/bioinformatics research training/education to undergraduate students. We intend to make use of their experience and expertise together with the core facilities and resources at the 2 research intensive universities to establish a KBRIN-centric genomics/bioinformatics training exercise in our outreach institutions. This will bring our functional genomics theme to an expanded network of undergraduate students (see administrative core). The bioinformatics core narrative is described under the following headings:   (1) Infrastructure (2) Research (3) Education and Training (4) The Next Five Years. (1) Infrastructure: At Uofl we initially had a major problem building interest and collaborations between interdisciplinary/multi-disciplinary investigators on multiple campuses. These include investigators in Anatomical Science and Neurobiology Biochemistry and. Molecular Biology Bioinformatics and Biostatistics on the Health Sciences campus and Chemistry Computer Engineering and Computer Science Biology Psychology and Mathematics on the main/undergraduate campus geographically separated by several miles. To enhance collaboration between these researchers and engage more biomedical researchers a bioinformatics the PI negotiated with the EVPRI and the Dean oUhe School of Medicine to develop a dedicated 1900 ft2 space and a state-of-the-art videoconferencing facility on the University of Louisville's Health Science Campus (Figure 20) in this past 5 year funding cycle. This space is fully operational and allows for KBRIN to further develop bioinformatics research capability and provide a mechanism for keeping close contact with bioinformatics researchers across campus and throughout the state. It is currently inhabited by KBRIN-affiliated researchers and can accommodate visiting faculty from other campuses and/or KBRIN institutions. We hope to grow this space as additional needs and resources become available.

project_terms:
Anatomy;Biochemistry;Bioinformatics;Biological Sciences;Biology;Biomedical Research;Biometry;Chemistry;Clinical Research;Clinical and Translational Science Awards;Collaborations;Computer software;Computers;Core Facility;Data Analyses;Development;Education;Educational Curriculum;Engineering;Exercise;Faculty;Flowers;Funding;Genomics;Geography;Health;Health Sciences;Information Sciences;Institution;Mathematics;Mediation;Mission;Modeling;Molecular Biology;Movement;Neurobiology;Output;Provider;Psychology;Research;Research Infrastructure;Research Personnel;Research Training;Resources;Science;Services;Training;Training and Education;Translational Research;Universities;Videoconferencing;Visit;biomedical informatics;clinical translation;computer science;experience;functional genomics;interest;medical schools;member;multidisciplinary;outreach;programs;undergraduate student


