# projects

application_id: 8878297
project_number: 5R25GM102776-04
project_title: Kentucky Bridge to a Biomedical Doctorate for Appalachian Students
administering_ic: NIGMS
award_notice_date: 2015-06-30
opportunity_number: PAR-11-279
application_type: 5
activity_code: R25
ic: GM
serial_number: 102776
program_official: BROWN, PATRICK
project_start_date: 2012-09-01
project_end_date: 2016-06-30
study_section: Minority Programs Review Subcommittee A[MPRC-A]
contact_pi_person_id: 1879406
contact_pi: SPEAR, BRETT
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This Bridges to Doctorate Program is an initiative by faculty at Eastern Kentucky University (EKU) and the University of Kentucky (UK) to prepare underrepresented students for careers in biomedical research. The primary target student population for this Bridges grant will be those from Appalachian counties considered to be "distressed" or "at-risk" due to their significant unemployment and poverty rates. The rationale tofocus on distressed Appalachian counties is that they comprise a large part of the EKU service region although this Bridges program will also endeavor to recruit students from other underrepresented groups. EKU and UK are ideal partners for this particular Bridges program; both are geographically situated close to the region targeted in this grant a strong relationship already exists between these two institutions and their proximity will allow Bridge students to travel easily from EKU to UK for symposia and classes. A comprehensive plan is proposed to provide strong masters level training to Bridge students while at EKU to prepare them to transition to the UK Integrated Biomedical Sciences (IBS) program where they will pursue doctoral studies in biomedical research. The aims of this proposal are to: (1) recruit talented Appalachian students to a comprehensive interdisciplinary master's program to EKU with mentoring from EKU and UK faculty (2) provide Appalachian Bridge students with the skill sets needed for continued training at the PhD level including an intensive research experience that requires a written research proposal and thesis workshops courses and seminars (3) provide opportunities to showcase the achievements of Appalachian Bridge students at local regional and national meetings and (4) develop a series of metrics to rigorously evaluate the success of the EKU-UK Bridges to Doctorate program and make adjustments/improvements when warranted. With an excellent group of faculty from EKU and UK who have agreed to serve as mentors for this program we anticipate the ability to recruit 5 students/year to this 2-year master's program.

project_terms:
Achievement;Address;Admission activity;Appalachian Region;Attention;Award;Bachelor's Degree;Biomedical Research;Books;Country;County;Data;Data Reporting;Degree Completion;Disadvantaged;Distress;Doctor of Philosophy;Doctor's Degree;Educational Background;Educational Curriculum;Educational Status;Educational aspects;Educational workshop;Ensure;Ethics;Evaluation;Faculty;Financial Support;Goals;Grant;Institution;Joints;Kentucky;Lead;Life;Master's Degree;Measures;Mentors;Methods;Online Systems;Oral;Peer Review;Population;Poverty;Preparation;Publications;Recruitment Activity;Research;Research Proposals;Resources;Rest;Risk;Schools;Science;Scientist;Series;Services;Students;Training;Travel;Underrepresented Minority;Underrepresented Students;Unemployment;Universities;Work;Writing;abstracting;base;career;college;experience;improved;meetings;news;programs;skills;sobriety;success;symposium;undergraduate education

public_health_relevance:
The goal of this Bridges to Doctorate program is to prepare underrepresented baccalaureate students with master level training at Eastern Kentucky University in preparation for transition to the Integrated Biomedical Sciences PhD program at the University of Kentucky. This Bridges program will primarily target students from Appalachia a disadvantaged region that is already a large part of the Eastern Kentucky University service region. The aims of this grant will provide comprehensive research-intensive training and includes an evaluation plan to insure that the program is achieving its stated objectives.


application_id: 8878151
project_number: 5R01AG045833-03
project_title: Circadian rhythms and melatonin signaling in the aging gastrointestinal system
administering_ic: NIA
award_notice_date: 2015-06-09
opportunity_number: RFA-AG-13-007
application_type: 5
activity_code: R01
ic: AG
serial_number: 045833
program_official: MACCHIARINI, FRANCESCA
project_start_date: 2013-08-15
project_end_date: 2016-05-31
study_section: ZAG1-ZIJ-5(M2)
contact_pi_person_id: 1862567
contact_pi: CASSONE, VINCENT M
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Biological circadian clocks are fundamental properties of all living organisms studied in any detail. In animals clocks regulate the timing of sleep: wake cycles as well as the coordination of internal body functions such as temporal variations in temperature hormone levels aspects of disease and gastrointestinal physiology. The molecular bases for biological rhythms are at least in part regulated by the expression of "clock genes" a group of genes whose complex interactions govern 24-hour rhythms. Work in our lab has demonstrated that clock genes are important in the regulation of colonic motility: the mouse colon possesses a functional circadian clock that regulates rhythms of a wide array of genes as well as intestinal motility. Further we have shown that the colonic clock regulates multiple downstream processes associated with normal intestinal motility absorption cell proliferation and cell signaling as well as potential pathological processes. In addition in mammals there is a hierarchical organization in which a central pacemaker in the hypothalamic suprachiasmatic nucleus (SCN) coordinates multiple peripheral processes as well as entrains the entire system to the light: dark cycle (LD) through specialized photic pathways. Our general hypothesis is that the global regulation of gastrointestinal circadian rhythms involves the complex bi-directional interaction of central SCN clockworks and intestinal clocks themselves and that disruption of any of these predisposes us to disease. The overall objective of this proposal is to determine the underlying mechanism through which colonic motility varies with the time of day under normal circumstances and to determine the consequences of aging on circadian patterns of colonic motility. Our hypothesis is that one factor mediating changes in intestinal function during aging is the circadian secretion of the hormone melatonin by the pineal gland and by intestinal tissues themselves. We will therefore ask what aspects of gastrointestinal rhythms are affected by normal aging (Specific Aim 1). We will then ask whether pineal melatonin influences gastrointestinal rhythmicity in young vs aged mice at several levels of biological organization. Finally we will ask whether interference in the production of melatonin affects aging aspects of gastrointestinal rhythmicity by comparing melatonin deficient strains of mice (C57/Bl6) with strains of mice capable of producing melatonin cycles (C3H) and whether these processes are dependent the known melatonin receptor molecules by comparing wild-type with MT1 receptor MT2 Receptor and MT2/MT2 receptor knockout mice.

project_terms:
Acetylcholine;Address;Affect;Age;Aging;Aging-Related Process;Animals;Biological;Biological Rhythm;Cell Proliferation;Circadian Rhythms;Colon;Complex;Data;Disease;Exhibits;Future;Gastrointestinal Physiology;Gene Expression;Gene Expression Profile;Genes;Harvest;Health;Hormones;Hour;Hypothalamic structure;In Vitro;Intestinal Motility;Intestines;Knock-out;Knockout Mice;Life;Light;Mammals;Measures;Mediating;Melatonin;Melatonin Receptors;Molecular;Mouse Strains;Mus;Muscle;Organism;Pacemakers;Pathologic Processes;Pathway interactions;Pattern;Periodicity;Peripheral;Phase;Physiological;Pineal gland;Process;Production;Property;Publishing;RNA;Receptor Melatonin MT1;Receptor Melatonin MT2;Regulation;Reporter;Role;Signal Transduction;Sleep Wake Cycle;Symptoms;System;Temperature;Testing;Time;Tissues;Variant;Wild Type Mouse;Work;absorption;aged;base;cell motility;circadian pacemaker;design;gastrointestinal;gastrointestinal function;gastrointestinal system;in vivo;interest;nano-string;normal aging;pressure;receptor;research study;response;suprachiasmatic nucleus

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Disruption of circadian clocks has deleterious effects on the health of most people especially among the aged and many of these issues are reflected in deteriorating gastrointestinal health. Further there is evidence that the pineal hormone melatonin may ameliorate symptoms associated with both sleep: wake cycles and gastrointestinal health in young and old people. This study will determine the mechanisms of circadian patterns of gastrointestinal gene expression and motility in young and old mice and will determine whether decreased melatonin signaling contributes to declining gastrointestinal health. The data may point to future treatments for normal but discomforting gastrointestinal health during aging.


application_id: 8878145
project_number: 4R01AG042419-03
project_title: Modulation of microRNA pathways by gemfibrozil in predementia Alzheimer disease
administering_ic: NIA
award_notice_date: 2016-07-13
opportunity_number: PAR-11-100
application_type: 4
activity_code: R01
ic: AG
serial_number: 042419
program_official: RYAN, LAURIE M
project_start_date: 2013-07-15
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1-BBBP-V(55)R]
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY A
other_pis: NELSON, PETER T.
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Our preliminary data indicate that miR-107 plays an important role in AD pathogenesis. Fibrates (PPAR agonists) increase miR-107 expression and down-regulated BACE1 protein an essential enzyme contributing to AD in cultured H4 cells. We plan to test our hypotheses and evaluate a potential therapy for Alzheimer's disease (AD) based on this novel microRNA (miRNA) pathway. Preclinical work in this area using animal models of AD has been thwarted by the species-specific hepatotoxicity not seen in humans. Thus human clinical trials are necessary to test this important hypothesis on the disease modifying properties of fibrates in AD. Specifically we propose an evaluation of the safety and efficacy of gemfibrozil administration on micro-RNA modulation of AD mechanisms in a parallel-design double- blind placebo-controlled study. We will evaluate both safety and target engagement of miR- 107 by gemfibrozil as well as alterations in relevant AD biomarkers. Gemfibrozil is a safe orally- administered FDA-approved drug for treatment of hyperlipidemia in aged individuals. The FDA has indicated IND exemption status for these studies. This study is designed to provide the foundation for future large-scale Phase II & III studies of fibrates in AD and AD prevention trials and represents the first attempt we are aware of designed to modulate disease progression in AD through influences on novel micro-RNA pathways. As such the proposed study represents a cutting-edge data-driven exploration of a novel disease relevant pathway that may hold promise for our global efforts targeting this major health priority among developing and developed nations.

project_terms:
5 year old;Adult;Adverse event;Age;Agonist;Alzheimer disease prevention;Alzheimer's Disease;Amyloid;Animal Model;Area;Attenuated;Biological Markers;Cells;Clinical;Clinical Trials;Clinical Trials Design;Cognition;Cognitive;Cohort Studies;Data;Dementia;Developed Countries;Development;Disease;Disease Progression;Double-Blind Method;Elderly;Enzymes;Epidemic;Evaluation;FDA approved;Fibrates;Foundations;Frequencies;Future;Gemfibrozil;Glucose;Health;Health Priorities;Hepatotoxicity;Human;Hyperlipidemia;Impaired cognition;Individual;Intervention;Lipids;Measurement;Measures;Metabolic;Metabolism;MicroRNAs;Monitor;Mus;Outcome Measure;Pathogenesis;Pathology;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Pharmacotherapy;Phase;Placebo Control;Placebos;Plasma;Play;Population;Prevention trial;Primary Prevention;Production;Property;Proteins;Publishing;Randomized;Regulation;Research;Role;Safety;Secondary Prevention;Staging;Target Populations;Testing;Visit;Work;aged;base;beta-site APP cleaving enzyme 1;cognitive testing;cost;design;drug discovery;human subject;mild cognitive impairment;novel;novel therapeutics;peptide A;placebo controlled study;pre-clinical;primary outcome;secondary outcome;tau Proteins;trial design

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Widespread recognition of the current and projected impact of the AD epidemic has spurred research into novel drug discovery efforts. This proposal seeks to further progress in this area investigating the novel actions of PPAR agonists as a disease modifying therapy in AD through their modulation of novel miRNA pathways that influence A production repurposing an existing drug therapy. As such the proposed study represents a cutting-edge data-driven low-cost exploration of a novel disease relevant pathway that may hold promise for our global efforts targeting this major health priority among developing and developed nations.


application_id: 8877662
project_number: 5R03NS089433-03
project_title: microRNA-124 restores nerurogenesis in HIV-1 associated neurocognitve disorders
administering_ic: NINDS
award_notice_date: 2015-06-16
opportunity_number: PA-13-304
application_type: 5
activity_code: R03
ic: NS
serial_number: 089433
program_official: WONG, MAY
project_start_date: 2014-07-01
project_end_date: 2017-06-30
study_section: NeuroAIDS and other End-Organ Diseases Study Section[NAED]
contact_pi_person_id: 9742546
contact_pi: PENG, HUI
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: Neurological disorders associated with HIV-1 affect 40-70% of infected individuals and is characterized as HIV-1-associated neurocognitive disorders (HAND). While antiretroviral therapy (ART) has diminished disease severity milder forms of cognitive impairment remain commonplace. It is critical to discover new therapeutic strategies to fully prevent the neurocognitive impairment. Active neurogenesis occurs throughout life and relies upon the proliferation migration and proper differentiation of neural stem/progenitor cells (NPCs). Under pathological conditions of the central nervous system (CNS) associated with neuroinflammation such as HAND monocytes/macrophages infiltrating the CNS in concert with activated resident microglia play a major role in the neurodegenerative process of HAND. Activated macrophage/microglia produce inflammatory mediators such as cytokines and chemokines affect the capacity of brain stem cells and alter neurogenesis. Various types of macrophage/microglia activation depending on the conditions can either enhance or suppress neurogenesis. Inflammation-associated M1 macrophages/microglia can inhibit neurogenesis; whereas IL-4-activated M2 macrophages/microglia can induce both neurogenesis and oligodendrogenesis. In HAND HIV-1 infection in the brain inhibits neurogenesis with generation of fewer adult NPCs in the dentate gyrus of the hippocampus. Moreover NPCs preferably differentiate into astrocytes rather than neurons. Our previous studies demonstrated HIV-1-infected and LPS-activated (M1) Macrophages inhibit neurogenesis while enhancing gliogenesis through secretion of inflammatory cytokines such as IL-1 and TNF-. microRNA- 124 (miR-124) has recently been shown to deactivate M1 macrophages and skew their polarization from an M1 toward an M2 phenotype. miR-124 may serve as a useful tool to transfer detrimental pro-inflammatory M1 macrophages/microglia to beneficial M2 macrophages/microglia. Therefore we propose the following specific aims: Aim 1: To investigate how miR-124 deactivates HIV-1-infected M1 macrophages/microglia or polarizes them to an M2 phenotype and promotes neurogenesis in vitro. Aim 2: To investigate the therapeutic potential of miR-124 for ameliorating HIV-1-infection-mediated inhibition of neurogenesis in HIV-1 encephalitis (HIVE) and humanized mouse models. We will test our hypothesis using primary human NPC macrophage/microglia culture systems and HIVE and humanized mouse models. This novel system mimics the HIV-1-infection and immune-activation of brain macrophage/microglia as they occur within the CNS during HAND. We will validate the effect of miR-124 on modulating macrophage/microglia activation and its subsequent effect on neurogenesis in vitro and in vivo. The data generated from this study will help to identify a highl innovative strategy for HAND therapy. Furthermore these findings will provide insight into a range of other neurodegenerative and neuroinflammatory diseases in which macrophage/microglia activation plays an important role.

project_terms:
Adult;Affect;Alzheimer's Disease;Astrocytes;Automobile Driving;Brain;Brain Stem;Cell Culture System;Cells;Data;Dementia;Disease;Disease Progression;Employment;Encephalitis;Functional disorder;Generations;HIV;HIV Infections;HIV-1;Human;Immune;Impaired cognition;In Vitro;Individual;Infection;Inflammation;Inflammation Mediators;Inflammatory;Interleukin-4;Life;Mediating;MicroRNAs;Microglia;Molecular;Multiple Sclerosis;Natural regeneration;Nerve Degeneration;Nerve Regeneration;Neuraxis;Neurocognitive Deficit;Neurodegenerative Disorders;Neurons;Parahippocampal Gyrus;Parkinson Disease;Pathogenesis;Pharmaceutical Preparations;Phenotype;Play;Process;Production;Reaction;Role;Severity of illness;Signs and Symptoms;Stem cells;System;Testing;Therapeutic;Tumor Necrosis Factor-alpha;adult neurogenesis;antiretroviral therapy;base;chemokine;cytokine;dentate gyrus;gliogenesis;immune activation;in vivo;injured;innovation;insight;macrophage;migration;monocyte;mouse model;nerve stem cell;nervous system disorder;neurocognitive disorder;neurogenesis;neuroinflammation;novel;novel therapeutics;overexpression;prevent;public health relevance;relating to nervous system;stem;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: HIV infection of the central nervous system can result in HIV-1-associated neurocognitive disorders (HAND) while neural stem cell dysfunction may contribute to disease pathogenesis. This proposal is aimed at understanding the molecular mechanisms that regulate neurogenesis in HAND and testing the therapeutic potential of microRNA-124 for ameliorating disrupted neurogenesis.


application_id: 8877308
project_number: 5R01AR059810-05
project_title: TAK1/TRAF6 Signaling in Skeletal Muscle
administering_ic: NIAMS
award_notice_date: 2015-06-19
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AR
serial_number: 059810
program_official: BOYCE, AMANDA T
project_start_date: 2011-07-01
project_end_date: 2017-06-30
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1917770
contact_pi: KUMAR, ASHOK
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Skeletal muscle atrophy/wasting is a devastating complication of a wide range of diseases and conditions such as aging disuse chronic obstructive pulmonary disease space travel chronic heart failure sepsis and cancer. Myogenesis is the process that is required not only for the embryonic development of skeletal muscle but it is also an important element of certain types of postnatal growth and repair of injured myofibers. Impairment in myogenesis is the critical determinant of skeletal muscle-wasting in several chronic diseases and also development of rhabdomyosarcoma in children. Although significant progress has been made to understanding the processes of skeletal muscle formation and wasting the upstream signaling events regulating skeletal muscle mass in various physiological and pathophysiological conditions remain poorly understood. We have accumulated strong evidence that supports a crucial role of TAK1/TRAF6 signaling complex in the acquisition and maintenance of skeletal muscle mass. Our preliminary studies have shown that both TRAF6 and TAK1 stimulate myogenic differentiation through novel Lysine-63-linked poly-ubiquitination mechanisms. TAK1 and TRAF6 are also required for MyoD-induced transformation of non-muscle cells into skeletal muscles. In adult skeletal muscle the activation of TAK1/TRAF6 leads to inflammation impairment in myofiber regeneration and atrophy. To clearly establish the role and delineate the mechanisms of action of TAK1/TRAF6 complex in skeletal muscle we will use genetic approaches including conditional knockout mice. Based on our preliminary data we hypothesize that signaling through TAK1 and TRAF6 is required for the development of skeletal muscle but not for maintaining differentiated phenotype. Under stress conditions the activation of TAK1 and TRAF6 stimulates catabolic pathways leading to skeletal muscle atrophy. To test this hypothesis we propose to address the following three specific aims: 1) Investigate the signaling mechanisms by which TAK1 and TRAF6 regulate myogenic differentiation in cultured myoblasts; 2) Investigate the role and cellular mechanisms by which TAK1 and TRAF6 regulate skeletal muscle development in vivo; and 3) Delineate the mechanisms by which TAK1 and TRAF6 regulates regeneration and atrophy in adult skeletal muscles. Successful completion of this project will provide critical insights into the signaling mechanisms and establish TAK1 and TRAF6 as novel molecular targets to prevent skeletal muscle loss in various muscular disorders.

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

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


application_id: 8877009
project_number: 2R15AA019795-02
project_title: Acute effects of alcohol and energy drinks on behavioral control
administering_ic: NIAAA
award_notice_date: 2015-09-14
opportunity_number: PA-13-313
application_type: 2
activity_code: R15
ic: AA
serial_number: 019795
program_official: MATOCHIK, JOHN A
project_start_date: 2010-08-01
project_end_date: 2019-08-31
study_section: Special Emphasis Panel[ZRG1 RPHB-R (80)]
contact_pi_person_id: 10253421
contact_pi: MARCZINSKI, CECILE A.
other_pis: Not Applicable
congressional_district: 04
department: PSYCHOLOGY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Underage and binge drinking (i.e. drinking to intoxication) are serious public health problems. The harms and hazards associated with excessive alcohol use in young people begs the question of what unexamined factors may be contributing to the problem. One possible variable that may be contributing to excessive drinking in young people is the new trend of consuming alcohol mixed with energy drinks (AmED). Despite a dramatic increase in the use of AmED in young people little laboratory research has examined how these drinks alter objective and subjective measures of intoxication. The working hypothesis of this proposal is that there are two key reasons that explain why consumption of AmED may be riskier than alcohol consumption alone. First consumption of AmED enhances the desire to drink alcohol. Elevated levels of desire to drink alcohol following AmED consumption may lead to risks that are both immediate (e.g. binge drinking) and long-term (e.g. alcohol dependence). Second consumption of AmED leads to disconnect between subjective state and actual behavioral impairment. Decreased perceived intoxication impairment and sedation have been observed for AmED as compared to alcohol alone. However most behavioral impairments are equally evident in response to AmED consumption as they are to alcohol alone. This disconnect between subjective state and actual behavioral impairment may explain many immediate risks of AmED use including heightened rates of accidents experienced by AmED consumers (as compared to alcohol alone consumers). This research will examine the acute effects of alcohol energy drinks AmED or a placebo beverage in social drinkers using laboratory-based methods. The effects of these beverages will be determined by performance on tasks that measure cognition motor control and the subjective effects of alcohol. The specific aims of the proposed research are: 1) to determine whether the consumption of AmED leads to more drinking when compared with the consumption of alcohol alone particularly in novice drinkers and 2) to examine the disconnect between cognitive impairment motor impairment and subjective state for AmED as compared to alcohol alone. For both aims novice drinkers will be compared to more experienced drinkers. Novice drinkers are considered to be a high risk population as they have less experience with alcohol and thus are less tolerant to alcohol. It is predicted that the differences between AmED and alcohol alone may be more pronounced in novice drinkers since novice drinkers typically experience more sedative effects from alcohol. The results of these studies should elucidate how and why AmED may be riskier than alcohol alone. Consistent with AREA program objectives this work will also expand undergraduate student research in human psychopharmacology and better enable students from Kentucky a state traditionally underrepresented in biomedical sciences to successfully advance in biomedical graduate programs.

project_terms:
Accidents;Acute;Alcohol consumption;Alcohol dependence;Alcohols;Automobile Driving;Award;Behavior Control;Behavioral Mechanisms;Beverages;Cessation of life;Cognition;Cognitive;Consumption;Cues;Data;Decision Making;Dissociation;Dose;Double-Blind Method;Exhibits;Funding;Goals;Grant;Heavy Drinking;Human;Impaired cognition;Impairment;Injury;Institution;Intoxication;Kentucky;Laboratories;Laboratory Research;Lead;Measures;Methods;Neurocognitive;Outcome;Participant;Patient Self-Report;Performance;Placebos;Population;Property;Psychopharmacology;Reaction Time;Reporting;Research;Research Project Grants;Risk;Science;Sedation procedure;Sex Behavior;Students;Taste Perception;Training;United States National Institutes of Health;Universities;Weight;Wit;Work;alcohol effect;alcohol response;alcohol risk;base;behavioral impairment;binge drinking;drinking;equilibration disorder;experience;hazard;high risk;high risk sexual behavior;impaired driving performance;motor control;motor impairment;placebo controlled study;programs;public health medicine (field);public health relevance;research study;response;sedative;social;trend;underage drinking;undergraduate student;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Underage and binge drinking (i.e. drinking to intoxication) are serious public health problems leading to a significant number of accidents injuries unsafe sexual activities and deaths. The goal of this project is to understand if the consumption of alcohol mixed with energy drinks (AmED) increases alcohol consumption and escalates binge drinking in young people to a greater degree than if alcohol is consumed alone. This research will provide information about how AmED consumption may be increasing the risks of alcohol consumption by creating a disconnect between subjective state and actual behavioral impairment thus leading a drinker to perceive that he or she is less impaired than is actually the
case.


application_id: 8876979
project_number: 1R21CA188792-01A1
project_title: Oxidized redox state a new potential biomarker for prostate cancer progression
administering_ic: NCI
award_notice_date: 2015-03-23
opportunity_number: PAR-12-096
application_type: 1
activity_code: R21
ic: CA
serial_number: 188792
suffix: A1
program_official: SCHWARTZ, ELENA IVAN
project_start_date: 2015-04-01
project_end_date: 2017-03-31
study_section: Special Emphasis Panel[ZRG1 OBT-J (55)]
contact_pi_person_id: 11588541
contact_pi: CHAISWING, LUKSANA
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: UNIVERSITY-WIDE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Prostate cancer (PCa) is an increasingly common malignancy worldwide; progression to advanced cancer is highly unpredictable resulting in a need for new clinically relevant biomarkers or diagnosis tools. A better understanding of PCa pathologic progression would allow development of more sensitive and specific biomarkers. Based on preliminary results from analyses of human PCa tissues oxidized redox state and posttranslational modification of thioredoxin 1 (Trx1) protein levels were significantly increased in primary PCa with high Gleason scores and metastatic PCa in comparison to adjacent benign tissues. We hypothesize that increased oxidized redox state is contributed to redox imbalance in PCa leading to increased production of reactive oxygen species/reactive nitrogen species oxidative DNA damage mutation of tumor suppressor genes epigenetic changes and subsequent PCa progression. To fully understand the relationship of oxidized redox state and PCa progression a first step involves determining the correlation of oxidized redox state with PCa progression in patient samples. In Specific Aim 1 human PCa-tumor microarrays with different pathological stages will be constructed stained with oxidative damage products and analyzed using Vectra/Nuance system. Additionally thiol redox couples will be measured in human prostate frozen tissues with different pathological stages compared to adjacent benign epithelial prostate tissues. Defining the redox state of PCa and its correlation with disease stage
is a necessary first step to determine 1) if oxidized redox state may potentially be used as biomarker for PCa diagnosis and 2) whether oxidized redox state is the cause or consequence of PCa progression. Biochemical analyses of redox state in Aim 1 are time-and labor-intensive and require a large amount of tissues. To overcome these problems Specific Aim 2 will evaluate if TEMPOL-enhanced MRI could potentially be used in the diagnosis of intracellular redox state of prostate cancer in vivo. TEMPOL can undergo oxidation to the corresponding oxoammonium cation by variant oxidants and its paramagnetism property can be captured by MRI. Oxidizing tissues will exhibit longer-lived MRI signal than reducing tissues. We will scan nude mice with orthotopic xenograft transplant LNCaP-luc-M6 or PC3M-luc-C6 cells to evaluate the possibility and validity of TEMPOL-enhanced MRI. To our knowledge the present proposal will be the first to 1) attempting correlate tissue redox status with the aggressiveness of PCa in patient samples and 2) use cutting edge technique TEMPOL enhanced MRI to visualize redox state and diagnosis of PCa. Upon completion of these studies a better understanding of PCa pathologic/metabolic progression may allow development of more sensitive more relevant and more specific biomarkers for early prediction or prognosis of those patients destined for clinical cancer progression.

project_terms:
4 hydroxynonenal;Acceleration;Advanced Malignant Neoplasm;Affect;Antibodies;Antioxidants;Benign;Biochemical;Biological;Biological Markers;Cancer Etiology;Cations;Cells;Cessation of life;Characteristics;Clinical;Couples;Cysteine;Cystine;DNA Sequence Alteration;Deoxyguanosine;Detection;Development;Diagnosis;Disease;Disseminated Malignant Neoplasm;Environment;Epigenetic Process;Epithelial;Epithelium;Equilibrium;Exhibits;Freezing;Future;Gleason Grade for Prostate Cancer;Glutathione;Glutathione Disulfide;High Pressure Liquid Chromatography;Human;Image;Image Analysis;Imaging technology;Immunohistochemistry;LNCaP;Lead;Life;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Metabolic;Metastatic Neoplasm to the Bone;Metastatic Prostate Cancer;Methods;Molecular;Monitor;Mortality Vital Statistics;Mus;Mutation;Neoplasm Metastasis;Nuclear;Nude Mice;Oxidants;Oxidation-Reduction;Oxidative Stress;PC3 cell line;Pathologic;Pathologic Processes;Pathological Staging;Patients;Post-Translational Protein Processing;Production;Property;Prostate;Proteins;Reactive Nitrogen Species;Reactive Oxygen Species;Relative (related person);Resolution;Role;Sampling;Scanning;Sensitivity and Specificity;Signal Transduction;Site;Staging;Staining method;Stains;Sulfhydryl Compounds;System;Techniques;Thioredoxin;Time;Tissue Microarray;Tissues;Transplantation;Tumor Suppressor Genes;Variant;Western Blotting;Xenograft procedure;base;cancer diagnosis;clinically relevant;comparative;extracellular;imaging modality;improved;in vivo;interest;liquid crystal polymer;male;men;outcome forecast;overexpression;oxidation;oxidative DNA damage;oxidative damage;prognostic;protein expression;public health medicine (field);public health relevance;response;sensor;standard of care;targeted treatment;therapeutic target;tool;tumor;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This project is relevant to public health because prostate cancer (PCa) primarily affects men and is the second leading cause of cancer deaths in males in the US. Since most PCa mortality results from metastases to the bone more effective diagnosis tool and treatment of metastases is crucial. Defining intracellular redox state (reduction/oxidation) would aid in understanding the pathological process of PCa and may lead to potentially new biomarkers that possibly be used to differentiate benign prostate tissue from less aggressive or from highly aggressive prostate cancer. Thus developing non-invasive method for accuracy determination of intracellular redox state in prostate cancer in vivo herein TEMPOL-enhanced MRI is an important step toward developing redox state as a new biomarker for aggressiveness/metastatic prostate cancer and target-therapies for clinical utility.


application_id: 8876627
project_number: 5P50DA005312-25
project_title: Examining Urgency from Neurobiology to Prevention
administering_ic: NIDA
award_notice_date: 2015-06-18
opportunity_number: PAR-10-189
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
project_end_date: 2016-06-30
study_section: ZDA1-EXL-T
subproject_number: 6590
contact_pi_person_id: 3122080
contact_pi: LYNAM, DONALD R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
Impulsive behavior is an important contributor to substance misuse which is prevalent in college samples.Our center (CDART) has identified four distinct personality traits that underlie impulsive behaviors: NegativeUrgency (NU) lack of Premeditation (PRE) lack of Perseverance (PSV) and Sensation Seeking (SS). Ourprevious work clarified the roles of SS and PRE in substance misuse in the college population. In our morerecent work NU has emerged as an important and independent contributor to substance misuse. Even aftercontrolling for SS and PRE NU is related to the onset and escalation of substance misuse and other riskybehaviors and the relation between NU and alcohol use is mediated through different mechanisms than therelations for PRE and SS. Thus our previous work clearly shows that understanding NU is criticallyImportant to the prevention of substance misuse in college populations. The four proposed studies will use arange of methods to investigate the nature of NU and the mechanisms through which it exerts its effects.Study 1 will identify underlying biological substrates of NU using fMRI. It is predicted that regions in theprefrontal cortex associated with inhibitory control will show less activation in high NU participants whenparticipants are experiencing negative affect. Study 2 will identify the affective contexts and responsecharacteristics most important to NU. It is predicted that affect will be more important to NU than to otherimpulsivity traits and that NU will manifest in impulsive behavior on tasks that include prepotent responsesand/or tasks in which an impulsive response is negatively reinforced. Study 3 will examine the interactionsamong impulsivity traits affective contexts and interpersonal contexts in predicting impulsive behavior indaily life. It is predicted that NU will be related to impulsive behavior when high NU participants are under theinfluence of negative mood. Other impulsivity traits like SS may be more responsive to interpersonalcontexts. Study 4 will test whether an intervention designed to help high NU participants respond moreadaptively to their negative affect can reduce future impulsive behavior. It is predicted that mindfulnesstraining will reduce impulsive behaviors among high NU individuals but not among high SS individuals.RELEVANCE (See instructions):Prevention of substance misuse in college samples is important because of the associated public healthrisks including death injury long-term illness and disability. Negative urgency is a strong but understudiedpredictor of substance misuse. The proposed studies will contribute to prevention research by clarifying thenature of negative urgency and the mechanisms through which it exerts its effects on substance misuse.

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


application_id: 8876626
project_number: 5P50DA005312-25
project_title: Indivicual Differences in Drug abuse Liability
administering_ic: NIDA
award_notice_date: 2015-06-18
opportunity_number: PAR-10-189
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
project_end_date: 2016-06-30
study_section: ZDA1-EXL-T
subproject_number: 6589
contact_pi_person_id: 1901822
contact_pi: KELLY, THOMAS H.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
Prevention investigators in our Center and elsewhere have demonstrated that drug abuse preventionefficacy can be significantly enhanced by targeting individuals who are most vulnerable to developingproblems and tailoring message content and format based on the characteristics of these individuals. Ourprevious work focused on drug use initiation and identified behavioral mechanisms (neurobehavioralresponse to reinforcing novel and emotional stimuli) whereby the sensation seeking dimension of impulsivityis associated with vulnerability to drug use initiation and high sensation-value contexts enhance the efficacyof prevention interventions designed to reduce drug use initiation. Further development of laboratory modelsto identify individuals who are vulnerable to drug use escalation and development of associated problemsand identifying the characteristics of these individuals that predispose them to vulnerability and/or influencethe efficacy of targeted intervention materials is of critical importance for informing and advancing the field ofdrug abuse prevention. This application proposes five years of research to continue laboratory investigationsof individual differences associated with drug use escalation and associated exposure to heavy drug use.Growing evidence suggests that vulnerability to drug-use escalation is associated with self-controlmechanisms. A multidisciplimary approach combining personality measurement with laboratory abuseliability assessment behavioral inhibition task performance and brain imaging methodologies will be used toexamine impulsivity among matched groups of tobacco and marijuana users who have either maintainedstable patterns of intermittent/light use (escalation resistant) or who have escalated to heavy use with andwithout extended histories of heavy use (escalation; escalation + extended drug exposure) to test thehypothesis that drug use escalation is associated with inhibitory neurobehavioral dimensions of impulsivity.Knowledge of the association between component dimensions of impulsivity and drug-use escalation willenhance understanding of vulnerability to and consequences of drug use escalation and thus our ability todesign more efficacious tailored and targeted drug abuse prevention interventions.RELEVANCE (See instructions):Drug abuse prevention efficacy is improved by targeting at-risk individuals and tailoring interventions basedon the characteristics of those individuals. Impulsivity is closely linked with drug abuse vulnerability. Thisproject will support prevention science by identifying the neurobehavioral dimensions of impulsivity that areassociated with vulnerability to and adverse consequences of tobacco and marijuana use escalation.

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


application_id: 8876625
project_number: 5P50DA005312-25
project_title: Individual Differences in Facets of impulsivity: An Animal Model
administering_ic: NIDA
award_notice_date: 2015-06-18
opportunity_number: PAR-10-189
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
project_end_date: 2016-06-30
study_section: ZDA1-EXL-T
subproject_number: 6588
contact_pi_person_id: 1884463
contact_pi: BARDO, MICHAEL T
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
The central theme of CDART is that multiple facets of impulsivity defined by the UPPS scale of Whitesideand Lynam (2001) are related to different paths to drug use and that these paths are associated withdifferent neurobiological mechanisms. To the extent that we can link specific behavioral tasks to thesedifferent self-report facets animal models can be used to identify critical neural mechanisms that undedie theassociation between risk-related facets and drug use. A detailed understanding of the mechanisms thatmediate the link between different facets of impulsivity and drug use will provide information about designingpreventive interventions that target these risk-related facets. The overall goal of this preclinical project is to test two overarching hypotheses: (1) individual differencesin the facets termed "urgency" "disinhibition" and "sensation seeking" are related most strongly to problemuse escalation and initiation respectively as operationally defined within an animal model of drug self-administration; and (2) individual differences in urgency disinhibition and sensation seeking are related moststrongly to differences in amygdala prefrontal cortex and nucleus accumbens respectively as measured byin vitro neurochemistry and in vivo electrophysiology. The specific aims are to: Aim 1: Develop an animal model of urgency using a task similar to that developed in humans. Aim 2: Determine if individual differences in urgency disinhibition and sensation seeking predict problemuse escalation and/or initiation of amphetamine self-administration respectively. Aim 3: Determine if individual differences in facets of impulsivity differentially predict the ability ofnondrug interventions to reduce use escalation and/or initiation of amphetamine self-administration. Aim 4: Determine if individual differences in these risk-related facets of impulsivity are related toalterations in monoamine transporter function in amygdala prefrontal cortex and/or nucleus accumbens. Aim 5: Determine if individual differences in these risk-related facets of impulsivity are related to alteredpatterns of neuronal activity in amygdala prefrontal cortex and/or nucleus accumbens.RELEVANCE (See instructions): Anti-drug preventive interventions may be most effective if they are designed to target those at highestnsk. The current project will explore the basic neurobehavioral mechanisms that mediate risk. The long-term goal is to translate these basic research findings into the design of targeted biologically-relevantpreventive interventions that can be evaluated in field studies.

project_terms:
Address;Adolescent and Young Adult;Alcohol or Other Drugs use;Amphetamines;Amygdaloid structure;Animal Model;Basic Science;Behavior;Behavioral;Biological;Brain;Cocaine;Disinhibition;Drug abuse;Drug usage;Electrophysiology (science);Esthesia;Exanthema;Failure (biologic function);Goals;Human;Impulsivity;In Vitro;Individual Differences;Instruction;Intervention;Link;Measures;Mediating;Methylphenidate;Moods;Nicotine;Nucleus Accumbens;Patient Self-Report;Personality;Pharmaceutical Preparations;Population;Prefrontal Cortex;Preventive Intervention;Questionnaires;Rattus;Research Personnel;Risk;Self Administration;Staging;System;Testing;Translating;Translational Research;base;design;discounting;field study;follow-up;human subject;in vivo;instrument;monoamine;neurobehavioral;neurobiological mechanism;neurochemistry;neuromechanism;neuronal patterning;non-drug;pre-clinical;preference;programs;research study


application_id: 8876624
project_number: 5P50DA005312-25
project_title: Training and Pilot Core
administering_ic: NIDA
award_notice_date: 2015-06-18
opportunity_number: PAR-10-189
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
project_end_date: 2016-06-30
study_section: ZDA1-EXL-T
subproject_number: 6586
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
The new Training and Pilot Core for the Center for Drug Abuse Research Translation (CDART) has thespecific goal of encouraging trainees to develop implement and evaluate evidence-based preventiveinterventions that rely on multi-disciplinary perspectives and research. The central theme of CDART is thatdifferent facets of impulsivity (urgency disinhibition and sensation seeking) are associated most strongly withdifferent phases of drug use/abuse (problem use escalation and initiation respectively). As a keycomponent of CDART this core will require trainees to build bridges that connect different areas of researchand translate basic research into prevention practice. Pilot investigators will be encouraged to design andimplement preventive interventions that fit within the CDART theme. Thus we will expand and formalize theroles of training and pilot project development through the following Specific Aims: 1) Provide the structureto train graduate students and postdoctoral scholars in translational research relevant to drug abuseprevention; 2) Promote and manage our pilot project program that introduces faculty and researchassociates to translational research relevant to drug abuse prevention and CDART's research mission; 3)Identify promising minority candidates for recruitment into the training and pilot project programs relevant todrug abuse prevention. As part of the approach pre- and post-doctoral trainees will be introduced to the fieldof drug abuse prevention with a special emphasis on translational work by attending and presenting inmonthly trainee data presentations attending seminars by researchers in drug abuse and retreats designedto "brainstorm" with CDART faculty about future research plans taking relevant topic-specific courses andethics in research training and attending informal seminars. The pilot program will prioritize eariy careerinvestigators and minority scholars for funding as well as more advanced faculty new to the drug abusefield. Proposals will be required to demonstrate the relevance of the project to the science and practice ofdrug abuse prevention. As a result CDART trainees and pilot project principal investigators will be preparedto take lead roles in bridging the gap between basic and applied researchers.RELEVANCE (See instructions):Prevention strategies are important for reducing the incidence of drug abuse. The Training and Pilot Core willwill require CDART trainees to build bridges connecting and translating basic reearch into preventionscience. As such the core will be instrumental in preparing trainees and fostering pilot project investigatorsto take leading roles in bridging the gap between basic and applied research in prevention science.

project_terms:
Applied Research;Area;Award;Basic Science;Budgets;Clinical Psychology;Conflict (Psychology);Data;Data Set;Development;Disinhibition;Drug abuse;Drug usage;Esthesia;Ethics;Faculty;Fostering;Funding;Goals;Grant;Health Communication;Impulsivity;Incidence;Instruction;Kentucky;Lead;Length;Minority;Mission;Neurosciences;Personality;Pharmacy facility;Phase;Pilot Projects;Postdoctoral Fellow;Prevention;Prevention strategy;Preventive Intervention;Principal Investigator;Psychology;Psychopharmacology;Research;Research Personnel;Research Training;Role;Science;Structure;Time;Training;Translating;Translational Research;United States National Institutes of Health;Universities;Work;career;design;drug abuse prevention;evidence base;graduate student;medical specialties;pre-doctoral;programs;statistics;success;theories;training project


application_id: 8876622
project_number: 5P50DA005312-25
project_title: Administrative Core
administering_ic: NIDA
award_notice_date: 2015-06-18
opportunity_number: PAR-10-189
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
project_end_date: 2016-06-30
study_section: ZDA1-EXL-T
subproject_number: 6584
contact_pi_person_id: 8535872
contact_pi: MILICH, RICHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
The key functions of the Administrative Core in CDART are to: (1) provide thematic scientific integration ofthe different projects around the personality constructs under investigation; (2) create synergy across thethree proposed projects and other ongoing projects on campus; (3) facilitate interdisciplinary collaborationamong basic and prevention sciences using both neurobehavioral and psychosocial levels of analysis; and(4) oversee the long-range goal of translating our basic research into the development and implementation oftargeted prevention interventions. There are four specific aims in the Core: one scientific oneorganizational one that involves disseminating our research findings to practitioners in the field and one thatinvolves expanding leadership in the prevention science and drug abuse research communities.For the Scientific Aim the Core will provide the structure necessary to produce publications that extendbeyond the boundaries of the individual projects. The Core seeks to engender cross-cutting empiricaltheoretical and methodological articles that promote translation from basic science to prevention practice.For the Organizational Aimthe Core provides an intellectually stimulating and creative environment wherethe norm is to examine research questions and issues from a multilevel interdisciplinary perspective. Thiswill be accomplished by hosting a seminar series inviting nationally-prominent seminar speakers hosting anannual conference on issues relevant to CDART research and having an annual retreat of key personneland trainees. In terms of Dissemination of Results the Core will disseminate the research findings obtainedin the laboratory to the prevention/intervention being conducted by practitioners in the field. For theLeadership Aimthe Core will serve as a local regional national and international resource advocate andleader for the translation of basic science into efforts to prevent drug use/abuse. This will be accomplishedby building connections with other national NIDA-funded centers sponsoring workshops and trainingconferences and by having CDART faculty involved in professional organizations. The Core is alsocommitted to providing training to the next generation of drug abuse prevention researchers.RELEVANCE (See instructions):The Administrative Core is what makes the three proposed projects a Center rather than just a collection ofseparate grant proposals. The Core is the place where research questions are shared across projects ideasfor collaborative papers are generated and the actual translational research takes place.

project_terms:
Advocate;Applications Grants;Basic Science;Collection;Communities;Development;Drug abuse;Drug usage;Educational workshop;Environment;Faculty;Funding;Goals;Human Resources;Impulsivity;Individual;Individual Differences;Institution;Instruction;International;Investigation;Laboratories;Leadership;Mission;National Institute of Drug Abuse;Paper;Personality;Positioning Attribute;Prevention;Prevention Research;Preventive Intervention;Principal Investigator;Professional Organizations;Publications;Publishing;Research;Research Institute;Research Personnel;Resources;Science;Scientist;Series;Structure;Training;Translating;Translational Research;Translations;drug abuse prevention;evidence base;interdisciplinary collaboration;intervention program;neurobehavioral;next generation;outreach;psychologic;psychosocial;relating to nervous system;social;substance use prevention;symposium


application_id: 8876621
project_number: 5P50DA005312-25
project_title: CDART - Center for Drug Abuse Research Translation
administering_ic: NIDA
award_notice_date: 2015-06-18
opportunity_number: PAR-10-189
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
program_official: LLOYD, JACQUELINE
project_start_date: 1992-09-30
project_end_date: 2016-06-30
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
arra_indicator: N
project_terms:
Address;Adolescence;Advocate;Amygdaloid structure;Basic Science;Cessation of life;Characteristics;Communities;Development;Disease;Disinhibition;Drug abuse;Drug usage;Educational workshop;Emotional;Environment;Esthesia;Exanthema;Faculty;Funding;Goals;Health;Health Care Costs;Human;Human Resources;Impulsivity;Individual;Individual Differences;Informal Social Control;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;Publications;Publishing;Rattus;Relative (related person);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;efficacy trial;evidence base;improved;innovation;interdisciplinary collaboration;intervention program;mindfulness;neurobehavioral;neurochemistry;neuroimaging;neuromechanism;next generation;novel;outreach;programs;psychologic;psychosocial;public health medicine (field);public health relevance;relating to nervous system;response;social;statistics;substance use prevention;symposium;university student;young adult


application_id: 8875738
project_number: 5R01HL111040-04
project_title: Epigenetic Regulation of Inflammatory Gene Expression by Telomerase
administering_ic: NHLBI
award_notice_date: 2015-06-11
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: HL
serial_number: 111040
program_official: HASAN, AHMED A K
project_start_date: 2012-09-27
project_end_date: 2015-12-31
study_section: Special Emphasis Panel[ZRG1-VH-D(02)]
contact_pi_person_id: 8010784
contact_pi: BRUEMMER, DENNIS CHRISTOPHER
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): Innate immune responses are central to the pathogenesis of atherosclerotic cardiovascular disease and are orchestrated through transcriptional networks involving epigenetic modification of the chromatin architecture. There is now increasing evidence that the chromatin state is affected by telomerase. In addition to its well- established function to synthesize telomere repeats at the ends of chromosomes telomerase reverse transcriptase (TERT) serves a direct role in facilitating the activation of geneexpression programs. This second activity of TERT in permitting gene transcription appears to operate independently of its role in telomere homeostasis but may involve modification of the higher-order chromatin structure. Although TERT is expressed in macrophages of human atherosclerotic lesions a physiological role of this non-canonical activity of TERT in inflammation and atherosclerosis remains to be discovered. Our recent studies confirmed that TERT activates gene promoters in macrophages. Conversely TERT-deficiency alters macrophage inflammatory gene expression by inducing chromatin modifications reminiscent of gene silencing. Two specific aims are proposed to explore the significance of these findings and to test the hypothesis that TERT promotes inflammatory gene expression in macrophages through epigenetic chromatin modifications and contributes to the development of atherosclerosis. In Specific Aim 1 we will utilize a combination of cellular and molecular approaches to determine the transcriptional mechanisms by which TERT regulates macrophage inflammatory gene expression programs. In Specific Aim 2 we will determine the contribution of TERT to the development of atherosclerosis and test the hypothesis that TERT-dependent activation of inflammatory gene expression in macrophages constitutes an important mechanism for the development of the disease. Ultimately the results of these studies will not only characterize TERT as a chromatin modifier and novel regulatory protein orchestrating macrophage inflammatory gene expression but also advance our understanding of the inflammatory mechanisms contributing to the development of atherosclerosis.

project_terms:
Adult;Affect;American;Architecture;Arterial Fatty Streak;Atherosclerosis;Blood Vessels;Cardiovascular Diseases;Catalytic Domain;Cause of Death;Cell physiology;Cells;Chromatin;Chromosomes;DNA;Data;Development;Developmental Process;Disease;Environment;Epigenetic Process;Exhibits;Feeds;Funding;Gene Activation;Gene Expression;Gene Silencing;Generations;Genes;Genetic Transcription;Genetically Engineered Mouse;Higher Order Chromatin Structure;Histones;Homeostasis;Human;Immune response;Inflammation;Inflammatory;Inflammatory Response;Lead;Modification;Molecular;Nucleosomes;Pathogenesis;Pathway interactions;Physiological;Promotor (Genetics);Property;Recovery;Recruitment Activity;Relative (related person);Role;Signal Transduction;Somatic Cell;Staging;Telomerase;Telomere Maintenance;Telomere Shortening;Testing;Tissues;United States;Vascular Diseases;base;chromatin modification;chromatin remodeling;epigenetic regulation;genetic regulatory protein;in vivo;innate immune function;macrophage;novel;novel therapeutics;programs;protein complex;research study;response;telomerase reverse transcriptase;telomere;vascular inflammation

public_health_relevance:
Atherosclerotic cardiovascular disease is the leading cause of death in the United States and inflammatory pathways contribute to all stages of the disease. This application will investigate novel mechanisms that control the activation of inflammation during atherosclerosis formation. The results of these studies may ultimately characterize novel pathways contributing to vascular diseases and lead to new therapeutic opportunities.


application_id: 8875608
project_number: 5U19AI113182-02
project_title: Project 3: PREVENT: A first-in-human clinical trial of Griffithsin an HIV entry
administering_ic: NIAID
award_notice_date: 2015-06-18
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: 2015-07-01
budget_end_date: 2016-06-30
project_terms:
AIDS prevention;Address;Affinity;Animals;Antigens;Antiviral Agents;Anus;Awareness;Binding (Molecular Function);Biopsy;Carbopol;Cell surface;Cells;Clinical Trials;Community Health;Data;Data Set;Detection;Dimensions;Dose;Drug Exposure;Drug Formulations;Drug Kinetics;Environment;Epithelial;Epithelial Cells;Exposure to;Flow Cytometry;Gel;Gene Expression;Goals;HIV;HIV Entry Inhibitors;HIV Infections;HIV Receptors;HIV-1;HIV-2;Health;Hepatitis C virus;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;Staging;Structure;Surface;Systems Biology;T-Lymphocyte;Techniques;Tissues;Toxic effect;Vagina;Viral;adaptive immunity;base;crosslink;cytokine;design;healthy volunteer;human study;immunotoxicity;inhibitor/antagonist;men;men who have sex with men;microbial community;microbicide;microbiome;novel;preclinical safety;prevent;programs;prospective;rRNA Genes;rectal;rectal microbicide;response;transcriptomics;transmission process;trial design;volunteer


application_id: 8875607
project_number: 5U19AI113182-02
project_title: Project 2: PREVENT Preclinical safety and efficacy studies
administering_ic: NIAID
award_notice_date: 2015-06-18
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: 2015-07-01
budget_end_date: 2016-06-30
project_terms:
Address;Adult;Affect;Affinity;Anal Sex;Animals;Anti-Retroviral Agents;Antiviral Agents;Anus;Attention;Awareness;Binding (Molecular Function);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 Formulations;Drug Kinetics;Effectiveness;Environment;Enzyme-Linked Immunosorbent Assay;Epithelial;Epithelial Cells;Exposure to;Female;Flow Cytometry;Gel;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;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


application_id: 8875606
project_number: 5U19AI113182-02
project_title: Project 1: PREVENT Program Critical Path Project
administering_ic: NIAID
award_notice_date: 2015-06-18
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: 2015-07-01
budget_end_date: 2016-06-30
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;Drug Formulations;Drug Packaging;Ensure;Feedback;Gel;Goals;Guidelines;HIV;HIV vaccine;HIV-1;Human;Human Herpesvirus 2;Investigational Drugs;Investigational New Drug Application;Licensure;Marines;Marketing;Methodology;Methods;Mus;Nicotiana;Oryctolagus cuniculus;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;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;Work;base;cGMP production;clinical efficacy;genotoxicity;immunotoxicity;in vivo;inhibitor/antagonist;irritation;manufacturing process;meetings;microbial;microbicide;novel;pre-clinical;preclinical efficacy;preclinical safety;preclinical study;programs;prototype;rectal;rectal microbicide;safety study;transmission process


application_id: 8875605
project_number: 5U19AI113182-02
project_title: Core D: PREVENT Program Regulatory Affairs Core
administering_ic: NIAID
award_notice_date: 2015-06-18
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
study_section: ZAI1-BP-A
subproject_number: 6664
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: 2015-07-01
budget_end_date: 2016-06-30
project_terms:
Blinded;Clinical;Clinical Data;Clinical Trials;Code;Confidentiality;Cyclic GMP;Data;Development;Drug Kinetics;Ensure;Gel;Goals;Housing;Human;Monitor;Peer Review;Pharmaceutical Preparations;Pharmacodynamics;Phase I Clinical Trials;Practice Management;Prevention;Process;Publications;Quality Control;Randomized;Regulation;Regulatory Affairs;Reporting;Research;Research Infrastructure;Sampling;Site;Systems Biology;Technical Expertise;Time;Toxicology;Training;Training and Education;Viral;Work;base;innovation;microbicide;pre-clinical;programs;quality assurance;rectal;rectal microbicide;repository;response;symposium;volunteer


application_id: 8875604
project_number: 5U19AI113182-02
project_title: Core C: PREVENT Program Pharmacokinetics and Pharmacodynamics Services Core
administering_ic: NIAID
award_notice_date: 2015-06-18
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: 2015-07-01
budget_end_date: 2016-06-30
project_terms:
Adverse effects;Affinity;Anti-HIV Agents;Antibodies;Binding (Molecular Function);Biochemical;Biological;Biological Assay;Biological Markers;Blood specimen;Body Fluids;Cell Line;Cell fusion;Cells;Clinical Research;Complement;Complex;Cyclic GMP;Detection;Development;Drug Formulations;Drug Kinetics;Ensure;Environment;Enzyme-Linked Immunosorbent Assay;Epithelial Cell Junction;Evaluation;Fluorescence;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;Structure;Surface Plasmon Resonance;Systems Biology;Techniques;Technology Transfer;Testing;Tissues;Toxicology;Validation;Viral;adaptive immunity;analytical method;base;immunogenicity;in vivo;microbicide;pre-clinical;pre-clinical research;preclinical study;programs;rRNA Genes;rectal;rectal microbicide


application_id: 8875602
project_number: 5U19AI113182-02
project_title: Core B: PREVENT Product Development Core
administering_ic: NIAID
award_notice_date: 2015-06-18
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: 2015-07-01
budget_end_date: 2016-06-30
project_terms:
Achievement;Algorithms;Animals;Anti-Retroviral Agents;Biological Assay;Carbopol;Characteristics;Chemicals;Chemistry;Clinic;Clinical;Clinical Research;Clinical Trials;Critical Pathways;Cyclic GMP;Data;Development;Documentation;Dose;Drug Combinations;Drug Formulations;Drug Kinetics;Ensure;Evaluation;Gel;Generations;Goals;HIV;Human;Investigational New Drug Application;Knowledge;Laboratories;Lead;Macaca;Methods;Modeling;Modification;Mucous Membrane;Pharmaceutical Preparations;Pharmacodynamics;Physiological;Placebos;Plastics;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;condoms;design;dosage;immunogenicity;manufacturing scale-up;microbicide;oxidation;packaging material;pre-clinical;preclinical efficacy;preclinical safety;preclinical study;product development;programs;protocol development;prototype;rectal;rectal microbicide;safety testing;screening;transmission process


application_id: 8875601
project_number: 5U19AI113182-02
project_title: Core A: PREVENT Program Administrative Core
administering_ic: NIAID
award_notice_date: 2015-06-18
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
study_section: ZAI1-BP-A
subproject_number: 6661
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: 2015-07-01
budget_end_date: 2016-06-30
project_terms:
Archives;Award;Biometry;Calendar;Clinic;Clinical Trials;Collaborations;Communication;Consensus;Consult;Decision Making;Ensure;Experimental Designs;Gel;Goals;Grant;HIV-1;Information Dissemination;Leadership;Methods;Monitor;Online Systems;Paper;Prevention;Problem Solving;Progress Reports;Proteins;Protocols documentation;Research Project Grants;Secure;Sexual Transmission;Site;Structure;TimeLine;United States National Institutes of Health;Universities;Vaccines;Viral;Work;base;condoms;design;meetings;microbicide;novel;posters;prevent;programs;rectal;rectal microbicide;transmission process


application_id: 8875600
project_number: 5U19AI113182-02
project_title: Griffithsin-based Rectal Microbicides for PREvention of Viral ENTry (PREVENT)
administering_ic: NIAID
award_notice_date: 2015-06-18
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_terms:
Address;Affect;Animals;Antiviral Agents;Anus;Cells;Characteristics;Chemistry;Clinical;Clinical Protocols;Clinical Research;Clinical Trials;Colorectal;Confidentiality;Critical Pathways;Cyclic GMP;Data;Data Set;Development;Documentation;Dosage Forms;Dose;Drug Delivery Systems;Drug Formulations;Drug Kinetics;Ensure;Epidemic;Epithelium;Feedback;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;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


application_id: 8874961
project_number: 5R01DK074816-08
project_title: Albumin AFP Gene Family Regulation in Fetal and Adult Liver
administering_ic: NIDDK
award_notice_date: 2015-06-24
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: DK
serial_number: 074816
program_official: BURGESS-BEUSSE, BONNIE L
project_start_date: 2007-09-01
project_end_date: 2017-06-30
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 1879406
contact_pi: SPEAR, BRETT
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The liver performs numerous metabolic and homeostatic functions in the body including xenobiotic metabolism energy storage/production urea formation glutamine synthesis and cholesterol homeostasis. While some liver functions (such as albumin secretion) can be carried out by all hepatocytes other functions are limited to a subset of hepatocytes and determined by cell position within the lobule. Specifically certain enzymes are expressed only in cells surrounding the central vein whereas others are expressed only in hepatocytes surrounding the portal triads. This phenomenon is called positional (or zonal) heterogeneity or metabolic zonation. This compartmentalization of function enables the liver to perform multiple and sometimes opposing metabolic pathways in distinct hepatocyte subpopulations. Zonal gene regulation is essential for normal liver function. Disruption of zonallyregulated metabolic processes can alter carbohydrate and lipid metabolism ammonia detoxification and biliary function. A number of agents (alcohol drugs and toxins) preferentially damage hepatocytes surrounding the central veins due to restricted expression of P450 enzymes in these cells. Thus zonal control of gene expression has significant clinical implications. The overall objective of this proposal is to develop a better understanding of zonal gene regulation. Based on our studies on mouse alpha-fetoprotein (AFP) gene regulation we have developed a model of zonal regulation. Specifically we have found that AFP enhancer element E3 exhibits highly restricted activity in hepatocytes surrounding the central vein in the adult liver. Building on studies performed by our lab and others we will investigate the role of asubfamily of orphan nuclear receptors and the Wnt/b-catenin/TCF signaling pathway in the control of E3. These studies utilize a unique set of reagents and transgenic mouse lines developed in our lab. The long-term goal of these studies is to understand the basic mechanisms that govern the zonal regulation of many liver genes which will lead to better treatment of liver disease in humans.

project_terms:
Adult;Albumins;Alcohols;Ammonia;Architecture;Area;Biliary;Binding (Molecular Function);Binding Sites;Birth;Cells;Central Vein;Cholesterol Homeostasis;Clinical;Complex;Cultured Cells;Cytochrome P450;Development;Disease;Drug Metabolic Detoxication;Enhancer Elements (Genetics);Enhancers;Enzymes;Exhibits;Fetal Liver;Fluorescence-Activated Cell Sorting;Gene Expression;Gene Expression Regulation;Gene Family;Genes;Glutamate-Ammonia Ligase;Glutamine;Goals;Grant;Hepatic;Hepatocyte;Heterogeneity;Homeostasis;Human;Lead;Liver;Liver diseases;Lobular;Lobule;Metabolic;Metabolic Pathway;Metabolism;Modeling;Mus;Nuclear Orphan Receptor;Organ;Pattern;Pharmaceutical Preparations;Portal triad;Positioning Attribute;Production;Proliferating;Proteins;Reagent;Regulation;Role;Signal Pathway;Site;Structure;Testing;Toxin;Transgenic Mice;Urea;Xenobiotic Metabolism;alpha-Fetoproteins;base;carbohydrate metabolism;fetal;in vivo;interest;lipid metabolism;liver function;novel strategies

public_health_relevance:
The liver is a complex organ that must coordinately express numerous proteins to facilitate proper development and maintain normal physiological homeostasis. In the adult liver appropriate gene expression including zonal gene expression must be maintained during normal conditions when hepatocytes are generally quiescent and during disease when some hepatocytes may be damaged and others may be proliferating. Our ongoing studies on the control of alpha-fetoprotein enhancer activity described in this proposal will help elucidate aspects of zonal gene expression in the adult liver.


application_id: 8874905
project_number: 5R01AR061578-04
project_title: BISPHOSPHONATE USE AND BONE QUALITY
administering_ic: NIAMS
award_notice_date: 2015-08-01
opportunity_number: PA-10-009
application_type: 5
activity_code: R01
ic: AR
serial_number: 061578
program_official: LESTER, GAYLE E
project_start_date: 2012-07-01
project_end_date: 2017-06-30
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 7875292
contact_pi: MALLUCHE, HARTMUT H
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Bisphosphonates (BP) have been used to halt bone loss and prevent osteoporosis-related fractures but recent reports and our experience indicate that their long-term use may be related to "atypical" bone fractures. This poses a great public health concern because it could indicate a rising tide of difficult to treat costly atypical bonefractures now in the making. An understandable consequence of these reports is the growing mistrust from the public and physicians regarding use of BPs to treat bone loss. Thus additional "typical" osteoporosis-related fractures could result due to reluctance to use BPs. This scenario emanating from two different reasons for increasing fractures creates an urgent need to clarify the relationship between long-term BP use and bone quality. Bone quality is important because it is widely regarded that alterations in this parameter are linked to bone fragility. The central hypothesis to be evaluated is that long-term BP use is associated with slow but progressive abnormalities in bone quality. The specific aims of the proposed study are to use an engineering-based approach to: 1) quantify bone quality abnormalities associated with no short medium and long-term BP treatment and to evaluate the contributions of low bone turnover and/or osteoporosis as a disease per se and 2) analyze the relationship between bone quality parameters and the continuous duration of BP use to determine the nature of these relationships (linear second-order exponential etc.) with time. The availability of an unrivaledarchive of bone biopsy specimens (8000+) and the collaborative experience of our clinical laboratory and engineering-based research team offers the unique opportunity to efficiently achieve these specific aims. The proposed study will measure the microstructural material and mechanical parameters of cortical and cancellous bone quality in bone samples from: a) patients with osteoporosis or no short medium and long-term BP therapy and b) healthy age-matched volunteers. These measurements will be made by using histomorphometry Fourier Transform Infrared Spectroscopy and nanoindentation. The proposed research offers a strong prospect to provide a substantial and sustained benefit to patients with osteoporosis. The findings will generate new information regarding the relationship between the duration of BP treatment and bone quality. If bone quality abnormalities are observed with BP treatment then a basis will exist for reformulation of BP treatment guidelines. If no bone quality abnormalities areobserved with BP treatment then the findings will provide reassurance to patients and physicians allowing confident use of BPs. Thus either outcome will provide valuable information regarding the therapeutic use of BPs. This will result in improved health for millions of patients with osteoporosis.

project_terms:
Activities of Daily Living;Address;Advocate;Affect;Age;Archives;Biopsy;Biopsy Specimen;Carbonates;Caucasians;Clinical;Collagen;Competence;Control Groups;Diagnostic;Disease;Distress;Drug usage;Engineering;Fracture;Fright;Goals;Guidelines;Hardness;Health;Health Care Costs;Human;Knowledge;Laboratories;Laboratory Study;Life;Link;Measurement;Measures;Mechanics;Minerals;Morbidity - disease rate;Mortality Vital Statistics;Nature;Osteoporosis;Outcome;Patients;Pharmaceutical Preparations;Physicians;Porosity;Postmenopause;Quality of life;Reporting;Research;Research Personnel;Resolution;Sampling;Specimen;Spectroscopy Fourier Transform Infrared;Stress;Therapeutic Uses;Thick;Time;Tissues;Woman;base;bisphosphonate;bone;bone loss;bone mass;bone quality;bone turnover;crosslink;crystallinity;experience;improved;inorganic phosphate;meetings;nanoindentation;prevent;public health medicine (field);treatment duration;volunteer

public_health_relevance:
Bisphosphonates (BPs) are commonly used drugs that improve bone mass in millions of patients with osteoporosis but recent reports link long-term BP use with atypical bone fractures. This suggests that an abnormality in bone quality must accompany long-term BP use. The proposed laboratory study uses the PI's unrivaled archive of human diagnostic bone biopsy specimens to determine how long-term BP use affects bone quality. Knowledge gained from this study should provide a substantial and sustained benefit to human life by allowing the public to use bisphosphonates without fear of drug-related complications thereby reducing the morbidity mortality and healthcare costs linked to osteoporosis.


application_id: 8874888
project_number: 5R01HD070792-04
project_title: Indomethacin and delayed umbilical cord clamp for preterm infant IVH
administering_ic: NICHD
award_notice_date: 2015-04-03
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: 2018-03-31
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:
Abbreviations;Address;Adverse effects;Affect;Apoptotic;Biological Markers;Birth;Birth Weight;Blinded;Blood;Blood Volume;Brain;Brain Injuries;Brain imaging;Caring;Case Study;Cephalic;Cerebral Palsy;Child;Clinical;Cognitive;Communities;Costs and Benefits;Data;Developmental Delay Disorders;Developmental Disabilities;Effectiveness;Evaluation;Extremely Low Birth Weight Infant;FDA approved;Frequencies (time pattern);Gestational Age;Goals;Head;Health;Health Care Costs;Hemorrhage;Incidence;Indomethacin;Infant;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;Pediatric Hospitals;Performance;Periventricular Leukomalacia;Phenotype;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;clinical care;comparative efficacy;cost;design;disability;extreme prematurity;follow-up;hemodynamics;high risk;improved;intraventricular hemorrhage;patient population;prevent;primary outcome;prophylactic;social;vascular inflammation

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: 8874437
project_number: 1R01HL122676-01A1
project_title: Cardiovascular Toxicity of Tobacco Products and Constituents
administering_ic: NHLBI
award_notice_date: 2015-07-06
opportunity_number: RFA-OD-13-011
application_type: 1
activity_code: R01
ic: HL
serial_number: 122676
suffix: A1
program_official: ITURRIAGA, ERIN
project_start_date: 2015-07-01
project_end_date: 2020-04-30
study_section: Special Emphasis Panel[ZRG1 AARR-J (56)]
contact_pi_person_id: 8767000
contact_pi: CONKLIN, DANIEL JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Acetaldehyde;Acrolein;Address;Adult;Aerosols;Affect;Aldehydes;Animal Model;Animals;Biological Assay;Biological Markers;C57BL/6 Mouse;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Chronic Disease;Cigarette;Complex;Complex Mixtures;Cotinine;Creatinine;Data;Disease;Dose;Dyslipidemias;Electronic cigarette;Evaluation;Exposure to;Family Smoking Prevention and Tobacco Control Act;Female;Formaldehyde;Functional disorder;Future;Grant;Guidelines;Human;In Vitro;Individual;Injury;Insulin Resistance;Knowledge;Lead;Lipids;Measures;Mediating;Metabolism;Methods;Modification;Mus;Nicotine;Non-smoker;Organ;Plasma;Policies;Property;Relative (related person);Risk;Risk Factors;Smoke;Smokeless Tobacco;Smoker;Smoking;System;Thrombosis;Tobacco;Tobacco smoke;Tobacco use;Toxic effect;Validation;Variant;authority;body system;cardiovascular disorder risk;cardiovascular injury;cigarette smoke;cigarette smoking;cohort;disorder risk;environmental tobacco smoke exposure;male;primary outcome;public health medicine (field);public health relevance;research study;response;secondary outcome;tobacco exposure;urinary


application_id: 8874189
project_number: 5R21DA038248-02
project_title: Spinal AMPA receptors latent central sensitization and chronic pain
administering_ic: NIDA
award_notice_date: 2015-06-12
opportunity_number: PA-13-119
application_type: 5
activity_code: R21
ic: DA
serial_number: 038248
program_official: HILLERY, PAUL
project_start_date: 2014-07-01
project_end_date: 2016-06-30
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 10670168
contact_pi: DOOLEN, SUZANNE
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): There is an overwhelming need for research leading to a greater understanding of central nervous system mechanisms that regulate the transition from acute to chronic pain. The Institute of Medicine states that 116 million Americans are burdened with chronic pain costing over $600 billion annually. While opioid medications are commonly prescribed to treat pain they are only moderately efficacious and adverse side effects and potential for abuse stress the need for greater understanding of their analgesic mechanisms. A large body of research indicates that peripheral inflammation initiates maladaptive plasticity within the spinal cord and brain termed central sensitization-that contributes to chronic pain. Less appreciated however are data which suggest that central sensitization far outlasts overt signs of pain sensitivity in a silent form termed "latent centralsensitization" (LCS). This proposal is innovative in that it suggests a novel molecular mechanism of LCS; the central hypothesis is that inflammation produces an adenylyl cyclase 1 (AC1)- and AMPA receptor (AMPAR)-dependent LCS that is masked by spinal opioid receptors. This hypothesis will be tested with three specific aims: AIM 1 tests the hypothesis that tonic mu opioid receptor (MOR) activity decreases dorsal horn AMPAR-mediated Ca2+ signaling during long-lasting LCS after injury. Aim 1 uses innovative real-time Ca2+ imaging in adult spinal dorsal horn (DH) slices to determine whether opioid receptor blockade increases AMPAR-mediated DH Ca2+ signaling. AIM 2 tests the hypothesis that AMPAR subunit GluA2 phosphorylation and internalization maintains LCS. Aim 2 will test this hypothesis by measuring GluA2 Ser880 phosphorylation and internalization in the presence or absence of NTX. AIM 3 tests the hypothesis that injury-induced long- term increases in GluA2 internalization and Ca2+ permeability are maintained by AC1 activity. In DH from mice with AC1 deletion or pharmacological inhibition Aim 3 will compare AMPAR-mediated Ca2+ responses and determine total and phosphorylated GluA2 and cell surface expression in the presence or absence of opioid receptor blockade. The proposed research is significant because if our hypotheses are correct then any event that interferes with opioid receptor activity could unleash pronociceptive AC1-AMPAR signaling and thus allow the transition to chronic pain. The results and concepts generated in this proposal may lead to a vertical leap in our understanding of pain vulnerability after tissue inflammation and has the long-term potential to reveal novel targets toprevent the transition from acute to chronic pain.

project_terms:
AMPA Receptors;Acute;Adult;Adverse effects;American;Analgesics;Automobile Driving;Behavior;Brain;CTOP;Calcium;Cell surface;Complex;Data;Development;Equilibrium;Event;Freund's Adjuvant;Glutamates;Healed;Health;Healthcare;Hyperalgesia;Image;Inflammation;Inflammatory;Injury;Institute of Medicine (U.S.);Lead;Light;Masks;Measures;Mediating;Methods;Mission;Modeling;Molecular;Mus;N-Methyl-D-Aspartate Receptors;Naltrexone;Neuraxis;Neurons;Nociception;Olives - dietary;Opioid;Opioid Receptor;Pain;Pain management;Paper;Peripheral;Permeability;Pharmaceutical Preparations;Phosphorylation;Posterior Horn Cells;Process;Receptor Activation;Receptor Signaling;Receptors Opioid mu;Reporting;Research;Science;Signal Transduction;Slice;Spinal;Spinal Cord;Stress;Synapses;System;Testing;Therapeutic Intervention;Time;Tissues;adenylyl cyclase 1;behavioral study;central sensitization;chronic pain;cost;density;dorsal horn;healing;innovation;neurochemistry;neurophysiology;neurotransmission;novel;novel therapeutic intervention;pain inhibition;prevent;public health medicine (field);receptor function;response;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Chronic pain management is a major scientific and public health care challenge as current analgesic drugs rarely provide sufficient efficacy in the absence of serious side effects. We propose that injury triggers the development of a vicious cycle spinal of neuronal signaling that maintains sensitivity to pain long after tissue healing; ths is chronically masked by the body's naturally occurring pain inhibitory system that involves opioid receptors. Our studies aim to reveal the neurochemical mechanisms that maintain this vicious cycle of pain signaling. This project is relevant to NIH's mission that pertains to fundamental processes driving the transition from acute to chronic pain and promotes the development of therapeutic interventions for pain management.


application_id: 8873087
project_number: 1R03AI117361-01
project_title: Targeting NAD biosynthesis in Mycobacterium tuberculosis
administering_ic: NIAID
award_notice_date: 2015-04-24
opportunity_number: PA-13-304
application_type: 1
activity_code: R03
ic: AI
serial_number: 117361
program_official: LACOURCIERE, KAREN A
project_start_date: 2015-05-01
project_end_date: 2017-04-30
study_section: Special Emphasis Panel[ZRG1 IDM-T (82)]
contact_pi_person_id: 11365624
contact_pi: KOROTKOV, KONSTANTIN V
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): Emergence of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb) the causative agent of tuberculosis (TB) represents a major threat to TB control. There is an urgent need for development of new and more effective anti-tubercular drugs targeting previously unexplored cellular processes. The goal of this proposal is to find a novel class of antimicrobial compounds active against Mtb. Nicotinamide mononucleotide adenylyltransferase (NadD) an essential enzyme of NAD biosynthesis represents a highly promising target for drug development against bacterial pathogens. In recent years there have been a number of NadD inhibitors developed and validated against Escherichia coli Bacillus subtilis and B. anthracis. Published data indicate tha NadD is required for the growth and survival of mycobacteria. Thus this recent progress provides a starting point for pursuing this enzyme as a target for the development of novel anti-tubercular drugs. The experiments in this proposal are designed to find inhibitors of Mtb NadD using a combination of structural biology approach and our recently developed virtual screening (VS) methodology. We propose to use our crystal structure of Mtb NadD and previously identified scaffolds active against E. coli and B. anthracis NadD to apply an iterative ligand- an structure-based VS approach to discover the NadD inhibitors. The VS method will exploit databases with approved drugs that have already been shown to be safe in humans. Upon successful completion of this project we will obtain a number of potent and safe lead compounds that would be further validated in in vivo studies. The strategies developed in the proposed study will be also applicable to other medically relevant targets.

project_terms:
Address;Adverse effects;Anabolism;Animal Model;Anti-Bacterial Agents;Antibiotics;Antitubercular Agents;Bacillus anthracis;Bacillus subtilis;Biochemical Pathway;Biological Assay;Cell Death;Cell physiology;Communicable Diseases;Complex;Data;Databases;Development;Drug Targeting;Drug resistance in tuberculosis;Effectiveness;Enzyme Inhibitor Drugs;Enzyme Inhibitors;Enzymes;Escherichia coli;Extreme drug resistant tuberculosis;Fingerprint;Genus Mycobacterium;Goals;Growth;Homologous Gene;Human;In Vitro;Inhibitory Concentration 50;Intervention;Lead;Ligands;Metabolic Pathway;Methodology;Methods;Molecular Weight;Multi-Drug Resistance;Mycobacterium smegmatis;Mycobacterium tuberculosis;Nicotinamide adenine dinucleotide;Nicotinamide-Nucleotide Adenylyltransferase;Nicotinate-nucleotide adenylyltransferase;Pathway interactions;Pharmaceutical Preparations;Pharmacologic Substance;Property;Publishing;Recycling;Reporting;Research;Roentgen Rays;Role;Staging;Structure;Testing;Time;Tuberculosis;antimicrobial;base;chemotherapy;combat;design;drug development;drug discovery;improved;in vivo;inhibitor/antagonist;innovation;insight;mycobacterial;next generation;nicotinate mononucleotide;nicotinic acid adenine dinucleotide;novel;pathogen;programs;public health medicine (field);public health relevance;research study;resistant strain;scaffold;screening;small molecule;small molecule libraries;structural biology;success;treatment duration;treatment strategy;tuberculosis treatment;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The rapid rise in the occurrence of drug-resistant TB cases represents a major global public health problem. Our long-term goal is to develop novel classes of anti-mycobacterial compounds to combat the multidrug- resistant and extensively drug-resistant M. tuberculosis infections. We propose to discover inhibitors of an essential metabolic pathway in mycobacteria a yet unexplored drug target.


application_id: 8872623
project_number: 1R21EY025408-01
project_title: Exsomes derived from retinal astrocytes in the regulation of retinal vasculature
administering_ic: NEI
award_notice_date: 2015-03-26
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: EY
serial_number: 025408
program_official: SHEN, GRACE L
project_start_date: 2015-04-01
project_end_date: 2017-03-31
study_section: Diseases and Pathophysiology of the Visual System Study Section[DPVS]
contact_pi_person_id: 6193432
contact_pi: SHAO, HUI
other_pis: KAPLAN, HENRY JERROLD
congressional_district: 03
department: OPHTHALMOLOGY
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 normal retinal vasculature perfuses the macula of the neurosensory retina while avoiding interference with image resolution. The abnormal growth of blood vessels and associated bleeding and/or vascular leakage in retinopathy of prematurity (ROP) diabetics retinopathy (DR) exudative aged-related macular degeneration (AMD) and vascular occlusions are major causes of vision loss. Multiple cellular and soluble factors are involved in the formation stabilization and regression of new retinal vessels. Among the cellular components retinal astrocytes (RACs) play an important role in endothelial seeding of the primary retinal vasculature. However the mechanism of astrocyte- endothelial cell interaction is incompletely understood. This proposal investigates a novel mechanism in which exosomes released by RACs target endothelial cells and result in normal retinal vasculature development. To test our hypothesis that molecules in RAC exosomes are important in the development of normal retinal vasculature as well as the inhibition of aberrant retinal angiogenesis we will 1) test the effect of exosomes from murine postnatal day 2 (P2) RACs (developing RAC exosomes) on proliferation migration and tubule formation using retinal endothelial cells; 2) determine whether developing RAC exosomes can rescue aberrant angiogenesis induced by hypoxemia [i.e. oxygen-induced retinopathy (OIR)]; and 3) determine whether the angiogenic profiles of these exosomes reflect their function. Information derived from these results will further our understanding of the role of RAC exosomes in the development and maintenance of normal retinal vasculature. These observations may result in novel therapy to control aberrant retinal angiogenesis.

project_terms:
Adult;Affect;Age related macular degeneration;Angiogenic Proteins;Astrocytes;Blindness;Blood Vessels;Caliber;Cell Communication;Cell membrane;Cells;Choroidal Neovascularization;Development;Diabetic Retinopathy;Disease;Endostatins;Endothelial Cells;Extravasation;Exudative age-related macular degeneration;Goals;Growth;Hemorrhage;Hypoxemia;Image;Lasers;Lead;Life;Lipids;Maintenance;Mediating;Messenger RNA;MicroRNAs;Microglia;Modeling;Multivesicular Body;Mus;Neonatal;Neurophysiology - biologic function;Oxygen;Parents;Pathology;Phase;Phenotype;Physiological;Physiology;Plasma Cells;Play;Proteins;Proteomics;Regulation;Resolution;Retina;Retinal;Retinal Diseases;Retinopathy of Prematurity;Role;Staging;Testing;Tissue Inhibitor of Metalloproteinase-1;Vascularization;Vesicle;Visual;Western Blotting;angiogenesis;base;dehydroretinal;macula;migration;nanoscale;neovascular;novel;pigment epithelium-derived factor;postnatal;proliferative diabetic retinopathy;public health relevance;retina blood vessel structure;retinal angiogenesis;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Normal retinal vasculature is critical for visual integrity. Any abnormality affecting vessel formation and regression during development or at later stages of life will lead to severe pathologies resulting in blindness such as retinopathy of prematurity (ROP) proliferative diabetic retinopathy (PDR) and wet age-related macular degeneration (AMD). The goal of this application is to investigate a novel mechanism whereby exosomes released from retinal astrocytes (RACs) are involved in the development and maintenance of normal retinal vasculature and to explore a novel therapy to control abnormal retinal vasculature related diseases.


application_id: 8871633
project_number: 5R01AG046116-03
project_title: Pain and Well-being in Older Women: The Roles of Activity and Motivation
administering_ic: NIA
award_notice_date: 2015-06-29
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AG
serial_number: 046116
program_official: NIELSEN, LISBETH
project_start_date: 2013-07-01
project_end_date: 2016-03-31
study_section: Special Emphasis Panel[ZRG1-BBBP-T(03)M]
contact_pi_person_id: 1886687
contact_pi: SEGERSTROM, SUZANNE C.
other_pis: CROFFORD, LESLIE J
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The prevalence of chronic pain in older adults is high and prevalence increases with increasing age. Although adverse effects of pain on hedonic well-being (HWB) are well documented there is less evidence that pain has a direct effect on aspects of eudaemonic well-being (EWB) such as autonomy and social satisfaction. Evidence suggests that some older adults with high physical pain nonetheless maintain high EWB whereas others with low physical pain have low EWB. The present study tests a model in which qualities of the goal-directed and physical activities of older women determine whether and how pain affects EWB. When activity is externally motivated by guilt or control pain will inhibit activity and activity will adversely affect EWB; when activity is autonomously motivated by interest or self-definition pain will not inhibit activity and activity will enhance EWB. Furthermore when activities are accorded more time these effects will be stronger. A second aim tests effects of activity and EWB on biomarkers including diurnal cortisol and inflammation as measured by interleukin-6 and its soluble receptor. A third aim will test these relationships controlling for individual differences in personality genotype fitness and pain sensitivity. Oldr women (N = 300 aged 50-75) with varying levels of pain will be recruited from an existing registry to complete 7-day diary periods at 3-month intervals over 9 waves to test day- wave- and person-level relationships. Daily measures will include goal-directed and physical activities (including motivation for and time spent in the activities) cortisol slope subjective health pai pain interference HWB and psychological need satisfaction as a measure of day-level EWB. Wave-level measures will include the Scales of Psychological Well-Being HWB interleukin-6 and interleukin-6 receptor. Person-level measures will include optimism COMT polymorphism VO2max and sensory testing. Multi-level modeling will test for between-person and within-person relationships and lagged effects. The co-PIs bring expertise in pain goals well-being and physiology to these aims and have successfully completed longitudinal studies of older adults and pain patients including a diary study. The study will advance understanding of how a common age-relevant experience - physical pain - affects EWB and physical health.

project_terms:
Adverse effects;Affect;Age;Aging;Area;Arthritis;Back Pain;Biological Markers;Elderly;Feeling;Female;Genetic Polymorphism;Genotype;Goals;Guilt;Headache;Health;High Prevalence;Hydrocortisone;Individual;Individual Differences;Inflammation;Interleukin 6 Receptor;Interleukin-6;Link;Literature;Longitudinal Studies;Measures;Modeling;Moods;Motivation;Musculoskeletal Pain;Neurosecretory Systems;Outcome;Pain;Pain interference;Pain management;Patients;Personal Satisfaction;Personality;Persons;Physical activity;Physiological;Physiology;Prevalence;Prevalence Study;Recruitment Activity;Registries;Relative (related person);Reporting;Role;Sensory;Severities;Testing;Time;Woman;aged;chronic pain;diaries;experience;fitness;heart rate variability;hedonic;improved;interest;older women;optimism;physical conditioning;prognostic;psychologic;psychosocial;receptor;resilience;satisfaction;sex;social

public_health_relevance:
PUBLIC HEALTH RELEVANCE: As people age they are more likely to experience physical pain. However some older adults are able to maintain high feelings of well-being about themselves and their lives despite pain whereas some do not maintain well-being although they have little pain. This study tests whether daily activities determine whether pain does or does not result in decrements in well-being and whether activity and well-being affect immunological and neuroendocrine correlates of health.


application_id: 8871491
project_number: 5R01AG019223-11
project_title: Ceramide and acute phase protein elevation during aging
administering_ic: NIA
award_notice_date: 2015-05-15
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AG
serial_number: 019223
program_official: VELAZQUEZ, JOSE M
project_start_date: 2002-08-01
project_end_date: 2017-08-31
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 6730250
contact_pi: NIKOLOVA-KARAKASHIAN, MARIANA N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Our lab has a long standing interest in the mechanisms leading to the state of chronic low-grade inflammation which is an intrinsic component of the aging process and many aging-associated diseases. In the past we reported that the hepatic response to Interleukin 12 (IL-12) a major mediator of systemic inflammation is augmented during aging leading to excessive production of IGFBP1 a protein that is secreted by the liver binds to the Insulin-like Growth Factor 1 (IGF1) and neutralizes its bioactivity. Hepatic IL-12 hyperresponsiveness is caused by the intrinsic activation of an evolutionary conserved cellular stress response pathway involving neutral sphingomyelinase and its product ceramide.  Here we hypothesize that this IL-12 hyperresponsiveness impairs the insulin signaling pathway in liver. First we will investigate how aging-associated IL-12 hyperresponsiveness affects the insulin pathway and will study the interactions between key molecules in the two cascades PI3K Akt-1 and Foxo1 (for insulin) and ceramide IRAK-1 and JNK (for IL-12). Studies will be done in isolated hepatocytes in vitro and in animals in vivo. Young aged and aged calorie restricted rats will be used. The regulation of IGFBP1 mRNA transcription by the two pathways will be investigated. These molecular studies will be complemented by assays of insulin- and IGFBP1-dependent functions in vivo which include tests of IGF1 bioactivity muscle functions and glucose regulation. Throughout the experiments cause and effect relations will be tested by overexpression and silencing approach using adenovirus-mediated gene transfer. These studies may help to elucidate the cellular and molecular pathways responsible for muscle waste frailty and glucose dysregulation in the elderly. They may also reveal a novel mechanism for integration of inflammatory and metabolic signaling pathways and how aging affects these interactions. )

project_terms:
Acute-Phase Proteins;Adenoviruses;Affect;Aging;Aging-Related Process;American;Animals;Arthritis;Attenuated;Binding (Molecular Function);Biological Assay;CCAAT-Enhancer-Binding Proteins;Caloric Restriction;Cell membrane;Cells;Cellular Stress Response;Ceramides;Chronic;Complement;Disease;Dose;EMSA;Effectiveness;Elderly;Environment;Event;Exhibits;Funding;Gene Transfer;Genetic Transcription;Glucose;Goals;Health;Hepatic;Hepatocyte;IGF1 gene;Immune response;Impairment;In Vitro;Indium;Inflammation;Inflammatory;Insulin;Insulin Signaling Pathway;Insulin-Like Growth Factor I;Insulin-Like Growth-Factor Binding Protein 1;Interleukin-1;Interleukin-1 Receptors;Interleukin-12;Life;Link;Lipids;Liver;Longevity;Luciferases;MAPK8 gene;Mammals;Mediating;Mediator of activation protein;Messenger RNA;Metabolic;Molecular;Monitor;Muscle;Muscle function;Non-Insulin-Dependent Diabetes Mellitus;Organism;Pathway interactions;Phosphoenolpyruvate Carboxylase;Phosphorylation;Phosphotransferases;Play;Production;Promotor (Genetics);Protein Binding;Proteins;Rattus;Regulation;Reporting;Role;Serum;Signal Pathway;Signal Transduction;Sphingomyelinase;Testing;Tissues;Ubiquitination;Up-Regulation (Physiology);Work;aged;anakinra;blood glucose regulation;cytokine;drug metabolism;frailty;glucose tolerance;improved;in vivo;insulin sensitivity;insulin signaling;interest;juvenile animal;liver function;novel;overexpression;research study;response;sarcopenia;small hairpin RNA;success;tissue repair;transcription factor;wasting

public_health_relevance:
Understanding the mechanisms that dysregulate liver functions during aging is very important for improving the health of older Americans because liver plays critical role in many functions including glucose homeostasis innate immune response drug metabolism etc.).


application_id: 8871428
project_number: 5R01CA091901-13
project_title: Novel aureolic acid type antitumor agents
administering_ic: NCI
award_notice_date: 2015-06-11
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 091901
program_official: FU, YALI
project_start_date: 2001-06-01
project_end_date: 2016-06-30
study_section: Special Emphasis Panel[ZRG1-BCMB-B(02)M]
contact_pi_person_id: 2257319
contact_pi: ROHR, JURGEN T
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Aureolic acid-type anticancer agents such as mithramycin (MTM) chromomycin (CMM) and durhamycin (DHM) are potent anticancer and anti-HIV drugs with a unique mode-of-action. They inhibit the growth of cancer cells by cross-linking GC-rich DNA thereby shutting down specificity-protein (Sp)-dependent pathways toward various proto-oncogenes including c-myc and c-src the latter being associated with the unique hypocalcemic activity found for these drugs. Particularly MTM is important and has become a popular biochemical tool to study Sp-dependent signal transduction pathways but -due to its toxic side effects- is rarely used as anticancer agent except for the treatment of tumor hypercalcemia refractory to other chemotherapy. However MTM was identified in 2011 by the NCI as the only lead from a screen of 50000 compounds that inhibits the EWS-FLI1 transcription factor responsible for the highly malignant phenotype of Ewing sarcomas which often affect children and were untreatable for the past 40 years. In addition another NCI group found in June 2012 that MTM represses cigarette smoke induced ABCG2 efflux pumps responsible for the drug resistance of lung and esophageal cancers and inhibited multiple stem-cell related pathways relevant for tumorigenicity and proliferation of such cancers. A few years ago MTM was identified as a potential lead drug against neurological diseases arthritis and for the treatment of hematologic disorders. All these new applications require only very small less toxic concentrations of the drug although the mode-of-action in these contexts remains obscure particularly the mode affecting the EWS-FLI1 transcription factor. MTM's biosynthesis has been studied intensely during the previous funding periods of this research project and consequently pursued combinatorial biosynthetic efforts revealed various biosynthetic intermediates and many new MTM-analogues which allowed deducing important structure-activity-relationships. Two regions are of special interest: First a modification of the 3-side chain first exemplified in the superior analogues MTM SK and MTM SDK led to much better anticancer activity profiles with a greatly improved therapeutic index compared to MTM itself. Second exchange of the D-mycarose sugar in E-position of MTM's trisaccharide chain by D-digitoxose led to superior analogues with greatly reduced toxic side effects. This now allows for new strategies to further concentrate on these regions of the molecule for further drug optimization.  During the previous biosynthetic studies biosynthetic intriguing and interesting keyenzymes were discovered which need to be further investigated particularly the co-dependent enzymes MtmGIV/MtmC (bifunctional glycosyltransferase/methyltransferase-ketoreductase) MtmOIV/MtmW (C-C-bond cleaving oxygenase/ketoreductase) which play key roles for the 3-side chain and the trisaccharide chain formation. Furthermore the PKS release remains unclear and it is hypothesized that another co-dependent enzyme pair namely oxygenase MtmOII and cyclase MtmX play an important role for this process. The goal here is to gain a deeper understanding of the biosynthetic roles mechanisms and interactions of these key enzymes of the MTM pathway to pave the way for the optimization and re-engineering of these enzymes that are crucial for novel further improved MTM derivatives. It is planned to (a) further investigate unclear biosynthetic steps and mechanisms of the MTM and other aureolic acid pathways (b) to further develop strategies for the selective generation of new improved MTM analogues including selective 3-side chain and sugar exchange/glycorandomization strategies (c) to analyze intriguing enzymes particularly recently discovered co- dependent enzyme pairs. New resulting MTM analogues will be submitted to the NCI DTP (developmental therapeutics program) for further mechanistic investigations.

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

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


application_id: 8871275
project_number: 1R34MH106661-01
project_title: Systematically Adapted Delivery of the Family Check-Up in Underserved Communities
administering_ic: NIMH
award_notice_date: 2015-02-24
opportunity_number: RFA-MH-15-330
application_type: 1
activity_code: R34
ic: MH
serial_number: 106661
program_official: PINTELLO, DENISE
project_start_date: 2015-03-01
project_end_date: 2018-02-28
study_section: Special Emphasis Panel[ZMH1 ERB-I (01)]
contact_pi_person_id: 8804342
contact_pi: STUDTS, CHRISTINA RUTH
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): When disruptive behavior problems manifest in very young children the risk of later antisocial behaviors- including substance abuse school failure and criminality-escalates significantly. Evidence-based behavioral parent training (BPT) interventions have demonstrated efficacy and effectiveness in a range of settings in preventing the negative outcomes and costs associated with disruptive behavior problems. However the public health impact of these interventions has yet to be realized in part due to reliance on delivery by trained mental health professionals in clinic or community settings. Although implementation studies of BPT have been reported these results lack generalizability because of their methodological idiosyncrasies in implementation. To maximize the public health benefits of BPT systematic implementation studies are needed particularly in underserved community settings. In Appalachia a region recognized for its dramatic health disparities at least one in five children exhibits sub-clinical to clinical levels of disruptive behavior problems. Risk factor for child disruptive behavior problems are pervasive; Appalachian residents suffer high poverty rates low education levels disproportionately high rates of substance abuse and mental health disorders and persistent disparities in a wide range of health problems. A challenging combination of cultural barriers and poor access to mental health services hinders the usual delivery model for BPT in Appalachia (i.e. by trained mental health professionals). The vast majority of Appalachian counties are designated as mental health provider shortage areas and cultural considerations (e.g. distrust of outsiders the primacy of kinship networks history of authoritarian parenting styles strong self-reliance) may limit uptake of the few services available. The goal of this mixed-methods pilot study is to prepare for a future large-scale hybrid
effectiveness-implementation trial of an evidence-based BPT intervention across rural Appalachian communities. Our preliminary data revealed community preferences for brief BPT delivery by local community health workers. Thus to increase the accessibility and acceptability of BPT in this region we will use the ADAPT-ITT framework to systematically adapt the delivery model for the Family Check-Up a brief BPT intervention previously shown to be effective in reducing behavior problems and preventing negative outcomes when delivered by trained mental health professionals in clinic and community settings. Following the systematic adaptation of the Family Check-Up delivery model we will pilot-test its implementation by community health workers in four high-need under- resourced Appalachian communities to assess feasibility acceptability and costs. Our primary questions are whether we can effectively train community health workers in these communities to deliver the Family Check- Up with fidelity; whether we can enroll parents/caregivers and children to initiate and complete the intervention; and whether the battery of assessments and measures planned for the subsequent R01 effectiveness- implementation trial are feasible and appropriate for these community settings.

project_terms:
Address;Aggressive behavior;Appalachian Region;Area;Authoritarianism;Behavioral;Behavioral Model;Caregivers;Caring;Child;Child Behavior;Child Mental Health;Child Rearing;Child Welfare;Church;Clinic;Clinical;Communities;Community Health;County;Data;Development;Disruptive Behavior Disorder;Educational Background;Educational Intervention;Effectiveness;Enrollment;Ensure;Evidence based intervention;Exhibits;Failure (biologic function);Family;Feedback;Foundations;Future;Gap Junctions;Goals;Health;Health Benefit;Health Personnel;Health Professional;Health Services Research;Healthcare;Home environment;Hybrids;Individual;Intervention;Kinship Networks;Lead;Location;Longevity;Measures;Mental Health;Mental Health Services;Mental disorders;Methods;Modality;Modeling;National Institute of Mental Health (U.S.);Nursery Schools;Outcome;Parents;Pilot Projects;Poverty;Prevalence;Problem behavior;Protocols documentation;Recording of previous events;Reporting;Research Project Grants;Research Support;Resistance;Risk;Risk Factors;Rural;Schools;Services;Societies;Substance abuse problem;Testing;Training;Training Programs;Underserved Population;Work;aged;antisocial behavior;behavioral study;checkup examination;community setting;cost;early childhood;evidence base;experience;health disparity;implementation research;implementation science;implementation trial;innovation;medical specialties;preference;prevent;public health medicine (field);public health relevance;self reliance;social stigma;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Early childhood disruptive behavior problems lead to significant costs to families and society but can be reduced with behavioral parent training interventions. To increase the public health impact of these interventions their feasibility accessibility and acceptability in high-need underserved communities must be ensured. This pilot project will systematically adapt and pilot-test the delivery model of an existing effective parent training intervention for implementation in rural Appalachia a region with many documented health disparities high levels of poverty and shortages of mental health providers.


application_id: 8870460
project_number: 5R01NS083405-03
project_title: Multi-Mechanism Inhibition of Lipid Peroxidation in TBI
administering_ic: NINDS
award_notice_date: 2015-06-17
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: NS
serial_number: 083405
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2013-07-01
project_end_date: 2016-06-30
study_section: Special Emphasis Panel[ZRG1-BDCN-L(02)M]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): We have previously documented that generation of the potent reactive nitrogen species (RNS) peroxynitrite (PN) is responsible for oxidative damage by lipid peroxidation (LP) and protein modification (carbonylation and tyrosine nitration) to mitochondrial and other cellular elements during the first 72 hrs after traumatic brain injury (TBI). The PN-mediated oxidative damage leads to brain mitochondrial dysfunction and ultimately failure. As a consequence of oxidative compromise of mitochondrial function including calcium (Ca++) buffering) posttraumatic intracellular Ca++ overload is exacerbated leading to calpain-mediated cytoskeletal degradation neurodegeneration and neurological impairment. We have preliminarily shown that treatment with the potent LP inhibitor U-83836E with the LP-derived lipid aldehyde 4-hydroxynonenal (4-HNE) scavenger phenelzine or with the mitochondrial permeability transition inhibitor cyclosporine (CsA) can partially attenuate posttraumatic brain LP damage mitochondrial dysfunction and calpain-mediated cytoskeletal damage in a mouse TBI model. Most importantly the window for this effect is at least 12 hrs post-injury. However our preliminary results show only a partial attenuation of post-injury LP-related neural damage' even when any of these antioxidant compounds is individually administered after injury. This partial neuroprotective effect strongly points to the logic of an antioxidant neuroprotective strategy that combines either two or all three of these mechanistically complimentary antioxidant compounds to achieve a greater degree of neuroprotection. Therefore the overall goal of the proposed experiments is to explore the hypothesis that interrupting post-traumatic secondary LP oxidative damage at multiple points will produce a quantitatively greater neuroprotective effect with less variability that will have agreater chance of translational success in future TBI clinical trials. The combination approach should not only increase the maximal neuroprotective effect but may also prolong the therapeutic window for inhibition of secondary brain injury after TBI.

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

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


application_id: 8870448
project_number: 5R01NS072302-05
project_title: Preclinical evaluation of IGF1 therapy for traumatic brain injury
administering_ic: NINDS
award_notice_date: 2015-06-30
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: NS
serial_number: 072302
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2011-07-15
project_end_date: 2017-06-30
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 6875991
contact_pi: SAATMAN, KATHRYN E
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): Traumatic brain injury (TBI) afflicts an estimated 1.5 million people each year in the US. Survivors often suffer persistent neurological dysfunction compromising their quality of life and productivity. Despite the expanding base of knowledge regarding the complex pathophysiology of TBI no clinically proven therapeutic interventions have been identified. TBI produces acute neurovascular damage and cell death resulting in early functional deficits. Recovery of function may be limited by the inability of the injured brain to adequately harness endogenous repair mechanisms. The central hypothesis of this proposal is that treatment with insulin-like growth factor-1 (IGF-1) will improve neurobehavioral function through the attenuation of neurovascular damage and the augmentation of posttraumatic neurogenesis and angiogenesis. We previously showed that administration of recombinant human IGF-1 (rhIGF-1) improves motor and cognitive function in brain-injured rats. However no studies have examined the neuroprotective or neurorestorative capabilities of IGF-1 in the traumatized brain. We propose to conduct the first comprehensive investigation of the multiple potentially synergistic mechanisms underlying the behavioral efficacy of IGF-1. Importantly we will evaluate the efficacy of rhIGF-1 treatment initiated within a clinically relevant therapeutic window of 8 hr and demonstrate sustained protection up to 5 weeks postinjury. In the setting of TBI IGF-1 is a promising therapeutic candidate as it has neuroprotective properties and helps to sustain or enhance myelination. Therefore after demonstrating in Aim 1 that a 7 day systemic infusion of rhIGF-1 initiated at 15 min 3 hr or 8 hr postinjury improves motor and cognitive function in mice subjected to cortical impact brain injury in Aim 2 we will test the hypothesis that IGF-1 protects against neuronal loss and axonal degeneration. IGF-1 is also known to stimulate proliferation of progenitor cells promote neuronal oligodendroglial and endothelial differentiation and increase angiogenesis in the brain. Therefore in Aim 3 we will test the hypothesis that infusion of rhIGF-1 enhances neurogenesis in the subgranular and subventricular zones. In Aim 4 we will employ novel vascular perfusion techniques to quantify densities of total and angiogenic vessels in brain- injured mice treated with rhIGF-1 or vehicle to test the hypothesis that IGF-1 effectively enhances posttraumatic angiogenesis. Finally in Aim 5 we will test the hypothesis that rhIGF-1 administration delayed 48 hr can selectively enhance neurogenesis and angiogenesis resulting in cognitive recovery in the absence of acute neuroprotection. These data will provide unique and valuable insights into the neurovascular targets for IGF-1 in the injured brain. By establishing long term (up to 5 wks postinjury) histological benefits and correlating these with behavioral responses the proposed studies have the potential for high clinical impact. Ultimately our goal is to provide a catalyst to accelerate the translation of IGF-1 therapy into clinical application in order to improve the health and well-being of individuals burdened with TBI.

project_terms:
Acute;Age;Attenuated;Behavioral;Blood Vessels;Brain;Brain Injuries;Bromodeoxyuridine;Cause of Death;Cell Death;Cells;Cerebral Ischemia;Cessation of life;Clinical;Clinical Trials;Cognition;Complex;Contusions;Cortical Contusions;Data;Demyelinations;Enrollment;Evaluation;Functional disorder;Goals;Health;Hippocampus (Brain);Human;IGF1 gene;Impaired cognition;Individual;Infusion procedures;Injury;Insulin-Like Growth Factor I;Investigation;Isolectin;Label;Learning;Measurement;Memory;Motor;Mus;Myelin;Nerve Degeneration;Neurologic Dysfunctions;Neurons;Outcome;Patients;Perfusion;Personal Satisfaction;Productivity;Proliferating;Property;Quality of life;Rattus;Recombinants;Recovery of Function;Research;Silver Staining;Spinal cord injury;Staining method;Stains;Stem cells;Survivors;Techniques;Testing;Therapeutic;Therapeutic Intervention;Time;Translations;Traumatic Brain Injury;angiogenesis;attenuation;axonal degeneration;behavioral response;brain repair;catalyst;cell injury;cell type;central nervous system injury;clinical application;clinically relevant;cognitive function;cognitive recovery;cognitive rehabilitation;controlled cortical impact;density;disability;functional outcomes;improved;injured;insight;knowledge base;motor disorder;myelination;neurobehavioral;neurogenesis;neuron loss;neuronal survival;neuroprotection;neurorestoration;novel;preclinical evaluation;rehabilitation strategy;repaired;stem;subventricular zone;tissue repair;tomato lectin


application_id: 8870258
project_number: 5P30AG028383-10
project_title: Education and Information Transfer Core
administering_ic: NIA
award_notice_date: 2015-07-14
opportunity_number: RFA-AG-11-005
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_start_date: 2006-07-15
study_section: ZAG1-ZIJ-5
subproject_number: 6079
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
PROJECT SUMMARY (See instructions): The Education and Information Transfer Core (EITC) functions as a vital link between the UK-ADC and the local and state communities. EITC programs and activities have created and will maintain an educated local community eager to receive updated information on AD and to participate in our Center's research. Through EITC efforts the UK-ADC will continue to work with both the Commonwealth of Kentucky and UK in directing state and institutional response to meeting Kentucky's dementia health care needs. Over the past five years the EITC has taken a lead in developing innovative products to support research participation by African Americans the largest minority group in Kentucky. The EITC will continue strong relationships with the Council of Ministers and the Community Action Council so that activities and products developed such as the Book of Alzheimer's for African-American Churches and Granny Pearl a film to educate African- American adolescents about AD are responsive to local needs. EITC recruitment and outreach activities will be closely coordinated with the Clinical Core and the Gateway Satellite Clinic to ensure that appropriate participants are identified for ADC cohorts clinical trials and other research studies. Work in the EITC forthe five-year grant period will be designed to meet three specific aims. Aim 1 is to support recruitment and retention activities for our Center's research protocols clinical trials and NIH/NIA initiatives. The core places a special emphasis on minority recruitment and retention strategies and will continue its innovative and successful strategies for African American participants. An expanded goal is to increase research participation including brain donation in this population. Aim 2 is to increase community awareness of AD with an emphasis on maintaining a strong presence in the African-American community. Awareness efforts will be focused on the importance of early disease identification to support our Center theme of transitions and translation. Aim 3 is to expand UK community and regional partnerships to meet the educational needs of community and professional audiences and UK researchers. Strong collaborations with the local Alzheimer's Association and Geriatric Education Center will continue. Based on needs assessment and survey data our current and future professional educational efforts will focus on the following three areas: caregiver education medical student education and scientific conferences including a new William R. Markesbery scientific symposium in honor of our former director.

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

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


application_id: 8870257
project_number: 5P30AG028383-10
project_title: Neuropathology Core
administering_ic: NIA
award_notice_date: 2015-07-14
opportunity_number: RFA-AG-11-005
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_start_date: 2006-07-15
study_section: ZAG1-ZIJ-5
subproject_number: 6077
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
PROJECT SUMMARY (See instructions): The overall objective of the Neuropathology Core of the University of Kentucky Alzheimer's Disease Center (UK-ADC) is to support research on normal brain aging presymptomatic Alzheimer's disease (pAD) mild cognitive impairment (MCI) early and late AD mixed dementia syndromes and other dementing disorders. Autopsies will be performed by our Rapid Autopsy Team on longitudinally followed subjects from our Clinical Core. We will perform short post-mortem interval autopsies in relation to our clinical cohort and we will maintain a high autopsy rate. This Core is optimally tailored to help address important research questions. The Core will provide brain tissue specimens CSF and synaptosomes for investigators at UK other ADCs and outside investigators. The Core will also provide consensus conference determined diagnoses quantitation of neurofibrillary tangles (NFT) neuritic plaques and diffuse plaques from 8 brain regions AB 1-40 and 1-42 quantitation Braak staging CERAD and NIA-Reagan Institute staging on all autopsied cases to investigators. Since the brain bank has been operating continuously for over two decades with a strong track record special care will be taken to ensure diagnostic excellence consistency and continuity. The Core will maintain a tissue bank of the above specimens and frozen serum plasma buffy coats and CSF from living patients. Special emphasis will be placed on defining the neuropathological findings in the brains of the oldest old (>85 years) and providing investigators with specimens from cognitively intact control subjects with no AB deposition and sparse tau pathology (successful cerebral aging) and also cognitively intact subjects with abundant plaques and neurofibrillary tangles. Providing these samples will contribute to clinical-pathological correlation studies and cutting-edge research that include sponsored studies related to AD genomics oxidative stress hippocampal sclerosis dementia with Lewy bodies amyloid precursor protein processing Down syndrome and neuroinflammation. Frequent consensus conferences will be held with the Clinical Core and Biostatistics Core to help define clinicalpathological diagnoses on all autopsied subjects. This Core is strongly integrated with other Cores of the UK-ADC and exploits unique opportunities to conduct clinical-pathological correlative studies on longitudinally followed subjects. Through these methods we will better understand normal brain aging and the transition to dementia with the focused goal of contributing to therapeutic or preventive measures.

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

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


application_id: 8870256
project_number: 5P30AG028383-10
project_title: Biostatistics and Data Management Core
administering_ic: NIA
award_notice_date: 2015-07-14
opportunity_number: RFA-AG-11-005
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_start_date: 2006-07-15
study_section: ZAG1-ZIJ-5
subproject_number: 6075
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
PROJECT SUMMARY (See instructions): The Biostatistics and Data Management Core (BDMC) can be conceptualized as the lynchpin for integration of the ADC Cores and is vital to the success of the UK-ADC. Its critical roles include managing a large centralized database consulting with ADC-affiliated researchers and working to develop and apply innovative statistical methodology for data analysis. Data management efforts focus on collecting and storing high quality data. This focus begins with the leadership and vision and attention to detail provided by the BDMC. This core has an enviable track record of timely and accurate reporting of a high volume of data to NACC. Further weekly Core meetings are popular with UK-ADC investigators who find that the expert advice provided by our seasoned investigators improves their success in pilot studies grant applications and publications. This core also participates as a full partner to the research mission of the UK-ADC emphasizing transitions and translations. One such partnership with the Clinical and Neuropathology Cores relates to clinico-pathological models of mixed dementias. A key element of this BDMC is the well established track record of developing novel methodology to analyze data collected at the UK-ADC and from other cohorts with a focus on elderly subjects' transitions to MCI and eventually dementia. The BDMC also provides training for students enrolled in the graduate programs in Gerontology Public Health Epidemiology and Biostatistics Psychology and Statistics. In keeping with the mission of the UK-ADC faculty in this core also contribute to the dementia research community at large through service on external advisory committees study sections manuscript reviews and data safety monitoring boards. The BDMC will continue these critical responsibilities through the following specific aims. 1. Maintain a centralized database of the information collected by all ADC Cores and affiliated research projects in an integrated manner. 2. Provide expertise on experimental design and statistical analysis (and developing new analytical approaches). 3. Interact dynamically with other Cores to contribute to the clinical neuropathological and educational/outreach missions of the ADC.

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

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


application_id: 8870255
project_number: 5P30AG028383-10
project_title: Clinical Core
administering_ic: NIA
award_notice_date: 2015-07-14
opportunity_number: RFA-AG-11-005
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_start_date: 2006-07-15
study_section: ZAG1-ZIJ-5
subproject_number: 6071
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
PROJECT SUMMARY (See instructions): Central to the success of the UK-ADC over the past 25 years is Clinical Core productivity that has allowed the development and perpetuation of a large longitudinally-followed well-characterized continuously-replenishing cohort focused on normal aging and early transitional disease states. All subjects undergo autopsy at death supporting clinical-pathologic research in aging and dementia. This practice has allowed major contributions in the area of clinical-pathological correlative studies and our understanding of early preclinical and predementia disease states such as mild cognitive impairment (MCI). UK-ADC productivity in terms of contributions to national collaborative initiatives such as NACC (2nd in overall productivity) ADCS (2nd in overall productivity) ADNI (2nd in overall productivity) NCRAD (597 normal control cell lines) and GWAS/ADGC is well recognized by involved researchers participating in these initiatives. The Clinical Core of the UK-ADC has contributed to the success of 31 independent research studies using living subjects (in addition to the many that rely on our data for work in the area of biospecimens and neuropathology) and has led to an impressive 159 publications supported by this core over the last funding cycle. In the upcoming cycle under the leadership of Dr. Greg Jicha we will focus our efforts on supporting investigations in the detection and treatment of preclinical AD and MCI of the AD-type as outlined in the new proposed NIA criteria released at ICAD 2010. As such our center is in critical transition developing and expanding biomarker capabilities (target normal to MCI/dementia transitions n=270 over the next funding period and n=50 high risk normals for the development of preclinical AD) while maintaining the size of our existing cohort to ensure sufficient transitions from normal to MCI and dementia (n=500 normals and n=300 impaired) continuing to work towards the development of more sensitive cognitive measures recommended by the NIA proposed criteria for preclinical AD and fully supporting our continued leadership position in the area of clinical-pathological correlative studies under the NR Core leadership of Dr. Peter Nelson. The clinical core fully supports the leadership role of Dr. Linda Van Eldik as center director after the loss of Dr. Markesbery earlier this year. We are committed to remaining one of the top ADCs in the nation and across the globe. We have further strengthened our resolve and commitment to advancing research and moving diagnostic strategies and therapeutic development forward as we transition into a new era of research with the NIA..

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

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


application_id: 8870254
project_number: 5P30AG028383-10
project_title: Administrative Core
administering_ic: NIA
award_notice_date: 2015-07-14
opportunity_number: RFA-AG-11-005
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
project_start_date: 2006-07-15
study_section: ZAG1-ZIJ-5
subproject_number: 6070
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
PROJECT SUMMARY (See instructions): The primary mission of Core A is to provide leadership coordination and integration of all the components of the UK-ADC so that our programmatic and scientific goals are achieved. Our overall scientific objective is to support and facilitate research aimed at elucidating the pathogenic mechanisms underlying the transitions from normal cognitive aging to the development of AD with a long-term goal of enabling more effective translation of this mechanistic knowledge to intervention strategies. The UK-ADC has historically been at the forefront of supporting research in identification of the early manifestations of disease and the pathogenic mechanisms underlying the transitions from normal cognitive aging to the development of AD. In the renewal period we will build upon this highly successful focus as well as leverage several recent positive developments at UK that will expand our translational research capability and thereby help to increase the rate of progress toward new therapies to delay or prevent AD. The UK-ADC functions in a multidisciplinary integrated and supportive environment that catalyzes high-quality AD research within the UK community and throughout Kentucky and beyond. The ADC also enhances education and outreach within UK and in the community and provides clinical diagnoses and care of patients with cognitive impairment. The ADC serves as the focal point of all AD-related activities in Kentucky providing the infrastructure and resources to enhance scientific interactions and develop new collaborations. The ADC also reaches beyond Kentucky to enhance AD research education and clinical practice on a national level through its interactions with other ADCs as well as other regional and national institutions including the Alzheimer's Association NIA and industry. An effective Administrative Core is essential for transforming ADC goals into accomplishments. Therefore Core A will continue to support the ability of our UK-ADC to serve as a critical resource for the university community state region and nation through a set of integrated and intertwined specific aims.  Aim 1: Provide leadership and an organizational framework for management and coordination of all ADC activities to ensure optimal resource utilization to meet the overall goals of the ADC. Aim 2: Enable the ADC to serve as the focal point of AD-related activities in Kentucky by continuing to coordinate facilitate and promote scientific interactions. Aim 3: Contribute to and interact with other ADCs and other national collaborative activities and the lay community to increase visibility of the ADC and maximize progress in AD research throughout the country.

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

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


application_id: 8870251
project_number: 5P30AG028383-10
project_title: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2015-07-14
opportunity_number: RFA-AG-11-005
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
program_official: SILVERBERG, NINA B
project_start_date: 2006-07-15
project_end_date: 2016-06-30
study_section: ZAG1-ZIJ-5(M2)
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This application seeks to renew the Alzheimer's Disease Core Center (P30 AG028383) at the University of Kentucky (UK-ADC) a mature and experienced ADC that was originally funded in 1985. Our principal mission is to serve as the focal point for all AD-related activities at UK and the Commonwealth of Kentucky by providing an environment and core resources that catalyze innovative research outreach and education and clinical programs that benefit elderly Kentuckians. Over the past 25 years we have developed a vigorous program in the clinical neuropathological educational and research aspects of AD that serves as a critical resource for the university community state region and nation. UK-ADC initiatives are innovative and are shifting the current research and clinical practice paradigms. Two of the historically outstanding facets of our ADC are: 1) a strong program in clinical-neuropathological correlations and short postmortem interval autopsies and 2) a unique normal control group of -500 subjects followed longitudinally with all committed to brain autopsy upon death. These resources have contributed to us becoming one of the premier Centers in defining pathogenic mechanisms underlying the transitions from normal cognitive aging to AD. With the recent change in leadership of our ADC we are poised to build on these strengths and capitalize on emerging opportunities to more effectively translate this knowledge into therapeutic strategies aimed at slowing progression or preventing development of AD. Thus the UK-ADC will focus on two interrelated themes: Transitions and Translation. Our emphasis moving forward will be to more effectively bridge the gap between basic research and clinical studies by providing support and the necessary infrastructure to facilitate translational efforts. Efforts are focused across the spectrum of cognitive impairment (normal/ preclinical AD/ MCI/ dementia) with an overall goal of more effective translation of knowledge to intervention strategies. The UK-ADC provides an infrastructure and environment that focuses on these integrated themes and advances multidisciplinary innovative AD research through five highly interactive and effective Cores: A: Administrative B: Clinical (including our successful Minority Gateway Satellite) C: Biostatistics and Data Management D: Neuropathology and E: Education and Information Transfer Cores.

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

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


application_id: 8869094
project_number: 1R21EB020107-01
project_title: Immuno-vasculogenic hydrogels for islet engraftment and localized tolerance
administering_ic: NIBIB
award_notice_date: 2015-04-13
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: EB
serial_number: 020107
program_official: HUNZIKER, ROSEMARIE
project_start_date: 2015-04-15
project_end_date: 2017-03-31
study_section: Biomaterials and Biointerfaces Study Section[BMBI]
contact_pi_person_id: 1894295
contact_pi: SHIRWAN, HAVAL
other_pis: GARCIA, ANDRES J
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:  Type 1 diabetes (T1D) is an autoimmune disease caused by immune destruction of insulin-producing pancreatic  cells. T1D affects 3 million children and adults in the US with healthcare costs exceeding $14.9 billion. Allogeneic islet transplantation has proven effective in improving metabolic control/quality of life and in preventing severe hypoglycemia in patients with T1D. However broad clinical application of allogeneic islets is limited by i) immune
rejection despite the chronic use of immunosuppression and its sequelae ii) transplantation into the liver which compromises immediate post-graft islet engraftment as well as long-term survival and iii) insufficient human islet supply from cadaveric pancreata. Thus there is a significant need for innovative strategies that overcome these limitations of islet transplantation
for a broader clinical practice.  This R21 application is formulated to overcome graft rejection without chronic use of immunosuppression and establish the small bowel mesentery as an extrahepatic site for islet transplantation thereby overcoming two critical barriers of islet transplantation. This will be achieved by engineering dual-action immunomodulatory and vasculogenic hydrogels for controlled delivery of a novel form of PD-L1 and VEGF for islet transplantation in the small bowel mesentery. PD-L1 (programmed death-ligand 1) is an important immunoregulatory molecule involved in tolerance to self-antigens and has extensively been exploited by chronic infections and cancer for immune evasion. PD-L1 interaction with PD-1 receptor on various adaptive and innate immune effector cells results in inhibition of effector function and/or physical elimination of these cells. Importantly PD-1/PD-L1 interaction is involved in the generation of tolerogenic DCs and induced CD4+CD25+FoxP3+ Treg cells that are critical to peripheral tolerance to self-antigens and acquired tolerance to foreign antigens in
various experimental settings. VEGF has recently been shown to confer a stable tolerogenic phenotype to DCs by inducing the expression of indoleamine 23-dioxygenase (IDO). IDO is an important immunoregulatory enzyme and signaling molecule that is involved in fetomaternal tolerance and generation of Treg cells. Our central hypothesis is that PD-L1 and VEGF delivered by biomaterials will work in synergy to induce localized tolerance and promote islet vascularization for long-term allogeneic islet survival and function without continuous use of immunosuppression. The overall objective will be accomplished by testing our central hypothesis through two Aims: 1) Engineer PD-L1/VEGF- presenting hydrogels to generate Treg cells in vitro and facilitate allogeneic islet engraftment vascularization and survival in short-erm in vivo studies; and 2) Test the efficacy of the PD-L1/VEGF hydrogels to support long-term engraftment vascularization tolerance induction and treatment of diabetes. Studies will be conducted to elucidate the mechanistic basis of graft failure and/or long-term survival with particular focus on innate and adaptive effector immune and regulatory (tolerogenic dendritic cells and Treg cells) responses.

project_terms:
Abdomen;Adult;Affect;Allogenic;Antigens;Apoptosis;Autoantigens;Autoimmune Diseases;Beta Cell;Biocompatible Materials;Biotin;Cells;Cessation of life;Child;Chronic;Dendritic Cells;Development;Diabetes Mellitus;Diabetic mouse;Drug Formulations;Effector Cell;Encapsulated;Engineering;Engraftment;Enzymes;Extrahepatic;Generations;Goals;Graft Rejection;Graft Survival;Health Care Costs;Homeostasis;Human;Hydrogels;Hypoglycemia;IL2RA gene;Immune;Immune Tolerance;Immune response;Immune system;Immunology;Implant;In Vitro;Infection;Inflammatory Infiltrate;Insulin;Insulin-Dependent Diabetes Mellitus;Islets of Langerhans;Islets of Langerhans Transplantation;Label;Lead;Lectin;Life;Ligands;Liver;Longitudinal Studies;Maintenance;Malignant Neoplasms;Mesentery;Metabolic Control;Monitor;Mus;Natural immunosuppression;Nature;Pancreas;Patients;Performance;Phenotype;Population;Proteins;Quality of life;Regulatory T-Lymphocyte;Research;Signaling Molecule;Sirolimus;Site;Small Intestines;Source;Streptavidin;Testing;Therapeutic;Transplantation;Tryptophan 23 Dioxygenase;Vascular Endothelial Growth Factors;Vascularization;Work;base;clinical application;clinical practice;cytokine;density;efficacy testing;graft failure;improved;in vivo;innovation;islet;novel;novel strategies;peripheral tolerance;prevent;programs;public health relevance;receptor;response;standard care

public_health_relevance:
PUBLIC HEALTH RELEVANCE:   Type 1 diabetes (T1D) is a chronic autoimmune disorder that affects more than 1% of population worldwide. Insulin as a standard treatment although effective in treating T1D has major long-term complications. Therefore the development of novel approaches to prevent and treat T1D is a significant therapeutic goal. In this application we propose the engineer hydrogels with vasculogenic and immunomodulatory proteins to deliver allogeneic pancreatic islets (a source of insulin producing beta cells) into the abdomen of
diabetic mice to treat T1D by enhancing islet engraftment of and controlling rejection for indefinite graft survival in the absence of chronic use of immunosuppression. If effective this approach may have immediate and important implications for the use of allogeneic islets for the treatment of T1D in humans.


application_id: 8869062
project_number: 5R21NS085660-02
project_title: Use of IL-1alpha to Promote Angiogenesis and Functional Recovery After Experiment
administering_ic: NINDS
award_notice_date: 2015-06-16
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: NS
serial_number: 085660
program_official: KOENIG, JAMES I
project_start_date: 2014-07-01
project_end_date: 2016-06-30
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 7568819
contact_pi: BIX, GREGORY JAYE
other_pis: PINTEAUX, EMMANUEL
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): Treatments for stroke-induced cerebral ischemia (CI) have failed in part due to lack of efficacy against post- stroke neuroinflammation. However while acute inflammation may contribute to worse patient outcomes w e h y p o t h e s i z e t h a t chronic/delayed inflammation could promote brain repair and may b e an attractive therapeutic target. In particular we have demonstrated a significant role for the inflammatory cytokine interleukin-1 (IL-1) in CI. Although the deleterious role of IL-1 (the main isoform of IL-1 released following CI) in CI is established IL-1 is also critically important and in contrast toIL-1 may play a beneficial role. We have recently shown that IL-1 causes c u l t u r e d cells of the neurovascular unit to generate laminin globular domain 3 (LG3) the neuroprotective and pro-angiogenic protein fragment of the extracellular matrix component perlecan. Importantly LG3 is persistently (weeks) generated in the brain after stroke but whether this is caused even in part by IL-1 or is of any pathophysiologic or therapeutic benefit is completely unknown. Our preliminary data now suggest that IL-1 activates brain endothelium is pro-angiogenic in vitro remains chronically elevated in stroked brains where it could persistently impact recovery and when absent (IL-1 knockout mice (KO)) results in or contributes to diminished post-stroke angiogenesis. Therefore we hypothesize that IL-1 is a key enhancer of angiogenesis (a brain repair mechanism) after stroke-induced CI via generation of LG3. To explore this hypothesis we propose the following specific aims: 1) Determine the role of IL-1 in modulating angiogenesis in brain endothelium under normal conditions and after CI 2) Determine the role of perlecan LG3 in IL-1 regulation of angiogenesis under normal conditions and after CI. We will use a number of in vitro angiogenesis assays and a transient middle cerebral artery occlusion model in wild-type and IL-1 KO mice to determine the angiogenic effects of IL-1 in vitro and in vivo. Functional/behavioral analysis will also be performed to correlate the extent of angiogenesis and infarct volume with functional recovery. The importance of LG3 to IL-1 angiogenesis effects in vitro and in vivo (after stroke) will be determined using a perlecan transgenic mouse that expresses 10% of normal total perlecan levels (pln -/-). Finally we will employ various genetic and biochemical methods to determine how IL-1 increases LG3 generation in brain endothelial cells in vitro with a focus on key cellular proteases and determine whether disruption of this impacts IL-1 angiomodulatory activity. Successful completion of this proposal will demonstrate a novel beneficial effect of inflammatory cytokines specifically IL-1 in brain recovery after stroke.

project_terms:
Acute;Angiogenic Proteins;Behavioral;Biochemical;Biological Assay;Brain;Bromodeoxyuridine;C-terminal;Cathepsin L;Cathepsins;Cause of Death;Cell Line;Cells;Cerebral Ischemia;Chronic;Clinical Trials;Data;Endothelial Cells;Endothelium;Enhancers;Extracellular Matrix;Generations;Genetic;Goals;Health;Immunohistochemistry;In Vitro;Infarction;Inflammation;Inflammatory;Inflammatory Response;Injury;Interleukin-1;Interleukin-1 alpha;Ischemic Penumbra;Knockout Mice;Label;Laminin;Methods;Middle Cerebral Artery Occlusion;Modeling;Mus;Outcome;Oxidative Stress;Patients;Peptide Hydrolases;Peripheral;Play;Process;Production;Protein Fragment;Protein Isoforms;Recovery;Recovery of Function;Regulation;Role;Therapeutic;Transgenic Mice;Western Blotting;angiogenesis;behavior test;behavioral outcome;brain repair;brain tissue;cytokine;disability;excitotoxicity;immunocytochemistry;improved;in vivo;innovation;interest;neurogenesis;neuroinflammation;neurovascular unit;novel;perlecan;post stroke;prevent;repaired;research study;stroke;stroke therapy;therapeutic target;tissue repair

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cerebral ischemia (CI) caused by stroke is one of the leading causes of death and disability worldwide and is critically regulated by inflammation. Although acute inflammation after stroke is detrimental to the brain and contributes to a poor outcome components of chronic inflammation may promote recovery. Our goal is to understand how one such chronic inflammatory component interleukin-1 alpha promotes recovery with the aim to develop new stroke therapies.


application_id: 8868174
project_number: 5U10NS058967-09
project_title: UK NETT Clinical Site Hub
administering_ic: NINDS
award_notice_date: 2015-06-18
opportunity_number: PAR-11-342
application_type: 5
activity_code: U10
ic: NS
serial_number: 058967
program_official: JANIS, SCOTT
project_start_date: 2007-05-03
project_end_date: 2016-05-31
study_section: ZNS1-SRB-N(01)
contact_pi_person_id: 8686194
contact_pi: HUMPHRIES, ROGER LOYD
other_pis: Not Applicable
congressional_district: 06
department: EMERGENCY 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): This proposal describes the re-establishment of a Neurological Emergencies Treatment Trials (NETT) Network Clinical Site Hub at the University of Kentucky Chandler Medical Center (UKCMC) in Lexington Kentucky in response to NIH/NINDS PAR-11-342. The overall goal of this proposal is to identify UKCMC as an academic medical facility with regional affiliate partners adept in "the evaluation of treatments for patiens with a broad spectrum of neurological emergencies." The NETT Clinical Hub Site at UKCMC (UK NETT) has been a vigorous participant in the NETT Network since its competitive selection as one of the original 17 Network sites in 2007. During the past 4 years as a participating Clinical Hub Site UK NETT has enrolled more than 50 subjects in the Phase 111 clinical trials undertaken within the NETT Network to include RAMPART (midazolam v. lorazepam in status epilepticus) ALIAS Part 2 (albumin v. placebo in acute ischemic stroke) POINT (clopidogrel loading for stroke prevention after transient ischemic attack) and ProTECT (progesterone v. placebo in traumatic brain injury). Emergency Medicine is well represented within this venture as the original and proposed UK NETT are based within the Department of Emergency Medicine at UKCMC. UK NETT is founded upon an intra-institutional collaboration that extends beyond Emergency Medicine to include physician faculty members in the Departments of Neurology Neurosurgery Surgery/Trauma Surgery and Anesthesiology/Intensive Care Medicine. Regional affiliate medical care facilities aligned with UK NETT include "spoke" community hospitals located within Kentucky. The following Specific Aims are proposed: 1) To demonstrate the existence of an infrastructure for high-volume subject recruitment in "large simple" clinical trials performed in acute-onset neurological disorders and 2) To demonstrate experience in successfully conducting clinical trials in acute-onset neurological disorders requiring Exception from Informed Consent as regulated by the United States Food & Drug Administration.

project_terms:
Accident and Emergency department;Acute;Affect;Air;Albumins;Ambulances;American;Anesthesiology;Area;Beds;Brain;Caring;Cause of Death;Clinical;Clinical Research;Clinical Trials;Collaborations;Communities;Community Hospitals;Conduct Clinical Trials;Disease;Emergency Medicine;Emergency treatment;Enrollment;Evaluation;Faculty;Goals;Grant;Healthcare;Hospitals;Human;Individual;Informed Consent;Intensive Care;Internet;Ischemic Stroke;Kentucky;Lorazepam;Medical;Medical center;Medicine;Midazolam;Modeling;National Institute of Neurological Disorders and Stroke;Nervous system structure;Network-based;Neurological emergencies;Neurology;Operative Surgical Procedures;Participant;Patients;Pharmacists;Phase;Phase III Clinical Trials;Physicians;Placebos;Positioning Attribute;Progesterone;Progress Reports;Recruitment Activity;Regulation;Research;Research Infrastructure;Resources;Rural;Seizures;Services;Site;Source;Speed (motion);Spinal cord injury;Status Epilepticus;Stream;Stroke prevention;Telecommunications;Transient Ischemic Attack;Trauma;Traumatic Brain Injury;United States Dept. of Health and Human Services;United States Food and Drug Administration;United States National Institutes of Health;Universities;Urban Population;base;clinical research site;clopidogrel;disability;experience;high risk;meetings;member;nervous system disorder;neurosurgery;programs;public health medicine (field);response;square foot;stroke;success;trauma centers;treatment trial

public_health_relevance:
The relevance of this proposal for public health is to identify the University of Kentucky Chandler Medical Center in Lexington Kentucky as a regional center for clinical research in acute illnesses affecting the human nervous system. These conditions include stroke seizures traumatic brain or spinal cord injury and other disorders among the most common causes of death and serious disability affecting American citizens.


application_id: 8868098
project_number: 5R01DE024509-02
project_title: Filifactor alocis interactions with neutrophils
administering_ic: NIDCR
award_notice_date: 2015-02-26
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DE
serial_number: 024509
program_official: LUNSFORD, DWAYNE
project_start_date: 2014-07-01
project_end_date: 2019-03-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 8652094
contact_pi: URIARTE, SILVIA M
other_pis: Not Applicable
congressional_district: 03
department: 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:
Adult;Affect;Animal Model;Bacteria;Bacterial Infections;Biology;Cells;Chronic;Communicable Diseases;Cytoplasmic Granules;Data;Development;Diagnostic;Disease;Enzymes;Etiology;Exocytosis;Functional disorder;Future;Gingiva;Goals;Health;Health Status;High-Throughput Nucleotide Sequencing;Human;Immune;Immune response;Immune system;In Vitro;Infection;Inflammation;Inflammatory;Integration Host Factors;Intention;Killings;Knockout Mice;Knowledge;Lesion;Leukocytes;Maintenance;Matrix Metalloproteinases;Modeling;Mus;Neutrophil Activation;Neutrophil Infiltration;Oral;Oral health;Organism;Outcome;Oxygen;Particulate;Pathogenesis;Pathogenicity;Periodontal Diseases;Periodontitis;Phagosomes;Population;Porphyromonas gingivalis;Process;Research;Research Personnel;Respiratory Burst;Rods (Retina);Role;Site;Staging;Stimulus;TLR2 gene;Technology;Testing;Tissues;Tooth structure;United States;abstracting;antimicrobial;combat;in vivo;innovation;microbial;microbial host;neutrophil;novel therapeutic intervention;novel therapeutics;oral bacteria;oral pathogen;pathogen;pathogenic bacteria;response;subcutaneous;trafficking


application_id: 8867967
project_number: 5R21AA022416-02
project_title: FGF21 and adipose lipolysis in alcoholic fatty liver
administering_ic: NIAAA
award_notice_date: 2015-06-24
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: AA
serial_number: 022416
program_official: OROSZ, ANDRAS
project_start_date: 2014-07-01
project_end_date: 2017-06-30
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 8029790
contact_pi: FENG, WENKE
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alcoholic fatty liver is considered as the earliest pathological alteration of progression in alcoholic liver disease (ALD) from hepatic steatosis to hepatitis fibrosis cirrhosis and even hepatocellular carcinoma. Hepatic reverse transport of freefatty acids (FFAs) derived from adipose hyperlipolysis resulting from alcohol ingestion plays a critical role in fatty liver formation. However the mechanisms by which alcohol regulates adipose tissue lipolysis are unclear. Recently fibroblast growth factor 21 (FGF21) has emerged as a hepatic regulatory factor that acts on multiple targets including the liver itself in an autocrine fashion and importantly on white adipose tissue to regulate lipid homeostasis. We have found that FGF21 plays a critical role in alcohol-induced adipose lipolysis and in hepatic fat accumulation in animal models of ALD and circulating FGF21 levels are significantly increased in patients with ALD and in experimental animal models. However how FGF21 regulates adipose tissue lipolysis during alcohol exposure is not known. The aims of this project are to investigate the role of FGF21 in adipose tissue lipolysis in response to alcohol exposure to improve our understanding of the molecular mechanisms in the regulation and action of this hormone in ALD and to assess the therapeutic potential in alcohol-induced fatty liver formation. To achieve this goal we will carry out the following specific aims. In aim 1 we will determine whether FGF21 plays a stimulatory role in adipose tissue lipolysis and the underlying mechanisms associated with hormone sensitive lipase and perilipin pathway during alcohol exposure using FGF21 knockout and transgenic overexpression mouse models. In the second aim we will test our hypothesis that adipose tissue specific disruption of FGF21 decreases FFA release and hepatic uptake and attenuates alcohol-induced fatty liver formation using adipose selective -klotho knockout mice.

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

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


application_id: 8867889
project_number: 5R01NR014189-04
project_title: Early Detection and Prevention of Mild Cognitive Impairment due to Cerebrovascular Disease
administering_ic: NINR
award_notice_date: 2015-06-22
opportunity_number: RFA-NR-12-010
application_type: 5
activity_code: R01
ic: NR
serial_number: 014189
program_official: TULLY, LOIS
project_start_date: 2012-09-26
project_end_date: 2016-06-30
study_section: ZNR1-REV-T(13)
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY A
other_pis: MOSER, DEBRA KAY
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): There is a great unmet need to distinguish clinically between the different causes of cognitive impairment in elderly individuals for the sake of early diagnosis and therapeutic intervention designed to improve outcomes for patients. The University of Kentucky Alzheimer's Disease Center (UK-ADC) has been at the forefront of studying the most prevalent causes of Non-AD MCI demonstrating that over two-thirds of elderly patients have non-AD brain conditions that deleteriously affect cognition. We have chosen to focus on MCI due to cerebrovascular disease (MCI-CVD). This application focuses on defining the pathological underpinnings and relationships of specific risk factors to MCI-CVD developing clinical diagnostic criteria for MCI-CVD using imaging serum and CSF biomarkers that will also allow longitudinal evaluation and assessment of therapeutic interventions in MCI-CVD. As such the current application represents a comprehensive bench-to-bedside translational program designed to directly increase our understanding of and impact the major cause of cognitive decline in the elderly population today. The multidisciplinary team represents leaders in the field with proven track histories of scientific accomplishments and collaborative enterprise in the area of MCI. Successful completion of project aims will allow an integrated understanding of MCI-CVD with the potential for tremendous impact on one of the major healthcare crises facing the nation today.      PUBLIC HEALTH RELEVANCE: Mild cognitive impairment (MCI) is often conflated with early Alzheimer's disease (AD) although a large proportion of individuals with MCI lack AD pathology. Especially among individuals beyond 85 years of age the prevalence of non-AD brain diseases such as cerebrovascular disease (CVD) surpasses that of advanced AD. We have chosen to focus on MCI due to cerebrovascular disease (MCI-CVD). The current application represents a comprehensive bench-to-bedside translational program designed to directly increase our understanding of and impact the major cause of cognitive decline in the elderly population today. The multidisciplinary team represents leaders in the field with proven track histories of scientific accomplishments and collaborative enterprise in the area of MCI. Successful completion of project aims will allow an integrated understanding of MCI-CVD with the potential for tremendous impact on one of the major healthcare crises facing the nation today.

project_terms:
Affect;Age-Years;Alzheimer's Disease;Area;Autopsy;Biological;Biological Markers;Blood;Brain;Brain Diseases;Brain Pathology;Cardiovascular Diseases;Cerebrospinal Fluid;Cerebrovascular Disorders;Clinical;Clinical Trials;Cognition;Cognitive;Data;Dementia;Diagnostic;Diagnostic Imaging;Doctor of Philosophy;Early Diagnosis;Elderly;Ensure;Etiology;Evaluation;Healthcare;Image;Impaired cognition;Individual;Intervention;Kentucky;Medical;Microvascular Dysfunction;Modification;Natural History;Neuropsychological Tests;Outcome;Pathology;Patients;Persons;Placebo Control;Population;Prevalence;Prevention;Randomized;Recording of previous events;Research Personnel;Risk Factors;Scientific Advances and Accomplishments;Serum;Staging;Statistical Models;Testing;Therapeutic Intervention;Universities;bench to bedside;cohort;design;digital;disorder risk;improved;mild cognitive impairment;multidisciplinary;older patient;programs;public health relevance;standard of care;success;therapy design

public_health_relevance:
Mild cognitive impairment (MCI) is often conflated with early Alzheimer's disease (AD) although a large proportion of individuals with MCI lack AD pathology. Especially among individuals beyond 85 years of age the prevalence of non-AD brain diseases such as cerebrovascular disease (CVD) surpasses that of advanced AD. We have chosen to focus on MCI due to cerebrovascular disease (MCI-CVD). The current application represents a comprehensive bench-to-bedside translational program designed to directly increase our understanding of and impact the major cause of cognitive decline in the elderly population today. The multidisciplinary team represents leaders in the field with proven track histories of scientific accomplishments and collaborative enterprise in the area of MCI. Successful completion of project aims will allow an integrated understanding of MCI-CVD with the potential for tremendous impact on one of the major healthcare crises facing the nation today.


application_id: 8867214
project_number: 5R01DE014605-13
project_title: Inter-kingdom signaling by A. actinomycetemcomitans
administering_ic: NIDCR
award_notice_date: 2015-06-26
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DE
serial_number: 014605
program_official: LUNSFORD, DWAYNE
project_start_date: 2003-02-01
project_end_date: 2019-07-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 1859425
contact_pi: DEMUTH, DONALD R
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
ATP-Binding Cassette Transporters;Actinobacillus actinomycetemcomitans;Address;Adult;Antitoxins;Atherosclerosis;Bacterial Proteins;Binding (Molecular Function);Binding Proteins;Bordetella;Catecholamines;Cell Density;Cells;Cellular Stress;Cellular Stress Response;Complex;Coupled;Data;Disease;Enterobactin;Environment;Expenditure;Family;Funding;Genes;Genome;Genomics;Gingival Pocket;Goals;Growth;Health;Heart Diseases;Hormones;Infection;Inflammatory;Iron;Lactoferrin;Ligands;Mediating;Microbial Biofilms;Mouth Diseases;Operon;Oral cavity;Organism;Orphan;Pathway interactions;Peptide Hydrolases;Periodontitis;Phagocytes;Phenotype;Population;Prevention;Production;Proteins;Regulation;Regulon;Rheumatoid Arthritis;Role;Siderophores;Signal Transduction;Stimulus;Stress;System;Testing;Toxin;Transferrin;United States;Virulence;Work;biological adaptation to stress;deprivation;functional outcomes;macrophage;mouse model;mutant;neutrophil;pathogen;periplasm;prevent;quorum sensing;receptor;response;sensor;solute;targeted treatment;therapeutic target;uptake


application_id: 8867192
project_number: 5K02DA035116-03
project_title: Social Networks and HIV Risk Behaviors of Special Populations of Drug Users
administering_ic: NIDA
award_notice_date: 2015-06-12
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: 2016-06-30
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:
Accounting;African American;Applications Grants;Attitude;Biological Assay;Centers for Disease Control and Prevention (U.S.);Communities;Crime;Criminal Justice;Data;Data Collection;Development;Drug Prescriptions;Drug abuse;Drug usage;Drug user;Emotional;Female;Foundations;Future;Gender;Goals;Grant;HIV;HIV Infections;HIV diagnosis;HIV risk;Health;Health Services;Healthcare;Hepatitis C virus;Imprisonment;Independent Scientist Award;Individual;Instruction;Intervention;Kentucky;Knowledge;Life;Link;Measures;Medical;Methodology;National Institute of Drug Abuse;Network-based;Oxycodone;Pathway Analysis;Patient Self-Report;Pharmaceutical Preparations;Physicians;Population;Prevalence;Prisons;Race;Research;Research Personnel;Risk;Risk Behaviors;Rural;S-nitro-N-acetylpenicillamine;Services;Social Network;Spirituality;Strategic Planning;Structure;System;Training;Training Activity;United States National Institutes of Health;Unsafe Sex;Woman;career;density;disorder prevention;experience;falls;health care service utilization;health disparity;high risk;high risk sexual behavior;improved;injection drug use;innovation;instrument;male;men;multilevel analysis;named group;practical application;probation;public health medicine (field);recidivism;responsible research conduct;rural area;skills;social;substance abuse treatment;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: 8867031
project_number: 5F30CA186640-02
project_title: Integration of Glycolysis with the Epithelial-Mesenchymal Transition
administering_ic: NCI
award_notice_date: 2015-06-23
opportunity_number: PA-11-110
application_type: 5
activity_code: F30
ic: CA
serial_number: 186640
program_official: DAMICO, MARK W
project_start_date: 2014-07-07
project_end_date: 2015-08-31
study_section: Special Emphasis Panel[ZRG1-F09B-P(20)L]
contact_pi_person_id: 11888394
contact_pi: SPAULDING, ROBERT T
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 SUMMARYOverexpression of Zinc finger E-box binding homeobox 1 (ZEB1) in tumor cells promotes the epithelial-mesenchymal transition (EMT) that is associated with enhanced invasive and metastatic capabilities and theacquisition of cancer-stem cell characteristics. Understanding how ZEB1 is regulated should permit theidentification of druggable targets that can be exploited for the treatment of metastatic cancers that over-express ZEB1 including pancreatic and non-small cell lung cancers (NSCLC). The HIF-1-inducible 6-phosphofructo-2-kinase/fructose-26-bisphosphase-3 (PFKFB3) is over-expressed in tumors activatesglycolysis via its product fructose-26-bisphosphate and was recently found to be an activator of cyclin-dependent kinases (Cdks). Given the accumulating evidence suggesting a role for cell cycle regulators such asthe Cdks in the EMT we postulated that PFKFB3 may be essential for the acquisition/maintenance ofmesenchymal traits in tumor cells. In preliminary studies we demonstrate that PFKFB3 silencing in A549NSCLC cells and MIA PaCa-2 pancreatic cancer cells causes a marked decrease in ZEB1 expressionand reverses the EMT as assessed by increased E-cadherin (an epithelial marker) and decreasedvimentin/fibronectin (mesenchymal markers) levels. We further show that knockdown of PFKFB3 decreasesthe phosphorylation of the retinoblastoma (RB) protein a Cdk target and the expression of the STAT3 proteinboth of which have recently been found to regulate ZEB1 expression. We therefore hypothesize thatupregulation of PFKFB3 in tumor cells increases ZEB1 expression via an RB and/or STAT3-dependentmechanism leading to the acquisition/maintenance of a mesenchymal phenotype associated with increasedmetastatic ability and stemness. The following specific aims will be pursued to test this hypothesis: (1) To studythe functional interaction of PFKFB3 with ZEB1 and its effect on invasion and cancer stem cell properties invitro; and (2) To examine the functional interaction of PFKFB3 with ZEB1 in the progression of metastaticpancreatic adenocarcinoma in vivo. At the end of these studies we expect to have established a novel functionfor PFKFB3 in the regulation of the ZEB1 gene and EMT which may have therapeutic implications for thetreatment of aggressive metastatic cancers such as pancreatic adenocarcinoma.

project_terms:
6-Phosphofructo-2-kinase;6-Phosphofructokinase;A549;Adjuvant;Advanced Malignant Neoplasm;Binding (Molecular Function);Boxing;Cancer cell line;Cancer stem cell;Cell Cycle;Cells;Cessation of life;Characteristics;Clinic;Clinical;Cyclin-Dependent Kinases;Data Set;Development;Disseminated Malignant Neoplasm;E-Cadherin;Embryonic Development;Epithelial;Fibronectins;Fructose;Genes;Glycolysis;Homeobox;In Vitro;Invaded;KRAS2 gene;Lead;Maintenance;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Mesenchymal;Metastatic Pancreatic Adenocarcinoma;Metastatic to;Molecular Profiling;Mutate;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Oncogenic;Operative Surgical Procedures;Organ;PTEN gene;Pancreas;Pancreatic Adenocarcinoma;Patients;Phase I Clinical Trials;Phenotype;Phosphorylation;Play;Property;Proteins;Regulation;Resected;Resistance;Retinoblastoma;Retinoblastoma Protein;Role;STAT3 gene;Solid Neoplasm;Testing;Therapeutic;Transcription Repressor/Corepressor;Treatment Protocols;Up-Regulation (Physiology);Vimentin;Xenograft Model;Zinc Fingers;active method;cancer cell;design;drug development;epithelial to mesenchymal transition;fructose 26-diphosphate;fructose-6-phosphate;in vivo;inhibitor/antagonist;molecular phenotype;neoplastic cell;novel;novel therapeutic intervention;overexpression;pancreatic cancer cells;prevent;public health relevance;stemness;trait;transcription factor;transcriptomics;tumor;tumor growth

public_health_relevance:
PROJECT NARRATIVEWe are proposing to determine the role of PFKFB3 in the regulation of the metastasis-causing ZEB1 protein inorder to develop better approaches to treat metastatic cancers marked by elevated ZEB1 protein levels.Importantly if PFKFB3 is found to regulate ZEB1 and to be required for metastatic potential then trials will bedesigned to specifically test the ability of the PFKFB3 inhibitor PFK158 to suppress the development ofmetastases in patients who have resected cancers or limited metastases. __SpecificAimsTextDelimiter__ SPECIFIC AIMS - Integrating Glycolysis with the Epithelial-Mesenchymal TransitionCancer-related deaths are predominantly due to the metastatic spread of neoplastic cells which subsequentlydisrupt vital organ vasculature and functions. Emerging evidence suggests the epithelial-mesenchymaltransition (EMT) is a driver towards a molecular signature that endows neoplastic cells with the ability toinvade metastasize and become secondary tumors [1-4]. Zinc finger E-box binding homeobox 1 (ZEB1) is akey transcriptional repressor involved in epithelial plasticity during embryonic development [5 6]. Re-expression of the ZEB1 protein in tumor cells induces the EMT that is associated with enhanced invasive andmetastatic capabilities [7-10] and acquisition of cancer stem cell properties [11-13]. ZEB1 expression has alsobeen implicated in conferring resistance to Ras-directed therapies in highly malignant pancreatic and lungcancer cell lines that carry mutated KRAS genes [13 14]. Although ZEB1 is an attractive target for drugdevelopment agents that selectively disrupt transcription factor functions are difficult to identify and have notproven useful in the clinic. Accordingly the identification of druggable targets that regulate ZEB1expression may enable the design of novel therapeutic approaches to inhibit the metastatic spread ofneoplastic cells that over-express ZEB1.The HIF-1-inducible 6-phosphofructo-2-kinase/fructose 26-bisphosphatase-3 (PFKFB3)catalyzes the conversion of the glycolytic intermediate fructose 6-phosphate (Fru-6-P) tofructose 26-bisphosphate (Fru-26-P2) [15 16]. Fru-26-P2 is recognized as the mostpotent allosteric activator of 6-phosphofructo-1-kinase (PFK1) [16 17] which catalyzes arate-limiting step of glycolysis [17]. Studies have shown that PFKFB3 is (1) highlyexpressed in tumors [15 18]; (2) essential in oncogenic transformation driven by RAS[19] and loss of PTEN [20]; and (3) required for tumor growth in various xenograft models[21 22]. Furthermore we have recently demonstrated that PFKFB3 increases the activityof cyclin-dependent kinases (CDKs) [23]. Importantly deregulation of CDK activity intumor cells is known to induce ZEB1 expression leading to the EMT and expression ofcancer stem cell markers [8 9 24]. Taken together these studies suggest that PFKFB3may play a crucial role in the acquisition of a mesenchymal phenotype and increasedmetastatic ability. Analysis of transcriptomic data sets from Oncomine revealed thatPFKFB3 expression highly correlates with ZEB1 expression. In preliminary studies wehave found that: (1) silencing of PFKFB3 decreases ZEB1 expression and promotes amolecular phenotype consistent with the reversal of EMT (i.e. MET) in A549 and MIAPaCa-2 cells ; (2) PFKFB3 is required for the invasive ability of A549 and MIA PaCa-2cells; and (3) silencing of PFKFB3 in A549 and MIA PaCa-2 cells markedly decreases thephosphorylation of the retinoblastoma (RB) protein a CDK target and the expression ofthe STAT3 protein both of which have recently been found to regulate the expression ofthe ZEB1 gene [8 9 25 26].The central hypothesis of this application is that upregulation of PFKFB3 integrates glycolysis with the EMTby increasing ZEB1 expression via an RB and/or STAT3-dependent mechanism leading to the acquisition of amesenchymal phenotype associated with increased metastatic ability and stemness. We will test thishypothesis by conducting the following specific aims:Aim 1. To study the functional interaction of PFKFB3 with ZEB1 and its effect on invasion and cancerstem cell properties in vitro.Aim 2. To examine the functional interaction of PFKFB3 with ZEB1 in the progression of metastaticpancreatic adenocarcinoma in vivo.A clinical grade inhibitor of PFKFB3 developed in our lab PFK158 (Advanced Cancer Therapeutics LLC) willbe tested in a phase I clinical trial in advanced solid tumor patients starting in November 2013. Thereforeconfirmation of a novel function for PFKFB3 in the regulation of the ZEB1 gene may promptly lead to thetesting of PFK158 as an adjuvant to surgery as well as part of an active treatment regimen to prevent/treatmetastatic cancers characterized by high ZEB1 expression.


application_id: 8866335
project_number: 272201000033I-2-27200001-1
project_title: Task A52:Testing Therapeutics for MDR Pseudomonas aeruginosa
administering_ic: NIAID
project_start_date: 2013-06-28
project_end_date: 2014-06-25
contact_pi_person_id: 12445345
contact_pi: WARAWA, JONATHAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_terms:
Animal Model;Communicable Diseases;Contracts;Development;Pseudomonas aeruginosa;Standardization;Testing;Therapeutic;animal model development;efficacy testing


application_id: 8866249
project_number: 5KL2TR000116-05
project_title: Kentucky Center for Clinical and Translational Science
administering_ic: NCATS
award_notice_date: 2015-04-30
opportunity_number: RFA-RM-10-001
application_type: 5
activity_code: KL2
ic: TR
serial_number: 000116
program_official: BRAZHNIK, OLGA
project_start_date: 2011-06-01
project_end_date: 2016-09-30
study_section: ZRR1-CR-1(01)
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
At the University of Kentucky (UK) we have established the Center for Clinical and Translational Science (CCTS) as a home for clinical and translational research. UK is located in Lexington on the western edge of mid-Appalachia one ofthe poorest areas ofthe country where there are unprecedented disparities in disease and mortality. Many of these disparities stem from risky behaviors such as smoking drug abuse and obesity. In this proposal our overarching goal is to transform the pace effectiveness and quality of translational research at UK which will result in better health for the people of mid-Appalachia. Scientific discovery offers the potential for improved care with community-based research offering a faster impact on health through a better dissemination of optimal medical care. However scientific discoveries often do not reach the community due to the many difficulties with navigating the complex process of clinical and translational research. In this application we will capitalize on our strengths in education basic and clinical sciences as well as our outstanding programs in practice- and community- based participatory research. These efforts will result in scientific discovery that will impact the health ofthe Appalachian rural community in the near term and prime the pipeline for the future. To accomplish these goals UK will form a collaboration with Marshall University which is 2 hr away in Huntington WV. In addition we will form an Appalachian Translational Reseach Network involving not only Marshall but also the CTSAs at the Ohio State University University of Cinncinati Morehead University and Pikeville School of Osteopathic Medicine. This network will be especially important in the further development of our strong programs in community based participatory research. To help integrate our efforts we have developed an innovative group of faculty CATalysts who will build collaborative team science programs backed by generous pilot funding that will target novel ideas at all levels of science. New CCTS programs in "Drug Development" "Novel Methodologies" and "Risk-Related Behavior Research" will capitalize on our strengths engage investigators with diverse areas of expertise and will more quickly impact the health ofthe Appalachian community. We have recently recruited a new leader in Biomedical Informatics and have invested heavily in this program which will greatly improve our ability to transform data into knowledge throughout the CCTS. Through these initiatives UK will fulfill its mandate as Kentucky's flagship university to improve the health of Central Appalachia and thereby add unique value to improvements in the health ofthe nation.

project_terms:
Address;Administrator;Aging;Appalachian Region;Area;Attention;Back;Basic Science;Behavior;Businesses;Cardiovascular Diseases;Caring;Censuses;Clinical;Clinical Research;Clinical Sciences;Collaborations;Communities;Complex;Country;County;Data;Dentistry;Development;Disease;Drug abuse;Economically Deprived Population;Educational aspects;Effectiveness;Environment;Faculty;Foundations;Funding;Future;Future Generations;Goals;Health;Health Sciences;Health education;Home environment;Huntington Disease;Institution;Instruction;Kentucky;Knowledge;Life;Malignant Neoplasms;Marshal;Medical;Medicine;Mentors;Methodology;Mortality Vital Statistics;Obesity;Ohio;Osteopathic Medicine;Pharmacy facility;Population;Positioning Attribute;Poverty;Process;Productivity;Professional Practice;Public Health Nurses;Public Health Nursing;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Research Training;Resources;Risk;Risk Behaviors;Rural;Rural Community;Rural Health;Rural Population;Schools;Science;Services;Smoking;Smoking Behavior;Solutions;Source;Students;Training;Training Programs;Training and Education;Translational Research;Underserved Population;Universities;base;biomedical informatics;cardiovascular health;career;career development;catalyst;college;community based participatory research;design;diabetes risk;drug development;improved;innovation;misuse of prescription only drugs;novel;practice-based research network;programs;stem

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


application_id: 8866248
project_number: 5TL1TR000115-05
project_title: Kentucky Center for Clinical and Translational Science
administering_ic: NCATS
award_notice_date: 2015-04-30
opportunity_number: RFA-RM-10-001
application_type: 5
activity_code: TL1
ic: TR
serial_number: 000115
program_official: BRAZHNIK, OLGA
project_start_date: 2011-06-01
project_end_date: 2016-09-30
study_section: ZRR1-CR-1(01)
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
At the University of Kentucky (UK) we have established the Center for Clinical and Translational Science (CCTS) as a home for clinical and translational research. UK is located in Lexington on the western edge of mid-Appalachia one of the poorest areas of the country where there are unprecedented disparities in disease and mortality. Many of these disparities stem from risky behaviors such as smoking drug abuse and obesity. In this proposal our overarching goal is to transform the pace effectiveness and quality of translational research at UK which will result in better health for the people of mid-Appalachia. Scientific discovery offers the potential for improved care with community-based research offering a faster impact on health through a better dissemination of optimal medical care. However scientific discoveries often do not reach the community due to the many difficulties with navigating the complex process of clinical and translational research. In this application we will capitalize on our strengths in education basic and clinical sciences as well as our outstanding programs in practice- and community- based participatory research. These efforts will result in scientific discovery that will impact the health of the Appalachian rural community in the near term and prime the pipeline for the future. To accomplish these goals UK will form a collaboration with Marshall University which is 2 hr away in Huntington WV. In addition we will form an Appalachian Translational Reseach Network involving not only Marshall but also the CTSAs at the Ohio State University University of Cinncinati Morehead University and Pikeville School of Osteopathic Medicine. This network will be especially important in the further development of our strong programs in community based participatory research. To help integrate our efforts we have developed an innovative group of faculty CATalysts who will build collaborative team science programs backed by generous pilot funding that will target novel ideas at all levels of science. New CCTS programs in "Drug Development" 'Novel Methodologies" and "Risk-Related Behavior Research" will capitalize on our strengths engage investigators with diverse areas of expertise and will more quickly impact the health of the Appalachian community. We have recently recruited a new leader in Biomedical Informatics and have invested heavily in this program which will greatly improve our ability to transform data into knowledge throughout the CCTS. Through these initiatives UK will fulfill its mandate as Kentucky's flagship university to improve the health of Central Appalachia and thereby add unique value to improvements in the health of the nation.

project_terms:
Address;Administrator;Aging;Appalachian Region;Area;Attention;Back;Basic Science;Behavior;Businesses;Cardiovascular Diseases;Caring;Censuses;Clinical;Clinical Research;Clinical Sciences;Collaborations;Communities;Complex;Country;County;Data;Dentistry;Development;Disease;Drug abuse;Economically Deprived Population;Educational aspects;Effectiveness;Environment;Faculty;Foundations;Funding;Future;Future Generations;Goals;Health;Health Sciences;Health education;Home environment;Huntington Disease;Institution;Instruction;Kentucky;Knowledge;Life;Malignant Neoplasms;Marshal;Medical;Medicine;Mentors;Methodology;Mortality Vital Statistics;Neurosciences;Obesity;Ohio;Osteopathic Medicine;Pharmacy facility;Population;Positioning Attribute;Poverty;Process;Productivity;Professional Practice;Public Health Nurses;Public Health Nursing;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Research Training;Resources;Risk;Risk Behaviors;Rural;Rural Community;Rural Health;Rural Population;Schools;Science;Services;Smoking;Smoking Behavior;Solutions;Source;Students;Training;Training Programs;Training and Education;Translational Research;Underserved Population;Universities;base;biomedical informatics;cardiovascular health;career;career development;catalyst;college;community based participatory research;design;diabetes risk;drug development;improved;innovation;misuse of prescription only drugs;novel;practice-based research network;programs;stem

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


application_id: 8864515
project_number: 1R01HL127682-01
project_title: Specific Lysis for Large-Volume High-Purity Endothelial Progenitor Cell Isolates
administering_ic: NHLBI
award_notice_date: 2015-07-14
opportunity_number: PAR-13-137
application_type: 1
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 viability
and 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 Therapy;Cells;Clinical;Clinical Research;Cytolysis;Data;Deterioration;Diagnostic;Environment;Follow-Up Studies;Future;Goals;Growth;Heart;Home environment;Hour;In Vitro;Individual;Injection of therapeutic agent;Leukocytes;Life;Light;Magnetism;Medical;Methodology;Methods;Modality;Morbidity - disease rate;Mortality Vital Statistics;Mus;Myocardial Infarction;Myocardial Ischemia;Neoplasm Circulating Cells;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 (motion);Stem cells;Sterilization;System;T-Lymphocyte;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;new technology;novel;novel strategies;peripheral blood;polymerization;prognostic;prototype;public health relevance;repaired;scale up;skills;subcutaneous;time use


application_id: 8858105
project_number: 1R21NS091096-01
project_title: Small G-protein signaling in brain injury
administering_ic: NINDS
award_notice_date: 2015-03-31
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: NS
serial_number: 091096
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2015-04-01
project_end_date: 2017-03-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 7875195
contact_pi: ANDRES, DOUGLAS ALLEN
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a leading cause of death and permanent disability in the United States with TBI being a contributing factor to a third of all injury-related deaths. Long-term TBI-related disability results in reduced quality of ife for the patient and prolonged medical social and economic effects on society. TBI is a heterogeneous disease. Mechanisms of brain damage underlying focal contusion are associated with localized regions of necrotic neuron death driven by oxidative damage and excitotoxicity. In contrast axonal injury and persistent tissue inflammation are thought to be major contributors to morbidity with diffuse mild TBI (mTBI). Due to the diversity of brain damage mechanisms that play a role in TBI therapeutic interventions that target multiple mechanisms are likely to have a maximal impact for improving the quality of life of patients. The long-term objective of these studies is to understand novel signaling pathways that promote acute neuron survival and limit axonal injury and neuroinflammatory processes following TBI with the hypothesis that manipulation of these pathways will have broad therapeutic potential. Our preliminary data indicates that Rin GTPase directed signaling plays a unique and critical role in functional recovery following TBI. First Rin deficiency promotes cell survival including activation of the Akt pathway to reduce neurodegeneration and cognitive dysfunction after contusion TBI. Second loss of Rin attenuates axonal degeneration and improves cognition after diffuse mild TBI. These data motivate the central hypothesis that: (1) Rin signaling plays a central role in cellular and functional recovery over a spectrum from mild to severe brain trauma and (2) that inhibition of Rin signaling will therefore have broad therapeutic potential in the setting of TBI. Using clinically-relevant mouse models of contusive brain injury and diffuse mTBI we will evaluate our hypothesis using two specific aims. Aim 1 will use Rin-/- mice to determine whether Rin deficiency protects against contusive TBI by reducing neuron death and improving cognitive function in part via modulation of a novel Akt signaling pathway. Aim 2 will examine whether Rin loss protects against inflammation and/or attenuates axonal injury to lessen neurobehavioral dysfunction following repeated mTBI. This innovative multi-system approach will generate insights into the molecular mechanisms of recovery and may lead to novel strategies to rescue or replace damaged or lost neurons after brain trauma.

project_terms:
Acute;Animal Model;Attenuated;Behavioral;Brain;Brain Injuries;Cause of Death;Cell Survival;Cessation of life;Clinical;Cognition;Contusions;Data;Diffuse;Diffuse Brain Injury;Disease;Economics;Functional disorder;GTP-Binding Proteins;Guanosine Triphosphate Phosphohydrolases;Hippocampus (Brain);Impaired cognition;Inflammation;Injury;Lead;Life;Mediating;Medical;Molecular;Molecular Analysis;Monomeric GTP-Binding Proteins;Morbidity - disease rate;Mus;Necrosis;Nerve Degeneration;Neurons;Outcome;Pathology;Pathway interactions;Patients;Persons;Play;Population;Process;Quality of life;Recovery;Recovery of Function;Role;Signal Pathway;Signal Transduction;Societies;System;Testing;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Tissues;Transgenic Animals;Traumatic Brain Injury;United States;axon injury;axonal degeneration;clinically relevant;cognitive function;design;disability;economic cost;effective therapy;excitotoxicity;improved;in vivo;innovation;insight;mild traumatic brain injury;mouse model;neurobehavioral;new therapeutic target;novel;novel strategies;novel therapeutics;oxidative damage;public health relevance;relating to nervous system;research study;social;therapeutic development

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a leading cause of death and disability in the United States often resulting in persistent deficits for which there are no effective treatments. The long-term objective of these studies is to understand Rin G-protein signaling mechanisms that promote acute neuron survival and limit axonal injury and neuroinflammatory processes following TBI with the hypothesis that manipulation of these pathways will have broad therapeutic potential in the setting of TBI.


application_id: 8857369
project_number: 5R01AI101373-04
project_title: Role of Rapid IFNg Secretion by CD*+ T cells in Clearance of Food Borne Listeria
administering_ic: NIAID
award_notice_date: 2015-05-05
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AI
serial_number: 101373
program_official: MILLS, MELODY
project_start_date: 2012-06-20
project_end_date: 2017-05-31
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
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:
DESCRIPTION (provided by applicant): Listeria monocytogenes (Lm) is important an important pathogen to study because: 1) it causes life threatening food borne infections of significant public health concern 2) it is a genetically tractable organism with a unique intracellular lifestyle used as a tool for understanding the cell biology of mammalian cells and 3 systemic (i.v.) listeriosis is a highly reproducible infection frequently used by immunologists to study cell- mediated immune responses. Due to the lack of a small animal model that closely mimics human disease we still know very little about oral transmission of Lm or why the innate susceptibility to developing severe gastroenteritis sepsis and meningoencephalitis varies among individuals. To address this knowledge gap we recently developed a new model of oral listeriosis using mice fed Lm-contaminated food. This natural feeding model revealed clear differences in the ability of Lm to colonize the gut and spread systemically in susceptible (BALB) vs. resistant (B6) mice. Thus for the first time we can now study how gut-adapted Lm that survive digestive processes in the stomach are able to colonize the intestinal mucosa and serve as a nidus for continual seeding of peripheral tissues in susceptible mice unable to quickly clear the gut infection. Since the vast majority of patients hospitalized with listeriosis can be considered immune compromised in some way it has long been thought that protective immune responses were critical for limiting the infection to a mild gastroenteritis in resistant individuas. Our central hypothesis predicts that one such innate immune mechanism is the rapid secretion of IFN by a subset of memory phenotype CD8+ T cells. We postulate that T cell-derived IFN can rapidly initiate clearance mechanisms in B6 mice and that the delay in activation of CD8+ T cells in BALB mice allows Lm to replicate exponentially and spread to systemic tissues. This application has three specific aims: (1) to identify the cell types in the colon that support Lm growth and thus serve as the targets of protective innate immune responses; (2) to identify the specific subsets of CD8+ T cells that rapidly secrete IFN after ingestion of Lm and show that this T cell-derived IFN can rapidly limit the intracellular growth of Lm in the colon; (3) to idenify IFN-dependent innate immune mechanisms that promote rapid clearance of Lm in peripheral tissues after dissemination from the gut. A key strategy in this application will be the use of a unique adoptive transfer system wherein T cells from a responsive mouse are injected into a MHC-matched non-responsive mouse. This powerful approach will allow us to specifically isolate the function of IFN rapidly produced by CD8+ T cells while leaving all other innate immune mechanisms intact. The expected outcomes of the proposed studies are: [1] significant new insights into the pathogenic life style of food borne Lm and [2] a better understanding of the innate immune mechanisms that determine host resistance/susceptibility to intracellular bacterial pathogens.

project_terms:
Address;Adoptive Transfer;Animal Model;Antigens;Bacteria;CD8-Positive T-Lymphocytes;CD8B1 gene;Cells;Cellular biology;Cheese;Colon;Dendritic Cells;Disease;Dose;Eating;Enterocytes;Feces;Food;Gastroenteritis;Gastrointestinal tract structure;Genes;Growth;Hepatocyte;Host resistance;Human;Immune;Immune response;Immunologist;In Vitro;Individual;Infection;Inflammatory;Ingestion;Interferons;Interleukin-12;Interleukin-18;Intestinal Mucosa;Intestines;Intravenous;Killings;Kinetics;Knowledge;Lamina Propria;Left;Life;Life Style;Listeria;Listeria monocytogenes;Listeriosis;Liver;Lymphocyte;M cell;Mammalian Cell;Meat;Memory;Meningoencephalitis;Modeling;Mortality Vital Statistics;Mus;Natural Immunity;Oral;Organism;Outcome;Pathway interactions;Patients;Peripheral;Phenotype;Population;Predisposition;Process;Proteins;Research Personnel;Resistance;Role;Seeds;Sepsis;Septicemia;Severities;Signal Transduction;Small Intestines;Source;Spleen;Stomach;Symptoms;System;T-Lymphocyte;T-Lymphocyte Subsets;Testing;Time;Tissues;adaptive immunity;cell mediated immune response;cell type;cytokine;feeding;foodborne;foodborne infection;human disease;in vivo;insight;macrophage;oral infection;pathogen;public health medicine (field);receptor;response;tool;transmission process;unpasteurized

public_health_relevance:
Listeria monocytogenes (Lm) is transmitted by ingestion of contaminated "ready-to-eat" food products such as unpasteurized cheeses deli meats and produce. Human infections vary greatly in severity from a mild self- limiting gastroenteritis to life-threatening septicemia and meningoencephalitis and the host susceptibility factors that contribute to this range of disease are not defined. In this study we test the idea that resistantindividuals respond to infection by rapidly producing a protective protein that activates multiple killing mechanisms that quickly clear the bacteria while susceptible individuals lack the ability t orchestrate this rapid immune response.


application_id: 8857365
project_number: 5R01AI095307-04
project_title: Alternative macrophage activation in acute Pseudomonas pneumonia
administering_ic: NIAID
award_notice_date: 2015-06-12
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AI
serial_number: 095307
program_official: DAVIDSON, WENDY F
project_start_date: 2012-07-01
project_end_date: 2016-06-30
study_section: Immunity and Host Defense Study Section[IHD]
contact_pi_person_id: 8968639
contact_pi: FEOLA, DAVID
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): Alternative macrophage activation regulates inflammatory responses to pathogenic organisms. Most work to date has characterized their role in Th2-type immune responses. Alternatively activated macrophages (AAM) have been shown to inhibit classically activated macrophage proliferation and function as well as to suppress T cell mediated immune responses through the production of the type II cytokine transforming growth factor (TGF)- and arginase-1. While primarily functioning to orchestrate remodeling and repair mechanisms arginase-1 and TGF are also important in controlling lung homeostasis and suppressing inflammation. The function of AAM in regulating the inflammatory response to extracellular Gram-negative bacterial infection in the lungs has not been characterized. Understanding the role of AAM in this setting is critical for advancing our understanding of immune mechanisms affecting patients with cystic fibrosis (CF) and other chronic pulmonary inflammatory conditions. CF causes progressive life-threatening lung damage due in large part to repeated dysregulated inflammatory responses to Pseudomonas aeruginosa infection. Therefore this work will address the hypothesis that alternatively activatedmacrophages decrease pulmonary inflammation in P. aeruginosa infection and that this is dependent upon production of TGF and arginase-1. We will utilize a model of P. aeruginosa pneumonia in normal and genetically engineered mice to address 3 distinct aims. Aim 1 will determine whether regulation of inflammation caused by P. aeruginosa lung infection is dependent upon alternative macrophage activation. Aim 2 will address whether AAM regulation of T cell disposition can control inflammation and lung damage through the production of TGF. Aim 3 will determine whether arginase-1 expression by macrophages is required to prevent inflammation induced by P. aeruginosa pneumonia. Mouse models with genetically altered AAM TGF signaling and macrophage-specific arginase-1 production will be used along with adoptive transfer methodologies and complementary in vitro experiments. The impact of these alterations will be evaluated in terms of inflammation classical macrophage function and T cell subset activation and function to determine the important mechanisms employed by macrophages in regulating these responses. Highlighting the clinical relevance of this work is the use of the antimicrobial agent azithromycin as an immunomodulator in patients with CF. This drug has been shown to slow pulmonary function decline and decrease morbidity in CF patients infected with Pseudomonas but the beneficial mechanistic effect is unknown. Recently it has been shown in both in vitro and animal studies that azithromycin polarizes macrophages to an alternative-like phenotype dramatically increasing the expression of arginase-1. This data along with the successful long-term use of azithromycin in patients with CF make studying the role of alternative macrophage activation in response to Pseudomonas pneumonia attractive and likely to yield novel therapeutic targets for intervention to alter this destructive cycle of inflammation and airway damage.

project_terms:
Acute;Address;Adoptive Transfer;Affect;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Attenuated;Azithromycin;Bacterial Infections;Bacterial Pneumonia;Cell physiology;Cells;Characteristics;Chronic;Chronic lung disease;Cystic Fibrosis;Data;Disease;Exposure to;Future;Genes;Genetically Engineered Mouse;Goals;Gram-Negative Bacterial Infections;Homeostasis;Immune;Immune response;Immunomodulators;In Vitro;Infection;Inflammation;Inflammatory;Inflammatory Response;Injury;Intervention;Knowledge;Lead;Life;Lung;Lung Inflammation;Macrophage Activation;Methodology;Methods;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mouse Strains;Mus;Organism;Pathology;Patients;Pattern;Pharmaceutical Preparations;Phenotype;Play;Pneumonia;Process;Production;Pseudomonas;Pseudomonas aeruginosa;Pulmonary Inflammation;Randomized Clinical Trials;Regulation;Role;Series;Signal Transduction;Staging;T cell differentiation;T cell regulation;T-Lymphocyte;T-Lymphocyte Subsets;Time;Transforming Growth Factors;Up-Regulation (Physiology);Work;airway inflammation;antimicrobial drug;arginase;base;cell mediated immune response;clinically relevant;cystic fibrosis mouse;cystic fibrosis patients;cytokine;evidence base;experience;extracellular;functional decline;in vivo;macrophage;mouse model;neutrophil;new therapeutic target;pathogen;prevent;pulmonary function decline;repaired;research study;response;therapeutic target

public_health_relevance:
Cystic fibrosis and other chronic lung diseases cause progressive life-threatening lung destruction due in part to excessive inflammation with frequent exacerbations caused by repeated bacterial infections. This project will investigate the regulatory role that macrophages play in the immune response to Pseudomonas aeruginosa one of the most common bacterial pathogens in these patients. This work will lead to the identification of therapeutic targets for intervention to delay the rate of pulmonary decline in these patients.


application_id: 8856570
project_number: 5R01ES021502-04
project_title: FRESH: Dual Home Screening for Lung Cancer Prevention
administering_ic: NIEHS
award_notice_date: 2015-05-08
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: ES
serial_number: 021502
program_official: THOMPSON, CLAUDIA L
project_start_date: 2012-09-01
project_end_date: 2016-05-31
study_section: Psychosocial Risk and Disease Prevention Study Section[PRDP]
contact_pi_person_id: 1906116
contact_pi: HAHN, ELLEN J
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    The purposes of this randomized controlled trial are to test the effectiveness of Freedom from Radon Exposure and Smoking in the Home (FRESH) a dual home screening and tailored environmental feedback intervention designed to reduce environmental risks for lung cancer and to identify factors associated with monetary incentives for radon mitigation. The combination of firsthand smoke secondhand smoke (SHS) and radon exposure increases the risk of lung cancer nearly tenfold. The long-term goals are to foster environmental justice by reducing home exposure to radon and SHS and to promote equity in radon mitigation by policy change to provide tax credits. A randomized controlled trial enrolling 550 primary care patients will test four hypotheses controlling for contextual factors of age gender home smoking and socioeconomic status (SES): 1) Those who receive FRESH will be more likely to take action to test and mitigate for radon and institute and enforce a smoke-free home policy compared to the control group; 2) Those receiving FRESH will have lower radon and home SHS levels at 15 months post-intervention compared to the control group; 3) Those who receive FRESH will have greater increases in perceived risk of lung cancer and synergistic risk perception (SHS x radon) health-related self-concept readiness to change and self-efficacy to prevent lung cancer and a greater decrease in lung cancer worry compared to controls at 15 months post-intervention; and 4) Those with at least one smoker in the home will be less likely to take action to reduce exposure to radon and SHS. The Treatment group (n = 275) will receive free test kits in the primary care clinic to measure their homes for radon and SHS at baseline receive their test results and the tailored environmental feedback intervention and take part in baseline and three follow up online surveys and home testing 15 months post-intervention. Those with high radon will receive a voucher for 30% of the cost up to $600 for radon mitigation. The Control group (n = 275) will receive information on how to request test kits for radon and SHS and a brochure on radon and SHS and take part in all study surveys. Participants in both groups will be asked to test their homes for radon and SHS 15 months post-intervention. Project      The proposal is directly relevant to public health in that it has the potential to prevent lung cancer by reducing exposure to radon and secondhand smoke in the home.

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

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


application_id: 8856248
project_number: 5F31NS086395-02
project_title: Investigating the Role of Pioglitazone mitoNEET and Mitochondria following TBI
administering_ic: NINDS
award_notice_date: 2015-06-22
opportunity_number: PA-11-111
application_type: 5
activity_code: F31
ic: NS
serial_number: 086395
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2014-07-01
project_end_date: 2016-01-25
study_section: Special Emphasis Panel[ZRG1-F01-F(20)L]
contact_pi_person_id: 11272831
contact_pi: YONUTAS, HEATHER
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) causes severe complications to the estimated 1.7 million Americans who are injured annually. This has precipitated a major focus on the discovery and development of neuroprotective and pro-regenerative therapeutic agents. One potential neuroprotective target which has been well supported in the literature is mitochondrial dysfunction resulting from TBI induced excitotoxicity This excitotoxicity is caused by excessive synaptic glutamate and the consequent over-excitation of neurons at the site of injury leading to large increases in mitochondrial Ca2+ cycling/Ca2+ overload. Ca2+ overload precedes a notable decrease in mitochondrial respiration which has been documented in the first 3 to 48 hours post-injury. This decreased mitochondrial respiration which is an indication of decreased mitochondrial bioenergetics (ability to generate ATP) leads to the initiation of cell death pathways. As the injured neurons die the extent of tissue damage increases and functional (motor and cognitive) abilities decrease. We believe mitochondrial dysfunction to be a pivotal component to the neuropathological sequelae of brain injury and an important therapeutic target for drug discovery research in TBI. An overall goal of our laboratory is to determine whether amelioration of mitochondrial dysfunction will decrease the neuronal cell death associated with TBI. Findings from our lab and others show that pioglitazone a known PPAR-? agonist is neuroprotective and increases functional recovery following TBI. In support of this and the goals of our lab pioglitazone not only reduces mitochondrial dysfunction following TBI but also binds to mitoNEET a novel mitochondrial membrane protein. However the contribution of mitoNEET to pioglitazone- mediated neuroprotection is unknown. Preliminary results indicate that pioglitazone-mediated neuroprotection is absent in mitoNEET knockout mice and a specific mitoNEET ligand (NL-1) is neuroprotective following TBI. Taken together these data suggest that mitoNEET is an essential component of pioglitazone mediated neuroprotection. Therefore in order to understand the mechanisms of pioglitazone I will test the hypothesis that pioglitazone's ability to improve mitochondrial bioenergetics thereby decreasing tissue loss and improving functional recovery following TBI hinges on binding mitoNEET. I further hypothesize that the protective effects of pioglitazone can be reproduced by NL-1 an exogenous mitoNEET ligand.

project_terms:
Agonist;American;Binding (Molecular Function);Bioenergetics;Brain Injuries;Cell Death;Clinical;Cognition;Data;Development;Diffusion Magnetic Resonance Imaging;Dose;FDA approved;Functional disorder;Glutamates;Goals;Health;Healthcare;Hippocampus (Brain);Homeostasis;Hour;Ideal 1;Injury;Intervention;Investigation;Knockout Mice;Laboratories;Ligands;Literature;Magnetic Resonance;Maintenance;Measures;Mediating;Methods;Mitochondria;Mitochondrial Membrane Protein;Motor;Mus;Neurologic;Neurons;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Pharmacological Treatment;Pioglitazone;Recovery of Function;Research;Respiration;Role;Science;Severities;Site;Synapses;Techniques;Testing;Therapeutic Agents;Therapeutic Effect;Tissues;Training;Traumatic Brain Injury;United States;Weight;Wild Type Mouse;behavioral outcome;cognitive ability;cognitive change;cognitive recovery;controlled cortical impact;dosage;drug discovery;excitotoxicity;improved;in vivo;injured;mitochondrial dysfunction;morris water maze;motor recovery;neuron loss;neuropathology;neuroprotection;novel;protective effect;regenerative therapy;response;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a devastating healthcare problem in the United States with no pharmacological treatments currently approved for clinical intervention following injury. Improved TBI treatment options are urgently needed. This proposal examines the potential of pioglitazone an FDA approved drug in limiting the brain damage and dysfunction resulting from TBI via maintenance of mitochondrial function.


application_id: 8856109
project_number: 5R01AA019953-04
project_title: Receptor-mediated effects of ethanol in lung tissue injury and repair
administering_ic: NIAAA
award_notice_date: 2015-05-15
opportunity_number: PA-08-164
application_type: 5
activity_code: R01
ic: AA
serial_number: 019953
program_official: JUNG, KATHY
project_start_date: 2012-09-01
project_end_date: 2016-05-31
study_section: Lung Injury, Repair, and Remodeling Study Section[LIRR]
contact_pi_person_id: 1876531
contact_pi: ROMAN, JESSE
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): Respiratory Distress Syndrome the most severe form of acute lung injury has been found to occur more frequently in alcoholics. In fact chronic alcohol use is not only associated with increased incidence of acute lung injury but also increased mortality. Despite its importance the exact mechanisms by which alcohol abuse renders the host susceptible to acute lung injury remain poorly defined. We have identified a cell surface sensor for alcohol in lung cells and believe that it mediates many of the detrimental effects of alcohol in lung. In view of its perceived importance this project seeks to further characterize this 'alcohol receptor' and investigate its role in the development of acute lung injury in the setting of chronic alcohol exposure. The work proposed was prompted by novel observations showing that: 1) receptors members of the nicotinic acetylcholine receptor (nAChR) family mediate the effects of ethanol in lung fibroblasts and 2) that ethanol-induced oxidant stress (through oxidation of the extracellular cysteine/cystine redox potential) might directly activate nAChRs. These observations have important implications in vivo since we have shown that subjects with chronic alcohol abuse who are otherwise 'healthy' show evidence of oxidant stress as well as activation of lung tissue remodeling. Based on the above we hypothesize that chronic ethanol exposure renders the host susceptible to acute lung injury by acting on nAChRs present on lung cells. Furthermore we hypothesize that oxidant stress can amplify these events by activating nAChRs directly through actions on specific cysteine residues strategically located near the ligand binding site of the receptor; new preliminary data support this hypothesis. Ultimately downstream signals triggered by nAChRs result in a cascade of events that render the host susceptible to acute lung injury. This hypothesis will be tested in specific aims designed to: 1) Characterize the role of nAChRs in mediating the effects of ethanol in lung cells 2) Examine the mechanisms by which a specific form of oxidant stress influences ethanol-induced nAChR activation and 3) Determine the role of nAChRs in mediating ethanol-induced susceptibility to acute lung injury in vivo.

project_terms:
Acetaldehyde;Adult Respiratory Distress Syndrome;Affect;Alcohol abuse;Alcohol consumption;Alcohols;American;Animals;Antioxidants;Binding (Molecular Function);Binding Sites;Biological Assay;Biology;Bronchoalveolar Lavage Fluid;Bungarotoxins;Cell surface;Cells;Chemicals;Chronic;Country;Cysteine;Cystine;Data;Development;Diagnosis;Diagnostic;Epithelial Cells;Ethanol;Event;Family;Fibroblasts;Fibronectins;Glycoproteins;Human;Incidence;Individual;Injury;Lead;Ligand Binding;Link;Lung;Lung Injury Acute;Matrix Metalloproteinases;Mediating;Methods;Mortality Vital Statistics;Neurotoxins;Nicotinic Receptors;Oxidants;Oxidation-Reduction;Phenotype;Point Mutation;Predisposition;Receptor Activation;Reporting;Research;Respiratory physiology;Risk;Rodent;Role;Signal Transduction;Small Interfering RNA;Structure of parenchyma of lung;Testing;Time;Tissues;Work;alcohol effect;alcohol exposure;alcohol use disorder;base;chronic alcohol ingestion;design;extracellular;in vivo;inhibitor/antagonist;injury and repair;interest;lung injury;lung repair;meetings;member;novel;oxidant stress;oxidation;problem drinker;receptor;respiratory distress syndrome;response;sensor

public_health_relevance:
Chronic ethanol use has been associated with increased susceptibility to acute lung injury a condition that affects over 200000 Americans and that is associated with ~40% mortality. This project will explore how ethanol exposure renders the host susceptible to this condition by examining the cellular mechanisms that mediate the effects of ethanol in lung cells and how this impacts lung injury and repair.


application_id: 8853943
project_number: 5R01HL122581-02
project_title: Cardiac pathophysiology of histidyl dipeptides
administering_ic: NHLBI
award_notice_date: 2015-04-17
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/R
injury 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;Outcome;Pathway interactions;Peptides;Perfusion;Physiological;Process;Property;Proteins;Pyruvaldehyde;Reactive Oxygen Species;Recovery;Relative (related person);Reperfusion Injury;Reperfusion Therapy;Role;Skeletal muscle structure;Stress;System;Testing;Therapeutic;Tissues;Toxic effect;Work;adduct;aldehyde dehydrogenases;analog;base;chelation;crosslink;design;effective intervention;effective therapy;link protein;multicatalytic endopeptidase complex;myocardial damage;myocardial infarct sizing;novel;overexpression;oxidation;prevent;protein aggregation;public health relevance;sugar


application_id: 8852028
project_number: 5R01AG039732-05
project_title: The Role of Adipose Tissue in Age-dependent Sensitivity to Critical Illness
administering_ic: NIA
award_notice_date: 2015-06-08
opportunity_number: PA-10-042
application_type: 5
activity_code: R01
ic: AG
serial_number: 039732
program_official: FRIDELL, YIH-WOEI
project_start_date: 2011-08-01
project_end_date: 2017-05-31
study_section: Special Emphasis Panel[ZRG1-BDCN-M(02)M]
contact_pi_person_id: 8163817
contact_pi: SAITO, HIROSHI
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Aging is characterized by an altered stress response that underlies a compromised resistance to disease or injury. Activation of inflammatory and coagulant pathways is a frequent consequence of severe critical illnesses and results in the progression of systemic inflammatory response syndrome (SIRS). Recent evidence suggests that adipose tissue-derived signaling proteins including cytokines coagulation factors and hormones may play an important role in the inflammatory response. Our long-term goals are to identify the mechanisms by which adipose tissue contributes to age-dependent severity of SIRS and to develop therapeutic strategies for decreasing vulnerability to critical illnesses in the aged. For these studies we will use two widely accepted mouse models of SIRS - acute endotoxemia induced by injection with bacterial endotoxin lipopolysaccharide and an intra-abdominal sepsis model induced by cecal ligation and puncture. The objective of this project is to identify and evaluate the expression of adipose-derived inflammatory and coagulant factors that differ by aging upon inflammatory stress. Our central hypothesis is that expression patterns of inflammatory / coagulant factors in the adipose tissue during SIRS are significantly altered by aging and that this alteration contributes to age-dependent severity of critical illnesses. To achieve the above goals we will pursue the following three specific aims: (1) To define the role of adipose tissue in age-related alterations of coagulation during critical illness. (2) To understand the mechanisms of age-related inflammatory cytokine production in the adipose tissue during critical illness. (3) To evaluate methods of body fat loss as potential therapies and preventative measures for reducing severity of critical illness in the aged. These studies will provide significant insight into the association of the previously neglected adipose organ in aging and critical illness.

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

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


application_id: 8851474
project_number: 5R01AG039621-05
project_title: Blood-brain barrier P-glycoprotein a new target for Alzheimers disease
administering_ic: NIA
award_notice_date: 2015-06-08
opportunity_number: PA-14-078
application_type: 5
activity_code: R01
ic: AG
serial_number: 039621
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2011-09-01
project_end_date: 2017-05-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 9238548
contact_pi: HARTZ, ANIKA M.S.
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): We have a fundamental lack in understanding the mechanism that reduces P-glycoprotein (P-gp) expression and transport activity at the blood-brain barrier in Alzheimer's disease (AD). Lack of this knowledge is a significant clinical problem since it prevents development of an effective therapy to enhance AB clearance from the brain lower AB brain levels and thus prevent cognitive decline in AD. The long-term goal of the investigator is to better understand the molecular mechanisms that regulate blood-brain barrier function in neurodegenerative disorders a goal which may lead to new therapeutic strategies to treat AD. The objectives of this particular application are to identify the mechanism responsible for P-gp reduction in AD to validate this mechanism as a target to protect P-gp and to test a novel therapeutic strategy for restoring P-gp. Accomplishing these objectives is expected to reduce A brain levels and improve cognition in AD. Based on preliminary data the central hypothesis is that A mediates proteasomal degradation of P-gp that blocking proteasomal degradation protects P-gp and that restoring P-gp levels through PXR activation reduces A brain burden and improves cognition in mice with AD. The rationale for the proposed research is that identifying the mechanism that reduces brain capillary P-gp and protecting and/or restoring P-gp to improve A brain clearance will potentially provide novel therapeutic targets to lower A brain levels in AD. To accomplish the objectives of this application we will test our central hypothesis by pursuing the following three specific aims: 1) Identify the mechanism of A-mediated P-gp reduction at the blood-brain barrier. 2) Validate the ubiquitin-proteasome system as a target to protect P-gp in an AD mouse model. 3) Develop a therapeutic strategy to reduce cognitive decline in an AD mouse model. In Aim 1 we will inhibit the ubiquitin-proteasome system to identify the steps involved in A-mediated P-gp reduction and determine expression transport activity and ubiquitination of P-gp. In Aim 2 we will treat hAPP mice with inhibitors of the ubiquitin-proteasome system monitor P-gp expression transport activity and ubiquitination and measure A brain levels. We will conduct brain perfusion to assess P-gp activity in vivo and perform tail-flick assays to determine the consequence of changes in P-gp. In Aim 3 we will con- duct a 2-year PCN-feeding study with hAPP mice to assess the long-term therapeutic effect of PXR-mediated P-gp restoration on AB brain levels. P-gp expression and transport activity A brain load and cognition will be periodically determined. The proposed research is innovative because it focuses on two independent strategies designed specifically to enhance A clearance from the brain in AD. The proposed research is significant because it holds the promise of two new therapeutic strategies to lower A brain burden and slow progression of AD. The proposed research is translational because drugs for either strategy inhibition of the ubiquitin- proteasome system and PXR activation are currently on the market and both therapeutic strategies could potentially be translated into the clinic for the treatment of AD patients.

project_terms:
Affect;Alzheimer's Disease;Amyloid;Amyloid beta-Protein Precursor;Autopsy;Biological Assay;Blood - brain barrier anatomy;Blood Vessels;Blood capillaries;Brain;Brain Diseases;Cell Line;Clinic;Clinical;Cognition;Data;Deposition;Development;Disease Progression;Duct (organ) structure;Goals;Human;Impaired cognition;Knowledge;Lead;Marketing;Measures;Mediating;Mission;Molecular;Monitor;Mus;National Institute of Neurological Disorders and Stroke;Neurodegenerative Disorders;Outcome;P-Glycoprotein;P-glycoprotein 2;Pathogenesis;Pathology;Patients;Perfusion;Pharmaceutical Preparations;Play;Receptor Activation;Research;Research Personnel;Role;Sampling;System;Tail;Testing;Therapeutic;Therapeutic Effect;Transgenic Organisms;Translating;Ubiquitin;Ubiquitination;United States National Institutes of Health;Work;base;capillary;design;effective therapy;feeding;improved;in vivo;inhibitor/antagonist;innovation;mouse model;multicatalytic endopeptidase complex;nervous system disorder;new therapeutic target;novel therapeutics;overexpression;pregnane X receptor;prevent;protein transport;public health medicine (field);restoration;therapeutic target

public_health_relevance:
The proposed research is relevant to public health because it will significantly advance understanding of blood-brain barrier function in brain diseases and potentially provide new opportunities for improving treatment of Alzheimer's disease. Worldwide millions of people are currently affected by Alzheimer's disease and patient numbers will increase tremendously over the next decades. Thus the proposed research is relevant to the mission of the NIH/NINDS which is to reduce the burden of neurological disease.


application_id: 8851454
project_number: 5R01AA020051-04
project_title: RAX PKR and ethanol neurotoxicity
administering_ic: NIAAA
award_notice_date: 2015-05-15
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AA
serial_number: 020051
program_official: REGUNATHAN, SOUNDAR
project_start_date: 2012-09-01
project_end_date: 2016-05-31
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 10212779
contact_pi: CHEN, GANG
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):  Fetal Alcohol Spectrum Disorders (FASD) are a range of permanent birth defects caused by maternal alcohol consumption during pregnancy. The prevalence of FASD in populations of younger school children is recently estimated as high as 2-5% in the United State and is more common than Down syndrome and autism. FASD-related costs are more than $6 billion annually. Identification of the mechanism of ethanol toxicity in the brain and determination of the effective therapeutic target(s) are cited as importat goals in the NIAAA Strategic Plan for 2009-2014.  Central nervous system (CNS) damage is a major feature observed in FASD patients. The cerebellum is one of the most sensitive areas in the CNS to ethanol toxicity. Neuronal loss is one of the most deleterious effects of ethanol and is responsible for many of the behavioral deficits observed in FASD. In the animal model exposure of infant rodents to ethanol during a portion of the brain growth spurt period - postnatalday (PD) 4 to 9 equivalent to the human third trimester - causes a significant loss of cerebellum Purkinje and granule neurons. However the underlying mechanism for ethanol-induced neuronal loss in the developing cerebellum is still largely unclear. The goal of this proposed study is to identify the mechanism underlying ethanol neurotoxicity and the novel target(s) for the prevention and treatment of FASD.  The double-stranded RNA (dsRNA)-activated protein kinase (PKR) organizes the cellular self-defense system in response to diverse physiochemical stresses or viral infection by regulating a variety of downstream target proteins and signal pathways. Activation of PKR by its intracellular activator RAX under physiochemical stress conditions leads to protein synthesis inhibition as well as apoptosis and has been implicated in the pathogenesis of a number of neurodegenerative diseases.  The central hypothesis of the proposed study is that RAX-mediated PKR activation regulates ethanol- induced neuronal loss in the developing cerebellum.  Specific Aim 1: To investigate whether PKR activation through RAX/PKR interaction regulates ethanol- induced neuronal apoptosis in the developing cerebellum of the mouse.  Specific Aim 2: To determine whether inhibition of PKR by targeting RAX or PKR expression or by PKR inhibitors alleviates ethanol-induced neuronal loss in the developing cerebellum of the mouse.  Specific Aim 3: To determine whether RAX+/- mice N-PKR-/- mice or PKR-inhibitor-injected mice are more resistant to ethanol-induced cerebellar behavioral dysfunction.

project_terms:
Affect;Animal Behavior;Animal Model;Animals;Apoptosis;Apoptotic;Area;Autistic Disorder;Behavioral;Binding (Molecular Function);Brain;Cells;Cerebellum;Child;Congenital Abnormality;Cytoplasmic Granules;Development;Disease;Dominant-Negative Mutation;Double-Stranded RNA;Down Syndrome;Ethanol;Ethanol toxicity;Exposure to;Fetal Alcohol Spectrum Disorder;Functional disorder;Goals;Growth;Health;Human;In Vitro;Infant;Inhibition of Apoptosis;Investigation;Learning Disabilities;Mediating;Mental Retardation;Molecular;Mus;National Institute on Alcohol Abuse and Alcoholism;Nerve Degeneration;Nervous System Trauma;Neuraxis;Neurodegenerative Disorders;Neurons;Outcome;Oxidative Stress;Pathogenesis;Patients;Play;Population;Prevalence;Prevention;Protein Synthesis Inhibition;Proteins;Psyche structure;Reporting;Resistance;Rodent;Role;Schools;Series;Severities;Signal Pathway;Social Problems;Strategic Planning;Stress;System;Testing;Third Pregnancy Trimester;Transgenic Mice;United States;Virus Diseases;Weight;alcohol consumption during pregnancy;alcohol effect;alcohol exposure;alcohol sensitivity;behavior test;behavioral impairment;behavioral study;cell type;cost;disability;eIF-2 Kinase;effective therapy;inhibitor/antagonist;innovation;mouse model;neuron apoptosis;neuron loss;neurotoxicity;novel;novel strategies;postnatal;public health medicine (field);response;therapeutic target

public_health_relevance:
This proposed study targets Fetal Alcohol Spectrum Disorders (FASD) a range of permanent birth defects caused by alcohol consumption during pregnancy. FASD is a national public health concern as those affected suffer a lifelong disability with no current cure. The outcome may identify therapeutic target(s) for the prevention or treatment of FASD.


application_id: 8851083
project_number: 1R21AI116517-01
project_title: Exploitation of host glycolysis by Legionella
administering_ic: NIAID
award_notice_date: 2014-12-31
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: AI
serial_number: 116517
program_official: ERNST, NANCY L
project_start_date: 2015-01-01
project_end_date: 2016-12-31
study_section: Special Emphasis Panel[ZRG1 IDM-B (80)]
contact_pi_person_id: 1877865
contact_pi: ABU KWAIK, YOUSEF A
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): Upon transmission to humans Legionella pneumophila (Lp) proliferates within alveolar macrophages causing pneumonia with high morbidity and mortality. Intracellular proliferation of Lp occurs within the endoplasmic reticulum-derived Legionella-containing vacuole (LCV) which evades lysosomal fusion. Biogenesis of the LCV is governed by the Dot/Icm type IV secretion system which injects into the host cell ~300 protein effectors that exploit a myriad of cellular processes to enable intra- vacuolar proliferatin of Lp. The generation time of intra-vacuolar Lp within human macrophages is ~40 min which is 3-4 times faster than growth in rich media. Amino acids are the major sources of carbon and energy for Lp which metabolize them through the TCA cycle as the major energy-yielding metabolic pathway in Lp which does not have a functional glycolytic pathway. However our recent studies indicate that the host basal cellular levels of amino acids are below the threshold needed as a major source of carbon and energy to feed the TCA cycle of intra-vacuolar Lp. To achieve that threshold Lp promotes host proteasomal degradation which is totally bypassed upon supplementation of amino acids or pyruvate. This indicates the import of pyruvate by the LCV and its utilization by intra-vacuolar Lp as a source of carbon and energy. Our preliminary data show a Dot/Icm-dependent up-regulation of the host glycolytic enzymes and production of pyruvate in Lp-infected human monocytes-derived macrophages (hMDMs). Importantly glucose deprivation or inhibition of glycolysis in hMDMs suppresses intra-vacuolar proliferation of Lp but
the suppression is totally relieved upon supplementation of pyruvate. This indicates that the LCV imports pyruvate to be utilized by intra-vacuolar Lp as a source of carbon and energy. Our findings indicate a multi-prong bacterial strategy to retrieve diverse host resources to feed the TCA cycle of Lp. The import of pyruvate across eukaryotic membranes is mediated by the plasma membrane-localized SLC16A1 and SLC16A7 transporters and by the mitochondrial membrane-localized MPC1 and MPC2 oligomeric complex. Our preliminary data derived from microarrays of Lp-infected hMDMs show that Lp triggers Dot/Icm-dependent up-regulation of the host MPC1 and MPC2 but not SLC16A1 or SLC16A7. Our profiling of the proteome of the LCV membrane shows that the MPC1 and MPC2 eukaryotic transporter is acquired by the LCV in a Dot/Icm-dependent manner but the SLC16A1 and SLC16A7 are not detectable in the LCV proteome. Therefore our hypothesis is: the host MPC pyruvate transporter is acquired by the LCV membrane through interaction with a Dot/Icm-translocated effector to import pyruvate into the LCV to be utilized by intra-vacuolar Lp as a source of carbon and energy. To test our hypothesis our specific aims are to determine and characterize the following: I. Acquisition of host MPC transporter by the LCV and its import of pyruvate as a source of carbon and energy for intra-vacuolar Lp; II. The Lp effectors that interact with the host MPC transporter in the LCV membrane. The significance of our studies stem from deciphering exploitation of host glycolysis by intra- vacuolar Lp; and determination of the mechanisms of import of host pyruvate from the cytosol of primary hMDMs into a pathogen-containing vacuole and its utilization by the pathogen as a source of carbon and energy. The innovations of our studies stem from: Novelty of the hypotheses; cutting-edge technologies and experimental design; Dot/Icm-dependent up-regulation of host glycolysis production of pyruvate; and up- regulation of the host MPC1 and MPC2 transporter; recruitment of the host MPC1 and MPC2 transporter into the pathogen-containing vacuole; import of pyruvate generated from host glycolysis by the pathogen- containing vacuolar membrane; and identification of novel bacterial effectors that interact with the host MPC1 and MPC2 transporter in the vacuolar membrane of an intra-vacuolar pathogen.

project_terms:
Alveolar Macrophages;Amino Acids;Biogenesis;Bypass;Carbon;Cell membrane;Cell physiology;Cells;Citric Acid Cycle;Communicable Diseases;Complex;Cytosol;Data;Disease;Endoplasmic Reticulum;Enzymes;Experimental Designs;Generations;Glucose;Glycolysis;Glycolysis Inhibition;Growth;Human;Knowledge;Legionella;Legionella pneumophila;Mediating;Membrane;Metabolic Pathway;Metabolism;Microbe;Morbidity - disease rate;Mortality Vital Statistics;Nutrient;Nutritional;Pathway interactions;Pneumonia;Process;Production;Proliferating;Proteins;Proteome;Pyruvate;Resources;Retrieval;Source;Supplementation;Technology;Testing;Time;Type IV Secretion System Pathway;Up-Regulation (Physiology);Vacuole;Virulence;antimicrobial;deprivation;feeding;innovation;macrophage;microbial;mitochondrial membrane;monocyte;novel;pathogen;public health relevance;pyruvate carrier;stem;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Although microbial access to host nutrients is one of the most fundamental aspects of infectious diseases our understanding of this process remains very limited. In the host pathogens are faced with major nutritional challenges that include host nutritional limitation and the host innate defense of microbial deprivation of essential nutrients.
To counteract these nutritional challenges pathogens have evolved highly efficient nutrient retrieval strategies which are major potential targets for anti-microbial therapy. Our proposed studies will decipher the mechanisms of import of host pyruvate into the vacuole harboring Legionella pneumophila within human macrophages. Since host-generated pyruvate is an important source of carbon and energy needed by this pathogen to proliferate within the vacuole and cause pneumonia our studies are high impact.


application_id: 8850813
project_number: 5R03AI113648-02
project_title: The Borrelia burgdorferi transcriptional regulome
administering_ic: NIAID
award_notice_date: 2015-04-29
opportunity_number: PA-13-304
application_type: 5
activity_code: R03
ic: AI
serial_number: 113648
program_official: ILIAS, MALIHA R
project_start_date: 2014-06-01
project_end_date: 2017-05-31
study_section: Special Emphasis Panel[ZRG1-IDM-B(80)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:
DESCRIPTION (provided by applicant): All organisms from bacteria to humans need to "recognize" where they are and respond accordingly. A pathogen must sense its location in the infectious cycle then produce factors necessary for that site while repressing synthesis of inappropriate factors. This is particularly important for vector-borne pathogens such as the Lyme disease agent Borrelia burgdorferi which must not only infect two very different types of animals but efficiently transmit back-and-forth between vertebrate hosts and arthropod vectors. The planned studies bring together two experts in B. burgdorferi genetics and an expert bioinformatician into an integrated systems approach that will map the regulatory networks of B. burgdorferi. The results will yield significant insight on B. burgdorferi physiology its ability t cause disease and since disruption of key regulatory pathways can inhibit a pathogen's ability to cause infection identify strategic targets for developing novel antibiotics. The substantial quantity of derived data will also be made publicly available through electronic databases providing a treasury of valuable information that can be readily mined by the global research community.

project_terms:
Animals;Antibiotics;Arthropod Vectors;Back;Bacteria;Borrelia;Borrelia burgdorferi;Communities;Complement Factor B;Complementary DNA;Complex;Data;Data Analyses;Data Quality;Databases;Disease;Electronics;Environment;Funding;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Genetic;Genetic Transcription;Genome;Genus Mycobacterium;Health;Human;Infection;Libraries;Location;Lyme Disease;Mammals;Maps;Mining;Nature;Nucleotides;Operon;Organism;Physiology;Production;Proteins;Pseudomonas;RNA;Regulatory Pathway;Regulon;Research;Resolution;Sigma Factor;Site;Structure;System;Ticks;Time;United States National Institutes of Health;Untranslated RNA;cDNA Library;deep sequencing;genetic regulatory protein;insight;mutant;novel;novel therapeutics;pathogen;prevent;transcriptome sequencing;transmission process;vector

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Precise control of gene regulation by the Lyme disease agent Borrelia burgdorferi is critical for this bacterium to infect humans and other animals. The proposed studies will utilize deep sequencing of cDNAs (RNA-Seq) to map the regulatory networks employed by this pathogen to regulate gene expression. The results will provide significant insight on the bacterium's infectious nature and can be used to identify key checkpoints for developing novel therapeutics to prevent and cure Lyme disease.


application_id: 8850776
project_number: 5R01AG042475-03
project_title: CELLULAR CHANGES ALTERING SYNAPTIC CONNECTIVITY IN PRECLINICAL AD
administering_ic: NIA
award_notice_date: 2015-06-08
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: 2016-05-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 1884283
contact_pi: SCHEFF, STEPHEN W
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;Antioxidants;Area;Binding (Molecular Function);Biochemical;Biological Markers;Brain region;Clinical;Cognition;Cognitive;Cytoskeletal Proteins;Data;Dementia;Development;Disease;Disease Progression;Early Diagnosis;Enzymes;Etiology;Event;Free Radicals;Functional disorder;Health;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;Pathology;Play;Principal Investigator;Process;Production;Proteins;Reactive Oxygen Species;Research Support;Role;Sampling;Seminal;Source;Staging;Structural Protein;Subcellular Fractions;Symptoms;Synapses;Synaptic plasticity;System;Temporal Lobe;Testing;cofilin;cognitive ability;cognitive function;cognitive testing;cohort;dentate gyrus;design;differential expression;entorhinal cortex;frontal lobe;human tissue;hyperphosphorylated tau;insight;mental state;mild cognitive impairment;neurofibrillary tangle formation;novel;oxidative damage;pre-clinical;prevent;programs;research study;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: 8850704
project_number: 5R01DE023206-03
project_title: Structure-based design and synthesis of peptidominetics targeting P. gingivalis
administering_ic: NIDCR
award_notice_date: 2015-05-05
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: 2016-05-31
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:
3-Dimensional;A Mouse;Accounting;Address;Adherence (attribute);Adult;Alveolar Bone Loss;Animal Model;Antigens;Atherosclerosis;Back;Basic Science;Biochemical;Biological Assay;Boxing;C-terminal;Chemistry;Coupled;Development;Disease;Drug Formulations;Enzyme-Linked Immunosorbent Assay;Event;Expenditure;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;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;mimetics;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

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 theoral 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 impactperiodontal 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.             __SpecificAimsTextDelimiter__ Specific Aims: Porphyromonas gingivalis is strongly associated with adult periodontitis and has recently been suggested tofunction as a "keystone" pathogen that disrupts host-microbe homeostasis and induces populational changes in thesubgingival biofilm that drive inflammation and subsequent tissue destruction (23). Thus therapeutic approachesthat target P. gingivalis may significantly impact the subgingival biofilm and limit P. gingivalis-mediated disruptionof host-microbe homeostasis. Prior to colonizing its subgingival niche P. gingivalis associates with supragingivalplaque and interacts with oral streptococci. This initial event that promotes colonization of the oral cavity by P.gingivalis is an ideal point for targeted therapeutic intervention. In previous studies we showed that P. gingivalisadherence to streptococci is species specific and is driven by a protein-protein interaction between the minorfimbrial antigen (Mfa) of P. gingivalis and the antigen I/II (AgI/II) polypeptide of streptococci. An essential domainin AgI/II that resembles the eukaryotic nuclear receptor (NR) box protein-protein interaction domain was identifiedand variation in the sequence and structure of the NR box in different AgI/II proteins accounted for the selectivityof P. gingivalis adherence to streptococci. The NR box is comprised of two peptide motifs VXXLL and NITVK anda synthetic peptide containing both motifs (designated BAR) potently inhibits P. gingivalis adherence to streptococciand significantly reduces P. gingivalis virulence in a mouse model of periodontitis. These published studies providethe foundation for the overall hypothesis of this application; that P. gingivalis colonization of the oral cavitycan be controlled by preventing its initial association with streptococci and that inhibitors of the Mfa-AgI/II interaction represent potential therapeutic agents that may limit P. gingivalis-mediateddisruption of host-microbial homeostasis. However peptides have significant limitations for therapeuticapplications e.g. high cost of production and susceptibility to proteases including those expressed by P. gingivalisitself. To overcome these limitations the main objective of this proposal is to exploit the structural andbiochemical information of the Mfa-AgI/II interaction derived from our previous work to rationally designsynthesize and develop small molecule peptidomimetics that inhibit P. gingivalis adherence to streptococci. Thereare three specific aims:1) To design and synthesize potent non-peptide inhibitors of the Mfa-AgI/II interaction. The design ofactive compounds will be based on our structural modeling of the VXXLL and NITVK motifs and guided by theavailable 3-D structures of the NR box (11) and the C-terminal fragment of SspB (32). A variety of basic scaffoldswill be used to synthesize precursor compounds that mimic each motif. These building block compounds will thenbe coupled by click cycloaddition to generate peptidomimetics encompassing both functional motifs. The proposedsynthetic approaches are highly flexible and will facilitate the modification of active lead compounds.2) To determine the activity of peptidomimetics synthesized in Aim 1. Compounds will initially be testedas inhibitors of the Mfa-AgI/II interaction and of the adherence of intact P. gingivalis to streptococci using ELISA-based assays. Active compounds will subsequently be tested to determine if they inhibit biofilm formation using aP. gingivalis/S. gordonii dual species biofilm culture model. The results from these analyses will identify the mostpotent inhibitors and feed back into Aim 1 to initiate structural modification to generate even more potentcompounds.3) To determine if peptidomimetics limit colonization and P. gingivalis-mediated disruption of host-microbe homeostasis. A mouse model of periodontitis will be used to determine if the syntheticpeptidomimetics limit the initial colonization of mice by P. gingivalis or eliminate a pre-existing P. gingivalisinfection. Outcomes that will be followed include measuring alveolar bone loss overall microbial load andqualitatively assessing the composition of the oral biofilm to determine if the peptidomimetic compounds impact P.gingivalis-mediated disruption of host-microbe homeostasis.


application_id: 8849866
project_number: 5R01CA175003-03
project_title: Activating Bax as a therapeutic strategy for lung cancer
administering_ic: NCI
award_notice_date: 2015-05-08
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: 2016-05-31
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;Anus;Apoptosis;Apoptosis Regulator;Apoptotic;BCL-2 Protein;BCL2 gene;Bax protein;Binding (Molecular Function);Biochemical;Biological;Cancer Patient;Carboplatin;Cell Death;Cells;Cellular biology;Cessation of life;Computer Simulation;Development;Generations;Growth;Health;Human;In Situ;In Vitro;Inhibition of Apoptosis;Killings;Lead;Ligands;Link;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Membrane;Mus;Neoplasm Transplantation;Organelles;Patch-Clamp Techniques;Pathway interactions;Pharmaceutical Preparations;Process;Property;Protein Family;Relative (related person);Resistance;Role;Structure;Structure-Activity Relationship;Synthesis Chemistry;Testing;Therapeutic;Time;Toxic effect;Transplantation;Tumor Cell Line;Xenograft Model;base;cancer cell;cancer therapy;cytotoxic;cytotoxicity;design;improved;in vivo;inhibitor/antagonist;neoplastic;neoplastic cell;novel;novel therapeutics;pharmacophore;preclinical study;pro-apoptotic protein;research study;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: 8849426
project_number: 5R01DC011285-05
project_title: Response of aging intrinsic laryngeal muscles to chronic electrical stimulation
administering_ic: NIDCD
award_notice_date: 2015-05-08
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: DC
serial_number: 011285
program_official: SHEKIM, LANA O
project_start_date: 2011-06-22
project_end_date: 2017-06-30
study_section: Motor Function, Speech and Rehabilitation Study Section[MFSR]
contact_pi_person_id: 8274830
contact_pi: MCMULLEN, COLLEEN A
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): This application is in response to the NIH Research Project Grant (Parent R01) (PA-10-067). As individuals age muscle weakness and the development of neuromuscular disorders have the potential to severely diminish the quality of one's life. The larynx is part of a complex sensorimotor system that serves as both a vibratory source for phonation and as a regulatory valving mechanism that protects the airway from the incursion of foreign bodies and food. In the elderly age-related changes in the laryngeal muscles may compromise voice quality impairing the ability of individuals to communicate and diminishing their ability to remain socially active and engaged. More significantly laryngeal muscle dysfunction may contribute to the emergence of dysphagia and subsequent increases in the risk of aspiration factors that contribute to higher rates of mortality and morbidity. Our preliminary findings indicate that the intrinsic laryngeal muscles have a unique phenotype that is significantly altered by age. More specifically therapies for certain voice disorders contend to use common principles of skeletal muscle rehabilitation in the hope of increasing muscle mass strength and endurance. However the rationale and applicability of limb muscle rehabilitation concepts to the laryngeal muscles has not been empirically tested. Therefore this proposal has three principle objectives:(1) to use chronic electrical stimulation as a fictive endurance "exercise" program in aging rat laryngeal muscle; (2) to characterize the morphological changes consequent to the fictive exercise model; and (3) to provide the background data to eventually extend these findings to clinical treatments with humans using vocal exercises. We will test the central hypothesis that the physiology of aged laryngeal muscle can be modified as a function of chronically-induced activity using the Fisher 344-Brown Norway F1 hybrid rat model of aging. We will examine to what extent chronic electrical stimulation remodels the aging posterior cricoarytenoid (PCA vocal fold abductor) and thyoarytenoid (TA vocal fold adductor) laryngeal muscles. Specific Aim I will examine the effects of chronic electrical stimulation on muscle morphology in aging PCA and TA. Specific Aim 2 will test whether chronic stimulation modifies the metabolic capacity in the aging PCA and TA muscles. Specific Aim 3 will determine to what extent chronic nerve stimulation will reverse functional denervation in aging laryngeal muscles. These studies will be a first test of the applicability of limb muscle rehabilitation interventions intended to effectively alleviate reverse and/or compensate for age-related dysfunction in the laryngeal muscles. This project will generate novel data to assist in the development of interventions aimed at preventing reversing and/or compensating for age-related dysfunction in the human larynx providing a first step toward testing the efficacy and legitimacy of current voice disorder interventions.

project_terms:
Aerobic;Affect;Age;Aging;Animal Model;Biochemistry;Chronic;Clinical Treatment;Complex;Data;Deglutition Disorders;Denervation;Development;Elderly;Electric Stimulation;Exercise;Exercise Physiology;Food;Foreign Bodies;Functional disorder;Human;Hybrids;Individual;Intervention;Laryngeal muscle structure;Larynx;Legitimacy;Life;Limb structure;Measures;Metabolic;Mitochondria;Modality;Modeling;Morbidity - disease rate;Morphology;Mortality Vital Statistics;Motor;Muscle;Muscle Fibers;Muscle Weakness;Muscle denervation procedure;Muscle rehabilitation;Nerve;Neuromuscular Diseases;Neuromuscular Junction;Norway;Parents;Phenotype;Phonation;Physiological;Physiology;Population;Protocols documentation;Rattus;Rehabilitation therapy;Research Project Grants;Risk;Skeletal muscle structure;Source;Speech;Testing;Thyroarytenoid muscle structure;Training;United States National Institutes of Health;Voice;Voice Disorders;Voice Quality;Work;age related;aged;base;cricoarytenoideus;density;design;efficacy testing;indexing;muscle form;neurophysiology;novel;prevent;programs;rehabilitation paradigm;research study;response;sensorimotor system;therapy development;vocal cord;voice therapy

public_health_relevance:
In older individuals changes in the laryngeal muscles may compromise voice quality impairing the ability to communicate and diminishing the ability to remain socially active and engaged. This project examines the muscle biophysiological changes that occur as a function of exercise and training using a well-accepted animal model for aging. Understanding the consequences of these changes is deemed important for eventually developing preventative and rehabilitative strategies for laryngeal muscle-related dysfunction in the older human population.


application_id: 8849341
project_number: 5R44AI098179-03
project_title: Biological vector control reducing arboviruses including Dengue and Chikungunya
administering_ic: NIAID
award_notice_date: 2015-05-04
opportunity_number: PA-13-088
application_type: 5
activity_code: R44
ic: AI
serial_number: 098179
program_official: COSTERO-SAINT DENIS, ADRIANA
project_start_date: 2012-06-01
project_end_date: 2018-05-31
study_section: Special Emphasis Panel[ZRG1-IDM-V(12)B]
contact_pi_person_id: 11545088
contact_pi: MAINS, JAMES WILLIAM
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 780816091
primary_uei: F873ZJEX7615
duns_number: 780816091
uei: F873ZJEX7615
fips: US
organization_id: 10027931
organization_name: MOSQUITOMATE, INC.
organization_city: Lexington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40502
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): In the absence of effective approved drugs or vaccines vector control remains the only means of intervention for many against mosquito-borne diseases. This problem grows more complex with the recent establishment of multiple exotic mosquito species and mosquito-borne pathogens. Furthermore changing climate conditions are predicted to alter the traditional range for native mosquitoes. A notable example is Aedes albopictus the Asian Tiger mosquito introduced into the USA in the mid-1980s this invasive species has spread throughout the southeast and with warmer winters its range is now moving into New York and other northern states where it has become the primary biting mosquito. A stable infestation was discovered in California in 2011 which persists despite an ongoing elimination campaign. The cryptic biology of this mosquito makes it difficult to find and treat using traditional insecticidal approaches. In addition to its importance as a biting nuisance A. albopictus is a competent vector of over twenty pathogens. Epidemiological models show risk of returning travelers infected with chikungunya virus infecting A. albopictus and starting localtransmission. This hypothesized event would be similar to recent epidemics that have occurred in Europe India Sri Lanka and La Reunion. Our discussions with major mosquito control districts around the country (California Florida New York) demonstrate the need and commercial opportunity for new approaches against A. albopictus and an interest in the our product. Our Phase I results demonstrate feasibility of a Wolbachia biopesticide approach. Repeated releases of Wolbachia- infected males cause a form of conditional sterility capable of eliminating an A. albopictus population within eight weeks. In the proposed Phase II work we will continue the research and development of the Wolbachia biopesticide approach with the major goals of (1) demonstrating a prototype mass production unit (2) providing field performance data for Wolbachia-infected A. albopictus males and (3) measuring the pesticidal effect of Wolbachia- infected A. albopictus males against an indigenous field population.

project_terms:
Adult;Aedes (genus);American Samoa;Arboviruses;Asians;Bacteria;Biological;Biological Assay;Biology;Bite;California;Chikungunya virus;Collaborations;Complex;Country;Culicidae;Data;Dengue;Disease;Disease Vectors;Environment;Epidemic;Epidemiologist;Europe;Event;Female;Florida;Goals;Grant;Health;India;Indigenous;Insecticides;Intervention;Kentucky;Legal patent;Licensing;Longevity;Los Angeles;Marketing;Measures;Medical;Methods;Modeling;Monitor;Mosquito Control;Mosquito-borne infectious disease;Native-Born;New York;Partner in relationship;Performance;Pharmaceutical Preparations;Phase;Population;Positioning Attribute;Practice Management;Preparation;Production;Recommendation;Regulatory Pathway;Risk;Site;Sri Lanka;Sterility;System;Technology;Tigers;Time;Vaccines;Vision;Wolbachia;Work;chikungunya;climate change;commercialization;cost;density;design;effective therapy;epidemiological model;fitness;improved;interest;male;manufacturing process;novel strategies;pathogen;prototype;research and development;sex;tool;transmission process;vector;vector control;vector mosquito

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Effective control tools are needed against the invasive disease vector mosquito Aedes albopictus (Asian Tiger mosquito). Contained trials in Phase I have shown that the repeated release of males infected with Wolbachia bacteria can cause sterility and eliminate A. albopictus populations. The proposed Phase II work will (1) demonstrate efficacy of the control approach in the field against an established population and (2) improve product production to improve the overall production levels and reduce downstream cost.


application_id: 8848638
project_number: 7R01CA140605-05
project_title: Dietary prevention of prostate cancer
administering_ic: NCI
award_notice_date: 2014-09-12
opportunity_number: PA-14-078
application_type: 7
activity_code: R01
ic: CA
serial_number: 140605
program_official: MALONE, WINFRED F
project_start_date: 2014-06-01
project_end_date: 2016-05-31
study_section: Special Emphasis Panel[ZRG1-OTC-B(02)M]
contact_pi_person_id: 7649061
contact_pi: DAMODARAN, CHENDIL
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Our research focuses on natural compounds that possess chemotherapeutic and/or chemopreventive properties with respect to cancer. In the proposed study we will characterize the mechanism of action of the compound Withaferin-A (WA) a bioactive compound of Withania somnifera which is extensively used in Asian and African traditional medicine. WA displays impressive and selective activity against androgen- dependent and androgen-independent prostate cancer (ADPC and AIPC respectively) of which the latter is refractory to all current forms of treatment. Our preliminary in vitro and in vivo data indicate WA targets ADPC and AIPC cells by inhibiting the activity of Akt a protein kinase that activates cell survival pathways. Our preliminary data demonstrate that concomitant to Akt inhibition in ADPC and AIPC cells WA activates FOXO3a which in turn activates prostate apoptosis response-4 (Par-4) a protein that selectively induces apoptosis in cancer cells Based on our results we hypothesize WA overrides the negative effects of Akt on CREB/Par-4 signaling to achieve chemopreventive and/or chemotherapeutic effects on AIPC. To address this hypothesis we propose the following aims: investigate the interaction between Akt/CREB and Par-4 signaling (Aim 1); and how WA modulates the pro-apoptotic signaling in AIPC (Aim 2); evaluate the effects of WA on androgen- -independent prostate tumor growth in the transgenic adenocarcinoma of mouse prostate (TRAMP) model (Aim 3); and examine the mechanisms of WA-mediated tumor inhibition in TRAMP and/or TRAMP cell lines (Aim 4). For the in vitro arm of our studies we will use a variety of approaches (immunoprecipitation siRNA strategies immunofluorescence Western blot Northern blots Chip assays siRNA strategies pull down assays pharmacological blocking) in order to determine the molecular junction at which Akt/CREB 3aand Par-4 converge. For our in vivo studies we will conduct tumor regression studies yet we will also examine histopathology cell death expression patterns of pro-survival proteins and pro-apoptotic proteins in the tumor tissues and WA levels in the serum and prostate tissue. Our long term goal is to promote natural compounds to a clinical environment where these agents can be thoroughly assessed for their chemopreventive and chemotherapeutic properties. Our preliminary data indicate WA is a potential candidate for such clinical evaluation and our proposed studies will elucidate at a mechanistic level its potency against prostate cancer both from a chemopreventive and chemotherapeutic standpoint.

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

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


application_id: 8848164
project_number: 7R01CA138797-05
project_title: Targeting AR and Akt for the Treatment of Prostate Cancer
administering_ic: NCI
award_notice_date: 2014-09-12
opportunity_number: PA-14-078
application_type: 7
activity_code: R01
ic: CA
serial_number: 138797
program_official: ARYA, SURESH
project_start_date: 2014-05-15
project_end_date: 2016-04-30
study_section: Developmental Therapeutics Study Section[DT]
contact_pi_person_id: 7649061
contact_pi: DAMODARAN, CHENDIL
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The androgen receptor (AR) plays an important role in the development and progression of prostate cancer (PCa). Most PCa specimens express high levels of AR which is necessary and sufficient to convert androgen-dependent (AR+) PCa to the clinically more aggressive androgen-independent (AR-) PCa. Although inhibition of AR activity is a mainstay of AR+ PCa treatment there are no effective therapies for AR- PCa which is uniformly lethal. Studies reveal AR and Akt mutually activate one another and that together AR and Akt inhibit pro-apoptotic signaling and enhance the conversion of AR+ to AR- PCa. Targeting both AR and Akt signaling represents a powerful therapeutic approach for treating AR+ PCa and preventing the emergence of AR- PCa. We recently demonstrated Withaferin-A (WA) a natural compound specifically targets AR- PCa cells by inhibiting phosphorylated Akt; this inhibition leads to the activation of prostate apoptosis response-4 (Par-4)-dependent apoptosis in cell culture and in animal models. Similarly inhibition of AR in AR+ PCa cells facilitates WA-induced Par-4 activation and apoptosis. Over-expression of either Akt or AR inhibits WA-mediated Par-4 activation and blocks apoptosis in AR+ PCa suggesting both AR and Akt negatively regulate the pro-apoptotic functions of Par-4 in PCa cells. We hypothesize that WA in combination with hormone ablation is an effective strategy to control the progression of PCa. To address this hypothesis we will: Aim 1. Characterize the molecular link between AR signaling and Par-4 and determine the effects of WA on AR+ PCa cells (investigating AR binding to the Par-4 promoter via reporter constructs ChIP assays using AR antibodies and Western analysis of pro- and anti-apoptosis proteins); Aim 2. Examine the relationship between Par-4 and FOXO 3a which is regulated by Akt and how WA modulates this interaction in AR+ PCa (studying FOXO3a binding to the Par-4 promoter via reporter constructs ChIP assays using FOXO3a antibodies mobility shift assays Western analysis of pro- and -anti-apoptosis proteins and TUNEL and annexin-V assays following FOXO3a over-expression); and Aim 3. Determine the chemotherapeutic effects of WA on the development of PCa in prostate specific PTEN knockout mice (PS PTEN-KO; performing in vivo WA efficacy studies on PCa histopathology immunohistochemistry of pro-survival and pro-apoptotic proteins proliferation index apoptosis and serum WA levels). We anticipate these studies will provide molecular insight into the mechanism of WA action against AR+ PCa and will ultimately lead to novel therapeutic strategies for the treatment of PCa.

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

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


application_id: 8848100
project_number: 5R01HL055477-18
project_title: Toxicity and Detoxification of 4 Hydroxyalkenals in Heart
administering_ic: NHLBI
award_notice_date: 2015-05-08
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: HL
serial_number: 055477
program_official: WONG, RENEE P
project_start_date: 1998-12-01
project_end_date: 2017-05-31
study_section: Special Emphasis Panel[ZRG1-CVRS-K(02)M]
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): The overall goal of this project is to understand the role of lipid peroxidation products in inducing cardiac injury and dysfunction caused by chronic hemodynamic stress. Our working hypothesis is that the effects of reactive oxygen species generated in these hearts are in part mediated by 4-hydroxyalkenals produced as a result of lipid peroxidation. We propose that modification of myocardial proteins by these aldehydes is a significant source of cardiac injury and dysfunction induced by chronic hemodynamic stress and therefore metabolic detoxification of these aldehydes diminishes myocardial hypertrophy and heart failure. To test this hypothesis we will examine 4-hydroxyalkenal formation and metabolism in hearts subjected to transverse aortic constriction (TAC) and we will measure changes in the activity and the levels of aldehyde-metabolizing enzymes and cellular nucleophiles such as reduced glutathione and carnosine. To identify changes in aldehyde metabolism metabolites of 4-hydroxy-trans-2-nonenal (HNE) generated in hypertrophic hearts perfused with radiolabeled HNE will be identified and quantified along with HNE metabolites generated in vivo in the blood and urine of mice subjected to TAC. To determine the role of aldehyde metabolism in regulating cardiac injury and dysfunction induced by pressure overload we will examine whether genetic deletion of aldose reeducates (which catalyzes the reductive metabolism of aldehydes) or cardiospecific overexpression of carnosine synthase (which generates the aldehyde-quenching dipeptide - carnosine in the heart) affects myocardial injury and dysfunction after TAC. To examine the mechanism by which aldehydes induce myocardial injury we will examine whether exposure to HNE triggers autophagy; whether the pathways of autophagy activated by HNE are also stimulated by TAC; and whether changes in aldehyde metabolism via aldose reductase and carnosine alter autophagic responses in hypertrophic and failing hearts. Completion of this project will lead to a better understanding of the role of oxidative stress in myocardial hypertrophy and heart failure as well as other chronic conditions associated with an increase in lipid peroxidation such as diabetes atherosclerosis and cardiovascular aging. Our results could provide novel insights into the mechanisms by which hemodynamic stress induces myocardial injury and dysfunction and how these changes could be attenuated. We expect that these findings will have wide mechanistic prognostic and therapeutic implications for diagnosis management and treatment of pathological hypertrophy and heart failure.

project_terms:
Affect;Aging;Aldehyde Reductase;Aldehydes;Arrhythmia;Atherosclerosis;Attenuated;Autophagocytosis;Biochemical;Blood;Blood flow;Cardiac;Cardiovascular Diseases;Cardiovascular system;Carnosine;Chronic;Congestive Heart Failure;Development;Diabetes Mellitus;Diagnosis;Diet;Dipeptides;Drug Metabolic Detoxication;Enzymes;Exposure to;Functional disorder;Genetic;Glutathione S-Transferase;Goals;Growth;Heart;Heart Hypertrophy;Heart failure;Hypertension;Hypertrophy;Injury;Intake;Lead;Lipid Peroxidation;Measures;Mediating;Mediator of activation protein;Metabolic;Metabolism;Modification;Mus;Mutation;Myocardial;Oral;Oxidative Stress;Pathway interactions;Physiological;Pollution;Post-Translational Protein Processing;Process;Production;Proteins;Radiolabeled;Reactive Oxygen Species;Reduced Glutathione;Research;Risk;Risk Factors;Role;Side;Signal Transduction;Source;Stress;System;Testing;Therapeutic;Toxic effect;Urine;Work;adduct;aged;aldehyde dehydrogenases;base;constriction;hemodynamics;in vivo;insight;lipid metabolism;novel;overexpression;pressure;prognostic;radiotracer;response

public_health_relevance:
Exposure to environmental aldehydes through either pollution or diet is a significant source of cardiac injury and dysfunction induced by chronic hemodynamic stress therefore determining how these aldehydes are removed from the system could lead to ways to reduce their effect. To test this hypothesis we will examine a specific aldehyde formation and metabolism in hearts subjected to reduced blood flow and we will measure changes in the activity and the levels of aldehyde-metabolizing enzymes and cellular nucleophiles in an effort to determine how to either block their damage or increase their metabolism to remove them prior to their causing injury.


application_id: 8848016
project_number: 5K25AG043546-03
project_title: Statistical Genetics Methods for Mixed Pathologies
administering_ic: NIA
award_notice_date: 2015-06-09
opportunity_number: PA-11-196
application_type: 5
activity_code: K25
ic: AG
serial_number: 043546
program_official: MILLER, MARILYN
project_start_date: 2013-08-15
project_end_date: 2017-03-31
study_section: Basic Neuroscience of Aging Study Section[NIA-N]
contact_pi_person_id: 9594976
contact_pi: FARDO, DAVID WILLIAM
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
project_abstract:
DESCRIPTION (provided by applicant): This mentored career development grant application proposes a training program to integrate Dr. Fardo's previous research in biostatistics and statistical genetics into investigations of aging disorders including highly prevalent neurodegenerative diseases. His long-term career goal is to develop an independent research program focusing on the advancement of statistical methodologies to understand the genetics underlying complex diseases with an emphasis on diseases of brain aging. This will be achieved through acquiring knowledge in the area of brain diseases of aging through formal coursework and mentored experiences; training in the management analysis and interpretation of associated research data; comprehensive examination of the large-scale genetic data used in aging studies and the areas where novel cutting-edge biostatistical methodologies could improve analyses; application refinement and development of statistical genetic approaches to the analysis of this large-scale genetic data; and the continuation of training in the responsible conduct of research. Dr. Fardo's research training will involve an enthusiastic team of cross- disciplinary researchers with a strong research track record. An overall goal of this K25 application is to capitalize on the clinical and neuropathologic data available from large multicenter-derived databases to identify single nucleotide polymorphisms (SNPs) associated with specific neuropathologic endophenotypes. Most research investigating the genetic predisposition of age-related complex diseases has been conceptualized with a model directly comparing those with or without a disease for example with or without Alzheimer's disease (AD). However this disease/non-disease approach is inefficient and not appropriate for investigating the genetic risk factors for so-called mixed pathologies which are the norm in advanced age. The proposed research program will interrogate genetic associations with neuropathologic features of a large cohort of autopsied brains. This will be done by utilizing data collected from large NIH-funded resources. Neuropathology data and genome-wide genetic data will be merged from these resources and genetic associations for mixed-pathology dementias and neuropathologic features will be comprehensively tested. This work will result in new methods to analyze mixed-pathology dementias and neuropathologic features as well as the exploration of associated genetic risk factors and gene-environment interactions.

project_terms:
Achievement;Age;Aging;Alzheimer's Disease;Alzheimer's disease model;Applications Grants;Area;Autopsy;Biological;Biometry;Brain;Brain Diseases;Brain Pathology;Classification;Clinical;Complex;Data;Data Set;Data Storage and Retrieval;Databases;Dementia;Detection;Development;Diagnosis;Disease;Disease Progression;Drug Targeting;Elderly;Funding;Genes;Genetic;Genetic Predisposition to Disease;Genetic Risk;Goals;Health;Hippocampus (Brain);Impaired cognition;Impairment;Intervention;Investigation;Knowledge;Lewy Body Dementia;Link;Memory;Mentors;Methodology;Methods;Modeling;Multicenter Studies;National Institute on Aging;Neurodegenerative Disorders;Outcome;Pathology;Phenotype;Postdoctoral Fellow;Predisposition;Prevention;Process;Quality Control;Religion and Spirituality;Research;Research Personnel;Research Training;Resources;Risk Factors;Sclerosis;Series;Single Nucleotide Polymorphism;Site;Susceptibility Gene;Testing;Training;Training Programs;United States National Institutes of Health;Variation (Genetics);Vascular Dementia;Work;age related;aging brain;base;career;career development;case control;clinical Diagnosis;cohort;disease diagnosis;endophenotype;experience;gene environment interaction;genetic approach;genetic association;genetic risk factor;genome wide association study;genome-wide;improved;insight;interest;mixed dementia;neuroimaging;neuropathology;novel;programs;responsible research conduct;risk variant;skills

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Understanding better the biological mechanisms that underlie complex diseases of brain aging can aid in the ability to diagnose disease early track disease progression and identify drug targets for treatment. The genetic knowledge to be garnered from this proposal is critical to discover and refine risk factors and the associated biological mechanisms of diseases of brain aging.


application_id: 8847698
project_number: 5R21DA035376-02
project_title: Motivation for Cocaine and Non-Drug Reinforcers: Targeting Glutamate Homeostasis
administering_ic: NIDA
award_notice_date: 2015-05-06
opportunity_number: PA-10-269
application_type: 5
activity_code: R21
ic: DA
serial_number: 035376
program_official: GRANT, STEVEN J
project_start_date: 2014-06-01
project_end_date: 2018-12-31
study_section: Neurobiology of Motivated Behavior Study Section[NMB]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cocaine is the most commonly used illicit stimulant in the United States. Despite great strides in our understanding of the neuropharmacological underpinnings of cocaine addiction in the preclinical arena the number of cocaine users in the United States has remained relatively stable in recent years indicating that more clinical research is necessary to translate these findings to humans in an attempt to develop more effective means of reducing cocaine use. Emerging data suggest that perturbations in glutamate transmission following cocaine use (i.e. disrupted glutamate homeostasis) contribute to the maladaptive pattern of drug taking characterized by cocaine addiction. Specifically preclinical studies indicate that cocaine exposure results in increased motivation to take cocaine and decreased drive for non-drug reinforcers. This change in reinforcer salience corresponds with complex neuropharmacological changes in the glutamate system. Whereas preclinical data suggest that targeting glutamate systems specifically restoring glutamate homeostasis reduces drug reinforcer salience this research area remains relatively unexplored in humans. Some initial studies suggest that n-acetylcysteine pretreatment normalizes glutamate levels in cocaine users and that n-acetylcysteine maintenance attenuates desire for cocaine and attention to cocaine cues in abstinent cocaine-dependent subjects. Whether restoration of glutamate homeostasis impacts motivation for drug relative to non-drug reinforcers remains to be determined in humans. The research proposed here will demonstrate that restoration of glutamate homeostasis reduces motivation to take cocaine and increases motivation to obtain a non-drug alternative reinforcer (i.e. money) in cocaine-dependent humans using progressive-ratio schedules of reinforcer availability which are an accepted means to measure motivation. The use of concurrent progressive-ratio schedules of drug and non-drug reinforcer availability will allow inferences to be made about the influence of restored glutamate homeostasis on motivation to obtain these two types of reinforcers. Cognitive tasks that assess domains relating to reinforcer choice also will be included to complement the self-administration outcomes. This study will translate findings from preclinical research and provide the initial clinical evidence tat restoration of glutamate homeostasis shifts reinforcer salience away from drug reinforcers towards non-drug reinforcers in active cocaine users. Outcomes of the experiment will not only contribute to our understanding of the clinical neuropharmacology of cocaine addiction they also can be used to guide development of treatments for cocaine use disorders.

project_terms:
Abstinence;Acetylcysteine;Acute;American;Area;Attention;Attenuated;Automobile Driving;Basic Science;Behavioral Mechanisms;Brain;Ceftriaxone;Chronic;Clinical;Clinical Research;Cocaine;Cocaine Dependences;Cocaine Users;Cognitive;Complement;Complex;Cues;Cystine;Data;Decision Making;Diagnostic;Disease;Dose;Drug Use Disorder;Glutamate Transporter;Glutamates;Goals;Health;Homeostasis;Human;Laboratories;Left;Link;Maintenance;Measures;Motivation;Neuropharmacology;Neurosciences Research;Oral;Outcome;Pattern;Pharmaceutical Preparations;Pharmacodynamics;Physiological;Placebos;Population;Pre-Clinical Model;Prevalence;Relative (related person);Reporting;Research;Role;Safety;Sampling;Schedule;Self Administration;System;Testing;Translating;United States;attentional bias;cocaine exposure;cocaine use;cognitive performance;cognitive task;flexibility;human subject;improved;insight;meetings;non-drug;pre-clinical;pre-clinical research;preclinical study;public health medicine (field);reinforcer;research study;restoration;therapy development;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Preclinical data implicate disrupted glutamate homeostasis in the disordered motivation that characterizes cocaine addiction. The goal of this project is to translate preclinical findings by determining how restoration of glutamate homeostasis impacts motivation for cocaine and non-drug reinforcers in active cocaine users which will improve our understanding of the clinical neuropharmacology of cocaine addiction and provide insights into treatment development.


application_id: 8847680
project_number: 5R01CA166327-03
project_title: Regulation of Tumor Metabolism by Retinoblastoma Protein
administering_ic: NCI
award_notice_date: 2015-05-08
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: 2016-05-31
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;Health;Histones;Human;Knock-out;Knockout Mice;Lipids;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Molecular Target;Mus;Neoplasm Metastasis;Neoplasms;Neoplastic Cell Transformation;Normal Cell;Normal tissue morphology;Nucleotide Biosynthesis;Oncogenes;Oxygen Consumption;Pathway interactions;Phenotype;Polychlorinated Biphenyls;Positron-Emission Tomography;Process;Production;Promoter Regions (Genetics);Promotor (Genetics);Proteins;Recruitment Activity;Regulation;Regulatory Pathway;Relative (related person);Retinoblastoma;Retinoblastoma Protein;Role;TOCSY;Testing;Transcription Repressor/Corepressor;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;neoplastic;neoplastic cell;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: 8847653
project_number: 5R21AI113386-03
project_title: Effect of the gut microbiota on malaria
administering_ic: NIAID
award_notice_date: 2015-05-06
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: AI
serial_number: 113386
program_official: PESCE, JOHN T
project_start_date: 2014-12-01
project_end_date: 2017-04-30
study_section: Pathogenic Eukaryotes Study Section[PTHE]
contact_pi_person_id: 11178918
contact_pi: SCHMIDT, NATHAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Plasmodium infections which cause malaria have been a scourge to humanity for thousands of years. Unfortunately we are still years away from an efficacious anti-malaria vaccine that is available to the >40% of the world's population that isat risk of malaria. Further complicating treatment and control of malaria is that both Plasmodium and the mosquito vector that transmits the parasite rapidly develop resistance to new drugs developed to treat malaria and control mosquito populations. Therefore it is imperative novel approaches to control malaria are explored. We propose an exploratory project to determine the impact of the gut microbiota on regulating the severity of malaria which has the potential to provide insights to novel and affordable approaches to treat malaria. The gut microbiota has been shown to shape susceptibility to obesity diabetes and regulate multiple aspects of host immunity. This is particularly true for components of the immune system that interface with the GI tract. Importantly the gut microbiota also augments host immunity to bacterial and viral infections that occur outside of the GI tract. However there are no reports as to how the gut microbiota influence host immune responses to non-GI tract parasitic infections including Plasmodium. Our preliminary data demonstrate that C57BL/6 mice purchased from different vendors which are known to have alterations in their gut microbiota exhibit substantially different levels of parasite burden following infection with Plasmodium yoelii 17XNL. We have also demonstrated that C57BL/6 mice from different vendors treated with a cocktail of antibiotics exhibit dynamic responses following infection with Plasmodium compared to control treated mice. Collectively our data suggest the gut microbiota regulates the severity of malaria. We hypothesize that specific gut bacteria and their metabolic by-products regulate susceptibility to malaria. We will address this hypothesis through the following specific aims: 1) Identify differences in gut microbiota populations that are associated with differential susceptibility to malaria 2) Determine ability of the gut microbiota to transfer resistance or susceptibility to malaria to another mouse and 3) Identify gut metabolites that drive differential susceptibility to malaria.

project_terms:
Address;Aldehydes;Antibiotics;Bacteria;Bacterial Infections;Base Sequence;C57BL/6 Mouse;Cells;Cessation of life;Communities;Data;Diabetes Mellitus;Diet;Disease;Drug resistance;Exhibits;Fermentation;Gastrointestinal tract structure;Goals;Health;Humanities;Immune response;Immune system;Immunity;Infection;Laboratories;Malaria;Malaria Vaccines;Measures;Metabolic;Mosquito Control;Mus;Obesity;Parasite Control;Parasites;Parasitic infection;Pharmaceutical Preparations;Phase III Clinical Trials;Phenotype;Plasmodium;Plasmodium yoelii;Population;Predisposition;Probiotics;Production;Regulatory T-Lymphocyte;Reporting;Research;Research Project Grants;Resistance;Resistance development;Risk;Rodent;Scourge;Severities;Shapes;Therapeutic;Transplantation;Vaccines;Vendor;Virus Diseases;Volatile Fatty Acids;Work;feeding;global health;gut microbiota;innovation;insight;interleukin-22;liquid chromatography mass spectroscopy;microbial;microbiome;novel;novel strategies;prebiotics;rRNA Genes;response;sobriety;vaccine candidate;vaccine development;vector mosquito

public_health_relevance:
PUBLIC HEALTH RELEVANCE: In spite of tremendous effort an efficacious malaria vaccine that can be deployed in large quantities is still years away and current malaria control measures are hampered by drug resistance. Completion of this project will identify populations of the gut microbiota and/or metabolome that confer protection from severe malaria. These results will be critical in developing affordable novel probiotic and prebiotic approaches to control severe malaria.


application_id: 8847362
project_number: 5P01HL078825-10
project_title: Flow Cytometry and Cell Sorting Core
administering_ic: NHLBI
award_notice_date: 2015-06-18
opportunity_number: PAR-10-285
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2005-04-15
project_end_date: 2018-05-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7463
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
The function of the Flow Cytometry and Cell Sorting Core (Core D) is to provide each Project with the expertise equipment and facilities required for the flow cytometric analyses and cell sorting procedures that are needed for studies of cardiac progenitor cells (CPCs). Accurate identification characterization and quantitation of cells in a complex heterogeneous population are technically demanding and require specialized and expensive equipment and personnel. One of the maior advantages of this Program Proiect is that it will make available to all four Proiects the facilities and techniques of flow cytometry and cell sorting. which otherwise would not be affordable to any Proiect in isolation. Flow cytometry-based analysis for the identification of specific cell populations changes in cell commitment or phenotype and characterization of cell functions such as cell cycle viability signal transduction or potential will be crucial to all Projects. A central common facility that performs these technically challenging analyses is therefore indispensable to achieve the goals of the Program Project. Besides the obvious advantages of efficiency and cost savings the Core will also enable four investigators with diverse and complementary backgrounds (Drs. Rokosh McCracken Ratajczak and O'Toole) to combine their technical and biological expertise in order to ensure that the proposed work is successfully executed.  The Core will offer the Program Project investigators the ability to identify and characterize specific cell types from complex populations. Specifically the Core will perform analysis of marker expression in various cells including CPCs and more differentiated cells and including changes in marker expression during differentiation; detect intracellular generation of radicals (i.e. using DAFDA for NO and DCFDA for ROS); examine mitochondrial membrane integrity membrane potential and function; assess cell viability; determine changes in cell signaling; isolate stem cells utilizing multiple markers; and quantify cells at each phase of the cell cycle. The Core is also active in identifying and characterizing novel cell markers that will be useful for the various Projects.

project_terms:
Area;Biological;Budgets;Cardiac;Cardiomyopathies;Cell Cycle;Cell Separation;Cell Survival;Cell physiology;Cells;Centers of Research Excellence;Complex;Cost Savings;Coupled;Diabetes Mellitus;Ensure;Equipment;Flow Cytometry;Foundations;Funding;Generations;Goals;Human Resources;Institutes;Maintenance;Membrane Potentials;Myocardial Ischemia;Nature;Obesity;Phase;Phenotype;Population;Population Heterogeneity;Procedures;Reperfusion Therapy;Research Personnel;Signal Transduction;Stem cells;Techniques;United States National Institutes of Health;Work;base;cell type;diacetyldichlorofluorescein;mitochondrial membrane;novel;operation;programs;stem cell biology;stem cell therapy


application_id: 8847361
project_number: 5P01HL078825-10
project_title: Stem Cell and Pathology Core
administering_ic: NHLBI
award_notice_date: 2015-06-18
opportunity_number: PAR-10-285
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2005-04-15
project_end_date: 2018-05-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7462
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
The Stem Cell and Pathology Core will be a critical resource to this PPG. It will provide the four Projects with access to a wide array of reagents procedures and analyses including i) CPC isolation sorting and characterization ii) assays of CPC function in vitro and iii) histopathology of cardiac samples obtained in vivo. It will provide the facilities and expertise necessary to isolate maintain and manipulate CPCs from several genetically engineered mice. The individual Projects do not have the facilities or expertise needed to isolate and characterize CPCs consistently or to perform the extensive histopathological analyses required. Consolidation of all CPC work into a Core facilitv will decrease the costs of supplies and eguipment because the Core will make bulk purchases of supplies (thereby reducing expenses) and because waste and unnecessary duplication of supplies reagents and equipment will be eliminated with the maintenance of centralized stocks and inventories. Consolidating CPC work into a Core facilitv is also time-effective because the techniques involved in this work are very labor intensive and require dedicated skilled personnel. The Core staff a full-time team of six dedicated individuals under the immediate supervision of the Core Leaders will provide consistency and reproducibility of analvsis. This is crucial because it will ensure that all four Proiects will use CPCs isolated expanded and sorted the same way thereby making the results comparable. A single source of CPCs with rigorous standardization to ensure consistency will result in transplantation of uniform CPC populations in all four Proiects and thus is extremely important for the integration and comparison of results from each of the Projects. Similarly the uniform histopathologic analyses conducted by the Core in a blinded and rigorously standardized fashion will make it possible to compare results of different experiments within the same Project and among different Projects.   The methods used by the Core to prepare CPCs are extremely efficient; CPCs in culture as determined by c-kit expression (FACS). average 953% at passages 2 to 10 and remain at -95% at passage 10. In summary the Core will ensure guality control and by eliminating duplication of effort and maximizing the use of personnel and supplies will enable an efficient use of resources.

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


application_id: 8847360
project_number: 5P01HL078825-10
project_title: Surgery and Physiology Core
administering_ic: NHLBI
award_notice_date: 2015-06-18
opportunity_number: PAR-10-285
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2005-04-15
project_end_date: 2018-05-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7461
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
The function of the Surgery and Physiology Core (Core B) is to provide the expertise equipment and facilities needed for all of the in vivo murine studies. Specifically Core B will be responsible for all surgical procedures (coronary artery occlusion/reperfusion and CPC delivery) echocardiographic analyses invasive hemodynamic studies and maintenance and genotyping of transgenic and knockout mouse lines. Accurate physiological measurements and surgical procedures in mice represent technically demanding tasks that cannot and should not be attempted in every laboratory but rather should be performed by a group of dedicated investigators who focus on studies in mice and thereby acquire extensive experience with this difficult model. One of the main advantages of this Program Project is that it provides all four Proiects with access to complex and technically challenging in vivo mouse models of mvocardial infarction (Ml) and ceil therapy expert physiology and surgery and state-of-the-art technigues that otherwise would not be available to these investigators. This is a major benefit to all investigators. Core B consists of a team of skilled highly- experienced investigators who have worked together cohesively for many years focusing exclusively on murine studies (they have performed >16.000 surgical procedures in mice) have developed and perfected murine models of Ml and cell therapy utilizing state-of-the-art facilities and equipment and have collaborated extensively with the other investigators in this PPG.  An important feature of Core B is that it will use a new technique for delivering CPCs - intracoronary infusion in the mouse which has never been used before in this species. Compared with standard intramyocardial injection intracoronary infusion is much more clinically relevant. Furthermore it enables uniform distribution of CPCs throughout the infarct and in the noninfarcted region which is not possible with intramyocardial injection and produces superior results as shown by our data. Another feature is that all echocardiographic and hemodynamic analvses will be performed off-line by blinded observers. The capacity of the Core has been tested in the preparation of this submission. To produce the preliminary data needed for this application. Core B has operated upon >300 mice and performed 231 studies of CPC transplantation 390 echocardiographic studies and 108 hemodynamic studies. All of this has been done in the past 10 months. These numbers eloquently illustrate the research output that the Core can produce.

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


application_id: 8847359
project_number: 5P01HL078825-10
project_title: Administrative Core
administering_ic: NHLBI
award_notice_date: 2015-06-18
opportunity_number: PAR-10-285
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2005-04-15
project_end_date: 2018-05-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7460
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Core A will provide scientific budgetary administrative logistic and biostatistical oversight to all aspects of the Program Project. The Core will facilitate communication among investigators and sharing of reagents tools specimens and data; will ensure appropriate allocation of funds to each Project and appropriate use of these funds; will provide clerical support; will coordinate the Projects with subcontracted institutions; will organize regular investigator meetings; and will provide biostatistical assistance. Dr. Bolli Core Leader will be responsible for the overall coordination integration and administration of the Program Project for the appropriate utilization of the funds for compliance with institutional and federal regulations for the scientific productivity of the Program and for any issues related to the Program. The Principal Investigator will be assisted by the other members of the Executive Committee which will be composed of the four Project Leaders and the four Core Leaders. The Principal Investigator and the executive Committee will meet on a monthly basis to discuss the scientific progress data problems and future directions for the four Projects. Scientific responsibilities include (1) providing leadership in maintaining the focus of the investigators (2) providing statistical assistance and (3) weekly meetings of all Program Project Investigators. Administrative and financial responsibilities include (1) implementing guidelines for Program Project support (2) administering the budget according to NIH guidelines (3) monitoring budgets for each Project and Core and (4) ensuring compliance with the institutional and NIH regulations. The Biostatistician working in the Core will be Dr. Maiying Kong. She will attend the monthly meetings of the Executive Committee review the experimental data analyze them and calculate group sizes for future studies. She will devote 10% of his/her time to this Program Project. An important aspect of this Program Project is that the investigators performing in vivo studies of CPCs will be blinded to the treatment until the final data analysis is released by Dr. Kong. Another important aspect is that all sample sizes will be selected before the experiments are started (based upon power analysis by Dr. Kong) and will not be changed; the experiments will be carried out until the predetermined sample sizes are achieved without any knowledge of interim results. After the predetermined sample sizes are achieved all data will be given to Dr. Kong where they will be unblinded and analyzed by appropriate statistical methods. Each Project will utilize 25% of Core A.

project_terms:
Blinded;Budgets;Communication;Data;Data Analyses;Ensure;Funding;Future;Guidelines;Institution;Knowledge;Leadership;Logistics;Monitor;Myocardial Ischemia;Principal Investigator;Productivity;Reagent;Regulation;Research Personnel;Review Committee;Sample Size;Specimen;Statistical Methods;Time;United States National Institutes of Health;Work;base;in vivo;meetings;member;programs;research study;tool


application_id: 8847358
project_number: 5P01HL078825-10
project_title: Diabetic Dyfuntion of CPCs
administering_ic: NHLBI
award_notice_date: 2015-06-18
opportunity_number: PAR-10-285
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2005-04-15
project_end_date: 2018-05-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7459
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
The overall goal of Project 4 is to detemine how diabetes affects cardiac progenitor cell (CPC)-mediatedmyocardial repair after infarction and how CPC therapy could be optimized for the diabetic heart.Although stem cell therapy with CPCs offers new hope for the treatment of heart failure the efficacy ofstem cell therapy in diabetes remains uncertain. Our preliminary observations show that diabetesimpairs CPC growth and differentiation and in contrast to non-diabetic hearts diabetic hearts do notbenefit from CPC therapy. We propose that diabetes decreases CPC competence by inducing insulinresistance. Excessive nutrients in diabetes increase the production of reactive oxygen species (ROS)that triger inflammation and establish insulin resistance in CPCs. This in turn impairs their capacity topromote myocardial repair. To test this hypothesis three specific aims are proposed. (1) To examineglucose transport and glucose and fattty acid metabolism in CPCs we will measure the rates ofglycolysis and fatty acid metabolism in lin-/kit+ CPCs isolated from the mouse heart under basalcondition and in the presence of high glucose and palmitic acid and determine how nutrient excessaffects the fundamental parameters of CPC competence. To determine the effect of diabetes we willisolate CPCs from db/db and high-fat fed mice and compare their competence with CPCs from non-diabetic mice. (2) To elucidate the mechanisms by which nutrient excess affects CPCs we will examinethe role of inflammation and oxidative stress in inducing insulin resistance and test the hypothesis thatin conditions of nutrient excess or diabetes hyperactivity of the mitochondrial electron transport chainleads to an increase in ROS production which triggers pro-inflammatory responses resulting in insulinresistance. (3) To determine the impact of diabetes on CPC-mediated myocardial repair we willtransplant diabetic CPCs in non-diabetic hearts and non-diabetic CPCs in diabetic hearts aftermyocardial infarction and measure changes in CPC-mediated changes in myocardial function and testwhether anti-inflammatory or anti-oxidant interventions that resolve insulin resistance promote CPCmediated myocardial repair in the diabetic and non-diabetic hearts.RELEVANCE (See instructions):A majority of patients with heart failure have diabetes yet the effects of diabetes on stem cell therapyare unknown. By providing new understanding of the underlying mechanisms by which diabetes affectsstem cell therapy in heart failure and how stem cell therapy could be optimized for the diabetic heartthis project could lead to the development of new therapies for the treatment of heart failure in diabeticand non-diabetic patients..

project_terms:
Acids;Affect;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Apoptosis;Attenuated;Cardiac;Cell Therapy;Cell physiology;Cells;Competence;Cytoprotection;Development;Diabetes Mellitus;Diabetic mouse;Differentiation and Growth;Doctor of Medicine;Electron Spin Resonance Spectroscopy;Electron Transport;Fatty Acids;Fatty acid glycerol esters;Functional disorder;Generations;Glucose;Glycolysis;Goals;Growth Factor;Heart;Heart failure;Heme Oxygenase (Decyclizing);Hyperactive behavior;Inflammation;Inflammatory Response;Instruction;Insulin Resistance;Intervention;Lead;Length;Measures;Mediating;Metabolism;Mitochondria;Mortality Vital Statistics;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Non-Insulin-Dependent Diabetes Mellitus;Nutrient;Oxidative Stress;Oxygen Consumption;Palmitic Acids;Patients;Principal Investigator;Process;Production;Reactive Oxygen Species;Regimen;Resistance;Risk Factors;Role;Stem cells;Stimulus;Telomerase;Testing;Therapeutic Intervention;Transplantation;Tumor Necrosis Factor Receptor;UCP2 protein;adiponectin;cardiac repair;cell growth;cytokine;design;diabetic;diabetic patient;fatty acid metabolism;feeding;glucose transport;glucose uptake;improved;in vivo;insulin sensitivity;insulin signaling;migration;mouse model;non-diabetic;nutrient metabolism;outcome forecast;overexpression;prevent;receptor;repaired;senescence;stem cell therapy;telomere


