# projects

application_id: 8900401
project_number: 2R01HD064993-06
project_title: Aging and Dementia in Down Syndrome: Connectivity Inflammation and Cerebrovascular Contributions
administering_ic: NICHD
award_notice_date: 2015-04-03
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: HD
serial_number: 064993
program_official: PARISI, MELISSA
project_start_date: 2009-09-30
project_end_date: 2020-01-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 8662513
contact_pi: HEAD, ELIZABETH
other_pis: SCHMITT, FREDERICK
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):  Down syndrome (DS) is the major cause of intellectual disability in humans and it is estimated there are over 300000 individuals with this genetic disorder in the United States. Virtually all DS individuals have sufficient neuropathology for a diagnosis of AD in their 40th year. However dementia may not develop until up to a decade later and some people remain cognitively intact. In this competitive renewal we propose to continue following (and expand) our cohort of aging adults with DS as well as recruit younger individuals to establish the role of white matter (WM) integrity losses cerebrovascular dysfunction (CVF) and neuroinflammation on cognitive decline. Aim 1 will continue to cognitively characterize a cohort of adults with DS and follow individuals for a period of 5 years as well as recruit a younger cohort that is pre-AD pathology. Magnetic resonance imaging (MRI) using diffuse tensor imaging will be used to track losses in WM integrity. Aim 2 will use MRI methods to detect cerebrovascular dysfunction by susceptibility weighted imaging fluid attenuated inversion recovery and arterial spin labeling. Aim 3 will use magnetic resonance spectroscopy and blood biomarkers to detect neuroinflammation as a function of age AD neuropathology and declines in cognition. Aim 4 will measure proteins and RNA to reflect protein and RNA changes to determine the neurobiological mechanisms underlying losses in WM integrity CVF and shifts in neuroinflammation in the brains of autopsy cases with DS. We will be able to identify targets for intervention studies (Aim 4) that could be implemented to promote healthy brain aging and would result in cognitive (Aim 1) WM structural integrity (Aim 1) and CVF improvements (Aim 2) and reduced neuroinflammation (Aim 3) in future clinical trials. Identifying the earliest signs
of dementia and indicators of individual variation in cognitive decline provides opportunities to implement DS appropriate preventative approaches to slow or halt the development of AD neuropathology and significantly improve the quality of life of DS individuals who are vulnerable to neurodegeneration.

project_terms:
Adult;Age;Age-Years;Aging;Alzheimer's Disease;Amyloid beta-Protein;Antigen-Antibody Complex;Attenuated;Autopsy;Behavior;Biological Markers;Blood;Brain;Case Series;Chromosomes Human Pair 21;Classification;Clinical;Clinical Trials;Cognition;Cognitive;Cognitive aging;Data;Dementia;Dependency (Psychology);Deposition;Development;Diagnosis;Diffuse;Down Syndrome;Employee Strikes;Encephalitis;Event;Functional disorder;Future;Genes;Goals;Hereditary Disease;Human;Image;Impaired cognition;Individual;Inflammation;Inflammatory;Intellectual functioning disability;Intervention Studies;Link;Liquid substance;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Measures;Mediating;Molecular;Molecular Target;Nerve Degeneration;Neurobiology;Neurofibrillary Tangles;Outcome;Parietal Lobe;Pathology;Pathway interactions;Pattern;Phenotype;Plasma;Play;Predisposition;Proteins;Quality of life;RNA;Recovery;Recruitment Activity;Reporting;Research;Research Design;Role;Senile Plaques;Signal Transduction;Spin Labels;Syndrome;Testing;United States;United States National Institutes of Health;Variant;Weight;abeta accumulation;age related;aging brain;brain tissue;cerebrovascular;cognitive function;cohort;functional decline;imaging modality;improved;middle age;neurobiological mechanism;neuroinflammation;neuropathology;novel;prevent;public health relevance;white matter

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  The proposed study will identify early changes in brain inflammation cerebrovascular dysfunction and white matter integrity losses that signal changes in cognition behavior and functioning reflecting Alzheimer disease (AD) in adults with Down syndrome (DS). Identifying the earliest signs of dementia and indicators of individual variation in
cognitive decline provides opportunities to implement DS appropriate preventative approaches to slow or halt the development of AD neuropathology and significantly improve the quality of life of DS individuals who are vulnerable to neurodegeneration. .


application_id: 8899542
project_number: 5R01ES021771-02
project_title: Apoptosis resistance and Cr(VI) carcinogenesis
administering_ic: NIEHS
award_notice_date: 2015-04-22
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 021771
program_official: REINLIB, LESLIE J
project_start_date: 2014-08-01
project_end_date: 2019-04-30
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 10011919
contact_pi: ZHANG, ZHUO
other_pis: SHI, XIANGLIN
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Animal Model;Antioxidants;Apoptosis;Apoptotic;BCL2 gene;Binding (Molecular Function);Carcinogens;Cell Nucleus;Cell Proliferation;Cell Survival;Cells;Chromates;Cleaved cell;Comparative Study;DNA Damage;Down-Regulation;Epithelial;Equilibrium;Event;Exhibits;Generations;Health;Heme;Human;Induction of Apoptosis;Industry;Lung;Malignant - descriptor;Mediating;Modification;Mutate;NQO1 gene;Neoplasm Metastasis;Normal Cell;Nuclear;Oxidases;Oxidoreductase;Oxygenases;Pathway interactions;Play;Poisons;Poly(ADP-ribose) Polymerases;Process;Production;Proliferating;Promoter Regions (Genetics);Proteins;Quinine;Reaction;Reactive Oxygen Species;Regulation;Resistance;Response Elements;Role;Staging;Superoxide Dismutase;System;Testing;Up-Regulation (Physiology);antioxidant enzyme;carcinogenesis;caspase-9;catalase;cell transformation;chromium hexavalent ion;exposed human population;genetic regulatory protein;migration;overexpression;small hairpin RNA;tumor;tumorigenesis


application_id: 8899519
project_number: 5R01DK091584-05
project_title: Novel biomarker validation and dosing algorithms for anemia management in ESRD
administering_ic: NIDDK
award_notice_date: 2015-09-01
opportunity_number: PA-09-204
application_type: 5
activity_code: R01
ic: DK
serial_number: 091584
program_official: GOSSETT, DANIEL ROBERT
project_start_date: 2011-09-20
project_end_date: 2017-08-31
study_section: ZDK1-GRB-G(O5)S
contact_pi_person_id: 8638276
contact_pi: MERCHANT, MICHAEL L
other_pis: BRIER, MICHAEL E
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):  Erythropoietin (EPO) and erythropoiesis-stimulating agents (ESAs) are used to treat the anemia of chronic renal disease in greater than 90% of all in-center hemodialysis patients at a cost of approximately 2 billion dollars per year. Despite protocols for anemia management in the end stage renal disease (ESRD) population a large proportion of patients do not respond predictably to typical doses of EPO. Several recent randomized controlled trials looking to increase hemoglobin (Hb) in patients with the anemia of renal disease have uncovered many questions about the treatment of anemia with ESAs not previously addressed in new drug applications or in subsequent research. A call has been made for the establishment of the optimal Hb target dosing algorithm and monitoring approach for patients with anemia from chronic renal disease. We suggest that our poor understanding of the mechanisms leading to EPO resistance prevents the ability to objectively predict and design dosing algorithms for anemia management. We propose that this problem is best addressed with a semi-empirical method which uses surrogate markers of EPO responsiveness and computer-directed algorithms to achieve a specific Hb target range and to exaggerated oscillations in Hb levels. The broad-based long term goals of our research are to address a critical barrier to the progress with personalization of anemia management by developing more objective patient specific approaches to EPO dosing in ESRD populations.  Data developed in our labs suggests that the abundances of specific serum proteins and protein fragments correlate with EPO responsiveness in ESRD patients receiving dialysis therapy. These data suggest these proteins and protein fragments classify EPO response with more sensitivity and specificity than C-reactive protein and hepcidin. We hypothesize that specific serum proteins and peptides are candidate surrogate biomarkers for EPO responsiveness and can be used to improve existing algorithms for predictive EPO response indexing. We propose 2 aims. Aim 1 - We propose to validate selected candidate surrogate biomarkers in a larger population of ESRD patients enrolled from three geographically distinct centers. Within this aim we will address the null hypothesis that EPO resistance is characterized by altered expression of Th1- and Th2-cytokines and address the hypothesis that serum peptides and proteins can predict EPO responsiveness. In Aim 2 - We propose to investigate the contribution of our surrogate biomarkers to dosage prediction in long-term administration of EPO and compare models base on these new biomarkers to established models. Using a novel Model Predictive Control (MPC) tool that we have previously published and demonstrated to be superior to standard EPO dosing techniques we will access and incorporate the validated surrogate biomarkers to develop a refined clinical tool for dosing of ESAs.

project_terms:
Address;Algorithms;Anemia;Biological Markers;C-reactive protein;Chronic Kidney Failure;Clinical;Computer Assisted;Computers;Data;Decision Support Systems;Development;Dialysis procedure;Dose;End stage renal failure;Enrollment;Enzyme-Linked Immunosorbent Assay;Erythropoiesis;Erythropoietin;Goals;Grant;Hemodialysis;Hemoglobin;Hemoglobin concentration result;Inflammatory;Investigation;Iron;Kidney Diseases;Kidney Failure;Knowledge;Laboratories;Methods;Modeling;Monitor;Morbidity - disease rate;Mortality Vital Statistics;Nutritional status;Outcome;Overdose;Patient risk;Patients;Peptides;Pharmaceutical Preparations;Plasma;Population;Process;Protein Fragment;Proteins;Proteome;Protocols documentation;Publishing;Randomized Controlled Clinical Trials;Randomized Controlled Trials;Research;Resistance;Sensitivity and Specificity;Serum;Serum Proteins;Surrogate Markers;Techniques;Testing;Treatment outcome;Validation;base;cardiovascular risk factor;cost;cytokine;design;dosage;hepcidin;improved;indexing;novel;predictive modeling;prevent;response;tool;trend

public_health_relevance:
The empirical treatment of anemia with erythropoiesis stimulating agents does not achieve optimal results in a significant number of end-stage renal disease patients receiving hemodialysis. Our laboratories have independently identified candidate surrogate serum biomarkers of erythropoiesis in end-stage renal disease hemodialysis patients that are associated with treatment outcome and have led the development and testing of computation methods for dosing of erythropoiesis stimulating agents. We propose to merge these two novel advances and determine their combined utility to improve erythropoiesis stimulating agent dosing in end-stage renal disease.


application_id: 8898930
project_number: 4R00DA033373-03
project_title: Tonic and Phasic Glutamate Release in Incentive Salience and Cocaine Reinforcemen
administering_ic: NIDA
award_notice_date: 2014-09-03
opportunity_number: PA-11-197
application_type: 4
activity_code: R00
ic: DA
serial_number: 033373
program_official: RADMAN, THOMAS C
project_start_date: 2014-09-15
project_end_date: 2017-08-31
study_section: NSS
contact_pi_person_id: 9713925
contact_pi: BECKMANN, JOSHUA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The proposed career development plan is designed to provide the PI with a unique skill set and experience tomeet the short-term goal of becoming a productive independent researcher and long-term goal of becoming asignificant contributor to the understanding and treatment of substance abuse disorders. The plan will becarried out at the University of Kentucky an institution with a rich history of interdisciplinary substance abuseresearch. The PI will be mentored by Dr.Michael Bardo and co-mentored by Dr. Greg Gerhardt establishedexperts in neuropsychopharmacology and neurochemistry respectively. The plan proposes to use enzyme-based microelectrode arrays to uncover the role of sub-second tonic/phasic mesocorticolimbic glutamaterelease in individual differences in incentive salience/value attribution to reward-related cues and cocainereinforcement in a preclinical rat model. When a stimulus reliably predicts reward some animals attributeincentive value to the stimulus and thus will approach and contact it (sign-trackers); other animals use thestimulus as a simple signal of forthcoming reward and thus will approach the receptacle into which reward willbe delivered (goal-trackers). Recently it has been demonstrated that differences in sign and goal tracking arerelated to novelty seeking impulsivity initial vulnerability to cocaine reinforcement and relapse vulnerability.In addition to mesocorticolimbic dopamine stimulus-reward learning and drugs of abuse are known to altermesocorticolimbic glutamate signaling. The overall proposed hypothesis is that differences in incentive valueattribution are mediated by differential mesocorticolimbic glutamate release upon cue exposure; thisdifferential release is then exacerbated by repeated cocaine self-administration giving rise to differentialsubstance abuse vulnerability and relapse. Specific Aim 1 will determine if second-by-second tonic/phasicglutamate signaling is differentially affected by food-associated cues in sign- vs. goal-tracking animals.Specific Aim 2 will determine the role of dopaminergic receptor function on the expression of sign-/goal-tracking and underlying tonic/phasic glutamate signaling. Specific Aim 3 will determine if second-by-secondtonic and phasic glutamatergic signaling in sign- and goal-tracking animals changes differentially withrepeated cocaine self-administration. Specific Aim 4 will then determine the role of dopaminergic receptorfunction on cocaine self-administration and tonic/phasic glutamate signaling in sign- and goal-trackers.Collectively these results will provide insight into the role of tonic/phasic glutamate signaling in stimulus-reward learning incentive value attribution to reward-associated stimuli and cocaine reinforcement whileproviding the PI with unique training in neuropsychopharmacology and neurochemistry by experts in bothfields.

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

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


application_id: 8898908
project_number: 5U01HL121807-03
project_title: The Impact of Oxidative Stress on HIV-induced Lung Disease
administering_ic: NHLBI
award_notice_date: 2015-07-27
opportunity_number: RFA-HL-13-026
application_type: 5
activity_code: U01
ic: HL
serial_number: 121807
program_official: CALER, ELISABET V
project_start_date: 2013-09-26
project_end_date: 2016-07-31
study_section: ZHL1-CSR-S(S1)
contact_pi_person_id: 8816315
contact_pi: RAMIREZ, JULIO ALBERTO
other_pis: ROMAN, JESSE
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Lung diseases are major causes of morbidity and mortality in patients infected with the Human Immunodeficiency Virus (HIV). Currently antiretroviral therapy (ART) has changed HIV into a chronic disease. In the pre-ART era pulmonary infections were very common. In patients with ART however pulmonary infections are less frequent and noninfectious lung disorders such as COPD pulmonary hypertension lung cancer and pulmonary fibrosis are emerging as important causes of illness. These are important cause of morbidity and mortality yet the mechanisms responsible for these disorders in HIV patients are unknown. All pulmonary disorders mentioned above are associated with among other things lung inflammation and tissue remodeling characterized by alterations in matrix expression deposition and degradation. Interestingly HIV infection is also associated with oxidant stress caused by oxidation of the thiol disulfide couple cysteine (Cys)/cysteine (CySS) redox potential (Eh); also termed Eh Cys/CySS. This is important because in vitro studies show that an oxidized Eh Cys/CySS stimulates lung cells to produce more fibronectin (a matrix glycoprotein implicated in tissue injury and repair) transforming growth factor b (a pro-fibrotic growth factor) and pro-inflammatory cytokines like interleukin-1b. It also stimulates theproliferation and epithelial- mesenchymal transformation of lung fibroblasts processes implicated in tissue remodeling. These data suggest that HIV-related oxidation of Eh Cys/CySS may promote lung tissue remodeling. We have shown that one mechanism by which oxidation of Eh Cys/CySS stimulates tissue remodeling is through the activation of nicotinic acetylcholine receptors (nAChRs). This is intriguing considering that HIV-1 proteins like gp120 bind and increase the expression and signaling of nAChRs expressed in brain and this mechanism has been implicated in HIV-related dementia. We hypothesize that patients with HIV infection have oxidation of the Eh Cys/CySS which together with gp120 activates nAChR-mediated signaling in lung cells and leads to their expression of cellular products with pro-inflammatory and pro-fibrotic effects such as cytokines and growth factors matrix glycoproteins and tissue proteases. The persistent and exaggerated production of these factors activates lung tissue remodeling thereby promoting HIV-related lung disease. The type of disease developed (e.g. COPD versus pulmonary hypertension) however is dependent on both the genetic makeup of the subject and external factors such as smoking and infection. It is important that this hypothesis be tested considering that diet and other interventions have been shown to influence Eh Cys/CySS (9). If found to be causal Eh Cys/CySS and nAChRs can be targeted for intervention in the hope of reducing the incidence and/or severity of HIV-related non-infectious lung disease.

project_terms:
Address;Binding (Molecular Function);Blood;Brain;Bronchoalveolar Lavage Fluid;Cause of Death;Cells;Chronic Disease;Chronic Obstructive Airway Disease;Chronic lung disease;Clinical Research;Cysteine;Data;Data Analyses;Databases;Dementia;Deposition;Deterioration;Diet;Disease;Disulfides;Epidemiologic Studies;Epithelial;Fibroblasts;Fibronectins;Glycoproteins;Goals;Growth Factor;HIV;HIV Envelope Protein gp120;HIV-1;Health;Immunologist;In Vitro;Incidence;Individual;Infection;Inflammatory;Interleukins;Intervention;Lung;Lung Inflammation;Lung diseases;Malignant neoplasm of lung;Mediating;Mesenchymal;Morbidity - disease rate;Mortality Vital Statistics;Myofibroblast;Nicotinic Receptors;Oxidation-Reduction;Oxidative Stress;Patients;Peptide Hydrolases;Physicians;Process;Production;Proteins;Pulmonary Fibrosis;Pulmonary Hypertension;Research Personnel;Scientist;Severities;Signal Transduction;Smoking;Structure of parenchyma of lung;Sulfhydryl Compounds;Testing;Tissues;Transforming Growth Factors;Universities;Virus Diseases;antiretroviral therapy;base;clinical investigation;cytokine;design;env Gene Products;follow-up;genetic makeup;injury and repair;oxidant stress;oxidation;prevent;programs;pulmonary function;research and development;transdifferentiation

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


application_id: 8898799
project_number: 5U01ES022564-04
project_title: Countermeasures for chlorine-induced airway fibrosis
administering_ic: NIEHS
award_notice_date: 2015-09-01
opportunity_number: PAR-11-155
application_type: 5
activity_code: U01
ic: ES
serial_number: 022564
program_official: NADADUR, SRIKANTH
project_start_date: 2012-09-25
project_end_date: 2016-06-30
study_section: Special Emphasis Panel[ZRG1-MDCN-J(50)R]
contact_pi_person_id: 2736750
contact_pi: HOYLE, GARY W.
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Chlorine gas is a highly toxic respiratory irritant that is considered a chemical threat agent because of the possibility that it could be released in industrial accidents or terrorist attacks. Acute effects of chlorine inhalation include dyspnea hypoxemia pneumonitis and pulmonary edema. Longer term consequences of chlorine inhalation include pulmonary function impairment and airway structural changes that have been observed in some exposed individuals. We have developed a mouse chlorine inhalation model in which animals develop pulmonary edema inflammation airway obstruction and airway hyperreactivity within one day after exposure. In new studies related to the current application we have characterized injury and repair of the lung at longer times after chlorine inhalation. We have observed that airways with a partial loss of epithelium are repaired quickly by the proliferation and differentiation of epithelial cells that survive chlorine exposure. In contrast portions of airways with few surviving epithelial cells are repaired inefficiently and fibroproliferative lesions develop at such sites within a week after chlorine exposure. This development of airway fibrosis is associated with impaired lung function including increased respiratory system resistance and airway hyperreactivity to inhaled methacholine. In the current application we propose to develop countermeasures that can be administered following a chemical attack or accidental release to prevent chlorine-induced airway disease. The hypothesis to be tested in the proposed studies is that inefficient repair of airway epithelium following chlorine lung injury leads to airway fibrosis and impaired lung function; agents that mimic anti-fibrotic effects of airway epithelium or stimulate airway repair will ameliorate chlorin- induced airway disease. Specific Aim 1 will characterize airway epithelial repair airway fibrosisand lung function impairment following chlorine exposure in mice. Specific Aims 2-5 will evaluate the efficacy of the following potential countermeasures for the treatment of chlorine-induced airway disease: the prostanoid receptor agonists butaprost and iloprost; the long-lasting ss-agonist formoterol and the type 4 phosphodiesterase inhibitor rolipram; stimulation of plasminogen activation with urokinase-type plasminogen activator or the plasminogen activator inhibitor-1 inhibitor tiplaxtinin; and manipulation of Wnt/ss-catenin signaling with lithium chlorie or pyrvinium. Specific Aim 6 will involve development of a ferret model of chlorine-induced airway disease and testing of countermeasures in this non-rodent species. The proposed studies are expected to identify a countermeasure for prevention of chronic airway disease that develops as a result of an acute high level exposure to chlorine.

project_terms:
Acute;Adrenergic Agonists;Affect;Agonist;Airway Obstruction;Animals;Breathing;Cell Proliferation;Chemical Warfare;Chemicals;Chlorine;Chronic;Cyclic AMP;Development;Disease;Dyspnea;Epithelial;Epithelial Cells;Epithelium;Exposure to;Ferrets;Fibrosis;Goals;Health;Human;Hypoxemia;Iloprost;Impairment;Individual;Industrial Accidents;Inflammation;Irritants;Kinetics;Lesion;Lithium;Lithium Chloride;Lung;Measurement;Modeling;Mus;Non-Rodent Model;Phosphodiesterase Inhibitors;Plasminogen;Plasminogen Activator;Plasminogen Activator Inhibitor 1;Poisons;Prevention;Production;Prostaglandins;Pulmonary Edema;Pulmonary Inflammation;Recording of previous events;Research;Resistance;Resolution;Respiratory System;Respiratory physiology;Rodent;Rolipram;Signal Pathway;Signal Transduction;Site;Structure;Structure of respiratory epithelium;Symptoms;Testing;Time;Toxic effect;Unconscious State;United States;Urokinase;airway epithelium;airway hyperresponsiveness;animal rule;butaprost;chemical threat;chlorin;chlorine gas;efficacy testing;formoterol;inhibitor/antagonist;injury and repair;lung development;lung injury;methacholine;novel;phosphoric diester hydrolase;prevent;pulmonary function;receptor;repaired;research study;respiratory;restoration

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The goal of the proposed experiments is to develop novel ways to treat chronic airway disease caused by acute high level exposure to chlorine gas. This type of research is important because of concerns that U.S. civilians could be adversely affected by the accidental or intentional release of highly toxic chemicals such as chlorine.


application_id: 8898524
project_number: 5F31AG048692-02
project_title: Maintenance of Positive Affect Following Pain in Older Adults
administering_ic: NIA
award_notice_date: 2015-06-19
opportunity_number: PA-11-112
application_type: 5
activity_code: F31
ic: AG
serial_number: 048692
program_official: NIELSEN, LISBETH
project_start_date: 2014-07-27
project_end_date: 2016-07-26
study_section: Special Emphasis Panel[ZRG1-F16-L(20)L]
contact_pi_person_id: 11936065
contact_pi: BOGGERO, IAN ANDRES
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Up to 80% of those over age 65 report experiencing some degree of physical pain yet older adults appear remarkably adept at maintaining positive emotionality in the face of pain. Whereas studies find that older adults are at least as good at managing pain as their younger counterparts the strategies they use to do so remain largely unknown. Guided by a socio-emotional selectivity framework which posits that older adults strategically use positivity-enhancing mechanisms the proposed research has a primary aim of investigating whether older and younger adults differ in their use of positivity mechanisms to maintain positive affect in the face of pain. Additionally little is known about the factors that make some older adults better able to cope with pain than others. Previous research has shown that high levels of executive functioning (EF) and heart rate variability (HRV) predict positive physical health outcomes for those experiencing pain but no research to date has examined how individual differences in these factors interact with pain to influence positive affect. Thus the proposed project has a second aim of testing whether EF or HRV moderate the relationship between pain and maintenance of positive affect in older adults. Both of the aims of the project contribute to a larger goal of expanding theoretical knowledge of factors contributing to health and psychological wellbeing in older age. The proposed project will allow the PI to gain invaluable skills and expand on his previous research experiences by using experimental laboratory and archival data to test hypotheses pertaining to both aims. In the laboratory study older and younger adults will be asked to provide affect EF and HRV data. They will be randomly assigned to a painful or non-painful task. After the pain task participants will undergo tasks assessing positivity mechanisms and will then be asked to provide a final affect rating. An archival longitudinal dataset of community-dwelling older adults will be used to test whether pain levels interact with EF within people to predict positive affect. It is hypothesized that 1) when i pain older adults will use positivity-enhancing mechanisms with greater success than younger adults; 2) older adults will maintain positive affect following pain better than younger adults; an 3) those with better EF and HRV will be most effective at maintaining positive affect in the face of pain. In addition to providing theoretical insight into how positive affect is maintained after pain the project will contribute to a larger objective of promoting diversity in health research b providing the PI - a Hispanic first generation college student - a training opportunity to develop the skills necessary to become an independent researcher. To this end the project includes a detailed plan designed to build on and expand the PI's ability to disseminate cutting-edge research learn novel statistical and methodological techniques and expand his research program on the psychological and physiological consequences of the pain experience.

project_terms:
Acute;Adult;Affect;Affective;Age;Aging;Communities;Data;Data Set;Elderly;Emotional;Environment;Frequencies (time pattern);Generations;Goals;Health;Hispanics;Individual Differences;Knowledge;Laboratories;Laboratory Study;Learning;Life;Literature;Longevity;Maintenance;Masks;Mental Health;Motivation;Outcome;Pain;Painless;Participant;Patients;Peat;Persons;Physiological;Randomized;Relative (related person);Reporting;Research;Research Personnel;Sampling;Techniques;Testing;Time;Training;Translating;coping;design;executive function;experience;heart rate variability;indexing;insight;novel;older women;physical conditioning;programs;psychologic;response;satisfaction;skills;social;success;theories;university student;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Older adults are able to maintain positive affect despite physical pain as well as or better than younger adults but little is known how such affect is maintained. This project aims to test whether older adults use positivity- enhancing mechanisms differently than younger adults after experiencing acute physical pain and test the factors that allow some adults to manage pain better than others. The project will support the PI a Hispanic first-generation college student in his goal to develop a research program on the psychological and physiological consequences of the pain experience.


application_id: 8898374
project_number: 1R43ES025446-01
project_title: Electronic Platform for the Delivery of Site Specific Health and Safety Training
administering_ic: NIEHS
award_notice_date: 2015-05-07
opportunity_number: RFA-ES-14-003
application_type: 1
activity_code: R43
ic: ES
serial_number: 025446
program_official: AHLMARK, KATHY
project_start_date: 2015-05-07
project_end_date: 2017-04-30
study_section: Special Emphasis Panel[ZES1 JAB-D (EL)]
contact_pi_person_id: 10166727
contact_pi: NICOLALDE, ROBERTO JAVIER
other_pis: SHAPOREV, ALEKSEY
congressional_district: 06
department: Unavailable
primary_duns: 963949107
primary_uei: VKSAV1S1KC77
duns_number: 963949107
uei: VKSAV1S1KC77
fips: US
organization_id: 10027501
organization_name: NICOLALDE R AND D, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40509
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The Emergency Responder Health Monitoring and Surveillance (ERHMS) Technical Assistance Document (TAD) aimed at National Response Teams highlights the need for a technology platform for collecting data before during and after disasters to assess the effect training has on response-related illness and injury for emergency responders. This SBIR grant application is aimed at developing a software platform that will not only provide the means to efficiently collect data for the assessment of training impact; but also will provide the means to efficiently deliver pre-deployment and site specific training (SST) against which the assessment of training impact on responders' illness and injury can be evaluated. If successfully implemented the software platform will be a useful tool both for delivering just-in-time training and for supporting environmental health research relating to responders' exposure to potentially harmful environmental contaminants during and after disaster events. This research project proposes an innovative system for generation and distribution of incident-related knowledge (including manuals general and site-specific trainings)
with integrated monitoring and reporting functionality to address the needs described above. The system will allow the incident command official to generate training materials and data collection tools by simple and straightforward import from existing materials as well as to customize previously generated tools to better-fit the current situation. All the materials will be
delivered to emergency responders in the form of instantly generated smartphone (iOS Android) and web applications which will significantly reduce costs of logistics and latency of materials delivery. Materials encapsulation into mobile apps will address the prevalence of mobile devices (smartphones tablets) at the scene and will ensure that emergency responders can access the content of any situation and circumstances anywhere in the field in the most convenient form independently of what kind of device they have. Phase I will concentrate on assessing validating and prioritizing the most demanded tools together with a representative set of key stakeholders; developing a system prototype for digitization and modularization of training and data collection tools and instant distribution via rapidly created mobile application; prototyping specific interfaces for emergency responders and incident command personnel; testing and finally evaluating the first prototype. Phase II will concentrate on capabilities of electronic collection and distribution of health status and surveillance data on integration with an external IT system for two-way communication of hazard data outside incident command and on generation and delivery of additional materials in response to changed environmental conditions.

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

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


application_id: 8898181
project_number: 5R00HL105577-05
project_title: Role of MP-HBEGF-EGFR signaling for inflammatory action of oxidized phospholipids
administering_ic: NHLBI
award_notice_date: 2015-07-30
opportunity_number: PA-10-063
application_type: 5
activity_code: R00
ic: HL
serial_number: 105577
program_official: CHEN, JUE
project_start_date: 2011-08-01
project_end_date: 2016-07-31
study_section: NSS
contact_pi_person_id: 10232950
contact_pi: LEE, SANGDERK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract:This K99/R00 will support candidate's career goal to become a researcher in the area of cardiovasculardisease with a focus on atherosclerosis. The candidate has past educational background related with cellbiology and pharmacology mainly on receptor signaling projects and simple array analysis. The candidate iscurrently a postdoctoral fellow at UCLA and the K99 training will be executed under mentor Dr. Judith A.Berliner and co-mentor Dr. Aldons J. Lusis at UCLA. The university system is well equipped with highlyproductive and supportive research facilities including systemized training of conduct of research. Theuniversity administrative system is very supportive for the success of new investigators. Dr. Berliner is apioneering researcher who identified important roles of oxidized phospholipids in the vascular inflammatoryresponses. Her experience with analysis of immuno-histochemistry will be important to the success of theproposed studies. Dr. Lusis is an outstanding researcher in the field of systems genetics whose work has beenimportant in identifying genetic factors and novel signaling pathways controlling the development ofatherosclerosis. During this K99 training phase the candidate will meet frequently with mentor and co-mentor.The candidate will also meet with advisory board committee every 6 months. During the K99 mentoring phasethe candidate will focus on mastering immuno-histochemistry and lesion analysis methods which is one of bigadvantages of current lab and associated Core labs. Another important aspect of the K99 will be learning theanalytical tools to do analyze high-throughput transcript and genotyping datasets; these studies are beingperformed by a large number of those in the Lusis group. During the independent R00 phase the candidatewill mainly focus on the in-depth mechanistic studies for MP activation by Ox-PAPC in the endothelial cellsand the validation study of the significance of the genetic factors and cellular pathways identified via systemsgenetics approach. The main goal of this proposed study is to define proximal events in oxidized phospholipid(Ox-PAPC) activation of this inflammatory pathway. In this study in Aim 1 candidate will identify themechanism by which Ox-PAPC induces activation of the MPs using in vitro culture of endothelial cells. In Aim2 candidate will determine if this pathway is activated for inflammation and lesion formation in mouse model ofatherosclerosis. Finally in Aim 3 a systems genetics approach will be used to identify genetic factors andnovel pathways controlling proximal inflammatory responses in vascular endothelium. For this study thecandidate will use transcript and genotyping data sets of the aortic endothelial cells isolated from 96 humandonors which datasets and cells are currently available. The K99 training phase under mentor and co-mentorin the current lab clearly fill the technical gaps to execute the projects proposed. After the training phase thecandidate will be equipped with more diverse tools and approaches to study the cardiovascular disease forsuccessful transit to the independent R00 phase.

project_terms:
Animal Model;Area;Atherosclerosis;Binding (Molecular Function);Blood Vessels;CCL2 gene;Cardiovascular Diseases;Cell surface;Cells;Cellular biology;Cholesterol;Chronic;Cysteine;Data Set;Development;Disease;Educational Background;Endothelial Cells;Endothelium;Epidermal Growth Factor Receptor;Event;Gene Expression;Generations;Genes;Genetic;Genetic Polymorphism;Genotype;Goals;Histocytochemistry;Human;IL8 gene;In Vitro;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Kinetics;Knockout Mice;Learning;Lesion;Life Expectancy;Lipids;Mediating;Membrane Microdomains;Mentors;Metalloproteases;Methods;Modification;Mus;Oxidative Stress;Pathway Analysis;Pathway interactions;Pharmacology;Phase;Phospholipids;Population;Postdoctoral Fellow;Predisposition;Preventive;Reagent;Receptor Activation;Receptor Signaling;Research;Research Personnel;Role;Signal Pathway;Signal Transduction;Structure;System;Testing;Training;Transcript;Universities;Variant;Vascular Endothelial Cell;Vascular Endothelium;Vascular System;Weight;Work;abstracting;aged;analytical tool;career;cytokine;experience;genetic approach;heparin-binding EGF-like growth factor;in vivo;macrophage;meetings;mouse model;novel;oxidation;oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine;public health medicine (field);research facility;response;success;therapeutic target;tool;validation studies;vascular inflammation

public_health_relevance:
Relevance to Public Health: This study is to find preventive and therapeutic targets for the chronic vascular inflammatory diseaseslike atherosclerosis. The primary aim is to contribute to the development of reagents targeting critical step ofvascular inflammation to increase life expectancy of human population especially for aged people. Oxidativestress and the oxidation products of lipids have been shown to be involved in the development ofcardiovascular diseases. This study will test the hypothesis that the oxidized phospholipids produced byvascular oxidative stress will activate metalloproteinases on the endothelial cell surface for proinflammatorycytokine expression leading to chronic inflammatory conditions in the vessel. These studies also have thepotential to identify additional therapeutic targets and identify genetic factors that increase susceptibility ofatherosclerosis.


application_id: 8898122
project_number: 5P30GM106396-03
project_title: Animal Model Core
administering_ic: NIGMS
award_notice_date: 2015-06-22
opportunity_number: PAR-10-196
application_type: 5
activity_code: P30
ic: GM
serial_number: 106396
project_end_date: 2016-06-30
study_section: ZGM1-TWD-C
subproject_number: 8530
contact_pi_person_id: 1923745
contact_pi: CHESNEY, JASON A.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
PROJECT SUMMARY (See instructions): The goal of the University of Louisville Molecular Targets COBRE Core D is to facilitate the rapid translation of novel approaches to cancer prevention diagnosis and treatment through the use of transgenic mouse models of cancer. In particular. Core D will facilitate the translational objectives of University of Louisville COBRE-related investigators by developing coordinated resources techniques expertise and several colonies of transgenic mice for the safety and efficacy testing of novel anti-cancer approaches. The initial goal will be to establish colonies of the transgenic mice and to develop methods for longitudinal monitoring of tumor progression or regression without the need to euthanize the animals. Once the core is established the long-term objectives will be to provide access of transgenic mouse models of cancer to junior and senior cancer researchers at the University of Louisville including past and present COBRE investigators in order to facilitate the testing of novel anti-cancer compounds and strategies. The specific objectives are to: (i) Maintain distribute and provide pre-clinical toxicity and efficacy support for transgenic mouse models of melanoma childhood neuroblastoma lung breast prostate colon pancreatic and hematological cancers; (ii) Provide technical support for transgenic mouse genotyping specimen collection and processing and PK analyses of novel anti-cancer agents; and (iii) Conduct state-of-the-art diagnostic imaging services for the detection of tumors and response to novel therapeutic agents. In summary we propose a core facility that will procure and breed transgenic mouse models of several common cancer types and that will provide technical services to facilitate the testing of novel strategies and drugs developed at the University of Louisville.

project_terms:
Animal Model;Animals;Antineoplastic Agents;Breast;Breeding;Centers of Research Excellence;Childhood Melanoma;Clinic;Colon;Core Facility;Detection;Diagnosis;Diagnostic Imaging;Genotype;Goals;Instruction;Laboratories;Lung;Malignant Neoplasms;Methods;Modality;Modeling;Molecular Target;Monitor;Neuroblastoma;Pancreas;Pharmaceutical Preparations;Phase;Prostate;Research Personnel;Resources;Safety;Services;Site;Specimen Handling;Techniques;Testing;Therapeutic Agents;Time;Toxic effect;Transgenic Mice;Translations;Universities;Xenograft Model;cancer prevention;cancer type;cost;efficacy testing;efficacy trial;human disease;human subject;mouse model;novel;novel strategies;novel therapeutics;phase I trial;pre-clinical;prevent;research study;response;safety testing;sample collection;success;tumor;tumor progression

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


application_id: 8898121
project_number: 5P30GM106396-03
project_title: Molecular Modelling Core
administering_ic: NIGMS
award_notice_date: 2015-06-22
opportunity_number: PAR-10-196
application_type: 5
activity_code: P30
ic: GM
serial_number: 106396
project_end_date: 2016-06-30
study_section: ZGM1-TWD-C
subproject_number: 8529
contact_pi_person_id: 7821204
contact_pi: TRENT, JOHN O
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
PROJECT SUMMARY (See instructions):  One of the overriding goals of the Brown Cancer Center is translational research. One way to achieve this is to provide a conduit for investigators studying particular molecular targets to conduct structure-based drug design. The Molecular Modeling Core Facility is an integral part of the COBRE which is used by all the COBRE investigators and many NIH funded investigators. It provides a natural entryway for structural biological approaches developed by COBRE scientists and through its close interaction with the NMR Center biophysicists molecular biologists chemists medicinal chemists computer scientists and biochemists. The overall goal of the Facility is rationalization prediction and design i.e. the rationalization of experimental data the prediction of new empirical experiments and the structure-based drug design of new agents. The aims of the Core are to: 1. provide equipment and expertise for a variety of modeling applications 2. facilitate structure-based drug design for drug discovery and drug development including facilitating testing of targeted compounds. 3. provide a bridge between crystallography NMR medicinal chemistry and other disciplines 4. provide a collaborative environment for the BCC 5. inform the Structural Biology Program of advances in the field and to implement them 6. educate the Structural Biology Program and others on possible enhancements to their research 7. train students on "state of the art" molecular modeling These aims will be met by maintaining state-of-the-art software and computafional resources which will support collaborative interactions with COBRE and other investigators.

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

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


application_id: 8898120
project_number: 5P30GM106396-03
project_title: NMR and Metabolomics Core
administering_ic: NIGMS
award_notice_date: 2015-06-22
opportunity_number: PAR-10-196
application_type: 5
activity_code: P30
ic: GM
serial_number: 106396
project_end_date: 2016-06-30
study_section: ZGM1-TWD-C
subproject_number: 8528
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
PROJECT SUMMARY (See instructions): The primary aims of the NMR core are to provide infrastructure and support for structural analysis of target macromolecules their mutual interactions and with candidate drug molecules obtained from in silico searches and optimization and metabolomics of cancer cells and tissue. This includes stable isotope labeling strategies including N-15 and C-13 precursors. Our goals continue to be to streamline both data collection and analysis as well as introduce new labeling strategies to provide more detailed information about specific metabolic pathways via Stable Isotope Resolved Metabolomics (SIRM). This includes NMR structural and biophysical analysis of macromolecules and their interactions with small molecules as well as extensive use of the metabolomics capabilities of the Core as a part of the drug discovery/development process. A large fraction of research projects that use the facility are translational using purified components as well as animal models and human subjects. The NMR-based studies operate in tandem with activates of other Cores especially the Modeling Core and in the future with the Transgenic Mouse Core. NMR is one of the few techniques that provides localized imaging and high resolution high information content spectroscopy in vivo. This will be a major new direction of the Core.  The overall goals of the Core will be achieved via the following Specific Aims: 1. Provide NMR instrumentation and expertise for characterizing macromolecules and their interactions; 2. Provide the instrumentation and expertise for metabolomics studies; 3. Facilitate structure-based drug design for drug discovery and drug development; 4. Develop and implement new experiments and capabilities including stable isotope resolved metabolomics on small animals in vivo; 5. Educate members of the community on the specific capabilities of NMR for their research projects; 6. Provide training of students and fellows in cancer biochemistry and drug development. These Aims complement those of the other Cores in terms of the overall research mission of the Cancer Center and the University.

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

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


application_id: 8898119
project_number: 5P30GM106396-03
project_title: Microarray Core
administering_ic: NIGMS
award_notice_date: 2015-06-22
opportunity_number: PAR-10-196
application_type: 5
activity_code: P30
ic: GM
serial_number: 106396
project_end_date: 2016-06-30
study_section: ZGM1-TWD-C
subproject_number: 8527
contact_pi_person_id: 1969307
contact_pi: ZACHARIAS, WOLFGANG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
PROJECT SUMMARY (See instructions): At the University of Louisville the instrument personnel and software resources for high-density microarray based gene expression and single nucleotide polymorphism (SNP) genotyping analyses are in place through an investment of the UofL James Graham Brown Cancer Center (JGBCC). Such global profiles can be obtained for tens of thousands of genes or SNP loci from cell populations or tissue material within one time saving and standardized experiment. Comparative analysis of global gene expression patterns on biological or pathologic material will provide crucial information on gene products and/or mutations which are involved in a cellular and/or disease process. The objective of the Microarray Core is to offer this highly advanced technology as well as sufficient opportunities for training and research applications for investigators. The Specific Aims of the Microarray Facility are to offer the following services to JGBCC investigators: 1. To provide high-quality services for microarray-based gene expression and genotyping analysis; 2. To continuously incorporate the newest array products and analysis tools into the menu of services provided; 3. To educate and train users in applications strengths and limitations of microarray technology; 4. To assist users in experimental design sample processing and data analysis; 5. To provide logistic support for project development grant applications and manuscript preparations applying microarray technology.  The Core presented here shall ensure that JGBCC investigators especially clinical faculty and research groups will be able to efficiently adopt this novel state-of-the-art technology for their research clinical and investigative goals using in vitro clinical specimen or animal model materials (using their approval protocols). It will be crucial for these investigators to have affordable access and expert support to the most advanced and sophisticated molecular technologies as part of the institutional resources provided to them.

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

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


application_id: 8898027
project_number: 5R01CA180986-03
project_title: Prevention of Breast Cancer Development by Epidermal Fatty Acid Binding Protein (
administering_ic: NCI
award_notice_date: 2016-06-30
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 180986
program_official: EMENAKER, NANCY J
project_start_date: 2015-08-01
project_end_date: 2019-07-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 9620088
contact_pi: LI, BING
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The increasing incidence of breast cancer poses a major threat to women's health in the USA and worldwide. How to prevent breast tumorigenesis and to identify new protective factors for the control of breast cancer represents a great challenge in this field. The objectives of this proposal are to unravel a protective role of epidermal fatty acid binding protein (E-FABP) in preventing breast cancer development and to determine the molecular mechanisms by which E-FABP regulates IFN production and signaling in a specific subset of tumor associated macrophages for antitumor responses. E-FABP abundantly expressed in macrophages has been recognized as an important regulator to coordinate cell metabolic and inflammatory pathways. Our preliminary studies demonstrate that E-FABP deficient mice exhibit significant increases in mammary tumor growth and lung metastasis compared to wild type mice suggesting a protective role of host expression of E-FABP in mammary tumor prevention. Further analysis of E-FABP expression profile indicates that E-FABP is specifically expressed in the subset of F4/80+CD11b+MHCII+CD11c+ cells. Microarray and qPCR experiments show that tumor-induced IFN production and signaling in macrophages are significantly impaired by E-FABP deficiency. Interestingly IFN stimulation specifically induces E-FABP upregulation in the process of M1 polarization. Moreover -3 fatty acids can greatly enhance E-FABP expression in macrophages. Thus we hypothesize that E-FABP may regulate macrophage function by promoting IFN production signaling and M1-like phenotype switch through enhancing cell lipid metabolism. E-FABP as a new cancer protective factor can prevent breast carcinogenesis through promoting macrophage anti-tumor responses. Therefore modulating E-FABP activity will represent a novel strategy for breast cancer prevention. Specific Aim 1 will determine how E-FABP regulates IFN production in macrophages. We hypothesize that E-FABP is an unidentified host-derived factor to regulate tumor-induced IFN production through impacting lipid-mediated signals in specific subsets of macrophages. Specific Aim 2 will determine how E-FABP regulates IFN signaling to promote anti-tumor responses. We will test the hypothesis that E-FABP-regulated IFN signaling promotes tumor specific T lymphocyte infiltration and IFN production which further upregulates E-FABP expression to facilitate macrophage M1 polarization for antitumor immunity. Specific Aim 3 will address whether host-derived E-FABP protects against breast cancer development in clinically relevant animal models and in humans. We will verify E-FABP as a host-derived protective factor in breast cancer prevention and establish an effective strategy for the control o breast cancer via dietary upregulation of E-FABP. In conclusion successful completion of this project will reveal E-FABP as a new protective factor in control of breast cancer development and help us develop an effective strategy to prevent breast cancer via targeting E- FABP.

project_terms:
Address;Animal Model;Antitumor Response;Basic Science;Breast Cancer Model;Breast Cancer Prevention;Breast Carcinogenesis;Cells;Clinical;Data;Development;Diet;Diet Modification;Exhibits;FABP5 gene;Hematopoietic;Human;ITGAM gene;ITGAX gene;Immunity;Incidence;Infiltration;Inflammatory;Interferon Type II;Killings;Lipids;Malignant Neoplasms;Mammary Neoplasms;Mammary Tumorigenesis;Mediating;Metabolic;Metastatic Neoplasm to the Lung;Molecular;Molecular Profiling;Mouse Mammary Tumor Virus;Mus;Omega-3 Fatty Acids;Pathway interactions;Phenotype;Population;Prevention;Preventive;Process;Production;Protein Deficiency;Role;Signal Transduction;T-Lymphocyte;Testing;Tissues;Transforming Growth Factor alpha;Up-Regulation;Wild Type Mouse;Women's Health;breast tumorigenesis;clinically relevant;design;fatty acid-binding proteins;in vivo;lipid metabolism;macrophage;malignant breast neoplasm;novel strategies;prevent;protein expression;public health relevance;research study;response;tumor;tumor growth


application_id: 8897307
project_number: 5R01CA185972-02
project_title: Chemoprevention of metastatic colorectal cancer
administering_ic: NCI
award_notice_date: 2015-07-23
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 185972
program_official: CHEN, WEIWEI
project_start_date: 2014-08-01
project_end_date: 2019-07-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 7649061
contact_pi: DAMODARAN, CHENDIL
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
AKT Signaling Pathway;AKT inhibition;Affinity;Animal Model;Animals;Apoptosis;Ashwagandha;BCL2 gene;Binding (Molecular Function);Biological Assay;Biotin;Cancer Etiology;Cause of Death;Cell Culture Techniques;Cell Line;Cell Proliferation;Cells;Cessation of life;Chemoprevention;Chemopreventive Agent;Clinical;Clinical Trials;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Data;Development;Diagnosis;Dietary Supplements;Disease;Disseminated Malignant Neoplasm;Docking;E-Cadherin;Epithelial;Event;Fluorouracil;Goals;Growth;HCT116 Cells;Health;Human;In Vitro;Investigation;Label;Laboratories;Large Intestine Carcinoma;Lead;Malignant Epithelial Cell;Mediating;Mesenchymal;Modeling;Molecular;Neoplasm Metastasis;Oral;Oral Administration;Patients;Pattern;Phenotype;Phosphotransferases;Polyps;Pre-Clinical Model;Prevention;Proteins;Proto-Oncogene Proteins c-akt;Radiosurgery;Regimen;Relapse;Research Personnel;Role;SW620;Sampling;Signal Transduction;Snails;Staging;Survival Rate;Therapeutic;Time;Transcription factor genes;Tumor Tissue;Woman;Xenograft Model;Xenograft procedure;analog;angiogenesis;base;cell growth;chemotherapy;high risk;insight;interest;meetings;men;metastatic colorectal;migration;neoplastic cell;novel;novel strategies;overexpression;pre-clinical;prevent;slug;survivin;tumor;tumor growth;tumor progression


application_id: 8897148
project_number: 5F31AA023459-02
project_title: Probing the Functional Relevance of Reactive Neurogenesis in Hippocampal Integrit
administering_ic: NIAAA
award_notice_date: 2015-06-24
opportunity_number: PA-11-111
application_type: 5
activity_code: F31
ic: AA
serial_number: 023459
program_official: REGUNATHAN, SOUNDAR
project_start_date: 2014-07-01
project_end_date: 2016-06-30
study_section: Neuroscience and Behavior Study Section[AA-4]
contact_pi_person_id: 11959897
contact_pi: GEIL, CHELSEA
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): Alcoholism or alcohol use disorders (AUDs) represent a major public health concern both locally and globally. Alcohol is responsible for 2.5 million deaths per year is the third largest risk factor for disease across the world and over 8%
of Americans meet the diagnostic criteria for an AUD. Critically excessive alcohol consumption results in neurodegeneration in brain regions such as the hippocampus which is known for its role in learning and memory. Recovery of hippocampal volume loss has been observed after protracted abstinence but the mechanism underlying this process is not well understood. Adult neurogenesis - the process by which neural progenitor cells (NPC) proliferate differentiate migrate and integrate into the granule cell layer of the hippocampal dentate gyrus - is thought to
contribute to this recovery. Alcohol intoxication produces deficits in neurogenesis in the hippocampus however after 7 days of abstinence a reactive increase in adult neurogenesis is observed. Reactive neurogenesis is the process by which CNS injury yields an increase in neurogenesis and is a potentially beneficial endogenous mechanism of brain recovery. At this time the role of alcohol-induced reactive neurogenesis in hippocampal recovery is not known. Therefore since alcohol reduces neurogenesis and adult neurogenesis produces mature granule cells we hypothesize that the alcohol-induced increase in reactive neurogenesis promotes the functional and structural recovery of the dentate gyrus following alcohol exposure. Aim 1 will utilize confocal microscopy and fluorescent triple-label immunohistochemistry (IHC) techniques to determine if granule cells born during this phase of reactive neurogenesis are functionally normal. Following training on the hippocampal-dependent Morris water maze task functional incorporation will be assessed via activation of granule cells born during alcohol-induced reactive neurogenesis. Aim 2 will examine the structural and behavioral effects of inhibiting alcohol-induced reactive neurogenesis to probe its significance in the recovery process. First we will determine the optimal dose of the antimitotic Temozolomide needed to attenuate alcohol-induced reactive neurogenesis in the dentate gyrus. Next the alcohol-induced reduction in granule cells will be quantified to determine if reactive neurogenesis serves to promote the structural recovery of the dentate gyrus following alcohol exposure. Finally the functional implications of inhibiting reactive neurogenesis will be examined by investigating changes in Morris water maze performance. The proposed studies are critical in evaluating the role of alcohol- induced reactive neurogenesis in recovery from AUDs. Furthermore these studies will provide valuable insight into modulation of the NPC pool as a potential therapeutic target for the treatment of AUDs.

project_terms:
Abstinence;Adult;Affect;Age;Alcoholic Intoxication;Alcoholism;Alcohols;Alzheimer's Disease;American;Antimitotic Agents;Area;Attenuated;Behavioral;Brain;Brain Injuries;Brain Stem;Brain region;Bromodeoxyuridine;Cell Count;Cell Proliferation;Cessation of life;Cognitive deficits;Confocal Microscopy;Consumption;Development;Diagnostic;Disease;Dose;Electrophysiology (science);Excitatory Amino Acid Antagonists;FOS gene;Generations;Heavy Drinking;Hippocampus (Brain);Human;Immunohistochemistry;Intervention;Intoxication;Label;Learning;Link;Magnetic Resonance Imaging;Mammals;Mediating;Memory;Modeling;Natural regeneration;Nerve Degeneration;Neurons;Newborn Infant;Opioid Receptor;Parahippocampal Gyrus;Performance;Pharmaceutical Preparations;Phase;Population;Process;Proliferating;Proliferation Marker;Reactive Inhibition;Recovery;Relapse;Research;Risk Factors;Rodent Model;Role;Schizophrenia;Staging;Stem cells;Structure;Techniques;Testing;Time;Training;United States;United States Food and Drug Administration;Ventricular;addiction;adult neurogenesis;alcohol abstinence;alcohol exposure;alcohol use disorder;alcoholism therapy;base;brain volume;central nervous system injury;cognitive function;defined contribution;dentate gyrus;granule cell;gray matter;insight;meetings;morris water maze;nerve stem cell;neurogenesis;novel;prevent;problem drinker;public health medicine (field);public health relevance;research study;temozolomide;therapeutic development;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: In the United States roughly 8.5% of the US population suffers from alcoholism and unfortunately treatment options although effective for some are severely limited in scope. This project will determine if brain stem cells already present in mammals of all ages are responsible for helping the brain recover from alcoholism. These brain stem cells represent a novel target for the treatment of alcoholism specifically for the treatment
of brain damage associated with alcoholism.


application_id: 8896760
project_number: 5P30CA177558-03
project_title: PROJECT 12. Protocal Review
administering_ic: NCI
award_notice_date: 2015-06-17
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_end_date: 2016-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8636
contact_pi_person_id: 9360703
contact_pi: HAYSLIP, JOHN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
The Markey Cancer Center (MCC) Protocol Review and Monitoring System (PRMS) provides thorough review of clinical trials for scientific validity feasibility and prioritization within the clinical trials portfolio and monitoring of scientific progress. The PRMS must approve all interventional cancer research prior to study initiation and has the authority to recommend closure of trials for lack of scientific progress or patient accrual. The PRMS provides a framework which aims to balance appropriate resource utilization while maximizing the opportunities for current and future patients with cancer in this region to participate in clinical trials including the underserved area of Appalachian Kentucky. The development of novel MCC investigator-initiated clinical trials and participation in high-priority national trials provide a robust portfolio of therapeutic research studies available to MCC patients.

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

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


application_id: 8896759
project_number: 5P30CA177558-03
project_title: PROJECT 11. Clinical Research and Data
administering_ic: NCI
award_notice_date: 2015-06-17
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_end_date: 2016-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8635
contact_pi_person_id: 9360703
contact_pi: HAYSLIP, JOHN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
: The Markey Cancer Center (MCC ) Clinical l Research and Data a Management Shared Resource Facility (CRD M SRF ) coordinates and facilitates clinical cancer trials at the MCC . The major goals of the shared resource are to provide support of the clinical trial process  including implementing and regulating trials provide a centralized clinical trial l database  and integrate with the following: investigational pharmacy support  financial accounting  data safety monitoring  and quality assurance . This shared resource also assist s physician investigators in the design and subsequent conduct of clinical l trials through its support of the Investigator Initiated Trial Protocol Development Unit . It performs all regulatory reporting and quality assurance needed to comply with Good Clinical Practice in the performance of clinical trials . The CRDM SRF has Standard Operating Procedures for all its activities including training of all new faculty an d staff . From Ma y 2011 through April 2012  254 2 new patient s with cancer were seen at the MCC . Of these  145 1 were from Appalachian Kentucky . During the s time period  the CRDM SRF administrated therapeutic cancer clinical l trials that engage d 25 3 (10% ) participants in therapeutic intent clinical trials . Importantly  14 1 Appalachian patient s were engage d in therapeutic intent clinical research  a 10 % accrual rate from these disadvantaged and unique.

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

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


application_id: 8896758
project_number: 5P30CA177558-03
project_title: PROJECT 10. Cancer Reserch SRF
administering_ic: NCI
award_notice_date: 2015-06-17
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_end_date: 2016-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8634
contact_pi_person_id: 9276771
contact_pi: DURBIN, ERIC B.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
The Markey Cancer Center (MCC) Cancer Research Informatics (CRI) Shared Resource Facility facilitates collaborative research among members of the MCC through the optimal application of informatics technologies and methods that maximize the accessibility and usability of data information and knowledge for cancer research. The primary goal of CRI is to provide comprehensive and centralized data acquisition and informatics support that is readily available to cancer center members.  The Specific Aims of the CRI are to:  1. Develop and support innovative technologies for funded research studies that facilitate  accurate timely and secure data acquisition and dissemination. 2. Maintain and support a comprehensive patient-centered data warehouse offering unique  opportunities for MCC investigators to utilize integrated data sets from diverse sources ranging from genetic biomarkers to population-based surveillance data. 3. Facilitate rapid and efficient recruitment of patients to investigator-initiated trials and other  research studies. 4. Facilitate investigator access to data biospecimens and patients from Kentucky's Appalachian population. 5. Ensure the interoperability of informatics systems in compliance with evolving data standards. 6. Collaborate with the University of Kentucky (UK) Division of Biomedical Informatics to provide novel and state-of-the-art informatics solutions that increase the efficiency and accuracy of information and knowledge derived from diverse data sources.

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

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


application_id: 8896755
project_number: 5P30CA177558-03
project_title: PROJECT 7. Free Radical
administering_ic: NCI
award_notice_date: 2015-06-17
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_end_date: 2016-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8631
contact_pi_person_id: 8329002
contact_pi: BUTTERFIELD, D. ALLAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
There is increasing evidence that oxidative damage and free radicals with sequelae of altered cellular energetics and protein alterations are important in the initiation promotion invasion metastasis and treatment of cancers. Moreover oxidative damage and free radicals also are implicated in the side effects of normal tissue injury following cancer therapy including chemotherapy radiafion and biological modifiers. The Free Radical Biology in Cancer Shared Resource Facility (FRBC SRF) was established to provide expertise in and analyses of free radicals cellular energetics and reactive species as well as proteomics in cancer and cancer biology for Markey Cancer Center (MCC) investigators who perform basic pre-clinical and clinical research. The four basic services provided by the FRBC SRF are: 1) Analysis of markers of oxidative and nitrosative stress; 2) Molecular biological manipulation of biological systems with which to investigate redox signals including measurements of mitochondrial function by Seahorse technology; 3) Proteomics identification of differentially expressed differentially oxidized or differentially covalently modified proteins in various cancer-related systems; 4) Electron paramagnetic resonance (EPR) detection of free radicals. Development of new applications and methodology for better understanding of the roles of free radicals in cancer and cancer chemotherapy and technical assistance with grant and manuscript preparation by MCC investigators will also be provided. Included in these functions of the considerable expertise of the FRBC SRF Technical Advisory Committee to educate MCC investigators on proper sample handling and preparation methods so that reliable precise and artifact-free assay results are obtained. Multiple investigators from all four research programs of the MCC (Redox Injury and Repair [RR]; Cancer Cell Biology and Signaling [CS]; Cancer Prevention and Control [CP]; and Drug Discovery Delivery and Translational Therapeutics [DT]) have used one or more services of the FRBC SRF. Indeed even as a relatively new shared resource the FRBC SRF still had usage by 26% of MCC investigators.

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

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


application_id: 8896754
project_number: 5P30CA177558-03
project_title: PROJECT 6. Flow Cytometry
administering_ic: NCI
award_notice_date: 2015-06-17
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_end_date: 2016-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8630
contact_pi_person_id: 1878476
contact_pi: COHEN, DONALD A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
The Markey Cancer Center (MCC) Flow Cytometry and Cell Sorting Shared Resource Facility (FCCS SRF) provides University of Kentucky (UK) cancer researchers with comprehensive state-of-the-art analytical flow cytometry and cell sorting services to support both human and animal studies. The goals of the FCCS SRF are to provide: 1) multiparameter cell phenotyping; 2) analysis of DNA content and cell cycle; 3) analysis of cellular apoptosis and necrosis; 4) quantification of cell cytotoxicity; 5) intracellular cytokine analysis; 6) measurement of cell activation parameters; 7) high speed cell sorting of live human and animal cells under biocontainment conditions; and 8) single cell cloning of sorted cells. Another important function of the shared resource is to assist researchers in data analysis of flow cytometric studies and to help investigators in the development of new flow cytometric assays or approaches as needed for their research efforts. Finally FCCS SRF addresses the future needs of investigators by adding new and updated instrumentation to the facility that will expand the number of techniques and approaches available to cancer researchers at the university.

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

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


application_id: 8896751
project_number: 5P30CA177558-03
project_title: PROJECT 4. Admin
administering_ic: NCI
award_notice_date: 2015-06-17
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_end_date: 2016-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8628
contact_pi_person_id: 9098327
contact_pi: GOSKY, DAVID M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
The Markey Cancer Center (MCC) Administration has as its primary focus the provision of efficient and effective managerial planning and financial leadership and by doing so adding value to all MCC research programs shared resource facilities and all other services. Within that role MCC Administration provides important administrative support services to facilitate and enhance scientific productivity and collaboration among its 108 faculty research members who are organized into four research programs and who utilize MCC-supported shared resources. Administrative services include:   Coordination and participation in center-wide strategic planning and evaluation efforts.  Stimulation and support of inter- and intra-programmatic activities including grant development consultation and direct service support meeting organization and documentation and retreat/seminar/symposia coordination.  Administrative oversight and support for MCC-supported shared resources including the establishment of user fees provision of billing and auditing services coordination of and participation in oversight committees and evaluations.  Oversight of all center-related development/fundraising activities.  Fiscal management of university and Markey Cancer Foundation accounts related to the center.  Facilities management and management of all other assigned MCC space and equipment  Coordination of new faculty recruitment in collaboration with other university departments.  Human resource management of center staff.  Management of MCC membership including new application processes and annual reviews.  Administration of pilot project and other internal research award processes.  Computer networking and design of research management databases.  Coordination of internal communications and public relations for all center members.  From 2009 to the present MCC Administration has expanded staffing levels from 11.5 FTE to 19.5 FTE and in that process further developed key areas of administrative support in research communications shared resource facility development and financial management. This unit also oversaw a dramatic 40% expansion of MCC-controlled space including new construction.

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

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


application_id: 8896750
project_number: 5P30CA177558-03
project_title: PROJECT 3. Dev Funds
administering_ic: NCI
award_notice_date: 2015-06-17
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_end_date: 2016-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8627
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
The Markey Cancer Center (MCC) will utilize developmental funds leveraged with institutional and philanthropic funds to support pilot grants and strategic new faculty recruitments. Pilot grant funding ($125000) from the CCSG will support collaborative and interdisciplinary cancer research focusing on MCC priority areas; funded projects will be carried out by interactions between MCC members in our four research programs and supported by our six shared resource facilities. Pilot funds will stimulate high return on investment research that makes a significant impact in the field of basic clinical population or translational cancer research. New faculty recruitment priorities have been established based on the MCC Strategic Plan in consultation with Senior and Program Leaders and include recruitment of: 1) a senior level molecular epidemiologist in years 1-3 ($50000 each year); and 2) a drug discovery scientist in years 4-5 ($50000 each year).

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

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


application_id: 8896749
project_number: 5P30CA177558-03
project_title: PROJECT 2. Planning and Evaluation
administering_ic: NCI
award_notice_date: 2015-06-17
opportunity_number: PAR-11-005
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
project_end_date: 2016-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 8626
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
Continual planning and evaluation have been key to the development and sustained excellence of the research infrastructure at the Markey Cancer Center (MCC). Planning and evaluation activities are accomplished through the internal and external advisory boards councils and committees that provide the Director and Senior Leadership ongoing guidance and support. The MCC External Advisory Board (EAB) is the primary external mechanism for review and advice on the MCC's progress in basic and translational research and community research. Internal mechanisms include the advice and support of MCC's Senior Leaders who formally comprise the MCC Director's Council; the MCC Scientific Advisory Panel; and an Internal Advisory Board (lAB) comprised of deans center directors and department chairs at the University of Kentucky. Other planning and evaluation efforts occur at the program and shared resource levels. Shortly after joining the MCC in 2009 Dr. Evers and the Senior Leadership developed a strategic plan for the MCC which has served as a road map to guide the development of scientific research programs and initiatives the reorganization of shared resources required to facilitate and achieve the scientific goals and strategic recruitments of basic and translational scientists who will synergize and further strengthen ongoing research efforts over a five-year period. The strategic plan outlines directions for research to be developed the need for expanded services within existing shared resources and organizational strategies to improve collaboration and interdisciplinary interactions. This strategic plan is regularly reviewed for progress and revised. The most recent review and revision process was conducted in 2012 to reflect the tremendous progress that has occurred over three years and to redefine the strategic goals for the next five years based on the stronger foundations that are now in place.

project_terms:
Address;Advertisements;Appalachian Region;Area;Award;Basic Science;Behavioral;Biological Markers;Cancer Burden;Cancer Center;Cancer Center Support Grant;Clinical;Clinical Research;Clinical Trials;Collection;Colorectal Cancer;Communities;Department of Defense;Development;Diagnosis;Enrollment;Environmental Exposure;Epigenetic Process;Evaluation;Faculty;Foundations;Future;Genetic;Goals;Growth;Health;Incidence;Interdisciplinary Study;Kentucky;Laboratories;Lead;Leadership;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of lung;Maps;Marketing;Measurable;Mentors;Molecular Epidemiology;Oncologist;Organ;Outcome;Patients;Policies;Population;Prevention;Process;Publications;Regulation;Research;Research Infrastructure;Research Personnel;Resource Sharing;Rural;Scientist;Services;Site;Site Visit;Strategic Planning;TNFRSF5 gene;Therapeutic;TimeLine;Tobacco;Translational Research;Universities;Update;Validation;Wages;West Virginia;Woman;Work;assay development;base;cancer health disparity;cancer research center director;cancer therapy;career;improved;interdisciplinary collaboration;lung carcinogenesis;malignant breast neoplasm;member;novel;population based;pre-clinical;programs;repository;research study;sarcoma;social;success;survivorship

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


application_id: 8896574
project_number: 5R01CA177679-03
project_title: The role of adipocyte/macrophage fatty acid binding protein in breast cancer deve
administering_ic: NCI
award_notice_date: 2016-05-12
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 177679
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2015-07-09
project_end_date: 2019-05-31
study_section: Tumor Microenvironment Study Section[TME]
contact_pi_person_id: 9620088
contact_pi: LI, BING
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Despite recent improvements in survival rates breast cancer still kills nearly half-a-million women worldwide annually. As the two most predominant populations in breast cancer stroma macrophages and adipocytes play central roles in breast tumorigenesis and progression. Thereby modifications in these cells can greatly influence tumor behavior. The objectives of this proposal are to determine the role of adipocyte/macrophage fatty acid binding protein (A-FABP) in promoting breast cancer development through simultaneously targeting both macrophages and adipocytes and to develop inhibitors to modulate A-FABP activity for breast cancer therapy. A-FABP abundantly expressed in macrophages and adipocytes has been identified as a central regulator of metabolic and inflammatory pathways in these cells. Our preliminary studies demonstrate that A- FABP is significantly upregulated in human and murine breast/mammary cancers. In response to tumor stimulation cytoplasmic A-FABP expression is markedly elevated in tumor associated macrophages (TAMs) whereas circulating A-FABP is mainly released by adipocytes. More importantly A-FABP deficiency alters macrophage phenotype and protects mice against mammary tumor growth and metastasis. While obesity is associated with poor prognosis and increased mortality in patients with breast cancer the mechanistic basis for this association remains unclear. We found that obesity increases A-FABP in both cytosol and the circulation and promotes breast cancer progression. It is likely that A-FABP links obesity and breast cancer via regulating macrophage and adipocyte functions. Thus we hypothesize that A-FABP as an unidentified link underlying the obesity-breast cancer association promotes the development of breast cancer through enhancing pro-tumor functions of macrophages and adipocytes. Therefore modulating A-FABP activity will represent a novel strategy for breast cancer therapy. Specific Aim 1 will answer how cytoplasmic A-FABP regulates macrophage functions for breast cancer progression. We hypothesize that upregulation of cytoplasmic A-FABP in TAMs reprograms the macrophages to promote a pro-tumor environment. Specific Aim 2 will delineate how circulating A-FABP released by adipocytes contributes to breast cancer invasion. Experiments will designed to test the hypothesis that circulating A-FABP released by adipocytes favors breast cancer progression by inducing oncogenic signaling in tumor cells to increase their aggressiveness. Specific Aim 3 will address whether obesity promotes breast cancer through increasing A-FABP expression. We propose that A-FABP represents an unidentified factor in obesity to promote breast cancer risk and inhibition of A-FABP with inhibitors may suppress breast cancer development and progression. In conclusion the data collected will help us unravel the critical role of A-FABP in breast cancer development and identify specific A- FABP inhibitors for potential breast cancer therapy.

project_terms:
Address;Adipocytes;Animal Model;Basic Science;Behavior;Biopsy;Blood Circulation;Breast;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Treatment;Breast Cancer therapy;Cell Cycle Regulation;Cells;Clinical;Cytosol;Data;Development;Environment;FABP4 gene;Health;Human;Infiltration;Inflammatory;Killings;Link;Mammary Neoplasms;Mediating;Metabolic;Mitotic Cell Cycle;Modification;Molecular;Mus;Neoplasm Metastasis;Obesity;Oncogenic;Pathway interactions;Patients;Phenotype;Play;Population;Protein Deficiency;Role;Signal Transduction;Survival Rate;Testing;Therapeutic;Tissues;Up-Regulation;Woman;Women's Health;anticancer research;base;breast tumorigenesis;cancer risk;design;fatty acid-binding proteins;in vivo;inhibitor/antagonist;macrophage;malignant breast neoplasm;mortality;mouse model;neoplastic cell;novel strategies;outcome forecast;protein expression;research study;response;tumor;tumor growth;tumor progression;tumorigenesis

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


application_id: 8896033
project_number: 5R00HL111354-05
project_title: Early Life Stress & Chronic Control of Blood Pressure
administering_ic: NHLBI
award_notice_date: 2015-07-14
opportunity_number: PA-10-063
application_type: 5
activity_code: R00
ic: HL
serial_number: 111354
program_official: MARIC-BILKAN, CHRISTINE
project_start_date: 2013-09-23
project_end_date: 2016-07-31
study_section: NSS
contact_pi_person_id: 10353675
contact_pi: LORIA, ANALIA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY Chronic adult diseases such as hypertension diabetes or obesity may develop as a consequence of earlylife stress (ELS). Adverse childhood events are highly correlated with enhanced cardiovascular response to asecondary stressor a "second hit". Maternal separation is an established model of chronic behavioral stress inrodents that involves separating pups from their mothers 3 hr/day from days 2-14 of life. Adult maternally separated (MS) rats show lower glomerular filtration rate under baseline conditionscompared to control un-separated littermates with no difference in blood pressure. Interestingly thephenylephrine-induced vasoconstriction in the kidney is attenuated but the drop in blood pressure elicited byganglion blockade is greater in MS rats. These data suggest increased sympathetic activation in MS rats. Incontrast the acute pressor response to angiotensin II (AngII) is comparable between MS and control ratswhereas MS rats show exaggerated chronic AngII-induced hypertension. Thus our data suggest that ELSimpairs the ability of the kidney to control blood pressure following a "second hit". Taken together wehypothesize that rats exposed to MS display increased renal sympathetic nerve activity (RSNA) whichenhances vascular tone in the kidneys and impairs the physiological regulation of blood pressure. Given thefact that RSNA can increase AngII type 1 (AT1) receptor expression we speculate that increased baselineRSNA in MS rats results in increased renal AngII system components predisposing these rats tocardiovascular disease. In an original approach to model the growing epidemic of children with extremely poor dietary lifestyleswe exposed the rats to a high fat diet (HFD) as a secondary stressor. Our data show a fat-induced increase inblood pressure develops in rats exposed to ELS compared to control rats. Furthermore we observed increasedplasma leptin corticosterone aldosterone and renin activity in MS rats. These compelling data support thehypothesis that ELS impairs maintenance of blood pressure homeostasis in response to "second hits" in adultlife. The mentored phase will focus on the investigation of the RSNA and AT1-dependent mechanisms by whichELS exacerbates AngII-induced hypertension in adult rats followed by the independent phase focused on thestudy of mechanisms by which ELS exacerbates blood pressure sensitivity to a HFD in adult rats. This novelproposal will investigate the following four aims: (1) to test the hypothesis that increased RSNA impairs renalcapacity to control blood pressure in response to chronic AngII infusion in adult MS rats; (2) to test thehypothesis that exaggerated AT1 receptor activation increases renal vasoconstriction and reduces basal renalfiltration capacity enhancing AngII-induced hypertension in adult MS rats; (3) To test the hypothesis that MSincreases sensitivity of blood pressure in response to a HFD through a renal mechanism; and (4) To test thehypothesis that HFD increases AngII in adipose tissue and induces AT1 dependent increase in blood pressurein MS rats.

project_terms:
Acute;Adipose tissue;Adrenergic Agents;Adult;Aldosterone;Angiotensin II;Attenuated;Behavioral;Biochemical;Biological;Blood Pressure;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Caring;Child;Childhood;Chronic;Corticosterone;Data;Development;Diabetes Mellitus;Diet;Disease;Drops;Environment;Epidemic;Event;Excretory function;Exposure to;Fatty acid glycerol esters;Filtration;Functional disorder;Ganglia;Glomerular Filtration Rate;Health Care Costs;Human;Hypertension;Infusion procedures;Investigation;Kidney;Kidney Diseases;Leptin;Life;Life Stress;Life Style;Maintenance;Mediating;Mentors;Minor;Modeling;Molecular;Mothers;Nerve;Obesity;Organ;Outcome;Pathway interactions;Pediatrics;Perinatal;Phase;Phenylephrine;Physiological;Plasma;Predisposition;Proteins;Rattus;Receptor Activation;Receptor Angiotensin Type 1;Renal Tissue;Renal function;Renin;Renin-Angiotensin-Aldosterone System;Reporting;Research;Risk Factors;Rodent;Secondary to;Stress;System;Techniques;Testing;Therapeutic;Variant;Vascular constriction (function);adrenergic;blood pressure regulation;desensitization;in vivo;maternal separation;novel;premature;pressure;programs;public health medicine (field);pup;receptor expression;response;stressor

public_health_relevance:
PROJECT NARRATIVEAdverse environment during early life is known to sensitize humans to stressors and risk factors forhypertension and cardiovascular disease later in life. Similarly early life stressors sensitize rats in theadulthood in part by exacerbating the responses to AngII. Diseases derived from pediatrics issues such asprematurity and adverse childhood increase dramatically the annual public health cost. Therapeutic strategiesduring perinatal life will be guided by the elucidation of novel mechanisms by which ELS elicits an organ-programmed dysfunction increasing the susceptibility to cardiovascular and renal disease.


application_id: 8895123
project_number: 1R01CA188118-01A1
project_title: Determine the Functional Role Dub3 in Breast Cancer Progression and Metastasis
administering_ic: NCI
award_notice_date: 2015-04-01
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: CA
serial_number: 188118
suffix: A1
program_official: AULT, GRACE S
project_start_date: 2015-04-01
project_end_date: 2020-03-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Basal-like breast cancer (BLBC) presents with an aggressive clinical history development of recurrence distant metastasis shorter survival and usually occurs in young women. BLBC has an activated epithelial-mesenchymal transition (EMT) program which provides cells with the increased phenotypic and cellular plasticity required during embryonic development tissue remodeling wound healing and metastasis. Our long-term goal is to discover the molecular circuitry that governs the functional plasticity of BLBC cells in metastasis and to identify molecules that may serve as druggable targets for treating this deadly disease. In the last nine years we have systematically studied the function of Snail and the molecular mechanism by which Snail represses E-cadherin expression in BLBC. Our studies clearly indicate that Snail levels are regulated predominantly through protein ubiquitination. High levels of Snail due to protein stabilization contribute significantly to the
increased invasion therapeutic resistance CSC-like properties and tumor recurrence. However the mechanism by which Snail escapes ubiquitination and degradation remains unknown; uncovering this mechanism is crucially important for the development of novel approaches to treat BLBC. Recently we discovered that Dub3 is a bona fide deubiquitinase of Snail and contributes to Snail stabilization in breast cancer. Dub3 is evolutionarily conserved from Drosophila to humans. Dub3-knockout downregulated Snail and disrupted gastrulation (an event that requires EMT) in Drosophila. Elevated expression of Dub3 correlates unequivocally with Snail expression in BLBC samples and cell lines. Overexpression of Dub3 in luminal breast tumor MCF7 and T47D cell lines which contain no detectable endogenous Dub3 and Snail induces transformation to a basal-like phenotype; whereas Dub3-knockdown downregulates Snail and suppresses cell migration. Intriguingly Dub3 was an early response gene that appeared after exposure to inflammatory cytokines. We hypothesize that Dub3 is the long-sought "missing molecule" that regulates cellular plasticity by controlling the level of Snail durig EMT and metastasis. The objective of this proposal is to characterize the function and regulation of the Dub3-Snail axis and explore the clinical value of Dub3 as a prognostic biomarker and a druggable target for treating metastatic breast cancer. Guided by strong preliminary data we will test this hypothesis by pursuing three specific aims: (1) to delineate th molecular mechanism by which Dub3 controls EMT; (2) to determine the function and regulation of Dub3 in breast cancer; and (3) to define the function and therapeutic efficacy of Dub3 in vivo. Our proposal is innovative and significant because it will not only uncover a new paradigm that significantly increases our understanding of the regulation of cellular plasticity during tumor progression and metastasis but also leads to the development of specific Dub3 inhibitors for treating metastatic breast cancer.

project_terms:
Address;Biological Markers;Brain;Breast;Breast Cancer Cell;Breast cancer metastasis;Cancer stem cell;Cell Line;Cells;Chromatin;Clinical;Coupled;Data;Deubiquitination;Development;Diagnosis;Diagnostic;Disease;Distant Metastasis;Drosophila genus;E-Cadherin;ERG gene;Embryonic Development;Environment;Enzymes;Epithelial;Event;Exposure to;Genes;Goals;Growth;Human;Inflammatory;Intrinsic factor;Investigation;Knock-out;Knowledge;Libraries;Location;Lung;MCF7 cell;Malignant Neoplasms;Mammary Neoplasms;Mass Spectrum Analysis;Mesenchymal;Metabolic;Metastatic breast cancer;Modeling;Molecular;Mus;Neoplasm Metastasis;Oncologist;Pathologist;Pharmaceutical Preparations;Phase;Phenotype;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Prognostic Marker;Promotor (Genetics);Property;Proteins;Reagent;Recording of previous events;Recruitment Activity;Recurrence;Regulation;Research;Role;Sampling;Signal Transduction;Site;Small Interfering RNA;Snails;Specimen;Stromal Neoplasm;Structural Biologist;Structure;T47D;Testing;Therapeutic;Tissues;Treatment Efficacy;Tumor Cell Invasion;Ubiquitination;Validation;Wound Healing;Xenograft procedure;aerobic glycolysis;base;beta-Transducin Repeat-Containing Proteins;cancer therapy;cell growth regulation;cell motility;cytokine;epithelial to mesenchymal transition;functional plasticity;gastrulation;in vivo;inhibitor/antagonist;innovation;loss of function;macrophage;malignant breast neoplasm;multidisciplinary;neoplastic cell;new therapeutic target;novel strategies;outcome forecast;overexpression;prevent;prognostic value;programs;public health medicine (field);public health relevance;research study;screening;success;targeted treatment;therapy resistant;tumor;tumor microenvironment;tumor progression;ubiquitin-protein ligase;virtual;young woman


application_id: 8895076
project_number: 5T32CA160003-05
project_title: Oncology Research Training for Surgeon-Scientists
project_terms: Research Training;Scientist;Surgeon;oncology
administering_ic: NCI
award_notice_date: 2015-06-23
opportunity_number: PA-10-036
application_type: 5
activity_code: T32
ic: CA
serial_number: 160003
program_official: PERKINS, SUSAN N
project_start_date: 2011-07-01
project_end_date: 2017-06-30
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The primary focus of our training program at the University of Kentucky (UK) is to provide intensive and interdisciplinary basic science research training for a minimal period of two years for qualified individuals who are committed to pursuing a career in academic oncologic surgery. Our training program is specifically designed to focus on the research training of academic surgeons so that they will be prepared to become independent scientists and incorporate the new and state-of-the-art techniques learned during their training period into a successful academic career. Also these trainees will be prepared to be active participants in multidisciplinary teams which are required for the optional treatment of the complex cancer patient. Our training program represents a collaboration between the Markey Cancer Center and the Department of Surgery and benefits greatly from the experience and collegiality of the program and associate directors who have worked together for many years and have led other successful training programs for clinician-scientists and basic researchers. The primary training faculty is composed of both basic and clinical-scientists who are collegial collaborative and multidisciplinary; each primary faculty mentor is a recognized expert in his or her field and has a long record of research productivity in the training of young investigators from the US and abroad. In the past 10 years our 15 primary faculty mentors have trained over 100 predoctoral students and more than 130 postdoctoral fellows. The diversity of our training program is further enhanced by the inclusion of seasoned adjunct faculty mentors who will provide additional clinical and biostatistical expertise. Also we have designed a "pipeline" mechanism to provide the time and instruction for promising junior faculty members to further hone their mentoring skills so that they can become effective primary mentors in the future. The breadth and depth of the basic research available in the laboratories of the various faculty mentors will allow the trainees to become familiar with and adept at the application of state-of-the-art techniques for the comprehensive care of the cancer patient. In addition to an intensive research experience the trainees will take formal courses (eg grant writing skills ethics and biostatistics). Furthermore the trainees will participate in regularly scheduled Cancer Center and Department of Surgery seminars and lectures. All of our trainees will be required to complete coursework for a Master's degree in Clinical and Translational Science (CTS). This requirement will further add depth to the program and increase interactions with other scientists on campus through the required supervisory committee. Trainees will also be mentored in the fine points of preparing abstracts scientific papers and presentations and writing successful grant proposals. We are concerned with the alarming decrease in the number of clinician-scientists; this decrease is most apparent in the diminishing number of surgeon-scientists. We are passionate motivated and committed to the training of future academic surgeons.

public_health_relevance:
The number of clinician-scientists and in particular surgeon-scientists is decreasing at an alarming rate; this reduction will negatively impact the ability and rapidity to "translate" basic discoveries made in cancer research to the patient. Our training program representing a collaboration between the Markey Cancer Center and the Department of Surgery at the University of Kentucky is focused on the interdisciplinary training of future academic surgeons. Of the more than 150 training programs funded by the NCI we are aware of only 2 others that are specifically training surgeon-scientists; we feel that this is an inadequate number to prepare surgeon- investigators to be competitive in the academic arena and to be active participants in multidisciplinary cancer teams which are required for the care of the complex cancer patient.


application_id: 8894348
project_number: 5R01AG026307-09
project_title: Self-Regulation Immunological Aging and Health in Older Adults
administering_ic: NIA
award_notice_date: 2015-04-30
opportunity_number: PA-09-216
application_type: 5
activity_code: R01
ic: AG
serial_number: 026307
program_official: NIELSEN, LISBETH
project_start_date: 2006-07-15
project_end_date: 2016-04-30
study_section: Special Emphasis Panel[ZRG1-BBBP-T(02)M]
contact_pi_person_id: 1886687
contact_pi: SEGERSTROM, SUZANNE C.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Older adults are at high risk for a number of health problems including cardiovascular disease infectious disease and cancer. Underlying at least part of this risk is immunological aging but not all older adults experience immunological aging to the same degree nor do they experience the same health risk and health problems. The purpose of this project is to measure individual differences and changes in self-regulation over time in older adults and to link self-regulation to subjective health health risks and clinicallyrelevant markers of immunological aging including inflammation and markers of lymphocyte terminal differentiation and replicative senescence. This is a competing renewal of this longitudinal study which began in 2001 and received R01 funding in 2006 submitted by a research team with expertise in aging self-regulation neuropsychology autonomic and inflammatory biology immunology and longitudinal design and analysis. The first period of the study focused on risk factors especially stress and repetitive thought and their effects on psychological well-being subjective health and immune response to vaccination. The renewal continues assessment of these risk factors to provide continuity in this longitudinal dataset and adds innovation in the assessment of factors that may promote healthy aging and mitigate against effects of risks. Specifically the aims of the study are first to test the effects of a elf-regulatory constellation (comprising self-regulation executive cognitive function and heart rate variability [HRV]) on subjective psychological social and physical health and markers of immunological aging. Second we will test the relationships between this constellation and risk factors such as age and stress. Third we will test the ability of the constellation to moderate rik effects. A further aim is to support a "call for collaboration" in which we propose to work with other investigators whose hypotheses can be tested with study data from 2001 through the current renewal. At 6- month intervals older adults (N = 150) will complete measures of the self-regulatory constellation: behavioral emotional social and cognitive self-regulation; executive cognitive functions including inhibition shifting and working memory; and resting HRV. They will complete measures of risk including stress pain physical activity BMI and waist circumference. Finally they will complete measures of psychosocial health including depression perceived cognitive and physical health and marital satisfaction. Blood draws will be synchronized with these visits and assays performed on these samples will capture two aspects of immunological aging: increases in serum proinflammatory cytokines and their soluble receptors and increases in markers of terminal differentiation and senescence in T cells and NK cells. This renewal will be innovative in its comprehensive assessment of self-regulation as well as risk; the longitudinal design that allows for the study of change and lagged mediational and bidirectional effects; and the focus on the role of self-regulation in healthy aging.

project_terms:
Accounting;Age;Aging;Back;Behavioral;Biological Assay;Biological Markers;Biology;Blood;Cardiovascular Diseases;Cell Aging;Cognitive;Collaborations;Communicable Diseases;Data;Data Set;Elderly;Emotional;Funding;Health;Immune;Immune response;Immune system;Immunology;Individual;Individual Differences;Inflammatory;Influenza vaccination;Informal Social Control;Interleukin-6;Link;Longitudinal Studies;Lymphocyte;Malignant Neoplasms;Measures;Mental Depression;Mental Health;Natural Killer Cells;Neuropsychology;Outcome;Pain;Personal Satisfaction;Physical activity;Psychological Factors;Research;Research Personnel;Resistance;Rest;Risk;Risk Factors;Role;Sampling;Serum;Short-Term Memory;Stress;T-Lymphocyte;Testing;Time;Vaccination;Visit;Work;age related;clinically relevant;cognitive function;cohort;cytokine;experience;feeding;healthy aging;heart rate variability;high risk;indexing;inflammatory marker;innovation;longitudinal analysis;longitudinal design;member;physical conditioning;prospective;psychologic;psychosocial;receptor;satisfaction;senescence;shift work;social;waist circumference

public_health_relevance:
PUBLIC HEALTH RELEVANCE: With age come changes in the immune system that can increase the risk of poor health. However not all older adults experience these changes to the same degree. This project will continue to track a cohort of older adults examining psychological factors that may be protective for psychological and physical health and delay immunological aging as well as those factors that may confer risk and the interactions between protective and risk factors.


application_id: 8894242
project_number: 3R15ES020053-01A1S1
project_title: Genetic Susceptibility to PCB-induced Motor Dysfunction
administering_ic: NIEHS
award_notice_date: 2014-08-06
opportunity_number: PA-10-070
application_type: 3
activity_code: R15
ic: ES
serial_number: 020053
suffix: A1S1
program_official: HOLLANDER, JONATHAN
project_start_date: 2012-06-01
project_end_date: 2017-05-31
study_section: Special Emphasis Panel[ZRG1-MDCN-E(96)A]
contact_pi_person_id: 8110072
contact_pi: CURRAN, CHRISTINE PERDAN
other_pis: Not Applicable
congressional_district: 04
department: BIOLOGY
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
project_abstract:
DESCRIPTION (provided by applicant): Polychlorinated biphenyls (PCBs) are persistent organic pollutants that bio-accumulate in the food supply and resist environmental degradation. Studies of human populations near the most polluted sites have found learning memory and motor impairments in children exposed during pregnancy and breast-feeding. Animal studies show that PCBs significantly alter dopamine concentrations in the brain and that toxicity may be mediated through the ryanodine receptor. Recent evidence suggests PCB exposures may increase the risk of Parkinson's Disease; [however PCBs also have significant effects on cerebellar development and function.] Not all exposed individuals experience the same level of adverse health effects indicating that genetic differences affect risk. Our previous studies in mice identified two genes that affect susceptibility to PCB-induced developmental neurotoxicity: the aryl hydrocarbon receptor (AHR) and cytochrome P450 1A2 (CYP1A2). AhrbCyp1a2(-/-) mice with a high-affinity AHR and lacking CYP1A2 showed deficits in spatial and non-spatial learning and memory following developmental PCB exposure while AhrbCyp1a2(+/+) mice were resistant. Our [published and new] preliminary data show motor deficits and [learning and memory deficits that vary by sex and genotype using a mixture of congeners with little to no activity toward the ryanodine receptor. Therefore we hypothesize that [additional pathways contribute to PCB developmental neurotoxicity in addition to toxicity mediated by the ryanodine receptor. To test this hypothesis we will use these three lines of mice to: 1.) Compare motor function in PCB-exposed offspring and corn oil-treated controls 2.) Assess gene expression changes and crosstalk in pathways associated with motor function. 3.) Quantify protein levels in brain regions essential to normal motor function.]

project_terms:
Adult;Affect;Affinity;Age;Animals;Aromatic Polycyclic Hydrocarbons;Aryl Hydrocarbon Receptor;Binding (Molecular Function);Brain;Brain region;Breast Feeding;Child;Corn Oil;Corpus striatum structure;Cytochrome P-450 CYP1A2;Data;Development;Dioxins;Dopamine;Enzymes;Female;Food Supply;Functional disorder;Gene Expression;Generations;Genes;Genetic;Genetic Predisposition to Disease;Genetic Transcription;Genotype;Goals;Health;Human;Individual;Intervention;Knowledge;Lead;Learning;Ligand Binding;Ligands;Link;Mediating;Memory;Memory impairment;Motor;Mus;Neural Pathways;Neuraxis;Parkinson Disease;Pathway interactions;Play;Polychlorinated Biphenyls;Predisposition;Pregnancy;Production;Promotor (Genetics);Proteins;Publishing;Receptor Activation;Research;Resistance;Risk;Rodent;Role;Ryanodine Receptor Calcium Release Channel;Site;Testing;Tetrachlorodibenzodioxin;Toxic Environmental Substances;Toxic effect;Tyrosine 3-Monooxygenase;Variant;Variation (Genetics);Work;activating transcription factor;aryl hydrocarbon receptor ligand;cell motility;design;developmental neurotoxicity;direct application;experience;exposed human population;granule cell;high risk;human population study;motor deficit;motor impairment;motor learning;mouse model;nervous system development;neurotoxic;neurotoxicity;nigrostriatal pathway;novel;offspring;pollutant;public health medicine (field);response;sex

public_health_relevance:
Significance: Polychlorinated biphenyls are persistent organic pollutants that are neurotoxic to the developing brain. Genetic differences can affect an individual's risk of adverse health effects from environmental toxicants. The proposed research is designed to identify neural pathways affected by PCB exposure and humans at highest risk of PCB developmental neurotoxicity using a mouse model that mirrors known genetic variations in humans.


application_id: 8893972
project_number: 5R01DK095662-09
project_title: Regulation of Intestinal Stem Cell Activation in Colitis
administering_ic: NIDDK
award_notice_date: 2015-06-25
opportunity_number: PA-12-270
application_type: 5
activity_code: R01
ic: DK
serial_number: 095662
program_official: SENGER, STEFANIA
project_start_date: 2013-09-20
project_end_date: 2017-06-30
study_section: Clinical, Integrative and Molecular Gastroenterology Study Section[CIMG]
contact_pi_person_id: 1883566
contact_pi: BARRETT, TERRENCE A.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Induction of mucosal healing in inflammatory bowel disease (IBD) is associated with reduced hospitalizations and surgeries. Healing of the mucosal barrier requires control of the destructive inflammatory response as well as restitution of the epithelial barrier through enhanced proliferation and generation of new crypt structures.  Although it is clear that induction of Wnt/B-catenin activation is a key factor in intestinal stem ell (ISC) and progenitor cell (PC) activation there are few researchers that examine the regulation of B-catenin activation in colitis where mucosal healing and inflammation-induced dysplasia are major clinical concerns. Studies performed during the prior award period demonstrated that Akt phosphorylation of B-catenin increases in ISCs during colitis and colitis-induced cancer. The present proposal makes use of a novel genetic model for reducing PI3K signaling in colonic intestinal epithelial cells (IEC) during colitis. Data already produced in VilCre/pik3r1fl/fl mice given DSS colitis suggest that PI3K-mediated B-catenin activation plays a major role in wound healing. Acute and chronic forms of DSS colitis will be generated in VilCre/pik3r1fl/fl mice for invivo studies in AIM 1 to examine the role of IEC class 1A PI3K in mucosal healing B-catenin activation and ISC/PC gene expression (using novel enteroid cultures). Studies in AIM 2 utilize bone marrow chimera (BMC) mice to examine TNF-induced IEC B-catenin signaling in radioresistant epithelial populations in DSS colitis mice. AIM 3 studies examine the role of Nox1 in B-catenin activation using B6->Nox1-/- BMC DSS colitis mice. Together the studies propose that TNF-induced NOX1 stimulates PI3K-mediated B-catenin activation and ISC/PC gene expression to determine crypt responses in IBD. The underlying hypothesis is that inflammation-induced B-catenin signaling enhances epithelial regeneration and induces chronic architectural distortion by increasing ISC and progenitor cell expansion during colitis. The clinical relevance of these studies is great given that we hope to identify novel approaches to IBD therapy and chemoprevention.

project_terms:
Acute;Attenuated;Award;Biopsy;Bone Marrow;Cell Culture Techniques;Cell Line;Chemoprevention;Chicago;Chimera organism;Chronic;Clinical;Clinical Trials;Colitis;Colon;Colon Carcinoma;Colorectal Cancer;Crohn's disease;Data;Dysplasia;Enrollment;Epithelial;Epithelial Cells;Figs - dietary;Focal Infection;Gene Expression;Generations;Genes;Genetic Models;Goblet Cells;Grant;Healed;Hospitalization;In Vitro;Inflammation;Inflammatory Bowel Diseases;Inflammatory Response;Inflammatory disease of the intestine;Intestines;Leukocytes;Malignant Neoplasms;Mediating;Modeling;Monoclonal Antibodies;Mucositis;Mus;Mutate;Natural regeneration;Operative Surgical Procedures;Pathway interactions;Patients;Phosphorylation;Phosphotransferases;Play;Population;Proteins;Publishing;Reactive Oxygen Species;Regulation;Research Personnel;Residual state;Risk;Role;Sampling;Severities;Severity of illness;Signal Transduction;Sodium Dextran Sulfate;Stem cells;Structure;Study models;Systemic infection;TNFRSF1A gene;Testing;Time;Tissues;Tumor Necrosis Factor-alpha;Ulcer;Ulcerative Colitis;Universities;Wound Healing;base;carcinogenesis;clinical predictors;clinical remission;clinically relevant;colitis associated cancer;healing;in vivo;kinase inhibitor;member;myoinositol;novel;novel strategies;radioresistant;repaired;response;stem;therapy outcome

public_health_relevance:
The proposal presented plans to examine how patients heal from ulcers (sores) in the bowel during colitis (ulcerative colitis and Crohn's disease). We find that in colitis small protein molecules made by white blood cells cause stimulation of epithelial cells that line the colon. In this grant we will examine mechanisms that control how inflammation in colitis stimulates epithelial stem cells and increases their risk of turning into colon cancer.


application_id: 8893100
project_number: 5R01GM107586-02
project_title: Light-responsive ruthenium compounds for applications in disease
administering_ic: NIGMS
award_notice_date: 2015-07-16
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: GM
serial_number: 107586
program_official: FABIAN, MILES
project_start_date: 2014-08-01
project_end_date: 2019-07-31
study_section: Synthetic and Biological Chemistry A Study Section[SBCA]
contact_pi_person_id: 8085279
contact_pi: GLAZER, EDITH C
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adverse effects;Animals;Benchmarking;Biological;Biological Assay;Biotin;Cancer cell line;Cell Death;Cell Survival;Cells;Cessation of life;Charge;Chemicals;Chemistry;Chromatography;Cisplatin;Combined Modality Therapy;Complex;DNA;DNA Damage;Development;Disease;Dose-Limiting;Drug Kinetics;Electron Microscopy;Engineering;Exhibits;Family;Genetic Transcription;Goals;Health;Image;Imaging Device;In Vitro;Killings;Knowledge;Label;Lead;Ligands;Light;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mass Spectrum Analysis;Maximum Tolerated Dose;Metals;Modality;Modeling;Modification;Molecular;Motivation;Mus;Neutropenia;Nucleic Acids;PUVA Photochemotherapy;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Photochemistry;Platinum;Process;Prodrugs;Property;Radiation;Reaction;Resistance;Resistance profile;Resolution;Ruthenium;Ruthenium Compounds;Sampling;Singlet Oxygen;Site;System;Therapeutic;Tissues;Toxic effect;United States;Variant;Xenograft Model;analog;base;biological systems;cancer cell;cancer therapy;cancer type;cell injury;cell killing;cell type;cellular targeting;chemotherapeutic agent;chemotherapy;clinical application;crosslink;cytotoxic;cytotoxicity;design;gel electrophoresis;in vivo;innovation;lung melanoma;novel;oxidative damage;preclinical study;screening;small molecule;translation assay;tumor


application_id: 8891457
project_number: 5P20GM103492-08
project_title: Project 5 - Metabolomic Analysis of Atherothrombosis
administering_ic: NIGMS
award_notice_date: 2015-08-20
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
project_end_date: 2016-06-30
study_section: ZGM1-TWD-Y
subproject_number: 5010
contact_pi_person_id: 9847182
contact_pi: DEFILIPPIS, ANDREW
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
Cardiovascular disease (CVD) is the leading cause of death in individuals with diabetes with rates of acute coronary syndrome (ACS) and total mortality several fold higher in younger adults with versus without type 2 diabetes (T2D). Nevertheless the mechanisms that impart greater CVD risk in T2D are not well understood and no diabetes-specific CVD treatment regimens have been developed. ACS occurs when intracoronary thrombus obstructs coronary flow to produce myocardial ischemia and is responsible for the majority of irreversible myocardial damage in T2D. Although great advances have been made in diagnosing ACS all of the current ACS biomarkers measure the result myocardial necrosis and not the cause and therapeufic target -atherothrombosis. The ability to identify atherothrombotic-MI at the start of the event prior to irreversible myocardial necrosis and quickly disfinguish atherothrombotic from non-atherothrombofic ACS would materially increase the safety and effectiveness of ACS treatment in T2D patients. The long-term goal of this project is to develop a biomarker which differentiates atherothrombotic from non-atherothrombotic Ml in patients with T2D. Such an approach will not only improve diagnostic accuracy but could also potentially identify events at the start of coronary thrombosis prior to "inevitable" myocardial necrosis allowing for more prompt and targeted interventions. Hence using both targeted and unbiased metabolomic approaches we plan to identify specific biomarkers of atherothrombosis. Our central hypothesis is atherothrombotic events are associated with increased production of metabolites derived from oxidized lipids in the culprit lesion or generated by the atherothrombotic event itself and that measurement of these metabolites will allow for eariy and accurate diagnosis of atherothrombotic Ml is T2D patients.

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

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


application_id: 8891456
project_number: 5P20GM103492-08
project_title: Project 4 - Cardiac Stem Cell Dysfunction in Diabetes
administering_ic: NIGMS
award_notice_date: 2015-08-20
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
project_end_date: 2016-06-30
study_section: ZGM1-TWD-Y
subproject_number: 5009
contact_pi_person_id: 11675369
contact_pi: HONG, KYUNG UK
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
Type II diabetes (T2D) is a growing pandemic and one ofthe most serious health threats of our time. In addition to the well-characterized central endocrine defects some T2D patients present with distinct manifestation of cardiomyopathy termed diabetic cardiomyopathy. Diabetic cardiomyopathy occurs in the presence of neither clinically identifiable coronary artery disease nor hypertension suggesting that independent of its vascular effects T2D has direct impact on the myocardium. Although its etiology is complex hyperglycemia and dyslipidemla leading to increased oxidative stress may play a central role in the pathogenesis of diabetic cardiomyopathy. Recent studies have proposed that stem cell dysfunction may be responsible for complications related to T2D. The mammalian heart contains a cardiac stem cell (CSC) population with the capacity to maintain and regenerate myocardium. However little is known about CSCs function in the diabetic heart or their involvement in pathogenesis of diabetic cardiomyopathy. Our preliminary data indicate that the growth and differentiation characteristics of CSCs are impaired in diabetes. We hypothesize that T2D alters CSC growth and differentiation and these changes in stem cell function contribute to structural abnormalities and contractile dysfunction in the diabetic heart. To test this hypothesis we will: 1) Identify central defects in CSC biology in the diabetic heart in vivo; 2) Elucidate the cellular defects provoked by diabetes and nutrient excess in CSCs in vitro; and 3) Rescue the CSCs' functional defects in the diabetic heart in vivo. The studies proposed here will 1) Establish correlation between CSC dysfunction and cardiac abnormalities in the diabetic heart; 2) Explore mechanisms by which diabetes and nutrient excess affect function of CSCs; and 3) Decipher whether or not CSC dysfunction significantly contributes to the pathogenesis of diabetic cardiomyopathy using an innovative transgenic mouse model. Results of this study will lead to a better understanding of how diabetes affects CSC competence and function and how these abnormalities contribute to diabetic cardiomyopathy. Successful completion of these studies could illuminate new avenues for preventing or treating T2D.

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

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


application_id: 8891455
project_number: 5P20GM103492-08
project_title: Project 3 - Regulation of Metabolism by Nitric Oxide
administering_ic: NIGMS
award_notice_date: 2015-08-20
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
project_end_date: 2016-06-30
study_section: ZGM1-TWD-Y
subproject_number: 5008
contact_pi_person_id: 9543696
contact_pi: HILL, BRADFORD GUY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
Obesity and type 2 diabetes (T2D) are epidemics in the U.S. and abroad. A better understanding ofthe mechanisms that promote obesity and induce T2D is urgently needed to stem the tide of these epidemics and to control their cardiovascular complications. We suggest that endothelial dysfunction induced by nutrient excess is the primary cause that leads to metabolic changes resulting in an increase in adiposity and whole-body insulin resistance. Our studies show that overexpression of eNOS in mice prevents diet-induced obesity. These changes are accompanied by systemic and adipose tissue-specific changes in metabolism. Our metabolomic analyses indicate that eNOS over expression increases the abundance of circulating bile acids which have been shown to be potent effectors of metabolism and regulators of adipose tissue phenotype. Nevertheless we do not know how NO regulates bile acid production or which metabolic pathways triggered by bile acids are responsible for the lean phenotype of eNOS-TG mice. Therefore we will test the hypothesis that NO exerts an anti-obesogenic effect by regulating bile acid metabolism which promotes the development of adipocytes into a novel "lean" phenotype characterized by high mitochondrial content and fat burning capacity. To test this hypothesis we will: (1) Examine the effects of NO on diet induced obesity; (2) Determine how NO regulates metabolism; and (3) Elucidate the mechanisms regulating adipocyte phenotype. The experimental approaches in these aims will test whether NO directly regulates obesity and whether the anti-obesity effects of NO are mediated through the ability of eNOS to increase bile acid production and to regulate adipose tissue phenotype. The results of these studies will develop a strong platform for constructing a competitive ROI application and will lead to a new understanding of the role of NO in regulating the metabolic changes that contribute to diabetes and obesity. These studies could lay the groundwork for the development of novel therapeutic interventions to prevent manage or reverse obesity and insulin resistance.

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

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


application_id: 8891454
project_number: 5P20GM103492-08
project_title: Project 2 - Effects of Particulate Matter on Insulin Resistance and Endothelial
administering_ic: NIGMS
award_notice_date: 2015-08-20
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
project_end_date: 2016-06-30
study_section: ZGM1-TWD-Y
subproject_number: 5007
contact_pi_person_id: 11375489
contact_pi: HABERZETTL, PETRA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
Inhalation of fine particulate matter air (PM) pollution (<2.5pm) is associated with an increased risk for cardiovascular disease (CVD) and Type 2 diabetes (T2D). Short-term exposure of mice to concentrated ambient air particulate matter (CAP) decreases vascular insulin sensivity and circulating endothelial progenitor cells (EPCs). EPCs are thought to be involved in endothelial maintenance thus we propose that CAP-induced suppression of circulating and tissue-resident EPCs leads to endothelial injury and insulin resistance which provokes systemic insulin resistance ultimatively increasing the risk for T2D and CVD. CAP exposure affects vascular health by triggering low-grade inflammation via Inflammasome activation. To elucidate both mechanism(s) and causal relationship of endothelial injury EPC depletion and vascular insulin resistance we will examine in the aim 1:1) whether CAP-exposure alone is sufficient to induce systemic insulin resistance or whether it only exacerbates the effects of obesity and 2) the physico-chemical composition and body deposition of CAP to establish a more precise dosimetry and to find potential particle properties responsible for the biological effects. In our second aim we will investigate whether alterations in circulating/tissue resident EPCs and endothelial health are causative for the development of vascular insulin resistance. Finally to find the mechanisms of CAP-induced vascular insulin resistance we will examine in aim 3 a possible role ofthe activation ofthe inflammasome. We will utilize a mouse model of diet-induced obesity (DIO) to investigate effects of HFD-feeding and use mice deficient in NLRP3 and Casp-1 to test the contribution of Inflammasome activation in the development of vascular insulin resistance. Completion of these studies will provide novel insights into the mechanism(s) by which inhaled ambient particles increase the risk for T2D and CVD and as such will provide unique and detailed information of particle dose composition and deposition and their correlation with biological responses which could lead to the development of novel biomarkers and strategies for the regulation of environmental pollutants and the prevention and management of insulin resistance obesity T2D and CVD.

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

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


application_id: 8891453
project_number: 5P20GM103492-08
project_title: Project 1 - Carnosine Metabolism in Diet-Induced Obesity
administering_ic: NIGMS
award_notice_date: 2015-08-20
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
project_end_date: 2016-06-30
study_section: ZGM1-TWD-Y
subproject_number: 5006
contact_pi_person_id: 11110260
contact_pi: BABA, SHAHID P
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
Obesity is a highly prevalent condition and is associated with an increased risk for the development of type 2 diabetes (T2D) and cardiovascular disease. As such an understanding of how obesity develops and the identification of novel therapeutics aimed at controling obesity and its metabolic consequences are of utmost importance. Recent studies demonstrate that the dipeptide carnosine is depleted in the skeletal muscle of patients with T2D and that carnosine feeding decreases diet-induced obesity. Carnosine (ala-his) is a dipeptide present in skeletal muscle brain and heart. It buffers protons during glycolysis and it is a strong antioxidant. Carnosine is synthesized by the enzyme carnosine synthetase and is hydrolysed back to alanine and histidine by carnosinase.The homeostatic balance of carnosine is also maintained by the peptide transporter Pept2 . Although obesity and T2D in humans is associated with a decrease in carnosine levels in the skeletal muscle the mechanisms underiying carnosine depletion and its protective effects against obesity are not entirely known. Our intial studies show that high fat feeding in mice decreases carnosine levels and that restoration of these levels by carnosine supplementation restricts weight gain increases energy expenditure insulin senstivity and glucose tolerance. Based on these observations we propose that chronic carnosine deficiency decreases energy expenditure and antioxidant capacity ofthe muscle resulting in insulin resistance and oxidative stress. To test this hypothesis we will: (1) elucidate the mechanism of carnosine depletion in obesity; 2) test whether carnosine supplementation prevents or reverses obesity and its metabolic consequences; and (3) investigate the mechanism by which carnosine regulates adiposity and insulin sensitivity. To evaluate the clinical relevance of our findings we will also measure carnosine and carnosinase activity in obese and non-obese children. The findings of this project could lead to the development of a novel and validated anti-obesity strategy that could also prevent or reverse diet-induced insulin resistance. Successful completion ofthis project would lay the foundaton and form the rationale for testing the anti-obesogenic and anti-diabetic effects of carnosine in humans.

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

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


application_id: 8891452
project_number: 5P20GM103492-08
project_title: Core E - Imaging and Physiology Core
administering_ic: NIGMS
award_notice_date: 2015-08-20
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
project_end_date: 2016-06-30
study_section: ZGM1-TWD-Y
subproject_number: 5005
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
The Imaging and Physiology Core (Core E) will play a key role in nurturing the growth ofthe Center and developing the Projects by promoting scientific excellence in investigations of cardiometabolic disease. Core E will provide investigators with access to state-of-the-art instrumentation and expert instruction related to confocal imaging assessment of cardiac function and performance of surgery in mice. The Core will promote education on the theory as well as sound technical comprehension related to the various instruments and approaches available. This group will also work closely with the Center members particulariy junior investigators to develop new tailored procedures to answer their experimental questions. The Director will provide guidance not only for the techniques provided by Core E but also mentorship to the junior faculty members in the Center. Dr. Steven Jones (Director Core E) brings approximately ten years of experience in confocal/fluorscent microscopic imaging and mitochondrial function assessment to Core E. The Core will enable Project leaders to use fluorescence microscopy to evaluate either fixed tissue (from Core C) or live cultured cells (from individual Projects). In addition. Dr. Jones' expertise in cardiovascular physiology will allow careful assessment of or surgery on mice generated by Core D. Furthermore the spatial resolution of confocal microscopy complements to high throughput techniques offered by Core B. Given the scope of approaches used in Core E Dr. Jones is perfectly suited to lead this Core. In addition to meeting the needs of the proposed Projects the Core has established a viable plan for a transition to financial independence during Phase II ofthe COBRE. The COBRE University Center and Members have all contributed to extensively to the expansive list of instrumentation in Core E. Such investments reflect the important role of Core E in the progress of the Center. Once the needs of the Projects and Center members are addressed the Director will continue developing new protocols acquiring additional instrumentation and initiating additional collaborations with other investigators in the UofL community. Core E will play a pivotal role in bringing this Center to national prominence in cardiometabolic research.

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

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


application_id: 8891451
project_number: 5P20GM103492-08
project_title: Core D - Animal Models and Phenotyping Core
administering_ic: NIGMS
award_notice_date: 2015-08-20
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
project_end_date: 2016-06-30
study_section: ZGM1-TWD-Y
subproject_number: 5004
contact_pi_person_id: 8767000
contact_pi: CONKLIN, DANIEL JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
The Animal Models and Phenotyping Core (Core D) has four major goals. 1) Its primary function is to support the research projects of COBRE-supported Junior Investigators by providing state-of-the-art facilities and intellectual capability for the development and characterization of new and existing animal models used in diabetes and obesity research. Other goals are: 2) to provide training and education to Diabetes and Obesity Center junior investigators and members; 3) to develop new models techniques and protocols to further diabetes and obesity research; and 4) to become a self-sustaining entity that supports the Diabetes and Obesity Center. While the Animal Core will preferentially address the needs of the COBRE-supported junior investigators it will also assist in the development of new protocols maintenance of unique mouse lines and creation of new models for other Diabetes and Obesity Center investigators. It will provide a comprehensive assessment of animal adiposity glucose insulin and pyruvate tolerance physical activity body temperature food and water intake oxygen consumption and carbon dioxide production in order to evaluate the overall metabolic condition ofthe model animal under environmental challenges including high fat diet. Training and educating investigators is an integral function of the Animal Core and it will continue to provide education to Center junior investigators and members. The Animal Core has trained personnel who in turn educate individual junior investigators on how to perform metabolic phenotyping tests correctly. The Animal Core has and will continue to develop new models of interest to investigators for specific mechanistic purposes. It will expand its operations to support future needs by adding infrastructure equipment and by developing state-of-the-art animal models and by establishing new methods refining assays and using statistical modeling approaches useful in metabolic phenotyping. The Animal Core intends to become a selfsustaining entity that will promote the long-term stability of the Center by providing essential services and developing new and unique capabilities for individual and multi-PI projects.

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

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


application_id: 8891450
project_number: 5P20GM103492-08
project_title: Core C - Pathology and Bio-analytics Core
administering_ic: NIGMS
award_notice_date: 2015-08-20
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103492
project_end_date: 2016-06-30
study_section: ZGM1-TWD-Y
subproject_number: 5003
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
Overarching goal of the Center is to understand the mechanisms of pathophysiology of diabetes and obesity and their cardiovascular complications. The Pathology and Bio-analytics Core is an integral part ofthe Center and will play a key role in the evolution of COBRE-funded projects. The Core will render services for rigorous and comprehensive pathological analysis of diabetic specimens. It will provide intellectual input with experimental design and state-of-the-art technical expertise to address the needs of investigators. The Core consists of a group of outstanding scientists with expertise in cardiovascular physiology pathology and analytical biochemistry. Director ofthe Core Dr. Sanjay Srivastava more than twenty years of research experience in analytical biochemistry and pathology and vascular inflammation atherosclerosis and diabetes. He will oversee all the Core operations and will work closely with junior investigators to teach them principles of histology chromatography and mass spectrometry. Dr Srivastava will also help the COBRE investigators with quantification and characterization of atherosclerotic lesions. Dr. Michael Merchant coinvestigator in the Core has extensive experience in analytical biochemistry and will assist the COBRE investigators with proteomics analyses. Drs. Srivastava and Merchant will provide hands on training to junior investigators for various histology and bio-analytical assays. The training acquired at the Core will facilitate them to grow as scientists and expand their repertoire of technical skills. The Core is equipped with state-ofthe- art pathology and analytical biochemistry equipment and is located in the Delia Baxter Building. In addition to address the current requirements of the COBRE projects the Core will continue to expand its knowledgebase and technical expertise to satisfy the future needs of the Center. Long term goal of the Core is to become a fiscally independent entity capable of providing cutting-edge pathology and bio-analytical services to researchers interested in diabetes and cardiovascular pathophysiology. Continued excellence in pathological analyses will foster collaborations which will not only help the Core financially but will also advance the field in combatting diabetic complications.

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

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


application_id: 8890919
project_number: 3R13AI108234-01S1
project_title: Autumn Immunology Conference
administering_ic: NIAID
award_notice_date: 2014-07-17
opportunity_number: PA-12-212
application_type: 3
activity_code: R13
ic: AI
serial_number: 108234
suffix: S1
program_official: COULTER, NANCY A
project_start_date: 2013-07-01
project_end_date: 2015-06-30
study_section: ZAI1-ESB-M(M1)
contact_pi_person_id: 1863468
contact_pi: WOODWARD, JEROLD G
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
project_abstract:
DESCRIPTION (provided by applicant): This proposal requests funds to support the annual Autumn Immunology Conference (AIC). The AIC was established in 1972 to promote Immunology research in the upper Midwest region of the United States. The conference provides a forum for the exchange of scientific data and ideas fosters collaboration between scientists at different institutions and provides career development and education opportunities to a diverse group of individuals with an interest in Immunology. The scientific focus of the meeting is intentionally broad; it includes basic Immunology and related biomedical fields such as cancer biology pathogenesis vaccine development inflammation and autoimmunity. Special emphasis is given to providing pre- and postdoctoral trainees with an opportunity to share their data participate in scientific and career discussions and to meet and exchange ideas with established investigators. The organizers also seek to attract involve and promote the careers of women and racial/ethnic minorities that are underrepresented in science. These objectives are met by inviting a group of outstanding Immunology researchers (12-13 each year) from around the world to speak at the meeting. All presenters present both an oral and poster presentation in sessions that are designed to provide the greatest opportunity for feedback to the trainees. Finally scholarship programs career development workshops and mentoring luncheons promote the inclusion of minority scientists and seek to recruit undergraduates into the discipline of Immunology.

project_terms:
Address;Allergic Disease;Applied Research;Autoimmunity;Award;Basic Science;Cancer Biology;Collaborations;Communicable Diseases;Data;Discipline;Educational aspects;Educational workshop;Equilibrium;Feedback;Fostering;Funding;Gender;Goals;Grant;Health;Immune System Diseases;Immunology;Individual;Inflammation;Institution;Mentors;Minority;Minority Groups;Mission;National Institute of Allergy and Infectious Disease;Oral;Participant;Pathogenesis;Preparation;Recruitment Activity;Request for Applications;Request for Proposals;Research;Research Personnel;Scholarship;Science;Scientist;Staging;Travel;Underrepresented Minority;United States;United States National Institutes of Health;Vendor;Woman;career;career development;design;interest;meetings;posters;pre-doctoral;prevent;programs;public health medicine (field);symposium;vaccine development

public_health_relevance:
PUBLIC HEALTH RELEVANCE: High quality scientific conferences are vital to the public health mission of the NIH. This application requests funding for an annual scientific conference called the Autumn Immunology Conference. The purpose of this meeting is to exchange and disseminate information and to explore contemporary problems in the field of Immunology. Thus it is consistent with the fiscal and programmatic priorities of the National Institutes of Allergy and Infectious Diseases (NIAID) which is to conduct and support basic and applied research to better understand treat and ultimately prevent infectious immunologic and allergic diseases.


application_id: 8890631
project_number: 5F31AA022263-02
project_title: Effects of alcohol and the environment on driving ability in high-risk drivers
administering_ic: NIAAA
award_notice_date: 2015-06-24
opportunity_number: PA-11-111
application_type: 5
activity_code: F31
ic: AA
serial_number: 022263
program_official: BLOSS, GREGORY
project_start_date: 2014-07-01
project_end_date: 2016-06-30
study_section: Epidemiology, Prevention and Behavior Research Study Section[AA-2]
contact_pi_person_id: 14733432
contact_pi: ROBERTS, WALTER MCRAINEY
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alcohol-impaired driving is a significant problem in the United States. The proposed research seeks to expand our understanding of the factors leading people to drive while impaired by testing the acute effects of alcohol in a group characterized by increased risk for alcohol-intoxicated driving (i.e. adults with ADHD). The project will examine alcohol responses in this group with a focus on how atypical alcohol responses may place this group at heightened risk to drive after drinking. First the proposed research will examine how alcohol interacts with environmental factors to impair driving ability in
adults with ADHD. Previous research has shown that the effects of alcohol are more pronounced in certain environmental circumstances such as the presence of visual distraction or motivational conflict. These findings are important because such environmental circumstances are quite common outside of the laboratory so they may explain why some drivers show appreciable impairment even at blood alcohol concentrations (BACs) below the legal limit of intoxication (i.e. 80mg/100ml). The proposed research will examine the interaction of alcohol intoxication and environmental factors in a group of high-risk drinkers (i.e. adults wih ADHD) under several doses of alcohol. This will test whether high-risk environmental circumstances cause adults with ADHD to show heightened behavioral impairment under alcohol even at BACs below the legal limit of intoxication. Second the proposed project will examine whether adults with ADHD overestimate their ability to drive after consuming alcohol. Previous research has shown that subjective evaluation of impairment informs people's decisions to drive after drinking. It is also well known that individuals with ADHD show impaired self-evaluation processes so they may underestimate the degree to which alcohol impairs their driving ability (Knouse et al. 2005; Weafer et al. 2008). Further they may not perceive how driving in high-risk scenarios exacerbates their level of behavioral impairment. These specific aims will be achieved by examining the interactive effects of alcohol and environmental factors on objective and perceived driving ability in adults with and without ADHD.

project_terms:
Acute;Address;Adolescent;Adult;Affect;Alcohol abuse;Alcohol consumption;Alcoholic Intoxication;Alcohols;Appointment;Attention deficit hyperactivity disorder;Automobile Driving;Behavior;Blood alcohol level measurement;Cellular Phone;Characteristics;Conflict (Psychology);Disinhibition;Dose;Environment;Environmental Risk Factor;Evaluation;Impairment;Impulsivity;Incidence;Individual;Intoxication;Laboratories;Legal;Light;Limb structure;Modeling;Motor Vehicles;Pattern;Performance;Population;Positioning Attribute;Process;Relative (related person);Reporting;Research;Risk;Risk Factors;Safety;Speed (motion);Sum;Testing;Time;United States;Visual;alcohol effect;alcohol response;alcohol risk;behavioral impairment;distraction;drinking;driving under influence;fitness;high risk;impaired driving performance;inattention;peer;public health medicine (field);public health relevance;response;simulation;skills;trafficking;vehicular accident

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed project will examine how characteristics of the environment alter the effects of alcohol on driving ability in adults with and without ADHD. The project will also examine the degree to which adults with ADHD underestimate the degree to which alcohol has impaired their behavior which may increase their risk of driving after drinking.


application_id: 8890528
project_number: 1R21NS088608-01A1
project_title: Optogenetic Mapping of Adult Newborn Neuron Projections
administering_ic: NINDS
award_notice_date: 2015-01-26
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: NS
serial_number: 088608
suffix: A1
program_official: WHITTEMORE, VICKY R
project_start_date: 2015-02-01
project_end_date: 2017-01-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 1911523
contact_pi: SMITH, BRET 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
project_abstract:
DESCRIPTION (provided by applicant): Over 2 million people in the United States have experienced unprovoked seizures or been diagnosed with epilepsy. In approximately 25% of cases seizures are refractory to medical therapies. Inability to effectively treat epilepsy reflecs a lack of understanding of the basic mechanisms of this disorder. Up to 50% of traumatic brain injury survivors develop epilepsy. Posttraumatic epilepsy (PTE) is associated with alterations in hippocampal circuits including cell loss and reactive plasticity. In the mammalian brain there is continual generation of new neurons in a few key brain regions throughout adulthood. This process referred to as adult neurogenesis represents a form of experience-dependent plasticity that is believed to support normal brain function. Brain insults including traumatic bran injury seizures and stroke are associated with increases in hippocampal adult neurogenesis and abnormal integration of adult-born neurons within hippocampal circuitry may provide a substrate for hyperexcitable circuits that contribute to seizures. Epilepsy is associated with the emergence of adult-born dentate granule cells (DGCs) that display abnormal dendritic fields and axons that may project to unexpected targets. Adult-born DGCs are associated with spontaneous seizures in experimental epilepsy and blockade of adult neurogenesis reduces spontaneous seizure expression in an animal model of PTE. Despite these reports inherent limitations of the techniques used have prevented the characterization of functional cellular connections formed by adult-born neurons with their synaptic targets. This proposal aims to develop a new technique to selectively label and stimulate newly-born neurons in the adult brain and then use this technique to assess functional outputs of hippocampal adult-born neurons in a mouse model of PTE. Work here aims to: 1) Selectively target expression of channelrhodopsin (ChR2) in adult-born progenitor cells based on their tamoxifen-inducible expression of nestin using Nestin-Cre mice. Nestin-Cre mice will be administered with a Cre-inducible adeno-associated virus (DIO-AAV) with double- floxed reverse cassettes containing channelrhodopsin (ChR2) and the fluorescent report mCherry (abbreviation: ChR2-mCherry; construct: pAAV-Ef1a-DIO-hChR2(H134R)-mCherry-WPRE-pA); and 2) Use blue-light stimulation parameters to activate adult-born neurons and drive signaling to their postsynaptic targets. Whole-cell patch-clamp recordings will be performed on DGCs in hippocampal slices from Nestin-Cre mice that have received injections of the ChR2-mCherry construct to describe the functional projections formed by adult-born neurons after brain injury. Improved understanding of how adult-born neurons incorporate into neural networks and signal during normal and PTE states will help define their relevance as therapeutic targets and will also provide new context for evaluation of clinically available drugs that have documented effects on adult-born cells.

project_terms:
Abbreviations;Adult;Animal Model;Axon;Behavior assessment;Biological Neural Networks;Brain;Brain Injuries;Brain region;Cells;Dependovirus;Development;Diagnosis;Disease;Employee Strikes;Epilepsy;Epileptogenesis;Evaluation;Experimental Models;Frequencies (time pattern);Generations;Hilar;Hippocampus (Brain);Injection of therapeutic agent;Injury;Intermediate Filament Proteins;Label;Laboratories;Light;Maps;Measures;Medical;Methodology;Methods;Mus;Neuronal Plasticity;Neurons;Newborn Infant;Outcome Measure;Output;Pharmaceutical Preparations;Population;Process;Property;Refractory;Reporting;Role;Seizures;Services;Severities;Signal Transduction;Slice;Stem cells;Stimulus;Survivors;Synapses;Tamoxifen;Techniques;Temporal Lobe Epilepsy;Testing;Transgenic Organisms;Traumatic Brain Injury;United States;Work;adult neurogenesis;base;calretinin;cell preparation;controlled cortical impact;experience;fundamental research;gene therapy;granule cell;improved;in vivo;injured;mossy fiber;mouse model;nerve stem cell;nestin protein;neural circuit;neurogenesis;neurotransmission;newborn neuron;optogenetics;patch clamp;postsynaptic;prevent;public health relevance;recombinase;response;selective expression;stroke;therapeutic target;vector;voltage

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The continual generation of new neurons in select regions of the adult brain a process referred to as adult neurogenesis is a form of experience-dependent neural plasticity that may critically contribute to posttraumatic epilepsy but remains poorly understood. This proposal aims to develop a new methodology to study functional projections of adult-born neurons by inducing their selective expression of channelrhodopsin (ChR2) allowing their activation and synaptic effects on downstream targets in order to determine how they contribute to neural circuitry. Comparisons of how adult-born neurons incorporate into local neural networks in normal states and after brain injury that leads to epilepsy will provide information that will help define the role of adult neurogenesis in brain plasticity during epileptogenesis and the relevance of modulating neurogenesis as a therapeutic target.


application_id: 8890026
project_number: 5R01AG038651-05
project_title: Role of impaired cognitive states & risk factors in conversion to mixed dementias
administering_ic: NIA
award_notice_date: 2015-07-03
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AG
serial_number: 038651
program_official: ANDERSON, DALLAS
project_start_date: 2011-09-01
project_end_date: 2018-01-31
study_section: Neurological, Aging and Musculoskeletal Epidemiology Study Section[NAME]
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
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 ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-15
project_abstract:
DESCRIPTION (provided by applicant): Population demographics suggest that with the expected dramatic increase in age-associated dementias a public health crisis is looming. Current emphasis is on disease prevention with a focus on elderly individuals who express some cognitive impairment. We propose to identify authoritatively the risk and protective factors for cognitive decline in older persons. We have shown how to define these impaired states retrospectively how to account for reverse transitions how to distinguish prevalence from incidence and how to account for competing risks by using a unique statistical (Markov) model. But sufficient longitudinal and neuropathological data is currently not available to distinguish among different types of dementia. No single Alzheimer's Disease Center (ADC) or cooperative study has an adequate sample size to reliably track transitions to dementia and differentiate Alzheimer's disease (AD) from other prevalent brain diseases that include vascular dementia (VaD) and Lewy body disease (LBD). This project will pool data from six well established longitudinal cohorts to identify risk factors for (1) preservation of intact cognition in those meeting neuropathological criteria for varying types of dementia and MCI and (2) specific forms of dementia (clinical and neuropathological). This will improve our understanding of intervening impaired states and factors that promote resistance to clinical symptoms despite the presence of neuropathology. These considerations lead to the specific aims below. Specific Aim 1: To merge databases from six large projects that follow cohorts of cognitively intact subjects to dementia for the purpose of rigorous statistical biologically-informed analyses that accentuate longitudinal follow-up: BRAiNS (University of Kentucky) Nun Study (University of Minnesota) Memory and Aging Project (Washington U) Kuakini Honolulu-Asia Aging Study Religious Orders Study (ROS Rush Medical University) and the OHSC ADC (Oregon Health & Science University). The database would be made publicly accessible. Specific Aim 2: To identify appropriate intervening states between intact cognition and dementia based on periodic assessments of cognition and functional skills from data collected at these centers. Specific Aim 3: To study transitions and associated risk factors (e.g. genetic medical time in an impaired state) using novel statistical methods. Specific Aim 4: To standardize the neuropathological findings across databases (including quantitative neuropathological assessments) to enable the analysis of novel pathogenetic determinants of outcomes. This aim allows us to evaluate how actual brain pathology (e.g. microinfarcts Lewy bodies hippocampal sclerosis and mixed pathologies) relates to antemortem states in the subset of participants coming to autopsy. This aim could support proposed revisions of current neuropathological and clinical research diagnostic criteria in dementia and preclinical dementia conditions.

project_terms:
Accounting;Age;Aging;Alzheimer's Disease;Americas;Asia;Autopsy;Biological Markers;Biological Preservation;Brain Diseases;Brain Pathology;Caring;Clinical;Clinical Data;Clinical Research;Clinical assessments;Cognition;Cognitive;Cohort Studies;Communities;Complement;Complex;Consensus;Data;Databases;Dementia;Diagnostic;Disease;Elderly;Epidemiology;Evaluation;Funding;Gray unit of radiation dose;Health Care Costs;Health Sciences;Hippocampus (Brain);Impaired cognition;Incidence;Individual;Investigation;Kentucky;Lead;Lewy Bodies;Lewy Body Disease;Magnetic Resonance Imaging;Measures;Medical;Medical Genetics;Memory;Meta-Analysis;Minnesota;Modeling;Multicenter Studies;National Institute on Aging;Oregon;Outcome;Participant;Pathology;Patients;Population;Prevalence;Prevention strategy;Registries;Religion and Spirituality;Research;Research Personnel;Resistance;Resources;Risk;Risk Factors;Role;Sample Size;Sampling;Sclerosis;Series;Statistical Methods;Statistical Models;Symptoms;Time;United States National Institutes of Health;Universities;Validation;Vascular Dementia;Washington;aging brain;base;cohort;cooperative study;cost;demographics;design;disorder prevention;experience;follow-up;improved;innovation;insight;markov model;meetings;mild cognitive impairment;mixed dementia;neuropathology;novel;pre-clinical;prevent;prevention clinical trial;public health medicine (field);skills;treatment strategy

public_health_relevance:
With the graying of America the cost of caring for demented elderly will rise substantially in the next few decades. Current emphasis is on preventing this disease. This project will identify risk factors for various forms of dementia as well as impaired states that precede this disease.

other_pis:
KAYE, JEFFREY A;LIM, KELVIN O.;LIPTON, RICHARD B.;MASAKI, KAMAL ;SCHMITT, FREDERICK ;TYAS, SUZANNE LEIGH;XIONG, CHENGJIE ;YU, LEI


application_id: 8889891
project_number: 2R01AI051517-11A1
project_title: Paramyxovirus F protein mediated membrane fusion
administering_ic: NIAID
award_notice_date: 2014-12-29
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: AI
serial_number: 051517
suffix: A1
program_official: CHALLBERG, MARK D
project_start_date: 2002-05-15
project_end_date: 2019-12-31
study_section: Virology - B Study Section[VIRB]
contact_pi_person_id: 8106840
contact_pi: DUTCH, REBECCA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Compelling work in the last decade has shown that transmembrane domains (TMDs) once thought to function solely as hydrophobic anchors are central players driving cellular protein oligomerization cell signaling and regulation of channel
function. However the role of TMDs in viral glycoprotein stability and function remains poorly understood. During the previous funding period our studies of the Hendra virus (HeV) fusion (F) protein identified key roles for TMDs in regulation of F protein stability cellular trafficking ad fusion function. Our novel studies utilizing sedimentation equilibrium (SE) analysis established that F protein TMDs efficiently trimerize separate from the rest of the protein. Altered TM-TM association was found for multiple functionally important mutations implicating TM-TM interactions in regulation of F protein folding and function. The long-term goal of our research is
to understand the molecular details and regulation of membrane fusion promoted by the paramyxovirus F proteins. The overall hypothesis of this proposal is that interactions of the TMD with itself and the lipid environment are critical for fusion protein stability and function makin these interactions potential targets for antiviral therapeutics. To test this important hypothesis
we will pursue three specific aims. First we will define key elements driving F protein TM-TM interactions including defining the role of a L/I heptad in TM-TM association and Hendra F protein stability. Second we will determine how the TMD affects fusion triggering and promotion of membrane fusion with a focus on the role of C-terminal -branched residues and a determination of the conformational changes that can occur when TM-TM interactions cannot be released. Third we will dissect the role of the lipid environment in prefusion F stability in the context of cellular and viral membranes. These important experiments will provide critical new insight into the role of TMDs in regulation of F protein stability and fusion promotion.

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


application_id: 8889813
project_number: 1K23DC014074-01A1
project_title: Promoting Early Diagnosis of Congenital Hearing Loss through Patient Navigation
administering_ic: NIDCD
award_notice_date: 2015-02-27
opportunity_number: PA-14-049
application_type: 1
activity_code: K23
ic: DC
serial_number: 014074
suffix: A1
program_official: RIVERA-RENTAS, ALBERTO L
project_start_date: 2015-03-01
project_end_date: 2018-02-28
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 11512687
contact_pi: BUSH, MATTHEW LEE
other_pis: Not Applicable
congressional_district: 06
department: OTOLARYNGOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): With the incidence of approximately 1.5 per 1000 births pediatric hearing loss is the most common neonatal sensory disorder in the United States. During the early years of life the sense of hearing is vital for the optimal development o speech language and cognition. Deafness in early childhood can result in lifelong learning delay and disability leading to adulthood challenges in education employment and social life. The economic costs of hearing loss and impaired language development are substantial. Early identification and intervention can prevent these adverse economic educational and social consequences. National standards dictate that infants who are deaf or hard of hearing should be diagnosed by 3 months of age and subsequent intervention services should be initiated no later than 6 months of age. Unfortunately 24% of infants have no diagnostic testing after abnormal infant screening and 29% of children with hearing loss are not enrolled in intervention services.1 Children from rural Appalachia and economically depressed regions have poor adherence to follow-up testing and are often delayed in diagnosis and treatment of pediatric hearing loss.2 The process of obtaining timely hearing health care for infants is complex and many factors such as communication breakdowns lack of decisional support and poor care coordination contribute to the disparity. Early infant hearing detection and intervention (EHDI) i coordinated on a state level and in spite of multiple initiatives to decrease EHDI non-adherence there is no established method to address this problem. In fact there is no evidence-based research that addresses the effectiveness of initiatives designed to decrease non-adherence for diagnosis or intervention.3 The research proposed in this application seeks to rectify this health disparity by addressing non-adherence and delays in the EHDI process during the first year of life through a novel intervention involving a patient navigator program (PNP). Navigators are trained healthcare workers who educate patients on health conditions and healthcare systems and expeditiously facilitate adherence to complex healthcare. PNPs have successfully decreased non- adherence to clinical testing and treatment in other health areas (e.g. cancer) but have not been utilized in the EHDI field. The hypothesis of this study is that a PNP will significantly decrease non-adherence to and timing of diagnostic audiological testing and intervention for infant hearing loss. The specific aims are to 1) examine the efficacy of a PNP to decrease non-adherence to and timing of recommended infant audiological testing within 3 months after birth in Appalachian and non-Appalachian participants 2) assess the efficacy of a PNP to decrease non-adherence to and timing of hearing aid fitting in infants diagnosed with hearing loss and 3) determine the maternal socioeconomic educational demographic and infant factors involved in non- adherence and delays to testing and treatment. We will accomplish Aim 1 by enrolling mother-child dyads in which the child fails newborn hearing screening into a randomized prospective study. The participants will be stratified into Appalachian and non-Appalachian based on county of residence and then within each stratum the subjects will be randomized into either the patient navigator group or the standard of care group. The navigator group will have weekly phone contact with a patient navigator after birth while the control group will receive the standard of care only and will have no contact with a navigator. Non-adherence to obtain audiological outpatient diagnostic testing before 3 months after birth (Aim 1) will be the primary outcome measure. Infants identified with hearing loss at our institution will be enrolled in Aim 2 and randomized into a patient navigator group or standard of care group similar to Aim 1. Non-adherence with fitting of hearing aids before 6 months of age will be the primary outcome for Aim 2. Secondary outcomes will include timing of diagnostic testing after birth (Aim 1) and the timing of hearing aid fitting after diagnosis (Aim 2. Aim 3 will characterize maternal and infant factors in non-adherence. The candidate is a clinician scientist at the University of Kentucky in the Department of Otolaryngology who has demonstrated commitment to a career in clinical and translational research. The mentors in this application Nancy Schoenberg Ph.D. Karl White Ph.D. Richard Kryscio Ph.D. will provide balanced training and guidance in the areas of health disparity infant hearing loss and intervention initiatives and clinical research design and implementation. The overall goal of this
K23 award is to provide the candidate with research and training activities that are focused on expediting diagnosis and treatment of infant hearing loss in the setting of health disparity. The training will expand the candidate's knowledge and experience with pediatric hearing health disparities research EHDI research and patient navigator integration and clinical trial design and analysis. The candidate is uniquely poised to investigate methods to expedite rural congenital hearing loss diagnosis and intervention. This application is intended to result in a research portfolio including subsequent R01 funding devoted to expediting hearing loss intervention in children who face barriers to care. The overall career goal of the candidate is to become an independently funded surgeon scientist focused on transforming the delivery of effective multidisciplinary hearing interventions. These goals are in line with NIH and NIDCD priority areas of improving diagnosis and treatment of hearing loss and developing evidence-based approaches that increase awareness access and affordability for those experiencing health disparities.

project_terms:
Address;Adherence (attribute);Adult;Affect;Age-Months;Appalachian Region;Area;Auditory;Awareness;Balance training;Behavioral;Birth;Caring;Child;Childhood;Clinical Research;Clinical Treatment;Clinical Trials Design;Cognition;Communication;Complex;Congenital Disorders;Control Groups;County;Data;Deafness;Decision Making;Depressed mood;Detection;Development;Diagnosis;Diagnostic;Diagnostic tests;Doctor of Philosophy;Early Diagnosis;Early Intervention;Early identification;Economics;Educational aspects;Effectiveness;Employment;Enrollment;Face;Family;Funding;Goals;Health;Health Personnel;Health Services Accessibility;Healthcare;Healthcare Systems;Hearing;Hearing Aids;Hearing Impaired Persons;Hearing Tests;Incidence;Infant;Infant Care;Institution;Intervention;Intervention Studies;Joints;Kentucky;Knowledge;Language;Language Development;Learning;Life;Literature;Malignant Neoplasms;Medical;Mentored Patient-Oriented Research Career Development Award;Mentors;Methods;Mothers;National Institute on Deafness and Other Communication Disorders;Nature;Neonatal;Newborn Infant;Otolaryngology;Outcome;Outcome Measure;Outpatients;Parents;Participant;Patients;Plant Roots;Process;Prospective Studies;Randomized;Recruitment Activity;Research;Research Activity;Research Design;Rural;Rural Health;Scientist;Sensory;Sensory Disorders;Services;Speech;Surgeon;Telephone;Testing;Therapeutic Intervention;Time;Training;Training Activity;Translational Research;Trust;United States;United States National Institutes of Health;Universities;base;career;design;disability;early childhood;economic cost;effective therapy;evidence base;experience;follow-up;health disparity;hearing impairment;hearing screening;improved;multidisciplinary;novel;prevent;primary outcome;programs;public health relevance;research clinical testing;residence;screening;secondary outcome;service intervention;social;socioeconomics;sound;standard care;standard of care;success;theories;therapy development

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Hearing loss is the most common sensory congenital disorder and this condition is diagnosable and treatable. Children who are born with hearing loss must undergo several hearing tests to diagnose the condition and many families are delayed in receiving this testing or never obtain the necessary testing and treatment. This research evaluates a new method for helping children with hearing loss obtain timely care by using a patient navigator which is a trusted layperson who provides educational support for parents of these children by making a personal connection.


application_id: 8889261
project_number: 5R01EY023561-02
project_title: Mid-level mechanisms of surface and binocular perception
administering_ic: NEI
award_notice_date: 2015-07-21
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: EY
serial_number: 023561
program_official: WIGGS, CHERI
project_start_date: 2014-08-01
project_end_date: 2019-07-31
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 1965646
contact_pi: HE, ZIJIANG
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
3-Dimensional;Affect;Aging;Amblyopia;Attention;Behavioral;Clinical;Code;Color;Complex;Crowding;Diagnosis;Ensure;Environment;Eye;Feedback;Frequencies (time pattern);Functional disorder;Goals;Grant;Health;Human;Image;Knowledge;Link;Location;Measurement;Motion;Occupations;Ownership;Pattern;Perception;Perceptual learning;Play;Process;Property;Protocols documentation;Psychophysics;Research;Resolution;Retinal;Role;Space Perception;Strabismus;Surface;System;Testing;Texture;Time;Training;Visual;Visual Perception;Visual system structure;base;detector;falls;feeding;improved;luminance;neurophysiology;object perception;object shape;operation;research study;visual information;visual process;visual processing;visual stimulus


application_id: 8888742
project_number: 1R01HL124170-01A1
project_title: Shear-Induced Hemostatic Dysfunction and Bleeding in CF-VAD Patients
administering_ic: NHLBI
award_notice_date: 2015-04-20
opportunity_number: PAR-13-137
application_type: 1
activity_code: R01
ic: HL
serial_number: 124170
suffix: A1
program_official: LEE, ALBERT
project_start_date: 2015-04-20
project_end_date: 2019-03-31
study_section: Clinical and Integrative Cardiovascular Sciences Study Section[CICS]
contact_pi_person_id: 7119111
contact_pi: WU, ZHONGJUN JON
other_pis: GRIFFITH, BARTLEY P
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: ORGANIZED RESEARCH UNITS
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Heart failure (HF) affects 5.1 million adult patients in the US. About 50% of people diagnosed with HF will die within 5 years. Ventricular assist device (VAD) therapy has evolved into a standard therapy for patients with advanced HF not only as a bridge to myocardial recovery or cardiac transplantation but also as a destination therapy. The recent data suggest that approximately 85 and 75% of patients supported with continuous flow VADs (CF-VADs) will survive at 12 and 24 months respectively. These survival rates are approaching those of heart transplant patients. However bleeding has become a significant problem for the CF-VAD therapy. Thus it is critical to understand the bleeding risk of CF-VAD support and their underlying mechanistic origins. Given the potential of the CF-VAD therapy for end-stage HF patients and the need to reduce significant device associated complications we propose to conduct a series of clinical biological and bioengineering experiments to seek a better understanding of shear-induced hemostatic dysfunction (SIHD) and bleeding in HF patients supported with CF-VADs and their link to blood flow dynamics of CF-VADs and pre-existing hemostatic disorder of HF patients. Further we seek to uncover the underlying molecular mechanisms of SIHD for better medical management and to create a database of SIHD for VAD design refinements. Three specific aims of the proposed project are: (1) To determine temporal changes of biomarkers of SIHD in HF patients prior to and during CF-VAD support and to link these changes to post-implant bleeding events; (2) To model shear stress indices (SSI) of CF-VADs and link them to measured biomarkers of SIHD and Bleeding in CF- VAD patients with consideration of pre-existing hemostatic disorder and patient-specific SIHD sensitivity to SSI prior to receiving a CF-VAD; and (3) To elucidate underlying molecular mechanisms of SIHD associated with CF-VADs and to establish a database of biomarkers of SIHD for VAD design improvement. Altogether a combination of clinical hematology biological as well as bioengineering approaches will be used to derive the basic knowledge behind bleeding complications and to investigate the influence of device-specific non- physiological fluid
dynamic characteristics like shear stress and exposure time on SIHD. The successful completion of this project will create a new knowledge of bleeding associated with CF-VADs. The new knowledge can be used by clinicians to refine bleeding risk stratification in patients for the improved quality of life and by engineers to develop less traumatic next generation biocompatible VADs.

project_terms:
Adult;Adverse event;Affect;Annual Reports;Biocompatible;Biological;Biological Markers;Biomedical Engineering;Blood;Blood Coagulation Factor;Blood Platelets;Blood flow;Blood specimen;Cells;Characteristics;Clinical;Clinical Management;Data;Databases;Destinations;Device Designs;Device or Instrument Development;Devices;Diagnosis;Disease;Elements;Engineering;Environment;Event;Failure (biologic function);Functional disorder;Goals;Heart Transplantation;Heart failure;Hematology;Hemorrhage;Hemostatic Agents;Hemostatic function;Implant;Infection;Injury;Interagency Registry for Mechanically Assisted Circulatory Support;Knowledge;Laboratories;Link;Liquid substance;Logistic Regressions;Measures;Mechanics;Medical;Modeling;Molecular;Molecular Profiling;Myocardial;Organ failure;Outcome;Patients;Physiological;Plasma;Quality of life;Recovery;Research;Risk;Series;Staging;Stratification;Structure;Survival Rate;Technology;Testing;Thrombosis;Time;Transplant Recipients;Ventricular;Weight;base;clinically significant;design;experience;hemodynamics;implantation;improved;indexing;next generation;novel;public health relevance;research study;shear stress;success;ventricular assist device

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Heart failure (HF) affects 5.1 million adult patients in the US. About 50% of people diagnosed with HF will die within 5 years. Ventricular assist device (VAD) therapy has evolved into a standard therapy for patients with advanced HF not only as a bridge to myocardial recovery or cardiac transplantation but also as a destination therapy. Bleeding is a significant problem for the VAD therapy. The goal of this project is to seek a better understanding of shear-induced hemostatic dysfunction and bleeding in CF-VAD patients. This knowledge can be used by clinicians to match patient specific pre-implant blood profiles with predicted fluid dynamics of CF- VADs to mitigate bleeding risks in patients and by engineers to develop less traumatic next generation biocompatible VADs. A significant portion of the 250000 patients with advanced HF in the US will benefit from the improved VAD technology and clinical management.


application_id: 8888597
project_number: 1R01GM109195-01A1
project_title: Reconciling Nanoceria's Jekyll and Hyde Reputation Toward Safer Nanotherapy
administering_ic: NIGMS
award_notice_date: 2015-05-18
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: GM
serial_number: 109195
suffix: A1
program_official: LEWIS, CATHERINE D
project_start_date: 2015-06-01
project_end_date: 2019-05-31
study_section: Nanotechnology Study Section[NANO]
contact_pi_person_id: 7876821
contact_pi: YOKEL, ROBERT ALLEN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Nanomaterial technological development has been underway for decades. Only in the pastdecade has serious attention been paid to potential unwanted effects. Many nanomaterials donot readily dissolve or disintegrate in biological and environmental milieu. As a result theypersist for months to years where they are sequestered (in mammals mostly in mononuclearphagocyte system organs such as the liver spleen and bone marrow) often associated withinflammatory/oxidative stress responses including granuloma. These unwanted effects havebeen seen with nanoceria (nanoscale cerium dioxide). On the other hand nanoceria has beenshown to be an effective anti-inflammatory/antioxidant in numerous acellular cell and wholeanimal models of inflammation/oxidative stress. Nanoceria's pro- and antioxidant effects resultfrom its auto-catalytic redox behavior (Ce(III) oxidation to Ce(IV); Ce(IV) reduction to Ce(III)).Specific aim 1 will determine if nanoceria can produce inflammatory/pro-oxidant effects in theabsence of elevated inflammation/oxidative stress and anti-inflammatory/antioxidant effectswhen inflammation/oxidative stress is elevated and determine the lowest observed adverse andlowest observed beneficial doses. Several nanoceria will be studied. Initially we will focus on the5 and 30 nm ceria that we have extensively studied to understand their behavior in thepresence of elevated oxidative stress/inflammation. We will obtain from Sudipta Seal et al orprepare the ~ 8 nm ceria they are investigating and compare it to the 5 nm ceria forphysicochemical similarities/differences and determine its ability to produce the adverse effectswe have seen with the 5 nm ceria. If the 5 and 8 nm ceria are not significantly different we willcontinue this project with the 5 but not 8 nm ceria. Due to the very low oral and pulmonaryabsorption of nanomaterials nanoceria will be delivered intravenously to establish sufficientlevels in multiple organs to study its biodistribution persistence biotransformation and effects.Preliminary findings indicate that nanoceria undergoes some bioprocessing in mammals overmonths to a more stable form. This appears to occur via dissolution and formation of very smallnanoceria particles which have a greater surface Ce(III) enrichment; therefore expected to haveenhanced anti-inflammatory/antioxidant properties. This biotransformation suggests enhancedbenefit over time associated with nanoceria's persistence and bioprocessing. Specific aim 2 willidentify factors that contribute to nanoceria dissolution and precipitation and mediate itsbioprocessing and precipitation in the liver. The proposed studies will test the hypothesis thatthe same nanoceria can both increase and decrease inflammation/oxidative stress dependingon the initial level of stress identify nanoceria doses that maximize its efficacy relative to itsunwanted effects and provide insight into its biotransformation that may enable safer by designnanoceria for use as a therapeutic agent with prolonged anti-inflammatory/antioxidant activity.

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

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


application_id: 8888525
project_number: 1R01HL120507-01A1
project_title: Lipid phosphate phosphatase 3 as a novel atherosclerosis suppressor
administering_ic: NHLBI
award_notice_date: 2015-03-27
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: HL
serial_number: 120507
suffix: A1
program_official: HASAN, AHMED A K
project_start_date: 2015-04-01
project_end_date: 2019-03-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S.
other_pis: MORRIS, ANDREW J
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Acute myocardial infarction;Alleles;Arterial Fatty Streak;Atherosclerosis;Attenuated;Binding (Molecular Function);Biological Availability;Blood Cells;Blood Vessels;CCAAT-Enhancer-Binding Proteins;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Cell Proliferation;Cell Survival;Cell surface;Cells;Clinical;Complement;Coronary Arteriosclerosis;Coronary artery;Cultured Cells;Data Analyses;Deposition;Development;Developmental Process;Diagnosis;Disease;Drosophila genus;Employee Strikes;Enhancers;Enzymes;Event;Experimental Models;Family;Gene Expression;Genes;Genetic;Genetic Polymorphism;Genetic Transcription;Goals;Homologous Gene;Human;Human Genetics;Hyperplasia;Inflammatory;Injury;Introns;Investigation;Knowledge;Lipids;Lysophospholipids;Mass Spectrum Analysis;Mediating;Mediator of activation protein;Membrane;Molecular;Mortality Vital Statistics;Mus;Myocardial Infarction;Myocardial Ischemia;Phospholipids;Phosphoric Monoester Hydrolases;Physiological Processes;Positioning Attribute;Predisposition;Publishing;Reagent;Recording of previous events;Research;Research Project Grants;Resolution;Risk;Risk Factors;Role;Series;Signal Transduction;Single Nucleotide Polymorphism;Site;Site-Directed Mutagenesis;Smooth Muscle Myocytes;Stable Isotope Labeling;Stimulus;Testing;Therapeutic;Tissues;United States;Up-Regulation (Physiology);Variant;Variation (Genetics);Work;base;cardiovascular disorder risk;cell motility;disorder risk;extracellular;genetic variant;genome wide association study;improved;innovation;inorganic phosphate;insight;lipid mediator;lipid metabolism;lipid phosphate phosphatase;lysophosphatidic acid;macrophage;monocyte;mouse model;novel;novel therapeutics;oxidized low density lipoprotein;prevent;public health relevance;response;risk variant;tool;vascular inflammation


application_id: 8888163
project_number: 1R01AA023190-01A1
project_title: Mechanisms of Probiotics in Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2015-09-14
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: AA
serial_number: 023190
suffix: A1
program_official: WANG, JOE
project_start_date: 2015-09-15
project_end_date: 2020-08-31
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
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
project_abstract:
DESCRIPTION (provided by applicant): Severe alcoholic liver disease (ALD) has a high morbidity and mortality. Recent studies demonstrated that probiotics reversed alcohol-induced hepatic steatosis and inflammation and improved liver enzymes in animal models and in patients. Our laboratory showed that administration of a probiotic strain Lactobacillus rhamnosus Gorbach-Goldin (LGG) significantly improved liver enzymes and histology in alcohol treated mice. However the beneficial mechanisms of action of LGG either in viable bacteria form or in culture supernatant form are not clear. Our overall hypothesis is that LGG increases intestinal cathelicidin-related antimicrobial peptide (CRAMP) intestinal trefoil factor (ITF) expression and intestinal short chain fatty acids (SCFAs) leading to improved gut microbiota homeostasis intestinal barrier integrity and hepatic fat metabolism and these are likely the mechanisms by which LGG supplementation attenuates alcohol induced liver injury. We evaluate mechanisms of LGG action with 4 specific aims: Aim 1 will determine the role of CRAMP in the alcohol-mediated changes in gut microbiota and the role of CRAMP in the beneficial effects of LGG in experimental ALD. We will use CRAMP knockout mouse model of ALD to determine the role of CRAMP and LGG in alcohol-induced changes in gut microbiota using a metagenomic approach. Aim 2 will determine the role of LGG in promoting ITF expression and evaluate whether ITF positively modulates intestinal tight junctions as a mechanism for improved intestinal barrier integrity in experimental ALD. We will use an ITF-secreting goblet cell line to evaluate the role of LGG in the production of ITF and the role of ITF
in the modulation of intestinal tight junctions in an epithelial cell line. We will also examine th strategy that oral administration of recombinant human ITF attenuates alcohol-induced intestinal barrier and liver injury. Aim 3 will determine the role and mechanisms of butyric acid in the beneficial effects of LGG on intestinal tight junctions in experimental ALD. A metabolomics approach will be used to analyze the changes in SCFAs induced by alcohol and LGG intervention in the intestinal lumen. We will explore the potential mechanisms underlying the role of butyric acid in the regulation of occludin expression involving intestinal histone deacetylases (HDACs) miR122a and HIF--mediated signaling in vitro and in vivo. Aim 4 will evaluate and compare the effectiveness of LGG supernatant (LGGs) with viable LGG (vLGG) and heat-inactivated LGG (hiLGG) in the prevention/therapy of ALD in mouse models. These three LGG preparations will be tested for the effectiveness in the prevention/therapy of ALD in three experimental models of ALD of steatosis steatohepatitis and fibrosis. This study will have a major impact on the development of probiotic-based new therapeutic strategy for the prevention and treatment of ALD.

project_terms:
Acute;Alcohol abuse;Alcohol consumption;Alcohol-Induced Disorders;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Model;Attenuated;Bacteria;Bacterial Translocation;Butyric Acids;Carbohydrates;Cell Line;Chronic;Cirrhosis;Data;Development;Disease Progression;Effectiveness;Endotoxins;Enzymes;Epithelial;Epithelial Cells;Experimental Models;Fatty Liver;Fibrosis;Functional disorder;Goals;Goblet Cells;Health;Heating;Hepatic;Histology;Histones;Human;Hypoxia Inducible Factor;Immune response;In Vitro;Inflammation;Injury;Intervention;Intestinal Diseases;Intestines;Knockout Mice;Laboratories;Lactobacillus casei rhamnosus;Life;Liver;Mediating;Metabolism;Metagenomics;Morbidity - disease rate;Mortality Vital Statistics;Mucous body substance;Mus;Oral Administration;Outcome;Patients;Permeability;Pilot Projects;Plasma;Play;Preparation;Prevention strategy;Prevention therapy;Probiotics;Process;Production;Proteins;Recombinants;Regulation;Reporting;Role;Sampling;Signal Transduction;Steatohepatitis;Supplementation;Testing;Tight Junctions;Volatile Fatty Acids;Work;alcohol exposure;antimicrobial peptide;base;cathelicidin;cathelicidin antimicrobial peptide;comparative efficacy;compare effectiveness;feeding;gastrointestinal epithelium;gut microbiota;gut microflora;improved;in vivo;intestinal homeostasis;lipid metabolism;liver inflammation;liver injury;metabolomics;mouse model;novel therapeutics;occludin;prevent;protective effect;public health relevance;repaired;transcription factor;trefoil factor


application_id: 8887884
project_number: 1R01ES024478-01A1
project_title: The role of chromatin structural and epigenetic changes in arsenic-induced gene expression
administering_ic: NIEHS
award_notice_date: 2015-04-07
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: ES
serial_number: 024478
suffix: A1
program_official: TYSON, FREDERICK L
project_start_date: 2015-04-07
project_end_date: 2020-01-31
study_section: Special Emphasis Panel[ZRG1 DKUS-C (90)]
contact_pi_person_id: 10313148
contact_pi: FONDUFE-MITTENDORF, YVONNE NSOKIKA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Adhesions;Affect;Arsenic;Binding (Molecular Function);Biochemical;Bioinformatics;Biological Markers;Cell Adhesion;ChIP-seq;Chromatin;Chromatin Structure;Cues;DNA;DNA Binding;DNA Methylation;DNA Sequence;Data;Development;Diagnostic;Disease;Ensure;Epigenetic Process;Etiology;Eukaryotic Cell;Exposure to;Failure (biologic function);Gene Expression;Gene Expression Profile;Gene Expression Regulation;Gene Structure;Generations;Genes;Genetic Transcription;Genome;Goals;Growth and Development function;Health;Heavy Metals;Histones;Human;ITGB4 gene;In Vitro;Integrins;Lead;Location;Malignant Neoplasms;Malignant neoplasm of lung;Mammalian Cell;Mediating;Modification;Molecular Profiling;Molecular Target;NCAM1 gene;Neoplasm Metastasis;Nucleosomes;Organism;Outcome;Pathogenesis;Play;Positioning Attribute;Post-Translational Protein Processing;Prevention;Process;Promotor (Genetics);Proteins;Reactive Oxygen Species;Research;Risk;Role;Site;Specific qualifier value;Stimulus;Structure;System;To specify;Toxin;Water;World Health Organization;Zinc Fingers;base;carcinogenesis;cell transformation;chromatin protein;chromatin remodeling;differential expression;drinking;epigenome;epigenomics;epithelial to mesenchymal transition;genome-wide;in vivo;insight;metaplastic cell transformation;novel;novel diagnostics;novel therapeutic intervention;novel therapeutics;pollutant;public health relevance;response;single-molecule FRET;therapeutic target;tool;transcription factor;tumorigenesis


application_id: 8887765
project_number: 3P50DA005312-24S1
project_title: CDART - Center for Drug Abuse Research Translation
administering_ic: NIDA
award_notice_date: 2014-07-08
opportunity_number: PAR-10-189
application_type: 3
activity_code: P50
ic: DA
serial_number: 005312
suffix: S1
program_official: LLOYD, JACQUELINE
project_start_date: 1992-09-30
project_end_date: 2017-06-30
study_section: ZDA1-EXL-T(02)P
contact_pi_person_id: 1884463
contact_pi: BARDO, MICHAEL T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Drug abuse is a significant health-related problem and novel preventive intervention strategies are needed to address this problem. The Center for Drug Abuse Translation (CDART) is a prevention center responding to the NIDA "Center of Excellence" (PA-10-189). CDART proposes to determine the biologically-based facets of personality that increase risk for drug abuse and to test different preventive interventions that target these multiple risk-related facets. The central theme of CDART is that: (1) sensation seeking involves the reward relevant dopamine system and is most closely related to initiation of use; (2) disinhibition involves the inhibition-relevant prefrontal cortex and is most closely relatd to escalation of use; and (3) urgency or mood-based rash action involves the stress-relevant amygdala and is most closely related to problem use. CDART hypothesizes that prevention interventions may be maximally effective if they are tailored specifically to these risk-related facets. Three integrated research projects are proposed; one will use laboratory rats and two will use college students transitioning from adolescence to young adulthood. Using neurochemical and electrophysiological techniques in rats as well as neuroimaging techniques in humans the basic neural mechanisms that mediate these different risk-related facets will be assessed. Humans varying in risk-related facets also will be tested for their response to drugs of abuse under controlled laboratory conditions. This basic research will be translated into the application of prevention in small-scale efficacy trials. An especially innovative aspect of the proposed work is that it will test the hypothesis that individuals high in urgency will be more responsive to an intervention that promotes emotional self-regulation (i.e. mindfulness training) relative to an intervention tailored to high sensation seekers. In addition to the specific researc proposed in the 3 research projects an administrative core a statistics/psychometrics core and a training/pilot program core will further synergize the projects. An outreach component also is proposed to enhance the bi-directional transfer of information between basic scientists and prevention practitioners. The long-range goal is to improve the design and implementation of targeted anti-drug preventive interventions.

project_terms:
Address;Adolescence;Advocate;Amygdaloid structure;Basic Science;Cessation of life;Characteristics;Commit;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

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


application_id: 8887469
project_number: 1R21AI112618-01A1
project_title: Improving the lead rF1-V plague vaccine using an SA-4-1BBL/alum adjuvant platform
administering_ic: NIAID
award_notice_date: 2015-01-14
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: AI
serial_number: 112618
suffix: A1
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2015-01-15
project_end_date: 2016-12-31
study_section: Vaccines Against Microbial Diseases Study Section[VMD]
contact_pi_person_id: 1894295
contact_pi: SHIRWAN, HAVAL
other_pis: LAWRENZ, MATTHEW B
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Yersinia pestis is the causative agent of bubonic and pneumonic plague and a potential bioweapon. Currently there is not a vaccine available to protect the public from a potential epidemic or bioterrorism event. While Y. pestis infection can be treated with antibiotics the effective treatment window for primary pneumonic infection is very short (less than 24 hrs after exposure). Furthermore naturally acquired resistance to antibiotics has been reported and weaponized Y. pestis could likely be modified to be resistant to antibiotic treatment. Therefore the development of an efficacious plague vaccine is an important scientific endeavor and public policy goal. The current lead vaccine against plague is a subunit vaccine formulation consisting of a recombinant F1-LcrV fusion protein (rF1-V) adjuvanted with alum. This vaccine has proven effective in rodent models but has decreased efficacy in primate models and variable antibody production in clinical trials. Therefore while rF1-V appears to be an excellent vaccine candidate for plague it needs further improvement for a better immunogenicity profile. A series of studies have demonstrated the important and critical role of Th1 cellular responses in protection against plague. Inasmuch as alum is a Th2 adjuvant that primarily generates a robust humoral response we hypothesized that the lead rF1-V vaccine formulation can benefit from an adjuvant system that generates a balanced mixed humoral and Th1 cellular immune responses. Towards this end we propose the use an adjuvant platform that includes alum and the novel adjuvant SA-4-1BBL. SA-4- 1BBL is a recombinant form of costimulatory ligand 4-1BBL with demonstrated robust efficacy in generating Th1 immune responses. Preliminary data with the lead rF1-V vaccine support our hypothesis and show that the addition of SA-4-1BBL to the lead vaccine formulation generates a robust rF1-V-specific Th1 cellular immune response. In Aim 1 we will extend these preliminary studies by establishing the SA-4-1BBL dose required to produce an optimized Th1 response that complements the Th2 response elicited by alum. In Aim 2 we will directly test the hypothesis that the Th1 response elicited by SA-4-1BBL contributes to protection against plague. This will be accomplished by using a combination of immune cell depletion and mutant mouse backgrounds to define the contribution of different cell types and cytokines to vaccine-induced protection against plague. Together these studies will demonstrate that a combinatorial adjuvant platform using alum and SA-4-1BBL can produce a balanced and protective Th1/Th2 immune response. Furthermore in addition to improving the lead candidate plague vaccine and its development for NHP and human clinical trials the proposed adjuvant system may also be used as a platform to generate subunit vaccines and or improve the efficacy of the existing ones against a host of other intracellular pathogens.

project_terms:
Adjuvant;Adjuvanticity;Agonist;Alhydrogel;Antibiotic Resistance;Antibiotic Therapy;Antibiotics;Antibody Formation;Antigen Targeting;Antigens;Attenuated Live Virus Vaccine;Automobile Driving;Bacteria;Bacterial Vaccines;Bioterrorism;Bubonic Plague;CD8B1 gene;Cells;Chimeric Proteins;Clinical Trials;Complement;Data;Development;Dose;Drug Formulations;Epidemic;Equilibrium;Event;Extracellular Domain;FDA approved;Future;Generations;Goals;Human;Immune;Immune response;Immune system;Immunologic Adjuvants;Inactivated Vaccines;Individual;Infection;Infectious Agent;Interferon Type II;Lead;Ligands;Malignant Neoplasms;Modeling;Mus;Mutant Strains Mice;Plague;Plague Vaccine;Pneumonic Plague;Primates;Production;Public Policy;Recombinant Proteins;Recombinants;Relative (related person);Reporting;Rodent Model;Role;Safety;Series;Signal Transduction;Streptavidin;Subunit Vaccines;System;T cell response;T-Lymphocyte;Testing;Th1 Cells;Time;Treatment Efficacy;Tumor Necrosis Factor-alpha;Vaccination;Vaccines;Work;Yersinia pestis;aluminum sulfate;base;cell mediated immune response;cell type;combinatorial;cytokine;defined contribution;effective therapy;immunogenicity;improved;long term memory;mouse model;nonhuman primate;novel;novel vaccines;pathogen;pre-clinical;preclinical study;prophylactic;protective efficacy;public health relevance;receptor;response;vaccine candidate;vaccine development;vaccine-induced immunity

public_health_relevance:
PUBLIC HEALTH RELEVANCE: No vaccine for plague is available in the US to protect the public from a future epidemic or bioterrorism attack. The main objective of this proposal is to fas track the development of the existing lead plague vaccine candidate by using a novel adjuvant system to improve efficacy. These studies will establish the vaccine formulation and characterize the role of different components of the immune system in vaccine protection. These data will guide future tests in primate models and human clinical trials.


application_id: 8887320
project_number: 5R01CA188354-02
project_title: Non-peptide proteasome inhibitors as a novel anticancer agent
administering_ic: NCI
award_notice_date: 2015-05-19
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 188354
program_official: VERMA, SHARAD KUMAR
project_start_date: 2014-07-07
project_end_date: 2019-05-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 8152159
contact_pi: KIM, KYUNG BO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Active Sites;Antineoplastic Agents;Bioavailable;Bortezomib;Cancer Patient;Cancer cell line;Cell Line;Chemicals;Clinic;Clinical;Clinical Trials;Data;Dose;Drug Kinetics;Drug Stability;Drug Targeting;Drug resistance;Effectiveness;Enzyme Kinetics;Evaluation;FDA approved;Goals;Health;Hematologic Neoplasms;Human;In Vitro;Lead;Left;Libraries;Malignant Neoplasms;Malignant neoplasm of lung;Metabolic;Mind;Molecular;Multiple Myeloma;Mus;Oral;Patients;Penetration;Peptides;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Pre-Clinical Model;Predisposition;Property;Proteasome Inhibitor;Pyrazoles;Refractory;Relapse;Research;Resistance;Resistance development;Safety;Solid;Specificity;Staging;Structure-Activity Relationship;Therapeutic;Toxic effect;Translating;Velcade;Vertebral column;Work;Xenograft procedure;anticancer activity;base;cancer cell;cancer site;cell killing;chymotrypsin;cytotoxic;design;drug candidate;drug development;effective therapy;improved;in vitro testing;in vivo;in vivo Model;inhibitor/antagonist;intraperitoneal;molecular dynamics;multicatalytic endopeptidase complex;next generation;novel;novel therapeutics;outcome forecast;pharmacophore;pre-clinical;scaffold;screening;small molecule;success;virtual


application_id: 8887163
project_number: 5R01NS079507-05
project_title: Blood-brain barrier function in epilepsy: new targets for therapy
administering_ic: NINDS
award_notice_date: 2015-07-06
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: NS
serial_number: 079507
program_official: KLEIN, BRIAN
project_start_date: 2012-09-30
project_end_date: 2017-07-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 9358186
contact_pi: BAUER, BJOERN
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): There is a lack in understanding the mechanism responsible for blood-brain barrier dysfunction in epilepsy. This is a significant clinical challene since it prevents development of a therapy to overcome antiepileptic drug (AED) resistance and reduce seizure burden. Our long-term goal is to elucidate the mechanisms that regulate blood-brain barrier function which may lead to new strategies to treat epilepsy and other neuro- logical diseases. The objectives in this application are to identify the mechanism(s) by which seizures trig- ger barrier dysfunction and map key signaling proteins that can potentially serve as targets to repair the blood-brain barrier in epilepsy. Accomplishing these objectives is expected to increase AED brain uptake and reduce seizure burden. Our central hypothesis is that 1) glutamate activates the two-arm LOX/COX pathway thereby decreasing expression and activity of influx transporters and upregulating expression and activity of efflux transporters through the COX arm that 2) glutamate triggers development of barrier leakage through the LOX arm; and that 3) inhibiting cPLA2 to block both arms of the LOX/COX pathway reverses barrier dysfunction and thereby reduces seizure burden. The rationale for this research is that identifying the mechanism(s) responsible for changes in transporter expression and activity and barrier leakage will potentially provide new targets to improve epilepsy treatment and better control seizures. To accomplish the objectives of this application our hypothesis will be tested by pursuing three specific aims: 1) Determine the mechanism of seizure-induced changes of transporter expression and activity; 2) Deter- mine the mechanism of seizure-induced blood-brain barrier leakage; and 3) Develop a therapeutic strategy to reduce seizures in chronic epileptic rats. In Aim 1 we will block cPLA2 and COX-2 to reverse seizure-induced changes in transporter expression and activity. We will monitor influx and efflux transporter expression and activity and determine AED brain uptake. In Aim 2 we will inhibit cPLA2 and 5-LOX to map the signaling pathway causing seizure-induced barrier leakage. We will determine expression of tight junction proteins and matrix metalloproteases and assess barrier leakage. In Aim 3 we will evaluate the therapeutic benefit of cPLA2 inhibition on seizure burden in a rat chronic epilepsy model by determining influx and efflux transporter expression and activity assessing barrier leakage and monitoring seizure frequency duration and severity. The proposed research is innovative because it is focused on a new integrated strategy that considers blood-brain barrier transporters as well as barrier leakage and it is designed specifically to repair te barrier to overcome AED resistance and reduce seizures. The proposed research is significant because the expected outcomes will potentially provide a new strategy to improve pharmacotherapy in patients with resistant epilepsy. The proposed research is translational because cPLA2 inhibitors are under development and our strategy has potential to be translated into the clinic.

project_terms:
Antiepileptic Agents;Blood;Blood - brain barrier anatomy;Blood capillaries;Brain;Chronic;Clinic;Clinical;Data;Development;Disease;Drug resistance;Epilepsy;Extravasation;Frequencies (time pattern);Functional disorder;Glutamates;Goals;Health;Knowledge;LOX gene;Lead;Leukotrienes;Link;Maps;Matrix Metalloproteinases;Metalloproteases;Mining;Mission;Modeling;Molecular;Monitor;National Institute of Neurological Disorders and Stroke;Outcome;PTGS2 gene;Pathology;Pathway interactions;Patients;Pharmacotherapy;Proteins;Rattus;Research;Resistance;Seizures;Severities;Signal Pathway;Signaling Protein;Testing;Therapeutic;Tight Junctions;Translating;United States National Institutes of Health;Up-Regulation (Physiology);arm;capillary;design;glutamatergic signaling;improved;inhibitor/antagonist;innovation;nervous system disorder;novel strategies;prevent;protein expression;public health medicine (field);repaired;sis Genes;targeted treatment;therapeutic target;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it will significantly advance our understanding of blood-brain barrier function in neurological diseases and potentially provide new treatment opportunities for epilepsy. Thus the proposed research is relevant to the mission of the NIH/NINDS which is to develop fundamental knowledge that will help reduce the burden of neurological diseases in people worldwide.


application_id: 8887092
project_number: 5R01AA023681-02
project_title: Mechanisms for alcohol induced gut barrier dysfunction in ALD
administering_ic: NIAAA
award_notice_date: 2015-06-25
application_type: 5
activity_code: R01
ic: AA
serial_number: 023681
program_official: GAO, PETER
project_start_date: 2014-07-05
project_end_date: 2019-06-30
study_section: ZAA1-GG(50)P
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
It is increasingly recognized that gut flora and gut barrier function play a pivotal role in thepathogenesis of several forms of liver disease including ALD. Gut-derived endotoxins normally penetrate thegut epithelium in only trace amounts due to tightly regulated intestinal barrier function. However endotoxinleakiness is increased under pathological conditions including alcohol abuse. The barrier function ofintestinal epithelium Is provided in part by paracellular apical junction complexes including tight andadherens junctions and by a mucus layer. In our initial systems biology approach to ALD we found that intestinal trefoil factor (ITF) was by far themost altered (~50-fold down regulated) protein in the liver following chronic alcohol feeding in rats andsubsequent studies also showed marked down regulation of ITF mRNA and protein in the intestines ofalcohol fed mice. ITF plays a critical role in the formation and stabilization of intestinal mucus barrier andenhancement of rapid intestinal repair "restitution". Formation and restitution ofthe barrier is also dependenton uninterrupted mucosal blood flow. Intestinal epithelial cells are positioned between an anaerobic lumenand a highly metabolic lamina propria forming a steep physiologic oxygen gradient. Increased hypoxia-inducible factor (HIF) signaling represents a major adaptive response to hypoxic stress by upregulating avariety of gene products such as ITF and mucins to form an integrated epithelial barrier. Our preliminarystudies demonstrated that chronic alcohol administration decreases intestinal HIF-2a ITF and tight junctionprotein expression resulting in increased endotoxemia and ultimately liver injury. Moreover supplementationwith a probiotic strain Lactobacillus rhamnosus GG (LGG) increased intestinal HIF-2a and ITF expressiondecreased endotoxemia and attenuated alcohol induced liver injury. We hypothesize that alcohol exposurecauses detrimental metabolic changes favoring intestinal oxidative stress inflammation and alterations ofHIF responsive signaling with decreased ITF leading to intestinal barrier dysfunction blood endotoxemiaand ALD. We postulate that probiotic supplementation will attenuate alcohol-induced intestine and liverinjury in part by increasing HIF-mediated expression of mucus protective factors such as ITF in the intestine.We test our hypothesis with 4 specific aims using in vitro animal and human studies approaches. Ourultimate goal is the development of new therapies for ALD.RELEVANCE (See instructions):Alcohol overuse/abuse induces organ injury in multiple organs. This translational research project willexamine the mechanisms of the beneficial effects of probiotics on the intestine and the liver in anexperimental mouse model of alcoholic liver disease (ALD) and in mild human alcoholic hepatitis (AH).

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


application_id: 8886769
project_number: 1R01CA195573-01
project_title: Novel pRNA Nanoparticle Delivery as Directed Therapy for Colorectal Cancer Metastasis
administering_ic: NCI
award_notice_date: 2015-09-25
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: CA
serial_number: 195573
program_official: FU, YALI
project_start_date: 2015-09-25
project_end_date: 2020-08-31
study_section: Bioengineering, Technology and Surgical Sciences Study Section[BTSS]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: GUO, PEIXUAN ;THORSON, JON SCOTT
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):  Although progress has been made in survival of patients with earlier stage colorectal cancer (CRC) only minimal improvement has been noted in patients with systemic metastases (Stage IV disease). Current chemotherapeutic agents while highly effective at killing CRC cells are limited by their systemic toxicity. If advances ar to be made in the survival of cancer patients highly innovative strategies are required for more targeted delivery of anti-cancer agents directly to CRC metastases. Our ultimate translational goal is to develop a highly effective and less toxic approach to specifically deliver anti-cancer agents to CRC metastases. To achieve this goal we have assembled a multidisciplinary and highly collaborative team who are at the forefront of molecular signaling pathways in CRC CRC treatment modalities medicinal chemistry novel nanoparticle synthesis and delivery systems. Over the last two years we have made significant progress to achieve our goals: (i) using a novel three-way junction (3WJ) motif we have constructed thermodynamically and chemically stable three-branched RNA nanoparticles with an aptamer against receptors that can deliver a small molecule inhibitor or chemotherapeutic agent specifically to CRC metastases in the liver (ii) we have constructed a variety of RNA nanoparticles using the pRNA-3WJ motif as a scaffold and have demonstrated in critical experiments that the resulting RNA constructs retained their folding and independent functionalities for specific cell binding cell entry and cancer targeting
both in vitro and in vivo (iii) we have shown that the RNA nanoparticles remain intact after systemic injection into mice and strongly bind to tumors with little accumulation in normal organs or tissues; these RNA constructs are non- toxic non-immunogenic and display favorable pharmacological profiles in mice and (iv) we have demonstrated localized in vivo delivery of pRNA-3WJ to CRC xenografts and liver metastases. Thus the central hypothesis of our proposal is that CRC receptor-specific delivery of chemotherapeutic agents using our pRNA-3WJ nanoparticles will provide a safe effective strategy to selectively target and inhibit CRC metastasis. To address our hypothesis we have designed experiments with the following Specific Aims: 1) to construct pRNA-3WJ nanoparticles coupled with anti-cancer agents and analyze their stability cellular uptake and anti-proliferative effects in vitro; 2) to determine te pharmacokinetics stability safety and drug delivery of pRNA-drug conjugates in vivo; and 3) to evaluate the selective delivery and in vivo anti-tumor effect of pRNA- 3WJ nanoparticles coupled with anti-cancer agents. In summary our enthusiasm for our current proposal is driven not only by its inherent scientific importance but also by its translational potential clinical impact and the possibility to provide a more effective and less toxic delivery system targeting CRC metastases.

project_terms:
Address;Antineoplastic Agents;Binding (Molecular Function);Biodistribution;Biological Models;Cancer Cell Growth;Cancer Etiology;Cancer Patient;Cell Adhesion Molecules;Cell-Adhesion Molecule Receptors;Cells;Cessation of life;Clinical;Colorectal Cancer;Coupled;Disease;Distant;Drug Delivery Systems;Drug Kinetics;Early treatment;Epithelial Cells;Excision;Goals;Growth;Human;In Vitro;Injection of therapeutic agent;Intestines;Kentucky;Killings;Laboratories;Liver;Malignant Neoplasms;Metastatic Neoplasm to the Liver;Modality;Molecular;Mortality Vital Statistics;Motor;Mucous Membrane;Mus;Nanotechnology;Neoplasm Metastasis;Organ;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacologic Substance;Process;RNA;Research;Resistance;Safety;Signal Pathway;Staging;Submucosa;System;Technology;Tissues;Toxic effect;Tumor Tissue;Universities;Xenograft procedure;antitumor effect;aptamer;base;cancer cell;cancer therapy;chemotherapeutic agent;design;human FOLR1 protein;immunogenic;improved;in vivo;inhibitor/antagonist;innovation;metastatic colorectal;multidisciplinary;nanoparticle;novel;public health relevance;receptor;research study;scaffold;small molecule;targeted delivery;targeted treatment;tumor;uptake


application_id: 8886749
project_number: 2R01AG033649-06A1
project_title: A healthy brain aging strategy to restore insulin signaling and Ca homeostasis
administering_ic: NIA
award_notice_date: 2015-04-09
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: AG
serial_number: 033649
suffix: A1
program_official: WISE, BRADLEY C
project_start_date: 2009-08-01
project_end_date: 2020-03-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 8361727
contact_pi: THIBAULT, OLIVIER
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):    
Peripheral metabolic dysregulation appears to increase the risk for cognitive decline with aging and susceptibility to dementing neurodegenerative disorders such as Alzheimer's disease. However the pathways and mechanisms underlying the relationship between metabolic dysregulation and age-related cognitive impairment are not clearly defined. Here we propose that insulin resistance in the brain can destabilize tightly regulated processes which maintain normal calcium homeostasis in neurons resulting in neuronal dysfunction and impaired cognition. Age-related neuronal calcium dysregulation is a well-recognized mechanism contributing to neurologic dysfunction and cognitive decline and we and others have extensively characterized this dysfunction in brain structures important for learning and memory. Interestingly peripheral tissues that are insulin resistant also show calcium dysregulation and provide supporting evidence for a similar relationship in the brain. In the prior funding cycle we
identified a previously unrecognized link between metabolic dysregulation and altered calcium signaling in hippocampal neurons. Together these findings provide support for the notion that overcoming insulin resistance in the hippocampus with insulin-raising strategies will reestablish neuronal calcium homeostasis. Several innovative approaches will be used to increase brain insulin signaling in aging. Specifically we will 1) utilize intranasal insulin delivery to increas insulin availability at the brain insulin receptor in vivo 2) increase insulin receptor signaling n the brain via AAV-mediated expression of a constitutively active human insulin receptor mutant ( subunit) and 3) increase endogenous insulin receptor trafficking through the use of a novel pharmacologic strategy. Using these approaches in the F344 rat model of aging we will investigate cognitive functions using different behavioral paradigms. In hippocampal tissue from these animals we will use single cell electrophysiology/imaging to directly measure calcium status (recordings of calcium-dependent potentials and calcium imaging) and complement these studies with molecular/biochemical assays. To determine whether increasing insulin in the brain affects other pathways independent of Ca2+ we will also quantify p-Akt signaling tyrosine phosphorylation glucose homeostasis (glucose imaging) and adiponectin levels. Type 2 diabetes has reached epidemic proportions among older adults accounting for approximately 26 million people and a $175 billion dollar toll to our health care system (CDC statistics). Our studies are designed to determine whether enhancing insulin action in the brain reduces the burden of cognitive decline in aging and helps to maintain healthy cognitive function. The outcomes from our studies will inform related clinical studies and may have significant impact for the aging population especially for those at increased risk for neurodegenerative diseases such as Alzheimer's disease. This work is clinically-oriented and directly addresses one of the missions of the NIA by establishing novel targets for the treatment of cognitive decline and/or dementia in brain aging.

project_terms:
21 year old;Accounting;Address;Affect;Age;Age-associated memory impairment;Aging;Alzheimer's Disease;Animal Model;Animals;Area;Behavior;Behavioral;Behavioral Paradigm;Biochemical;Biological Assay;Brain;Calcium;Calcium Signaling;Cell membrane;Cells;Centers for Disease Control and Prevention (U.S.);Clinical Research;Complement;Dementia;Diabetes Mellitus;Disease;Dorsal;Drug Formulations;Elderly;Electrophysiology (science);Epidemic;Event;Exhibits;Functional disorder;Funding;Gap Junctions;Glucose;Healthcare Systems;Hippocampus (Brain);Homeostasis;Hypothalamic structure;Image;Imaging Techniques;Impaired cognition;Inbred F344 Rats;Insulin;Insulin Receptor;Insulin Resistance;Intervention;Kinetics;Learning;Ligands;Link;Measures;Mediating;Memory;Metabolic;Mission;Modeling;Modification;Molecular;Neurodegenerative Disorders;Neurologic Dysfunctions;Neuronal Dysfunction;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Outcome Measure;Pathway interactions;Patients;Peripheral;Physiological;Positioning Attribute;Predisposition;Process;Receptor Signaling;Regulation;Research;Research Design;Risk;Risk Factors;Role;Satiation;Signal Transduction;Slice;Structure;Synapses;Techniques;Testing;Time;Tissues;Tyrosine Phosphorylation;Viral;Visceral;Work;adeno-associated viral vector;adiponectin;age related;aged;aging brain;aging hippocampus;aging population;animal tissue;base;blood glucose regulation;clinically relevant;cognitive function;cognitive performance;cognitive process;feeding;human INSR protein;improved;in vivo;innovation;insight;insulin sensitivity;insulin signaling;male;molecular imaging;morris water maze;mutant;neuronal excitability;novel;novel therapeutics;pre-clinical;public health relevance;receptor;response;sensory cortex;sigma-2 receptor;statistics;trafficking;treatment strategy

public_health_relevance:
PUBLIC HEALTH RELEVANCE:    
Our work will test if the mechanism of insulin actions in the brain modulates calcium-related functions inside cells. We will focus on one area of the brain that is known for its role in memory
function the hippocampus. We propose new ways to increase insulin signals in the brain.


application_id: 8885911
project_number: 5R01NS045734-12
project_title: Vascular responses as therapeutic targets after SCI
administering_ic: NINDS
award_notice_date: 2015-07-15
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: NS
serial_number: 045734
program_official: JAKEMAN, LYN B
project_start_date: 2004-05-03
project_end_date: 2017-07-31
study_section: Special Emphasis Panel[ZRG1-BDCN-W(02)M]
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: HAGG, THEO
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The endoplasmic reticulum (ER) stress response (ERSR) is one of the major defense mechanisms that protect against cellular insult but if unchecked leads to apoptotic cell death. The ERSR has three arms initiated by PERK IRE1 ATF6 respectively. Preliminary data show the acute activation of all three ERSR signaling pathways in endothelial cells (ECs) after SCI. Most importantly we show that attenuation of PERK signaling in CHOP-/- (the downstream effector of PERK) mice or after i.v. salubrinal (which sustains protein synthesis inhibition) leads to enhanced functional recovery after SCI in WT mice. We found an acute vasoconstrictive phase following SCI and can enhance EC protection by the vasodilator nimodipine plus the vasoprotector glibenclamide in WT mice. Specifically Aim 1 will delineate the specific effectors that underlie ERSR-mediated EC death by PERK signaling. We will determine if reducing PERK or ATF4 signaling in ECs after SCI will enhance functional recovery after SCI. This will be done using available transgenic mice (Aim 1a) and siRNA methods (Aim 1b). We hypothesize that the earlier in the ERSR pathway that inhibition occurs the more extensive the vasoprotection and recovery. Aim 2 will characterize the acute activation profile of the ERSR in FACS purified ECs when one signaling pathway is deleted (Aim 2a) their effects on spinal cord microvasculature (Aim 2b) and the functional consequences (Aim 2c). Aim 3 will test whether EC rescue by ER stress inhibitors can be improved when combined with the vasodilators nimodipine or MgSO4 the mainstay treatments for CNS vasospasm. Aim 3a will optimize vasodilation protocols. Aim 3b will optimize treatment regimens for salubrinal and two chemical chaperones that influence ERSR signaling: TUDCA (in clinical trials for ALS) and PBA (FDA-approved). We will then test whether optimized vasodilation would further improve the efficacy of those drugs using both pharmacological and genetic approaches. Aim 3c will define determine the therapeutic window. Collectively the experiments outlined in these 3 Aims delineate a strategy to optimally inhibit ER stress in ECs to maximize functional recovery after SCI and determine whether this approach is clinically relevant.

project_terms:
Acute;Apoptosis;Apoptotic;Binding Proteins;Blood Vessels;Blood flow;CD47 gene;Cell Death;Cell Survival;Cells;Chemicals;Clinic;Clinical Trials;Cytoprotection;Data;Defense Mechanisms;Dimerization;Drug Kinetics;Drug usage;Endothelial Cells;Event;FDA approved;Funding;Genes;Glyburide;Goals;Grant;Hypoxia;Inflammation;Integrins;Ligands;Mediating;Methods;Molecular Chaperones;Mus;Nervous System Physiology;Nimodipine;Notch Signaling Pathway;Outcome;Oxidative Stress;Pathway interactions;Peptides;Pharmaceutical Preparations;Phase;Phosphorylation;Promotor (Genetics);Protein Dephosphorylation;Protein Synthesis Inhibition;Protocols documentation;Recovery;Recovery of Function;Role;Safety;Signal Pathway;Signal Transduction;Small Interfering RNA;Spinal Cord;Spinal cord injury;Stress Response Signaling;TNFRSF10B gene;Testing;Therapeutic;Therapeutic Agents;Thinking function;Thoracic spinal cord structure;Thrombospondin 1;Tissues;Transgenic Mice;Translations;Traumatic CNS injury;Treatment Protocols;Vascular constriction (function);Vasodilation;Vasodilator Agents;Vasospasm;Work;angiogenesis;arm;attenuation;biological adaptation to stress;clinically relevant;cytotoxic;endoplasmic reticulum stress;excitotoxicity;genetic approach;improved;inhibitor/antagonist;nervous system disorder;offspring;research study;response;tauroursodeoxycholic acid;therapeutic target

public_health_relevance:
This grant examines the role of the endoplasmic reticulum stress response a cellular defense mechanism induced in every spinal cord cell after SCI which if unchecked leads to cell loss after SCI causing the loss of neurological functions. Our previous data show the crucial role of endothelial cell death of blood vessels in the spinal cord in the ensuing secondary loss of spinal cord tissue. Using both genetic approaches and current FDA approved and/or in clinical trial drugs to rescue the endothelial cells we expect to identify new acute therapeutic targets that will hopefully extend beyond SCI to other CNS trauma and neurological disease treatment.


application_id: 8885876
project_number: 5R01HL109501-06
project_title: Mechanisms of cardiac Ca dysregulation and arrhythmias in ankyrin B deficiency
administering_ic: NHLBI
award_notice_date: 2015-06-17
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: HL
serial_number: 109501
program_official: LATHROP, DAVID A
project_start_date: 2011-09-01
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1-CVRS-F(02)M]
contact_pi_person_id: 9983033
contact_pi: DESPA, SANDA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Ankyrin B (AnkB) is an "adaptor" protein that anchors several membrane proteins to the cytoskeleton. AnkB deficiency emerged as an important pro-arrhythmic factor a few years ago when it was found that AnkB loss- of-function mutations generate human long QT syndrome type 4 (LQT4) the only LQT produced by alterations in a protein other than an ion channel. Besides LQT4 humans with AnkB loss-of-function mutations display a complex cardiac phenotype that also includes bradycardia stress-induced ventricular arrhythmias and sudden cardiac death. The mechanisms responsible for such a phenotype are largely unknown. AnkB protein expression and distribution are drastically altered in the infarct border zone after myocardial infarction (MI). This may result in a mechanism for post-MI remodeling and arrhythmogenesis similar to that found in patients with AnkB loss-of-function mutations. Direct interaction with AnkB is required for the membrane targeting and stability of the Na/Ca exchanger (NCX) and Na/K-ATPase (NKA) which are essential in the regulation of cardiac [Na]i and [Ca]i and thus contractility and potential for triggered arrhythmias. The severity of the human cardiac phenotype generated by various AnkB loss-of-function mutants directly relates to the inability of those mutants to target NCX and NKA correctly to the cardiac myocyte sarcolemma. Thus altered NCX and NKA expression and membrane distribution are key to the cardiac phenotype generated by AnkB loss-of-function. This phenotype is largely reproduced in mice heterozygous for a null mutation in AnkB (AnkB mice). Myocytes from AnkB mice show modestly reduced NCX and NKA protein expression predominantly at the T-tubules larger cellular and sarcoplasmic reticulum (SR) Ca load and increased frequency of early afterdepolarizations (EAD) and delayed afterdepolarizations (DAD). Despite its physiological and pathophysiological significance the role of AnkB in regulating cardiac [Ca]i and arrhythmogenesis is poorly understood. The overall goal of this proposal is to decipher the mechanisms responsible for altered cardiac Ca regulation and triggered arrhythmias induced by AnkB loss-of-function (inherited and acquired). We will combine measurements of [Na]i and [Ca]i (in the bulk and junctional cleft) patch-clamp and molecular biology techniques in isolated cardiac myocytes in three Specific Aims. First I will test several specific hypotheses aimed at understanding how AnkB affects intracellular Ca in the heart. Aim 2 will focus on the mechanisms responsible for the occurrence of early and delayed afterdepolarizations in myocytes with AnkB deficiency. In the final aim I will test the hypothesis that AnkB proteolysis by calpain and the ensuing remodeling in NCX and NKA is a more general mechanism for triggered ventricular arrhythmias. These studies will both advance our understanding of how AnkB affects cardiac [Ca]i regulation and will provide key mechanistic information that could lead to the development of new treatments for patients with ventricular arrhythmias associated with inherited or acquired AnkB loss-of-function.

project_terms:
ATP phosphohydrolase;Action Potentials;Adaptor Signaling Protein;Affect;Ankyrins;Arrhythmia;Bradycardia;Caffeine;Calpain;Cardiac;Cardiac Myocytes;Cations;Cells;Characteristics;Cleaved cell;Complex;Cytoskeleton;Death Sudden Cardiac;Dependence;Development;Frequencies (time pattern);Genetic;Goals;Heart;Human;Infarction;Inherited;Ion Channel;Ischemia;Lead;Long QT Syndrome;Measurement;Measures;Mediating;Membrane;Membrane Proteins;Messenger RNA;Molecular Biology Techniques;Mus;Muscle Cells;Myocardial Infarction;Myocardial dysfunction;Na(+)-K(+)-Exchanging ATPase;Patients;Phenotype;Physiological;Protein Isoforms;Proteins;Proteolysis;Regulation;Reperfusion Therapy;Role;Sarcolemma;Sarcoplasmic Reticulum;Severities;Stress;Testing;Time;Ventricular;Ventricular Arrhythmia;Western Blotting;Wild Type Mouse;Work;cell injury;density;immunocytochemistry;loss of function;loss of function mutation;mutant;novel;null mutation;patch clamp;protein distribution;protein expression;sensor;voltage

public_health_relevance:
The proposed work will identify the main factors responsible for altered Ca regulation and triggered ventricular arrhythmias generated by ankyrin B deficiency. This project will also determine to what extent calpain- mediated proteolysis of ankyrin B which occurs in pathophysiological conditions such as ischemia/reperfusion leads to a mechanism for cardiac dysfunction and arrhythmogenesis similar to that seen with genetic loss-of- function of ankyrin B. Thus these studies will both advance our understanding of how ankyrin B affects cardiac Ca regulation and will provide key mechanistic information that could lead to the development of new treatments for patients with ventricular arrhythmias associated with inherited or acquired loss-of-function of ankyrin B.


application_id: 8885293
project_number: 261201300013I-0-26100003-1
administering_ic: NCI
project_start_date: 2014-06-01
project_end_date: 2015-04-30
contact_pi_person_id: 12445564
contact_pi: TUCKER, THOMAS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_title:
IGF::OT::IGF 402 - NORTH AMERICAN ASSOCIATION OF CENTRAL CANCER REGISTRIES INC. (NAACCR); TECHNICAL SUPPORT FOR CANCER SURVEILLANCE; POP 07/01/2014-06/30/2014

project_abstract:
The Surveillance Epidemiology and End Results (SEER) Program was established by the National Cancer Institute (NCI) to collect and report periodically on population-based cancer incidence and survival data. It is a core component of the NCI's surveillance activities which provide information used for planning cancer control and research programs and for evaluating the impact of such programs on cancer rates. The SEER Program was initiated in 1972 in response to requirements of the National Cancer Program for assessing the magnitude of the cancer burden in the United States and for identifying factors related to cancer risk and/or patient survival. Objectives of the SEER Program include: 1. Assemble and report on a periodic basis estimates of cancer incidence. 2. Monitor annual cancer incidence trends to identify unusual changes in specific forms of cancer occurring in population subgroups defined by geographic demographic and social characteristics. 3. Provide continuing information on changes over time in extent of disease at diagnosis trends in therapy and changes in cancer patient survival. 4. Identify the occurrence of possible iatrogenic cancers i.e. cancers that are caused by cancer therapy. 5. Serve as a research resource to the National Cancer Institute and conduct studies dealing with current cancer control issues as well as issues related to the operation of the SEER Program which may lead to improved and/or more cost-effective operating procedures.

project_terms:
American;Cancer Burden;Cancer Control;Cancer Control Research Program;Cancer Etiology;Cancer Patient;Data;Diagnosis;Disease;Incidence;Lead;Malignant Neoplasms;Monitor;National Cancer Institute;National Cancer Program;Patients;Population;Procedures;Reporting;Resources;SEER Program;Social Characteristics;Subgroup;Time;Treatment-Related Cancer;United States;base;cancer risk;cancer therapy;cost effective;improved;neoplasm registry;operation;population based;programs;response;trend


application_id: 8885073
project_number: 2R01DK056132-12
project_title: Neural Circuitry in the Dorsal Vagal Complex
administering_ic: NIDDK
award_notice_date: 2015-02-16
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: DK
serial_number: 056132
program_official: HYDE, JAMES F
project_start_date: 2001-06-01
project_end_date: 2020-01-31
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 1911523
contact_pi: SMITH, BRET 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_terms:
Abdomen;Address;Affect;Animal Model;Area;Autonomic Dysfunction;Blindness;Blood Glucose;Brain;Brain Diseases;Brain Stem;Cell Nucleus;Chronic;Complex;Data;Dependence;Development;Diabetes Mellitus;Diabetic mouse;Disease;Dorsal;Functional disorder;Future;GABA Receptor;Gastrointestinal tract structure;Genetic Transcription;Glucose;Goals;Health;Heart Diseases;Hepatic;Homeostasis;Human;Hyperglycemia;Hyperinsulinism;Hypertension;Insulin;Insulin-Dependent Diabetes Mellitus;Knowledge;Liver;Maintenance;Mediating;Metabolic Control;Modeling;Modification;Molecular;Motor Neurons;Motor output;Mus;Nervous System Trauma;Neurons;Neurophysiology - biologic function;Non-Insulin-Dependent Diabetes Mellitus;Nucleus solitarius;Organ;Output;Pancreas;Pathology;Patients;Peripheral;Physiological;Play;Regulation;Relative (related person);Role;Slice;Staging;Stomach;Streptozocin;Symptoms;Synapses;System;Testing;United States;Vagus nerve structure;Viscera;Visceral;Whole Blood;base;blood glucose regulation;cell motility;diabetes mellitus therapy;diabetic;dorsal motor nucleus;gamma-Aminobutyric Acid;gastrointestinal;glucose metabolism;glucose production;mouse model;neural circuit;public health relevance;receptor;research study;response;stroke;trafficking;type I and type II diabetes;type I diabetic


application_id: 8883697
project_number: 5R01HL118474-03
project_title: Hyperamylinemia in Diabetic Heart Disease: Mechanisms Responses and Prevention
administering_ic: NHLBI
award_notice_date: 2015-07-10
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: HL
serial_number: 118474
program_official: BUXTON, DENIS B
project_start_date: 2013-08-23
project_end_date: 2016-07-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 9696701
contact_pi: DESPA, FLORIN
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): Increased secretion of amylin by pancreatic beta-cells (hyperamylinemia) is common in obese and insulin resistant patients coincides with hyperinsulinemia and promotes formation of toxic amylin oligomers. Oligomeric amylin induces beta-cell apoptosis contributing to the development of type-2 diabetes. Recent studies demonstrate that amylin oligomers also affect the vascular system kidneys and heart. Our data show large deposits of oligomerized amylin in failing hearts from obese and T2D patients but not in hearts from controls. Oligomeric amylin was found in myocyte injury areas suggesting a role in the mechanism of injury. Indeed our pilot study on a "humanized" rat model of hyperamylinemia (the HIP rat) indicates that amylin oligomers attach to cardiac myocytes and induce oxidative stress and Ca2+ dysregulation leading to diastolic dysfunction and hypertrophy. The pilot study also suggests that endogenous molecules with anti-aggregation properties such as plasmin and epoxyeicosanoids limit cardiac accumulation of amylin and its myopathic response. Based on these preliminary results our research proposal will test the hypotheses that 1) cardiac accumulation of oligomerized amylin accelerates diabetic heart injury by inducing sarcolemmal damage and oxidative stress and 2) limiting amylin deposition in the heart may reduce/ delay the onset of diabetic heart failure. These hypotheses will mechanistically be assessed by using transgenic rat models overexpressing either the amyloido- genic human amylin (HIP rats) or the non-amyloidogenic rat amylin isoform (UCD rats). Specifically planned studies will determine how accumulation of oligomerized amylin in the HIP rat heart a) disrupts sarcolemmal processes b) induces oxidative stress and myocyte Ca2+ dysregulation and c) activates Ca2+-mediated CaMKII-HDAC and calcineurin-NFAT hypertrophy signaling pathways. Based on the results of our pilot study cardiac dysfunction in HIP rats is expected to develop even in pre-diabetes as often observed in humans. In contrast our pilot study predicts that UCD rats matched for age and glucose but lacking cardiac amylin deposition may show signs of cardiac dysfunction after the onset of diabetes. Our research will also determine if disrupting deposition of oligomeric amylin in the heart and recovering sarcolemmal integrity improve cardiac function in the HIP rat model. This innovative concept will be explored in longitudinal studies using membrane sealants and scavengers of circulating amylin oligomers. Hence our research project proposes that amylin buildup is a key contributor to the multifactorial pathogenesis of diabetic heart injury and that mitigating amylin oligomer accumulation could delay the onset of diabetic heart failure. If our hypothesis of cardiotoxic amylin oligomer is proven then circulating amylin oligomers are a feasible therapeutic target to reduce diabetic heart injury.

project_terms:
Adjuvant;Affect;Age;Apoptosis;Area;Beta Cell;Binding (Molecular Function);Blood;Calcineurin;Cardiac;Cardiac Myocytes;Cardiotoxicity;Cell membrane;Cells;Data;Deposition;Development;Diabetes Mellitus;Diagnosis;Epidemic;Excretory function;Figs - dietary;Functional disorder;Glucose;Health;Heart;Heart Diseases;Heart Hypertrophy;Heart Injuries;Heart failure;Histone Deacetylase;Hormones;Human;Hyperinsulinism;Hypertrophy;Injury;Insulin;Insulin Resistance;Ion Channel;Ions;Kidney;Left;Lipid Peroxidation;Longitudinal Studies;Mediating;Membrane;Membrane Potentials;Metabolic syndrome;Mitochondria;Modeling;Muscle Cells;Myocardial;Myocardial dysfunction;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oligonucleotides;Onset of illness;Oxidative Stress;Pancreas;Pathogenesis;Pathway interactions;Patients;Pilot Projects;Plasmin;Poloxamer;Poloxamers;Prediabetes syndrome;Prevention;Process;Production;Property;Protein Isoforms;Rattus;Research;Research Project Grants;Research Proposals;Risk;Role;Sarcolemma;Signal Pathway;Solubility;Structure;Structure of beta Cell of islet;System;Testing;Therapeutic;Tissues;Transgenic Organisms;Vascular System;Ventricular;base;calmodulin-dependent protein kinase II;catalyst;diabetic;high risk;improved;in vivo;inhibitor/antagonist;innovation;islet amyloid polypeptide;overexpression;response;therapeutic target;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Obesity and type-2 diabetes have reached epidemic proportions in the US1 and are associated with a high risk of heart failure. The pathogenesis of heart dysfunction in obesity and T2D is multifactorial and not fully elucidated which makes diagnosis and treatment of diabetic heart disease challenging. Our study aims at understanding how hyperamylinemia a common condition in obese and insulin resistant patients promotes toxic accumulation of oligomerized amylin in the heart and how the buildup of amylin affects cardiac function. Planned studies also attempt to find therapeutic tools that can mitigate cardiac accumulation of oligomerized amylin and its deleterious effects. The focus is on modulating the endogenous system of scavenging the amylin oligomers circulating in the blood as a possible mean to reduce cardiotoxicity of hyperamylinemia. If our hypothesis of cardiotoxic amylin oligomer is proven then hyperamylinemia and the oligomerized amylin circulating in the blood will be feasible therapeutic targets to limit the risk of diabetic heart injury.


application_id: 8883529
project_number: 5R01EB019036-02
project_title: Cancer specific and organ-avoiding RNA architectures for quantitative imaging
administering_ic: NIBIB
award_notice_date: 2015-07-13
opportunity_number: PAR-13-185
application_type: 5
activity_code: R01
ic: EB
serial_number: 019036
program_official: RAMPULLA, DAVID
project_start_date: 2014-07-01
project_end_date: 2016-01-16
study_section: Special Emphasis Panel[ZRG1-SBIB-Z(58)R]
contact_pi_person_id: 1878565
contact_pi: GUO, PEIXUAN
other_pis: EVERS, BERNARD MARK;QUINN, THOMAS P.
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): Development of image-guided drug delivery systems for real-time monitoring quantifying and validating the delivery and therapeutic action is very important for both research and clinical applications. Various multifunctional nanoparticles of different materials have been investigated over the last decade as prospective imaging and therapeutic platforms; however effective strategies to quantitatively evaluate delivery of therapeutic payloads to tumors and metastatic cancer cells in vivo are challenging due to low efficiency in specific cancer targeting and non-specific trapping in vital organs such as liver an lungs. Our goal is to adopt an innovative RNA nanotechnology approach to construct ultrastable multifunctional RNA Beacons and RNA Dendrimers as image-guided agents for quantitative real-time assessment of tumor and metastatic cancer targeted therapeutic delivery distribution uptake and response. We have shown that our RNA nanoparticles are non-toxic non-immunogenic and capable of penetrating across heterogeneous biological barriers to deliver high doses of therapeutics specifically to solid tumors and metastatic cells in mice with little accumulation in normal organs. This provides an ideal platform for non-invasive imaging of cancer therapeutics in vivo. Our multifunctional RNA nanoparticles will be designed to harbor: (1) imaging modules: NIR fluorophores for in vivo fluorescence imaging; radionuclides for PET/SPECT imaging; and gadolinium contrast agents for MRI; (2) targeting modules: such as RNA aptamers or chemical ligands for binding to cancer specific cell surface receptors resulting in internalization of RNA nanoparticles into cancer cells; and (3) therapeutic modules: siRNAs and anti-miRNA to silence the expression of oncogenic genes. The multifunctional RNA constructs will then be evaluated in our well established colon cancer animal models. We will employ multimodal imaging techniques (NIRF PET/SPECT and/or MRI) for monitoring the therapeutic delivery process in real-time at various spatial and temporal resolution scales. This approach is based on the consideration that each of the three imaging modalities has advantages and an integrated approach will lead to synergistic benefits with regards to image-guided therapy.

project_terms:
Adopted;Animal Model;Animals;Architecture;Binding (Molecular Function);Biological;Biological Models;Cancer Diagnostics;Cancer Model;Catalytic RNA;Cell Surface Receptors;Cells;Chemicals;Colon Carcinoma;Contrast Media;Dendrimers;Detection;Development;Disseminated Malignant Neoplasm;Dose;Drug Delivery Systems;Dyes;Evaluation;Future;Gadolinium;Gene Silencing;Genes;Goals;Heterogeneity;Image;Imaging Techniques;In Vitro;Injection of therapeutic agent;Iowa;Lead;Ligand Binding;Ligands;Liver;Lung;Magnetic Resonance Imaging;Malignant Neoplasms;Methods;MicroRNAs;Molecular;Monitor;Motor;Multimodal Imaging;Mus;Nanotechnology;Nature;Neoplasm Metastasis;Oncogenic;Organ;Positron-Emission Tomography;Process;RNA;RNA Transport;Radioisotopes;Radiolabeled;Radionuclide Imaging;Reporter;Research;Resistance;Side;Signal Transduction;Small Interfering RNA;Solid Neoplasm;System;Therapeutic;Therapeutic Agents;Time;Tissues;Tomography Emission-Computed Single-Photon;Toxic effect;Urea;aptamer;base;cancer cell;clinical application;design;fluorescence imaging;fluorophore;gadolinium oxide;image guided;image guided therapy;imaging agent;imaging modality;in vivo;innovation;mouse model;nano;nanoparticle;non-invasive imaging;prospective;public health relevance;quantitative imaging;radiotracer;response;scaffold;stem;temporal measurement;therapeutic siRNA;therapeutic target;trafficking;tumor;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: RNA nanoparticles derived from the phi29 pRNA three-way junction (3WJ) are ultrastable and efficiently target tumor and metastatic cells in mice with littl accumulation in normal organs and tissues after systemic injection. This proposal is to construct multifunctional RNA Beacons and RNA Dendrimers as image-guided agents using the pRNA-3WJ scaffold for monitoring the in vivo delivery of cancer therapeutics in real-time and consequences of therapy.


application_id: 8883105
project_number: 5U01AA021901-04
project_title: Novel therapies in alcoholic hepatitis University of Louisville
administering_ic: NIAAA
award_notice_date: 2015-06-12
opportunity_number: RFA-AA-12-007
application_type: 5
activity_code: U01
ic: AA
serial_number: 021901
program_official: WANG, JOE
project_start_date: 2012-09-15
project_end_date: 2016-06-30
study_section: ZAA1-JJ(07)R
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This application is the translational component of an overall UO1 application entitled "Novel therapies in alcoholic hepatitis - University of Louisvill." Alcoholic hepatitis (AH) has a high morbidity and mortality. In VA Cooperative Studies in which liver biopsies were performed only 35% of patients with AH and underlying cirrhosis and 60% of those with AH alone (no cirrhosis) were alive at the end of four years with most deaths occurring early in the study. There is no FDA-approved therapy for any stage of alcoholic liver disease (ALD). The most widely-used (off-label) drug therapies for AH are glucocorticoids and pentoxifylline. Both agents have anti-inflammatory activities and downregulate proinflammatory cytokines such as tumor necrosis factor (TNF). Unfortunately an important subset of AH patients treated with glucocorticoids have "steroid resistance" and some patients have contraindications to steroid therapy. Studies on pentoxifylline in AH are limited and efficacy appears highest in preventing/treating the hepatorenal syndrome. Thus new therapies as well as a better understanding of mechanisms/biomarkers for severity of disease and response to therapy are necessary. Our research team has been a leader in defining mechanisms of alcohol-induced liver injury using in vitro and animal models of ALD and in translating basic findings into the clinical setting. Our group is the first to describe dysregulated cytokine metabolism in AH. We have a long-standing interest in mechanisms of inflammation and liver injury. We also have extensive experience in the gut-liver axis and AH as well as in the development of novel therapies for AH.Building on the above translational research strengths of our program which focus on the gut-liver axis and inflammation in ALD we propose three highly translational Specific Aims which all relate to and utilize samples from our proposed UO1 clinical trial. Aim 1 will evaluate novel mechanisms for alcohol-induced alterations in gut integriy leading to endotoxemia and AH. We will study the therapeutic efficacy of both live probiotics and probiotic supernatants. Aim 2 will study the role of specific PDE4 inhibition in AH using animal models and our AH clinical patient population. There are recent data in the pulmonary literature showing that specific PDE4 inhibitors are effective in steroid resistant patients which may translate to AH. Lastly Aim 3 evaluates mechanisms for steroid resistance using both specimens from patients in our clinical trial and in vitro data. All three of our specific aims utiize specimens obtained from our U01 clinical trial and our protocol interacts with the two other translational protocols in our U01 consortium. Our goal is not only to better understand mechanisms for AH but also to develop new therapies (including those already available for other diseases) for AH either immediately transforming clinical practice or providing novel therapies for our clinical trial consortium.

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

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


application_id: 8882258
project_number: 5R21AI113253-02
project_title: Regulation of hyaluronic acid capsule biosynthesis in Streptococcus pyogenes
administering_ic: NIAID
award_notice_date: 2015-06-15
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: AI
serial_number: 113253
program_official: GU, XIN-XING
project_start_date: 2014-07-01
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1-IDM-B(80)S]
contact_pi_person_id: 8869391
contact_pi: KOROTKOVA, NATALIA
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):   Streptococcus pyogenes (Group A Streptococcus GAS) is an important human pathogen that causes numerous diseases ranging from minor skin and throat infections such as impetigo and pharyngitis to life-threatening invasive infections such as streptococcal toxic syndrome and necrotizing fasciitis. Worldwide GAS infections account for more than 600 million cases of pharyngitis and more than 650000 cases of invasive disease annually. Since the late 1980s there has been a worldwide increase in invasive GAS disease. Although the pathogen is susceptible to antibiotic therapy severe invasive GAS infections are often difficult to treat. Hyaluronic acid (HA) capsule is considered one of the major determinants of GAS virulence. Highly encapsulated GAS strains are associated with both invasive infections and outbreaks of acute rheumatic fever. GAS mutants lacking capsule are sensitive to neutrophil killing and have reduced virulence in murine model of GAS infection. In addition to its role in bacterial resistanceto host defense attack HA capsule mediates adherence and promotes GAS colonization of the pharynx. Capsule expression requires effective and sensitive control mechanisms to avoid excessive capsule overproduction. In the current model CovR binds to the promoter region of the has capsule gene operon comprised of hasABC genes and represses its transcription. However the details of this mechanism are mostly unclear. The primary objective of the proposed research is to understand the molecular mechanisms of HA capsule regulation. In our preliminary studies we identified a novel regulatory noncoding region that controls capsule operon transcription. We confirmed that the region is physiologically significant and is important for full virulence in a mouse model of GAS invasive disease. Moreover we found that the region is under strong selective pressure resulting in accumulation of spontaneous mutations in GAS clinical strains. We propose to define this novel capsule regulation mechanism using advanced genetic and biochemical techniques. The outcomes of this research are expected to have a positive impact on the development of diagnostic analysis during outbreaks of GAS infection and highly targeted therapeutics to control the invasive GAS disease.

project_terms:
Accounting;Acute;Adherence (attribute);Anabolism;Antibiotic Therapy;Bacteria;Bacterial Infections;Binding (Molecular Function);Biochemical;Biological;Clinical;Data;Development;Diagnostic;Disease;Disease Outbreaks;Encapsulated;Future;Genes;Genetic;Genetic Polymorphism;Genetic Transcription;Genome;Genomic Segment;Goals;Health;Host Defense;Human;Hyaluronic Acid;Immune response;Impetigo;Infection;Investigation;Killings;Knowledge;Lead;Life;Link;Mediating;Messenger RNA;Metabolism;Methods;Minor;Modeling;Modification;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Mus;Mutation;Necrotizing fasciitis;Nucleic Acid Regulatory Sequences;Operon;Organism;Outcomes Research;Pathogenesis;Pharyngeal structure;Pharyngitis;Phenotype;Production;Prokaryotic Cells;Promoter Regions (Genetics);Promotor (Genetics);Regulation;Regulator Genes;Research;Research Personnel;Resistance;Rheumatic Fever;Role;Series;Serotyping;Signal Transduction;Skin;Small RNA;Specificity;Streptococcal Infections;Streptococcus pyogenes;Syndrome;System;Techniques;Toxic Shock Syndrome;Variant;Virulence;Virulence Factors;Virulent;bacterial resistance;base;capsule (pharmacologic);follow-up;innovation;interest;mouse model;mutant;neutrophil;novel;novel therapeutics;pathogen;pressure;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed research investigates the mechanism of regulation of hyaluronic acid capsule biosynthesis in the important human pathogen Streptococcus pyogenes. Hyaluronic acid capsule is one of the major determinants of S. pyogenes virulence. The expected findings will guide a development of diagnostic analysis during outbreaks of infections and novel therapeutics to control S. pyogenes invasive disease.


application_id: 8882205
project_number: 5R01AG029623-10
project_title: Role of TWEAK in skeletal muscle metabolism
administering_ic: NIA
award_notice_date: 2015-05-15
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AG
serial_number: 029623
program_official: WILLIAMS, JOHN
project_start_date: 2007-02-01
project_end_date: 2016-05-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
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): During last funding period we identified and established that TWEAK cytokine is a major regulator of skeletal muscle mass during aging and disuse conditions. We have now obtained strong evidence suggesting that the TWEAK causes insulin resistance in skeletal muscle. However the mechanisms by which TWEAK induces muscle atrophy or insulin resistance remain less well understood. PGC-1 cofactor plays a major role in regulation of skeletal muscle mass fiber-type composition and mitochondrial biogenesis. Our preliminary studies have shown that TWEAK suppresses the expression of PGC-1 and mitochondrial content and inhibits insulin signaling in skeletal muscle. We have also found that disuse conditions or type II diabetes involve the inducible expression of TWEAK receptor Fn14 (but not TWEAK itself) in skeletal muscle. Our initial analysis has revealed that both human and mouse Fn14 promoter contains CpG rich regions and that demethylation of Fn14 promoter could be a crucial event for the induction of Fn14 expression in skeletal muscle. In the next phase of this project we will investigate the mechanisms by which TWEAK causes sarcopenia disuse-related muscle atrophy and insulin resistance and how the expression of Fn14 gets up regulated in skeletal muscle in different conditions. We will address the following three specific aims: AIM I. Investigate the role of PGC-1 in TWEAK-mediated skeletal muscle atrophy in vivo. Hypothesis 1: TWEAK causes muscle atrophy and fiber-type switching through down-regulation of PGC-1 expression. AIM II. Investigate the key mechanisms by which TWEAK-Fn14 system induces insulin-resistance in adult and/or aged skeletal muscle. Hypothesis 2: TWEAK induces insulin resistance by inhibiting insulin receptor substrate (IRS1) phosphorylation and diminishing oxidative phosphorylation in skeletal muscle. AIM III: Investigate the molecular events leading to increased expression of TWEAK receptor Fn14 in skeletal muscle. Hypothesis 3: Demethylation of CpG islands in Fn14 promoter followed by binding of SP1 transcription factor triggers the expression of Fn14 in skeletal muscle in catabolicstates. Successful completion of this project will provide critical insights about sarcopenia durin aging and type II diabetes and provide novel avenues for therapeutic interventions.

project_terms:
Ablation;Acquired Immunodeficiency Syndrome;Address;Adult;Age;Aging;Atrophic;Binding (Molecular Function);Binding Sites;Biogenesis;Chronic Disease;Computer Simulation;Consensus;CpG Islands;Denervation;Development;Diabetes Mellitus;Disease;Down-Regulation;Drug Targeting;Etiology;Event;Fiber;Funding;GLUT4 gene;Genetic;Glucose;HDAC5 gene;Health;Heart failure;Human;IRS1 gene;Immobilization;In Vitro;Injury;Insulin;Insulin Receptor;Insulin Resistance;Lead;MAP3K7 gene;Malignant Neoplasms;Mediating;Mediator of activation protein;Medicine;Methyltransferase;Mitochondria;Modeling;Molecular;Morbidity - disease rate;Mus;Muscle;Muscle Fibers;Muscle Proteins;Muscle function;Muscular Atrophy;NF-kappa B;Natural regeneration;Non-Insulin-Dependent Diabetes Mellitus;Oxidative Phosphorylation;PPAR gamma;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Phase;Phosphorylation;Physiological;Play;Population;Promotor (Genetics);Proteins;Regulation;Reporting;Role;Signal Transduction;Skeletal muscle structure;Specificity;Syndrome;System;TRAF6 gene;Testing;Therapeutic Intervention;Transcription Initiation Site;Transgenic Organisms;Ubiquitin;Up-Regulation (Physiology);aged;cofactor;cytokine;demethylation;diminished oxidative phosphorylation;epigenetic regulation;glucose uptake;human HDAC4 protein;improved;in vivo;insight;insulin sensitivity;insulin signaling;multicatalytic endopeptidase complex;muscle aging;muscle form;muscle metabolism;neuromuscular activity;novel;older patient;overexpression;prevent;receptor;research study;sarcopenia;skeletal muscle wasting;transcription factor;wasting

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Skeletal muscle wasting is a debilitating consequence of aging and many chronic diseases such as type II diabetes common at older age. However there is still no approved therapy for treatment of this disorder/syndrome. It is essential to develop new medicines that can preserve skeletal muscle mass during aging. The proposed studies will identify the mechanisms of action of TWEAK cytokine a recently identified mediator of muscle wasting. Successful completion of this project will improve the basic understating of etiology of muscle wasting and type II diabetes and will lead to the identification of a novel drugtarget to preserve muscle mass and function in aging human population.


application_id: 8882187
project_number: 7R01AA021434-03
project_title: Role of microRNAs in Ethanol-induced Apoptosis and Teratogenesis
administering_ic: NIAAA
award_notice_date: 2015-07-10
opportunity_number: PA-11-260
application_type: 7
activity_code: R01
ic: AA
serial_number: 021434
program_official: HERELD, DALE
project_start_date: 2013-07-20
project_end_date: 2018-06-30
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 7035096
contact_pi: CHEN, SHAO-YU
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Prenatal ethanol exposure is the leading known cause of mental retardation. Growing evidence suggests that excessive cell death is a major component of the pathogenesis of ethanol-induced birth defects. However there is a fundamental gap in understanding how ethanol leads to apoptotic cell death in embryos. MicroRNAs (miRNAs) are a recently discovered class of small 18-23 nucleotide non-coding RNA that have been implicated in the regulation of genes involved in apoptosis. We have recently discovered that miR-34a a pro-apoptotic miRNA and miR-125b an anti-apoptotic miRNA are involved in ethanol-induced apoptosis in neural crest cells (NCCs). Our long-term goal is directed toward the development of effective strategies against ethanol's teratogenesis; strategies based on prevention of ethanol-induced apoptosis through targeting specific pathways involved in apoptosis. The overall objective of this particular proposal is to establish miRNA as a feasible target for the prevention of ethanol-induced apoptosis and teratogenesis. The central hypothesis to be tested is that miR-34a and miR-125b modulate ethanol-induced apoptosis in NCCs by the regulation of p53 and Bcl2 signaling pathways and that the inhibition of miR-34a or overexpression of miR-125b can prevent ethanol-induced teratogenesis. Our hypothesis has been formulated on the basis of strong preliminary data produced in our laboratory. To test our hypothesis the following specific aims will be addressed: Aim1: To characterize the role of miR-34a and miR-125b in ethanol-induced apoptosis in NCCs. We will determine the effects of ethanol on miR-34a and miR-125b expression in NCCs and in mouse embryos and the involvement of miR-34a and miR-125b in ethanol-induced apoptosis. Aim2: To test the hypothesis that miR-34a and miR- 125b modulate ethanol-induced apoptosis in NCCs by the regulation of p53 and Bcl2 pathways. This will be accomplished by determining the role of miR-34a in ethanol-induced activation of p53 and suppression of Bcl2 signaling and the effects of down-regulation of miR-125b by ethanol on p53 and Bcl2 signaling in ethanol- exposed NCCs. Aim3: To test the hypothesis that modulation of miR-34a and miR-125b represents a novel therapeutic strategy for preventing ethanol-induced teratogenesis. We will determine whether knockdown of miR-34a or overexpression of miR-125b diminishes ethanol-induced malformations in mouse embryos. The proposed work is innovative because it focuses on a novel approach targeting miRNAs involved in apoptosis to preventing ethanol-induced teratogenesis. The theoretical concept described in this application is also highly innovative because this is the first study attempting to prevent ethanol-induced apoptosis and teratogenesis specifically through the newly recognized actions of miR-34a and miR-125b in apoptosis. The results from this study will be significant because the insights gained by the accomplishment of these aims will help in elucidating the role of miRNAs in modulating ethanol-induced teratogenesis. They are also expected to yield strategies for preventing ethanol's teratogenesis and to fundamentally advance the field of FASD research.

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

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


application_id: 8882184
project_number: 7R01AA020265-04
project_title: Role of Siah1 in ethanol-induced apoptosis and teratogenesis
administering_ic: NIAAA
award_notice_date: 2015-07-09
opportunity_number: PA-10-067
application_type: 7
activity_code: R01
ic: AA
serial_number: 020265
program_official: HERELD, DALE
project_start_date: 2012-07-05
project_end_date: 2017-06-30
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 7035096
contact_pi: CHEN, SHAO-YU
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Prenatal ethanol exposure is the leading known cause of mental retardation. Growing evidence suggests that excessive cell death is a major component of the pathogenesis of ethanol-induced birth defects. However there is a fundamental gap in understanding how ethanol leads to apoptotic cell death in embryos. Continued existence of this gap represents an important problem because until it is filled understanding of ethanol- induced apoptosis that leads to teratogenesis will remain largely incomprehensible. Our long-term goal is directed toward the development of effective strategies against ethanol's teratogenesis; strategies based on prevention of ethanol-induced apoptosis through targeting specific proteins involved in apoptosis. The overall objective of this particular proposal is to establish Siah1 a member of the seven in absentia homology family as a feasible target for the prevention of ethanol-induced apoptosis and teratogenesis. The central hypothesis to be tested is that Siah1 mediates ethanol-induced apoptosis in neural crest cells (NCCs) by activating the p53 pathway and that the inhibition of Siah1-mediated apoptosis can prevent ethanol-induced teratogenesis. Our hypothesis has been formulated on the basis of strong preliminary data produced in our laboratory. To test our hypothesis the following specific aims will be addressed: Aim1: To characterize the role of Siah1 in ethanol-induced apoptosis in NCCs. We will determine the effects of ethanol on Siah1 mRNA and protein expression and investigate the potential of ethanol to promote Siah1 nuclear translocation and induce apoptosis. Aim2: To test the hypothesis that Siah1 mediates ethanol-induced apoptosis in NCCs by activating the p53 pathway. This will be accomplished by determining the role of Siah1 in ethanol-induced activation of p53 signaling pathway and in the induction of p53 downstream proapoptotic proteins and apoptosis. Aim3: To define the role of the inhibition of Siah1 function in conferring protection against ethanol-induced teratogenesis. This will be accomplished by using whole embryo culture Siah1 knockout mice and an oral intake FASD model. We will determine whether knocking down Siah1 diminishes ethanol-induced malformations in cultured mouse embryos and whether Siah1 deficiency in Siah1-/- mouse embryos can confer in vivo protection against ethanol-induced teratogenesis. The proposed work is innovative because it focuses on a novel approach targeting specific proteins directly involved in the apoptotic pathway to preventing ethanol-induced apoptosis and teratogenesis. The theoretical concept described in the application is also highly innovative because this is the first study attempting to prevent ethanol-induced apoptosis and teratogenesis specifically through the newly recognized actions of Siah1 in apoptosis. The results from this study will be significant because the insights gained by the accomplishment of these aims will help in elucidating the role of Siah1 in mediating ethanol- induced teratogenesis. They are also expected to yield strategies for the prevention of ethanol's teratogenesis and to fundamentally advance the field of FASD research.

project_terms:
Acetylation;Address;Alcohol consumption;Alcohols;Antioxidants;Apoptosis;Apoptotic;Brain;Brain region;Cell Cycle Arrest;Cell Death;Cell Line;Cell physiology;Cells;Cessation of life;Congenital Abnormality;Data;Development;Disease model;EP300 gene;Embryo;Ethanol;Family;Fetal Alcohol Exposure;Fetal Alcohol Spectrum Disorder;Goals;Human;Intake;Intervention;Knockout Mice;Knowledge;Laboratories;Life;MAPK8 gene;Mediating;Mental Retardation;Mission;Molecular;Molecular Target;Mus;Neural Crest Cell;Neurons;Nuclear Translocation;Oral;Pathogenesis;Pathway interactions;Phosphorylation;Population;Prevention;Prevention strategy;Proteins;Research;Role;Signal Pathway;Signal Transduction;Site;Small Interfering RNA;Staging;Tertiary Protein Structure;Testing;Therapeutic;Third Pregnancy Trimester;Work;alcohol effect;alcohol exposure;base;effective intervention;embryo culture;fetal;in vivo;innovation;insight;knock-down;mRNA Expression;malformation;member;non-genetic;novel strategies;novel therapeutics;p53 Signaling Pathway;prevent;protein expression;public health medicine (field)

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


application_id: 8881239
project_number: 5P30GM110787-02
project_title: Pilot Grant Program
administering_ic: NIGMS
award_notice_date: 2015-03-25
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
study_section: ZGM1-TWD-C
subproject_number: 6094
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
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: 2015-05-01
budget_end_date: 2016-04-30
project_terms:
Am 80;Animal Model;Applications Grants;Area;Award;Basic Science;Categories;Cellular biology;Centers of Research Excellence;Clinical;Collaborations;Consultations;DNA;Data;Development;Diagnostic;Discipline;Evaluation;Evolution;Extramural Activities;Faculty;Feasibility Studies;Fostering;Foundations;Funding;Future;Generations;Goals;Grant;Growth;Kentucky;Knowledge;Mentors;Molecular;Molecular Medicine;Neurodegenerative Disorders;Participant;Patients;Phase;Philosophy;Pilot Projects;Positioning Attribute;Principal Investigator;Program Research Project Grants;Publications;RNA;Research;Research Personnel;Research Project Grants;Resources;Science;Signal Pathway;Sum;Technology;Therapeutic;Translational Research;United States National Institutes of Health;Universities;Work;base;career;design;experience;human disease;improved;innovation;interest;new technology;novel;operation;programs;success;tool;trafficking;translational study


application_id: 8881238
project_number: 5P30GM110787-02
project_title: Genetic Technologies Core
administering_ic: NIGMS
award_notice_date: 2015-03-25
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
study_section: ZGM1-TWD-C
subproject_number: 6093
contact_pi_person_id: 1893692
contact_pi: MENDENHALL, MICHAEL D.
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: 2015-05-01
budget_end_date: 2016-04-30
project_terms:
Adenoviruses;American;Animal Model;Biological Assay;Cell model;Cells;Centers of Research Excellence;Clinical;Complex;Consultations;DNA;DNA Sequence Alteration;DNA laboratory;Dependovirus;Development;Disease model;Doctor of Philosophy;Evolution;Exposure to;Fee-for-Service Plans;Fees;Funding;Genetic Engineering;Genome;Genomics;Grant;Individual;Institution;Instruction;Investments;Kentucky;Laboratories;Leadership;Master of Science;Medical;Medicine;Modeling;Molecular;Molecular Medicine;Nucleic Acids;Phase;Plasmids;Positioning Attribute;Preparation;Production;Reagent;Recombinant DNA;Recombinants;Recovery;Research;Research Personnel;Resources;Safety;Science;Services;Source;Speed (motion);Students;System;Techniques;Technology;Time;Tissue Culture Techniques;Training;Training Activity;Training Programs;United States National Institutes of Health;Universities;Viral;Work;base;cost;design and construction;genetic technology;graduate student;human disease;interest;mammalian genome;meetings;member;operation;outreach program;programs;recombinant virus;tool


application_id: 8881237
project_number: 5P30GM110787-02
project_title: Organic Synthesis Core
administering_ic: NIGMS
award_notice_date: 2015-03-25
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
study_section: ZGM1-TWD-C
subproject_number: 6092
contact_pi_person_id: 1964895
contact_pi: WATT, DAVID STEWART
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: 2015-05-01
budget_end_date: 2016-04-30
project_terms:
Affinity Chromatography;Biological;Biological Factors;Businesses;Centers of Research Excellence;Clinical Trials;Collaborations;Complement;Consult;Consultations;Detection;Deuterium;Development;Disease;Drug Industry;Elements;Equipment;Extramural Activities;Faculty;Fees;Funding;Grant;Health;Human;Industry;Institution;Investigation;Investigational Drugs;Investments;Kentucky;Label;Learning;Legal patent;Licensing;Ligands;Link;Lipids;Malignant Neoplasms;Mass Spectrum Analysis;Medicine;Molecular;Molecular Medicine;Molecular Probes;Monitor;NMR Spectroscopy;National Center for Research Resources;National Institute of General Medical Sciences;Nature;Neurodegenerative Disorders;Organic Chemicals;Organic Synthesis;Outcome;Peptide Nucleic Acids;Peptides;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacy facility;Phase;Polymers;Positioning Attribute;Postdoctoral Fellow;Preclinical Drug Evaluation;Private Enterprises;Proteins;Publications;Radiolabeled;Research;Research Personnel;Research Project Grants;Research Support;Resources;Services;Source;Structure;Students;Techniques;Testing;Time;Training;Translating;Translational Research;Universities;X-Ray Crystallography;analog;base;college;design;drug candidate;functional group;graduate student;human disease;improved;instrumentation;molecular mass;novel;operation;outreach;programs;radiotracer;screening;small molecule;small molecule libraries;therapeutic development;undergraduate student


application_id: 8881236
project_number: 5P30GM110787-02
project_title: Protein Core
administering_ic: NIGMS
award_notice_date: 2015-03-25
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
study_section: ZGM1-TWD-C
subproject_number: 6091
contact_pi_person_id: 7875214
contact_pi: RODGERS, DAVID W
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: 2015-05-01
budget_end_date: 2016-04-30
project_terms:
Area;Bacteria;Behavior;Biological;Biomedical Research;Bioreactors;Calorimetry;Cells;Centers of Research Excellence;Chromatography;Collaborations;Communities;Consult;Core Facility;Core Protein;Crystallization;Crystallography;Data Collection;Equipment;Faculty;Fees;Fluorescence;Fostering;Funding;Goals;Grant;Growth;High Pressure Liquid Chromatography;Housing;Human Resources;Individual;Insecta;Institution;Kentucky;Laboratories;Laboratory Research;Mammalian Cell;Mission;Molecular Medicine;Phase;Photons;Production;Protein Chemistry;Proteins;Recombinant Proteins;Research;Research Personnel;Resources;Schedule;Series;Services;Source;Structural Biologist;Structure;Techniques;Time;Titrations;Training;Universities;Work;X-Ray Crystallography;Yeasts;analytical ultracentrifugation;base;biophysical properties;cell type;design;experience;instrument;instrumentation;light scattering;macromolecule;member;operation;outreach;outreach program;programs;research study;structural biology;tissue culture;web site


application_id: 8881235
project_number: 5P30GM110787-02
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2015-03-25
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
study_section: ZGM1-TWD-C
subproject_number: 6090
contact_pi_person_id: 7875201
contact_pi: LOUIS HERSH, LOUIS HERSH LOUIS HERSH
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: 2015-05-01
budget_end_date: 2016-04-30
project_terms:
Achievement;Advisory Committees;Basic Science;Biochemistry;Budgets;Centers of Research Excellence;Collaborations;Core Facility;Data;Development;Educational Activities;Equipment;Extramural Activities;Faculty;Fostering;Foundations;Goals;Grant;Head;Housing;Institution;Kentucky;Leadership;Medicine;Mentors;Mission;Molecular;Molecular Medicine;Performance;Phase;Recruitment Activity;Reporting;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Running;Services;Solid;Techniques;Technology;Universities;Work;base;college;design;human disease;meetings;new technology;novel;programs;tool;voucher


application_id: 8881180
project_number: 5R01ES023470-03
project_title: Endocrine disruptor mediated activation of PXR causes dyslipidemia
administering_ic: NIEHS
award_notice_date: 2015-06-17
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: ES
serial_number: 023470
program_official: HEINDEL, JERROLD
project_start_date: 2013-09-26
project_end_date: 2016-06-30
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)S]
contact_pi_person_id: 8880095
contact_pi: ZHOU, CHANGCHENG
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The goal of this project is to investigate a novel mechanism linking exposure to endocrine disrupting chemicals (EDCs) with dyslipidemia and cardiovascular disease. The pregnane X receptor (PXR) is a nuclear receptor activated by numerous drugs xenobiotic and dietary chemicals. Many EDCs activate PXR including organochlorine and organophosphate pesticides alkylphenols phthalates polychlorinated biphenyls bisphenol A and its analogs. However the role of PXR in mediating the pathophysiological effects of EDCs in humans and animals remains elusive. Mounting evidence implicates EDC exposure in the development of chronic human diseases but the contribution of these EDCs to the etiology of cardiovascular disease (CVD) obesity and diabetes is poorly understood. We have recently revealed the pro-atherogenic effects of PXR in animal models and demonstrated that chronic PXR activation induces hyperlipidemia in wild-type mice and increases atherosclerosis in atherosclerosis-prone apolipoprotein E deficient (ApoE-/-) mice. Our central hypothesis is that EDCs which activate PXR will lead to hyperlipidemia and accelerated atherosclerosis in mice thereby increasing the risk of CVD in exposed individuals. We propose the following specific aims to test this hypothesis: 1) What are the molecular mechanisms through which intestinal PXR activation induces hyperlipidemia? 2) How does exposure to FDA-approved phthalate substitute plasticizers elevate plasma lipid levels in mice? 3) Is EDC-mediated PXR activation necessary and sufficient to increase atherosclerosis development in ApoE-/- mice? Our research will establish the role of PXR in linking exposure to EDCs with hyperlipidemia and CVD and will provide novel mechanistic links explaining how EDC exposure causes atherogenic effects. These studies are broadly translational and will provide strong evidence to inform future risk assessment for EDCs.

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

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


application_id: 8881139
project_number: 5K18DC014050-02
project_title: Odorant Receptor Expression and Sensitivity to Odorants
administering_ic: NIDCD
award_notice_date: 2015-06-10
opportunity_number: PAR-13-186
application_type: 5
activity_code: K18
ic: DC
serial_number: 014050
program_official: RIVERA-RENTAS, ALBERTO L
project_start_date: 2014-07-01
project_end_date: 2016-02-29
study_section: ZDC1-SRB-Y(56)
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The application proposes to allow an investigator experienced in the molecular biology of the olfactory epithelium to cross the gap from his expertise in microarray-based genomics to more computationally challenging next generation sequencing approaches. The plan includes: (1) training in R programming to allow the investigator take advantage of flexible analysis methods for ChIP-seq and RNA-seq techniques (2) mentored pilot experiments in both of these approaches and (3) mentored analyses of the data. The pilot studies take advantage of a unique resource that allows purification of olfactory neurons expressing subsets of odorant receptors to work toward testing two fundamental hypotheses about odorant receptors. (1) Active chromatin modifications (which can only be detected by enrichment for neurons expressing an odorant receptor) are critical for the tightly regulated expression of odorant receptors. Active chromatin modifications will be measured by ChIP-seq. The exquisitely specific control of odorant receptor expression is perhaps the greatest remaining mystery about the function of olfactory sensory neurons. (2) Odorants activate sets of odorant receptors that may overlap but must have at least one distinct member if the odorants can be discriminated. Enrichment for olfactory sensory neurons marked by expression of GFP from an activity-dependent gene locus will allow RNA-seq methods to identify sets of odorant receptors activated by specific odorants. Understanding the fundamental question of how hundreds of odorant receptors allow the detection and discrimination of thousands of odorant chemicals should help explain some causes of hyposmia and anosmia; and should allow the future development of odorant agonists and antagonists that could be used to improve the quality of human life.

project_terms:
Agonist;Alleles;Anosmia;Axon;ChIP-seq;Chemical Structure;Chemicals;Color Visions;Data;Data Analyses;Detection;Development;Dimensions;Discrimination (Psychology);Ear structure;Event;Future;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genomics;Health;Human;Life;Measures;Mentors;Methods;Modification;Molecular Biology;Molecular Biology Techniques;Mus;Nature;Neurons;Odorant Receptors;Odors;Olfactory Epithelium;Olfactory Pathways;Outcome;Pattern;Pilot Projects;Receptor Activation;Receptor Gene;Regulation;Research;Research Personnel;Research Project Grants;Resources;Role;Signal Transduction;Solutions;Stimulus;Techniques;Technology;Testing;Training;Variation (Genetics);Work;base;chromatin modification;detector;experience;flexibility;homeodomain;hyposmia;improved;in vivo;member;neural patterning;next generation sequencing;olfactory bulb glomeruli;olfactory sensory neurons;programs;receptor;receptor expression;receptor sensitivity;research study;response;tool;transcription factor;transcriptome sequencing

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Unlike color vision and pitch detection by the ear how the quality dimension of odorant stimuli (differences in chemical structure) is divided among the detectors (odorant receptors) remains a mystery. Differences in the pattern of receptors activated must exist between odorants that can be discriminated but these patterns are unknown. Given the strict expression of just one odorant receptor in each olfactory sensory neuron these patterns depend critically on mechanisms controlling expression of the odorant receptor genes mechanisms that remain mysterious and when defective may also contribute to hyposmias and anosmias.


application_id: 8880738
project_number: 1R03CA187839-01A1
project_title: The role of Sin1 in colorectal cancer progression
administering_ic: NCI
award_notice_date: 2015-02-27
opportunity_number: PAR-14-007
application_type: 1
activity_code: R03
ic: CA
serial_number: 187839
suffix: A1
program_official: SATHYAMOORTHY, NEERAJA
project_start_date: 2015-04-01
project_end_date: 2017-03-31
study_section: Special Emphasis Panel[ZCA1 RTRB-F (J1)]
contact_pi_person_id: 8737920
contact_pi: YANG, HSIN-SHENG
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Colon cancer is the third most fatal cancer in both men and women in the United States. For more than 90% of patients who develop hepatic metastases the disease is fatal within 5 years: often within 1-2 years. Inactivation of tumor suppressor genes is one type of somatic genetic changes that occur in colon cancer. Understanding the function and action mechanism of tumor suppressors in colon cancer metastasis will benefit the design of new therapeutic drugs to reduce the mortality rate of metastatic colon cancer. Programmed cell death 4 (Pdcd4) a novel tumor suppressor is frequently down-regulated in cancerous colon tissues compared to adjacent normal tissues. Indeed knockdown of Pdcd4 expression in colon tumor cells promotes invasion in cultured cells and metastasis in nude mice. Conversely over-expression of Pdcd4 inhibits colon tumor cell invasion and intravasation. Promotion of tumor invasion by Pdcd4 knockdown is believed to elevate Snail expression and thereby down-regulate E-cadherin and activate -catenin and AP-1 dependent transcription. In addition Pdcd4 has been demonstrated to inhibit protein translation through its ability to bind with translation initiation factor 4A (eIF4A). Pdcd4 has alo been shown to inhibit activation of Akt (also known as protein kinase B) a kinase frequently activated in human colon cancer. Preliminary studies showed that knockdown of Akt suppresses colon tumor cell invasion caused by Pdcd4 knockdown suggesting that Pdcd4 controls colon tumor invasion/metastasis via regulation of Akt activation. A key finding was that over-expression of Pdcd4 inhibits the level of Sin1 (stress-activated-protein kinase-interacting protein
1) whereas knockdown of Pdcd4 elevates Sin1. In addition knockdown of Pdcd4 increased Sin1 translation. Since Sin1 is a critical component of mammalian target of rapamycin complex 2 (mTORC2) which controls Akt activation these promising findings suggest a mechanism by which Pdcd4 regulates Akt activation through the control of Sin1 translation. However the clinical importance of Sin1 expression in colon cancer progression and the role of Sin1 in colon tumor cell invasion/metastasis are unknown. Since Pdcd4 suppresses colon tumor invasion/metastasis and inhibits Sin1 expression the hypothesis is that Pdcd4 suppresses colon tumor cell invasion/metastasis through inhibition of Sin1 translation. To test this hypothesis two specific aims are proposed. Aim 1: determine whether Sin1 expression correlates with colon cancer progression. Aim 2: determine whether suppression of Sin1 translation by Pdcd4 leads to inhibition of Akt activation thereby impeding invasion/metastasis. Accomplishment of the proposed study will establish the clinical significance of Sin1 expression in colon cancer progression and the promoter role of Sin1 in colon tumor invasion/metastasis. The proposed work is highly innovative and of significant impact given the translational value in providing a solid rationale for development of agents to target Sin1 as a unique strategy for colon cancer therapeutics.

project_terms:
Antineoplastic Agents;Apoptosis;Binding (Molecular Function);Cancerous;Cause of Death;Cell physiology;Clinical;Colon;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Complex;Cultured Cells;Data;Development;Diagnosis;Disease;Down-Regulation;E-Cadherin;Future;Genetic Transcription;Half-Life;Human;Lead;Liver;Malignant Neoplasms;Messenger RNA;Metastatic Neoplasm to the Liver;Mortality Vital Statistics;Mutation;Neoplasm Metastasis;Normal tissue morphology;Nude Mice;Patients;Peptide Initiation Factors;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Play;Promotor (Genetics);Proteins;Proto-Oncogene Proteins c-akt;Recurrence;Regulation;Role;Signal Pathway;Snails;Solid;Survival Rate;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;Transcription Factor AP-1;Translations;Tumor Cell Invasion;Tumor Suppressor Proteins;Tumor-Suppressor Gene Inactivation;United States;Up-Regulation (Physiology);Woman;Work;cancer diagnosis;cell motility;clinically relevant;clinically significant;colon cancer patients;design;helicase;implantation;inhibitor/antagonist;innovation;insight;lymph nodes;mTOR protein;men;mouse model;neoplastic cell;novel;novel therapeutics;public health relevance;stress activated protein kinase;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Colon cancer is the third most commonly diagnosed cancer and the third leading cause of death in both men and women in the United Sates largely due to the spread of cancer to the liver and lymph nodes. In this proposal we intend to understand the clinical relevance of an important protein Sin1 in colon cancer tissues and the role of Sin1 in the spread of the colon tumor. This work will provide an understanding of how Pdcd4 a novel tumor suppressor modulates Sin1 expression resulting in control of the spread of colon cancer and may lead to a new target for treatment of colon cancer.


application_id: 8880477
project_number: 1U01HL127518-01
project_title: The ExCITE Program: Expediting Commercialization Innovation Translation & Entrepreneurship
administering_ic: NHLBI
award_notice_date: 2015-03-20
opportunity_number: RFA-OD-14-005
application_type: 1
activity_code: U01
ic: HL
serial_number: 127518
program_official: ROUSCHE, KATHLEEN T
project_start_date: 2015-03-20
project_end_date: 2018-02-28
study_section: Special Emphasis Panel[ZHL1 CSR-O (F1)]
contact_pi_person_id: 6663799
contact_pi: BATES, PAULA J.
other_pis: KRENTSEL, EUGENE ;MILLER, DONALD M.
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overarching goal of this project is to increase the success rate and speed with which the results of basic biomedical research are translated into products that have a positive impact on human health. To do this we propose to create a commercialization program at the University of Louisville (UofL) with a structure that is designed to overcome the many obstacles that currently impede translation. Though UofL is a relatively small institution in an IDeA state it has invested in talent and infrastructure for translational research in order to create a pro-entrepreneurial culture. This has already paid dividends and UofL has been awarded numerous major grants including three current COBRE awards a Coulter Translational Partnership the NIH Cardioprotection Consortium the NIH-UofL RBL (a BSL-3 facility) and multiple P-/U- series grants. Moreover UofL discoveries have led to interventions that have already benefited patients such as a first-in- class anticancer drug a method to prevent transplant rejection and a protocol that has allowed paraplegic patients to stand again. Many more UofL innovations are now on their way to clinical trials including new vaccines and minimally invasive devices to detect cancer. The proposed UofL REACH program will be known as "the ExCITE Hub" to reflect its function as a central resource for Expediting Commercialization Innovation Translation and Entrepreneurship. The hub is designed to fulfill the goals of the FOA (RFA-OD- 14-005) but is tailored to match UofL's specific strengths and needs. In short the university will supply a robust pipeline of diverse technologies and the infrastructure/expertise required for translational research whereas the Hub will deliver the necessary funding education and access to business expertise to bridge the gap between a great idea and the marketplace. The ExCITE Hub has three major aims: (1) identify the most promising technologies and provide funding for product definition studies (2) promote commercialization of selected products and transition to a self-sustaining ExCITE program and (3) expand educational experiential and networking opportunities for stakeholders. Our approach includes innovative features: (1) a geographically focused program to expedite operations and maximize impact on the local eco-system (2) an innovative governance structure to integrate the three main goals and avoid silos (3) a proactive rather than passive approach to education (4) a mentored technology development grant program that requires early interactions between scientists tech transfer staff and industry consultants and (5) an emphasis on improving academia-industry relationships by increasing mutual understanding ensuring robust technologies and being responsive to industry needs. Institutional and regional commitment to the ExCITE Hub is evident from the >$3.1M in matching funds and 40 letters of support. Success in this project will have a major economic impact on the region and will speed the delivery of innovative new products to the patients that need them.

project_terms:
Academia;Antineoplastic Agents;Award;Back;Basic Science;Biomedical Research;Businesses;Centers of Research Excellence;Clinical Trials;Complement;Development;Development Plans;Devices;Economic Development;Educational aspects;Educational process of instructing;Ensure;Entrepreneurship;Environment;Evaluation;Faculty;Federal Government;Funding;Goals;Graft Rejection;Grant;Health;Human;Income;Incubators;Industry;Institution;Intellectual Property;Intervention;Investments;Kentucky;Knowledge;Leadership;Letters;Malignant Neoplasms;Marketing;Mentors;Mentorship;Methods;Mission;Monitor;Nature;Paraplegia;Patients;Positioning Attribute;Private Sector;Problem Solving;Protocols documentation;Research;Research Infrastructure;Research Personnel;Resources;Scientist;Series;Source;Speed (motion);Structure;System;Talents;Technology;Technology Transfer;Testing;Time;Translating;Translational Research;Translations;United States National Institutes of Health;Universities;Work;base;bench to bedside;biosafety level 3 facility;clinically relevant;commercialization;design;economic impact;experience;human disease;improved;innovation;member;minimally invasive;novel vaccines;operation;prevent;programs;public-private partnership;success;technology development

public_health_relevance:
The federal government invests billions of dollars per year in basic research which has led to great advances inunderstanding human diseases but it is difficult to translate these discoveries into new treatments or tests thathelp patients. This is mainly because university scientists generally do not know how to convert their greatideas into useful products plus there is relatively little funding for product-driven research. This project willattempt to solve this problem by providing grants for technology development and teaching researchers aboutbusiness.


application_id: 8880267
project_number: 5R01HL113494-03
project_title: Treatment of Skeletal Muscle Dysfunction in ICU Patients
administering_ic: NHLBI
award_notice_date: 2015-03-27
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: HL
serial_number: 113494
program_official: HARABIN, ANDREA L
project_start_date: 2013-08-01
project_end_date: 2016-04-30
study_section: Special Emphasis Panel[ZRG1-MOSS-A(02)S]
contact_pi_person_id: 1879110
contact_pi: SUPINSKI, GERALD S.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Recent studies indicate that mechanically ventilated MICU patients develop severe respiratory and limb muscle weakness and that weakness is associated with poor clinical outcomes in these patients. As a result administration of drugs thatimprove skeletal muscle strength should theoretically reduce the need for mechanical ventilation shorten hospital stay improve mortality and increase exercise tolerance in this patient population. The purpose of the present proposal is to address this issue and evaluate the impact of anabolic agents on strength and outcomes in a large diagnostically broad based MICU patient population. Two experiments are planned:  Aim 1 will test the hypothesis that limb and respiratory skeletal muscle weakness in critically ill patients can be attenuated by administration of hydroxymethylbutyrate (HMB) and/or eicosapentaenoic acid (EPA). We will first measure indices of muscle strength (magnetically stimulated diaphragm and quadriceps strength) muscle size (diaphragm and quadriceps thickness) and quadriceps muscle biopsy characteristics (force-pCa relationships biomarker levels). We will next randomize mechanically ventilated MICU patients to receive either placebo HMB EPA or both HMB+EPA for 10 days. We will then repeat parameter testing (muscle strength size and biopsy characteristics) on days 11 and 21. Data will be analyzed to determine if anabolic treatments improve muscle strength increase muscle size alter muscle biomarker levels and reduce the duration of mechanical ventilation.  Aim 2 will test the hypothesis that muscle training will augment the response to muscle strength enhancers (HMB+EPA) in mechanically ventilated MICU patients. We will measure muscle strength size and biomarker levels. We will then randomize patients to either placebo muscle strength enhancers (HMB+EPA) alone targeted muscle training alone (loaded breathing leg cycling exercise) or the combination of strength enhancers plus muscle training for 10 days. Parameter assessment will be repeated at days 11 and 21. We will determine if these treatments improve muscle strength muscle size alter biomarkers and reduce the duration of mechanical ventilation.  Our pilot study data suggest that both EPA and HMB can induce increases in both limb and respiratory muscle strength shortening the duration of mechanical ventilation in critically ill patients. These data support our hypotheses and suggest that the proposed studies are likely to define a new treatment that will have an important impact on the care of critically ill patients.

project_terms:
Activities of Daily Living;Address;Anabolic Agents;Attenuated;Biological Markers;Biopsy;Breathing;Caring;Characteristics;Clinical;Critical Illness;Data;Diaphragm (Anatomy);Disease;Drug Combinations;Eicosapentaenoic Acid;Enhancers;Exercise;Exercise Tolerance;Financial cost;Functional disorder;Health;Hospitals;Hyperglycemia;Intensive Care Units;Leg;Length of Stay;Limb structure;Measurement;Measures;Mechanical ventilation;Medical;Morbidity - disease rate;Mortality Vital Statistics;Muscle;Muscle Weakness;Muscle function;Outcome;Patient Care;Patients;Performance;Pharmaceutical Preparations;Pharmacotherapy;Physicians;Pilot Projects;Placebos;Pneumonia;Quadriceps Muscle of the Thigh;Randomized;Reporting;Respiratory Failure;Respiratory Muscles;Skeletal muscle structure;Testing;Thick;Training;Ventilator;Work;base;cytokine;design;improved;indexing;muscle strength;patient population;pressure;prevent;research study;respiratory;response;theories;treatment effect

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Skeletal muscle weakness is a major contributor to morbidity and mortality in critically ill MICU patients but currently there is no drug therapy available for his problem. The studies in this proposal are designed to identify a practical safe and potent therapy to prevent/reverse skeletal muscle weakness in these patients. We believe this work will define a new treatment that will have a major impact on the care of critically ill patients.


application_id: 8880166
project_number: 5K02DA031766-05
project_title: Medications Development for Cannabis-Use Disorders: Clinical Studies
administering_ic: NIDA
award_notice_date: 2015-06-25
opportunity_number: PA-10-057
application_type: 5
activity_code: K02
ic: DA
serial_number: 031766
program_official: HAMPSON, AIDAN
project_start_date: 2011-07-01
project_end_date: 2016-06-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Cannabis is the most commonly used illicit drug in the United States and its use is associated with rates of development of abuse and dependence treatment admission and relapse that are comparable to other illicit drugs. Currently there is no effective pharmacological treatment for cannabis-use disorders. The overarching goal of my career is to develop a clinical research program in which I am able to screen potential medications for cannabis-use disorders using an efficient evidence-based progression of laboratory procedures followed by an evaluation of the efficacy of promising leads in dependent treatment-seeking individuals. My graduate and post-doctoral training and K01 and R01 support have enabled me to build an independent research program in which rational targets for medications development are identified based on the neuropharmacology of 9-THC. My research has identified compounds that could represent major breakthroughs in cannabis-use treatment. The goal of this K02 award is to continue my career development trajectory by acquiring the additional skills and experience needed to move my research into the next steps of the screening process. In order to achieve this goal I have formulated a career development plan that includes additional coursework training with expert preceptors relevant research and data publication/presentation activities further grant development and the receipt and delivery of training in the responsible conduct of research. The research to be conducted during the funding period consists of a three-step screening process to 1) identify targets and/or specific compounds for subsequent screening; 2) test the safety and tolerability of cannabis administration during maintenance on candidate medications; and 3) test the ability of maintenance on putative pharmacotherapies to attenuate the reinforcing effects of cannabis under controlled laboratory conditions while simultaneously monitoring changes in cannabis use in the natural ecology. Importantly this last step represents an innovative approach that will enhance the efficiency of early phase clinical trial research direct the choice of candidate medications for full scale clinical efficacy testing and facilitate my eventual transition to clinical trials research. This research will be carried out in the Department of Behavioral Science at the University of Kentucky which is an exceptional environment having the necessary physical and intellectual resources for successful completion of the proposed career development plan. Moreover this institution is committed to my scientific development and has acknowledged that my research program is an integral part of its scientific community. I have a solid foundation of training and research experience have established a strong record of productivity and independent funding and have demonstrated a commitment to mentoring the next generation of scholars interested in the treatment of cannabis-use disorders. The career development activities supported by the K02 award will allow me to sustain and expand these efforts and thus meet my career goals which will directly impact the field of cannabis-use treatment.

project_terms:
Abstinence;Address;Admission activity;Adopted;Adverse effects;Agonist;Area;Attenuated;Baclofen;Behavioral Sciences;Biological Assay;Brain;CNR1 gene;Cannabinoids;Cannabis;Clinical;Clinical Data;Clinical Research;Clinical Treatment;Clinical Trials;Communities;Controlled Clinical Trials;Data;Dependence;Development;Development Plans;Diagnostic;Disease;Dose;Drug Combinations;Drug usage;Ecology;Environment;Foundations;Funding;Future;Goals;Gold;Grant;Hybrids;Illicit Drugs;Independent Scientist Award;Individual;Inpatients;Institution;Kentucky;Knowledge;Laboratories;Laboratory Procedures;Laboratory Research;Link;Maintenance;Marijuana Smoking;Measures;Mediating;Mentors;Methods;Monitor;Nabilone;Neurons;Neuropharmacology;Outpatients;Persons;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacotherapy;Phase;Population;Procedures;Process;Productivity;Publications;Relapse;Reporting;Research;Research Training;Resistance;Resources;Risk;Safety;Sampling;Screening procedure;Self Administration;Series;Solid;Stimulus;System;Testing;Therapeutic;Time;Toxicology;Training;Treatment Efficacy;Treatment outcome;United States;Universities;Urine;Withdrawal;absorption;base;cannabinoid drug;career;career development;clinical efficacy;clinical practice;cost effective;drug discrimination;drug of abuse;efficacy evaluation;efficacy testing;endogenous cannabinoid system;evidence base;experience;gabapentin;gamma-Aminobutyric Acid;improved;innovation;interest;marijuana use;marijuana use disorder;meetings;next generation;post-doctoral training;post-market research;programs;public health medicine (field);responsible research conduct;safety testing;screening;skills;synthetic cannabinoid;tiagabine

public_health_relevance:
Cannabis is the most commonly used illicit drug in the United States and its use is associated with rates of development of abuse and dependence treatment admission and relapse that are comparable to other illicit drugs. Currently there is no effective pharmacological treatment for cannabis-use disorders. Five years of funding is requested to support full-time (100% effort) research and training to support the development of an efficient evidence-based medication screening process.


application_id: 8880164
project_number: 5U01DA013519-13
project_title: Development of Novel Therapies or Methamphetamine Abuse
administering_ic: NIDA
award_notice_date: 2015-06-15
opportunity_number: PA-10-067
application_type: 5
activity_code: U01
ic: DA
serial_number: 013519
program_official: ACRI, JANE
project_start_date: 2000-08-15
project_end_date: 2016-06-30
study_section: Special Emphasis Panel[ZRG1-MDCN-C(56)S]
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Methamphetamine (METH) abuse continues to escalate and effective treatments are not currently available. METH interacts with the vesicular monoamine transporter-2 (VMAT2) promoting both dopamine (DA) release into the cytosol and reversal of the DA transporter to increase extracellular DA concentrations which is thought to be associated with its abuse liability. The overall objective of this project is to provide a clinical candidate for the treatment of METH abuse. Recently we identified a novel small molecule (GZ-793A) which potently and selectively inhibits DA uptake by VMAT2 inhibits METH-evoked DA release from synaptic striatal vesicles and slices and exhibits selectivity does not interact with nicotinic receptors or DA transporters. Off-target evaluation at a cadre of neurotransmitter-related steroid and ion channel sites second messenger prostaglandin growth factor and hormones brain/gut peptides and enzymes revealed outstanding selectivity. Translation to whole animals models revealed that GZ-793A specifically decreases METH self-administration without altering responding for sucrose does not produce tolerance to the decrease in METH self- administration upon repeated administration and decreases METH seeking in the cue-induced reinstatement. Acute GZ793A pretreatment also protects against the neurotoxic effects of METH as measured by striatal DA depletion. Although the physicochemical properties of GZ-793A are favorable in terms of druggability GZ-793A has only 2-3% oral bioavailability likely due to the presence of the hydroxyl functionalities in the molecule which are likely sites for high first-pass metabolism. Thus new optimized analogs of GZ-793A are the focus of the current application with the goal of identifying analogs with the required pharmacological properties druggability increased oral bioavailability and acceptable pharmacokinetic profile. Compounds with these characteristics would be high value preclinical candidates for advancement toward clinical trials as treatments for METH abuse. Thus we propose to expand our existing molecular library of analogs by performing the final steps of optimization of GZ-793A to identify a high value preclinical candidate as a potential therapeutics for METH abuse. In future work the best candidate will undergo comprehensive toxicological evaluation for subsequent preparation of an Investigational New Drug application to the FDA as a proposed treatment for methamphetamine abuse.

project_terms:
Acute;Affinity;Animal Model;Behavioral;Binding Sites;Bioavailable;Biological Availability;Brain;CYP2C19 gene;CYP2D6 gene;Characteristics;Chemical Structure;Clinical;Clinical Trials;Collaborations;Corpus striatum structure;Cues;Cytosol;Data;Development;Dopamine;Dose;Drug Kinetics;Enzymes;Evaluation;Event;Exhibits;Food;Future;Generations;Goals;Growth Factor;Half-Life;Health;Hepatic;Hydroxyl Radical;Ilex vomitoria;In Vitro;Intravenous;Investigational New Drug Application;Ion Channel;Lead;Libraries;Lobeline;Measures;Metabolism;Methamphetamine;Modification;Molecular Bank;National Institute of Drug Abuse;Neurotransmitters;Nicotinic Receptors;Oral;Oral Administration;Outcome;Peptides;Pharmaceutical Preparations;Phase;Plasma;Preparation;Prodrugs;Property;Prostaglandins;Rattus;Rewards;Route;Safety;Salts;Second Messenger Systems;Self Administration;Site;Slice;Somatotropin;Specificity;Steroids;Structure-Activity Relationship;Sucrose;Synapses;Synaptic Vesicles;Therapeutic;Therapeutic Agents;Translations;Variant;Vesicle;Work;analog;base;dihydrotetrabenazine;dopamine system;dopamine transporter;effective therapy;extracellular;improved;inhibitor/antagonist;methamphetamine abuse;neurotoxic;neurotoxicity;new therapeutic target;novel;piperidine;pre-clinical;preference;second messenger;small molecule;sulfation;uptake;vesicular monoamine transporter 2;water solubility

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Currently there is no pharmacotherapeutic available for methamphetamine abuse. The overall objective of this project is to provide a clinical candidate for the treatment of methamphetamine abuse. Recently we identified a novel small molecule (GZ-793A) which potently and selectively interacts with the vesicular monoamine transporter-2 and which exhibits potency and specificity in decreasing responding for intravenous methamphetamine in an animal model of self-administration. We propose to expand our existing molecular library by performing the final steps of optimization of the chemical structure of GZ-793A with the aim of providing additional leads that are druggable orally-bioavailable high value preclinical candidates. The outcome of the proposed project is to bring the best candidate to comprehensive toxicological evaluation for preparation of an Investigational New Drug application to the FDA as a proposed treatment for methamphetamine abuse.


application_id: 8879950
project_number: 7K01AG040164-03
project_title: Neuroimaging Assessments of Brain Integrity in Aging Mice
administering_ic: NIA
award_notice_date: 2014-08-27
opportunity_number: PA-14-078
application_type: 7
activity_code: K01
ic: AG
serial_number: 040164
program_official: WISE, BRADLEY C
project_start_date: 2014-07-01
project_end_date: 2017-07-31
study_section: Basic Neuroscience of Aging Study Section[NIA-N]
contact_pi_person_id: 10518078
contact_pi: LIN, AI-LING
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of my research career is to use state-of-the-art non-invasive brain imaging methods (magnetic resonance imaging and spectroscopy (MRI/MRS) and positron emission tomography (PET)) to assess brain metabolic hemodynamic and neuronal (structural and functional) integrity and its associations with cognitive function in animal models of healthy aging and of age-related neurodegenerative disorders. The goals of my training program are: 1) to "reversely translate" the neuroimaging methods for assessing hemodynamics and metabolism from humans to rodent models; 2) to receive training in the biology of aging using rodent models with an emphasis on metabolic physiology; 3) to apply these newly found skills to the investigation of the mechanisms of action of aging and potential protective effects of caloric restriction (CR); and 4) to have hands-on training in behavioral testing for rodents and identify the association between imaging and behavioral results. The research objective of this proposal is to use high-field MRI/MRS and PET to investigate the brain integrity of aging mice and identify possible protective effects of CR.  In the brain mitochondrial oxidative phosphorylation of glucose is the predominant source of energy (ATP production) supporting energy demands (maintaining neuronal integrity and basal firing rates). A widely accepted cause of the functional losses that accompany aging both in the brain and in other organs is decreased brain metabolism. In support of this viewpoint a host of neuroimaging studies show that cerebral metabolic rates of oxygen (CMRO2) glucose (CMRGlc) and cerebral blood flow (CBF) decline with age and decline still more rapidly and profoundly in neurodegenerative disorders such as Alzheimer's Disease (AD). It is generally believed therefore that preserving bioenergetics (i.e. glucose oxidative capacity) is critical fr optimizing lifespan and healthspan. Interventions have been introduced to preserve metabolism in aging process. CR perhaps is the most well-studied one for various model organisms of extended longevity including Saccharomyces cerevisiae Caenorhabditis elegans rodents and monkeys. In the neuronal system CR has shown to attenuate age-related metabolic dysfunction and neuromuscular synaptic loss and to enhance cognitive function.  The rationale of the study therefore is to characterize the effect of CR on in vivo brain metabolic hemodynamic and neuronal (structural and functional) integrity in aging using non-invasive multimodal neuroimaging methods and the association of the neuroimaging indices with the cognitive testing. The central hypothesis of this proposal is that cerebral metabolic function will decline i normal aging and consequently reduce brain structural functional and cognitive integrity; mice with CR intervention will demonstrate: preserved CMRO2 CBF CMRGlc total ATP concentration; and thus preserved brain structure functional connectivity and cognition during aging. The hypothesis will be tested by pursuing three specific aims: 1) Determine effects of normal aging on brain metabolic and hemodynamic integrity and possible protective effects of CR; 2) Determine effects of normal aging on neuronal (structural and functional) integrity and possible protective effects of CR; and 3) Determine effects of normal aging on cognitive integrity and possible protective effects of CR. The approach is innovative because it investigates the CR protective effect on in vivo brain metabolism in aging process with non-invasive neuroimaging methods; it uses complementary multi- parametric non-invasive imaging methods (MRI MRS and PET) to explore the physiological effects of mitochondrial alterations for the first time; it uses quantitative imaging techniques (developed by the PI for humans) at ultra-high field (11.7T) and in rodents the first time this has been done; and it willbe the first study to investigate the correlation between cognitive effects (memory and spatial information processing) and brain imaging results in the CR mouse model. The proposed research is significant because 1) physiological effects of metabolic alterations in aging and age-related neuronal disorders disease progression and treatment efficacy can be monitored non-invasively and nondestructively; 2) the interplay between brain metabolic structural and cognitive functions in aging can be identified; and 3) these multi-metric imaging methods can be translated seamlessly from rodents to non-human primates and to humans.  Collectively the training provide by the Career Development Award will place me at the cutting edge of aging research of animal neuroimaging and of their combination: translational neuroimaging of aging. Translational neuroimaging is an emerging field with extraordinary promise. My ambition is to become pioneer in this emerging discipline.

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

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


application_id: 8879344
project_number: 1R15GM109269-01A1
project_title: Investigation of Candidate Modifier Loci for Cancer Susceptibility
administering_ic: NIGMS
award_notice_date: 2015-07-23
opportunity_number: PA-13-313
application_type: 1
activity_code: R15
ic: GM
serial_number: 109269
suffix: A1
program_official: WILLIS, KRISTINE AMALEE
project_start_date: 2015-08-01
project_end_date: 2019-07-31
study_section: Special Emphasis Panel[ZRG1 GGG-R (80)]
contact_pi_person_id: 11294477
contact_pi: STROME, ERIN D
other_pis: Not Applicable
congressional_district: 04
department: BIOLOGY
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
project_abstract:
DESCRIPTION (provided by applicant):    
Variance in age of onset type of cancer developed and outcome occur in populations of women who carry the same BRCA1 mutations. One explanation for these different cancer risks relates to the potential for other genetic loci termed modifier genes to influence cancer risk. Commonly used methodologies to discover modifier genes rely either on prior knowledge of gene function or are discovered through genome-wide association studies which are capable of determining loci of interest but not specific genes. These methodologies have therefore resulted in limited discovery of secondary genetic loci impacting cancer incidence. Identification of modifier loci has the potential to save lives and the healthcare system money aiding in development of diagnostic tests for preemptive treatment as with BRCA1 testing and identifying mechanistic cause as a starting point for therapeutic treatments. Therefore we have sought to overcome the limitations of current approaches for identifying novel cancer susceptibility genes through development of an innovative approach utilizing the budding yeast S. cerevisiae to screen the genome for heterozygous mutations that modify genomic instability in strains that are deficient for genes that encode proteins functionally related to BRCA1. The utilization of a budding yeast model is appropriate in this situation as eukaryotes possess well-conserved pathways to monitor genomic stability and respond to DNA damage and furthermore are genetic malleable and tractable have high speeds of growth are easy of handle and are highly accessible to undergraduate students. In this application we propose studies that will help to determine the mechanism of action of these candidate modifiers thereby creating a ranked pipeline of genes whose homologs may be investigated for modifier status in human studies. Two particular groups of genes were identified based on their haploinsufficient effects on genomic instability those impacting nutrient availability and those whose impact is checkpoint-deficient dependent. In studying nutrient availability we seek to determine the scope of genes involved in these responses and their dosage sensitivities and then test our hypothesis that TOR pathway and autophagy regulation are altered leading to chromosome loss events. Modifiers shown to have checkpoint-deficient dependency where identified based on a rad9-deficiency in the DNA damage checkpoint pathway; to investigate the mechanism of this phenotype we will test double mutant combination with other DNA damage checkpoint genes and other point specific checkpoint deletions. Ultimately we will identify orthologous mammalian genes that can then serve as candidate genetic modifiers of cancer risk in ongoing epidemiologic studies. This information will provide new insights into cancer predisposition in susceptible individuals as well
as identify factors that may mediate a cancer cell's response to treatment modalities that damage DNA or interfere with chromosome segregation. By engaging undergraduate research students in genetic and molecular based projects the planned proposal meets the goals of the NIH AREA program.

project_terms:
Address;Age;Age of Onset;Animal Model;Area;Autophagocytosis;BRCA1 Mutation;BRCA1 Protein;BRCA1 gene;BRCA2 gene;Biological Assay;Biological Models;Biomedical Research;Cancer-Predisposing Gene;Candidate Disease Gene;Cell Line;Cells;Chromosomal Instability;Chromosome Segregation;Chromosomes;Code;Complex;DNA Damage;DNA damage checkpoint;Data Set;Databases;Dependency (Psychology);Development;Diagnosis;Diagnostic tests;Diploidy;Early Diagnosis;Early treatment;Environment;Epidemiologic Studies;Eukaryota;Evaluation;Event;Gene Mutation;Genes;Genetic;Genetic Polymorphism;Genome;Genome Stability;Genomic Instability;Goals;Growth;Healthcare Systems;High-Risk Cancer;Homologous Gene;Human;Incidence;Individual;Insertional Mutagenesis;Institution;Investigation;Kentucky;Knowledge;Maintenance;Malignant Neoplasms;Mammalian Cell;Mammary gland;Mediating;Metabolism;Methodology;Methods;Modality;Modeling;Modification;Molecular;Molecular Biology;Molecular Genetics;Monitor;Mutate;Mutation;Mutation Spectra;Nutrient;Other Genetics;Outcome;Pathway interactions;Penetrance;Phenotype;Population;Positioning Attribute;Predisposition;Proteins;Regulation;Reporter;Research;Role;Saccharomyces cerevisiae;Saccharomycetales;Secure;Signal Pathway;Signal Transduction;Small Interfering RNA;Specificity;Speed (motion);Students;System;Techniques;Tertiary Protein Structure;Testing;Therapeutic;Time;Training;United States National Institutes of Health;Universities;Woman;Yeast Model System;Yeasts;amino acid metabolism;base;cancer cell;cancer diagnosis;cancer genetics;cancer risk;cancer type;career;chromosome loss;dosage;gene function;genome wide association study;improved;innovation;insight;interest;meetings;mutant;mutation carrier;novel;programs;public health medicine (field);public health relevance;rad9 protein;response;statistics;therapeutic development;undergraduate research;undergraduate student

public_health_relevance:
PUBLIC HEALTH RELEVANCE:    
The objective of the proposed research is relevant to public health because it seeks to identify candidate cancer susceptibility modifier loci which will aid in diagnosis and uncover new targets for therapeutic development. Compared to currently used methods we are able to detect heterozygous mutations with haploinsufficiency effects on genome instability using the Saccharomyces cerevisiae model system. In this application we propose studies that will help to determine the mechanism of action of these candidate modifiers thereby creating a ranked pipeline of genes whose homologs may be investigated for modifier status in human studies. In addition to advancing the field of modifier loci identification this multi-disciplinary project mets the stated objectives of the AREA program by offering undergraduate students hands-on training in classical genetics and modern molecular techniques and strengthens the research environment at Northern Kentucky University.


application_id: 8879089
project_number: 5U01DA036158-03
project_title: Kentucky TRIALS Research Center
administering_ic: NIDA
award_notice_date: 2015-06-25
opportunity_number: RFA-DA-13-009
application_type: 5
activity_code: U01
ic: DA
serial_number: 036158
program_official: JONES, DIONNE
project_start_date: 2013-07-01
project_end_date: 2016-06-30
study_section: ZDA1-EXL-T(11)S
contact_pi_person_id: 1873108
contact_pi: LEUKEFELD, CARL G
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This cooperative agreement Center application the Kentucky TRIALS Substance Abuse and HIV Research Center (KY-TRIALS) is submitted by the University of Kentucky in cooperation with the Kentucky Department of Juvenile Justice community substance abuse service organizations and HIV service providers to respond to RFA-DA-13-009 "Translational Research on Interventions for Adolescents in the Legal System: TRIALS". This project focuses on filling the need for implementation studies to enhance continuity of care for juvenile justice Involved adolescents. Kentucky provides an ideal setting to study the implementation of evidence-based practices because of our longstanding Juvenile Justice and university relationship. KY-TRIALS is well-positioned to conduct rigorous research on implementing evidence-based practices. The Overall Aim of the KY-TRIALS Substance Abuse and HIV Research Center is to collaborate in developing and testing implementation strategies and associated measures to improve the continuum of substance abuse and HIV prevention and treatment services for youth under juvenile justice supervision. The KY-TRIALS approach Incorporates theoretical frameworks of implementation science (Proctor et. al. 2009; Aarons et al. 2011) and organizational change to examine how evidence-based practices are implemented into practice in organizational settings. Our conceptual approach draws upon our experience in implementation science and previous cooperative studies to carry out the KY-TRIALS research center vision and research. This application presents 4 proven and partner-rich Center Committees: 1) Design and Measures 2) Study Implementation 3) Data Management and Analysis and 4) Publications for achieving success in the aims of TRIALS in concert with our KY-TRIALS Center Steering Committee the national TRIALS Steering Committee and the National Institute on Drug Abuse. Letters of commitment include our state's Juvenile Justice Commissioner; Acting Director of the Division of Behavioral Health; Executive Director of the Kentucky Office of Drug Control Policy; juvenile justice officials; and community substance abuse and HIV service providers to support our innovative vision.

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

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


application_id: 8878521
project_number: 2R01NS070899-06
project_title: Regulation signaling and dynamics of glucan phosphatases
administering_ic: NINDS
award_notice_date: 2015-02-10
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: NS
serial_number: 070899
program_official: STEWART, RANDALL R
project_start_date: 2010-07-01
project_end_date: 2020-04-30
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Affect;Aminoglycosides;Binding (Molecular Function);Biochemical;Biochemistry;Biological Assay;Biology;Carbohydrates;Cell Culture Techniques;Cells;Clinical;Complex;Comprehension;Diagnosis;Disease;Disease Progression;Energy Metabolism;Enzymes;Epilepsy;Event;Family;Fibroblasts;Genes;Glucans;Glycogen;Glycogen Phosphorylase;Glycogen Storage Disease;Goals;Inherited;Lafora Disease;Lead;Life;Link;Liver;Metabolism;Methods;Missense Mutation;Modeling;Molecular;Mus;Muscle;Mutagenesis;Mutation;Mutation Spectra;Nature;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Nonsense Codon;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Physiological;Play;Point Mutation;Process;Progressive Myoclonic Epilepsies;Proteins;Proteome;Protocols documentation;Reading;Regulation;Reporting;Role;Signal Transduction;Starch;Structure;Symptoms;Testing;Therapeutic;Tissues;Translating;Ubiquitin;Ubiquitination;Water;Work;X-Ray Crystallography;biochemical tools;cell type;design;disease-causing mutation;glycogen metabolism;in vivo;insight;loss of function mutation;member;mouse model;neuron apoptosis;neurotoxicity;novel;novel therapeutics;particle;potency testing;public health relevance;screening;tool;ubiquitin-protein ligase


