# projects

application_id: 8241979
project_number: 5P01AG005119-24
project_title: Beta Amyloid and Oxidative Stress in Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2012-03-19
application_type: 5
activity_code: P01
ic: AG
serial_number: 005119
program_official: REFOLO, LORENZO
project_start_date: 1997-05-15
project_end_date: 2014-03-31
study_section: ZAG1-ZIJ-4(O4)
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
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
budget_start_date: 2012-04-01
project_abstract:
DESCRIPTION (provided by applicant):   Alzheimer's disease (AD) is one of the major health problems in this country and affects over 4.5 million persons. The key to the disease is understanding the pathogenesis of neuron degeneration in specific brain regions so that treatment and prevention can be based on solid data. This application is a resubmission of a competitive renewal of the program project "Beta-Amyloid and Oxidative Stress in AD" (P01 AG05119-20) by the Sanders-Brown Center on Aging at the University of Kentucky (UK). Abundant evidence indicates that free radical mediated oxidative damage in the brain is prominent in AD especially in the earliest detectable clinical phase of AD - mild cognitive impairment (MCI). The major hypothesis of this application is that beta amyloid peptide (AB) is one of the pivotal mechanisms in oxidative stress/damage to neurons in AD. The proposal consists of three cores including 1) an Administrative Core that provides supervision fiscal management biostatistical support and database management clinical and neuropathological data and brain specimens from the UK AD Center 2) a unique Beta-Amyloid Core that will provide the AB index (total AB{1-40} and AB{1-42} AB solubility oligomeric and fibrillar AB  quantitation and plaque quantitation) from human subjects and transgenic mice and also will provide toxic assembled AB  and non-toxic scrambled AB  for cell culture experiments and 3) an Animal Core that will supply APP/PS1 knock-in mutant mice and WT mice and primary rodent cortical neuron cultures for projects. Each project uses short postmortem brain specimens from longitudinally followed preclinical AD (PCAD) MCI late AD normal controls and frontotemporal dementia (as a disease control) subjects APP/PS1 transgenic mice and cell cultures and each has a therapeutic component and excellent preliminary data to support their hypotheses.

Project 1 examines the hypothesis that brain RNA oxidation is an early event in AD and is mediated at least in part by Ap and that the RNA oxidation impairs protein synthesis and contributes to neuron dysfunction. Project 2 examines the hypothesis that AB-mediated oxidative modifications of and subsequent dysfunction of Pin1
are fundamental to the genesis of specific pathological features in AD. Project 3 will examine the hypothesis that elevations in RAGE-ligand interactions occur in AD with soluble RAGE modulating Ap assembly and toxicity. Project 4 examines the hypothesis that sustained activation of NADPH oxidase by toxic forms of AB
triggers a cascade linking increased ROS to altered redox-based signaling and neurotoxic oxidative damage.
This well integrated program project will move the field of AB and oxidative stress in AD forward and gain insights into mechanisms of neuron degeneration so that successful interventions can be developed to treat or prevent the most dehumanizing disorder to affect humans.

project_terms:
APP-PS1;Address;Affect;Aging;Alzheimer's Disease;Amyloid beta-Protein;Animals;Autopsy;Brain;Brain region;Cell Culture Techniques;Clinical;Collection;Country;Data;Data Base Management;Databases;Deposition;Development;Disease;Event;Free Radicals;Frontotemporal Dementia;Functional disorder;Goals;Health;Human;Individual;Intervention;Kentucky;Knock-in Mouse;Knowledge;Left;Length;Ligands;Link;Mediating;Modification;Molecular;Mus;Mutant Strains Mice;NADPH Oxidase;Nerve Degeneration;Neurons;Neuropsychological Tests;Oxidation-Reduction;Oxidative Stress;Pathogenesis;Patients;Persons;Phase;Prevention;Process;Program Research Project Grants;Protein Biosynthesis;RNA;Research;Resources;Rodent;Role;Signal Transduction;Solid;Solubility;Specimen;Staging;Supervision;Therapeutic;Therapy Clinical Trials;Tissues;Toxic effect;Transgenic Mice;Universities;base;biomarker;defined contribution;disorder control;human data;human subject;in vivo;indexing;insight;member;mild cognitive impairment;mouse model;neurochemistry;neurotoxic;novel;oxidation;oxidative damage;pre-clinical;prevent;programs;research study;successful intervention


application_id: 8241392
project_number: 3U10NS053368-05S2
project_title: Neuroprotection Exploratory Trials in PD (NET-PD)
administering_ic: NINDS
award_notice_date: 2011-03-18
opportunity_number: RFA-NS-05-004
application_type: 3
activity_code: U10
ic: NS
serial_number: 053368
suffix: S2
program_official: MOY, CLAUDIA S
project_start_date: 2006-05-17
project_end_date: 2012-11-30
study_section: ZNS1-SRB-K(30)
contact_pi_person_id: 1868189
contact_pi: CAMBI, FRANCA
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Parkinson's disease (PD) is a slowly but relentlessly progressive neurodegenerative disorder resulting in atime-dependent worsening of clinical symptoms. Anti-PD drugs effectively ameliorate most of the majorparkinsonian signs and symptoms in a majority of patients. However traditional drug therapies do notmodify the progressive deterioration of motor function and functional disability worsens over time. Thusdisease modifying drugs that can slow clinical progression enhance repair of damaged neurons restore orenhance function of residual parts of the dopamine (DA) system are much needed. Since diseaseprogression is generally slow treatment with compounds that target multiple pathogenic mechanisms can beimplemented over a relatively long period of time.The NET-PD multicenter trial is aimed at testing theefficacy of potential neuroprotective compounds in early stage PD patients. Compounds that areascertained to be effective in the Futility studies will be tested in large double-blinded placebo controlstudies. The Neurodegeneration and Clinical Trial Groups of the NINDS are requesting applications for newcenters to collaborate in clinical trials to test potential neuroprotective agents. We are proposing to becomea NET-PD center. The Movement Disorders Center at University of Kentucky serves the greater Lexingtonarea a primarily urban community and the largely rural 63-county area of central eastern and southeasternKentucky. In addition we treat several PD patients (-25) who reside in West Virginia and Southern Ohio.We follow -600 PD patients and we diagnose on average 5 new PD patients per month. Therefore weexpect to be able to enroll 1-2 early stage PD patients per month into the Pilot Trials.

project_terms:
Area;Clinical;Clinical Trials;Clinical Trials Cooperative Group;Communities;County;Deterioration;Diagnosis;Disease;Disease Progression;Double-Blind Method;Enrollment;Futility;Kentucky;Motor;Movement Disorders;Multicenter Trials;National Institute of Neurological Disorders and Stroke;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Neuroprotective Agents;Ohio;Parkinson Disease;Parkinsonian Disorders;Patients;Pharmaceutical Preparations;Pharmacotherapy;Request for Applications;Residual state;Rural;Signs and Symptoms;Staging;Symptoms;Testing;Time;Universities;West Virginia;dopamine system;efficacy testing;functional disability;neuroprotection;pilot trial;placebo controlled study;repaired


application_id: 8240040
project_number: 5R01ES017244-02
project_title: Prevention of UV-induced carcinogenesis by cyanidin-3-glucoside
administering_ic: NIEHS
award_notice_date: 2012-04-24
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: ES
serial_number: 017244
program_official: QUINN, ASHLINN KO
project_start_date: 2011-08-01
project_end_date: 2016-03-31
study_section: Special Emphasis Panel[ZRG1-OTC-N(03)M]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
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): Epidemiological clinical and laboratory studies have implicated that ultraviolet radiation (UV) is a complete environmental carcinogen and that repeated exposures can lead to the development of melanoma and nonmelanoma skin cancers. In addition to sunscreens chemoprevention of skin cancer by natural non-toxic compounds is suggested as an effective strategy to prevent the incidence of skin cancer. Our in vitro and in vivo studies on cyanidin-3-glucoside (C3G) a compound found in blackberries and other foods show that this compound is able to inhibit NF-:B AP-1 COX2 and TNF1 activation/expression neoplastic transformation cancer cell migration and invasion and induction of apoptosis in HL60 cells. C3G also functions as an antioxidant by inhibiting the generation of reactive oxygen species and inducing antioxidant-regulative transcription factors. These preliminary studies indicate that C3G may function as a potential chemopreventive and chemotherapeutic agent. The overall hypothesis of this application is that C3G functions as an antioxidant and inhibits oxidative stress activation of transcription factors and inflammatory signaling proteins leading to protection against UVB-induced carcinogenesis. Specific Aim 1. In vitro and in vivo investigation of antioxidant properties of C3G. Electron spin resonance (ESR) spin trapping will be used to determine the reaction rates of C3G toward hydroxyl (7OH) and superoxide (O27-) radicals using Fenton reaction (Fe(II) + H2O2) and xanthine/xanthine oxidase as sources of these free radicals in a non-cellular system and to investigate antioxidant activities against UVB-induced 7OH and O27- radicals in a cellular system. Low frequency (in vivo) ESR will be also used to study antioxidant activities of C3G against UVB-generated O27- and 7OH radicals in the skin of SKH-1 hairless mice. Specific Aim 2. In vivo investigation of the effects of C3G on UVB-induced oxidative stress and activation of oxidative stress sensitive transcription factors. We will investigate the effects of C3G on UVB-induced lipid peroxidation protein oxidation and oxidative DNA damage in KSH mice. We will also study the effects of C3G on UVB-induced activation of activation protein (AP)-1 nuclear factor (NF)-:B and nuclear factor of activated T cells (NAFT) in transgenic mice. Specific Aim 3. Investigate the effects of C3G on UVB-induced inflammatory mediators. These inflammatory mediators include infiltrating leukocytes and myeloperoxidase (MPO) COX-2 PGE2 and several pro-inflammatory cytokines TNF-1 IL-2 and IL-6. Specific Aim 4. Investigation of the effects of C3G on UVB-induced tumorigenesis and early biomarkers. These markers include changes in thymine-positive cells proliferative cell nuclear antigen terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and apoptotic cells together with a change in p53 and p21/cip1- positive cell population in epidermis. These studies will provide a mechanistic rationale for an early on C3G efficacy in skin cancer prevention.    PUBLIC HEALTH RELEVANCE: The incidence of UV-induced skin cancer is a major public health concern. Present study attempts to identify cyanidin-3-glucoside a plant-derived compound as a mechanism-based preventive agent against UV-induced skin cancers.

project_terms:
Acetates;Animal Model;Anthocyanins;Anthracenes;Antioxidants;Apoptosis;Apoptotic;Berry;Cabbage - dietary;Cells;Chemicals;Chemoprevention;Chemopreventive Agent;Chronic;Chronic Disease;Clinical Research;Complement Factor B;Consumption;DNA Nucleotidylexotransferase;Development;Diet;Dinoprostone;EGF gene;Electron Spin Resonance Spectroscopy;Environmental Carcinogens;Enzymes;Epidemiologic Studies;Epidermis;Epigallocatechin Gallate;Exhibits;Family;Food;Free Radicals;Frequencies (time pattern);Generations;Glucosides;Grapes;Green tea (dietary);Growth Factor;HL-60 Cells;Human;Hydrogen Peroxide;Hydroxyl Radical;In Vitro;Inbred HRS Mice;Incidence;Individual;Induction of Apoptosis;Inflammation;Inflammation Mediators;Inflammatory;Interleukin-2;Interleukin-6;Investigation;Label;Laboratories;Laboratory Study;Lead;Leukocytes;Link;Lipid Peroxidation;MAP Kinase Gene;Malignant Neoplasms;Mediating;Mediator of activation protein;Methods;Micronutrients;Milk Thistle;Minerals;Mus;Neoplastic Cell Transformation;Non-Malignant;Nuclear;Nuclear Antigens;Oxidative Stress;PTGS2 gene;Peroxidases;Phytochemical;Pigments;Plants;Population;Prevention;Preventive;Property;Prostaglandins;Proteins;Reaction;Reactive Oxygen Species;Signal Pathway;Signaling Protein;Skin;Skin Cancer;Skin Carcinoma;Source;Spin Trapping;Stimulus;Sunlight;Sunscreening Agents;Superoxides;System;TNF gene;Therapeutic;Thymine;Topical application;Transgenic Mice;Tumor Necrosis Factor-alpha;UVB induced;Ultraviolet B Radiation;Ultraviolet Rays;Vitamins;Xanthine Oxidase;Xanthines;ascorbate;base;biomarker;cancer cell;carcinogenesis;cell motility;cell transformation;chemotherapeutic agent;cyclooxygenase 2;cytokine;fruits and vegetables;high risk;in vivo;melanoma;member;nuclear factor 1;nuclear factors of activated T-cells;oxidation;oxidative DNA damage;prevent;protein activation;public health medicine (field);public health relevance;reaction rate;silibinin;skin cancer prevention;transcription factor;tumorigenesis

public_health_relevance:
Narrative summary:The incidence of UV-induced skin cancer is a major public health concern. Present study attempts to identifycyanidin-3-glucoside a plant-derived compound as a mechanism-based preventive agent against UV-inducedskin cancers.


application_id: 8239902
project_number: 5R01AG019241-10
project_title: Prevention of Alzheimer's Diseae by Vitamin E and Selenium
administering_ic: NIA
award_notice_date: 2012-02-14
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AG
serial_number: 019241
program_official: RYAN, LAURIE M
project_start_date: 2001-09-30
project_end_date: 2015-08-31
study_section: Neurological, Aging and Musculoskeletal Epidemiology Study Section[NAME]
contact_pi_person_id: 9662252
contact_pi: SCHMITT, FREDERICK
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) the most common late-onset dementing disorder affects approximately four million individuals in the USA and is projected to affect 14 to 16 million individuals by the year 2050. Prevention may be the key to eliminate AD. It is clear that oxidative damage plays a role in the pathogenesis of AD and our studies show that it is present in mild cognitive impairment (MCI) the earliest phase of AD and thus preventive measures should be initiated in the presymptomatic stages. This research project is an add-on study to the Selenium (Se) and Vitamin E Prostate Cancer Prevention Trial (SELECT). The SELECT study is funded by the NCI to assess the effect of Se and vitamin E alone and in combination on the reduction of incidence of prostate cancer in 35534 healthy men age 55 or older (50 or older if African American). The Prevention of Alzheimer's Disease by Vitamin E and Selenium (PREADVISE) evaluates the effectiveness of these supplements on reducing incident AD and other dementias in a group of more than 6100 men (17% of whom are minorities recruited from the SELECT Study). The study duration is 12 years. While SELECT has reached its recruitment goal PREADVISE has permission to continue recruiting to exceed 6500 participants. This is the first randomized controlled trial to evaluate the effect of antioxidants (vitamin E and Se) on preventing dementia in the elderly. The specific aims are:1) To define the effect of Se and vitamin E in combination and alone in the reduction of the incidence of AD as determined by the clinical evaluation in a population of men age 62 or older (60 if minority) participating in SELECT; 2) To assess the effect of Se and vitamin E on the reduction of other neurodegenerative dementing diseases while also ascertaining the effect of the supplements on transition from normal to MCI and from MCI to AD and dementia;. 3) To validate the two-stage screening methodology with in-depth longitudinal cognitive assessments in a subset of 500 subjects who "pass" their initial screen; 4) To increase the number of subjects in PREADVISE to 6504 or more; and 5) To emphasize retention of subjects in PREADVISE and SELECT.

project_terms:
Affect;African American;Age;Aging-Related Process;Alzheimer disease prevention;Alzheimer's Disease;Antioxidants;Authorization documentation;Clinical Trials;Cognitive;Country;Critiques;DNA;Data;Dementia;Diagnostic Procedure;Disease;Double-Blind Method;Early treatment;Effectiveness;Elderly;Etiology;Evaluation;Event;Frontotemporal Dementia;Funding;Goals;Incidence;Individual;Lewy Body Disease;Lipid Peroxidation;Lipids;Malignant neoplasm of prostate;Measures;Methodology;Minority;Monitor;National Cancer Institute;Nerve Degeneration;Neurodegenerative Disorders;Oxidative Stress;Participant;Pathogenesis;Phase;Play;Population;Prevalence;Prevention;Preventive;Progressive Supranuclear Palsy;Prostate Cancer Prevention Trial;Proteins;RNA;Randomized Controlled Trials;Recruitment Activity;Research Personnel;Research Project Grants;Role;Screening procedure;Selenium;Selenium and Vitamin E Efficacy Trial;Solid;Staging;United States;Vascular Dementia;Vitamin E;age effect;base;cognitive function;corticobasal degeneration;cost;disorder prevention;effective therapy;ethnic minority population;experience;men;men's group;mild cognitive impairment;normal aging;oxidation;oxidative damage;prevent;research clinical testing;treatment duration


application_id: 8239698
project_number: 1R21NS077434-01
project_title: Inhibition of Lipid Peroxidation in SCI
administering_ic: NINDS
award_notice_date: 2011-09-16
opportunity_number: PA-10-069
application_type: 1
activity_code: R21
ic: NS
serial_number: 077434
program_official: KLEITMAN, NAOMI
project_start_date: 2011-09-16
project_end_date: 2013-08-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): We have previously shown that generation of the potent reactive nitrogen species (RNS) peroxynitrite (PN) is responsible for oxidative damage by lipid peroxidation (LP) and protein modification (carbonylation and tyrosine nitration) to mitochondrial and other cellular elements during the first hrs after spinal cord injury (SCI). The PN-mediated oxidative damage leads to brain mitochondrial dysfunction and ultimately failure. As a consequence of oxidative compromise of mitochondrial function including calcium (Ca++) buffering) posttraumatic intracellular Ca++ overload is exacerbated leading to calpain-mediated cytoskeletal degradation neurodegeneration and neurological impairment. We have further shown that treatment with the potent LP inhibitor U-83836E can partially attenuate posttraumatic brain LP damage mitochondrial dysfunction and calpain-mediated cytoskeletal damage in a mouse TBI model. Most importantly the window for this effect is at least 12 hrs post-injury. However our preliminary results showing a partial attenuation of post-injury LP-related neural damage' even when the LP inhibitor is administered within the first 15 min. after injury strongly point to the logic of an antioxidant neuroprotective strategy that combines a LP inhibitor U-83836E with the LP-derived lipid aldehyde 4-hydroxynonenal (4-HNE) scavenger phenelzine to achieve a greater degree of neuroprotection. Therefore the overall goal of the proposed experiments is to explore the hypothesis that interrupting post-traumatic secondary oxidative damage at multiple points will produce a quantitatively greater neuroprotective effect with less variability that will have a greater chance of translational success in future SCI clinical trials. The combination approach should not only increase the maximal neuroprotective effect but may also prolong the therapeutic window for inhibition of secondary brain injury after TBI.  
  
PUBLIC HEALTH RELEVANCE: This project will examine the potentially greater benefits that might be obtained in the rat thoracic spinal cord contusion injury model when multiple neuroprotective compounds that target oxidative secondary injury mechanisms are administered together. Specifically we will test a dual treatment strategy involving the combination of the potent lipid peroxidation-inhibiting drug U-83836E with phenelzine a commercially available compound that scavenges the neurotoxic lipid peroxidation-derived lipid aldehyde 4-hydroxynonenal (4-HNE). Each of the compounds will also be tested by themselves in order for comparison to the combination treatments.

project_terms:
2266-tetramethyl-4-piperidinol-N-oxyl;3-nitrotyrosine;4 hydroxynonenal;Acute;Aldehydes;Antioxidants;Attenuated;Bladder Control;Brain;Brain Injuries;Buffers;Calcium;Calpain;Carbonates;Cell physiology;Clinical Trials;Contusions;Cytoplasm;Cytoskeletal Proteins;Dose;Early treatment;Elements;Failure (biologic function);Free Radicals;Functional disorder;Future;Generations;Goals;Hour;Hydroxyl Radical;Impairment;Injury;Lead;Lipid Peroxidation;Lipids;Locomotor Recovery;Logic;Mediating;Membrane Lipids;Mental Depression;Mitochondria;Modeling;Mus;Nerve Degeneration;Neurologic;Neurological outcome;Nitric Oxide Synthase;Nitrogen Dioxide;Peroxonitrite;Pharmaceutical Preparations;Phenelzine;Post-Translational Protein Processing;Production;Proteolysis;Rattus;Reactive Nitrogen Species;Reactive Oxygen Species;Recovery;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;Stress;Testing;Therapeutic;Thoracic spinal cord structure;Tissues;Traumatic Brain Injury;Treatment Efficacy;Tyrosine;Work;attenuation;controlled cortical impact;improved;lipid peroxidation inhibitor;mitochondrial dysfunction;neuroprotection;neurotoxic;nitration;oxidative damage;perhydroxyl radical;relating to nervous system;research study;respiratory;success;treatment strategy;uptake;white matter

public_health_relevance:
This project will examine the potentially greater benefits that might be obtained in the rat thoracic spinal cord contusion injury model when multiple neuroprotective compounds that target oxidative secondary injury mechanisms are administered together. Specifically we will test a dual treatment strategy involving the combination of the potent lipid peroxidation-inhibiting drug U-83836E with phenelzine a commercially available compound that scavenges the neurotoxic lipid peroxidation-derived lipid aldehyde 4-hydroxynonenal (4-HNE). Each of the compounds will also be tested by themselves in order for comparison to the combination treatments.


application_id: 8239577
project_number: 5R01ES018883-03
project_title: HIF-alphia in Cr(VI) carcinogenesis
administering_ic: NIEHS
award_notice_date: 2012-02-29
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: ES
serial_number: 018883
program_official: QUINN, ASHLINN KO
project_start_date: 2010-08-09
project_end_date: 2015-03-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 10011919
contact_pi: ZHANG, ZHUO
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): Although the carcinogenicity of Cr(VI) has been well documented by studies both in vitro and in vivo its mechanism of action remains to be investigated. Our recent studies indicate that Cr(VI) induces HIF-11 activation. MAP kinase p38 and reactive oxygen species (ROS) are involved in this process. HIF-11 is a key regulatory protein for angiogenesis which is a physiological process involving the growth of new blood vessels from pre-existing vessels. Solid tumors of smaller than 1 to 2 cubic millimeters are not vascularized. To spread they need to be supplied by blood vessels that bring oxygen and nutrients and remove metabolic wastes. Inhibition of HIF-11 decreases cell transformation capacity in hypoxia and tumor growth in vivo while overexpression of HIF-11 allows anchorage-independent growth in normoxia and development of more aggressive tumors. Since HIF-11 is important in cancer initiation and progression it is likely that HIF-11 activation and angiogenesis could be important in Cr(VI)-mediated carcinogenesis. We hypothesize that ROS and HIF-11 activation play an important role in Cr(VI)-induced carcinogenesis. Human bronchial epithelial BEAS-2B cells and athymic female nude mice (3-4 weeks old) deficient in thymus-dependent (T-cell) immunological functions will be used in the present study. Three specific aims are proposed. Aim 1 will investigate the mechanism of Cr(VI)-induced ROS generation and the role of ROS in activation of HIF-11 and angiogenesis in vitro. The regulation of HIF-1 activity could occur at multiple levels: transcription translation and post-translational modifications. The questions remain open concerning at what level Cr(VI) induces HIF-11 activation. Aim 2 will answer that question in cell system. Aim 3 will investigate the roles of ROS and HIF-1 signaling in Cr(VI)-induced cell transformation in vitro tumorigenesis tumor growth and metastasis in vivo. We anticipate that Cr(VI) induces angiogenesis via HIF-11 activation through ROS and MAP kinase p38 promoting Cr(VI)-induced cell transformation tumorigenesis tumor growth and metastasis. .    PUBLIC HEALTH RELEVANCE: Hexavalent chromium [Cr(VI)] is a known human carcinogen. The carcinogenicity of Cr(VI) has been well documented by studies both in vitro and in vivo. We hypothesize that Cr(VI) induces oxidative stress and activate HIF-1 angiogenesis signalling pathway leading to cell transformation tumorigenesis tumor growth and metastasis. The goal of this proposal is to test that hypothesis.

project_terms:
Anchorage-Independent Growth;Blood Vessels;Carcinogens;Cell Hypoxia;Cell Line;Cells;Development;Diffuse;Dominant-Negative Mutation;Environmental Carcinogens;Epithelial;Exposure to;Female;Generations;Genetic Transcription;Goals;Human;Hydrogen Peroxide;Hydroxyl Radical;Hypoxia;In Vitro;Incidence;Inhalation Exposure;International Agency for Research on Cancer;MAPK14 gene;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Metabolic;NADPH Oxidase;Neoplasm Metastasis;Nose;Nude Mice;Nutrient;Occupational;Occupational Groups;Oxidative Stress;Oxygen;Pathway interactions;Physiological Processes;Play;Post-Translational Protein Processing;Process;Reactive Oxygen Species;Regulation;Reporting;Role;Signal Pathway;Signal Transduction;Small Interfering RNA;Solid Neoplasm;Source;Superoxides;System;T-Lymphocyte;Testing;Thymus Gland;Translations;Vascular Endothelial Growth Factors;Writing;angiogenesis;cancer initiation;carcinogenesis;carcinogenicity;cell transformation;chromium hexavalent ion;genetic regulatory protein;hypoxia inducible factor 1;in vivo;insight;millimeter;mitogen-activated protein kinase p38;new growth;overexpression;public health relevance;tumor;tumor growth;tumor progression;tumorigenesis;wasting

public_health_relevance:
Hexavalent chromium [Cr(VI)] is a known human carcinogen. The carcinogenicityof Cr(VI) has been well documented by studies both in vitro and in vivo. We hypothesizethat Cr(VI) induces oxidative stress and activate HIF-1 angiogenesis signalling pathwayleading to cell transformation tumorigenesis tumor growth and metastasis. The goal ofthis proposal is to test that hypothesis.


application_id: 8239234
project_number: 1R01DK091584-01A1
project_title: Novel biomarker validation and dosing algorithms for anemia management in ESRD
administering_ic: NIDDK
award_notice_date: 2011-09-19
opportunity_number: PA-09-204
application_type: 1
activity_code: R01
ic: DK
serial_number: 091584
suffix: A1
program_official: GOSSETT, DANIEL ROBERT
project_start_date: 2011-09-20
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZDK1 GRB-G (O5)]
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
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.   
   
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.

project_terms:
Address;Algorithms;Anemia;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;Patients;Peptides;Pharmaceutical Preparations;Plasma;Population;Process;Protein Fragment;Proteins;Proteome;Protocols documentation;Publishing;Randomized Controlled Clinical Trials;Randomized Controlled Trials;Research;Resistance;Risk;Sensitivity and Specificity;Serum;Serum Proteins;Surrogate Markers;Techniques;Testing;Treatment outcome;Validation;base;biomarker;cardiovascular risk factor;cost;cytokine;design;dosage;hepcidin;improved;indexing;novel;predictive modeling;prevent;response;tool;trend


application_id: 8239203
project_number: 1R01HL107640-01A1
project_title: Mechanisms of mitochondrial dysfunction in brain vasculature
administering_ic: NHLBI
award_notice_date: 2012-02-22
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: HL
serial_number: 107640
suffix: A1
program_official: REID, DIANE M
project_start_date: 2012-03-01
project_end_date: 2017-02-28
study_section: Special Emphasis Panel[ZRG1 VH-J (02)]
contact_pi_person_id: 9959914
contact_pi: TYAGI, NEETU
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Clinical data suggest an association between elevated levels of Hcy also known as hyperhomocysteine-mia (HHcy) and stroke. HHcy is generated due to increase in de-methylation of methionine by S-adenosine- homocysteine hydrolase (SAHH) and a decrease in methyltetrahydrofolate reductase (MTHFR) and cystathionine-y-lyase (CSE an enzyme responsible for Hcy metabolism to H2S a most potent vasodilator antioxidant and anti-hypertensive agent) contribute to mitochondria dysfunction (mitophagy) and ischemic stroke. Cytochrome-C transports electrons and facilitates mitochondrial bioenergetics. Interestingly during HHcy cytochrome-C becomes homocysteinylated (N-Hcy-cyt-c). However it's consequence to mitophagy and stroke is unclear. The long-term goal of this project is to understand the mechanism of mitophagy mitochondrial repair and permeability in brain vasculature during I/R injury. Our preliminary studies suggest that during I/R total Hcy levels increases causes N-Hcy-cyt-C  increases mitochondrial matrix metalloproteinase-9 (mtMMP-9) in-part degradation of mt-matrix (connexin and tight junction protein TJP) which led to mitophagy and permeability in brain vasculature. Interestingly THC decreases Hcy level and mitigates brain damage. Tetra hydro-curcumin (THC) a major herbal antioxidant and anti-inflammatory agent has shown to protect brain against I/R injury. The central hypothesis of this proposal is that HHcy contributes to mitophagy mediated brain damage through N-Hcy-cyt-C in part by increasing oxidative stress mtMMP-9 degrades connexin-43 and TJP (Figure 1). The treatment with THC CSE gene and SAHH shRNA gene transfer attenuates mitophagy and permeability. We will test this hypothesis by following three specific aims: Specific Aim #1: To determine whether the Hcy contributes to mitophagy in part by inducing oxidative stress exacerbating homocysteinylation of cytochrome-c in ischemia reperfusion and if THC CSE and SAHH shRNA gene therapy mitigates these changes. Specific Aim #2: To determine whether the homocysteinylation of cytochrome-c activates mt-MMP-9 disruption of collagen/elastin ratio mtCxn43 and mt-tight junction proteins in ischemia reperfusion and if THC CSE and SAHH shRNA gene therapy ameliorate. Specific Aim #3: To determine whether Hcy alters mitochondrial (mt) bioenergetics and cerebro-vascular remodeling in ischemia reperfusion and if THC CSE and SAHH shRNA gene therapy alleviate. These studies will demonstrate the novel mechanism of cerebrovascular remodeling and have therapeutic ramifications for mitochondrial repair in cerebral ischemic stroke.  
  
PUBLIC HEALTH RELEVANCE:  These studies will delineate the mechanisms of mitophagy and cerebrovascular remodeling in brain vasculature. The treatment with dietary herbal antioxidant tetrahydrocurcumin naked CSE DNA and SAHH shRNA gene therapy mediated stabilization of mitochondrial membrane potential by inhibition of mitochondrial DNA methylation; oxidant and proteolysis stress via novel mechanistic pathways will be powerful therapeutic strategy for preventing ischemic stroke.


application_id: 8238304
project_number: 5P01HL086670-05
project_title: Administrative Core
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 086670
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 9003
contact_pi_person_id: 7875298
contact_pi: VAN DER WESTHUYZEN, DENEYS REM
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: 2011-04-01
budget_end_date: 2012-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The purpose of this Core is to provide a central location for administrative and fiscal support for all projects.Specifically this Core will offer the following services:1. Coordinate all internal and external meetings related to the program project2. Provide fiscal management support including budgeting purchasing and account managements3. Assist in personnel matters including hiring payroll and travel4. Ensure adherence to regulatory guidelines for animal care chemical hygiene radioactivity biosafety and use of human subjects5. Facilitate the submission of progress reports in timely manner6. Provide server and web site management7. Provide support for statistical analysesCentralization of these functions will permit an efficient use of resources for the Program and ensure that alladministrative needs are performed in a manner that adheres to regulatory guidelines.

project_terms:
Accounting;Adherence (attribute);Budgets;Chemicals;Ensure;Guidelines;High Density Lipoproteins;Human Resources;Hygiene;Inflammation;Location;Metabolism;Progress Reports;Radioactivity;Resources;Services;Travel;animal care;human subject;meetings;programs;web site


application_id: 8238303
project_number: 5P01HL086670-05
project_title: Core C
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 086670
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 9002
contact_pi_person_id: 8817787
contact_pi: RATERI, DEBRA
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: 2011-04-01
budget_end_date: 2012-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The purpose of this Core is to provide a central location for the supply of mice and services related to mouse
care maintenance genotyping and experimentation. Specifically this Core will offer the following services:
1. Managing the mouse colony that includes the oversight of the generation maintenance and supply
of single and compound genetically altered mice
2. Harvesting DNA from mouse tail clips and performing PCR-based genotyping
3. Performing bone marrow transplantation
4. Preparing primary cultures of peritoneal macrophages and hepatocytes
5. Collecting plasma for isolation of lipoprotein fractions
6. Maintaining mice on specialized diets and administer pharmacological reagents as needed
7. Performing adenovirus infusions
8. Introducing radiolabeled macrophages and lipoprotein ligands into mice and collecting plasma and
tissue samples for kinetic studies
Centralization of these facilities will permit an efficient use of resources for the Program and will provide
optimal quality control and standardization across Projects.

project_terms:
Adenoviruses;Bone Marrow Transplantation;Breeding;Caring;Clip;DNA;Development;Diet;Equipment;Generations;Genotype;Harvest;Hepatocyte;High Density Lipoproteins;Housing;Inflammation;Infusion procedures;Kinetics;Ligands;Lipoproteins;Location;Maintenance;Metabolism;Methodology;Mus;Peritoneal Macrophages;Plasma;Preparation;Primary Cell Cultures;Procedures;Quality Control;Radiolabeled;Reagent;Resources;Services;Standardization;Tail;Tissue Sample;Training;base;macrophage;programs;radiotracer


application_id: 8238302
project_number: 5P01HL086670-05
project_title: Analytical and Preparative Core
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 086670
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 9001
contact_pi_person_id: 1884301
contact_pi: DE BEER, FREDERICK C.
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: 2011-04-01
budget_end_date: 2012-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The purpose of Core B is to facilitate research and stimulate collaboration between the individual projects.
Specifically Core B will offer the following services:
1. Lipoprotein isolation and characterization
2. Plasma lipoprotein analysis
3. Plasma lipid analysis
4. Labeling of proteins/lipoproteins with radioisotopes and fluorescent dyes
5. HDL remnant particle purification and characterization
6. Production of replication-defective adenoviral vectors and helper-dependent adenoviral vectors
7. Purification of total SAA and SAA isoforms
8. Isoelectric focusing
Centralization of these facilities will permit an efficient use of resources for the Program and experienced
technical staff will provide optimal quality control and standardization across Projects.

project_terms:
2-Mercaptoethanol;Acrylamides;Acute;Acute-Phase Reaction;Adenovirus Vector;Adenoviruses;Aliquot;Ampholyte Mixtures;Animals;Antibodies;Apolipoproteins;Apolipoproteins A;Argon;Autoradiography;Binding (Molecular Function);Biological Assay;Blood;Bolus Infusion;Buffers;CETP gene;COS-7 Cell;Canada;Cardiovascular system;Cells;Cellulose;Centrifugation;Chemicals;Cholesterol;Chromatography;Collaborations;Collection;Coupled;Culture Media;Cultured Cells;Cyanogen Bromide;Cytolysis;Density Gradient Centrifugation;Diagnostic;Drug or chemical Tissue Distribution;Dyes;Edetic Acid;Exclusion;Fat emulsion;Fluorescence;Fluorescent Dyes;Fractionation;Freeze Drying;Freezing;Gases;Gel;Gel Chromatography;Generations;Genes;Glass;Hand;Helper Viruses;High Density Lipoproteins;Human;Human Volunteers;Imagery;In Vitro;Incubated;Individual;Inflammation;Injection of therapeutic agent;Instruction;Iodination reaction;Iodine;Ion-Exchange Chromatography Procedure;Isoelectric Focusing;Kentucky;Label;Ligands;Lipids;Lipoproteins;London;Low-Density Lipoproteins;Lysophospholipids;Manufacturer Name;Mediating;Metabolism;Methods;Methylene Chloride;Modification;Mus;Natural regeneration;Nitrogen;Nonesterified Fatty Acids;Phase;Phospholipase;Phospholipids;Plant Resins;Plaque Assay;Plasma;Preparation;Procedures;Process;Production;Protein Isoforms;Proteins;Pyroxylin;Quality Control;Radioactivity;Radioisotopes;Radiolabeled;Reaction;Recombinant Proteins;Recombinants;Recovery;Research;Resources;Sampling;Sepharose;Serum;Services;Solid;Speed (motion);Standardization;Sterility;Structure of jugular vein;Superose 12;Tail;Techniques;Temperature;Thick;Time;Triglycerides;Tube;Tyramine;Ultracentrifugation;Universities;Urea;Veins;Very low density lipoprotein;Vial device;Viral;Virion;Virus;Western Blotting;cholesteryl oleyl ether;citrate carrier;defective adenoviral vector;density;evaporation;experience;fast protein liquid chromatography;gel electrophoresis;helper-dependent adenoviral vector;immunoaffinity chromatography;in vivo;interest;iron oxide;mouse model;particle;polyacrylamide gels;pressure;programs;radiotracer;reconstitution;research study;scale up;sodium sulfate;uptake;vector


application_id: 8238301
project_number: 5P01HL086670-05
project_title: Macrophage Cholesterol Efflux During Inflammation
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 086670
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0003
contact_pi_person_id: 7875305
contact_pi: WEBB, NANCY R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-04-01
budget_end_date: 2012-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Macrophages possess a number of mechanisms to regulate the balance between cholesterol
uptake/synthesis and export. Of major importance are transport mechanisms that promote the efflux of
excess cholesterol to extracellular acceptors. The removal of excess cholesterol is critical in the vessel wall
where macrophage uptake of lipoprotein-derived lipid can lead to a pathological cholesterol load in the
absence of sufficient removal systems. Two members of the ATP binding cassette (ABC) superfamily of
transmembrane transporters ABCA1 and ABCG1 play critical roles in preventing cholesterol lipid
accumulation in macrophages. Extensive studies have shown that ABCA1 promotes efflux of both
cholesterol and phospholipids to lipid-poor apolipoproteins in particular apoA-l. In contrast ABCG1 appears
to promote efflux by redistributing intracellular cholesterol to plasma membrane domains accessible for
removal by HDL but not lipid-poor apoA-l. Thus factors that affect the lipidated state of apoA-l may
modulate the activity of these two transporters. During inflammation HDL undergoes extensive remodeling
that leads to the generation of particles that are significantly altered in size charge and apolipoprotein and
lipid content. These alterations are primarily brought about by the acute phase reactants serum amyloid A
(SAA) and Group IIA secretory phospholipase A2. Accumulating evidence from multiple laboratories
including ours has established that SAA either delivered as acute phase HDL or in a lipid-free form can
enhance macrophage cholesterol efflux. In Preliminary Data we provide evidence that in the presence of
cholesterol ester transfer protein phospholipid depletion of HDL particles by Group IIA sPLA2 can lead to the
generation of small lipid-depleted HDL particles. We aim to show that a major consequence of the acute
phase response is an increase in the mobilization of cholesterol from the periphery and an accelerated rate
of macrophage reverse cholesterol transport. We hypothesize that SAA and sPLA2 promote macrophage
lipid efflux by modifying HDL acceptors and through direct interactions with macrophage cells. To test this
hypothesis we propose the following Specific Aims: 1) To demonstrate that inflammation-induced
remodeling of HDL generates substrates that enhance ABCA1 and ABCG1-dependent efflux; 2) To
investigate the mechanism(s) by which SAA and sPLA2 promote macrophage cholesterol efflux; and 3) To
test the hypothesis that SAA protects against atherosclerotic lipid accumulation through an ABCA1 and/or
ABCG1 -dependent mechanism.

project_terms:
ATP-Binding Cassette Transporters;Acute;Acute-Phase Proteins;Acute-Phase Reaction;Affect;Antiatherogenic;Apolipoprotein E;Apolipoproteins;Apolipoproteins A;Arterial Fatty Streak;Atherosclerosis;Binding (Molecular Function);Cell membrane;Cells;Charge;Cholesterol;Cholesterol Ester Transfer Proteins;Data;Development;Equilibrium;Excision;Generations;High Density Lipoproteins;Human;Immunohistochemistry;In Vitro;Inflammation;Inflammation Mediators;Inflammatory;Laboratories;Lead;Lipids;Lipoproteins;Mediating;Metabolism;Modification;Molecular;Mus;Pathogenesis;Phase;Phospholipase A2;Phospholipids;Play;Protein Isoforms;Proteins;Research Personnel;Role;Serum;Serum amyloid A protein;Structure;System;Testing;atherogenesis;extracellular;gain of function;in vivo;loss of function;macrophage;member;particle;prevent;programs;response;reverse cholesterol transport;uptake


application_id: 8238300
project_number: 5P01HL086670-05
project_title: Inflammation HDL and class B Scavenger Rectors
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 086670
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0002
contact_pi_person_id: 7875298
contact_pi: VAN DER WESTHUYZEN, DENEYS REM
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: 2011-04-01
budget_end_date: 2012-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Atherosclerosis is the leading cause of mortality in the western world. HDL the levels of which are inversely
correlated with the risk of atherosclerosis exerts its protective effect in large part through its ability to
mobilize cholesterol from peripheral cells and to stimulate reverse cholesterol transport to the liver.
Atherosclerosis and inflammation share many common features and the atherosclerotic process exhibits
characteristics of chronic inflammation. Inflammation significantly alters HDL structure composition and
levels but the underlying mechanisms and the consequences of such modifications are not understood. In
studying the impact of HDL on atherosclerosis it is therefore critical to understand how such HDL
modifications that can result both systemically and within the microenvironment of the atherosclerotic lesion
influence HDL metabolism and its role in cholesterol transport. Inflammatory modifications in HDL may also
alter the protective effect of HDL in neutralizing the inflammatory effects of bacterial lipopolysaccharides.
Inflammation and the acute-phase response results in a marked induction of acute phase proteins including
serum amyloid A (SAA) which becomes a major HDL apolipoprotein. Recently we identified two Class B
scavenger receptors SR-BI and CD36 as high-affinity receptors for SAA and also showed that SAA
promotes cellular cholesterol efflux. Further SR-BI and CD36 were shown to efficiently take up SAA into
cells a process that may be important in the function and metabolism of SAA. In this proposal we will
examine the overall hypothesis that HDL cholesterol transport by Class B scavenger receptors is significantly
altered during inflammation through the effects of acute phase proteins and modifications in HDL structure.
Aim 1 will examine the hypothesis that the Class B scavenger receptors mediate the cellular uptake and
catabolism of SAA. Studies will investigate the roles of SR-BI and CD36 in the cellular uptake recycling and
degradation of SAA in hepatocytes and macrophages. Aim 2 will determine how SAA and HDL remodeling
during inflammation impacts HDL cholesterol transport by Class B scavenger receptors. Studies will
investigate how SAA and acute phase modifications of HDL influence SR-BI-dependent cholesterol efflux
from hepatocytes and macrophages and SR-BI-mediated selective lipid uptake into hepatocytes. Aim 3 will
test the hypothesis that Class B scavenger receptors and SAA regulate the LPS-induced inflammatory
response. Studies will examine the roles of SR-BI and CD36 in LPS- and LTA-induced inflammation and the
modulating effects of SAA. These studies are expected to provide greater understanding of how
inflammation influences the protective function of HDL.

project_terms:
Acute;Acute-Phase Proteins;Acute-Phase Reaction;Affinity;Apolipoproteins;Arterial Fatty Streak;Atherosclerosis;CD36 gene;Cardiovascular Diseases;Catabolism;Cells;Characteristics;Cholesterol;Chronic;Exhibits;Hepatocyte;High Density Lipoprotein Cholesterol;High Density Lipoproteins;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Lipids;Lipopolysaccharides;Liver;Mediating;Metabolism;Modification;Mortality Vital Statistics;Pathway interactions;Peripheral;Phase;Phospholipase;Play;Post-Translational Protein Processing;Process;Proteins;Recycling;Research Personnel;Risk;Role;SR-B proteins;Serum amyloid A protein;Structure;Testing;Western World;macrophage;programs;protective effect;receptor;reverse cholesterol transport;therapeutic target;trafficking;uptake


application_id: 8238299
project_number: 5P01HL086670-05
project_title: HDL Structure and Metabolism During Inflammation
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 086670
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0001
contact_pi_person_id: 1884301
contact_pi: DE BEER, FREDERICK C.
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: 2011-04-01
budget_end_date: 2012-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Intimate associations exist between atherosclerosis and inflammation. The atherosclerotic process itself has
features of chronic inflammation. Furthermore the process of atherosclerosis is profoundly accelerated by
chronic inflammatory disease states such as rheumatoid arthritis. Recently higher rates of first and
subsequent myocardial infarctions as well as strokes were observed in patients with acute urinary and
respiratory infections. Perhaps most notable amongst the plethora of metabolic changes that affect lipid and
lipoproteins during inflammation are the structural and metabolic alterations of HDL. In practically all species
there is a significant decrease of HDL cholesterol and apolipoprotein A-l (apoA-l). Serum amyloid A protein
(SAA) is dramatically induced by cytokines and can even become the major apolipoprotein of HDL. The
same cytokines concomitantly induce the inflammatory phospholipases particularly group MA secretory
phospholipase A2 (group IIA sPLA2) that hydrolyze HDL surface phospholipids with significant metabolic
sequelae. In the short term these changes are likely required for survival but if chronically maintained could
have long-term pathological consequences.
The thesis of this proposal is that the acute phase phospholipases (group IIA sPLA2) act in concert
with cholesterol ester transfer protein (CETP) to propel the apolipoproteins (SAA and apoA-l)
associated with spherical HDL to distinct lipid-poor SAA or apoA-l entities (including prep HDL)
and/or even "free" apolipoproteins. This process hold major implications for HDL function and
metabolism during inflammation. Specifically the lipid-poor apoA-l and SAA entities likely promote
cholesterol efflux whilst at the same time being susceptible to accelerated catabolism.

project_terms:
Acute;Adenovirus Vector;Affect;Animal Model;Apolipoproteins;Apolipoproteins A;Atherosclerosis;Binding (Molecular Function);Blood Vessels;Catabolism;Charge;Cholesterol;Cholesterol Ester Transfer Proteins;Chronic;Deposition;Disease;Equilibrium;Generations;Hepatic;High Density Lipoprotein Cholesterol;High Density Lipoproteins;Human;Hydrolysis;Inflammation;Inflammatory;Label;Lipase;Lipids;Lipoproteins;Metabolic;Metabolism;Movement;Myocardial Infarction;Nature;Patients;Phase;Phospholipase;Phospholipids;Plasma;Process;Reaction;Research Personnel;Respiratory Tract Infections;Rheumatoid Arthritis;Serum amyloid A protein;Site;Structure;Surface;Testing;Time;Tissues;Transgenic Mice;Validation;base;cytokine;hepatic lipase;human PLA2G2A protein;in vivo;metabolic abnormality assessment;particle;programs;stroke;uptake;urinary


application_id: 8238295
project_number: 5R01AA015407-08
project_title: GSK3beta a mediator of ethanol neurotoxicity
administering_ic: NIAAA
award_notice_date: 2012-02-17
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AA
serial_number: 015407
program_official: REGUNATHAN, SOUNDAR
project_start_date: 2005-08-01
project_end_date: 2016-02-29
study_section: Special Emphasis Panel[ZRG1-IFCN-C(02)M]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
other_pis: SHI, XIANGLIN
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):  Alcohol is a neuroteratogen; alcohol consumption during pregnancy may cause Fetal Alcohol Spectrum Disorders (FASD) among which fetal alcohol syndrome (FAS) is the most severe form. The depletion of neurons in the developing CNS is the most deteriorating effect of ethanol. The loss of CNS neurons may underlie many of the behavioral deficits observed in FASD. Glycogen synthase kinase 3 (GSK3) a serine/threonine kinase is an important mediator of neuron degeneration. We have demonstrated that ethanol activates GSK3 and the activation of GSK3 leads to neuronal death. Oxidative stress is also considered an important contributor to ethanol-induced neurotoxicity. We have purified a potent antioxidant from blackberries cyanidin-3-glucoside (C3G). Our study indicates that C3G inhibits GSK3 activity and alleviates oxidative stress in cultured neuronal cells. In addition C3G protects neuronal cells against ethanol-induced cell death. C3G-mediated neuroprotection is much more potent than other antioxidants and GSK3 inhibitors. C3G can cross the blood brain barrier (BBB) and distribute in the brain. C3G diminishes ethanol-induced activation of caspase-3 and Bax in the developing brain. Pharmacologically relevant concentrations of C3G are achievable through oral administration or intravenous (iv) injection in animals and no adverse effect is observed. These findings suggest that C3G is a promising neuroprotective agent that may ameliorate/prevent ethanol-induced neuronal damage. We hypothesize that C3G's potent protection against ethanol-induced neuronal loss is mediated by the combined action of its antioxidant property and inhibition of pro-apoptotic signaling GSK3/Bax pathways. To test the hypothesis we will (1) investigate the antioxidant property of C3G and its metabolites and their effects on GSK3 activity; (2) determine whether C3G protection against ethanol- induced neuronal loss is mediated by the combined action of its antioxidant property and the inhibition of GSK3; (3) determine whether C3G ameliorates ethanol-induced behavioral deficits.  C3G is a potent natural antioxidant and has diverse potential benefits for human health. It is a promising neuroprotective agent against ethanol toxicity due to its dual functions as an antioxidant and a GSK3 inhibitor. As a unit the proposed experiments will elucidate the novel role of C3G and provide an important basis for future clinical trials to evaluate the feasibility of C3G to treat ethanol neurotoxicity. Our study will potentially offer a new therapeutic strategy.    PUBLIC HEALTH RELEVANCE:  Alcohol consumption during pregnancy may cause Fetal Alcohol Spectrum Disorders (FASD) among which fetal alcohol syndrome (FAS) is the most severe form. The developing central nervous system (CNS) is particularly sensitive to ethanol. The loss of CNS neurons may underlie many of the behavioral deficits observed in FASD. Both glycogen synthase kinase 3 (GSK3) and oxidative stress contributes to ethanol neurotoxicity. We have purified a potent antioxidant from blackberries cyanidin-3-glucoside (C3G) which can also inhibit GSK3 and reduce oxidative stress. The current study is to determine whether C3G ameliorates ethanol-induced neuronal loss as well as behavioral deficits. The proposal will potentially develop a new therapeutic strategy.

project_terms:
Acids;Acute;Adverse effects;Alcohol-Induced Disorders;Alcohol-Induced Neurotoxicity;Alcohols;Animals;Anthocyanins;Antioxidants;Apoptotic;Behavior;Behavioral;Blood - brain barrier anatomy;Brain;C57BL/6 Mouse;Cell Death;Cells;Cerebellum;Cerebral cortex;Cessation of life;Clinical Trials;Drug Kinetics;Electron Spin Resonance Spectroscopy;Episodic memory;Equilibrium;Ethanol;Ethanol toxicity;Exposure to;Family;Fetal Alcohol Spectrum Disorder;Fetal Alcohol Syndrome;Funding;Future;Generations;Glucosides;Glycogen Synthase Kinases;Health;Hippocampus (Brain);Human;Hydrogen Peroxide;Hydroxyl Radical;Hyperactive behavior;In Vitro;Learning;Life;Mediating;Mediator of activation protein;Memory;Mental Retardation;Microglia;Modeling;Motor;Mus;Neonatal Alcohol Exposure;Nerve Degeneration;Neuraxis;Neurons;Neuroprotective Agents;North America;Oral;Oral Administration;Oxidative Stress;Pathway interactions;Production;Property;Protein Kinase;Protein-Serine-Threonine Kinases;RAPGEF1 gene;Role;Signal Transduction;Superoxides;Testing;Therapeutic;Third Pregnancy Trimester;alcohol behavior;alcohol consumption during pregnancy;alcohol effect;alcohol exposure;base;caspase-3;free radical oxygen;in vivo;in vivo Model;inhibitor/antagonist;intravenous administration;intravenous injection;member;neuroblastoma cell;neuron apoptosis;neuron loss;neuroprotection;neurotoxicity;novel;novel therapeutics;postnatal;prenatal;prevent;public health relevance;research study

public_health_relevance:
Alcohol consumption during pregnancy may cause Fetal Alcohol Spectrum Disorders (FASD) amongwhich fetal alcohol syndrome (FAS) is the most severe form. The developing central nervous system (CNS) isparticularly sensitive to ethanol. The loss of CNS neurons may underlie many of the behavioral deficitsobserved in FASD. Both glycogen synthase kinase 3beta (GSK3) and oxidative stress contributes to ethanolneurotoxicity. We have purified a potent antioxidant from blackberries cyanidin-3-glucoside (C3G) which canalso inhibit GSK3 and reduce oxidative stress. The current study is to determine whether C3G amelioratesethanol-induced neuronal loss as well as behavioral deficits. The proposal will potentially develop a newtherapeutic strategy.


application_id: 8237747
project_number: 1R01MH092317-01A1
project_title: Predicting trajectories of flourishing and failing in new nursing home residents
administering_ic: NIMH
award_notice_date: 2012-08-23
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: MH
serial_number: 092317
suffix: A1
program_official: ROWLAND, LAURA
project_start_date: 2012-08-23
project_end_date: 2014-07-31
study_section: Social Psychology, Personality and Interpersonal Processes Study Section[SPIP]
contact_pi_person_id: 1908020
contact_pi: MEEKS, SUZANNE
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
project_abstract:
DESCRIPTION (provided by applicant): Admission to a nursing home represents a crisis point with implications for physical recovery mental illness and quality of life. In this project we will follow a sample of nursing home residents from admission through the first year of nursing home residence. Our purpose is to examine not only predictors of traditional mental illness and well-being outcomes but also what factors determine the shape and direction of change over time for individual residents. There are two specific aims: (1) to identify psychological social physical and demographic resources and processes that promote resilience and predict change in mental illness (depression and anxiety) and mortality during the year following admission to a nursing home; and (2) to identify psychological social physical and demographic resilience resources and processes that predict change in flourishing (quality of life positive affect and social engagement). We will collect data from 400 newly admitted nursing home residents their families nursing home staff members and from medical charts. These data will include residents' pre-admission psychological social and physical characteristics that will facilitate or detract from their capacity for resilience including demographic and personality characteristics social networks physical health and disability cognitive impairment and mental health history. We will evaluate levels of depression anxiety and quality of life at admission and then measure resident experiences with treatment activity and social interactions during the nursing home stay and resident regulation of positive and negative affect that should promote resilience. We will also use blood draws to collect information on biomarkers indicative of stress response at the time of admission and after a year. We will assess residents quarterly for one year a total of 4 assessments after the baseline evaluation. Results of this study will contribute to improving care for older adults who enter nursing facilities in three ways. First results will highlight attributes associated with resilience and risk that can be measured at the time of admission and used to prioritize interventions. Second we will identify resiliency processes that are potential treatment targets for improving mental illness outcomes and promote flourishing. Finally inclusion of indicators of flourishing in addition to measures of mental illness will permit conceptual exploration of the notion of flourishing at the end of life broadening our goals for care to include not only absence of mental illness but also the promotion of well-being.  
  
PUBLIC HEALTH RELEVANCE: Forty-five percent of Americans over the age of 65 will use a nursing home in 2010 and about 24% will stay for a year or more usually at the end of their lives. These residents often suffer from comorbid physical cognitive and mental disorders that diminish quality of life at the end of life and represent a costly burden to society. Prevention or amelioration of depression and anxiety and improving well-being are important for maximizing life quality and decreasing health care costs for nursing home residents.

project_terms:
Address;Admission activity;Affect;Affective;American;Anxiety;Behavioral;Blood;Caring;Characteristics;Cognitive;Data;Dimensions;Discipline of Nursing;Elderly;Emotional;Ethnicity aspects;Evaluation;Family;Friends;Functional disorder;Gender;Goals;Health Care Costs;Impaired cognition;Individual;Institution;Intervention;Life;Long-Term Care;Measures;Mediating;Mediator of activation protein;Medical;Mental Depression;Mental Health;Mental disorders;Mortality Vital Statistics;National Institute of Mental Health (U.S.);Nursing Homes;Outcome;Personal Satisfaction;Personality;Prevention;Process;Promotor (Genetics);Quality of life;Recording of previous events;Recovery;Regulation;Religion and Spirituality;Research;Resources;Risk;Risk Factors;Sampling;Severity of illness;Shapes;Social Interaction;Social Network;Societies;Strategic Planning;Time;United States National Institutes of Health;Work;allostasis;biological adaptation to stress;biomarker;cohort;disability;end of life;experience;frailty;improved;innovation;member;nursing home length of stay;optimism;physical conditioning;psychologic;residence;resilience;social;social cognition

public_health_relevance:
Forty-five percent of Americans over the age of 65 will use a nursing home in 2010 and about 24% will stay for a year or more usually at the end of their lives. These residents often suffer from comorbid physical cognitive and mental disorders that diminish quality of life at the end of life and represent a costly burden to society. Prevention or amelioration of depression and anxiety and improving well-being are important for maximizing life quality and decreasing health care costs for nursing home residents.


application_id: 8236901
project_number: 5R01HL087039-05
project_title: Delayed Rectifier K Channel Biogenesis is Unveiled in Models of Long QT Syndrome
administering_ic: NHLBI
award_notice_date: 2012-03-12
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 087039
program_official: KRULL, HOLLY
project_start_date: 2008-04-15
project_end_date: 2015-03-31
study_section: Electrical Signaling, Ion Transport, and Arrhythmias Study Section[ESTA]
contact_pi_person_id: 7001509
contact_pi: DELISLE, BRIAN P
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): Every year sudden cardiac death claims up to 25000 people that do not have structural heart disease. Genetic and acquired causes for these cases of sudden cardiac death are increasingly being sought and hundreds of mutations have been linked to the pro-arrhythmia disease Long QT (LQT) syndrome. Most congenital LQT syndrome patients have mutations in either the KCNQ1 or KCNH2 (human ether a-go-go- related) genes which encode the voltage-gated K+ channel 1-subunits Kv7.1 and Kv11.1 that underlie the delayed rectifier K+ current in the heart. Studies suggest that KCNQ1 (LQT1) mutations and KCNH2 (LQT2) mutations typically result in a loss of function. Many LQT1 and most LQT2 mutations cause Kv7.1 and Kv11.1 to be retained in Endoplasmic Reticulum (ER) thereby decreasing the number of functional channels expressed at the cell surface. Thus far mechanisms that increase the ER export and functional expression have only been identified for trafficking deficient LQT2 mutations and unfortunately most of these mechanisms do not have therapeutic potential. In order to rationally develop therapeutic strategies for treating patients with trafficking deficient LQT1 or LQT2 mutations we propose to study cellular properties that direct the ER retention for LQT1 and LQT2 mutations and the ER export and trafficking for wild type (WT) Kv7.1 and Kv11.1. We will test that hypothesis: The ER retention of LQT1 and LQT2 mutations is regulated by different components of cellular quality control and Kv7.1 and Kv11.1 traffic in distinct vesicular transport pathways. We anticipate that modulating interactions between chaperones co-chaperones and Kv7.1 or Kv11.1 will selectively increase the functional expression for different trafficking deficient LQT1 and LQT2 mutations and that the vesicular transport properties for Kv7.1 and Kv11.1 can be manipulated to increase their functional expression. PUBLIC HEALTH RELEVANCE: Every year sudden cardiac death claims up to 25000 people that do not have structural heart disease. Genetic and acquired causes for these cases of sudden cardiac death are increasingly being identified and hundreds of mutations have been linked to the pro-arrhythmia disease Long QT (LQT) syndrome. About one in 7000 people have LQT1 or LQT2 which is caused by mutations in either the KCNQ1 or KCNH2 genes respectively. These genes encode the voltage-gated K+ channel 1-subunits Kv7.1 and Kv11.1 that underlie the delayed rectifier K+ current in the heart. Studies suggest that LQT1 and LQT2 mutations typically result in a loss of function. The mechanisms that underlie the loss of function varies but it is now recognized that many of these mutations decrease the number of functional channels expressed at the cell surface because they are retained inside the cell in the Endoplasmic Reticulum (ER). Thus far mechanisms that increase the functional expression for these mutations have only been identified for LQT2 and do not have therapeutic potential. In order to rationally develop therapeutic strategies for treating patients with trafficking deficient LQT1 or LQT2 mutations we propose to study the cellular quality control and vesicular transport properties for Kv7.1 and Kv11.1. We will test the hypothesis that the ER retention of LQT1 and LQT2 mutations is regulated by different components of cellular quality control and Kv7.1 and Kv11.1 traffic in distinct vesicular transport pathways. We anticipate that we will identify novel ways to increase the functional expression for trafficking deficient LQT1 and LQT2 mutations.

project_terms:
Action Potentials;Affect;Arrhythmia;Biochemical;Biogenesis;Cardiac;Cell surface;Cells;Complex;Data;Death Sudden Cardiac;Degradation Pathway;Disease;Endoplasmic Reticulum;Environment;Ethers;Gene-Modified;Genes;Genetic;Genotype;Goals;Health;Heart;Heart Diseases;Human;Imaging Techniques;Inherited;Intracellular Transport;Link;Long QT Syndrome;Mammalian Cell;Membrane;Missense Mutation;Modeling;Molecular;Molecular Chaperones;Mutation;Palpitations;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Phenotype;Potassium Channel;Property;Quality Control;Rare Diseases;Research;Seizures;Syncope;Syndrome;Testing;Therapeutic;Transport Vesicles;Voltage-Gated Potassium Channel;cytotoxic;intracellular protein transport;loss of function;new therapeutic target;novel;prevent;protein folding;protein misfolding;trafficking


application_id: 8236894
project_number: 5R01HL088389-05
project_title: A Novel Mechanism by which iPLA2 Links Diabetes to Cardiovascular Diseases
administering_ic: NHLBI
award_notice_date: 2012-02-14
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 088389
program_official: SRINIVAS, POTHUR R
project_start_date: 2008-03-06
project_end_date: 2014-02-28
study_section: Vascular Cell and Molecular Biology Study Section[VCMB]
contact_pi_person_id: 8664760
contact_pi: GUO, ZHENHENG
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): iPLA2 (calcium independent phospholipase A2) is a member of the phospholipase A2 superfamily that is expressed in vascular smooth muscle and exhibits diverse cellular functions. Our preliminary data show that iPLA2 is activated/up-regulated in the vasculature of type 2 diabetic db/db mice and high-fat diet-fed mice and by high glucose in primary cultured vascular smooth muscle cells (VSMC). Moreover inhibition of iPLA2 by BEL a pharmacological inhibitor or genetic deletion abolishes whereas overexpression of iPLA2 exacerbates high glucose-induced NAD(P)H oxidase-mediated superoxide production in cultured VSMCs. These data clearly show that iPLA2 is required for high glucose-induced NAD(P)H oxidase-mediated ROS production in cultured VSMCs and thus implicate an potentially important role of iPLA2 in the diabetes induced ROS increase in vascular wall. While the increased ROS may affect multiple cellular functions our data show that CPI-17 a downstream player in RhoA/ROCK/PKC pathway is regulated by ROS suggesting that iPLA2 regulates RhoA/ROCK/CPI-17 pathway via ROS. Therefore we hypothesize that type 2 diabetes activates iPLA2 in vascular smooth muscle leading to enhanced NAD(P)H oxidase-mediated ROS production and consequent RhoA/ROCK/PKC/CPI-17 pathway activation and thereby significantly contributes to type 2 diabetes- associated vascular smooth muscle hyper-contractility and hypertension. Three Specific Aims are: 1) To test the hypothesis that iPLA2 is required for type 2 diabetes-induced ROS production by NAD(P)H oxidase in vascular smooth muscle tissues. 2) To test the hypothesis that iPLA2 is required for the type 2 diabetes- induced activation of RhoA/ROCK/CPI-17 via NAD(P)H oxidase in vascular smooth muscle tissue. 3) To determine the in vivo significance of iPLA2 in type 2 diabetes-associated vascular smooth muscle hyper- contractility and hypertension. Two type diabetic animal models (the high-fat diet-fed mice and db/db mice) in combination with the genetic modified mice (the iPLA2 transgenic iPLA2 knockout and p47phox deficient mice) will be used. The activities of iPLA2 NAD(P)H oxidase and RhoA/ROCK/PKC/CPI-17 and vascular tone will be assayed in isolated vasculatures and blood pressure will be determined in animals by telemetry. While the development of hypertension in type 2 diabetes seems to be the result of multiple maladaptive pathways results from the proposed studies will elucidate specific mechanisms that could lead to the identification of iPLA2 as a potential novel therapeutic target for the prevention and treatment of cardiovascular complications associated with type 2 diabetes.

project_terms:
Affect;Agonist;Animal Model;Animals;Antisense Oligonucleotides;Aorta;Biological Assay;Blood Pressure;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cell physiology;Data;Development;Diabetes Mellitus;Diabetic Angiopathies;Diet;Exhibits;Fatty acid glycerol esters;GTP-Binding Proteins;Genetic;Glucose;Goals;Hypertension;Knock-out;Knockout Mice;Lead;Link;Measurement;Mediating;Mesenteric Arteries;Molecular;Molecular Weight;Morbidity - disease rate;Mortality Vital Statistics;Mus;Muscle Contraction;Muscle Smooth Vascular;Non-Insulin-Dependent Diabetes Mellitus;Oxidases;Pathway interactions;Phospholipase A2;Phosphoric Monoester Hydrolases;Play;Prevention;Production;Protein Kinase C;Proteins;Reactive Oxygen Species;Rho-associated kinase;Role;Scheme;Smooth Muscle Myocytes;Smooth muscle (tissue);Superoxides;Telemetry;Testing;Tissues;Transgenic Mice;Transgenic Organisms;Vascular Smooth Muscle Tissue;db/db mouse;diabetic;diabetic patient;feeding;human PLA2G6 protein;in vivo;inhibitor/antagonist;member;mouse leptin receptor;new therapeutic target;novel;overexpression;response


application_id: 8236603
project_number: 1R01AA019953-01A1
project_title: Receptor-mediated effects of ethanol in lung tissue injury and repair
administering_ic: NIAAA
award_notice_date: 2012-08-14
opportunity_number: PA-08-164
application_type: 1
activity_code: R01
ic: AA
serial_number: 019953
suffix: A1
program_official: JUNG, KATHY
project_start_date: 2012-09-01
project_end_date: 2017-05-31
study_section: Lung Injury, Repair, and Remodeling Study Section[LIRR]
contact_pi_person_id: 1876531
contact_pi: ROMAN, JESSE
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Respiratory Distress Syndrome the most severe form of acute lung injury has been found to occur more frequently in alcoholics. In fact chronic alcohol use is not only associated with increased incidence of acute lung injury but also increased mortality. Despite its importance the exact mechanisms by which alcohol abuse renders the host susceptible to acute lung injury remain poorly defined. We have identified a cell surface sensor for alcohol in lung cells and believe that it mediates many of the detrimental effects of alcohol in lung. In view of its perceived importance this project seeks to further characterize this 'alcohol receptor' and investigate its role in the development of acute lung injury in the setting of chronic alcohol exposure. The work proposed was prompted by novel observations showing that: 1) receptors members of the nicotinic acetylcholine receptor (nAChR) family mediate the effects of ethanol in lung fibroblasts and 2) that ethanol-induced oxidant stress (through oxidation of the extracellular cysteine/cystine redox potential) might directly activate nAChRs. These observations have important implications in vivo since we have shown that subjects with chronic alcohol abuse who are otherwise 'healthy' show evidence of oxidant stress as well as activation of lung tissue remodeling. Based on the above we hypothesize that chronic ethanol exposure renders the host susceptible to acute lung injury by acting on nAChRs present on lung cells. Furthermore we hypothesize that oxidant stress can amplify these events by activating nAChRs directly through actions on specific cysteine residues strategically located near the ligand binding site of the receptor; new preliminary data support this hypothesis. Ultimately downstream signals triggered by nAChRs result in a cascade of events that render the host susceptible to acute lung injury. This hypothesis will be tested in specific aims designed to: 1) Characterize the role of nAChRs in mediating the effects of ethanol in lung cells 2) Examine the mechanisms by which a specific form of oxidant stress influences ethanol-induced nAChR activation and 3) Determine the role of nAChRs in mediating ethanol-induced susceptibility to acute lung injury in vivo.  
PUBLIC HEALTH RELEVANCE: Chronic ethanol use has been associated with increased susceptibility to acute lung injury a condition that affects over 200000 Americans and that is associated with ~40% mortality. This project will explore how ethanol exposure renders the host susceptible to this condition by examining the cellular mechanisms that mediate the effects of ethanol in lung cells and how this impacts lung injury and repair.


application_id: 8235920
project_number: 5R01DK080770-04
project_title: Renal Osteodystrophy: A Fresh Approach
administering_ic: NIDDK
award_notice_date: 2012-03-07
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 080770
program_official: KIMMEL, PAUL
project_start_date: 2009-03-01
project_end_date: 2014-02-28
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 7875292
contact_pi: MALLUCHE, HARTMUT H
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Patients with chronic kidney disease (CKD) present with abnormalities in mineral and bone metabolism which are associated with high morbidity and mortality. The most relevant bone abnormalities encompass suppressed or extremely elevated bone turnover and bone loss. Both turnover abnormalities and bone loss are associated with progressive calcifications explaining the high morbidity and mortality. Bone biopsies are the gold standard for the diagnosis of bone abnormalities but are rarely performed. Noninvasive means to diagnose renal bone disease are urgently needed for implementation of targeted therapy to reduce morbidity and mortality. The long-term goal of the proposed study is to improve survival and quality of life in CKD patients by noninvasive detection of abnormalities in bone turnover and prevention of bone loss. This will allow administration of specific therapies and should contribute to reduction of disease burden and cost of a pervasive health problem affecting over 20 million patients in the United States. The central hypothesis is that renal osteodystrophy (ROD) can be defined noninvasively. Specifically we will test the following hypotheses: 1. a) Bone volume component of ROD (bone loss) can be assessed by dual energy X-ray absorptiometry (DXA) and by quantitative computed tomography (QCT); however QCT is more sensitive in recognizing bone loss; and b) Bone loss occurs in patients with high and low turnover. Among patients with bone loss there are at least 20% with low bone turnover. 2. The turnover component of ROD can be assessed noninvasively by PTH combined with established and/or novel biochemical markers of bone resorption and formation. The following specific aims will be pursued: 1. Comparison of DEXA and QCT for diagnosis of bone loss in CKD-5 patients and determination of the prevalence of low bone turnover in CKD-5 patients with bone loss. 2. Identification of the optimal combination of noninvasive tests for definition of the turnover component of ROD: For this purpose 230 patients will be followed prospectively over 2 years bone mass will be determined by QCT and DXA annually to establish the most sensitive means of identifying bone loss. Patients with osteoporosis at baseline and patients who develop bone loss at 1 or 2 years will be offered to undergo bone biopsy and blood drawing to measure serum markers of bone turnover formation and resorption. The best marker or combination of markers for definition of the turnover component ROD will be identified. Attainment of these goals will allow implementation of specific therapies without the use of invasive work-up and will assist in reducing morbidity increasing survival and improving quality of life in this unfortunate patient population. PUBLIC HEALTH RELEVANCE: Cardiovascular and cerebrovascular calcifications are linked to abnormalities in bone turnover and bone loss resulting in high morbidity and mortality. Bone turnover abnormalities and bone loss occur in chronic kidney disease patients and bone biopsy (an invasive test) is considered essential for diagnosis of these bone abnormalities. The proposed studies will establish noninvasive means (a panel of blood tests and imaging methods) for recognition and characterization of these bone abnormalities which has significant implications regarding diagnosis prevention treatment and a better understanding of the pathogenic mechanisms.

project_terms:
Address;Adult;Affect;Alkaline Phosphatase;Aluminum;Award;Awareness;Biochemical;Biochemical Markers;Biopsy;Blood;Blood Tests;Blood specimen;Bone Diseases;Bone Resorption;Cardiovascular system;Caring;Chronic Kidney Failure;Clinical Research;Clinical Sciences;Cost of Illness;DEXA;Detection;Development;Diagnosis;Dialysis procedure;Dual-Energy X-Ray Absorptiometry;Early identification;Foundations;Funding;Goals;Gold;Health;Health Care Costs;Histologic;Histology;International;Investigation;Kentucky;Kidney;Kidney Diseases;Laboratories;Letters;Link;Low Prevalence;Maintenance;Measurement;Measures;Medical;Minerals;Morbidity - disease rate;Mortality Vital Statistics;Osteogenesis;Osteoporosis;Outcome;Patients;Physiologic calcification;Prevalence;Prevention;Procedures;Procollagen;Protocols documentation;Quality of life;Renal Osteodystrophy;Resources;Serum Markers;Skeleton;TRANCE protein;Testing;Therapeutic;Time;Translational Research;Tumor necrosis factor receptor 11b;United States;United States National Institutes of Health;Universities;Vascular calcification;Vitamin D Analog;X-Ray Computed Tomography;base;bone;bone loss;bone mass;bone metabolism;bone turnover;burden of illness;calcification;cancer type;cerebrovascular;cohort;diagnosis standard;experience;follow-up;imaging modality;improved;inorganic phosphate;mineralization;novel;patient population;prevent;quality assurance;skeletal abnormality;tartrate-resistant acid phosphatase

public_health_relevance:
Project NarrativeCardiovascular and cerebrovascular calcifications are linked to abnormalities in bone turnover and bone lossresulting in high morbidity and mortality. Bone turnover abnormalities and bone loss occur in chronic kidneydisease patients and bone biopsy (an invasive test) is considered essential for diagnosis of these boneabnormalities. The proposed studies will establish noninvasive means (a panel of blood tests and imagingmethods) for recognition and characterization of these bone abnormalities which has significantimplicationsregarding diagnosis prevention treatment and a better understanding of the pathogenicmechanisms.


application_id: 8235917
project_number: 5R01DA025591-04
project_title: GABAA Modulation as a Target for Developing Medications for Methamphetamine Abuse
administering_ic: NIDA
award_notice_date: 2012-02-23
opportunity_number: PA-07-333
application_type: 5
activity_code: R01
ic: DA
serial_number: 025591
program_official: HAMPSON, AIDAN
project_start_date: 2008-09-15
project_end_date: 2013-06-28
study_section: ZDA1-MXH-H(22)
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABTRACT Methamphetamine dependence is a significant public-health concern. Dopamine plays a prominent role inmediating the behavioral effects of methamphetamine. -Aminobutyric-acid (GABA) systems inhibit dopaminesystems. Increasing GABA activity may result in greater inhibition of dopamine systems and thus attenuate thebehavioral effects of methamphetamine thought to contribute to its abuse. Preclinical and human laboratoryexperiments have demonstrated that high-efficacy GABAA receptor modulators attenuate the behavioral effectsof stimulants under a variety of behavioral arrangements. These findings suggest that GABAA receptormodulation might be a viable target for the development of medications to manage methamphetamine abuse. The overarching goal of this application is to demonstrate targeting GABAA receptor modulation is a viablestrategy for the development of medications to manage methamphetamine dependence. This goal will beachieved through the conduct of two "proof-of-concept" experiments designed to accomplish two specific aims. The first specific aim is to demonstrate that a GABAA receptor modulator attenuates the reinforcing effects ofmethamphetamine. To accomplish this aim we will determine the reinforcing effects of intranasalmethamphetamine during maintenance on a high-efficacy GABAA receptor modulator using a progressive-ratioprocedure (Exp. 1). The reinforcing effects of stimulants are central to their abuse potential. By inference thenan effective pharmacotherapy for managing stimulant dependence will modify drug self-administration. Thesecond specific aim is to demonstrate that a GABAA receptor modulator attenuates the discriminative-stimuluseffects of methamphetamine. To accomplish this aim we will teach volunteers to discriminate intranasalmethamphetamine using a drug-discrimination procedure (Exp. 2). A range of doses of methamphetamine willthen be tested during maintenance on a GABAA receptor modulator and placebo. The discriminative effects ofmethamphetamine may be involved in relapse to drug-taking behavior in that an initial dose (i.e. a lapse) mayfunction as a discriminative stimulus signaling the availability of more drug. Pharmacotherapies that attenuatethe discriminative-stimulus effects of methamphetamine may be effective for preventing relapse. The proposed research will provide initial clinical information regarding the viability of targeting GABAAreceptor modulation for the development of medications for methamphetamine abuse. In addition to the clinicalinformation the proposed research will provide basic-science and translational information. First the inclusionof drug self-administration and discrimination measures along with subjective-effect questionnaires willprovide information concerning the relationship between the reinforcing discriminative and subjective effects ofmethamphetamine. Second because GABAA receptor modulators have been tested as pharmacotherapies forstimulant dependence in laboratory animals using similar behavioral procedures the proposed research willdetermine albeit indirectly the extent that findings from preclinical studies generalize to humans. PROJECTIVE NARRATIVEMethamphetamine dependence is a significant public health concern. The proposed research will provideimportant clinical information regarding the viability of targeting GABAA receptor modulation for thedevelopment of medications to manage methamphetamine dependence.

project_terms:
Admission activity;American;Aminobutyric Acids;Attenuated;Basic Science;Behavior;Behavioral;Central Nervous System Stimulants;Clinical;Cocaine;Dependence;Development;Discrimination (Psychology);Dopamine;Dose;Drug Kinetics;Educational process of instructing;Epidemiology;Foundations;Goals;Great Lakes Region;Human;Institution;Intelligence;Kentucky;Laboratories;Laboratory Animals;Learning;Location;Maintenance;Measures;Mediating;Methamphetamine;Methamphetamine dependence;Molecular;Nerve;Neurotransmitters;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Pharmacotherapy;Placebos;Play;Procedures;Psychostimulant dependence;Questionnaires;Relapse;Reporting;Research;Role;Self Administration;Serotonin;Signal Transduction;Stimulus;Synapses;System;Testing;Vesicle;design;dopamine system;drug discrimination;effective therapy;gamma-Aminobutyric Acid;methamphetamine abuse;monoamine;noradrenaline transporter;novel;pre-clinical;preclinical study;prevent;public health medicine (field);receptor;research study;reuptake;topiramate;volunteer


application_id: 8235801
project_number: 5R37AG004542-23
project_title: Hippocampal Synaptic Structure
administering_ic: NIA
award_notice_date: 2012-03-21
opportunity_number: PA-10-067
application_type: 5
activity_code: R37
ic: AG
serial_number: 004542
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 1998-01-01
project_end_date: 2016-02-29
study_section: Neurobiology of Learning and Memory Study Section[LAM]
contact_pi_person_id: 2405844
contact_pi: LANDFIELD, PHILIP W.
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):  This is the resubmission of a renewal application for a longstanding project on dysregulation of calcium (Ca2+)-related processes in hippocampal neurons during aging and the consequences for altered neuronal function/vulnerability. The project initially derived from the finding that the Ca2+-dependent slow afterhyperpolarization (sAHP) that follows a burst of action potentials in hippocampal pyramidal neurons is larger in aged than in young-adult animals. Importantly larger sAHPs are correlated with reduced neuronal excitability and impaired learning and memory. Conversely smaller sAHPs are found in animals that learn a task. Since then we and others have determined that Ca2+ action potentials Ca2+ transients and L-type Ca2+ currents also are increased in aged neurons. These results led to a Ca2+ dysregulation hypothesis of brain aging in which increased activity of L-channels plays a key initiating role and the resulting larger sAHP reduces neuronal excitability. It also has become apparent that enhanced Ca2+-induced Ca2+ release (CICR) from ryanodine receptors (RyRs) modulates the magnitude of aging-related Ca2+ transients and sAHPs in pyramidal neurons. The major objective of this project is to fundamentally advance our understanding of the underlying molecular mechanisms of Ca2+ dysregulation that lead to unhealthy brain aging. Based on our new intriguing results we have formulated a novel working hypothesis of age-related Ca2+ dysregulation that suggests that downregulation of immunophilins particularly FK-506 binding protein 1b and/or 1a (FKBP1b/1a) leads to a cascade of RyR destabilization greater CICR and larger sAHPs. The resulting effect is impaired neuronal excitability and behavioral plasticity. These studies will manipulate hippocampal expression/function of FKBP1b/1a and other proteins in the FKBP- Ca2+ regulatory pathway in vivo using microinjection of viral vectors. Multiple outcomes will be assessed in the same animals using a multidisciplinary approach comprising extensive behavioral testing state-of-the-art intracellular electrophysiology with concomitant Ca2+ imaging immunohistochemistry and gene microarray analysis. These studies should substantially elucidate aging changes that depend on Ca2+ dysregulation and should clearly test the role of FKBPs in Ca2+ dysregulation and hippocampal function during aging. Chronic intervention studies are proposed that could have direct translational relevance and lead directly to novel preventative and therapeutic treatments against aging-related decline of brain function. Given the dramatic increase in the aging population it is becoming increasingly important to identify and develop such therapies to maintain cognitive function in the elderly.    PUBLIC HEALTH RELEVANCE:   The aging population of the United States is projected to increase at a dramatic rate with numbers that will undoubtedly impact our healthcare system (20% of the population will be >65 years of age by the year 2030). Cognitive decline frequently accompanies aging and depending on the severity can significantly affect quality of life. Our results indicate that a specific pathway (FKBP-Ca2+) that plays a major role in cardiac failure may also play a critical role in brain aging and cognitive decline; thus the goal of this project is to use gene therapy techniques to determine whether such interventions can prevent or slow the onset of age-related brain decline. The outcomes may have substantial therapeutic implications.

project_terms:
Action Potentials;Affect;Age-Years;Aging;Alzheimer's Disease;Animals;Base of the Brain;Behavior;Behavioral;Binding (Molecular Function);Binding Proteins;Brain;Brain-Derived Neurotrophic Factor;Calcium;Chronic;Control Animal;Data;Disinhibition;Down-Regulation;Elderly;Electrophysiology (science);Exposure to;Fostering;Genes;Genomics;Goals;Healthcare Systems;Heart failure;Hippocampus (Brain);Image;Immunohistochemistry;Immunophilins;Impaired cognition;Intervention;Intervention Studies;Lead;Learning;Maze Learning;Mediating;Memory;Methods;Microarray Analysis;Microinjections;Modeling;Molecular;Muscle Cells;Neurons;Open Reading Frames;Outcome;Outcome Measure;Pathway interactions;Pattern;Pharmaceutical Preparations;Play;Population;Process;Progress Reports;Protein Isoforms;Proteins;Protocols documentation;Quality of life;RNA;Rattus;Regulation;Regulatory Pathway;Role;RyR2;Ryanodine Receptors;Severities;Sirolimus;Slice;Small Interfering RNA;Structure;Synapses;Tacrolimus Binding Proteins;Techniques;Testing;Therapeutic;United States;Up-Regulation (Physiology);Viral Vector;Work;adeno-associated viral vector;age related;aged;aging brain;aging hippocampus;aging population;base;behavior test;biomarker;cognitive function;gene therapy;hippocampal pyramidal neuron;human FRAP1 protein;in vivo;innovation;interdisciplinary approach;knock-down;mTOR protein;mature animal;neuronal excitability;novel;overexpression;prevent;protein expression;public health relevance;response;vector;voltage;young adult

public_health_relevance:
Project NarrativeThe aging population of the United States is projected to increase at a dramatic rate withnumbers that will undoubtedly impact our healthcare system (20% of the population will be >65years of age by the year 2030). Cognitive decline frequently accompanies aging and dependingon the severity can significantly affect quality of life. Our results indicate that a specific pathway(FKBP-Ca2+) that plays a major role in cardiac failure may also play a critical role in brain agingand cognitive decline; thus the goal of this project is to use gene therapy techniques todetermine whether such interventions can prevent or slow the onset of age-related braindecline. The outcomes may have substantial therapeutic implications.


application_id: 8235049
project_number: 5R01MH082762-03
project_title: 2/2-Computer-Assisted Cognitive-Behavior Therapy for Depression
administering_ic: NIMH
award_notice_date: 2012-02-15
opportunity_number: PAR-09-153
application_type: 5
activity_code: R01
ic: MH
serial_number: 082762
program_official: PEARSON, JANE L
project_start_date: 2010-06-16
project_end_date: 2014-01-31
study_section: Interventions Committee for Adult Disorders[ITVA]
contact_pi_person_id: 9075017
contact_pi: WRIGHT, JESSE H.
other_pis: Not Applicable
congressional_district: 03
department: PSYCHIATRY
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): We propose a two center randomized controlled trial evaluating the efficacy and cost-effectiveness of computer-assisted cognitive-behavior therapy (CCBT) for outpatients with major depressive disorder (MDD). Results of a preliminary study indicated that despite reducing the amount of therapist contact by about 50% CCBT was at least as effective as an 8 week course of conventional individual CBT on depression outcomes with greater effects on dysfunctional attitudes and knowledge about CBT. We now propose to conduct a more rigorous test of the therapeutic equivalence and cost-effectiveness of CCBT versus a full 16 week 20 session course of individual CBT which provides three times the amount of therapeutic contact. A total of 172 male and female outpatients (86 per site) meeting SCID/DSM-IV criteria for MDD will be randomized across five years. Outcomes will be assessed by independent evaluators without knowledge of the treatment received. The study is designed to have the statistical power to test the equivalence of CCBT and the full course of CBT at both the end of acute phase therapy and across 6 months of follow-up. In addition to effects on depressive symptoms and categorical outcomes (i.e. response and remission rates) dependent variables will include measures of dysfunctional attitudes social functioning quality of life and health care costs and utilization. It is predicted that: 1) CCBT will be equivalent to CBT at week 16 and across the 6 month follow-up; and 2) CCBT will be significantly more cost-effective than CBT. Secondary aims include testing potential moderators of treatment outcome and the predicted absence of site differences (as an indicator of disseminability). This trial has significant implications for the public health because it will provide a rigorous test the clinical utility of CCBT against a model of conventional individual therapy that offers three times as much clinical contact. If equivalence and cost- effectiveness are demonstrated the proposed research will set the stage for larger scale studies evaluating broader dissemination of CCBT.    PUBLIC HEALTH RELEVANCE: Although Cognitive Behavior Therapy (CBT) is an effective treatment for major depressive disorder its utility is limited by cost and availability of trained therapists. Computer-assisted delivery of this therapy (CCBT) has shown promise and may offer similar benefits as CBT with as little as one third the amount of therapist time. The proposed study will test the therapeutic equivalence and cost-effectiveness of CCBT versus CBT across a 16 week acute phase and a 6 month follow-up.

project_terms:
Acute;Attitude;Characteristics;Clinical;Cognitive;Cognitive Therapy;Computer Assisted;Computer-Assisted Therapy;Control Groups;DSM-IV;Data;Data Analyses;Development;Disease remission;Elements;Female;Grant;Health Care Costs;Hour;Individual;Intervention;Investigation;Knowledge;Major Depressive Disorder;Measures;Mental Depression;Methods;Modeling;Multimedia;Outcome;Outpatients;Patient Preferences;Patients;Pennsylvania;Phase;Protocols documentation;Psychotherapy;Quality of life;Randomized;Randomized Controlled Trials;Recruitment Activity;Relapse;Research;Research Design;Research Methodology;Sampling;Services;Site;Social Functioning;Staging;Testing;Therapeutic;Thinking function;Time;Training;Treatment outcome;Universities;Waiting Lists;base;behavior change;clinically significant;comparative efficacy;conventional therapy;cost;cost effective;cost effectiveness;depressive symptoms;design;effective therapy;efficacy testing;experience;follow-up;health care service utilization;improved;male;meetings;programs;public health medicine (field);public health relevance;response

public_health_relevance:
Project NarrativeAlthough Cognitive Behavior Therapy (CBT) is an effective treatment for major depressivedisorder its utility is limited by cost and availability of trained therapists. Computer-assisteddelivery of this therapy (CCBT) has shown promise and may offer similar benefits as CBT withas little as one third the amount of therapist time. The proposed study will test the therapeuticequivalence and cost-effectiveness of CCBT versus CBT across a 16 week acute phase and a6 month follow-up.


application_id: 8234886
project_number: 5R01AR055246-05
project_title: Circadian rhythms and skeletal muscle
administering_ic: NIAMS
award_notice_date: 2012-03-21
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AR
serial_number: 055246
program_official: BOYCE, AMANDA T
project_start_date: 2008-03-01
project_end_date: 2013-02-28
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 8263548
contact_pi: ESSER, KARYN A
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary:Circadian rhythms have long been known to influence behavioral and biological processes such as physicalactivity and feeding behavior. The fundamental importance of this system which works to link physiology withthe day/night cycle is underscored by its presence in every known species and the growing evidence linkingalterations in core clock function and diseases such as cancer diabetes and mental health.Recent studies from our laboratory have shown that mutations of the canonical circadian genes Clock andBmal1 dramatically disrupt muscle function. This is the first genetic evidence linking skeletal muscle functionto circadian rhythms. Expression profiling studies of skeletal muscle over 48 hours identified that MyoD is acircadian gene. Molecular experiments went on to demonstrate that the MyoD promoter is directly bound andregulated by the core clock factors CLOCK and BMAL1.The studies outlined in this proposal combine molecular cell biological and biophysical approaches tounderstand the mechanisms by which the core clock mechanism is regulated in skeletal muscle and how lossof this rhythm leads to altered MyoD expression and loss of muscle function. The hypotheses for thisproposal are 1) Synchronization of core clock gene expression in skeletal muscle requires intact innervation2) Muscle specific mutations of Bmal1 or Clock will be sufficient to cause arrhythmic MyoD expression andmuscle dysfunction 3) Loss of maximal force capacity/specific tension in muscle of circadian clock-compromised mice is due to decreased actin:myosin interaction resulting from disruption of sarcomericstructure and/or altered stoichiometry of myofilament proteins.The results of the experiments outlined in this proposal have significant implications for maintenance ofmuscle with an impact on our understanding and treatment of sarcopenia muscle wasting/cachexia andproblems associated with metabolic diseases such as insulin resistance. In addition our understanding ofcircadian regulation of skeletal muscle will have likely applications for rehabilitation therapies for spinal cordinjury patients and people that are exposed to prolonged periods of bedrest. Project NarrativeThe results of the proposed work will determine the role of the biological clock in maintainingnormal skeletal muscle structure and function. The findings have significant implications formaintenance of muscle with an impact on our understanding and treatment of sarcopeniamuscle wasting/cachexia and problems associated with metabolic diseases such as insulinresistance. In addition our understanding of circadian regulation of skeletal muscle will havelikely applications for rehabilitation therapies for spinal cord injury patients and people that areexposed to prolonged periods of bedrest.

project_terms:
Actinin;Actins;Aging;Bed rest;Behavior;Binding (Molecular Function);Biological;Biological Clocks;Biological Process;Brain;Cachexia;Cell physiology;Cells;Chronic Disease;Circadian Rhythms;Clinical;Complement;Confocal Microscopy;Development;Diabetes Mellitus;Disease;Down-Regulation;Electron Microscopy;Enhancers;Feedback;Feeding behaviors;Fiber;Fluorescence Microscopy;Functional disorder;Gel;Gene Expression;Gene Proteins;Gene Targeting;Genes;Genetic;Genetic Transcription;Hour;Hypothalamic structure;In Situ Hybridization;Insulin Resistance;Intrinsic drive;Knock-out;Laboratories;Lesion;Link;Liver;Maintenance;Malignant Neoplasms;Mammals;Measures;Mechanics;Mental Health;Metabolic Diseases;Microfilaments;Molecular;Molecular Profiling;Mus;Muscle;Muscle Fibers;Muscle function;Mutant Strains Mice;Mutation;Myopathy;Myosin ATPase;Myosin Heavy Chains;Normal Cell;Operative Surgical Procedures;Pattern;Peripheral;Physical activity;Physiology;Promotor (Genetics);Protein Isoforms;Proteins;Regulation;Rehabilitation therapy;Role;Skeletal muscle structure;Spinal cord injury patients;Structure;System;Time;Tissues;Translations;Work;behavior influence;circadian pacemaker;connectin;cryptochrome;design;extensor digitorum;mutant;nebulin;nerve supply;novel;rehabilitation strategy;research study;sarcopenia;skeletal;stoichiometry;suprachiasmatic nucleus;transcription factor;wasting


application_id: 8234739
project_number: 1R01NS077284-01
project_title: Role of FUS in ALS
administering_ic: NINDS
award_notice_date: 2011-08-05
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: NS
serial_number: 077284
program_official: GUBITZ, AMELIE
project_start_date: 2011-08-15
project_end_date: 2015-04-30
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 7875249
contact_pi: ZHU, HAINING
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): Amyotrophic lateral sclerosis (ALS also known as Lou Gehrig's disease) is a progressive and fatal neurodegenerative disease. A general symptom of ALS is muscle weakness and wasting triggered by denervation at neuromuscular junctions. The majority of ALS cases are sporadic and approximately 10% are familial. Several ALS genes have been identified as their mutation can lead to familial ALS including two genes encoding RNA processing proteins TDP-43 and fused in sarcoma/translocated in liposarcoma (FUS/TLS). FUS is a ubiquitously expressed multi-domain RNA-binding protein. In neurons and glial cells FUS is almost exclusively localized to the nucleus but is also reported to transport mRNA for local translation in dendrites in neurons. In addition FUS plays a role in a variety of processes including nucleocytoplasmic shuttling of mRNA transcriptional regulation and mRNA splicing. However little is known regarding how FUS mutations cause motor neuron degeneration and ALS which is the focus of this study.  We recently published that the C-terminus of FUS where the ALS-causing mutations are clustered functions as an effective nuclear localization sequence (NLS). Our newly generated data suggest that a FUS- interacting protein Gemin3 plays a critical role in the perturbations caused by FUS mutations. Gemin3 can be sequestered by ALS mutant FUS which causes reduced Gemin3-positive nuclear structures (Gems) decreased assembly of snRNPs and attenuated spliceosome activity. The Drosophila model we established showed motor function deficiency when FUS was over-expressed in motor neurons. Interestingly Gemin3 was also reported to be required for larval motor function in Drosophila. Moreover we generated FUS/Gemin3 double transgenic flies and showed that expression of Gemin3 rescued the phenotypes of FUS transgenic flies. We thus hypothesize that the ALS-related FUS mutants or WT FUS with deregulated over-expression can accumulate in cytoplasm and sequester Gemin3 which results in decreased assembly of snRNPs in cytoplasm and compromised spliceosome function in the nucleus. To test the central hypothesis three specific aims have been designed to determine the role of FUS in ALS.  Aim 1 is to understand the regulation of FUS subcellular localization by the localization sequence elements within FUS as well as by its RNA binding ability. In Aim 2 we will first determine the molecular mechanism how FUS and Gemin 3 interact. We will further characterize how FUS mutations disturb Gemin 3- mediated snRNP assembly and spliceosome activity. Aim 3 will test the molecular mechanisms defined in Aims 1 and 2 using the Drosophila model. We will first determine whether motor neuron death and neuromuscular denervation are prominent in the transgenic flies with motor neuron-specific FUS expression. FUS-mediated Gemin3 sequestering and subsequent spliceosome changes will be especially tested in flies since Gemin3 over-expression rescued the motor function deficit phenotype caused by FUS. Furthermore the significance of FUS subcellular localization and RNA binding in producing toxicity in motor neurons will be investigated. Lastly we will carry out RNA-Seq experiment to determine the FUS-mediated splicing alterations.  This project will utilize the combination of cellular and Drosophila models to investigate the FUS- mediated ALS etiology. The findings are expected to provide critical insights into the mechanisms by which FUS mutations perturb the RNA processing pathways and ultimately lead to the disease.  
  
PUBLIC HEALTH RELEVANCE: Several amyotrophic lateral sclerosis (ALS) genes have been identified as their mutation can lead to familial ALS including two genes encoding RNA processing proteins TDP-43 and fused in sarcoma (FUS). The major challenge in the field is that little is known how FUS mutations cause motor neuron degeneration in ALS. We propose to test the hypothesis that the ALS-related FUS mutants or WT FUS with deregulated over- expression can accumulate in cytoplasm and sequester Gemin3 which results in decreased assembly of snRNPs in cytoplasm and compromised spliceosome function in the nucleus. To test the central hypothesis three specific aims have been designed to determine the role of FUS in ALS. We have produced novel preliminary data developed unique tools generated nearly all critical reagents and established collaborations with leading experts. We propose to use the combination of cellular and Drosophila models to test the hypothesis. The findings are expected to provide critical insights into the mechanisms by which FUS mutations perturb the RNA processing pathways and ultimately lead to the disease. The knowledge generated in the proposed research will also provide much-needed future direction for developing ALS treatment.

project_terms:
Amyotrophic Lateral Sclerosis;Attenuated;C-terminal;Cell Nucleus;Cells;Cessation of life;Collaborations;Complex;Cytoplasm;DNA Repair;Data;Dendrites;Denervation;Disease;Drosophila genus;Elements;Etiology;Familial Amyotrophic Lateral Sclerosis;Future;Gemin3;Genes;Knowledge;Lead;Locomotion;Mediating;Messenger RNA;Modeling;Molecular;Motor;Motor Neurons;Muscle Weakness;Mutation;Names;Neurodegenerative Disorders;Neuroglia;Neuromuscular Junction;Neurons;Nuclear;Nuclear Structure;Outcome;Pathology;Pathway interactions;Phenotype;Physiological;Play;Process;Proteins;Proteomics;Publishing;RNA;RNA Binding;RNA Processing;RNA Splicing;RNA-Binding Proteins;Reagent;Regulation;Reporting;Research;Role;Small Nuclear Ribonucleoproteins;Spliceosome Assembly Pathway;Spliceosomes;Symptoms;Testing;Toxic effect;Transcriptional Regulation;Transgenic Organisms;Translations;design;fly;in vivo;insight;interest;liposarcoma;mRNA Precursor;motor neuron degeneration;mutant;nerve supply;neuromuscular;novel;nucleocytoplasmic transport;protein TDP-43;research study;sarcoma;tool;wasting


application_id: 8234586
project_number: 2R01GM077422-04A1
project_title: Targeting Nucleic Acids with an Integrated Virtual and Actual Screen
administering_ic: NIGMS
award_notice_date: 2012-03-09
opportunity_number: PA-10-067
application_type: 2
activity_code: R01
ic: GM
serial_number: 077422
suffix: A1
program_official: PREUSCH, PETER
project_start_date: 2007-02-01
project_end_date: 2016-03-31
study_section: Macromolecular Structure and Function B Study Section[MSFB]
contact_pi_person_id: 1863983
contact_pi: CHAIRES, JONATHAN B.
other_pis: TRENT, JOHN O
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):  DNA remains an underrepresented target for small molecule therapeutic agents. There is mounting evidence to indicate that non-B DNA structures play prominent roles in gene expression and in the function of telomeres. Targeting these structural elements is an attractive and innovative strategy for the development of new therapeutic agents. The use of small molecules in such an antigene strategy is promising for many reasons. Targeting the gene before its amplification to produce multiple mRNA and protein molecules is advantageous because there are fewer targets to hit. In addition is easier to manipulate small molecules (rather than therapeutic DNA or RNA molecules) chemically to optimize binding and pharmacological properties. We seek renewal for our innovative and highly productive program to develop an integrated virtual and actual screening platform for the discovery of new lead compounds that bind selectively to unique DNA structures of biological significance. Progress during the initial funding period was outstanding and we achieved most of the specific aims proposed in our initial proposal. We have discovered several compounds that bind selectively to particular quadruplex structures a target of intense current interest. We propose studies that will continue to develop and optimize the integrated screening platform. During the next funding period we will focus on the discovery of lead compounds that bind selectively to biologically important quadruplex and DNA-RNA hybrid structures. In order to do this we will develop structural models for complex quadruplex structures using a novel approach that integrates molecular dynamics simulations with rigorous experimental validation. We will characterize the biophysical and functional properties of the novel quadruplex binders we have discovered during the initial funding period. Specific aims include: 1. Development and refinement of the virtual screening platform. 2. Development of higher-throughput assays for ligand binding. 3. Discovery of lead compounds that bind to functionally important nucleic acid structures. 4. Biophysical and biological characterization of novel G-quadruplex binding agents discovered during the initial funding period. The proposed studies will deliver an improved integrated platform for the discovery of novel lead compounds and a thorough characterization of several newly-discovered quadruplex binders with unique chemical scaffolds.  
  
PUBLIC HEALTH RELEVANCE: This project will develop an integrated computational and experimental screening platform for the discovery of new drugs that target specific structures of functional importance within the genome. The initial funding period for this project was successful and productive and we will continue our efforts. Several novel lead compounds were discovered that bind to functionally important quadruplex structures. We will characterize the biophysical and biological properties of these novel agents.

project_terms:
Active Sites;Antineoplastic Agents;Area;Beryllium;Binding (Molecular Function);Biological;Biological Assay;Chemicals;Complex;Computer Simulation;DNA;DNA Structure;Detection;Development;Dialysis procedure;Drug Delivery Systems;Elements;Fluorescence;Fluorescence Resonance Energy Transfer;Funding;G-Quartets;Gene Expression;Gene Targeting;Genome;Hybrids;Indium;Intercalating Agents;Label;Laboratories;Lead;Libraries;Ligand Binding;Ligands;Measures;Messenger RNA;Methods;Metric;Modeling;Nucleic Acid Binding;Nucleic Acids;Oncogenes;Pharmaceutical Preparations;Play;Promotor (Genetics);Property;Proteins;RNA;RNA-Directed DNA Polymerase;Role;Screening procedure;Specificity;Structural Models;Structure;Telomerase;Telomere Maintenance;Temperature;Therapeutic;Therapeutic Agents;Validation;Work;antigene;c-myc Genes;cancer cell;high throughput screening;improved;innovation;interest;melting;molecular dynamics;novel;novel strategies;novel therapeutics;nucleic acid structure;overexpression;programs;quadruplex DNA;receptor;scaffold;small molecule;telomere;virtual


application_id: 8234363
project_number: 7R42CA120616-03
project_title: Development of a Perfusion-induced Systemic Hyperthermia Delivery Apparatus
administering_ic: NCI
award_notice_date: 2011-06-02
opportunity_number: PA-09-081
application_type: 7
activity_code: R42
ic: CA
serial_number: 120616
program_official: BEYLIN, DAVID M
project_start_date: 2007-09-25
project_end_date: 2012-06-30
study_section: Special Emphasis Panel[ZRG1-SBTS-E(10)B]
contact_pi_person_id: 2422224
contact_pi: ZWISCHENBERGER, JOSEPH B
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 965569747
duns_number: 965569747
fips: US
organization_id: 10028623
organization_name: EXATHERM, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-06-02
budget_end_date: 2011-06-30
project_abstract:
DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer-related deaths in men and women. The prognosis for patients with advanced stage non-small cell lung cancer (NSCLC) which accounts for 75% of all new lung cancer cases is dismal with currently available chemotherapy regimens providing only a 9-12 month median survival. Thus our long term goal is to develop a more effective treatment for late stage NSCLC. One potential candidate for advanced lung cancer therapy is hyperthermia. Our group developed a venovenous perfusion-induced systemic hyperthermia (vv-PISH) system. In a previous phase I clinical trial the vv-PISH significantly improved median survival in advanced stage NSCLC patients by 363 days. Although our vv-PISH system functioned adequately in the clinical trial the vv-PISH system was too complex with a multi-site cannulation and numerous  
dialysis problems. Our Phase I STTR results showed the feasibility of a simple and inexpensive vv-PISH system in delivering a predictable therapeutic hyperthermia dose. The objective of this Phase II STTR proposal is to establish the feasibility of our finalized vv-PISH circuit to safely deliver therapeutic hyperthermia. Specific Aim 1: To finalize and produce an integrated clinical vv-PISH prototype. In this specific aim our system will be finalized to incorporate new developments and integrate "off the shelf" components into a vv-PISH prototype suitable for preclinical and clinical testing. We will assemble the: 1) peristaltic roller pump (MC3 pump) 2) adult ECMO heat exchanger (ECMOtherm-II(tm)) 3) hemofilter (Renaflow II(r)) 4) water heater (Hemotherm(r)) and 5) double lumen cannula (Avalon Elite(tm)). Once assembled we will perform bench testing to confirm that design requirements are met. Specific Aim 2: To determine the temperature control performance and in vivo safety of the clinical vv-PISH circuit. In this specific aim we will establish the safety and reproducibility of the vv-PISH circuit in achieving the target therapeutic dose (42C for 120 minutes) in adult swine. We will examine major organ function during hyperthermia and end organ damage or emboli will be examined in a detailed necropsy. Adult swine will also be monitored for five days after hyperthermia administration. Parameters used to assess the safety of the vv-PISH system will include: 1) survival 2) multiple organ function and 3) quality of life. This outcomes study is an essential part of the preclinical testing that must precede the clinical trial. Specific Aim 3: To determine the clinical feasibility of the vv-PISH circuit in a prospective randomized clinical trial. In this specific aim a phase I clinical trial will be performed to test the clinical feasibility of the vv-PISH circuit. Advanced stage (IIIb or IV) NSCLC patients will be randomized into: 1) standard of care treatment consisting of cisplatin and etoposide chemotherapy with concurrent radiation therapy (n=10) and 2) standard of care therapy followed by systemic hyperthermia treatment via our vv-PISH clinical prototype (n=10). Hyperthermia will be given 2 weeks after the last chemotherapy dose. The impact of this work is that we have developed a new treatment strategy for a relatively unresponsive cancer.  
  
PUBLIC HEALTH RELEVANCE: Advanced stage lung cancer which has a median survival of only 10 months is present in 75% of all new cases. We developed a new circuit to deliver whole body hyperthermia which significantly increased advanced lung cancer patient survival in a previous phase I clinical trial. Since our Phase I STTR results showed the feasibility of a more simple and inexpensive hyperthermia delivery system the goal of this Phase II STTR proposal is to establish the feasibility of our finalized circuit to safely deliver therapeutic hyperthermia.

public_health_relevance:
NarrativeAdvanced stage lung cancer which has a median survival of only 10 months is present in 75% of all newcases. We developed a new circuit to deliver whole body hyperthermia which significantly increased advancedlung cancer patient survival in a previous phase I clinical trial. Since our Phase I STTR results showed thefeasibility of a more simple and inexpensive hyperthermia delivery system the goal of this Phase II STTRproposal is to establish the feasibility of our finalized circuit to safely deliver therapeutic hyperthermia.


application_id: 8233533
project_number: 5R01HL095593-03
project_title: Atherogenic mechanism of lipid peroxidation-derived aldehydes
administering_ic: NHLBI
award_notice_date: 2012-03-13
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 095593
program_official: FLEG, JEROME L
project_start_date: 2010-03-15
project_end_date: 2014-02-28
study_section: Vascular Cell and Molecular Biology Study Section[VCMB]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this project is to understand the role of lipid peroxidation-derived aldehydes in atherosclerosis. Aldehydes such as 4-hydroxynonenal (HNE) and 1-palmitoyl-2-(5-oxovaleroyl)-3- glycero- phosphatidyl choline (POVPC) are the major bioactive products generated from the oxidation of LDL. Based on supportive preliminary studies we propose to test hypothesis that accumulation of lipid-derived aldehydes in macrophages induces endoplasmic reticulum (ER) stress and triggers the unfolded protein response (UPR) leading to cytokine production and foam cell formation. The specific aims of this project are to: (1) delineate the contribution of ER stress and UPR to aldehyde-mediated macrophage activation; (2) elucidate the role of UPR in regulating atherogenesis; and (3) examine the role of aldehyde metabolism in preventing ER stress and UPR in atherosclerotic lesions. To accomplish these aims we will examine whether exposure of murine bone marrow derived macrophages to model lipid-derived aldehydes - HNE or POVPC induces ER stress and UPR. We will determine the extent and the nature of this response and identify which specific UPR-dependent signaling pathways are activated by aldehydes and how they contribute to macrophage activation foam cell formation and apoptosis. To examine the role of ER-stress and UPR during atherosclerotic lesion formation we will determine stage-specific changes in ER stress and UPR in the arterial lesions of apoE-null mice. To probe causality we will examine whether treatment with chemical chaperones which assist protein folding would decrease lesion formation and improve plaque stability. In addition we will test whether genetic ablation of activating factor 3 (ATF3) a UPR-responsive gene which is dramatically induced by lipid aldehydes increases lesion progression and inflammation. To elucidate the role of aldehydes in inducing ER stress in atherosclerotic lesions we will examine how genetic deletion or overexpression of aldose reductase an enzyme which detoxifies both HNE and POVPC affects aldehyde-induced macrophage activation and foam cell formation in culture and ER stress UPR induction in the arterial lesions of apoE-null mice. Successful completion of this project may lead to a better understanding of the mechanisms by which lipid-derived aldehydes affect atherogenesis and how the effects of these aldehydes could be prevented or therapeutically minimized to decrease atherosclerosis.    PUBLIC HEALTH RELEVANCE:  Oxidized lipids have been suggested to play a pivotal role in the formation of atherosclerotic lesions nevertheless the mechanisms by which these lipids or their products induce vascular injury and promote plaque formation or rupture are unknown. Our studies are designed to test the hypothesis that accumulation of lipid-derived aldehydes in macrophages induces endoplasmic reticular (ER) stress and triggers unfolded protein response (UPR). We propose that lipid-derived aldehydes induce the transcription factor 3 (ATF3) which is associated with the alarm phase of UPR and genetic ablation of ATF3 exacerbates and pharmacological inhibition of ER-stress decreases atherogenesis. To examine that aldehydes are indeed causally involved in ER-stress and atherogenesis we will examine whether macrophage specific overexpression or deletion of aldose reductase which converts toxic aldehydes to innocuous alcohols affects their atherogenic effects. Results obtained from this project will help in developing a better understanding and potentially novel therapeutic strategies for decreasing or managing atherosclerosis.

project_terms:
4 hydroxynonenal;Ablation;Affect;Alcohols;Aldehyde Reductase;Aldehydes;Apolipoprotein E;Apoptosis;Arterial Fatty Streak;Asses;Atherosclerosis;Binding (Molecular Function);Blood Vessels;Bone Marrow;Cell Death;Chemicals;Choline;Drug Metabolic Detoxication;Endoplasmic Reticulum;Enzymes;Etiology;Exposure to;Foam Cells;Genes;Genetic;Goals;Inflammation;Inflammatory;Injury;Knockout Mice;Laboratories;Lead;Lecithin;Lesion;Lesion by Stage;Lipid Peroxidation;Lipid-Laden Macrophage;Lipids;Lipoproteins;Low Density Lipoprotein oxidation;Macrophage Activation;Mediating;Metabolism;Mitogen-Activated Protein Kinases;Modeling;Molecular;Molecular Chaperones;Mus;Natural Immunity;Nature;Pathway interactions;Phase;Phospholipids;Play;Production;Proteins;Proteolysis;Relative (related person);Research;Research Design;Role;Rupture;Side;Signal Pathway;Signal Transduction;Staging;Stress;Testing;Toxic effect;Transcription Factor 3;activating transcription factor;adduct;arterial lesion;atherogenesis;base;biological adaptation to stress;cytokine;endoplasmic reticulum stress;improved;in vivo;macrophage;novel therapeutics;overexpression;oxidation;oxidized lipid;prevent;protein degradation;protein folding;public health relevance;response

public_health_relevance:
Oxidized lipids have been suggested to play a pivotal role in the formation of atherosclerotic lesionsnevertheless the mechanisms by which these lipids or their products induce vascular injury and promoteplaque formation or rupture are unknown. Our studies are designed to test the hypothesis that accumulation oflipid-derived aldehydes in macrophages induce endoplasmic reticular (ER) stress and triggers unfolded proteinresponse (UPR). We propose that lipid-derived aldehydes induce the transcription factor 3 (ATF3) which isassociated with the alarm phase of UPR and genetic ablation of ATF3 exacerbates and pharmacologicalinhibition of ER-stress decreases atherogenesis. To examine that aldehydes are indeed causally involved inER-stress and atherogesis we will examine whether macrophage specific overexpression or deletion of aldosereductase which converts toxic aldehydes to innocuous alcohols affects their atherogenic effects. Resultsobtained from this project will help in developing a better understanding and potentially novel therapeuticstrategies for decreasing or managing atherosclerosis.


application_id: 8233453
project_number: 5R01ES015518-05
project_title: Reactive oxygen species in Ni(II) carcinogenesis
administering_ic: NIEHS
award_notice_date: 2012-02-15
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: ES
serial_number: 015518
program_official: QUINN, ASHLINN KO
project_start_date: 2008-03-01
project_end_date: 2015-02-28
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
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:
Nickel-containing compounds are human carcinogens. The mechanisms of theircarcinogenic actions remain to be investigated. Recent studies have indicated thatreactive oxygen species (ROS) may play an important role. We hypothesize that nickelinduces generation of ROS which activate nuclear transcription factors leading to celltransformation and tumorigenesis. Specific Aim 1 will detect and identify ROS generatedin human bronchial epithelial cells (BEAS-2B) and mouse embryo fibroblast cellsexposed to nickel compounds and investigate the mechanism involved. We hypothesizethat nickel (Ni3S2 and NiCl2) can stimulate the cells to activate NADPH oxidase viacdc42 and p47phox to produce superoxide radical which is then converted to hydrogenperoxide and hydroxyl radical. Specific Aim 2 will test the hypothesis that ROS arerequired for activation of NFAT and NFkappaB in cells and in vivo in response to nickelcompounds. The role of ROS in nickel-induced activation of NFAT and NFkappaB incells will be evaluated by co-transfection of NFkappaB-luciferase or NFAT-luciferasereporter plasmids and specific ROS scavenger enzymes. For in vivo study BALB/ctransgenic mice with alternation of antioxidant enzymes or NADPH oxidase (ROSgenerating enzyme) will be employed. Specific Aim 3 will Investigate the role of ROSNFAT and NFkappaB in nickel-induced cell transformation and tumorigenesis. Wehypothesize that ROS activate transcription factors and cause cell transformation andtumorigenesis. We will use overexpression of DN-NFAT DN-IkappaBalpha and DN-IKKbeta to investigate the involvement of NFAT and NFkappaB in nickel-celltransformation and induced tumorigenesis. The role of ROS will be investigated usingspecific antioxidant enzyme expressions and NADPH oxidase alternation. We anticipatethat nickel causes activation of NFAT and NFkappaB through ROS reactions leading tocell transformation and tumorigenesis. We attempt to link the cell transformation andtumorigenesis with specific transcription factors and specific reactive oxygen species.The results obtained from this proposal will elucidate the role of ROS andNFAT/NFkappaB signaling in Ni compounds-induced carcinogenesis. The long termgoals are to provide a fundamental understanding concerning the mechanism ofcarcinogenic actions of Ni; to fill a need for the mechanistic information of cancer riskassessment for exposure; to propose methods for early detection; and to developintervention and prevention strategies. Nickel-containing compounds are human carcinogens. This project will investigate themechanism of Ni-induced carcinogenesis by testing the hypothesis that nickel inducesgeneration of ROS which activate nuclear transcription factors leading to celltransformation and tumorigenesis. The long term goals are to understand themechanism of Ni-carcinogenesis; to propose methods for early detection; and to developintervention and prevention strategies.

project_terms:
Animal Experiments;Animals;Antioxidants;Biological Assay;Breathing;Carcinogenicity Tests;Carcinogens;Cells;Chemicals;Confocal Microscopy;Development;Dominant-Negative Mutation;Down-Regulation;Early Diagnosis;Electron Spin Resonance Spectroscopy;Embryo;Enzymes;Epidemiology;Epithelial Cells;Fibroblasts;Gene Expression Regulation;Generations;Goals;Human;Hydrogen Peroxide;Hydroxyl Radical;I Kappa B-Alpha;In Vitro;Inbred BALB C Mice;Intervention;Investigation;Link;Luciferases;Malignant Neoplasms;Manganese Superoxide Dismutase;Measures;Mediating;Mediator of activation protein;Methods;Mitochondria;Molecular;Mus;NADPH Oxidase;Nature;Nickel;Nuclear;Nude Mice;Plasmids;Play;Prevention strategy;Protein Overexpression;Reaction;Reactive Oxygen Species;Reporter;Research;Risk Assessment;Role;Signal Transduction;Signaling Protein;Source;Spin Trapping;Structure of parenchyma of lung;Superoxides;Techniques;Testing;Transfection;Transgenic Mice;Tumor Promotion;activating transcription factor;cancer risk;carcinogenesis;catalase;cell transformation;in vivo;nuclear factors of activated T-cells;overexpression;response;transcription factor;tumorigenesis


application_id: 8232753
project_number: 7K08HL077533-05
project_title: Role of Smad3 in obiliterative bronchiolitis
administering_ic: NHLBI
award_notice_date: 2011-04-29
opportunity_number: PA-06-512
application_type: 7
activity_code: K08
ic: HL
serial_number: 077533
program_official: COLOMBINI-HATCH, SANDRA
project_start_date: 2007-08-15
project_end_date: 2012-07-31
study_section: ZHL1-CSR-O(M1)
contact_pi_person_id: 7852167
contact_pi: RAMIREZ, ALLAN
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):   
  
Obliterative bronchiolitis (OB) considered to be a manifestation of chronic allograft dysfunction in lung  transplant recipients is an irreversible fibroproliferative process that represents the major barrier to long term survival. Hence research directed at identifying the factors involved in the development of OB in lung transplant recipients is paramount to finding effective treatment for this otherwise untreatable disease. We have found that Transforming Growth Factor-p (TGFp) via its signal transducer SmadS is necessary for the development of OB as well as the myofibroblast transdifferentiation that accompanies OB. Hence we have focused on the mechanisms regulating TGFp/Smad signaling in OB and have made a number of key observations. First oxidation of the extracellular cysteine-cystine (Cys/CySS) redox couple induces upregulation and activation of TGFp and SrnadS. Second SmadS expression and DNA binding in lung fibroblasts and consequently myofibroblast transformation is augmented by aberrant transitional matrix components e.g. fibronectin and type I collagen which are invariably found in the setting of OB. And third activation of the nuclear transcription factor peroxisome proliferator-activated receptor-y (PPARy) inhibits TGFpl -induced myofibroblast transdifferentiation by disrupting SmadS-dependent gene transcription. These findings led us to the hypothesis that activation of TGFp1/Smad3 signaling in airway fibroblasts is a critical driver of myofibroblast transdifferentiation in OB that is intensified by the presence of chronic extracellular oxidant stress aberrant transitional matrices and defective PPARy signaling. This hypothesis will be tested in fibroblast cultures and in experimental models of OB in three specific aims designed to: 1) examine the mechanisms by which chronic extracellular oxidative stress activates TGFp1/Smad3-dependent signaling events in vitro and in vivo through the Cys/CySS redox couple 2) examine how transitional matrices promote activation of TGFpl /SmadS signaling and myofibroblast transdifferentiation through integrin-dependent signals 3) determine the mechanisms by which PPARy affects the SmadS signaling pathway and the induction of myofibroblast transdifferentiation and matrix expression in experimental OB. These complex issues will be addressed with the assistance of expert advisors and collaborators with the broader objective of unveiling novel targets for therapy.  
(End of Abstract)


application_id: 8232580
project_number: 1R15NS072870-01A1
project_title: Treatment of traumatically brain injured rats with gamma glutamylcysteine ethyl e
administering_ic: NINDS
award_notice_date: 2011-09-23
opportunity_number: PA-10-070
application_type: 1
activity_code: R15
ic: NS
serial_number: 072870
suffix: A1
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2011-09-15
project_end_date: 2015-08-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 9835336
contact_pi: REED, TANEA TYLETTE
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 074051269
primary_uei: K69HFP3FKJ11
duns_number: 074051269
uei: K69HFP3FKJ11
fips: US
organization_id: 2274301
organization_name: EASTERN KENTUCKY UNIVERSITY
organization_city: RICHMOND
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 404753100
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The main function of an Academic Research Enhancement Award (AREA) is to stimulate meritorious research at primarily undergraduate institutions that are not major recipients of NIH support as mandated by the National Institutes of Health. Two additional objectives are to strengthen the research environment at such institutions and expose students in these environments to research. This research proposal fits all the objectives of this directive. The goal of this project is to evaluate the efficacy of gamma glutamylcysteine ethyl ester a glutathione mimetic as a post therapeutic strategy for moderate traumatic brain injury. Traumatic brain injury (TBI) is defined as a sudden trauma followed by secondary damage. It occurs in approximately 10 million people worldwide. There is no known cure for traumatic brain injury; however immediate medical attention after incident is most beneficial for patient recovery. Since TBI is a sudden injury post therapeutic strategies are the only viable approach to therapy. Gamma glutamylcysteine ethyl ester (GCEE) is an ethyl ester moiety of gamma glutamylcysteine which upregulates glutathione (GSH) a potent antioxidant in brain. Preliminary data from our laboratory show a significant reduction in oxidative stress levels when GCEE is administered 10 minutes post TBI; however early management of injury is the best preventative measure of progressive secondary injury. This proposal will investigate a potential GSH-based therapeutic for TBI post injury at several time points (30 minutes 60 minutes 90 minutes and 120 minutes) to determine the best time course of protection against secondary injury of TBI. The specific hypothesis is that GCEE administration is still neuroprotective at 30 minutes post injury and may possibly be neuroprotective at 60 minutes 90 minutes and 120 minutes post injury to a lesser extent. Should GCEE given post TBI be protective against TBI-induced secondary injury for longer than 10 minutes this would be an effective intervention that could feasibly be administered in the field. Such an outcome would be highly beneficial for post-TBI modulation of secondary injury and recovery outcomes. This proposal would also contribute to increasing scientific knowledge in the field of traumatic brain injury research and create a strong research environment for students at Eastern Kentucky University. The funding of this AREA application will expand biomedical research for students and better enable students from Kentucky a traditionally underrepresented state in biomedical sciences to advance in biomedical graduate programs.  
  
PUBLIC HEALTH RELEVANCE: Approximately ten million people worldwide suffer from a traumatic brain injury (TBI) for which there is currently no therapeutic intervention. The proposed studies in this application would evaluate the pharmacological efficacy of gamma glutamylcysteine ethyl ester (GCEE) as a post therapeutic treatment and investigate its remediation of traumatic brain injury. The use of GCEE as a neuroprotective agent against oxidative stress in this TBI study would demonstrate the prevention of functional neurological decline and restoration of function following brain injury.

project_terms:
3-nitrotyrosine;ATP Synthesis Pathway;Academic Research Enhancement Awards;Affect;Aftercare;Alkenes;Animals;Antioxidants;Biological Assay;Biomedical Research;Brain;Brain Injuries;Data;Electrophoresis;Environment;Enzymes;Esters;Funding;Glutathione;Glutathione Disulfide;Glutathione Reductase;Glutathione S-Transferase;Goals;Health;Hippocampus (Brain);Injury;Institution;Kentucky;Knowledge;Laboratories;Mass Spectrum Analysis;Measurement;Measures;Mitochondria;Modification;Neurologic;Neurons;Neuroprotective Agents;Nitrates;Outcome;Oxidative Stress;Patients;Prevention;Proteins;Proteomics;Rattus;Recovery;Reduced Glutathione;Research;Research Proposals;Role;Sampling;Science;Staining method;Stains;Students;System;Techniques;Testing;Therapeutic;Therapeutic Intervention;Time;Trauma;Traumatic Brain Injury;United States National Institutes of Health;Universities;Wistar Rats;base;effective intervention;glutathione peroxidase;injured;medical attention;mimetics;mitochondrial dysfunction;neuroprotection;nitration;programs;protein profiling;remediation;restoration

public_health_relevance:
Approximately ten million people worldwide suffer from a traumatic brain injury (TBI) for which there is currently no therapeutic intervention. The proposed studies in this application would evaluate the pharmacological efficacy of gamma glutamylcysteine ethyl ester (GCEE) as a post therapeutic treatment and investigate its remediation of traumatic brain injury. The use of GCEE as a neuroprotective agent against oxidative stress in this TBI study would demonstrate the prevention of functional neurological decline and restoration of function following brain injury.


application_id: 8231976
project_number: 5F31DE021304-02
project_title: Counteracting microbial immune evasion for the treatment of periodontitis
administering_ic: NIDCR
award_notice_date: 2012-01-06
opportunity_number: PA-10-108
application_type: 5
activity_code: F31
ic: DE
serial_number: 021304
program_official: FRIEDEN, LESLIE A
project_start_date: 2011-02-02
project_end_date: 2013-02-01
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 10310860
contact_pi: MCINTOSH, MEGAN LAVONNE
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Periodontitis is a destructive inflammatory disease instigated by a number of microbial pathogens which have evolved mechanisms to manipulate the innate immune response for their own benefit. Among those microbes Porphyromonas gingivalis stands as a primary contributor to pathology significantly via its ability to interact with and manipulate Toll-like receptors (TLRs) and other pattern-recognition receptors (PRRs) that trigger innate immune responses. P. gingivalis is predominantly recognized by TLR2 and this interaction leads to two independent downstream pathways: the TLR2 antimicrobial pathway and the TLR2 proadhesive pathway which transactivates complement receptor 3 (CR3) and allows P. gingivalis to hijack CR3 for safe entry into macrophages. This proposal hypothesizes that P. gingivalis exploits the chemokine receptor CXCR4 not only to suppress the TLR2 antimicrobial pathway (as recently shown) but also to upregulate the TLR2 proadhesive pathway the focus of Aim 1. Both of these activities have the potential to increase the survival capacity of the pathogen thereby prolonging P. gingivalis infection and potentiating its impact on periodontal disease. This notion will be tested in vivo using a mouse model of periodontitis (Aim 2). Regarding Aim 1 in vitro immunological approaches using transfected cell lines or primary cells will elucidate the mechanistic basis of P. gingivalis-induced CXCR4/TLR2 crosstalk which transactivates CR3. It is hypothesized that the CXCR4 and TLR2 signaling pathways crosstalk via cAMP-dependent protein kinase A and the small GTPase Rac1 respectively. Aim 2 is designed to show that P. gingivalis exploits CXCR4 leading to increased pathogen persistence and periodontal disease activity in vivo. Treatment with AMD3100 a mouse/human CXCR4 antagonist which has a proven safety record in HIV clinical trials will be assessed for its potential to prevent the progression of periodontal disease in an established preclinical mouse periodontitis model. Also transgenic CXCR4 conditional knockout mice will be used to substantiate our AMD3100 studies as well as provide mechanistic insight into the role CXCR4 plays in P. gingivalis-mediated periodontal disease. This investigation will involve evaluation of the host response and persistence of the infection as well as induction of periodontal bone loss. Aim 2 is expected to provide proof-of-principle evidence that by antagonizing CXCR4 with AMD3100 or ablating CXCR4 in mice therefore preventing P. gingivalis from exploiting it protection against the destructive periodontal inflammation can be provided. The long-term objective is to identify effective small- molecule antagonists like AMD3100 which can counteract microbial immune evasion mechanistically and thus redirect the immune response to benefit the host.    PUBLIC HEALTH RELEVANCE: Periodontitis is perhaps the most common chronic disease of infectious origin in humans and is moreover associated with systemic inflammatory diseases such as atherosclerosis. This research proposal is based on evidence that periodontal bacteria exploit a host receptor namely CXCR4 for undermining host immunity and promoting their virulence. Using a preclinical periodontitis model this application proposes to test AMD3100 (a potent antagonist of mouse/human CXCR4 shown to be safe in clinical trials for HIV treatment) as an intervention treatment in periodontitis. This work is expected to help propel development of prophylactic and post-infection treatments which could drastically improve the quality of life of periodontal patients.

project_terms:
6H8H-34-dihydropyrimido(45-c)(12)oxazin-7-one;AMD3100;Address;Alveolar Bone Loss;Anaerobic Bacteria;Atherosclerosis;Bacteria;Binding (Molecular Function);Biological Response Modifiers;CXC Chemokines;Cell Line;Cells;Chronic Disease;Clinical Trials;Cyclic AMP-Dependent Protein Kinases;Data;Development;Disease;Evaluation;Exhibits;Figs - dietary;HIV;Host Defense;Human;Immune;Immune response;Immunity;Immunosuppressive Agents;In Vitro;Infection;Inflammation;Inflammation Mediators;Inflammatory;Intercept;Intervention;Investigation;Killings;Knockout Mice;Lead;Macrophage-1 Antigen;Mediating;Microbe;Modeling;Molecular;Monomeric GTP-Binding Proteins;Mus;Natural Immunity;Nitric Oxide;Oral cavity;Pathogenesis;Pathology;Pathway interactions;Patients;Pattern recognition receptor;Periodontal Diseases;Periodontitis;Play;Porphyromonas gingivalis;Quality of life;Research Proposals;Research Training;Role;Safety;Signal Pathway;Signal Transduction;Systemic infection;TLR2 gene;Testing;Therapeutic;Toll-like receptors;Transgenic Mice;Transgenic Organisms;Virulence;Virulent;Work;adaptive immunity;antimicrobial;base;bone loss;chemokine receptor;cytokine;design;fimbria;fitness;improved;in vivo;insight;macrophage;microbial;microbial host;mouse model;mutant;novel;pathogen;pre-clinical;prevent;prophylactic;public health relevance;receptor;response;small molecule

public_health_relevance:
PROJECT NARRATIVEPeriodontitis is perhaps the most common chronic disease of infectious origin in humans and is moreoverassociated with systemic inflammatory diseases such as atherosclerosis. This research proposal is based onevidence that periodontal bacteria exploit a host receptor namely CXCR4 for undermining host immunity andpromoting their virulence. Using a preclinical periodontitis model this application proposes to test AMD3100 (apotent antagonist of mouse/human CXCR4 shown to be safe in clinical trials for HIV treatment) as anintervention treatment in periodontitis. This work is expected to help propel development of prophylactic andpost-infection treatments which could drastically improve the quality of life of periodontal patients.


application_id: 8231489
project_number: 5R01AA017226-06
project_title: Alcohol and Breast Cancer
administering_ic: NIAAA
award_notice_date: 2012-02-28
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AA
serial_number: 017226
program_official: JUNG, KATHY
project_start_date: 2008-03-05
project_end_date: 2013-05-28
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
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): Alcoholism alcohol abuse and the medical complications of excessive drinking are major world-wide health problems. Alcohol is a tumor promoter. Epidemiological studies indicate that heavy alcohol consumption increases risk of breast cancer and is associated with advanced and invasive breast tumors. However the etiology of alcohol-induced tumor promotion is elusive. Cellular/molecular mechanisms underlying alcohol-promoted tumor development and progression remain unknown. ErbB2 a member of the epidermal growth factor receptor tyrosine kinase family is frequently over-expressed in human breast cancers. We have demonstrated that alcohol dramatically promotes migration/invasion of mammary epithelial cells and breast cancer cells over-expressing ErbB2. We also reveal that the human transmembrane mucin (MUC1) is highly sensitive to alcohol. ?-catenin is a proto-oncogene and plays an important role in tumorigenesis and cancer progression. The E-cadherin/?-catenin complex a critical component of cell-cell adherens maintains the integrity of epithelial cell interactions and regulates cell migration/invasion. We propose a novel role of MUC1 as an adaptor protein that bridges ErbB2 and ?-catenin and facilitate ErbB2/?-catenin interaction and the dissociation of E- cadherin/ ?-catenin complex. Our central hypothesis is that ethanol-induced oxidative stress up- regulates MUC1 as an adaptor protein to promote ErbB2/ ?-catenin interaction which induces dissociation of the ?-catenin/E-cadherin complex leading to cell transformation and cell migration/invasion. Both in vitro and in vivo models will be utilized to test this novel hypothesis. Specific Aim 1 will establish the pivotal role of MUC1 in ethanol-promoted ErbB2/ ?-catenin interaction. Specific Aim 2 will determine whether ethanol-promoted cell transformation and cancer cell migration/invasion is mediated by MUC1-dependent dissociation of the E-cadherin/2-catenin complex. Specific Aim 3 will investigate in vivo effects of ethanol. We will investigate the effect of ethanol on mammary tumorigenesis/metastasis in MMTV-Neu transgenic mice. We will further investigate the effect of ethanol on the interactions among MUC1 ErbB2 ?-catenin and E-cadherin as well as the role of ROS and MUC1 in ethanol- mediated tumorigenesis/metastasis in the transgenic and nude mice. As a cohesive unit the multi-disciplinary approaches using in vitro and in vivo models will systematically explore the mechanisms underlying alcohol-promoted tumorigenesis and malignant progression of breast cancer. The study will elucidate a novel function of ErbB2 and MUC1 in alcohol-induced tumor promotion. The expression/activity of ErbB2 and MUC1 is frequently aberrant in many other human cancers and in a variety of human diseases; their levels are also developmentally regulated. Understanding the interactions among alcohol ErbB2 and MUC1 will also provide an important insight into the pathogenesis of some human diseases related to alcohol abuse as well as alcohol's teratogenic effect during development.

project_terms:
Adaptor Signaling Protein;Alcohol abuse;Alcohol consumption;Alcoholism;Alcohols;Breast Cancer Cell;Cell Communication;Cells;Cellular Structures;Complex;Development;Dissociation;E-Cadherin;Epidemiologic Studies;Epidermal Growth Factor Receptor;Epithelial Cells;Ethanol;Etiology;Family;Health;Heavy Drinking;Human;In Vitro;Malignant - descriptor;Malignant Neoplasms;Mammary Neoplasms;Mammary Tumorigenesis;Mammary gland;Mediating;Molecular;Mouse Mammary Tumor Virus;Mucin-1 Staining Method;Mucins;Names;Neoplasm Metastasis;Nude Mice;Oxidative Stress;Pathogenesis;Play;Principal Investigator;Protein Tyrosine Kinase;Proto-Oncogenes;Research;Risk;Role;Testing;Transgenic Mice;Tumor Promoters;Tumor Promotion;alcohol effect;cancer cell;cell motility;cell transformation;human disease;in vivo;in vivo Model;insight;malignant breast neoplasm;medical complication;member;migration;novel;programs;tumor;tumor progression;tumorigenesis


application_id: 8231488
project_number: 5R01AA016166-05
project_title: Developmental Transitions and Risk for Alcohol Use
administering_ic: NIAAA
award_notice_date: 2012-03-01
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AA
serial_number: 016166
program_official: RUFFIN, BEVERLY
project_start_date: 2008-03-10
project_end_date: 2015-02-28
study_section: Risk, Prevention and Intervention for Addictions Study Section[RPIA]
contact_pi_person_id: 2092801
contact_pi: SMITH, GREGORY T.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): We propose to test an integrative model for adolescent risky behavior that incorporates key psychological features of the transition into adolescence the centrality of affect in adolescent risky behavior and the role of classic dispositional traits in shaping psychosocial learning. As individuals make the transition into adolescence they tend to experience increases in negative affectivity decreases in positive affectivity increases in sensation seeking and increases in urgency (the tendency to act impulsively when distressed). Many of these trait changes involve affectivity which we believe is important because affect appears to play a central if previously underappreciated role in adolescent risky behavior (Steinberg 2004). These trait changes are particularly important in light of advances in person-environment transaction theory. It appears that individual differences in personality cause individuals to learn different things from the same learning event: dispositional traits shape psychosocial learning (Smith et al. 2006). We propose to study the influence of trait changes on learning that disposes one to risky behaviors. We believe the trait of urgency is particularly important because urgency reflects mood-based impulsivity and is strongly related to several risky behaviors (Fischer et al. 2003; Smith et al. 2007a; Whiteside & Lynam 2003; Whiteside et al. 2005). In a longitudinal study of children from 5th grade (before the start of middle school) through 8th grade we will show the following. Following the onset of adolescence individual differences in the growth of urgency will predict subsequent individual differences in the growth of expectancies for problem drinking and other risky behaviors. Growth in those expectancies will predict subsequent individual differences in the onset of problem drinking and the other behaviors. Urgency's role will be different from that of sensation seeking: for example sensation seeking will predict quantity/frequency of drinking and urgency will predict problem drinking. Urgency's role will be different from that of negative and positive affectivity: the latter two traits will predict subsequent growth in depression but urgency will not. Urgency will predict growth in risky behaviors but affectivity will not. PUBLIC HEALTH RELEVANCE: This research will help us understand how the transition into adolescence can leave some children at risk for beginning to engage in risky behaviors. It will highlight the importance of emotion for some adolescents' risky behaviors and it will suggest mood-based interventions that might reduce risk.

project_terms:
Address;Adolescence;Adolescent;Affect;Alcohol abuse;Alcohol consumption;Behavior;Binge Eating;Child;Development;Developmental Process;Distress;Emotions;Environment;Esthesia;Event;Expectancy;Frequencies (time pattern);Growth;Health;Impulsivity;Individual;Individual Differences;Intercept;Intervention;Investigation;Learning;Left;Light;Longitudinal Studies;Measures;Mental Depression;Modeling;Moods;National Institute on Alcohol Abuse and Alcoholism;Personality;Persons;Play;Process;Psychological reinforcement;Recording of previous events;Research;Risk;Risk Behaviors;Role;Shapes;Smoking;Testing;Time;Variant;alcohol expectancy;base;behavior change;drinking;early onset;experience;girls;middle school;prospective;psychologic;psychosocial;purge;theories;trait;underage drinking


application_id: 8231475
project_number: 5F32AG037280-03
project_title: Harnessing microglia towards repair vs. damage: Does p38 MAPK hold the reins?
administering_ic: NIA
award_notice_date: 2012-02-06
opportunity_number: PA-09-210
application_type: 5
activity_code: F32
ic: AG
serial_number: 037280
program_official: REFOLO, LORENZO
project_start_date: 2010-04-15
project_end_date: 2012-09-14
study_section: Special Emphasis Panel[ZRG1-F01-L(20)L]
contact_pi_person_id: 10095513
contact_pi: BACHSTETTER, ADAM 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
project_abstract:
DESCRIPTION (provided by applicant): A primary pathological component of Alzheimer's disease (AD) is brain inflammation. Activation of microglia the "macrophages of the brain" is known to occur in AD and believed to contribute to the neuronal damage. Studies of peripheral macrophages have determined that multiple distinct activation states of macrophages exist and recent studies have confirmed these findings in microglia. Macrophages/microglia can be broadly defined as being classically activated or alternatively activated. Classically activated macrophages are typified by the release of proinflammatory cytokines (e.g. IL-12 TNF-1) and reactive oxygen and nitrogen species which are components of the inflammatory response that is known to cause neuronal damage. However not all forms of microglia activation are detrimental. Some forms of microglia activation are beneficial such as alternative activation responses that lead to removal or clearance of amyloid beta (A2). This proposal will test the hypothesis that the p381 MAP kinase signaling cascade leads to the detrimental forms of microglia activation and that blocking the p381 pathway will decrease the detrimental responses of activated microglia without affecting the beneficial responses. Aim 1 will test the hypothesis that activation of the p381 MAP kinase signaling cascade occurs in microglia during the early phase of pathogenesis in an AD-relevant transgenic mouse model (the Tg6799 mouse). Aim 2 will use a novel brain-penetrant small molecule inhibitor of p381 to test the hypothesis that suppression of p381 activity will slow the pathology in the Tg6799 mouse. This aim will provide training in the use of pharmacological tools transgenic models of neurodegenerative disease and therapeutic target validation. Aim 3 will evaluate the relative contribution of p381 in microglia vs. other neural cell types in the damage produced by A2. To test this aim we will use an A2 infusion AD-relevant model in a mouse with a genetic deletion of p381 only in the microglia. This aim will provide training in the use of conditional knockout mouse models using the cre/lox system and stereotaxic surgery in mice. Successful completion of this project will provide mechanistic insight into how the key regulatory protein p381 is involved in CNS pathophysiology mechanisms and intervention responses and will form the foundation for follow-on CNS therapeutic development campaigns targeting this important protein kinase. A Career Development Plan has been formalized and includes a combination of formal classroom and specialty workshop participation regular presentations of proposed research plans and results at the laboratory and research group level presentation of independent research results in seminar format participation in national and international scientific meetings preparation of research proposals and publications and development of additional career- enhancing skills. An experienced mentor a rich scientific environment and an organized educational and training plan will assure that the applicant has optimal opportunities for scientific growth career enhancement and development into an independent academic investigator.

project_terms:
Affect;Aging;Alzheimer's Disease;Amyloid beta-Protein;Astrocytes;Attenuated;Brain;Cells;Chronic;Degenerative Disorder;Development;Development Plans;Disease;Disease Progression;Edema;Educational workshop;Effector Cell;Encephalitis;Environment;Equilibrium;Excision;Family;Foundations;Functional disorder;Future;Genetic;Goals;Growth;Growth Factor;Homeostasis;Immune;Immune response;Immune system;Immunity;Inflammation;Inflammatory;Inflammatory Response;Infusion procedures;Interleukin-12;International;Intervention;Investigation;Killings;Knockout Mice;Knowledge;Laboratory Research;Lead;Learning;MAP Kinase Gene;MAP Kinase Modules;MAPK14 gene;Mentors;Microglia;Modeling;Mus;Neuraxis;Neurodegenerative Disorders;Neuroglia;Neurons;Nitrogen;Operative Surgical Procedures;Oxygen;Pathogenesis;Pathology;Pathway interactions;Peripheral;Phase;Play;Preparation;Process;Production;Protein Isoforms;Protein Kinase;Protein Secretion;Publications;Regulation;Relative (related person);Research;Research Personnel;Research Proposals;Rest;Role;Signal Transduction;Stimulus;Synapses;System;TNF gene;Testing;Therapeutic;Training;Transgenic Mice;Transgenic Model;Up-Regulation (Physiology);Validation;age related;base;career;career development;cell type;cytokine;effective therapy;experience;genetic regulatory protein;inhibitor/antagonist;insight;macrophage;medical specialties;meetings;mouse model;neuroinflammation;neuron loss;novel;oxidative damage;pathogen;repaired;response;skills;small molecule;stressor;therapeutic development;therapeutic target;tool

public_health_relevance:
7. Project Narrative  Neuroinflammation is increasingly being recognized as a contributor to pathology in many neurodegenerative diseases such as Alzheimer's disease a devastating disease of aging with no effective treatment or cure. Successful completion of this project will provide mechanistic insight into how the key regulatory protein p38 MAPK is involved in brain pro-inflammatory responses and CNS dysfunction caused by disease-relevant stressors. In addition the results will delineate the relative importance of microglial p38 MAPK to the disease-relevant pathological responses. Longer term the insights and knowledge generated by the proposed studies will provide a firmer foundation for future development of new classes of disease- modifying therapeutics and fuller interpretation of disease progression investigations.


application_id: 8230775
project_number: 5R01CA129967-04
project_title: Amplification of tumor hypoxic responses by MIF-dependent HIF stabilization
administering_ic: NCI
award_notice_date: 2012-03-22
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 129967
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2009-05-01
project_end_date: 2014-02-28
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 7360475
contact_pi: MITCHELL, ROBERT A
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) has the grim distinction of being one of the most prognostically unfavorable human cancers. It has been suggested that low oxygen tensions within PDAC tumors contribute significantly to its metastatic potential and chemotherapeutic resistance. Hypoxia-inducible factors (HIFs) transcribe gene products that contribute to metabolic adaptation neo-angiogenic potential metastatic spread and therapeutic resistance. We recently discovered that macrophage migration inhibitory factor (MIF) one of the oldest cytokines ever described is elevated in PDAC patient's plasma and induced by hypoxia-induced HIF-1a-dependent transcription in pancreatic cancer cells. Intriguingly MIF was found to reciprocally modulate hypoxia- induced HIF-1a stabilization. Several human PDAC cell lines transfected with siRNA against MIF recapitulate MIF-/- fibroblasts in defective hypoxia-induced HIF-1a stabilization and subsequent HIF-dependent transcription. Moreover MIF-deficient PDAC cells display defective xenograft tumor outgrowth less HIF-1a and significantly reduced microvascular density than MIF-containing xenografts. Finally our results indicate that MIF promotes HIF-1a stability by functionally regulating a subunit of the COP9 signalosome CSN5 in repressing a unique HIF-1-specific ubiquitin E3 ligase. Our central hypothesis is that MIF overexpression in pancreatic adenocarcinoma lesions acts to modulate either the levels or activity of free CSN5 that in turn serves to repress or mask a unique oxygen-independent ubiquitin E3 ligase specific for HIF-1a. Studies outlined in this application seek to identify the contribution and requirements for MIF in PDAC growth pathophysiology and hypoxic adaptation. We will additionally delineate the precise mechanisms and molecular determinants involved in MIF-dependent HIF-1 stabilization. In order to fulfill the stated objectives of this application the following experimental aims are proposed: 1) Elucidate the basic mechanism by which MIF contributes to hypoxia-induced HIF-1a stabilization 2) Define the molecular determinants and effectors of HIF-1 degradation in MIF-deficient cells and 3) Determine if MIF contributes to pancreatic ductal adenocarcinoma growth pathophysiology and hypoxic adaptation. PUBLIC HEALTH RELEVANCE: All solid tumors require microenvironmental adaptation throughout tumorigenesis. One of the hallmarks of this adaptive response is the development of intratumoral hypoxia that stimulates HIF-directed expression of pro-angiogenic/metastatic gene products. Our findings establish that one of these gene products MIF is elevated in the plasma of a subset of pancreatic cancer patients. We further describe a unique functional inter-relationship between the extracellular cytokine/growth factor MIF and the transcription factor HIF-1a in pancreatic ductal adenocarcinoma (PDAC) cells. This point is demonstrated by our data showing that cells lacking MIF exhibit defective hypoxia and PHD inhibitor-induced HIF-1a stabilization and subsequent transcription of metabolic and angiogenic gene products. More importantly xenograft mouse models of PDAC tumorigenesis reveal that MIF-deficient tumor outgrowth HIF-1a expression and tumor-associated angiogenesis are severely impaired when compared to cells containing MIF. Because HIF expression contributes directly to tumor aggressiveness and cancers of the pancreas are reportedly very hypoxic it is likely that MIF functionally contributes to tumor maintenance environmental adaptation and ultimately prognosis of pancreatic adenocarcinoma patients.

project_terms:
Ablation;Adenocarcinoma Cell;Apoptosis;Binding (Molecular Function);Biochemical;Cancer Patient;Cell Line;Cells;Complement;Complex;Cullin Proteins;Data;Development;Disease Progression;Exhibits;Fibrinogen;Functional disorder;Gene Targeting;Genetic;Genetic Transcription;Growth;Growth Factor;Health;Human;Hypoxia;Hypoxia Inducible Factor;Image;In Situ Nick-End Labeling;In Vitro;In-Migration;Injection of therapeutic agent;JAB1 protein;Laboratories;Lesion;Maintenance;Malignant Neoplasms;Malignant neoplasm of pancreas;Masks;Mediating;Metabolic;Migration Inhibitory Factor;Molecular;Mus;Mutant Strains Mice;Neoplasm Metastasis;Nude Mice;Oxygen;Oxygen measurement partial pressure arterial;PECAM1 gene;Pancreatic Adenocarcinoma;Pancreatic Ductal Adenocarcinoma;Pathology;Pathway interactions;Patients;Pimonidazole;Plasma;Post-Translational Protein Processing;Proteins;Relative (related person);Resistance;Role;SLC2A1 gene;Signal Transduction;Small Interfering RNA;Solid Neoplasm;Staining method;Stains;Subgroup;Therapeutic;Transgenes;Transgenic Mice;Tumor Burden;Vascular Endothelial Growth Factors;Work;Xenograft procedure;angiogenesis;bHLH-PAS factor HLF;base;cell motility;cytokine;density;environmental adaptation;extracellular;fibroblast migration inhibitory factor;human cancer mouse model;hypoxia inducible factor 1;in vivo;inhibitor/antagonist;mouse model;neovascularization;novel;outcome forecast;overexpression;pancreatic cancer cells;pancreatic neoplasm;phenylpyruvate tautomerase;prevent;protein degradation;response;transcription factor;tumor;tumor progression;tumor xenograft;tumorigenesis;ubiquitin ligase;ubiquitin-protein ligase

public_health_relevance:
PROJECT NARRATIVE All solid tumors require microenvironmental adaptation throughout tumorigenesis. One ofthe hallmarks of this adaptive response is the development of intratumoral hypoxia thatstimulates HIF-directed expression of pro-angiogenic/metastatic gene products. Our findingsestablish that one of these gene products MIF is elevated in the plasma of a subset ofpancreatic cancer patients. We further describe a unique functional inter-relationship betweenthe extracellular cytokine/growth factor MIF and the transcription factor HIF-1 in pancreaticductal adenocarcinoma (PDAC) cells. This point is demonstrated by our data showing that cellslacking MIF exhibit defective hypoxia and PHD inhibitor-induced HIF-1 stabilization andsubsequent transcription of metabolic and angiogenic gene products. More importantlyxenograft mouse models of PDAC tumorigenesis reveal that MIF-deficient tumor outgrowthHIF-1 expression and tumor-associated angiogenesis are severely impaired when comparedto cells containing MIF. Because HIF expression contributes directly to tumor aggressivenessand cancers of the pancreas are reportedly very hypoxic it is likely that MIF functionallycontributes to tumor maintenance environmental adaptation and ultimately prognosis ofpancreatic adenocarcinoma patients.


application_id: 8230569
project_number: 5R01AG037868-02
project_title: Psychosocial stress interactions with electrophysiology and brain aging
administering_ic: NIA
award_notice_date: 2012-02-23
opportunity_number: PA-09-216
application_type: 5
activity_code: R01
ic: AG
serial_number: 037868
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 2011-03-01
project_end_date: 2016-02-29
study_section: Neuroendocrinology, Neuroimmunology, and Behavior Study Section[NNB]
contact_pi_person_id: 8915754
contact_pi: BLALOCK, ERIC
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): This application proposes to address a fundamental unresolved question in the field of psychosocial stress and brain aging the nature of the neurobiological pathways through which psychosocial stress promotes unhealthy brain aging (UBA). The focus of the studies will be on brain aging markers developing near the age of divergence of unhealthy from healthy brain aging as these seem particularly likely to be susceptible to stress. This project will also test the hypothesis that midlife changes in the brain's responses to stress promote the emergence of UBA. This view derives from our recent work with both electrophysiological and microarray techniques showing that stress hormone-sensitive markers of brain aging emerge around midlife in rats the same age range in which unhealthy cognitive aging begins to appear. The proposed studies will comprise a large multidisciplinary project aimed at obtaining a unique integrated perspective on neurobiological pathways affected by psychosocial stress in an established rat model of aging. It will involve state-of-the-art intracellular electrophysiology in brain slices immunohistochemistry with a battery of stains separate microarray analysis of individual rat brains EEG monitoring of sleep patterns and behavioral testing. Multiple techniques will be applied in each animal. These studies will pursue the aims of correlating electrophysiological and genomic markers of unhealthy brain aging in the same animals and will relate exposure to psychosocial stress to the development of UBA as a function of age and under acute vs. chronic conditions. Importantly behavioral and pharmacological interventions to reduce stress and protect sleep patterns will be used to test whether the course of UBA can be altered in long-term studies. Aged animals subjected to psychosocial stress-reducing and sleep-promoting interventions will be evaluated on a battery of behavioral electrophysiological sleep monitoring microarray and immunohistochemical analyses to test the proposition that conversion these interventions may reduce/reverse UBA symptoms and if so to determine through which brain pathways this occurred. Overall these studies should substantially elucidate neurobiological pathways through which psychosocial stress influences brain aging markers and should importantly determine the role of age in modulating stress impact. Further the proposed intervention studies should have direct translational relevance.    PUBLIC HEALTH RELEVANCE: This proposed research will investigate the impact of acute and chronic psychosocial stress on brain function in an established rat model of aging. These studies will elucidate neurobiological markers of and processes influencing the divergence of healthy and unhealthy brain aging focusing on changes beginning around midlife and will also evaluate stress reducing and sleep promoting interventions' ability to combat the effects of psychosocial stress. Therefore the proposed studies should have both predictive and therapeutic value in determining the course of human brain aging.

project_terms:
21 year old;Accounting;Acute;Address;Adrenal Glands;Affect;Age;Age-Months;Aging;Animals;Area;Behavioral;Blood;Brain;Chronic;Chronic stress;Cognition;Cognitive aging;Development;Electroencephalography;Electrophysiology (science);Ensure;Exhibits;Exposure to;Gene Expression;Genomics;Glial Fibrillary Acidic Protein;Hippocampus (Brain);Hormones;Human;Immunohistochemistry;Inbred F344 Rats;Individual;Inflammatory;Intervention;Intervention Studies;Killings;Link;Literature;Longitudinal Studies;Mediating;Microarray Analysis;Mifepristone;Modeling;Monitor;NIH Program Announcements;Nature;Neurobiology;Outcome;Outcome Measure;Pathway interactions;Pattern;Polysomnography;Predisposition;Process;Psychosocial Stress;RU-486;Rattus;Research;Resistance;Role;Sleep;Sleep disturbances;Slice;Staining method;Stains;Steroids;Stress;Symptoms;Techniques;Testing;Therapeutic;Time;Trazodone;Wireless Technology;Work;age group;age related;aged;aging brain;behavior test;biological adaptation to stress;brain pathway;combat;environmental enrichment for laboratory animals;functional outcomes;genome-wide;interdisciplinary approach;interest;intervention effect;middle age;morris water maze;multidisciplinary;novel;prevent;public health relevance;research study;response;restraint;restraint stress;serotonergic regulation;steroid hormone;stressor;transmission process;voltage clamp;young adult

public_health_relevance:
This proposed research will investigate the impact of acute and chronic psychosocial stress on brain function inan established rat model of aging. These studies will elucidate neurobiological markers of and processesinfluencing the divergence of healthy and unhealthy brain aging focusing on changes beginning around midlifeand will also evaluate stress reducing and sleep promoting interventions' ability to combat the effects ofpsychosocial stress. Therefore the proposed studies should have both predictive and therapeutic value indetermining the course of human brain aging.


application_id: 8230284
project_number: 4R37DK039176-24
project_title: Regulation of lipoprotein lipase in adipocytes
administering_ic: NIDDK
award_notice_date: 2011-07-29
application_type: 4
activity_code: R37
ic: DK
serial_number: 039176
program_official: HAFT, CAROL R
project_start_date: 1988-09-01
project_end_date: 2013-07-31
study_section: NSS
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-08-01
project_abstract:
The mechanism of LPL regulation is complex and we have focused on the translational regulation of LPL which occurs in response to diabetes and in response to hormones such as thyroid hormone and epinephrine. LPL translation is controlled by an RNA binding complex consisting of a member of the A-Kinase Anchoring Protein (AKAP) family which tethers PKA to specific cellular sites and PKA subunits. AKAP121 contains a consensus KH RNA binding region and is a component of the RNA binding complex. Therefore we plan to examine LPL translation regulation by studying both the RNA binding complex and the LPL mRNA. Hypothesis 1. LPL translation is regulated by an RNA binding complex which interacts with the LPL 3'UTR. This complex depends on specific sequence elements of PKA AKAP and possibly other components.  Aim 1. Examine AKAP149/121 interactions with other elements of the PKA complex and examine the interactions between PKA and PKC with regards to LPL regulation.  Aim 2. Is the increase in LPL translation from hypothyroidism due to changes in AKAP expression?  Aim 3. Identify LPL 3'UTR sequence elements that alterthe interaction with the RNA binding complex especially targeting the gain of function variant Known as LPLS447X:  Aim 4 (new). Are miRNAs involved with the translational regulation of LPL? Hypothesis 2. By preventing the interaction between the RNA binding complex with the LPL 3'UTR LPL will become unresponsive to epinephrine and adipose tissue will accumulate more lipid diverting lipid from other insulin target organs yielding improved insulin sensitivity.  Aim 5. Examine the phenotype of a transgenic mouse that expresses LPL lacking the proximal 3'UTR. Will this cause lipid partitioning into adipose tissue and improve insulin sensitivity?  Aim 6. Examine insulin sensitivity and other phehotypic feaitures ofid-AKAPI knocl<out mice.

project_terms:
3' Untranslated Regions;A kinase anchoring protein;Accounting;Address;Adipocytes;Adipose tissue;Arkansas;Atherosclerosis;Catabolism;Cells;Chylomicrons;Clinical;Complement;Complex;Consensus;Cyclic AMP-Dependent Protein Kinases;Data;Diabetes Mellitus;Elements;Enzymes;Epinephrine;Funding;Grant;Hormones;Human Resources;Hypothyroidism;Instruction;Insulin;Kentucky;Knockout Mice;Lipids;Lipoproteins;Messenger RNA;Mitochondria;Mus;Muscle Cells;Organ;Paper;Phenotype;Positioning Attribute;Preparation;Protein Family;Proteins;Publishing;RNA Binding;RNA-Binding Proteins;Regulation;Research;Site;Staging;Thyroid Hormones;Time;Transgenic Mice;Translational Regulation;Translational Repression;Translations;Triglycerides;Universities;Variant;Very low density lipoprotein;gain of function;improved;insulin sensitivity;lipid metabolism;lipoprotein lipase;member;prevent;protein expression;response

public_health_relevance:
RELEVANCE (See instructions): Lipoprotein lipase (LPL) is a central enzyme in lipid metabolism. LPL is synthesized and secreted by adipocytes and muscle cells and hydrolyzes the triglyceride core of circulating VLDL and chylomicrons. Abnormalities in LPL are important in atherosclerosis and diabetes where the inefficient catabolism of triglyceride rich lipoproteins leads to the formation of highly atherogenic remnant lipoproteins.


application_id: 8229971
project_number: 7R01GM086891-03
project_title: P450 Protein-Protein Interactions Determined by Selective Protein Manipulation
administering_ic: NIGMS
award_notice_date: 2011-06-22
opportunity_number: PA-07-070
application_type: 7
activity_code: R01
ic: GM
serial_number: 086891
program_official: OKITA, RICHARD T
project_start_date: 2009-09-01
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZRG1-DIG-F(02)M]
contact_pi_person_id: 1903121
contact_pi: TRACY, TIMOTHY S.
other_pis: GANNETT, PETER M.
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: Y
project_abstract:
During the past decade it has become evident that in vitro enzyme data obtained insolution frequently fail to provide an accurate profile of in vivo enzyme kineticparameters. This may be due to oligomer formation. Efforts to separate the effect ofoligomer formation on P450 kinetics from factors that might influence kinetic parametershave been incomplete and are necessary to quantify the contribution that oligomerformation has on P450-mediated metabolism kinetics to improve estimations of in vivodrug clearance. Our long-term goal is to accurately predict in vivo drug pharmacokineticsfrom in vitro data to improved assessments of drug safety and efficacy. Our overallobjective here is to determine the important factors influencing in vitro P450-mediatedmetabolism kinetics through studies of homo- and hetero-oligomer formation using ourrecently developed immobilized enzyme methods. Our central hypothesis is thatCYP2C9-mediated metabolism kinetics measured in vitro are critically dependent onthe state of oligomerization and to accurately predict in vivo pharmacokinetics using invitro data requires inclusion of this variable. Our rationale for this project is thatsuccessful completion would provide a solid scientific foundation to more accuratelyassess in vivo kinetics of metabolism based upon in vitro data. To achieve our overallobjectives we propose to quantitate the modulatory effects of CYP2C9 homo andhetero-oligomer formation on enzyme kinetics. Successful achievement of this goalwill well position us to determine the key factors that explain altered enzyme kinetics ofoligomers versus monomers. The proposed research is innovative as a novelimmobilized P450 methodology will be employed to unequivocally evaluate the effect ofoligomerization on the kinetics of metabolism. Our expected outcomes are 1)determination of selected physical-chemical factors that affect CYP2C9 kinetics usingnanoscale methods for protein manipulation and 2) to have quantitated the extent towhich oligomer formation modulates CYP2C9-mediated metabolism kinetics. Theseoutcomes are significant as they will help to further delineate the mechanistic details ofP450 metabolism an enzyme system responsible for metabolism of the majority ofdrugs and should lead to improved pharmacokinetic data necessary for determinationof correct dosages and thus ultimately improve patient care.

public_health_relevance:
Data from in vitro experiments are routinely used during the drug development processto predict the disposition of a drug in humans to better determine initial doses. Howeverit has now become apparent that interactions between the drug metabolism proteinsmay alter the these results and affect the ability to correctly predict human doses. Betterunderstanding of these protein-protein interactions will lead to more accurate predictionsof drug disposition and thus improved patient safety and drug efficacy.


application_id: 8227982
project_number: 5R21ES019249-02
project_title: Quercitrin functions as an antioxidant and protects UV-induced carcinogenesis
administering_ic: NIEHS
award_notice_date: 2012-02-01
opportunity_number: PA-10-069
application_type: 5
activity_code: R21
ic: ES
serial_number: 019249
program_official: HUMBLE, MICHAEL C
project_start_date: 2011-02-15
project_end_date: 2015-01-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
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_abstract:
DESCRIPTION (provided by applicant): Reactive oxygen species (ROS) and related oxidative stress are linked with various diseases including cardiovascular disease cancer chronic lung diseases and diabetes mellitus. Interventions favoring the scavenging of ROS to attenuate the oxidative stress may prevent oxidant stress associated diseases. Recent studies suggest that various fruits and vegetables contain high concentrations of antioxidants. Quercitrin is a glycosylated form of flavonoid compounds widely distributed in nature and is ubiquitous in plants fruits seeds and vegetables. Our preliminary studies show that this compound displayed a stronger antioxidant activity than that of ascorbic acid over the same concentration range. It blocked TPA-induced neoplastic transformation in JB6 P+ cells. Pretreatment of JB6 cells with quercitrin down-regulated activation of AP-1 NF- :B induced by UVB or TPA. In the skin of AP-1-luciferase transgenic mice topical treatment of mouse with quercitrin markedly blocked the TPA-induced AP-1 activation. Further studies indicated that these inhibitory actions appear to be mediated through the inhibition of MAPKs phosphorylation including ERKs p38 kinase and JNKs. In addition quercitrin stimulated the activation of NF-E2-related factor (Nrf2) and GST ARE- luciferase activity. Comet assays showed that quercitrin could block DNA damage induced by UVB. These preliminary studies indicate that quercitrin may function as a potential chemopreventive and chemotherapeutic agent. The overall hypothesis of this application is that quercitrin functions as an antioxidant and protects UV- induced carcinogenesis. The goal of this proposal is to test this hypothesis. Aim 1 will investigate the antioxidant properties of quercitrin in both non-cellular and cellular. We will study whether quercitrin scavenges free radicals or inhibits their generation and determine reaction rate constants of the reactions between quercitrin and oxygen radicals. Moreover we will detect the UV-induced free radical generation from UV- irradiated skin of living animal using in vivo electron spin resonance (ESR) spin trapping and identify the radicals generated. Aim 2 will investigate the inhibitory effects of quercitrin against the UV-induced oxidative damage to lipid protein and DNA and UV-induced tumorigenesis and cell proliferation in SKH-1 hairless mice. This study represents first detection of free radicals generated by UV-irradiated skin of living animals and may potentially open a new avenue to evaluate the properties of antioxidant against free radicals generated in living animals. Another significance of the study is the identification of qucertrin as a preventive agent against UV-induced skin cancers.    PUBLIC HEALTH RELEVANCE: Reactive oxygen species (ROS) and related oxidative stress are linked with various diseases including cardiovascular disease cancer chronic lung diseases and diabetes mellitus. Interventions favoring the scavenging of ROS to attenuate the oxidative stress may prevent oxidative stress associated diseases. This proposal will test the hypothesis that quercitrin a compound found in blackberries and other foods functions as an antioxidant and protects UV-induced carcinogenesis.

project_terms:
Animal Model;Animals;Antioxidants;Apoptosis;Ascorbic Acid;Attenuated;Cardiovascular Diseases;Cell Proliferation;Cells;Chemicals;Chemopreventive Agent;Chronic Disease;Chronic lung disease;Comet Assay;Consumption;Cutaneous Melanoma;DNA;DNA Damage;Detection;Diabetes Mellitus;Diet;Disease;Electron Spin Resonance Spectroscopy;Enzymes;Epidemiologic Studies;Epigallocatechin Gallate;Exhibits;Flavonoids;Food;Free Radical Scavenging;Free Radicals;Frequencies (time pattern);Fruit;Generations;Goals;Green tea (dietary);Human;Hydrogen Peroxide;Hydroxyl Radical;In Vitro;Inbred HRS Mice;Incidence;Individual;Intervention;Investigation;JNK-activating protein kinase;Laboratories;Life;Link;Lipids;Luciferases;MAP Kinase Gene;MAPK14 gene;Malignant Neoplasms;Mediating;Milk Thistle;Mus;Nature;Neoplastic Cell Transformation;Oxidative Stress;Pathway interactions;Phase;Phosphorylation;Phytochemical;Plants;Preventive;Property;Proteins;Reaction;Reactive Oxygen Species;Seeds;Signal Transduction;Skin;Skin Cancer;Source;Spin Trapping;Staging;Sunlight;Superoxides;System;Testing;Therapeutic;Topical application;Trans-Activation (Genetics);Transcription Factor AP-1;Transgenic Mice;UV carcinogenesis;UV induced;UV-induced melanoma;UVB induced;Ultraviolet B Radiation;Vegetables;Xanthine Oxidase;Xanthines;carcinogenesis;chemotherapeutic agent;free radical oxygen;fruits and vegetables;high risk;in vivo;oxidant stress;oxidative damage;prevent;public health relevance;reaction rate;research study;silibinin;tumorigenesis;ultraviolet irradiation

public_health_relevance:
Narrative:Reactive oxygen species (ROS) and related oxidative stress are linked with various diseases includingcardiovascular disease cancer chronic lung diseases and diabetes mellitus. Interventions favoring thescavenging of ROS to attenuate the oxidative stress may prevent oxidative stress associated diseases. Thisproposal will test the hypothesis that quercitrin a compound found in blackberries and other foods functions asan antioxidant and protects UV-induced carcinogenesis.


application_id: 8226911
project_number: 1R21AR062356-01
project_title: Non-contact Diffuse Optical Assessment of Pressure Ulcer and Therapy
administering_ic: NIAMS
award_notice_date: 2012-02-13
opportunity_number: PA-10-069
application_type: 1
activity_code: R21
ic: AR
serial_number: 062356
program_official: TSENG, HUNG H
project_start_date: 2012-02-15
project_end_date: 2014-01-31
study_section: Special Emphasis Panel[ZRG1 BMIT-J (01)]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Pressure ulcers affect 1-3 million American adults. Prolonged pressure results in poor peripheral circulation and tissue hypoxia and may cause significant tissue damage. As one of the adjunctive therapies electrical stimulation (ES) is less labor intensive with lower costs compared to conventional therapies for ulcer treatment. However ES parameters are often selected arbitrarily and treatment outcomes are evaluated by visible estimates of tissue mass and/or wound volume changes rather than intrinsic hemodynamic changes in ulcerous tissues. Early detection of pressure ulcers is the key for effective ulcer management and for reducing subsequent treatment costs. Since pressure ulcers usually originate from deep tissues attached to the bone (e.g. gluteal muscles surrounding the sacrum) measurement of deep tissue hemodynamics is essential for early diagnosis of ulcers and for optimization of ES treatment. However no easy methods exist yet that are able to detect the early stages of ulcer development in deep tissues. A new advanced technology near- infrared diffuse optics can noninvasively monitor blood flow and oxygenation in deep tissues (up to several centimeters) with fiber-optic probes that gently contact the skin surface and has recently been demonstrated in our preliminary studies. However measurements of tissue hemodynamics using contact probes are not appropriate for ulcerous tissues that are prone to infection. This proposed project is to develop and validate a novel non-contact diffuse optical system (Aim 1) for early hemodynamic assessment of ulcer development in deep tissues. This non-contact system will completely avoid tissue deformation and potential infections induced by probe-tissue contact. This study will also integrate the non-contact system with an ES stimulator for treatment and therapeutic monitoring of pressure ulcers. After the integrated non-contact system is validated in healthy muscles and ES treatment parameters are optimized to maximize tissue hemodynamic responses to ES (Aim 2) the non-contact optical system will be used to detect blood flow and tissue oxygenation in gluteal muscles surrounding the sacrum in patients with or without pressure ulcers (stages I-IV) before during and after ES treatments over 4 weeks (Aim 3). It is expected that measurement of deep tissue hemodynamics that affect tissue damage/healing will provide unique value for the early diagnosis of ulcer development the objective optimization of ES parameters and the longitudinal evaluation of ES treatment effects. Our long-term goal is to conduct extensive studies on statistically significant populations from multiple rehabilitation centers to translate and commercialize this innovative integrated system for the effective clinical management of pressure ulcers. Given the health burden of long-term care for pressure ulcers this translational technology project has the potential to significantly advance our understanding of pressure ulcer development and treatment ultimately leading to significant improvements in human health and substantial cost savings.  
  
PUBLIC HEALTH RELEVANCE: Early detection of pressure ulcers is the key for effective ulcer management and for reducing subsequent treatment costs. Measurement of deep tissue hemodynamics that affect tissue damage/healing is essential for the early diagnosis of ulcers and for the optimization of treatment (e.g. electrical stimulation (ES)) since pressure ulcers usually originate from deep tissues attached to the bone. The objective of this study is to develop and validate a novel non-contact near-infrared diffuse optical system which will allow us to probe blood flow and oxygenation in deep tissues during ES without touching vulnerable/ulcerous tissue surfaces.

project_terms:
Accounting;Adult;Affect;American;Blood Circulation;Blood flow;Clinical Management;Computers;Cost Savings;Cutaneous;Decubitus ulcer;Development;Diffuse;Early Diagnosis;Early identification;Electric Stimulation;Evaluation;Fiber Optics;Forearm;Goals;Healed;Health;Healthcare;Heterogeneity;Human;Hypoxia;Impairment;Individual;Infection;Long-Term Care;Measurement;Measures;Methods;Monitor;Muscle;Optics;Pain Threshold;Patients;Peripheral;Population;Prevention;Procedures;Property;Recruitment Activity;Rehabilitation Centers;Sacral Region;Skin;Source;Spinal cord injury;Staging;Surface;System;Technology;Therapeutic;Tissues;Touch sensation;Translating;Treatment Cost;Treatment outcome;Ulcer;Validation;Variant;bone;conventional therapy;cost;detector;healing;hemodynamics;high risk;improved;innovation;lens;novel;patient population;pressure;response;sacrum;therapy development;tissue oxygenation;treatment effect;wound

public_health_relevance:
Early detection of pressure ulcers is the key for effective ulcer management and for reducing subsequent treatment costs. Measurement of deep tissue hemodynamics that affect tissue damage/healing is essential for the early diagnosis of ulcers and for the optimization of treatment (e.g. electrical stimulation (ES)) since pressure ulcers usually originate from deep tissues attached to the bone. The objective of this study is to develop and validate a novel non-contact near-infrared diffuse optical system which will allow us to probe blood flow and oxygenation in deep tissues during ES without touching vulnerable/ulcerous tissue surfaces.


application_id: 8222810
project_number: 5F31NS071804-02
project_title: Calpastatin overexpression as a therapeutic approach to traumatic brain injury
administering_ic: NINDS
award_notice_date: 2011-11-17
opportunity_number: PA-10-108
application_type: 5
activity_code: F31
ic: NS
serial_number: 071804
program_official: HICKS, RAMONA R
project_start_date: 2011-01-05
project_end_date: 2013-07-04
study_section: Special Emphasis Panel[ZRG1-F01-L(20)L]
contact_pi_person_id: 9791904
contact_pi: SCHOCH, KATHLEEN MARIE
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): Traumatic brain injury (TBI) afflicts approximately 1.4 million individuals in the U.S. each year. Following TBI a variety of cellular mediators contribute to neuronal death and dysfunction including the cysteine proteases calpains. Prolonged activation of calpains occurs within neurons due to a rapid and sustained rise of intracellular free calcium. Although an endogenous inhibitor of calpains calpastatin is co- expressed the sustained activation of these calcium-dependent proteases suggests endogenous calpastatin levels may be insufficient. The overall hypothesis of this proposal is that overexpression of calpastatin will reduce the proteolytic activity of calpains and associated neuronal death after trauma thereby attenuating motor and cognitive deficits. Calpastatin overexpression will be induced in two ways-transgenic overexpression of human calpastatin (hCAST) (Aim 1) and calpastatin expression via lentiviral vector delivery into brain regions vulnerable to TBI (Aim 2).  Aim 1 will use a novel transgenic mouse line with human calpastatin under control of the ubiquitous prion promoter. This mouse line exhibits a 9-fold greater expression of calpastatin in the cortex and hippocampus compared to wildtype mice. hCAST transgenic and wildtype littermates will be subjected to severe controlled cortical impact (CCI) injury or sham treatment. To confirm that calpastatin overexpression decreases calpain activity cortical and hippocampal homogenates will be evaluated for calpain-mediated cytoskeletal and membrane protein breakdown via immunoblot. Both motor and cognitive functions will be assessed after injury after which mice will be euthanized for analysis of hippocampal neurodegeneration and cortical tissue damage to assess the neuroprotective actions of hCAST overexpression. The expectation is that hCAST transgenic mice will have reduced posttraumatic calpain proteolytic activity offering a neuroprotective advantage. Aim 2 establishes an alternative approach to hCAST overexpression through lentiviral vector delivery. After injection of control lentivirus or calpastatin lentivirus into the cortex or hippocampus mice will be subjected to 1.0mm CCI brain injury or sham treatment and assessed as in Aim 1. Targeting of calpastatin to vulnerable neuronal regions prior to injury should spare affected neurons and reduce behavioral deficits.    PUBLIC HEALTH RELEVANCE: Given the scope of traumatic brain injury it is imperative to understand the mechanisms of neuronal damage and death in order to develop effective treatment strategies. My research aims will not only seek to establish a functional neuroprotective role for calpastatin in brain trauma but also advance translational efforts for the treatment of brain injury.

project_terms:
Address;Affect;Area;Attenuated;Behavior;Behavioral;Brain Injuries;Brain region;C-terminal;Calcium;Calpain;Cells;Cessation of life;Cleaved cell;Cognitive;Cognitive deficits;Convection;Cysteine Protease;Cytoskeletal Proteins;Diffusion;Elements;Exhibits;Functional disorder;Genes;Goals;Hippocampus (Brain);Human;Image;Immunoblot Analysis;Immunoblotting;Immunohistochemistry;Individual;Infusion procedures;Injection of therapeutic agent;Injury;Lentivirus Vector;Location;Measurement;Mediating;Mediator of activation protein;Membrane;Membrane Proteins;Methods;Mitochondrial Proteins;Motor;Mus;Nerve Degeneration;Neurologic;Neurons;Pathogenesis;Peptide Hydrolases;Performance;Placebos;Prions;Promotor (Genetics);Proteolysis;Regulatory Element;Research;Role;Severities;Subfamily lentivirinae;Testing;Therapeutic;Tissues;Transgenic Mice;Transgenic Organisms;Trauma;Traumatic Brain Injury;Variant;Viral;behavior measurement;brain tissue;calpain inhibitor;calpastatin;cognitive function;cohort;controlled cortical impact;effective therapy;expectation;improved;inhibitor/antagonist;injured;morris water maze;motor deficit;novel;overexpression;public health relevance;receptor;response;treatment strategy

public_health_relevance:
8. Project NarrativeGiven the scope of traumatic brain injury it is imperative to understand the mechanisms of neuronal damageand death in order to develop effective treatment strategies. My research aims will not only seek to establish afunctional neuroprotective role for calpastatin in brain trauma but also advance translational efforts for thetreatment of brain injury.


application_id: 8221519
project_number: 2U54OH007547-11
project_title: Southeast Center for Agricultural Health and Injury Prevention-Renewal
administering_ic: NIOSH
award_notice_date: 2011-09-12
opportunity_number: PAR-11-022
application_type: 2
activity_code: U54
ic: OH
serial_number: 007547
program_official: ROBISON, WILLIAM
project_start_date: 2001-09-30
project_end_date: 2016-09-29
study_section: Special Emphasis Panel[ZOH1 EEO (51)]
contact_pi_person_id: 2080884
contact_pi: MCKNIGHT, ROBERT H.
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The Southeast Center for Agricultural Health and Injury Prevention at the University of Kentucky (UK) proposes to continue serving as a NIOSH Agricultural Center for 2011-2016. The Center founded in 1992 is one of seven Centers of excellence in the UK College of Public Health. Our location on a land-grant campus allows substantive trans-disciplinary collaboration within this renewal from disciplines including agriculture public health epidemiology engineering education social work communications economics nursing medicine and Cooperative Extension. We propose 9 projects: 3 are comprehensive R01 research; 2 are R18 prevention/intervention; 1 is an ROS education/translation project and 3 are R18 education/translation projects. The application includes an administrative/planning core and separate strategic plans for outreach pilot/feasibility studies and evaluation. The Center's theme "Trans-disciplinary approaches to agricultural safety and health in the Southeast" is further distinguished by our emphasis on serving limited resource and vulnerable farm populations while addressing persistent and emerging agricultural occupational safety concerns. The region served by the Center will continue to be the 10 southeastern states of AL FL GA KY MS NC SC TN VA and WV. With this renewal the Southeast Center expects to have a substantial impact on the following priorities: Hispanic farmworker safety and work organization; tractor overturns; cancer incidence in farmers/cancer surveillance; hazards in aquaculture; the personal operational and societal costs of injuries and the cost-effectiveness of prevention; safety communication in the logging industry; nurses' education service and clinical practice in farm safety and health; graduate education in agricultural occupational safety and health and Native American farm safety. While projects are based in our 10-state region each holds wider relevance as well as real potential for national impact. The Center benefits from a strong institutional commitment and support from 9 colleges within the University of Kentucky system at the Lexington campus. The Center also enjoys substantive collaboration with researchers at Auburn University Wake Forest University the Northeast Center for Agricultural & Occupational Health and diverse grassroots stakeholders.   
   
PUBLIC HEALTH RELEVANCE: In concert with regional stakeholders and with trans-disciplinary teams of highly qualified investigators the Southeast Center for Agricultural Health and Injury Prevention has developed an integrated mutually reinforcing package of research prevention/intervention and education/translation projects aimed at achieving measurable improvements in agricultural occupational safety and health practice and outcomes.


application_id: 8221004
project_number: 5R01DA027981-03
project_title: Victimization and Women in the Criminal Justice System
administering_ic: NIDA
award_notice_date: 2012-03-02
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DA
serial_number: 027981
program_official: DEEDS, BETHANY
project_start_date: 2010-04-01
project_end_date: 2015-02-28
study_section: Community Influences on Health Behavior Study Section[CIHB]
contact_pi_person_id: 6472821
contact_pi: GOLDER, SEANA
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF SOCIAL WELFARE/WORK
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposed study (R01; PA-07-070) will examine the heterogeneity of victimization its' relationship with substance use and psychological distress as well as the combined affect of these factors on the health seeking process among victimized women in the criminal justice (CJ) system. Study aims are to 1) identify and characterize latent class trajectories based on victimization substance use and psychological distress among 400 victimized women on probation and parole; 2) determine the extent to which women in the identified trajectory classes vary over a two year time period in levels of risk and protection in the health seeking process; and 3) examine the theory based components of the health seeking process among 400 victimized women on probation and parole. Findings from this research will be used to identify those groups of women that are most at risk for engagement in high risk behaviors (current drug use; psychological distress; HIV risk behavior; lawbreaking and continued CJ involvement) and to identify and characterize their associated levels of risk and protection in the health seeking process across a two year time period. Study findings will provide a theoretically guided understanding of the relationship among the component parts of the health seeking process that affect engagement in high risk behavior over time among this population. These data are necessary prerequisites to the development of tailored intervention strategies that target specific groups of women within the CJ system; these data can provide practitioners administrators and policy makers with direct information about which groups of women will be most amenable to which intervention/prevention approaches. Study findings have the potential to have broad relevance within the CJ system and other care systems (e.g. substance abuse and mental health treatment systems) that provide services to this marginalized and growing population.    PUBLIC HEALTH RELEVANCE: The confluence of race and class among women in the CJ system means that increases in this population disproportionately affect the health and well-being of women of color particularly poor women of color; the increased involvement of women in the CJ system has perpetuated and fueled racial disparities and biases in the areas of child well-being and the child welfare system infectious diseases and other markers of public health and other domains of psychosocial functioning such as employment and educational attainment. Results of this study will contribute directly to the development of targeted intervention strategies to address the needs of this population; study results will allow for the identification of those groups of victimized women in the CJ system that are most at risk for engagement in high risk behaviors (current drug use; psychological distress; HIV risk behavior; lawbreaking and continued CJ involvement) and to characterize their associated levels of risk and protection in the health seeking process across time. Results will also provide a theoretically guided understanding of the health seeking process by which these women come to engage in high risk behavior.

project_terms:
Address;Administrator;Adult;Affect;Age;Alcohol or Other Drugs use;Area;Behavior;Child;Child Welfare;Childhood;Cognitive;Color;Communicable Diseases;Communities;Crime;Criminal Justice;Data;Development;Drug usage;Emotions;Employment;Ethnicity aspects;Family;Goals;Growth;HIV;Health;Heterogeneity;Housing;Imprisonment;Individual;Intervention;Justice;Longevity;Mental Health;Methodology;Nature;Pathway interactions;Pattern;Personal Satisfaction;Policy Maker;Population;Prevention approach;Preventive Intervention;Process;Race;Research;Resources;Rewards;Risk;Risk Behaviors;Security;Services;Social support;Stress;Subgroup;Substance abuse problem;System;Testing;Time;Victimization;Woman;Women's Group;base;care systems;cohesion;coping;high risk;high risk behavior;men;parole;peer;person centered;physical conditioning;probation;psychological distress;psychosocial;public health medicine (field);public health relevance;response;self esteem;social;theories;therapy development;virtual

public_health_relevance:
The confluence of race and class among women in the CJ system means that increases inthis population disproportionately affect the health and well-being of women of colorparticularly poor women of color; the increased involvement of women in the CJ systemhas perpetuated and fueled racial disparities and biases in the areas of child well-beingand the child welfare system infectious diseases and other markers of public health andother domains of psychosocial functioning such as employment and educationalattainment. Results of this study will contribute directly to the development of targetedintervention strategies to address the needs of this population; study results will allowfor the identification of those groups of victimized women in the CJ system that aremost at risk for engagement in high risk behaviors (current drug use; psychologicaldistress; HIV risk behavior; lawbreaking and continued CJ involvement) and tocharacterize their associated levels of risk and protection in the health seeking processacross time. Results will also provide a theoretically guided understanding of the healthseeking process by which these women come to engage in high risk behavior.


application_id: 8220787
project_number: 5R01DA024598-05
project_title: Social networks and HIV risk among rural drug users
administering_ic: NIDA
award_notice_date: 2012-02-16
opportunity_number: PA-07-103
application_type: 5
activity_code: R01
ic: DA
serial_number: 024598
program_official: HARTSOCK, PETER
project_start_date: 2008-04-05
project_end_date: 2014-01-31
study_section: Behavioral and Social Science Approaches to Preventing HIV/AIDS Study Section[BSPH]
contact_pi_person_id: 7018622
contact_pi: HAVENS, JENNIFER R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  This application is in response to PA-06-478 "Research on Rural Mental Health and Drug Abuse Disorders". One of the research areas highlighted by this PA is the examination of rural HIV transmission using social network analysis. The overall goal of the study is to examine the prevalence incidence and risk factors for HIV and other blood borne infections (BBIs) such as hepatitis B (HBV) and C (HCV) among rural Appalachian drug users using social network analysis and multilevel modeling. HIV continues to be a major public health problem in the United States especially among drug users. However little is known about HIV in rural areas in which there are marked health disparities. Therefore given that studies among urban drug users have found that social network indicators are robust predictors of HIV risk both social network and individual characteristics will be measured for their association with HIV risk among rural drug users. The specific aims are: 1) To determine the prevalence and incidence of HIV HCV and HBV among rural injection and non- injection drug users; 2) To examine HIV and other BBI risk among rural injection and non-injection drug users; and 3) To examine longitudinal changes in rural HIV HCV and HBV risk at 6-months 12-months and 18- months post-baseline. To meet these aims a sample 500 rural injection and non-injection drug users will be recruited using respondent driven sampling (RDS). In addition to biologic testing for HIV HCV and HBV rural participants will be given an interviewer-administered questionnaire pertaining to their social networks (drug sexual and support networks) sociodemographics drug use HIV risk behaviors psychiatric diagnoses intravention and norms. Since individuals will be nested within networks data will be analyzed using multilevel random effects regression that allows for the simultaneous examination of social network and individual-level risk. Consistent with the priorities of the NIDA AIDS Research Program this proposal will explore the social network structure in a rural drug using population in order to better understand how network factors may affect HIV risk in rural areas using an innovative multilevel approach. Results from the proposed study will inform the design and implementation of HIV interventions in rural areas and help to determine the appropriate population for which to target such activities in order to reduce the morbidity and mortality associated with HIV and other BBIs.     Although HIV remains a significant public health problem in the United States especially among drug users little is known about HIV risk in rural areas such as Appalachia. It has been shown in urban populations that relationships among drug users also known as social networks are important predictors of HIV risk. Therefore this study seeks to characterize rural HIV risk by measuring both social network and individual behaviors in order to inform prevention activities in health resource-deprived rural areas.

project_terms:
Acquired Immunodeficiency Syndrome;Affect;Appalachian Region;Area;Automobile Driving;Behavior;Blood;Centers for Disease Control and Prevention (U.S.);Characteristics;Communities;Data;Disease;Drug Prescriptions;Drug abuse;Drug usage;Drug user;Epidemic;Goals;Growth;HIV;HIV Infections;Health Resources;Hepatitis B;Hepatitis B Virus;Hepatitis C;Hepatitis C virus;Human immunodeficiency virus test;Incidence;Individual;Individual Adjustment;Infection;Injecting drug user;Injection of therapeutic agent;Intervention;Interview;Interviewer;Kentucky;Measures;Mental Health;Modeling;Morbidity - disease rate;Mortality Vital Statistics;National Institute of Drug Abuse;Participant;Pathway Analysis;Pharmaceutical Preparations;Population;Prevalence;Prevention;Principal Investigator;Psychiatric Diagnosis;Questionnaires;Recruitment Activity;Reporting;Research;Research Priority;Respondent;Risk;Risk Behaviors;Risk Factors;Rural;Rural Population;Sampling;Serologic tests;Seroprevalences;Social Network;Structure;Testing;Time;United States;Urban Population;design;disorder prevention;health disparity;high risk;innovation;meetings;multilevel analysis;programs;public health medicine (field);response;rural area;transmission process;urban area


application_id: 8220771
project_number: 5R01HL082835-05
project_title: The role of Prostaglandin E2 in Angiotensin II-induced vascular disease
administering_ic: NHLBI
award_notice_date: 2012-01-30
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 082835
program_official: GAO, YUNLING
project_start_date: 2008-02-01
project_end_date: 2014-07-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8341067
contact_pi: KING, VICTORIA L
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): Prostanoids including prostaglandin E2 (PGE2) have been implicated in the pathophysiology of a number of cardiovascular diseases. Preliminary data demonstrates that selective pharmacological inhibition of cyclooxygenase-2 (COX-2) markedly attenuates the incidence of abdominal aortic aneurysms (AAA) in mice infused with angiotensin II (AngII) suggesting that prostanoids play a critical role in the development of AAAs. Hallmarks of AAA formation are inflammation and increased expression and activation of matrix metalloproteinases (MMPs) in the vascular wall. During inflammation both COX-2 and microsomal prostaglandin E synthase-1 (m-PGES-1) are rapidly upregulated resulting in increased concentrations of PGE2. PGE2 regulates MMP expression and activation therefore reductions in COX-2 generated PGE2 may result in decreases in MMP expression and activation. Previous studies have associated reductions in PGE2 with decreases in MMPs and aneurysmal expansion. Preliminary data demonstrates that m-PGES1 deficiency attenuates AngII-induced AAA formation. PGE2 concentrations were markedly decreased in the mPGES-1 deficient mice however there was a concomitant increase in prostacyclin (PGI2) concentrations. Blockade of the PGI2 receptor protects against that development of other vascular disease. Therefore the direct role of PGE2 in mediating the development of AAAs has not been elucidated. PGE2 mediates its actions by binding to EP receptors. The EP4 receptor is expressed in aneurysmal tissues and is required for the activation MMPs. The long-term objective of this proposal is to elucidate the role of the PGE2 in AngII-induced AAA formation. We propose to test the hypothesis that mPGES-1 generated PGE2 mediates the initial stage of AngII-induced AAA formation via the EP4 receptor. To test this hypothesis we propose to: 1) define the role of mPGES-1 generated PGE2 in AngII-induced AAAs; 2) define the role of the PGE2-EP4 receptor axis in MMP expression and activation in cells implicated in the development of AAAs and; 3) determine if the EP4 receptor is critical for the development of AngII-induced AAAs. To date there are not therapeutic treatments for AAAs. With the suggestion that an increased risk for cardiovascular events is a class specific effect of COX-2 inhibitors data from these studies will be important in defining which prostanoids generated by COX-2 mediate the initial events in AAA formation and provide us with critical information for targeting specific prostanoid synthases and receptors as therapeutic treatment for this disease.

project_terms:
Abdominal Aortic Aneurysm;Alleles;Angiotensin II;Apolipoprotein E;Atherosclerosis;Attenuated;Binding (Molecular Function);Blood Vessels;Cardiovascular Diseases;Cell Transplants;Cells;Coxibs;Cyclic GMP-Dependent Protein Kinases;Data;Development;Dinoprostone;Disease;EP4 receptor;Epoprostenol;Epoprostenol Receptors;Event;Exhibits;Fetal Liver;Functional disorder;Gene Expression;Gene Targeting;Genetic Recombination;Guanylate Cyclase;Hepatocyte;Incidence;Inflammation;Intestines;Knock-in Mouse;Laboratories;Matrix Metalloproteinases;Mediating;Messenger RNA;Modeling;Mortality Vital Statistics;Mus;Neonatal Mortality;Phenotype;Play;Prostaglandins;Prostaglandins I;Regulation;Reporter;Reporting;Role;Smooth Muscle Myocytes;Smooth muscle (tissue);Staging;Staining method;Stains;Suggestion;Tamoxifen;Testing;Therapeutic;Tissues;Vascular Diseases;Venous;cardiovascular risk factor;cyclooxygenase 2;follow-up;mouse PGE synthase 1;prostaglandin E synthase-1;receptor;receptor expression


application_id: 8220488
project_number: 1R01AR062083-01
project_title: Skeletal muscle biology in rheumatoid arthritis
administering_ic: NIAMS
award_notice_date: 2012-09-15
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: AR
serial_number: 062083
program_official: BOYCE, AMANDA T
project_start_date: 2012-09-17
project_end_date: 2014-08-31
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1869134
contact_pi: REID, MICHAEL B
other_pis: CROFFORD, LESLIE J;WESTERBLAD, HAKAN
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):  Rheumatoid arthritis (RA) is the most common chronic inflammatory disease affecting up to 1% of the population. Beyond joint pain and stiffness muscle weakness is among the most prevalent symptoms of RA patients. Weakness affects most major muscle groups and limits basic activities such as walking sitting and rising from chairs opening containers dressing oneself and personal hygiene. Weakness also contributes to postural instability in RA predisposing individuals to fall-related injuries and dramatically lessens the overall quality of life. There is no drug therapy for RA-related weakness no clinical standard of care to address this debilitating problem. The goal of this project is to define processes that cause weakness in RA and identify biological targets for future drug development. Weakness far exceeds muscle atrophy in RA patients. Therefore the focus of our project is loss of contractile function as reflected by specific force i.e force per cross-sectional area. Our experimental model proposes that RA increases muscle exposure to proinflammatory cytokines that stimulate production of nitric oxide (NO) derivatives and reactive oxygen species (ROS) by muscle fibers. The resulting oxidative stress depresses specific force and causes weakness. Interventions that disrupt this chain of events are expected to preserve specific force opposing RA-related weakness. We will test this model by using muscles from RA patients and a well-established mouse model of RA (collagen-induced arthritis CIA) to address four specific aims: Specific Aim 1. To identify cytokines essential for RA-induced weakness. Specific Aim 2. To define changes in skeletal muscle oxidant production caused by RA. Specific Aim 3. To define cellular mechanisms of contractile dysfunction in RA. Specific Aim 4.To test therapeutic approaches for preserving muscle function in RA.  
  
PUBLIC HEALTH RELEVANCE:  Rheumatoid arthritis (RA) is the most common chronic inflammatory disease. Muscle weakness is among the most prevalent symptoms limiting basic activities of daily living predisposing individuals to fall-related injuries and lessening the quality of life. The goal of this project is to define the processes that cause weakness in RA and identify biological targets for future drug development.

project_terms:
Activities of Daily Living;Address;Adverse effects;Affect;Animal Experiments;Animals;Antimetabolites;Antioxidants;Area;Arthralgia;Biochemical;Biological;Biology;Blood Circulation;Calcium;Chronic;Clinical;Collagen Arthritis;Data;Depressed mood;Disease;Endocrine;Event;Experimental Arthritis;Experimental Models;Exposure to;Folic Acid Antagonists;Functional disorder;Future;Goals;Homeostasis;Human;Hygiene;Individual;Inflammatory;Injury;Interleukins;Intervention;Joints;Limb structure;Link;Mediator of activation protein;Modeling;Mus;Muscle;Muscle Fibers;Muscle Mitochondria;Muscle Weakness;Muscle function;Muscular Atrophy;Neurons;Nitric Oxide;Nitric Oxide Synthase;Nitric Oxide Synthase Type I;Oxidants;Oxidation-Reduction;Oxidative Stress;Patients;Peroxonitrite;Pharmacologic Substance;Pharmacotherapy;Population;Process;Production;Proteins;Quality of life;Reactive Oxygen Species;Research;Rheumatoid Arthritis;Ryanodine;Skeletal muscle structure;Source;Sterile coverings;Stimulus;Sulfhydryl Compounds;Symptoms;Testing;Therapeutic;Tissues;Tumor Necrosis Factor-alpha;Walking;arthritis therapy;clinical care;clinically relevant;cytokine;design;drug development;falls;joint stiffness;mouse model;research study;response;standard of care

public_health_relevance:
Rheumatoid arthritis (RA) is the most common chronic inflammatory disease. Muscle weakness is among the most prevalent symptoms limiting basic activities of daily living predisposing individuals to fall-related injuries and lessening the quality of life. The goal of this project is to define the processes that cause weakness in RA and identify biological targets for future drug development.


application_id: 8219407
project_number: 1R01AI097318-01
project_title: Underlying Mechanisms of ApoE in HCV Infection and Assembly
administering_ic: NIAID
award_notice_date: 2012-02-24
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: AI
serial_number: 097318
program_official: KOSHY, RAJEN
project_start_date: 2012-03-01
project_end_date: 2012-09-30
study_section: Virology - B Study Section[VIRB]
contact_pi_person_id: 6801917
contact_pi: LUO, GUANGXIANG GEORGE
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this application is to determine the importance of the cellular protein apolipoprotein E (apoE) in hepatitis C virus (HCV) infection and production in vivo and to define the underlying molecular mechanism of apoE in HCV infection and assembly. HCV chronically infects approximately 170 million people worldwide. HCV infection is the most common indication for liver transplantation in the United States. HCV is also the major cause of hepatocellular carcinoma (HCC) the most rapidly increasing cancer with more than 14000 deaths each year in the U.S. Pegylated interferon-a in combination with ribavirin is the only option for treatment of hepatitis C. However more than 50% patients infected with HCV genotype 1 the dominant virus accounting for ~70% infections do not respond to IFN and ribavirin therapy. Therefore there is an urgent need to develop more efficacious anti-HCV drugs. Identification of novel targets is key to discovery of new classes of antiviral drugs. We have demonstrated that apoE is a structural component of HCV and plays important roles in HCV infection and virion assembly. We have also demonstrated that apoE interacts with HCV NS5A and that the apoE-NS5A interaction is important for HCV assembly. More importantly our preliminary studies found that apoE but not HCV E2 mediates HCV attachment. However these findings were derived from the studies with a cell culture grown HCV of genotype 2a (JFH1). The significance of apoE in the HCV life cycle in vivo has not been experimentally examined. In specific aim 1 we will determine the importance of apoE in HCV infection and production in vivo. The HCV-neutralizing activity of an apoE-specific monoclonal antibody and the therapeutic efficacy of an apoE-silencing shRNA will be evaluated in a humanized HCV mouse model using clinical HCV isolates of genotype 1. In specific aim 2 we will define the underlying molecular mechanism of apoE in HCV infection. Specific domain and critical residues of apoE important for receptor-binding will be determined by mutagenesis studies. Additionally we will identify specific cell surface receptor(s) that mediate apoE-binding and HCV attachment. In specific Aim 3 we will illustrate the mechanism of action of apoE in HCV assembly. Specifically we will determine the molecular basis underlying the apoE-NS5A interaction and identify cellular mechanism and/or pathways responsible for the apoE-mediated HCV assembly. These specific aims will be successfully accomplished using multidisciplinary approaches including a robust HCV reverse genetics system site-directed mutagenesis RNA silencing cell biological immunological and biochemical methodologies. That HCV uses a cellular protein (apoE) for cell attachment is unprecedented and challenges the current dogma that viral envelope proteins mediate virus attachment by binding to cell surface receptors. New knowledge originating from these studies will result in a paradigm change regarding the roles of viral and cellular proteins in virus infection. The studies described in this application will also provide novel targets for anti-HCV drug discovery.  
  
PUBLIC HEALTH RELEVANCE: Hepatitis C virus (HCV) is the major cause of human liver diseases including hepatocellular carcinoma. The overall goal of this project is to determine the importance of the cellular protein apolipoprotein E in HCV infection and production in vivo and the underlying molecular mechanism of apoE in the HCV life cycle. New knowledge originating from this project will result in a paradigm change regarding the role of viral and cellular proteins in HCV infection.

project_terms:
Accounting;Antibodies;Antiviral Agents;Apolipoprotein E;Binding (Molecular Function);Biochemical;Biological;Biology;Cell Culture Techniques;Cell Surface Receptors;Cell-Matrix Junction;Cells;Cessation of life;Clinical;Clinical Trials;Combined Modality Therapy;Confocal Microscopy;Coupled;Drug resistance;Elements;Genes;Genotype;Glycoproteins;Goals;Hepatitis C;Hepatitis C virus;Hepatocyte;Human;Infection;Interferons;Knowledge;Life Cycle Stages;Liver diseases;Malignant Neoplasms;Mediating;Methodology;Molecular;Monoclonal Antibodies;Mutagenesis;Mutation;N-terminal;Pathway interactions;Patients;Pharmaceutical Preparations;Play;Primary carcinoma of the liver cells;Production;Proteins;RNA;RNA Interference;Research;Ribavirin;Role;SCID Mice;Site-Directed Mutagenesis;Small Interfering RNA;System;Testing;Transplantation;Treatment Efficacy;United States;Viral;Viral Envelope Proteins;Virion;Virus;Virus Assembly;Virus Diseases;Virus Replication;anti-hepatitis C;base;cell attachment protein;clinical efficacy;design;drug discovery;glycosylation;hepatitis C virus envelope 2 protein;in vivo;inhibitor/antagonist;interdisciplinary approach;liver transplantation;mouse model;novel;positional cloning;receptor binding;small hairpin RNA;synthetic peptide;virology;virus envelope

public_health_relevance:
Hepatitis C virus (HCV) is the major cause of human liver diseases including hepatocellular carcinoma. The overall goal of this project is to determine the importance of the cellular protein apolipoprotein E in HCV infection and production in vivo and the underlying molecular mechanism of apoE in the HCV life cycle. New knowledge originating from this project will result in a paradigm change regarding the role of viral and cellular proteins in HCV infection.


application_id: 8219306
project_number: 1R01ES020870-01
project_title: Cell survival and arsenic carcinogenesis
administering_ic: NIEHS
award_notice_date: 2012-01-09
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: ES
serial_number: 020870
program_official: THOMPSON, CLAUDIA L
project_start_date: 2012-01-15
project_end_date: 2016-10-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
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): Although the molecular mechanism of arsenic-induced carcinogenesis remains to be investigated reactive oxygen species (ROS) generated by arsenic are considered to be important. Arsenic-generated ROS could cause DNA damage lipid peroxidation and protein modification leading to various carcinogenic responses. Our preliminary studies have shown that the capacity of ROS generation induced by arsenic is substantially reduced in arsenic-transformed human lung bronchial epithelial (BEAS-2B) cells relative to the non-transformed cells. Such a reduction in ROS generation endows cells with premalignant features including rapid growth. Arsenic- transformed cells exhibit a decreased apoptosis (apoptosis resistance) upon arsenic exposure. This proposal hypothesizes that due to a low potency of ROS generation arsenic-transformed cells develop apoptosis resistance and increased cell survival contributing to the overall mechanism of arsenic-induced carcinogenesis. Three aims are proposed to test this hypothesis. Aim 1 will investigate the mechanism of decreased ROS generation in the arsenic-transferred cells. We will investigate whether impairment of the ROS generating pathway is responsible for a low level of arsenic-induced ROS generation in arsenic transformed BEAS-2B cells. We will also investigate whether the increased level of antioxidant enzymes in transformed cells contributes to the decreased level of ROS generation. The completion of this aim will establish the mechanism of decreased ROS generation in arsenic-transformed cells. Aim 2 will investigate the role of reduced ROS generation in apoptosis resistance of arsenic-transformed cells. We investigate (a) whether reduced ROS generation of arsenic- transformed cells is responsible for apoptosis resistance in arsenic-transformed cells; (b) whether arsenic- transformed cells have higher antioxidant activities of SOD and catalase than their passage-matched control cells; (c) whether knock-down of antioxidant enzymes or overexpressing NADPH oxidase in the transformed cells increases ROS generation and enhances apoptosis in response to arsenic stimulation; (d) whether knocking down of Bcl-2 increases apoptosis of arsenic-transformed cells; and (e) whether arsenic- transformed cell will show fast growth and enhanced invasion and migration due to the decreased ROS generation and apoptosis resistance. Overall this aim will demonstrate the role of ROS in apoptosis resistance of arsenic-transformed cells. Aim 3 will investigate the arsenic-transformed cells-induced tumorigenesis and the role of apoptosis. We will investigate the role of apoptosis resistance in tumorigenesis of arsenic-transformed cells. We will also investigate the roles of ROS and apoptosis regulatory proteins Bcl-2 in arsenic-transformed cells-induced tumorigenesis using both skin tumorigenesis model and orthotopic lung cancer model. It is expected that the increase of apoptosis of arsenic-transformed cells by Bcl-2 knockdown will decrease tumor growth. Similarly alterations in the ROS generating capacity of the cells i.e. by ectopic overexpression and knockdown of the ROS-scavenging and producing enzymes will have an effect on tumorigenesis of arsenic-transformed cells.  
  
PUBLIC HEALTH RELEVANCE: Health effects of chronic exposure to arsenic are one of the major health concerns. The present study will investigate the mechanism of arsenic-induced carcinogenesis with a focus on decreased generation of reactive oxygen species and apoptosis resistance in arsenic transformed cells. The results will help understand the mechanism of arsenic carcinogenesis and to develop preventive strategy.

project_terms:
Antioxidants;Apoptosis;Apoptotic;Arsenic;Arsenites;Cancer Model;Cell Death;Cell Survival;Cells;Characteristics;Chronic;DNA Damage;Dose;Enzymes;Epithelial;Epithelial Cells;Exhibits;Exposure to;GADD45;Generations;Growth;Health;Human;Impairment;Kidney;Lipid Peroxidation;Liver;Lung;Malignant neoplasm of lung;Malignant neoplasm of urinary bladder;Microfilaments;Modeling;Molecular;NADPH Oxidase;Pathway interactions;Post-Translational Protein Processing;Premalignant;Prevention strategy;Property;Reactive Oxygen Species;Relative (related person);Resistance;Role;Skin;Testing;Toxic effect;Transcription Factor AP-1;cancer cell;carcinogenesis;catalase;cell growth;cell motility;cell transformation;genetic regulatory protein;knock-down;migration;novel;overexpression;rapid growth;response;tumor growth;tumorigenesis


application_id: 8217189
project_number: 5R01NS073584-02
project_title: ER stress and oligodendrocyte survival after spinal cord injury
administering_ic: NINDS
award_notice_date: 2012-02-01
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: NS
serial_number: 073584
program_official: HICKS, RAMONA R
project_start_date: 2011-02-01
project_end_date: 2016-01-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: HETMAN, MICHAL
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) is the intracellular organelle in which secretory and membrane proteins are synthesized and folded by resident chaperone proteins. The ER stress response (ERSR) is an evolutionarily conserved cell defense mechanism that protects against excessive accumulation of malfolded proteins in the ER. These malfolded proteins are translocated to the cytoplasm by the machinery of the ER- associated degredation (ERAD) where they are degraded. The ERSR is initiated after multiple cellular stresses including hypoxia inflammation trauma excitotoxicity and oxidative damage. The ERSR is initially protective but if malfolded proteins cannot be cleared apoptotic cell death initiates. The 3 pathways involved in the ERSR involve PERK IRE1/XBP-1 and ATF6 signaling. Preliminary data demonstrate upregulation of all 3 ERSR pathways following SCI. Mice null for CHOP a pro-apoptotic transcription factor that is downstream of PERK and activated during ERSR showed enhanced functional recovery after SCI and we identified oligodendrocytes as highly vulnerable to ER stress. We hypothesize that enhancing the protective or inhibiting the apoptotic aspects of the ERSR will enhance functional recovery after SCI. In Aim 1 we will potentiate the protective effectors of ERSR and in Aim 2 suppress those that initiate oligodendrocyte apoptosis. We will use a combination of pharmacological agents constitutive and conditional null mice as well as cell culture studies using wild type (WT) and available null oligodendrocyte precursor cells (OPCs) and/or siRNAs to address these questions.    PUBLIC HEALTH RELEVANCE: Spinal cord injury (SCI) is a devastating injury for both patients and their families and at present there is no effective treatment either acutely or for chronic patients. This grant examines the role of the endoplasmic reticulum stress response a cellular defense mechanism induced in every spinal cord cell after SCI in mediating survival or death of myelinating oligodendrocytes after SCI. We expect to identify new acute therapeutic targets that will hopefully extend beyond SCI to other CNS trauma and neurological disease treatment.

project_terms:
Acute;Address;Apoptosis;Apoptotic;Cell Culture Techniques;Cell Death;Cell Survival;Cells;Cellular Stress;Cessation of life;Chemicals;Chemosensitization;Chronic;Coculture Techniques;Commit;Cytoplasm;Cytoprotection;Data;Defense Mechanisms;Disease;Endoplasmic Reticulum;Family;Functional disorder;Genes;Genetic;Grant;Hand;Hypoxia;In Vitro;Inflammation;Injury;Knockout Mice;Locomotor Recovery;Mediating;Mediator of activation protein;Membrane Proteins;Methods;Modeling;Molecular Chaperones;Mus;Neurons;Oligodendroglia;Organelles;Pathology;Pathway interactions;Patients;Phosphorylation;Protein Dephosphorylation;Proteins;Recovery of Function;Role;Signal Transduction;Small Interfering RNA;Spinal Cord;Spinal Ganglia;Spinal cord injury;TNFRSF10B gene;Translational Repression;Translations;Trauma;Traumatic CNS injury;Tunicamycin;Up-Regulation (Physiology);arm;biological adaptation to stress;cytotoxic;effective therapy;endoplasmic reticulum stress;excitotoxicity;improved;in vitro Assay;in vivo;inhibitor/antagonist;insight;loss of function;nervous system disorder;new therapeutic target;novel;oligodendrocyte precursor;oxidative damage;precursor cell;protective effect;public health relevance;research study;response;secretory protein;tauroursodeoxycholic acid;therapeutic target;transcription factor

public_health_relevance:
Project Narrative. Spinal cord injury (SCI) is a devastating injury for both patients and their families and atpresent there is no effective treatment either acutely or for chronic patients. This grant examines the role ofthe endoplasmic reticulum stress response a cellular defense mechanism induced in every spinal cord cellafter SCI in mediating survival or death of myelinating oligodendrocytes after SCI. We expect to identify newacute therapeutic targets that will hopefully extend beyond SCI to other CNS trauma and neurological diseasetreatment.


application_id: 8216525
project_number: 1R01DK093496-01
project_title: MIF: a pro-inflammatory cytokine as a novel target to reduce bladder inflammation
administering_ic: NIDDK
award_notice_date: 2012-03-27
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: DK
serial_number: 093496
program_official: KIRKALI, ZIYA
project_start_date: 2012-04-01
project_end_date: 2017-03-31
study_section: Urologic and Kidney Development and Genitourinary Diseases Study Section[UKGD]
contact_pi_person_id: 8093598
contact_pi: VERA, PEDRO L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078344581
primary_uei: JCSKALYM8HU6
duns_number: 078344581
uei: JCSKALYM8HU6
fips: US
organization_id: 10030991
organization_name: LEXINGTON BIOMEDICAL RESEARCH INSTITUTE
organization_city: LEXINGTON
organization_state: KY
organization_type: Research Institutes
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Experimental evidence supports the pro-inflammatory effect of Macrophage Migration Inhibitory Factor (MIF) in bladder inflammation but how MIF mediates bladder inflammation is poorly understood. The long-term goal is to understand the mechanisms of MIF-mediated bladder inflammation with the aim of altering these processes to reduce or abolish bladder inflammation in patients with chronic painful conditions of the lower urinary tract. The overall objective of this proposal is to determine the contribution of specific urothelial receptors to MIF release and to MIF-mediated signaling and bladder inflammation. The central hypothesis is that there are two components to inflammation involving MIF: 1) increased release of MIF; and 2) upregulation of MIF receptors and subsequent increased signaling via MIF/receptor interactions that enhances and/or maintains inflammation. This hypothesis has been formulated based on preliminary data generated in the applicants' laboratory. The rationale for propos- ing these studies is that by increasing our understanding of signaling events both upstream and downstream of MIF in the bladder will identify potential therapeutic targets.  The hypothesis will be tested by the following specific aims: 1) Determine the contribution of urothelial Protease Activated Receptors (PAR) to a novel mechanism of urothelial MIF release: Agonists with specificity for different PAR receptors will be used to induce MIF release from urothelial cells (both human in vitro and in vivo using mice) to determine which receptors are involved in MIF release. To determine the contribution of MIF to PAR-mediated bladder inflammation in vivo bladder inflammation will be induced in mice by instilling specific PAR agonists while simultaneously antagonizing MIF. Physiological histological and molecular changes in the bladder will be measured. 2) Identify the contribution of urothelial MIF receptors (CD74; CXCR4) to MIF signaling and cystitis: MIF receptor blockade will be used to examine changes in MIF-mediated signaling during a well-established model of cystitis (cyclophosphamide) in mice. These experiments will also determine the effect of MIF receptor blockade on mediating cystitis by measuring physiological histological and molecular changes in the bladder. 3) Determine MIF and MIF receptor levels in clinical conditions with bladder inflammation: Urinary MIF levels will be determined in UTI radiation cystitis and PBS/IC (Hunner ulcer vs non-Hunner ulcer) patients. MIF CD74 and CXCR4 urothelial immunostaining will be examined in PBS/IC (Hunner ulcer vs non-Hunner ulcer) and MIF-mediated cytokine production in human detrusor smooth muscle cells from PBS/IC patients will be examined.  This proposal is innovative because it focuses on MIF a novel mediator of bladder inflammation. The pro- posed research is significant because a greater understanding of the mechanisms of MIF release during bladder inflammation and of the signaling pathways activated by MIF binding to urothelial MIF receptors is expected to result in the identification of novel therapeutic targets for inflammatory conditions of the lower urinary tract.   
  
PUBLIC HEALTH RELEVANCE:  Inflammation of the lower urinary tract occurs in several diseases including urinary tract infections radiation cystitis and chronic painful conditions such as Painful Bladder Syndrome/Interstitial Cystitis. This proposal will examine Macrophage Migration Inhibitory Factor a novel regulator of bladder inflammation and will describe new potential targets to decrease or abolish bladder inflammation. Research into the mechanisms of bladder inflammation will provide new information that may benefit a large group of patients suffering from this condition and may suggest potential targets for ameliorating this disease.

project_terms:
Acute;Agonist;Binding (Molecular Function);Biology;Bladder;Bladder Tissue;CXCR4 gene;Chronic;Clinical;Complex;Cyclophosphamide;Cystitis;Data;Development;Disease;Etiology;Event;F2R gene;Goals;Human;In Vitro;In-Migration;Inflammation;Inflammation Mediators;Inflammatory;Interstitial Cystitis;Knock-out;Laboratories;Lesion;Link;Lower urinary tract;Maintenance;Measures;Mediating;Mediator of activation protein;Migration Inhibitory Factor;Modeling;Molecular;Mus;Outcome;PAWR gene;Pain;Patients;Phosphotransferases;Physiological;Play;Process;Production;Proteinase-Activated Receptors;Quality of life;Radiation;Recurrence;Regulation;Research;Role;Signal Pathway;Signal Transduction;Smooth Muscle Myocytes;Specificity;Spinal cord injury;Syndrome;System;Testing;Tetracyclines;Therapeutic;Therapeutic Intervention;Thrombin;Transgenic Mice;Ulcer;Up-Regulation (Physiology);Urinary tract infection;Urination;Urine;Urothelial Cell;Urothelium;Work;base;chronic pain;cytokine;in vivo;innovation;insight;new therapeutic target;novel;novel strategies;painful bladder syndrome;phenylpyruvate tautomerase;prevent;receptor;research study;therapeutic development;therapeutic target;urinary


application_id: 8216454
project_number: 5F31NS070329-02
project_title: Interactions between Urological and Locomotor Systems during Treadmill Training i
administering_ic: NINDS
award_notice_date: 2011-12-21
opportunity_number: PA-10-108
application_type: 5
activity_code: F31
ic: NS
serial_number: 070329
program_official: HICKS, RAMONA R
project_start_date: 2011-01-04
project_end_date: 2012-10-31
study_section: Special Emphasis Panel[ZRG1-F01-L(20)L]
contact_pi_person_id: 10107392
contact_pi: WARD, PATRICIA JILL
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): Spinal cord injury (SCI) results in detrimental effects on the upper and lower urinary tract. Currently there is no effective therapy for urological dysfunction. Having control over voiding function is of primary importance to this patient population as this affects independence overall health and self-image. Current attempts at treatments with various drugs and surgeries have unwanted side effects and limited success. One of our goals is to provide a natural therapeutic alternative. Body weight supported treadmill training is advancing our knowledge on how the spinal cord can learn and adapt and the results of its positive effects for SCI patients continues to grow. We have clinical observations from patients that step training can have beneficial outcomes on bladder maintenance and that there is an inhibitory interaction between the limbs and the bladder. Therefore we propose to study these observations in a clinically relevant animal model to identify mechanisms involved. Eighty-six male rats will receive a 225 kdyn force contusion injury at the T8 spinal level using the IH impact or device. Twenty-six rats will be implanted with a bladder catheter and EMG wires in the soleus and tibialis anterior muscles to determine the influence of noxious and innocuous bladder afferent input on locomotor (vesico-somatic) performance in intact SCI and inflammatory conditions. The role of C-fiber inputs will also be determined via capsaicin pre-treatment. Inflammation and distention from bladder may be altering sensory inputs for the lumbosacral cord in turn altering the ability for locomotor output and spinal learning. Beginning 14 days post-injury twenty rats will undergo daily step training on a treadmill with manual assistance for 8 weeks. Two other groups forelimb trained (n=20) and non-trained (n=20) will be tested simultaneously. Functional urological data will be obtained with 1) conscious cystometry- catheter infused saline and 2) natural voiding patterns gathered using a metabolic monitoring system. Terminal molecular studies eleven weeks post- SCI will assess the exercise's regulation of bladder mRNA content of various neurotrophic factors which have been identified as important modulators in both the exercise and bladder dysfunction literature. Thus this study will be the first to investigate the influence of exercise therapy on the spinally mediated reflexive relationship between viscera and somatic structures involving detrusor external urethral sphincter and limb musculature. Although partially masked in normal subjects these reflexes are highly apparent after an upper motor neuron disease or SCI. Each part of this study is specifically designed to be applicable to the SCI patient and activity based therapies such as locomotor training.      PUBLIC HEALTH RELEVANCE: Both quadriplegics and paraplegics rank bladder function as one of the most important factors affecting their quality of life and 96.5% of 681 survey respondents believe that exercise is an important part of functional recovery yet at least 63.6% do not have access to a trained therapist to oversee their regiments. With over 1 million people in the U.S. alone affected by SCI and the annual cost in federal funds estimated at $9.7 billion the knowledge gained from our study on locomotor training effects on bladder function will not only be immediately applicable to patients providing immense improvements in quality of life but also reduce life-long burdens on patient family and care centers.

project_terms:
Adverse effects;Affect;Afferent Neurons;Animal Model;Animals;Behavioral;Bladder;Bladder Control;Bladder Dysfunction;Body Size;Body Weight;C Fiber;Capsaicin;Caring;Catheterization;Catheters;Chemicals;Clinical;Conscious;Contusions;Cystitis;Data;Development;Devices;Electromyography;Equilibrium;Exclusion Criteria;Exercise;Exhibits;Family;Forelimb;Functional disorder;Funding;Goals;Growth Factor;Health;Hindlimb;Implant;Infective cystitis;Inflammation;Inflammatory;Injury;Investigation;Knowledge;Lead;Learning;Life;Limb structure;Literature;Lower urinary tract;Maintenance;Manuals;Masks;Measures;Mediating;Messenger RNA;Metabolic;Methods;Molecular;Monitor;Morphology;Muscle;Operative Surgical Procedures;Organ;Outcome;Output;Paraplegia;Patient observation;Patients;Pattern;Performance;Pharmaceutical Preparations;Physical therapy exercises;Play;Polyuria;Quadriplegia;Quality of life;Rattus;Recovery;Recovery of Function;Reflex action;Regulation;Reporting;Respondent;Role;Saline;Self Perception;Sensory;Skeletal muscle structure;Source;Sphincter;Spinal;Spinal Cord;Spinal cord injury;Spinal cord injury patients;Step training;Stimulus;Structure;Surveys;System;Testing;Therapeutic;Tibialis anterior muscle structure;Training;Upper Motor Neuron Disease;Urethral sphincter;Urodynamics;Viscera;Visceral;Walking;Water;arm;base;cell body (neuron);clinically relevant;cost;desensitization;design;effective therapy;irritation;male;neurotrophic factor;patient population;prevent;public health relevance;response;success;urinary;urologic

public_health_relevance:
NarrativeBoth quadriplegics and paraplegics rank bladder function as one of the most important factors affectingtheir quality of life and 96.5% of 681 survey respondents believe that exercise is an important part offunctional recovery yet at least 63.6% do not have access to a trained therapist to oversee theirregiments. With over 1 million people in the U.S. alone affected by SCI and the annual cost in federalfunds estimated at $9.7 billion the knowledge gained from our study on locomotor training effects onbladder function will not only be immediately applicable to patients providing immense improvements inquality of life but also reduce life-long burdens on patient family and care centers.


application_id: 8215933
project_number: 5R24MD002757-05
project_title: Faith Moves Mountains: A CBPR Appalachian Wellness & Cancer Prevention Program
administering_ic: NIMHD
award_notice_date: 2012-01-25
opportunity_number: RFA-MD-07-003
application_type: 5
activity_code: R24
ic: MD
serial_number: 002757
program_official: DANKWA-MULLAN, IRENE
project_start_date: 2008-05-22
project_end_date: 2014-01-31
study_section: ZMD1-RN(01)R
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Appalachian communities are disproportionately affected by many of the leading risk factors associated with cancer incidence and mortality factors amenable to primary and secondary prevention. Extensive involvement with our community partners has demonstrated strong community preference for a holistic approach toward cancer prevention; The proposed intervention extends our successful faith-based trained lay health advisor tailored intervention "Faith Moves Mountains" (R01CA108696) initiated three years ago to administer a culturally appropriate CBPR intervention. Working in partnership with 70 faith based institutions in rural Southeastern Kentucky we propose to administer evaluate and disseminate a tailored wellness and cancer prevention program focused on four of the most common prevention activities that have the potential of greatly preventing and reducing cancer morbidity and mortality. These prevention activities include smoking cessation (targeting all chronic diseases cervical and lung cancer); energy balance including dietary modification and physical activity promotion (targeting all chronic diseases and colorectal cancer (CRC)) and cancer screenings (targeting CRC cervical and breast cancer).    Consistent with our Faith Moves Mountains and cancer control approach faith-based organizations will sponsor a "kick off event" or health fair in which participants will undergo a health risk appraisal (baseline). Participants will then select one or more wellness activities (smoking cessation energy balance cancer screening); then trained lay health advisors will offer modules on each of these wellness activities. Smoking cessation will include the culturally relevant Cooper-Clayton method (outcome: smoking abstinence). For those targeting dietary modification and physical activity a rural Appalachian modified Healthy Body/Healthy Spirit program will be administered (outcome: dietary change and physical activity participation). Tailored cancer screening promotion will be based on our current Faith Moves Mountains design (outcome: receipt of any recommended CRC screening test Pap test for cervical cancer and/or mammogram). To assess the intervention but remain consistent with community norms we will employ a staggered intervention design. Throughout the project the RE-AIM model will inform our evaluation. During phase three this CBPR wellness approach to cancer prevention will undertake qualitative process evaluation interviews and disseminate the intervention to medically underserved Appalachian Ohio in collaboration with partners at Ohio State University. This collaboration will facilitate dissemination of successful intervention to additional rural Appalachian populations with high rates of cancer health disparities.

project_terms:
Abstinence;Address;Affect;Cancer Control;Cervical;Chronic Disease;Collaborations;Colorectal Cancer;Communities;Diet;Diet Modification;Effectiveness of Interventions;Ensure;Evaluation;Event;Fostering;Goals;Health;Health Fairs;Health Risk Appraisals;Incidence;Institution;Intervention;Intervention Studies;Interview;Kentucky;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Mammography;Methods;Modeling;Monoclonal Antibody R24;Morbidity - disease rate;Mortality Vital Statistics;National Center on Minority Health and Health Disparities;Ohio;Outcome;Pap smear;Participant;Phase;Physical activity;Population;Prevention;Prevention program;Primary Prevention;Process;Randomized;Regimen;Research;Research Design;Risk Factors;Rural;Rural Health;Screening for cancer;Secondary Cancer Prevention;Secondary Prevention;Smoking;Testing;Training;Trust;Universities;Work;base;cancer health disparity;cancer prevention;cancer risk;colorectal cancer screening;community based participatory research;design;diet and exercise;energy balance;health disparity;holistic approach;malignant breast neoplasm;medically underserved;member;preference;prevent;programs;response;smoking cessation;successful intervention;therapy design


application_id: 8215854
project_number: 5R01NS045954-09
project_title: Neuropeptidergic Inhibition of Spinal Pain Transmission
administering_ic: NINDS
award_notice_date: 2012-02-06
opportunity_number: PA-07-282
application_type: 5
activity_code: R01
ic: NS
serial_number: 045954
program_official: PORTER, LINDA L
project_start_date: 2002-09-10
project_end_date: 2014-01-31
study_section: Special Emphasis Panel[ZRG1-IFCN-B(04)M]
contact_pi_person_id: 1879170
contact_pi: TAYLOR, BRADLEY K.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Work performed during the previous funding periods indicates that intrathecal administration of NPY reduces the mechanical and thermal hypersensitivity associated with inflammation or nerve injury. The objective of the present application is to establish NPY as an endogenous pain modulator and to identify the mechanisms underlying NPY-mediated inhibition of inflammatory or neuropathic pain. The central hypothesis is that tissue or nerve injury sensitizes the dorsal horn to the pain inhibitory actions of NPY receptor signaling. Our approach involves transgenic biochemical neurophysiological anatomical and behavioral methods to determine: the anti-allodynic actions of endogenous NPY (Aim 1); the effect of injury on NPY receptor coupling to G-proteins (Aim 2); the effect of injury on the inhibition by NPY of SP release and subsequent NK1 receptor (NK1) activation in the spinal cord (Aim 3A); and the effect of NPY on the activity of spinal neurons that express the NPY Y1 receptor (Aim 3B). Our long-term goal is to understand endogenous neuropeptidergic inhibition of spinal pain transmission and to establish the therapeutic potential of NPY receptor agonists for chronic pain. AIM #1 tests the hypothesis that endogenous NPY tonically inhibits allodynia. To address the contribution of endogenous NPY to chronic pain Aim #1 will utilize transgenic mice (NPYtet) that contain a doxycycline-regulated cassette (tetracycline trans-activator tTA) at the promoter region of the npy locus. We describe data indicating that inducible NPY depletion increases behavioral signs of allodynia after tissue or nerve injury. These data led us to determine the effect of conditional NPY knockdown on the induction maintenance and reinstatement of chronic pain. We predict that NPY depletion will speed the development increase the intensity and extend the duration of inflammatory and neuropathic pain. AIM #2 tests the hypothesis that injury increases NPY receptor-G protein signaling in the dorsal horn. To determine whether and when injury increases NPY receptor-G protein coupling we will evaluate Y1- and Y2-agonist-stimulated [35S GTP3S binding at multiple time points after inflammation or nerve injury. AIM #3 tests the hypothesis that injury increases NPY inhibition of spinal pain neurotransmission. Primary afferent terminals in dorsal horn express NPY receptors. Our preliminary data indicate that NPY acts at Y1 and Y2 receptors to reduce substance P release and subsequent NK1 activation (assessed with NK1 internalization) in spinal cord slices and in vivo. We predict that injury will increase these inhibitory actions. Because dorsal horn neurons express Y1 we will test for postsynaptic actions of NPY on SP-induced nociceptive behavior NK1 internalization and spinal neuron gene action (Fos) on Y1-expressing cells. New preliminary data with the selective neurotoxin NPY-saporin suggest that Y1-expressing cells in the dorsal horn facilitate neuropathic pain transmission. We predict that the activity of this population of spinal neurons will be decreased by NPY administration and increased by NPY knockdown or Y1 / Y2 receptor antagonism.    PUBLIC HEALTH RELEVANCE: Chronic pain management is a major scientific and health care challenge as current analgesic drugs rarely provide sufficient efficacy in the absence of serious side effects. Our preliminary data suggest that new drugs acting at the neuropeptide Y receptor system in the spinal cord will overcome these problems but further studies are required to determine how NPY works. Such studies are critical not only to determine whether NPY is a natural long-lasting analgesic that reduces the duration of pain but also to harness its therapeutic potential towards the development of new analgesic drugs.

project_terms:
Accounting;Address;Adverse effects;Agonist;Analgesics;Behavior;Behavioral;Binding (Molecular Function);Biochemical;Cells;Coupling;Data;Development;Doxycycline;Freund's Adjuvant;Funding;G-Protein-Coupled Receptors;GTP-Binding Proteins;Gene Activation;Gene Silencing;Genes;Goals;Healthcare;Hypersensitivity;Inflammation;Injury;Interruption;Maintenance;Measures;Mechanics;Mediating;Methods;Modeling;NPY gene;Neurons;Neuropeptide Y Receptor;Neurotoxins;Nociception;Pain;Pain management;Pharmaceutical Preparations;Population;Posterior Horn Cells;Promoter Regions (Genetics);Receptor Activation;Receptor Signaling;Signal Transduction;Slice;Speed (motion);Spinal;Spinal Cord;Substance P;System;TACR1 gene;Testing;Tetracyclines;Therapeutic;Time;Tissues;Trans-Activators;Transgenic Mice;Transgenic Organisms;Work;allodynia;chronic pain;dorsal horn;in vivo;inflammatory neuropathic pain;inflammatory pain;mouse model;nerve injury;neuropeptide Y-Y1 receptor;neurophysiology;neurotransmission;painful neuropathy;postsynaptic;public health relevance;receptor;receptor coupling;receptor expression;sham surgery;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE STATEMENTChronic pain management is a major scientific and health care challenge as current analgesic drugsrarely provide sufficient efficacy in the absence of serious side effects. Our preliminary data suggestthat new drugs acting at the neuropeptide Y receptor system in the spinal cord will overcome theseproblems but further studies are required to determine how NPY works. Such studies are critical notonly to determine whether NPY is a natural long-lasting analgesic that reduces the duration of painbut also to harness its therapeutic potential towards the development of new analgesic drugs.


application_id: 8215822
project_number: 5R01AG024377-07
project_title: Characterization of the Sch9 -Longevity Pathway in Yeast
administering_ic: NIA
award_notice_date: 2011-12-30
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AG
serial_number: 024377
program_official: GUO, MAX
project_start_date: 2004-09-01
project_end_date: 2013-12-31
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 1879389
contact_pi: DICKSON, ROBERT CARL
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):  Model organisms such as Saccharomyces cerevisiae have proven effective in elucidating genes and metabolites that modulate life span and this knowledge forms a basis for understanding human aging and longevity. These studies have identified the Akt/PKB protein kinases as conserved regulators of aging. However it is not entirely clear how they work. One focus of our research is the S. cerevisiae Sch9 protein kinase an AKT homolog that regulates chronological life span (CLS). From in vitro studies we identified sphingolipid long chain bases (LCBs) and Pkh1 a homolog of human phosphoinositide-dependent protein kinase 1 (PDK1) as the first upstream regulator of Sch9. In addition we identified the first Sch9 substrates Rli1 involved in translation initiation and ribosome biogenesis and Ahp1 an alkyl hydroperoxide reductase that protects against oxidative stress. We will build upon these novel results and determine if phosphorylation of Rli1 and Ahp1 by Sch9 plays a role in CLS. We will also determine in vivo if LCBs and Pkh1 act upstream to regulate Sch9 during chronological aging. Although we have successfully identified Sch9 substrates there are likely to be others and we propose to search for new substrates by classical biochemical strategies newer automated but complementary strategies and a genetic screening strategy. In summary the results of these studies will provide the much needed mechanistic understanding of how Akt (Sch9) activity is regulated in yeast and how it regulates CLS through downstream substrates. This knowledge will help to provide a molecular basis for understanding human aging and longevity. PUBLIC HEALTH RELEVANCE:  The proposed research will determine how the Sch9 protein kinase a functional homolog of mammalian Akts/PKBs regulates chronological life span in the Baker's yeast Saccharomyces cerevisiae. Signal transduction pathways that contain Akt/PKB type protein kinases play important roles in regulating aging and life span and these pathways have been conserved from yeast to mammals. Thus information gained from these studies should provide a more mechanistic basis for understanding how aging and life span are regulated in humans.

project_terms:
Affect;Aging;Alanine;Alleles;Animal Model;Binding (Molecular Function);Biochemical;Biogenesis;Biological Assay;Caloric Restriction;Cell Fraction;Cell Fractionation;Cells;Cellular Membrane;Chimeric Proteins;Chromatin;Density Gradient Centrifugation;Down-Regulation;Enzymes;Genes;Genetic;Genetic Screening;Glass;Health;Homologous Gene;Human;In Vitro;Ion-Exchange Chromatography Procedure;Knowledge;Label;Libraries;Longevity;Longevity Pathway;Mammals;Mass Spectrum Analysis;Measures;Mediator of activation protein;Membrane;Molecular;Mutate;Organelles;Oxidative Stress;Pathway interactions;Phase;Phosphatidylinositols;Phosphorylation;Physiological;Play;Protein Binding;Protein Biosynthesis;Protein Kinase;Proteins;Proto-Oncogene Proteins c-akt;Research;Ribosomes;Role;Saccharomyces cerevisiae;Serine;Signal Transduction Pathway;Slide;Sphingolipids;Temperature;Testing;Translation Initiation;Work;Yeasts;alkyl hydroperoxide reductase;analog;base;cell type;dihydroceramide desaturase;dosage;in vivo;mutant;novel;prevent;uptake;yeast protein

public_health_relevance:
Project NarrativeThe proposed research will determine how the Sch9 protein kinase a functional homologof mammalian Akts/PKBs regulates chronological life span in the Baker's yeastSaccharomyces cerevisiae. Signal transduction pathways that contain Akt/PKB typeprotein kinases play important roles in regulating aging and life span and these pathwayshave been conserved from yeasts to mammals. Thus information gained from thesestudies should provide a more mechanistic basis for understanding how aging and lifespan are regulated in humans.


application_id: 8215724
project_number: 5R01GM070559-08
project_title: Molecular analysis of juvenile hormone action
administering_ic: NIGMS
award_notice_date: 2012-01-30
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 070559
program_official: CHIN, JEAN
project_start_date: 2005-02-01
project_end_date: 2014-01-31
study_section: Vector Biology Study Section[VB]
contact_pi_person_id: 7355989
contact_pi: PALLI, SUBBA R
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): There has been a continuous demand for the development of insect control methods that are target-specific. Juvenile hormone (JH) and ecdysteroids (20-hydroxyecdysone 20E is the most active form) are the major hormones that regulate development and reproduction in insects. Since these hormones are not present in vertebrates they represent attractive targets for the development of insect control methods. Hindering this effort is the lack of understanding of the molecular basis of JH action. During the current grant period seven proteins that are components of multi-protein complexes involved in JH signal transduction and its cross-talk with 20E were identified. Ligand binding studies performed using labeled JH showed that none of these proteins bind to JH with high affinity. While these proteins are likely involved in JH action and its cross-talk with 20E none of them are JH receptors. Search for a better system to study JH action without interference from ecdysteroids discovered JH regulation of reproduction in Tribolium castaneum an ideal system to study JH action without interference from ecdysteroids. In this insect JH without the interference from ecdysteroids regulates vitellogenin gene expression in the fat body and vitellogenin uptake by the oocytes. These two systems provide a unique opportunity to study both genomic (fat body) and non-genomic (ovary) actions of JH in the same insect at the same time. Therefore the renewal application proposes to study mechanism of JH action in regulation of vitellogenin gene expression in the fat body and vitellogenin uptake into the oocytes with a major goal of identifying receptors transcription factors and protein modifiers critical for JH signal transduction. Completion of whole genome sequencing availability of microarrays functioning of systemic RNA interference (RNAi) and excellent response to JH and its analogs make T. castaneum an excellent model system for studies on JH action. In the first specific aim microarray RNAi qRT-PCR electrophoretic mobility shift assays and ligand-binding assays will be employed to identify and characterize receptors transcription factors and protein modifiers involved in JH regulation of vitellogenin gene expression. In the second specific aim a panel of in vivo cell culture and in vitro assays will be used to determine whether any of the 51 G- protein-coupled receptors indentified in T. castaneum as those required for egg production and embryogenesis are activated by JH to regulate vitellogenin uptake into the oocytes. JH analogs are being used for mosquito control but some mosquitoes are already developing resistance to these analogs. The results from these studies will aid in understanding the mode of action of JH analogs thus facilitating their judicious use. The genes identified will be useful to develop screening assays to identify new insect disease vector control agents. The receptors identified can also be used in medicine by developing gene switches for various applications such as gene therapy tissue engineering and therapeutic protein production. PUBLIC HEALTH RELEVANCE Insect juvenile hormone analogs are being used for mosquito control but some mosquitoes are already developing resistance to these analogs. The results from these studies will aid in understanding the mode of action of JH analogs thus facilitating their judicious use. The genes identified will be useful to develop screening assays to identify new insect disease vector control agents and for developing gene switches useful for various applications such as gene therapy tissue engineering and therapeutic protein production.

project_terms:
Adult;Affinity;Agonist;Anabolism;Biological;Biological Assay;Biological Metamorphosis;Biological Models;Cell Culture Techniques;Code;Culicidae;Data;Development;Disease;Disease Vectors;Ecdysone;Ecdysteroids;Ecdysterone;Electrophoretic Mobility Shift Assay;Embryonic Development;Event;Extracellular Space;Fat Body;Female;Flour;Food;G-Protein-Coupled Receptors;Gene Expression;Genes;Genome;Genomics;Goals;Grant;Health;Homologous Gene;Hormone Receptor;Hormones;Human;Insect Control;Insecta;Juvenile Hormones;Label;Life Cycle Stages;Ligand Binding;Livestock;Medicine;Membrane;Messenger RNA;Methods;Methoprene;Molecular;Molecular Analysis;Molting;Mosquito Control;Oocytes;Oogenesis;Ovary;Play;Production;Promoter Regions (Genetics);Protein Binding;Protein Precursors;Proteins;RNA Interference;Regulation;Reproduction;Resistance development;Role;Screening procedure;Set protein;Signal Transduction;Switch Genes;System;Time;Tissue Engineering;Tribolium (beetle);Vertebrates;Vitellogenesis;Vitellogenins;analog;base;egg;follicular epithelial cell;gene therapy;genome sequencing;hormone analog;hormone biosynthesis;hormone regulation;in vitro Assay;in vivo;insect disease;knock-down;non-genomic;prevent;protein complex;receptor;reproductive;research study;response;therapeutic protein;transcription factor;uptake;vector control

public_health_relevance:
PROJECT NARRATIVEInsect juvenile hormone analogs are being used for mosquito control but some mosquitoes are alreadydeveloping resistance to these analogs. The results from these studies will aid in understanding the mode ofaction of JH analogs thus facilitating their judicious use. The genes identified will be useful to developscreening assays to identify new insect disease vector control agents and for developing gene switches usefulfor various applications such as gene therapy tissue engineering and therapeutic protein production.


application_id: 8214970
project_number: 5F31DC010281-02
project_title: Deaf infants' cognitive skills and their post-cochlear implant language outcomes
administering_ic: NIDCD
award_notice_date: 2011-12-08
opportunity_number: PA-10-108
application_type: 5
activity_code: F31
ic: DC
serial_number: 010281
program_official: SKLARE, DAN
project_start_date: 2011-01-01
project_end_date: 2013-06-30
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 9702555
contact_pi: SHAFTO, CARISSA LYNN
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term research goal is to identify predictors of spoken language development in profoundly deaf children who receive a cochlear implant (CI). Decades of research have demonstrated that children with severe-to-profound deafness (including children who receive a CI) on average exhibit deficits in language and literacy as compared to their normally-hearing (NH) peers (e.g. Geers 2004; Miller 2009; Paul 1998). These literacy and spoken language deficits are thought to be responsible for the significant academic achievement gaps that are observed between deaf and NH children (e.g. Harris & Beech 1998). Further research is needed to determine the skills underlying spoken language development in deaf children so that more effective early intervention strategies can be developed.  The goal of the proposed project is to compare cognitive skills (known to be important for language acquisition) in children with profound hearing loss to those of children with NH and to examine the relationship between a nonverbal cognitive skill (VSL ability) and spoken language ability.  The first specific aim is to examine visual sequence learning (VSL) in infants aged 8 to 23 months with severe-to-profound deafness that will be undergoing cochlear implantation. Their performance on the VSL task will be compared to the performance of aged-matched infants with NH. Infants with CIs will be tested on the VSL task just prior to the initial activation of their CI (i.e. prior to auditory input). Differences in performance between the two groups will serve as an index of the effects of early auditory deprivation on VSL ability.  The second specific aim is to determine the relationship between VSL ability and later spoken language in deaf infants who use CIs. Correlational analyses will be conducted between scores on the VSL task prior to cochlear implantation and vocabulary and grammatical scores on the MacArthur-Bates Communicative Development Inventories (CDIs; Fenson et al. 2006) one year following cochlear implantation.  Because language development begins at birth infancy is an opportune time to investigate predictors of spoken language ability. A potential clinical implication of this work is the identification of early nonverbal predictors of spoken language outcome which may be used in the future to develop new early intervention strategies designed to promote spoken language development. These strategies may narrow the achievement gap between NH and deaf children. A strong positive correlation between VSL in infancy and spoken language ability one year later would suggest that early sequence learning skills are important for spoken language development. In contrast a weak correlation might suggest that VSL ability is not that important for spoken language development in deaf infants. Either pattern of results clarifies the effects of auditory deprivation on the development of cognitive skills that underlie spoken language development.    PUBLIC HEALTH RELEVANCE: This research addresses the issue of why some deaf children with cochlear implants learn spoken language very well while others have poor language outcomes and consequently struggle with developing literacy skills and perform poorly in school. Discovering early predictors of language outcomes will enable clinicians to identify infants who are at risk for poor language outcomes and design appropriate early intervention strategies to reduce the chances that they will not develop adequate language to succeed in school.

project_terms:
Academic achievement;Achievement;Address;Age;Age-Months;Auditory;Beech;Birth;Child;Clinical;Cochlear Implants;Cochlear implant procedure;Cognitive;Data;Deafness;Development;Early identification;Early treatment;Equipment and supply inventories;Exhibits;Foundations;Future;Goals;Hearing;Hearing Impaired Persons;Individual;Infant;Intervention;Laboratories;Language;Language Development;Language Disorders;Learning;Linguistics;Link;Outcome;Pattern;Performance;Relative (related person);Research;Research Training;Risk;Running;School-Age Population;Schools;Short-Term Memory;Testing;Time;Training;Visual;Vocabulary;Work;aged;auditory deprivation;base;design;experience;hearing impairment;improved;indexing;infancy;literacy;meetings;peer;public health relevance;sequence learning;skills

public_health_relevance:
Relevance This research addresses the issue of why some deaf children with cochlear implants learn spoken languagevery well while others have poor language outcomes and consequently struggle with developing literacy skillsand perform poorly in school. Discovering early predictors of language outcomes will enable clinicians toidentify infants who are at risk for poor language outcomes and design appropriate early intervention strategiesto reduce the chances that they will not develop adequate language to succeed in school.


application_id: 8214606
project_number: 5R01DA022451-03
project_title: Enhancement of Sexual Motivation
administering_ic: NIDA
award_notice_date: 2012-02-01
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DA
serial_number: 022451
program_official: WETHERINGTON, CORA LEE
project_start_date: 2010-02-01
project_end_date: 2015-01-31
study_section: Special Emphasis Panel[ZRG1-BBBP-T(03)M]
contact_pi_person_id: 7876913
contact_pi: AKINS, CHANA K.
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): There is considerable evidence for a co-morbid relationship between cocaine abuse and risky sexual behavior. Clinical studies have shown a correlation between cocaine use and risky sexual practices such as increased frequency an increased number of partners and unprotected sex. These sexual practices have been linked to adverse health consequences including high prevalence rates for sexually-transmitted diseases. Controlled preclinical studies that utilize animal models have demonstrated that prior repeated exposure to cocaine enhances sexual motivation and behavior. However no parametric or systematic studies further investigating the basic mechanisms underlying this relationship have been conducted. The goal of the proposed experiments is to utilize an animal model whose sexual behavior system has been well-studied Japanese quail. In addition to the benefits of using quail to study sexual behavior the use of a visually-oriented species in studying drug effects may be of additional relevance to studying human drug addiction. We currently have preliminary evidence in male Japanese quail that preexposure to cocaine enhances sexual motivation. This finding ties in well with clinical observations that indicate that cocaine use in humans may increase sexual motivation thereby increasing the likelihood of the occurrence of high-risk sexual behavior. The overall working hypothesis of this proposal is that the magnitude of the sexual response depends on several cocaine preexposure parameters including dose amount of exposure time between exposures and the withdrawal period before sexual behavior testing. Additionally we hypothesize that cocaine preexposure increases the resistance to extinction (harder to eliminate) and facilitates the reacquisition of a sexual response that has been extinguished. The proposed research has the potential to contribute to our understanding of cocaine preexposure effects on sexual motivation using a visually-oriented animal model. For example in males sexual motivation may be enhanced by prior cocaine exposure. Such an enhancement might translate in humans as high risk or compulsive sexual behaviors such as increased frequency of sexual activity sex with multiple partners and unprotected sex. These risky sexual behaviors have been linked with considerable health consequences such as the transmission of HIV and hepatitis C. The goal of the proposed project is to contribute to understanding underlying mechanisms of cocaine's effects on sexual motivation.  PUBLIC HEALTH RELEVANCE: Clinical studies have shown a correlation between cocaine use and risky sexual practices such as increased frequency an increased number of partners and unprotected sex. These sexual practices have been linked to adverse health consequences including high prevalence rates for sexually-transmitted diseases. The current application is a preclinical model used to investigate how drugs of abuse alter sexual motivation.

project_terms:
Acute;Animal Model;Animals;Association Learning;Behavior;Brain region;Breeding;Chronic;Clinical;Clinical Research;Cocaine;Cocaine Abuse;Conditioned Stimulus;Coturnix japonica;Cues;Dependence;Dose;Drug Addiction;Drug abuse;Drug usage;Empirical Research;Ethics;Event;Extinction (Psychology);Female;Food;Frequencies (time pattern);Goals;HIV;Health;Hepatitis C;High Prevalence;Human;Investigation;Learning;Length;Light;Link;Long-Term Effects;Measures;Memory;Mentored Research Scientist Development Award;Methods;Modeling;Motivation;Multiple Partners;Partner in relationship;Performance;Pharmaceutical Preparations;Phase;Physiological Effects of Drugs;Pre-Clinical Model;Procedures;Property;Publishing;Quail;Recovery;Research;Research Training;Resistance;Rewards;Rodent;Saline;Seasons;Sensory;Sex Behavior;Sexually Transmitted Diseases;Signal Transduction;Simulate;Stimulus;System;Testing;Time;Translating;United States;Unsafe Sex;Visual;Withdrawal;Work;addiction;approach behavior;behavior test;clinically relevant;cocaine exposure;cocaine use;conditioning;drug of abuse;drug testing;experience;high risk;high risk sexual behavior;indexing;male;neural circuit;preclinical study;public health medicine (field);research study;response;sex;transmission process

public_health_relevance:
NarrativeClinical studies have shown a correlation between cocaine use and risky sexual practices such as increasedfrequency an increased number of partners and unprotected sex. These sexual practices have been linked toadverse health consequences including high prevalence rates for sexually-transmitted diseases. The currentapplication is a preclinical model used to investigate how drugs of abuse alter sexual motivation.


application_id: 8214456
project_number: 1K18DE022324-01
project_title: Physiological and Emotional Reactivity to Pain after Physical and Sexual Abuse
administering_ic: NIDCR
award_notice_date: 2011-09-23
opportunity_number: RFA-DE-11-003
application_type: 1
activity_code: K18
ic: DE
serial_number: 022324
program_official: CLARK, DAVID
project_start_date: 2011-09-23
project_end_date: 2012-12-31
study_section: Special Emphasis Panel[ZRG1 BBBP-T (52)]
contact_pi_person_id: 6346300
contact_pi: WESTLUND-HIGH, KARIN N.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal details a short-term career enhancement plan for a seasoned pain research scientist paired with experienced clinical behavioral scientists in the College of Dentistry at the University of Kentucky as mentors. The proposed training opportunity for the faculty level candidate includes: (1) formal Certificate training in Clinical and Translational Science (CTS) and (2) mentored training in a clinical orofacial pain study. Chronic pain is a long lasting but less well documented outcome associated with post-traumatic stress disorder (PTSD) after exposure to interpersonal violence. The mentored pilot study will be performed in women with a history of physical and/or sexual abuse from local community shelters. Laboratory findings of mentor Dr. Charles Carlson and his colleagues have established a link between PTSD and chronic orofacial pain for women. Coincident physiological response changes in these chronic pain sufferers include decreased heart rate variability (HRV). Alterations in responsivity of this physiological biomarker suggest it as an appropriate target for interventional strategies. Recent evidence suggests controlling rate and pattern of respiration can restore an increase in HRV. Dr. Carlson has developed a method of individual skills training in self-regulation of respiration that may help offset enduring physiological changes precipitated by exposure to traumatic events. Hypothesis: Improved self-regulation of autonomic nervous system function with controlled breathing can offset altered physiological responses to a painful heat stress precipitated by exposure to traumatic events. AIM 1: To evaluate differences in physiological activity and emotional reactivity in participants with/without PTSD symptoms who have experience physical or sexual abuse. Physiological activation and emotional reactivity will be assessed in 60 participants who have experienced interpersonal violence. Participants will fill out questionnaires: Emotion Assessment Scale (EAS) Pittsburgh Sleep Quality Index (PSQI) Post Traumatic Stress Disorder Checklist (PCL-C) Self Report Depression Scale (CES-D) and Current Stage of Menstrual Cycle. Baseline physiologic measures will include heart rate end- tidal CO2 (ETCO2) and respiration rate. AIM 2: To study responses to a physical stressor (heat stimulation) and the effects of a brief physical self-regulation breathing intervention on the physiological variables. A physical stressor consisting of application of unilateral intermittent painfully hot stimulation will be applied to the orofacial area while physiological recordings (heart rate ETCO2 respiration rate) continue. The procedure will be repeated after instruction in a slow diaphragmatic breathing intervention that is introduced to one-half of the participants selected at random using a table of random numbers. The long-term goal of this training is to prepare the candidate to design perform and analyze clinical translational studies in patients with chronic orofacial pain after formal CTS training and participation in a mentored pilot study to understand adverse physiological outcomes of PTSD after physical/sexual abuse.  
  
PUBLIC HEALTH RELEVANCE: Severe psychological trauma produced by abuse can produce well characterized chronic physiological and psychological responses including decreased heart rate variability and increased responsivity to pain. Individual skills training in self-regulation of respiration will be used to offset persisting physiological changes and increased reactivity to noxious heat-induced orofacial pain precipitated by exposure to traumatic physical or sexual abuse.

project_terms:
Anger;Area;Arousal;Attention;Autonomic nervous system;Basic Science;Behavior Therapy;Behavioral;Biological;Breathing;Carbon Dioxide;Cardiovascular system;Characteristics;Chronic;Chronic Post Traumatic Stress Disorder;Clinical;Clinical Research;Clinical Sciences;Communication;Communities;DSM-IV;Dentistry;Emotional;Emotions;Event;Exposure to;Faculty;Future;Goals;Hand;Heart Rate;Heat Stress Disorders;Heating;Hormonal;Human;Hydrocortisone;Impairment;Individual;Informal Social Control;Instruction;Interpersonal Violence;Intervention;Kentucky;Laboratories;Laboratory Finding;Lead;Link;Long-Term Effects;Mandible;Measures;Mediating;Menstrual cycle;Mental Depression;Mentors;Methods;Nervous System Physiology;Neurologic;Occupational;Oral health;Orofacial Pain;Outcome;Pain;Pain Clinics;Pain Research;Participant;Patient Self-Report;Patients;Pattern;Persons;Physiological;Pilot Projects;Post-Traumatic Stress Disorders;Procedures;Protocols documentation;Psychophysiology;Questionnaires;Recording of previous events;Recruitment Activity;Research;Research Personnel;Respiration;Scientist;Seasons;Sexual abuse;Shelter facility;Side;Sleep;Staging;Stimulus;Structure;Symptoms;System;Techniques;Testing;Training;Translational Research;Trauma;Trigeminal Neuralgia;Trigeminal System;Trigeminal nerve structure;Universities;Woman;biomarker;career;chronic pain;college;design;experience;glucose metabolism;heart rate variability;hypothalamic-pituitary-adrenal axis;improved;indexing;orofacial;physical abuse;psychologic;respiratory;response;skills;skills training;social;stressor;translational study

public_health_relevance:
Severe psychological trauma produced by abuse can produce well characterized chronic physiological and psychological responses including decreased heart rate variability and increased responsivity to pain. Individual skills training in self-regulation of respiration will be used to offset persisting physiological changes and increased reactivity to noxious heat-induced orofacial pain precipitated by exposure to traumatic physical or sexual abuse.


application_id: 8212608
project_number: 5F31NS067899-02
project_title: Alterations in Glutamate Neurotransmission after Experimental Brain Injury
administering_ic: NINDS
award_notice_date: 2011-05-12
opportunity_number: PA-09-208
application_type: 5
activity_code: F31
ic: NS
serial_number: 067899
program_official: HICKS, RAMONA R
project_start_date: 2010-07-04
project_end_date: 2012-05-19
study_section: Special Emphasis Panel[ZRG1-F01-L(20)L]
contact_pi_person_id: 9814689
contact_pi: HINZMAN, JASON MICHAEL
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Glutamate the predominant excitatory neurotransmitter in the central nervous system is released from multiple stores after a TBI as primary mechanical forces from the injury can breakdown the blood-brain-barrier and create pores in cell membranes leading to glutamate release into the extracellular space. In addition redistribution of ions after the injury can create a massive depolarization leading to neuronal release of glutamate [1-3]. Glutamate plays a pivotal role in the pathophysiology of secondary damage after injury by excessively activating ionotropic glutamate receptors disrupting ionic homeostasis increasing the energy demand of the cell and producing reactive oxygen species [4-7]. Increased glutamate levels could produce excessive excitation and neuronal damage that may be responsible for motor behavioral and cognitive deficits following TBI.  Central hypothesis: TBI alters glutamate regulation elevating the extracellular concentration of glutamate. Specific Aims: (1) TBI increases tonic glutamate levels and neuronal release of glutamate (2) TBI decreases the ability of glutamate transporters to clear glutamate from the extracellular space (3) Elevated extracellular levels of glutamate contribute to the post-traumatic pathophysiology (4) Pretreatment with a recently developed adeno-associated virus expressing the glutamate transporter GLT-1 (AAV1-GLT-1) will improve glutamate regulation and motor function after injury.  The proposed project examines TBI induced alterations in glutamate signaling using a novel technology enzyme-based microelectrode arrays (MEAs) coupled with in vivo amperometry. MEAs allow for selective measures of extracellular glutamate and measure the fast dynamics of glutamate release and uptake involved in glutamate neurotransmission. Examining injury-induced alterations in glutamate signaling in different regions of the central nervous system may reveal specific mechanisms responsible for increased extracellular glutamate levels. Monitoring extracellular levels of glutamate in awake animals for multiple days after injury will examine if increases in extracellular glutamate contribute to post-traumatic pathophysiology. These studies may reveal important mechanistic discoveries and the therapeutic window available to improve motor behavioral and cognitive outcomes following TBI. Finally we will examine if pretreatment with AAV1- GLT-1 can improve glutamate regulation and reduce motor deficits after injury.  
  
PUBLIC HEALTH RELEVANCE: Approximately 1.5 million Americans suffer from a traumatic brain injury (TBI) each year with mild TBI accounting for as many as 75% of all the injuries [8]. Survivors of TBI suffer from a wide spectrum of deficits including impairments in working memory attention learning cognitive function and motor function [9-13]. Future research needs to examine the pathological mechanisms responsible for producing these deficits which may provide novel therapeutic targets to improve outcomes after injury.

project_terms:
Accounting;Affect;American;Amino Acid Transporter;Anesthesia procedures;Animal Model;Animals;Attention;Behavioral;Biochemical;Blood - brain barrier anatomy;Brain Injuries;Brain region;Cell Death;Cell membrane;Cells;Cessation of life;Closed head injuries;Cognitive;Cognitive deficits;Corpus striatum structure;Coupled;DL-TBOA;Dependovirus;Detection;Development;Diffuse;Diffuse Axonal Injury;Enzymes;Event;Excitatory Amino Acids;Experimental Designs;Extracellular Space;Functional disorder;GLAST Protein;Glutamate Receptor;Glutamate Transporter;Glutamates;Homeostasis;Hour;Human;Impairment;Injury;Ions;Learning;Measures;Mechanics;Microdialysis;Microelectrodes;Modeling;Monitor;Motor;Motor Activity;Neuraxis;Neurologic;Neurons;Neurotransmitters;Outcome;Pathology;Performance;Play;Population;Potassium Chloride;Prefrontal Cortex;Proteins;Reactive Oxygen Species;Regulation;Resolution;Role;Sampling;Series;Short-Term Memory;Signal Transduction;Sodium Channel Blockers;Survivors;Synapses;Techniques;Tetrodotoxin;Therapeutic;Tissues;Transfection;Traumatic Brain Injury;Variant;astrogliosis;awake;base;benzyloxyaspartate;cognitive function;dentate gyrus;extracellular;fluid percussion injury;improved;in vivo;inhibitor/antagonist;insight;motor deficit;neurotransmission;new technology;new therapeutic target;novel strategies;prevent;public health relevance;research study;therapeutic target;uptake

public_health_relevance:
7. Project Narrative Approximately 1.5 million Americans suffer from a traumatic brain injury (TBI) each year withmild TBI accounting for as many as 75% of all the injuries [8]. Survivors of TBI suffer from a widespectrum of deficits including impairments in working memory attention learning cognitive functionand motor function [9-13]. Future research needs to examine the pathological mechanisms responsiblefor producing these deficits which may provide novel therapeutic targets to improve outcomes afterinjury.


application_id: 8212602
project_number: 5F32DK089717-02
project_title: Insulin effects in the vagal complex
administering_ic: NIDDK
award_notice_date: 2011-11-17
opportunity_number: PA-10-110
application_type: 5
activity_code: F32
ic: DK
serial_number: 089717
program_official: CASTLE, ARTHUR
project_start_date: 2010-12-01
project_end_date: 2013-11-30
study_section: ZDK1-GRB-W(O1)S
contact_pi_person_id: 10299496
contact_pi: KASERMAN, CAMILLE BLAKE
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 dorsal vagal complex (DVC) is essential to integrating visceral sensory afferents and various other inputs in order to produce appropriate parasympathetic motor outputs via the vagus nerve which is vital for energy homeostasis. Certain pathologies such as diabetes can cause disruption of this circuit. Diabetes mellitus is a metabolic disorder that results in dysfunctional glucose regulation by insulin deficiency (type-1) or resistance (type-2). Hyperglycemia a condition of diabetes significantly alters central vagal function and diabetics often experience gastric dysfunction gastroparesis and other visceral symptomatology. Insulin crosses the blood brain barrier and is transported into the brainstem over twice as rapidly as into whole brain and neuronal insulin receptors are expressed in the DVC. Neuronal insulin and insulin receptors are required for normal control of glucose homeostasis and the regulation of peripheral energy homeostasis and glucose metabolism. Despite the importance of the DVC and the evidence that insulin action in the brain is critical for homeostasis very little is known about insulin's action in the brain specifically the DVC. This proposal will test the effects of insulin on cellular communication within the DVC. The general hypothesis is that insulin is inhibiting neurons in the dorsal motor nucleus (DMV). I predict that this occurs directly and indirectly by acting on glutamatergic neurons of in the nucleus of the solitary tract (NTS) that project to the DMV. Electrophysiological studies will be conducted in brainstem slice preparations from adult mice. Gastric-related neurons of DMV and NTS will be identified by their anatomical connection with the proximal stomach. With whole-cell patch clamp recordings the effects of insulin will be examined on: 1) input to DMV neurons and 2) glutamatergic neurons of the NTS identified with RT-PCR that project to the DMV by "uncaging" glutamate in these neurons and examining paired-pulse responses in the DMV to electric stimulation of the NTS. These results will be coordinated with pharmacological and molecular biological analyses to generate models of insulin action in the vagal complex in mice.    PUBLIC HEALTH RELEVANCE: This proposal will test the effects of insulin on the dorsal vagal complex which controls gastric function. Because this region is located in the brainstem which is adjacent to an incomplete portion of the blood brain barrier hormones found in the bloodstream such as insulin can readily access this part of the brain. Diabetic patients often experience gastric dysfunction; thus the actions of insulin in this brain region are important to our understanding of the physiology of this disease. The results of this study will provide a clearer understanding of how insulin regulates autonomic function which could lead to new insights in designing treatments for diabetes.

project_terms:
Adult;Affect;Area;Binding (Molecular Function);Biological;Blood - brain barrier anatomy;Blood Circulation;Brain;Brain Part;Brain Stem;Brain region;Cells;Communication;Complex;Data;Diabetes Mellitus;Disease;Dorsal;Eating;Electric Stimulation;Event;Frequencies (time pattern);Functional disorder;Gastric Emptying;Gastrointestinal tract structure;Gastroparesis;Glutamates;Homeostasis;Hormones;Hyperglycemia;Hypothalamic structure;In Vitro;Insulin;Insulin Receptor;Label;Lead;Mediating;Metabolic Diseases;Methods;Modeling;Molecular;Motor output;Mus;Neurons;Nucleus solitarius;Output;Pathology;Peripheral;Phosphotransferases;Physiologic pulse;Physiology;Potassium Channel;Preparation;Regulation;Resistance;Reverse Transcriptase Polymerase Chain Reaction;Satiation;Sensory;Signal Transduction;Slice;Stomach;Synapses;Testing;Vagus nerve structure;Visceral;blood glucose regulation;cell body (neuron);diabetic;diabetic patient;dorsal motor nucleus;experience;glucose metabolism;hepatic gluconeogenesis;insight;male;patch clamp;postsynaptic;presynaptic;public health relevance;receptor;research study;response;therapy design

public_health_relevance:
Project Narrative This proposal will test the effects of insulin on the dorsal vagal complex which controls gastric function.Because this region is located in the brainstem which is adjacent to an incomplete portion of the blood brainbarrier hormones found in the bloodstream such as insulin can readily access this part of the brain. Diabeticpatients often experience gastric dysfunction; thus the actions of insulin in this brain region are important to ourunderstanding of the physiology of this disease. The results of this study will provide a clearer understanding ofhow insulin regulates autonomic function which could lead to new insights in designing treatments fordiabetes.


application_id: 8212557
project_number: 5R01DA022967-05
project_title: African American Female Drug Users: HIV Health Disparities & Criminality
administering_ic: NIDA
award_notice_date: 2012-02-01
opportunity_number: PA-07-114
application_type: 5
activity_code: R01
ic: DA
serial_number: 022967
program_official: JONES, DIONNE
project_start_date: 2008-04-01
project_end_date: 2015-01-31
study_section: Behavioral and Social Consequences of HIV/AIDS Study Section[BSCH]
contact_pi_person_id: 6264981
contact_pi: OSER, CARRIE BETH
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this study is to understand how drug use and criminality are related to health disparities particularly HIV and service utilization among African American drug using and non-drug using women across criminal justice status. While drug use is similar across racial groups in the US African Americans are disproportionately more likely to experience severe health consequences and criminal involvement as a result of drug misuse. Adequate health care may not be received by African American female offenders because they experience the burden of their race class gender and criminal offender status. There is limited scientific data to help understand the linkages between health disparities such as HIV untreated drug abuse barriers to service utilization and status as a criminal offender among African American females. This study is significant because of its potential to identify differences in health disparities and service utilization among African American drug using and non-drug using women in selected levels of criminal justice status (intensive correctional supervision-prison (n=200) moderate correctional supervision-jail (n=200) community supervision-probation (n=200) and no criminal justice involvement (n=200)). All 800 African American females will be followed longitudinally for three 6-month intervals to examine health status and the use of health services across time. The specific aims are: (1) To describe the prevalence of health problems among African American women across criminal justice status and drug use status; (2) To determine the cultural predisposing historical health and potential enabling factors that are predictors of health problems among African American drug using and non-drug using women across criminal justice status over 18 months; (3) To describe the prevalence of untreated health problems the patterns of health services utilization and the cultural barriers to service utilization among African American women across criminal justice status and drug use status; and (4) To examine the factors that predict the likelihood of using health services among African American drug using and non-drug using women across criminal justice status over 18 months. The significance of this study includes the potential to provide criminal justice systems-level data for health planning and health policy for prevention intervention and treatment of African American female drug users.     This study is significant to the public health field because of its potential to understand the severity of health disparities among African American women across criminal justice status and drug use status and to predict health status and the use of health services over time. This knowledge of African American females can be used as a foundation for future criminal justice systems-level interventions to increase the use of preventative health care and subsequently reduce the need for expensive medical services as well as to decrease HIV risk behaviors including drug use unprotected sex and recidivism.

project_terms:
Accident and Emergency department;African American;Alcohol or Other Drugs use;Alcohols;Applications Grants;Biological Assay;Chlamydia;Communities;Criminal Justice;Data;Dependence;Development;Drug abuse;Drug abuser;Drug usage;Drug user;Economics;Enabling Factors;Epidemiology;Event;Female;Foundations;Fright;Future;Gender;General Population;Goals;Gonorrhea;HIV;Health;Health Personnel;Health Planning;Health Policy;Health Services;Health Status;Healthcare;Hepatitis C;Hepatitis C virus;Hospitalization;Imprisonment;Incidence;Individual;Inpatients;Intervention;Interview;Jail;Kentucky;Knowledge;Life;Literature;Location;Mediating;Medical;Mental Health;Modeling;Multivariate Analysis;NIH Program Announcements;Participant;Patient Self-Report;Pattern;Pharmaceutical Preparations;Physicians;Population;Prevalence;Preventive Intervention;Prisoner;Prisons;Race;Recruitment Activity;Reporting;Research;Risk Behaviors;Sampling;Series;Seroprevalences;Services;Severities;Sexually Transmitted Diseases;Structure;Supervision;Surveys;System;Time;Trust;Universities;Unsafe Sex;Woman;Women's Health;Work;alcohol research;base;criminal offending;experience;follow-up;health care service utilization;health disparity;innovation;longitudinal design;non-drug;offender;physical conditioning;probation;probationer;public health medicine (field);racism;recidivism;service utilization;substance abuse treatment;time use


application_id: 8212536
project_number: 5R01NS065052-03
project_title: Neural circuit disruption by diffuse brain injury: basis for morbidity & therapy
administering_ic: NINDS
award_notice_date: 2012-03-29
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 065052
program_official: HICKS, RAMONA R
project_start_date: 2010-02-01
project_end_date: 2012-05-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 2048186
contact_pi: LIFSHITZ, JONATHAN
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Our long term goals are to develop effective pharmacological and rehabilitative treatment strategies that promote adaptive reorganization of brain-injured circuits to mitigate neurological dysfunction (morbidity) after diffuse traumatic brain injury (TBI). To achieve these goals we will exploit a novel reproducible late-onset neurological deficit that we have observed in the diffuse brain-injured rat analogous to agitation in brain injury survivors. In contrast to the soothing and pacifying nature of facial whisker stimulation in uninjured rats brain- injured rats react to whisker stimulation by cowering freezing and guarding the mystacial pads. This aberrant behavior is concomitant with axonal damage neuronal atrophy persistent inflammation and neuroplasticity such that whisker stimulation activates brain regions outside the conventional somatosensory whisker circuit. The current proposal tests the hypothesis that diffuse brain injury-induced inflammation drives the maladaptive structural plasticity responsible for aberrant behavioral responses to whisker stimulation. The model system afforded by the brain-injured somatosensory whisker circuit provides a reductionistic approach to the complexity of diffuse TBI to address pathological and reparative mechanisms associated with post-traumatic morbidity. This circuit in diffuse brain-injured adult male rats will be evaluated for (Aim 1) aberrant behaviors elicited by whisker stimulation (Aim 2) chronic neuropathology neuronal activation and circuit reorganization and (Aim 3) neuroinflammation-driven neuroplastic responses that contribute to circuit reorganization and morbidity. An anti-inflammatory therapeutic regimen may provide a clinically relevant intervention to prevent circuit rewiring and the onset of morbidity. The innovative combination of behavioral anatomical functional and therapeutic approaches directed at the brain-injured somatosensory whisker circuit addresses the underlying mechanisms associated with unregulated structural plasticity in the injured brain. Uncovering these processes can direct treatments to mitigate the onset reduce the duration and/or promote the resolution of neurological dysfunction. Results from this circuit can ultimately be expanded to other circuits in rodents and then man to improve quality of life for millions of TBI survivors and potentially others suffering from progressive neurodegenerative diseases.    PUBLIC HEALTH RELEVANCE: The present proposal focuses on the persistent morbidity experienced by diffuse brain injury survivors for whom treatment options are limited. In diffuse brain-injured rats aberrant responses to whisker stimulation will be employed as a tool to identify pathological and reparative mechanisms associated with somatosensory whisker circuit disruption. By developing validating and implementing an animal model of one discrete post-traumatic morbidity significant advancements can be made towards reshaping first one then other brain- injured circuits in rodents and man.

project_terms:
Acute;Address;Adult;Agitation;Animal Model;Anti-Inflammatory Agents;Anti-inflammatory;Atrophic;Attenuated;Axon;Behavior;Behavioral;Biological Models;Blood Vessels;Brain;Brain Injuries;Brain region;Cellular Membrane;Chronic;Communities;Diffuse;Diffuse Brain Injury;Dose;Face;Figs - dietary;Freezing;Functional disorder;Gene Expression;Goals;Ibuprofen;Immediate-Early Genes;Inflammation;Inflammatory;Injury;Intervention;Left;Liquid substance;Measures;Mechanics;Medical;Modeling;Molecular;Morbidity - disease rate;Nature;Neurodegenerative Disorders;Neurologic;Neurologic Dysfunctions;Neuronal Plasticity;Neurons;Pathologic Processes;Percussion;Performance;Pharmaceutical Preparations;Process;Quality of life;Rattus;Regimen;Rehabilitation therapy;Research;Resolution;Rodent;Sensory;Severities;Societies;Somatosensory Cortex;Survivors;Symptoms;Testing;Therapeutic;Time;Traumatic Brain Injury;Ventral Posterior Nucleus;Vibrissae;base;clinically relevant;effective therapy;experience;improved;in vivo Model;injured;innovation;mRNA Expression;male;man;neural circuit;neuroinflammation;neuropathology;novel;organic base;prevent;protein expression;psychologic;public health relevance;response;somatosensory;tool;treatment strategy

public_health_relevance:
7. Project Narrative The present proposal focuses on the persistent morbidity experienced by diffuse brain injury survivors forwhom treatment options are limited. In diffuse brain-injured rats aberrant responses to whisker stimulation willbe employed as a tool to identify pathological and reparative mechanisms associated with somatosensorywhisker circuit disruption. By developing validating and implementing an animal model of one discrete post-traumatic morbidity significant advancements can be made towards reshaping first one then other brain-injured circuits in rodents and man.


application_id: 8212455
project_number: 5K01ES017105-03
project_title: Ubiquitous pollutant acrolein inhibits IFN?? antiviral signaling: relevance to HC
administering_ic: NIEHS
award_notice_date: 2012-01-10
opportunity_number: PA-09-040
application_type: 5
activity_code: K01
ic: ES
serial_number: 017105
program_official: SHREFFLER, CAROL A
project_start_date: 2010-01-01
project_end_date: 2014-12-31
study_section: ZES1-LKB-J(K6)
contact_pi_person_id: 9367807
contact_pi: JOSHI-BARVE, SWATI
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):  Chronic Hepatitis C virus (HCV) infection remains a global health concern with nearly 200 million carriers worldwide. It can be a precursor to cirrhosis hepatocellular carcinoma and end-stage liver disease. In the absence of a vaccine the current FDA approved standard of care for chronic hepatitis C is a combination of pegylated interferon-alpha (IFN1) and ribavirin. Unfortunately this regimen is only effective in about 50% of patients emphasizing the need for studies defining the molecular mechanisms underlying resistance to IFN1. Clinical studies have identified several potential cofactors that may contribute to the failure of anti-HCV therapy including obesity diabetes alcohol abuse oxidative stress cigarette smoking and environmental pollutants. Acrolein is a ubiquitous highly reactive environmental and industrial pollutant and is designated by the U.S. Environmental Protection Agency (EPA) as a high priority air and water pollutant. Notably acrolein is also formed endogenously as a byproduct of lipid peroxidation (LPO) and is itself known to cause oxidative stress. Moreover acrolein is a major component of cigarette smoke and recent studies suggest that smokers with chronic hepatitis C have a lower response rate to IFN1 compared to non-smokers. We have convincing preliminary data showing that non-toxic concentrations of acrolein significantly down-regulate IFN1 signaling and antiviral gene expression in vitro (cultured human hepatic cells) and in vivo (mice).  Published literature and our own compelling data strongly support our hypothesis that acrolein adversely influences IFN1 therapy outcomes by inhibiting or disrupting IFN1 mediated signaling and antiviral gene expression in hepatocytes and that high acrolein exposure (environmental and/or endogenous) will correlate with poor IFN1 response in HCV infected individuals. Our hypotheses will be tested by examining the effects of acrolein on early IFN1-mediated signaling (including components of the Jak/STAT pathway) and antiviral gene expression using well established in vitro and in vivo experimental systems as well as an HCV replicon that directly reports on HCV viral replication. Additionally the investigators will establish a clinical/translational aspect of our hypothesis by conducting a retrospective analysis using banked serum urine and/or liver biopsy samples from healthy uninfected individuals and HCV-infected patients (responders and non-responders). This analysis will explore a possible correlation between acrolein exposure and poor IFN1 response (lack of sustained virologic response SVR).  The investigators expect their studies will elucidate critical mechanisms underlying resistance to IFN1 treatment and will identify potential targets for novel therapeutic intervention.    Public Health Relevance:  Acrolein is one of the major reactive aldehydes ubiquitously present in foods water and in the environment. It is a major constituent of cigarette smoke. Recent data suggest that HCV- infected smokers have worse IFN1 therapeutic outcomes compared with non-smokers. Acrolein is also generated endogenously due to cellular metabolism and this may constitute a significant source of intracellular acrolein in situations of oxidative stress and inflammation. Elevated acrolein adducts have been detected in several disease conditions that are also known to be associated with failure of IFN therapy. Hence based on available literature and the investigators' own compelling preliminary results they have opted to use acrolein as the model compound for this study. The aim of the study is to determine the contribution of acrolein to the mechanisms of IFN1 resistance. The investigators have preliminary evidence to demonstrate that acrolein at nontoxic concentrations significantly down-regulates IFN1 signaling and antiviral/anti-HCV gene expression.

project_terms:
Acrolein;Acrylates;Air Pollutants;Alcohol abuse;Aldehydes;Alzheimer's Disease;Amino Acids;Antiviral Agents;Atherosclerosis;Automobile Exhaust;Binding (Molecular Function);Biocide;Biological Models;Biology;Biopsy Specimen;Cell Line;Cessation of life;Chemical Weapons;Chronic Disease;Chronic Hepatitis C;Cirrhosis;Clinical;Clinical Research;Cysteine;Data;Development;Diabetes Mellitus;Disease;Dose;Double-Stranded RNA;Environment;Environmental Exposure;Environmental Pollutants;Exposure to;FDA approved;Failure (biologic function);Family;Fatty acid glycerol esters;Food;Free Radicals;Functional disorder;Future;Gene Expression;Genes;Genotype;Hepatitis C;Hepatitis C virus;Hepatocyte;Histidine;Human;Hydroxyl Radical;Imidazole;In Vitro;Individual;Industrial Waste;Inflammation;Interferons;Kidney Failure;Ligand Binding;Ligase;Lipid Peroxidation;Literature;Liver;Liver diseases;Lysine;Mediating;Medicine;Messenger RNA;Metabolism;Methionine;Modeling;Modification;Molecular;Mus;Non-Insulin-Dependent Diabetes Mellitus;Non-smoker;Nucleic Acids;Obesity;Organic Chemicals;Outcome;Oxidative Stress;PTPN11 gene;Pathway interactions;Patients;Pegylated Interferon Alfa;Phospholipids;Phosphorylation;Plastics;Play;Polyamines;Polymers;Primary carcinoma of the liver cells;Protein Phosphatase 2A Regulatory Subunit PR53;Protein Tyrosine Kinase;Protein phosphatase;Proteins;Publications;Publishing;Rattus;Regimen;Replicon;Reporting;Research;Research Personnel;Resistance;Response Elements;Ribavirin;Role;STAT protein;STAT1 gene;STAT2 gene;Serum;Side;Signal Transduction;Smoke;Smoker;Smoking;Source;Specimen;Staging;System;TYK2;Testing;Therapeutic;Tissues;Transcriptional Activation;Treatment outcome;United States;United States Environmental Protection Agency;Urine;Vaccines;Viral;Water;Water Pollutants;Wood material;adduct;amino group;anti-hepatitis C;base;biomarker;chronic liver disease;cigarette smoke;cigarette smoking;cofactor;cooking;eIF-2 Kinase;efficacy testing;global health;improved;in vivo;insight;liver biopsy;mouse model;novel therapeutic intervention;oligoadenylate;pollutant;protein activation;public health relevance;receptor;receptor internalization;response;standard of care;therapy outcome

public_health_relevance:
Acrolein is one of the major reactive aldehydes ubiquitously present in foods water and in theenvironment. It is a major constituent of cigarette smoke. Recent data suggest that HCV-infected smokers have worse IFN therapeutic outcomes compared with non-smokers. Acroleinis also generated endogenously due to cellular metabolism and this may constitute a significantsource of intracellular acrolein in situations of oxidative stress and inflammation. Elevatedacrolein adducts have been detected in several disease conditions that are also known to beassociated with failure of IFN therapy. Hence based on available literature and our owncompelling preliminary results we have opted to use acrolein as the model compound for thisstudy. The aim of this study is to determine the contribution of acrolein to the mechanisms ofIFN resistance. We have preliminary evidence to demonstrate that acrolein at nontoxicconcentrations significantly down-regulates IFN signaling and antiviral/anti-HCV geneexpression.


application_id: 8212058
project_number: 5R01HL089380-05
project_title: Cardioprotective Mechanisms of Glutathione S-transferase P
administering_ic: NHLBI
award_notice_date: 2012-03-02
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 089380
program_official: SCHWARTZ, LISA
project_start_date: 2008-04-11
project_end_date: 2015-01-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 8767000
contact_pi: CONKLIN, DANIEL JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The glutathione S-transferases (GSTs) are a superfamily of ubiquitously expressed enzymes that conjugate reduced glutathione (GSH) with toxic electrophiles. The GST isoforms have also been show to regulate ASK-1 and JNK activation via protein-protein interactions. In human populations the GST isoforms are distributed in a race- and gender-specific manner. The GSTs are expressed in cardiovascular tissues but the role of GST in cardiovascular physiology and pathology has not been studied. We propose that GSTP the most abundant cardiac isoform is an essential component of myocardial defense against oxidative stress and it protects the heart from acute oxidative damage during ischemia-reperfusion (I/R). To test this hypothesis we will assess the contribution of GSTP to cardiac protection during I/R in situ (Aim 1) metabolism of lipid peroxidation- derived aldehydes (acrolein and 4-hydroxy-trans-2-nonenal; HNE) which are the preferred endogenous substrates of this enzyme (Aim 2) and aldehyde detoxication (Aim 3). As a loss of function test GSTP-null mice will be exposed to I/R while in gain of function tests transgenic (TG) and TG mice crossed with null mice with cardiac-restricted expression of human polymorphic GSTP1-1 genes will be exposed to I/R and infarction determined. Using tracer kinetics and mass spectrometric analysis we will measure the extent to which glutathiolation accounts for the metabolism of these aldehydes before during and after ischemia in the heart (Aim 2). To delineate the contribution of GSTP we will compare metabolic pathways including aldehyde conjugation and peroxidase activity in hearts isolated of GSTP WT null and TG mice. In Aim 3 we will determine whether GSTP protects the heart from I/R-induced injury by increasing glutathione conjugation of aldehydes decreasing aldehyde formation decreasing aldehyde-protein adducts decreasing peroxide formation decreasing oxidative post-translation protein modifications (e.g. sulfenic acid) by glutathiolation and protecting myocardial GSH level. In addition we will determine if GSTP regulates JNK activation and JNK signaling thereby investigating a non-catalytic role of GSTP in protein-protein interactions. Successful completion of these studies may lead to the identification of a novel mechanism of cardioprotection by GSTP which may be useful in assessing the relative ischemic susceptibility of human populations polymorphic in GSTP and in developing more targeted anti-ischemic interventions.  PUBLIC HEALTH RELEVANCE The glutathione S-transferases (GSTs) are widely expressed enzymes that detoxify reactive compounds. In human populations the GSTs are distributed in a race- and gender-specific manner and GST polymorphisms are associated with increased cardiovascular disease risk. This study will assess if GSTP is an essential component of myocardial defense against injury of heart attacks. Successful completion of these studies may lead to the identification of a novel mechanism of cardioprotection by GSTP which may be useful in understanding the relative susceptibility of human populations polymorphic in GSTP to coronary heart disease and in developing more targeted cardioprotective interventions.

project_terms:
Ablation;Accounting;Acrolein;Acute;Affect;Affinity;Aldehydes;Antioxidants;Attenuated;Biochemical Pathway;Cardiac;Cardiac Myocytes;Cardiovascular Pathology;Cardiovascular Physiology;Cardiovascular system;Coronary Occlusions;Coronary heart disease;Doctor of Philosophy;Drug Metabolic Detoxication;Drug resistance;Enzymes;Epidemiology;Excision;Foundations;Future;GSTP1 gene;Gender;Genes;Genetic;Genetic Polymorphism;Glutathione;Glutathione S-Transferase;Glutathione S-Transferase P;Health;Heart;Human;In Situ;Individual;Infarction;Injury;Intervention;Ischemia;Kinetics;Knockout Mice;Lead;Link;Lipid Peroxidation;MAPK8 gene;Measures;Mediating;Metabolic;Metabolic Pathway;Metabolism;Modeling;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardial Reperfusion;Myocardial Reperfusion Injury;Natural regeneration;Oxidative Stress;Pathway interactions;Peroxidases;Peroxides;Phenotype;Population;Post-Translational Protein Processing;Predisposition;Principal Investigator;Production;Protein Isoforms;Proteins;Race;Reactive Oxygen Species;Reduced Glutathione;Relative (related person);Reperfusion Injury;Reperfusion Therapy;Role;Signal Pathway;Signal Transduction;Stress;Sulfenic Acids;Testing;Tissues;Tracer;Transgenic Mice;Transgenic Organisms;Translations;adduct;base;carcinogenesis;cardiovascular disorder risk;detoxication;enzyme substrate;gain of function;heart metabolism;insight;loss of function;novel;overexpression;oxidative damage;oxidized lipid;prevent;programs;protein protein interaction;translational study


application_id: 8212027
project_number: 5R01AI071047-05
project_title: Adjuvant Functions of Detoxified LPS
administering_ic: NIAID
award_notice_date: 2012-02-03
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AI
serial_number: 071047
program_official: LEITNER, WOLFGANG W
project_start_date: 2008-02-01
project_end_date: 2013-01-31
study_section: Immunity and Host Defense Study Section[IHD]
contact_pi_person_id: 1941645
contact_pi: MITCHELL, THOMAS C.
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Monophosphoryl lipid A (MLA) is a detoxified form of TLR4 agonist LPS that is approved for use as a vaccine adjuvant in Europe and is nearing approval for use in the US. Extensive testing shows that MLA in its clinical grade from MLA adjuvant is as safe as the current adjuvant standard alum but is far more effective at generating protective antibody responses. In spite of this extensive testing for safety and efficacy very little is known about the mechanism by which MLA efficiently triggers TLR4 signaling while showing so little of the endotoxic properties of its parent compound LPS. TLR4 is unique among TLRs in that it signals by activating both MyD88 and TRIF signaling pathways. This proposal will test the central hypothesis that MLA's adjuvant effects are associated with preferential stimulation of the TLR4/Trif pathway. Because MLA is manufactured from endotoxin synthetic forms are preferred by vaccine manufactures. However the synthetic forms that are feasible to manufacture on a mass scale have variations of structure relative to MLA that cause them to have a wide range of distinct adjuvant functions. These functional variations are interesting but also make it more difficult to predict which will ultimately be best suited for widespread use in prophylactic vaccination. This proposal is designed to elucidate the molecular basis for MLA's TRIF- biased adjuvant effects on T and B cell so that its success can be replicated and improved in next generation synthetic forms. The specific aims of this proposal are: I. To identify the molecular mechanism(s) of MLA's Trif-biased signaling in monocytes. II. To identify TLR4 signaling pathways required for low toxicity adjuvant effects on T cells. III. To identify pro-inflammatory requirements for TLR4-mediated adjuvant effects on B cells. PUBLIC HEALTH RELEVENCE: Non-infectious vaccines are typically the safest way to protect against infectious disease and bioterrorism but vaccines are relatively inefficient unless "adjuvants" that boost the human immune response are added. This proposal will decipher the means by which new adjuvants that are just beginning to be used in human vaccines influence the responses of T cells an important component of the immune system. Our work will allow next- generation adjuvants to be improved for use in new vaccines against a broad array of infectious threats.

project_terms:
Acids;Adjuvant;Agonist;Antibody Formation;B-Lymphocytes;Bioterrorism;CD4 Positive T Lymphocytes;Clinical;Clonal Expansion;Communicable Diseases;Data;Drug Formulations;Endotoxins;Europe;Future;Gout;Health;Human;Immune response;Immune system;In Vitro;Inflammatory;Mediating;Molecular;Nature;Nucleic Acids;Parents;Pathway interactions;Principal Investigator;Production;Property;Proteins;Publishing;Reagent;Relative (related person);Science;Signal Pathway;Signal Transduction;Structure;System;T cell response;T-Lymphocyte;TLR4 gene;Testing;Time;Toxic effect;Uric Acid;Vaccination;Vaccine Adjuvant;Vaccines;Variant;Work;aluminum sulfate;base;design;improved;in vivo;interest;monocyte;monophosphoryl lipid A;next generation;novel vaccines;programs;prophylactic;safety testing;success


application_id: 8211666
project_number: 2R01NS045734-08
project_title: Vascular responses as therapeutic targets after SCI
administering_ic: NINDS
award_notice_date: 2011-05-31
opportunity_number: PA-10-067
application_type: 2
activity_code: R01
ic: NS
serial_number: 045734
program_official: KLEITMAN, NAOMI
project_start_date: 2004-05-03
project_end_date: 2016-07-31
study_section: Special Emphasis Panel[ZRG1 BDCN-W (02)]
contact_pi_person_id: 6902570
contact_pi: HAGG, THEO
other_pis: WHITTEMORE, SCOTT R
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.  
  
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: 8211426
project_number: 4R42DA030001-02
project_title: Intranasal Naloxone: An Opioid Overdose Antidote
administering_ic: NIDA
award_notice_date: 2011-03-30
opportunity_number: PA-09-081
application_type: 4
activity_code: R42
ic: DA
serial_number: 030001
program_official: BOUGH, KRISTOPHER J
project_start_date: 2010-07-15
project_end_date: 2012-07-31
study_section: Special Emphasis Panel[ZRG1-IMST-D(13)B]
contact_pi_person_id: 10086391
contact_pi: WERMELING, DANIEL PAUL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_uei: DC9CX5GXZSU4
duns_number: 831025338
uei: DC9CX5GXZSU4
fips: US
organization_id: 10023078
organization_name: ANTIOP, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405151273
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-04-01
project_abstract:
DESCRIPTION (provided by applicant): There is a significant unmet medical need to provide additional pharmacologic treatments for treatment and prevention of opioid overdose. This Fast Track STTR project proposes to apply drug delivery technologies to develop a novel use for a nasally delivered pharmaceutical - naloxone (NLX) hydrochloride - for the emergency treatment of opioid overdose by emergency medical services. Emergency medical service personnel would prefer a non-injection based antidote to avoid accidental needle-sticks in the revival of opioid overdose victims. This approach would markedly reduce the risks of contracting hepatitis or HIV by first responders. It might also reduce time to first treatment by obviating the need to establish an injection site and preparation of the injectable device or intravenous access. The specific objective is to create a nasal spray that offers a novel therapeutic option for a rapid-acting interventional medication intended to acutely reverse the effects of prescription (e.g Oxycontin(R)) and illicit opioids (e.g heroin). The hypothesis of this project is that nasally delivered NLX will have biopharmaceutics comparable to NLX subcutaneous (SC) and intramuscular (IM) injection without the use of a needle. The project hypothesis will be tested by the following Specific Aims: 1. Develop prototype formulations of NLX meeting standards for potency & stability 2. Manufacture the preferred formula and complete product stability testing 3. Manufacture animal and human clinical testing batches of NLX nasal spray 4. Assess upper and lower airway toxicity in vivo to beagle pups 5. Conduct a bioavailability study comparing the nasal spray system to SC and IM injection in healthy  human volunteers For Phase 1 (aim 1) formulation chemistry (see Section 5 Aim 1) will be applied to design chemically stable microbiologically safe nasal delivery formulae for delivery by a unit-dose nasal spray device. For Phase 2 (aim 2) the pilot formula will be manufactured into the sprayer and have formal stability testing completed. For aim 3 the naloxone nasal spray product will be manufactured for animal and human testing. The formula will be administered in vivo to beagle pups in order to test upper and lower airway toxicity (aim 4). For Phase 2 (aim 5) an IND will be filed with FDA and nasally delivered NLX biopharmaceutics will be attained by manufacture of a NLX nasal spray batch of the selected prototype formula and conducting a pilot bioavailability study in healthy human volunteers. Milestones for this project include the development of stable formulae selection of a final formula and stability testing of the manufactured product production of the NLX nasal spray for preclinical and human studies no or reversible irritation in beagle pups and attainment of rapid absorption and bioavailability in human comparable to SC and IM injection.  
  
PUBLIC HEALTH RELEVANCE: There is a significant unmet medical need to provide additional pharmacologic treatments for treatment and prevention of opioid (morphine like medications) overdose. The specific objective is to create a nasal spray that offers a novel therapeutic option for a rapid-acting interventional medication intended to acutely reverse the effects of prescription (e.g Oxycontin(R)) and illicit opioids (e.g heroin).

project_terms:
Acute;Address;Animals;Antidotes;Biological Availability;Biopharmaceutics;Blood;Chemistry;Clinical Research;Contracts;Data;Development;Devices;Dose;Drug Delivery Systems;Drug Formulations;Drug Kinetics;Emergency Situation;Emergency medical service;Emergency treatment;HIV;Health Personnel;Hepatitis;Heroin;Human;Human Resources;Human Volunteers;Injectable;Injection of therapeutic agent;Intramuscular;Intramuscular Injections;Intravenous;Investigation;Investigational Drugs;Investigational New Drug Application;Life;Medical;Morphine;Naloxone;Naloxone Hydrochloride;Needles;Needlestick Injuries;Nose;Opioid;Oryctolagus cuniculus;Outcome;Overdose;Oxycodone;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Preparation;Prevention;Production;Property;Risk;Route;Safety;Site;Small Business Technology Transfer Research;Solutions;System;Technology;Testing;Therapeutic Intervention;Time;Toxic effect;United States Food and Drug Administration;absorption;base;design;emergency service/first responder;in vivo;irritation;meetings;novel;novel therapeutics;opioid abuse;patient population;phase 3 study;pre-clinical;preclinical study;prototype;public health relevance;pup;research clinical testing;stability testing;subcutaneous;volunteer

public_health_relevance:
PROJECT NARRATIVEThere is a significant unmet medical need to provide additional pharmacologic treatments for treatment andprevention of opioid (morphine like medications) overdose. The specific objective is to create a nasal spraythat offers a novel therapeutic option for a rapid-acting interventional medication intended to acutelyreverse the effects of prescription (e.g Oxycontin(R)) and illicit opioids (e.g heroin).


application_id: 8211350
project_number: 1R34DE022274-01
project_title: Oral Health Intervention for Intellectually/Developmentally Disabled Persons
administering_ic: NIDCR
award_notice_date: 2011-09-15
opportunity_number: RFA-DE-12-001
application_type: 1
activity_code: R34
ic: DE
serial_number: 022274
program_official: CLARK, DAVID
project_start_date: 2011-09-15
project_end_date: 2013-08-31
study_section: Special Emphasis Panel[ZDE1 JR (17)]
contact_pi_person_id: 7034912
contact_pi: BINKLEY, CATHERINE J
other_pis: JOHNSON, KNOWLTON WILLIAM
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): People with intellectual and/or developmental disabilities (IDD) living in family or group homes receive less preventive medical care than those living in institutions and are less likely to receive routine dental care. These individuals are more likely to have poor oral hygiene increased decay and periodontal disease than the general population-a significant health disparity. More importantly poor oral health in persons with IDD may also contribute to respiratory infections including aspiration pneumonia. The oral health of this population is compromised not only by the lack of preventive dental treatment every six months but also their inability to adequately brush and/or floss their own teeth. Many of the moderately to profoundly disabled are dependent on their caregivers to maintain oral health but there is evidence that caregiver psychosocial factors serve as barriers to optimal oral hygiene behavior  The proposed oral health planning grant is in conjunction with conducting a five-year randomized controlled trial with an oral health theory-based intervention delivered by case managers. The research will extend previous findings from a pilot study to a different population by using an empirical grounded theoretical framework refined intervention strategy larger sample size and pilot tested process and outcome measures. The U01 cooperative agreement trial would be the first outcome study properly powered to evaluate the effect of a dental case management strategy on oral health related quality of life and respiratory infections with caregivers and IDD participants in 124 community group homes.  The two-year planning grant is requested to pilot test recruitment strategies acceptability of the intervention fidelity monitoring methods and validity and reliability of study measures including intervention processes mediators moderators and outcomes. The pilot will be conducted with a sample of caregivers in 25 group homes with approximately 112 IDD participants. Upon completion of the planning grant a full protocol and manual of operations will have been developed for the clinical trial (U01 cooperative agreement) grant application. Personnel from the University of Louisville and the Pacific Institute for Research and Evaluation will participate in these activities.  The results of this study will impact the field of social and behavioral research by demonstrating whether dental case management improves the oral health and related quality of life of persons with IDD. If the results are positive we would advocate for a larger multi-site randomized controlled trial to produce results that may be generalized to different populations with oral health disparities in diverse geographic areas. Ultimately the results could impact healthcare reform and integrate dental case management into medical case management for disadvantaged persons.  
  
  
PUBLIC HEALTH RELEVANCE: In the short term the results of the proposed study have the potential to provide evidence that public health policies should include dental case management especially for IDD participants living in the community. Additionally this study may show that a behavioral intervention targeting caregivers could produce a greater impact on oral health outcomes in other dependent populations. In the long term we hope this research can develop evidence for an oral health intervention for caregivers of cognitively impaired persons. We believe oral health can be positively impacted preventing poor oral health and oral health related quality of life and possibly respiratory infections in these vulnerable populations. Moreover if future studies show that oral health outcomes are positively impacted by this intervention then the overall healthcare cost could be reduced because cognitively impaired individuals will have less need for expensive procedures resulting from lack of proper oral health behaviors.

project_terms:
Address;Administrator;Advocate;Applications Grants;Aspiration Pneumonia;Behavior;Behavior Therapy;Behavioral;Behavioral Research;Caregivers;Caring;Case Management;Case Manager;Child;Clinical Trials;Communities;Consent;Data;Data Analyses;Data Collection;Dental;Dental Care;Dental Hygiene;Dentists;Developmental Disabilities;Disabled Persons;Disadvantaged;Ensure;Evaluation Research;Exhibits;Family;Future;General Population;Geographic Locations;Grant;Group Homes;Health;Health Care Costs;Health Care Reform;Health Planning;Health Policy;Health Services;Health Services Accessibility;Health Status;Health behavior;Home environment;Housing;Human Resources;Impaired cognition;Individual;Institution;Institutional Review Boards;Insurance;Intervention;Intervention Trial;Kentucky;Learning;Letters;Life;Manuals;Measurement;Measures;Mediator of activation protein;Medicaid;Medical;Methodology;Methods;Modeling;Monitor;Oral Examination;Oral health;Outcome;Outcome Measure;Outcome Study;Parents;Participant;Patients;Periodontal Diseases;Persons;Pilot Projects;Population;Preparation;Preventive;Procedures;Process;Process Measure;Protocols documentation;Psychosocial Factor;Quality of life;Randomized;Randomized Controlled Trials;Recruitment Activity;Reporting;Research;Research Institute;Respiratory Tract Infections;Risk;Safety;Sample Size;Sampling;Sedation procedure;Site;Support Groups;Target Populations;Testing;Tooth structure;U-Series Cooperative Agreements;Universities;Validity and Reliability;Vulnerable Populations;base;community setting;developmentally disabled;effective intervention;health disparity;health literacy;health related quality of life;improved;intervention effect;member;operation;prevent;public health medicine (field);respiratory;social;success;theories

public_health_relevance:
In the short term the results of the proposed study have the potential to provide evidence that public health policies should include dental case management especially for IDD participants living in the community. Additionally this study may show that a behavioral intervention targeting caregivers could produce a greater impact on oral health outcomes in other dependent populations. In the long term we hope this research can develop evidence for an oral health intervention for caregivers of cognitively impaired persons. We believe oral health can be positively impacted preventing poor oral health and oral health related quality of life and possibly respiratory infections in these vulnerable populations. Moreover if future studies show that oral health outcomes are positively impacted by this intervention then the overall healthcare cost could be reduced because cognitively impaired individuals will have less need for expensive procedures resulting from lack of proper oral health behaviors.


application_id: 8210950
project_number: 5R01DA025032-04
project_title: Agonist Replacement Therapy for Methamphetamine Dependence: Human Lab Studies
administering_ic: NIDA
award_notice_date: 2012-01-27
opportunity_number: PA-07-333
application_type: 5
activity_code: R01
ic: DA
serial_number: 025032
program_official: HAMPSON, AIDAN
project_start_date: 2009-01-01
project_end_date: 2013-12-31
study_section: ZDA1-MXH-H(20)
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Methamphetamine dependence is a significant public-health concern. The results of clinical trials suggest that agonist replacement therapies (e.g. d-amphetamine) may be effective for methamphetamine dependence. The present project has three specific aims. The first specific aim is to demonstrate the safety tolerability and behavioral effects of intranasal methamphetamine in humans maintained on d-amphetamine. To accomplish this aim we will conduct one experiment in which non-treatment seeking volunteers with recent histories of illicit stimulant use will receive ascending doses of intranasal methamphetamine while maintained on increasing doses of d-amphetamine (Exp. 1). Cardiovascular indices will be used to determine the safety and tolerability of the d-amphetamine-methamphetamine combinations while subjective-effect questionnaires will be used to characterize the behavioral effects. The results of this experiment will guide the selection of doses to be tested in subsequent studies. The second specific aim is to demonstrate that d-amphetamine maintenance attenuates the reinforcing effects of methamphetamine. To accomplish this aim we will determine the reinforcing effects of intranasal methamphetamine during d-amphetamine maintenance using a progressive-ratio procedure (Exp. 2). Pharmacotherapies that attenuate the reinforcing effects of methamphetamine may be effective for initiating abstinence. The third specific aim is to demonstrate that d-amphetamine maintenance attenuates the discriminative-stimulus effects of methamphetamine. To accomplish this aim volunteers will learn to discriminate intranasal methamphetamine (Exp. 3). The discriminative effects of methamphetamine may be involved in relapse to drug-taking behavior in that an initial dose (i.e. a lapse) may function as a discriminative stimulus signaling the availability of more drug. Pharmacotherapies that attenuate the discriminative-stimulus effects of methamphetamine may be effective for preventing relapse. The proposed research will provide important additional clinical information regarding the efficacy of agonist replacement therapies for methamphetamine dependence. By using two sophisticated human laboratory procedures one to model abstinence initiation (i.e. drug self-administration) and the other to model relapse prevention (i.e. drug discrimination) the proposed research will determine the mechanisms that mediate the clinical efficacy of d-amphetamine for methamphetamine dependence. By inference then the proposed research will identify the optimal conditions under which d-amphetamine would be effective as a pharmacotherapy for methamphetamine dependence (i.e. initiate abstinence or prevent relapse). Finally because d-amphetamine reduces methamphetamine use these clinical findings can be used as a reference to determine the predictive validity of human laboratory procedures. Identifying procedures for assessing the efficacy of putative pharmacotherapies via a "beside-to-bench" or "reverse engineering" strategy is important because human laboratory studies can be conducted more rapidly and efficiently than clinical trials. PUBLIC HEALTH RELEVANCE: Methamphetamine dependence is a significant public health concern. The proposed research will provide important clinical information regarding the efficacy of agonist replacement therapy for methamphetamine dependence. The proposed research will also identify the optimal conditions under which d-amphetamine would be effective as a pharmacotherapy for methamphetamine dependence (i.e. initiate abstinence or prevent relapse). Finally the proposed research will determine appropriate human laboratory procedures for testing pharmacotherapies for methamphetamine dependence. Identifying appropriate human laboratory procedures for assessing the efficacy of pharmacotherapies for methamphetamine dependence is important because laboratory studies can be conducted more rapidly and efficiently than clinical trials.

project_terms:
Abstinence;Admission activity;Agonist;American;Attenuated;Behavior;Behavioral;Behavioral Mechanisms;Cardiovascular system;Clinical;Clinical Trials;Cocaine;Cocaine Dependences;Cocaine Users;Dextroamphetamine;Dose;Educational process of instructing;Engineering;Epidemiology;Goals;Great Lakes Region;Health;Human;Institution;Intelligence;Kentucky;Laboratories;Laboratory Animals;Laboratory Procedures;Laboratory Study;Learning;Location;Maintenance;Mediating;Methadone;Methamphetamine;Methamphetamine dependence;Methods;Modeling;Nicotine Dependence;Opiate Addiction;Pharmaceutical Preparations;Pharmacotherapy;Placebos;Procedures;Psychostimulant dependence;Questionnaires;Recording of previous events;Relapse;Replacement Therapy;Reporting;Research;Safety;Self Administration;Signal Transduction;Stimulus;Testing;Uncertainty;bench to bedside;clinical effect;clinical efficacy;design;disorder later incidence prevention;drug abstinence;drug discrimination;effective therapy;indexing;methamphetamine abuse;nicotine replacement;novel;preclinical study;prevent;public health medicine (field);research study;volunteer


application_id: 8210894
project_number: 5R01CA138623-04
project_title: Role of leukotriene B4 receptors in the interplay of inflammation and infection
administering_ic: NCI
award_notice_date: 2012-02-24
opportunity_number: PA-07-256
application_type: 5
activity_code: R01
ic: CA
serial_number: 138623
program_official: HOWCROFT, THOMAS K
project_start_date: 2009-04-01
project_end_date: 2014-01-31
study_section: Gastrointestinal Mucosal Pathobiology Study Section[GMPB]
contact_pi_person_id: 6074575
contact_pi: BODDULURI, HARIBABU
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): Colon cancer is a leading cause of cancer related deaths in the United States. Exposure to a number of hazardous environmental agents and consumption of the Western diet are known to contribute to the pathogenesis of malignant colon cancer. While chronic inflammation is known to be a major promoter of tumor development the role of gut microflora in contributing to the colon cancer is unknown. Our laboratory has identified leukotriene B4 receptor BLT1 as a major regulator of inflammation and host response to infections. In a mouse model of spontaneous intestinal cancer (ApcMin/+) we have made the observation that absence of BLT1 greatly enhances intestinal tumor development. This has led to the central hypothesis that Absence of BLT1 enhances colon tumor development by defective immune surveillance and/or altered microbial gut homeostasis. This apparently paradoxical result that loss of a proinflammatory mediator increases inflammation and tumor development suggests that the ever changing micro environment of intestine can have a major influence on the development of colorectal cancer. The current proposal will test this hypothesis in three specific aims. In aim 1 we will examine the mechanisms of leukotriene B4 pathway mediated protection of intestinal cancers in ApcMin/+ mice. Aim 2 will establish the immune functions in tumor bearing mice in the context of BLT1+/+ and BLT1-/- mice. Aim 3 will test the novel concept that defective host response and altered gut microbiota are responsible for rapid development of colon tumors in BLT1-/- mice. These studies will provide a comprehensive model system to examine the interplay of inflammation and infections to the development of colon cancer. Since the mouse ApcMin/+ model is highly related to human colon cancers the result will have direct and immediate impact for the treatment of human colon cancer. PUBLIC HEALTH RELEVANCE: Leukotrienes are involved in the pathophysiology of many acute and chronic inflammatory diseases such as systemic anaphylaxis asthma atherosclerosis and arthritis. The novel finding that leukotriene B4-leukotriene B4 receptor1 axis may have a protective function in the development of colon cancer offers a unique opportunity to understand the role of these mediators in tumor development. Understanding the precise function of distinct leukotriene B4 receptors in mice and defining the role of these receptors in host defense and shaping the gut microflora will provide novel approaches to the treatment of colon cancer.

project_terms:
APC gene;Acute;Adoptive Transfer;Affinity;Anaphylaxis;Antibiotics;Arthritis;Asthma;Atherosclerosis;Azoxymethane;Biological Models;Bone Marrow;Cancer Etiology;Cancer Model;Cells;Cessation of life;Chimera organism;Chronic;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Consumption;Defect;Development;Diet;Disease;Environment;Environmental Risk Factor;Event;Exposure to;Functional disorder;Genes;Health;Homeostasis;Host Defense;Human;Immune;Immune System Diseases;Immune response;Immune system;Immunologic Surveillance;Infection;Infiltration;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory disease of the intestine;Integration Host Factors;Intestinal Cancer;Intestinal Neoplasms;Intestines;LTB4R gene;Laboratories;Leukotriene B4;Leukotriene B4 Receptors;Leukotrienes;Link;Malignant - descriptor;Malignant Neoplasms;Mediating;Mediator of activation protein;Modeling;Molecular Carcinogenesis;Mus;Mutation;Pathogenesis;Pathway interactions;Phenotype;Play;Process;Proteins;Role;Shapes;Sodium Dextran Sulfate;Testing;Toll-Like Receptor Pathway;Transgenic Mice;Tumor Promoters;United States;Variation (Genetics);airway hyperresponsiveness;base;body system;cell type;environmental agent;gut microbiota;gut microflora;immune function;mRNA Expression;microbial;microbial colonization;microbicide;microorganism interaction;mouse model;novel;novel strategies;protein expression;receptor;tumor

public_health_relevance:
Project NarrativeLeukotrienes are involved in the pathophysiology of many acute and chronic inflammatory diseases such assystemic anaphylaxis asthma atherosclerosis and arthritis. The novel finding that leukotriene B4-leukotrieneB4 receptor1 axis may have a protective function in the development of colon cancer offers a uniqueopportunity to understand the role of these mediators in tumor development. Understanding the precisefunction of distinct leukotriene B4 receptors in mice and defining the role of these receptors in host defense andshaping the gut microflora will provide novel approaches to the treatment of colon cancer.


application_id: 8209253
project_number: 5R01AR049010-08
project_title: Microsomal Prostaglandin E Synthase in Rheumatoid Arthritis
administering_ic: NIAMS
award_notice_date: 2012-02-07
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AR
serial_number: 049010
program_official: MAO, SU-YAU
project_start_date: 2004-09-29
project_end_date: 2014-12-31
study_section: Arthritis, Connective Tissue and Skin Study Section[ACTS]
contact_pi_person_id: 1888793
contact_pi: CROFFORD, LESLIE J
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The effectiveness of non-specific and cyclooxygenase (COX)-2-specific non-steroidal anti-inflammatory drugs for treatment of the pain swelling and stiffness of arthritis provides clinical evidence that increased prostaglandin (PG) production is an important contributor to the disease process. PG biosynthesis requires the sequential action of COX-1 or COX-2 and terminal synthases to generate PGs that function as pleiotropic mediators by acting on a variety of cell surface receptors. After stimulation with pro-inflammatory cytokines there is a preferential increase of PGE2 in many different cell types and tissues including the synovium. We demonstrated that increased PGE2 in these tissues requires the inducible PGE synthase microsomal PGE synthase (mPGES)-1. We have also shown that absence of mPGES-1 results in a shift of the PG profile of cells and tissues with the specific profile dependent on the other synthases present. For this reason absence or inhibition of mPGES-1 is a markedly different biology than absence or inhibition of COX. The overall goal of this proposal is to characterize the role of mPGES-1 in immune inflammatory arthritis and how it differs from the role of COX-2. We hypothesize that upregulated mPGES-1 is required for the production of PGE2 and that its specific absence or inhibition results in an altered eicosanoid profile that fundamentally changes the immune inflammatory response. To evaluate this hypothesis we will make use of mice genetically deficient in mPGES-1 (Dba1/LacJ.mPGES-1 -/-) and inhibition of mPGES-1 using a specific inhibitor with activity in humans and mice (AF3485). We will determine the role for mPGES-1-derived PGE2 in comparison with other eicosanoids for initiation and progression of inflammation and immunity. We will determine the specific role of mPGES-1 deficiency for the developing immune response. Having shown profound differences in T- dependent humoral immune responses and in the Th phenotype we will determine the mechanism by which mPGES-1 deficiency leads to these changes. In order to translate these findings we will evaluate the differences between COX inhibition and mPGES-1 inhibition in human immune and inflammatory responses. We will determine effects of different compounds that inhibit PG production on T-helper phenotype and induced T-regulatory cells. These data will provide the scientific basis by which to determine if mPGES-1 is an appropriate target for therapeutic intervention in arthritis.    PUBLIC HEALTH RELEVANCE: The discovery of COX-2 and subsequent development of specific COX-2 inhibitors represented an enormous conceptual advance in eicosanoid biology and opened new possibilities for pharmacologic treatment of inflammation and pain. It is clear however that COX-2-specific NSAIDs have their own toxicities. The finding of a PGE synthase isoform induced during inflammation and required for high level PGE2 production represents a conceptual advance of similar magnitude. In view of the existence of multiple PGES enzymes and other PG subclasses the specific role of mPGES-1-derived PGE2 in inflammation and autoimmunity remains uncertain. Furthermore information on the biology that will inform the development of mPGES-1 as a therapeutic target remains incomplete. It is our expectation that our work will yield new insights into the role of PGs in the functioning of eicosanoids during initiation and resolution of inflammation and the transition from the innate to the acquired immune response.

project_terms:
9-deoxy-delta-9-prostaglandin D2;Acute;Alprostadil;Anabolism;Aneurysm;Anti-Inflammatory Agents;Anti-inflammatory;Antibodies;Antigen Presentation;Arachidonic Acids;Arthritis;Autoimmune Process;Autoimmunity;Back;Biology;Blood Platelets;Blood Vessels;Bone Marrow;CD4 Positive T Lymphocytes;Cardiovascular system;Cell Surface Receptors;Cell physiology;Cell surface;Cells;Chimera organism;Clinical;Clinical Data;Clinical Trials;Collagen;Collagen Arthritis;Collagen Type II;Coxibs;Cytokine Signaling;Data;Dendritic Cells;Development;Dinoprostone;Disease;Effectiveness;Effector Cell;Eicosanoids;Embryo;Enzymes;Epoprostenol;Equilibrium;Event;Exhibits;Failure (biologic function);Fever;Fibroblasts;Generations;Genetic;Goals;Hematopoietic;Homeostasis;Human;Immune;Immune response;Immunity;Inflammation;Inflammatory;Inflammatory Response;Interleukin-12;Interleukin-17;K/BxN model;Knockout Mice;Lead;Learning;Leukotriene B4;Lipids;Literature;Lymphocyte;Matrix Metalloproteinases;Mediator of activation protein;Mesenchymal;Modeling;Mus;Pain;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Phenotype;Phospholipase A2;Phospholipids;Play;Process;Production;Property;Prostaglandin D2;Prostaglandin H2;Prostaglandin Production;Prostaglandin-Endoperoxide Synthase;Prostaglandins;Protein Isoforms;Regulatory T-Lymphocyte;Resistance;Resolution;Rheumatoid Arthritis;Risk;Role;Serum;Shunt Device;Small Interfering RNA;Stimulus;Swelling;Synovial Membrane;T-Cell Receptor;T-Lymphocyte;Therapeutic;Therapeutic Intervention;Tissues;Toxic effect;Transgenic Mice;Translating;Up-Regulation (Physiology);Work;analog;base;cell type;cyclooxygenase 1;cyclooxygenase 2;cytokine;expectation;gastrointestinal;human NOS2A protein;immunoregulation;inhibitor/antagonist;insight;mouse PGE synthase 1;peripheral blood;pre-clinical;prostaglandin E synthase;public health relevance;research study;response;therapeutic target

public_health_relevance:
PROJECT NARRATIVEThe discovery of COX-2 and subsequent development of specific COX-2 inhibitorsrepresented an enormous conceptual advance in eicosanoid biology and opened newpossibilities for pharmacologic treatment of inflammation and pain. It is clear howeverthat COX-2-specific NSAIDs have their own toxicities. The finding of a PGE synthaseisoform induced during inflammation and required for high level PGE2 productionrepresents a conceptual advance of similar magnitude. In view of the existence ofmultiple PGES enzymes and other PG subclasses the specific role of mPGES-1-derivedPGE2 in inflammation and autoimmunity remains uncertain. Furthermore information onthe biology that will inform the development of mPGES-1 as a therapeutic target remainsincomplete. It is our expectation that our work will yield new insights into the role of PGsin the functioning of eicosanoids during initiation and resolution of inflammation and thetransition from the innate to the acquired immune response.


application_id: 8209084
project_number: 5R03MH087448-02
project_title: A Cell-Based HTS to Discover Molecules that Inhibit VEEV Replication
administering_ic: NIMH
award_notice_date: 2011-12-23
opportunity_number: PAR-09-129
application_type: 5
activity_code: R03
ic: MH
serial_number: 087448
program_official: YAO, YONG
project_start_date: 2011-01-01
project_end_date: 2013-04-30
study_section: Special Emphasis Panel[ZRG1-BST-F(50)R]
contact_pi_person_id: 9658299
contact_pi: CHUNG, DONGHOON
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):  This project seeks to discover small molecules active in inhibiting replication of Venezuelan Equine Encephalitis Viruses (VEEV) by utilizing a high throughput screening (HTS) campaign from the Molecular Library Program Center Network (MLPCN). VEEV an encephalitic alphavirus is listed as a select agent for its ability to cause severe disease during epidemics as well as its potential use a bioterror weapon. However there is no FDA-approved treatment or prophylaxis of VEEV-related diseases at this time. Antiviral drug discovery for select agents has been impractical due to restrictions on handling the agents. Progress has been made toward the goal of efficacious treatment by developing a robust cytopathic effect (CPE)-based assay employing an attenuated VEEV strain TC-83. The attenuated strain is not a select agent and can be handled in a BSL-2 lab. Because the attenuated strain has a significantly high homology between its genome sequence and the wild type VEEV I hypothesize that the anti-viral compounds screened through this assay would be active for wild type VEEV as well. Thus the result of achieving the specific aims will be assays that can be used as a primary screen to discover active compounds from the Molecular Libraries Small Molecule Repository (MLSMR) library and the follow-up studies to verify activities for the attenuated and wild type virus strains. The first specific aim will be to screen the MLSMR library with a verified cell-based assay measuring CPE caused by VEEV strain TC-83 as a primary HTS. The second specific aim will be to verify the selected compounds from the primary screen in two ways 1) a dose-response cytotoxicity and efficacy assay and 2) re-screening with second attenuated strain V3526 which has a higher similarity with wild types. Finally a third battery of assays will be provided those are crucial for developing and characterizing chemical probes. The selected compounds will be subsequently verified using titer reduction assays with the wild-type strain V3000. Last for the compounds selected as probes mode of action studies will be performed with reporter- based molecular and biochemical assays. The screening pathway provided here may identify novel chemical scaffolds that can be pursued as therapeutics for encephalitic alphavirus infections including Eastern or Western equine encephalitis viruses. . Hence successful outcomes from this project will benefit the public and military a goal that aligns with the MLPCN and the NIH.    PUBLIC HEALTH RELEVANCE: Venezuelan Equine Encephalitis Virus (VEEV) is transmitted to humans and equine by mosquitoes and represents neuroinvasive diseasees. In general disease is rare in US however epizootic strains of VEEV infected horses and approximately 70000 ~ 100000 people in South America in last epidemics in 1995 - 1996. There have also been reports of aerosol transmission of VEEV. VEEV has been weaponized and is a CDC/NIAID category B select agent for biodefense research. Despite of the importance in medical and bioterror needs there are no treatments for VEEV infection. There is a need for new assays to identify compounds that inhibit VEEV replication. This work represents an unmet medical need for re-emerging viruses which has classified as a select agent. Of importance Western Eastern and Venezuelan equine encephalitis viruses are close in a phylogenetic analysis therefore successful outcomes from the proposed project will enlighten the way of discover potential therapeutics for important select agents which are closely related each other.

project_terms:
Aerosols;Alphavirus;Alphavirus Infections;Animal Model;Antiviral Agents;Attenuated;Base Pairing;Biochemical;Biological Assay;Categories;Cell Death;Cell Survival;Cells;Centers for Disease Control and Prevention (U.S.);Chemicals;Collaborations;Culicidae;Disease;Docking;Dose;Epidemic;Equus caballus;Escherichia coli;Evaluation;FDA approved;Genes;Goals;Human;Image;In Vitro;Inhibitory Concentration 50;Libraries;Luc Gene;Measures;Medical;Methods;Military Personnel;Modeling;Molecular;Molecular Bank;Mutation;National Institute of Allergy and Infectious Disease;Outcome;Pathway interactions;Peptide Hydrolases;Phylogenetic Analysis;Polymerase Chain Reaction;Process;Prophylactic treatment;Proteins;Reading;Reporter;Reporting;Research;Screening procedure;Series;South America;Specificity;System;Testing;Therapeutic;Time;Toxic effect;United States National Institutes of Health;Universities;Validation;Venezuelan Equine Encephalitis Virus;Viral;Viral Physiology;Viral Proteins;Viral load measurement;Virus;Virus Diseases;Virus Replication;Western Equine Encephalitis Virus;Work;anti-viral efficacy;base;biodefense;cytotoxicity;drug discovery;efficacy testing;epizootic;fluoromethyl 22-difluoro-1-(trifluoromethyl)vinyl ether;follow-up;genome sequencing;high throughput screening;in vivo;inhibitor/antagonist;luminescence;novel;programs;public health medicine (field);public health relevance;repository;response;scaffold;small molecule;transmission process;weapons

public_health_relevance:
PROJECT NARRATIVEVenezuelan Equine Encephalitis Virus (VEEV) is transmitted to humans and equine by mosquitoes andrepresents neuroinvasive diseasees . In general disease is rare in US however epizootic strains of VEEVinfected horses and approximately 70000 ~ 100000 people in South America in last epidemics in 1995 -1996. There have also been reports of aerosol transmission of VEEV. VEEV has been weaponized and is aCDC/NIAID category B select agent for biodefense research. Despite of the importance in medical andbioterror needs there are no treatments for VEEV infection. There is a need for new assays to identifycompounds that inhibit VEEV replication. This work represents an unmet medical need for re-emerging viruseswhich has classified as a select agent. Of importance Western Eastern and Venezuelan equine encephalitisviruses are close in a phylogenetic analysis therefore successful outcomes from the proposed project willenlighten the way of discover potential therapeutics for important select agents which are closely related eachother.


application_id: 8209012
project_number: 5R01DK090460-02
project_title: Maternal Exercise Protects Offspring from Obesity and Insulin Resistance
administering_ic: NIDDK
award_notice_date: 2011-11-18
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: DK
serial_number: 090460
program_official: SILVA, CORINNE M
project_start_date: 2011-01-01
project_end_date: 2015-12-31
study_section: Integrative Physiology of Obesity and Diabetes Study Section[IPOD]
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
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 intrauterine environment affects the development of the growing embryo and an unsuitable environment can lead to termination of pregnancy. However emerging research has shown that more subtle factors can potentially influence long-term health in the offspring. For instance malnourished pregnant mothers produce smaller offspring that have a higher incidence of obesity diabetes and heart disease during adulthood. To this point most published studies have focused on negative changes in offspring caused by detrimental diets or stressful behavior. However in the Western world maternal obesity is an ever-increasing problem and epidemiology studies are now pointing to metabolic derangements in their offspring. In an attempt to be pro-active maternal voluntary exercise during pregnancy was chosen as a potential short-term intervention to improve health outcomes in offspring. Fasting circulating glucose and insulin levels were lower in offspring born to exercised dams compared to those born to non-exercised dams and glucose disposal and insulin sensitivity were significantly improved. As a result our hypothesis for this proposal is that maternal voluntary exercise during pregnancy and nursing will improve glucose regulation and decrease obesity and hypertension in offspring. The first aim is designed to determine whether maternal voluntary exercise can improve insulin sensitivity in offspring fed a normal standard diet and protect against obesity insulin resistance and hypertension progression in high calorie diet-fed offspring. The second aim hopes to elucidate the mechanism for long-lasting insulin sensitivity in offspring born to exercised dams which is likely through enhanced insulin signaling. The third aim will determine whether maternal exercise can be used as an intervention to improve pathology outcomes in offspring resulting from maternal consumption of a high calorie diet or gestational diabetes mellitus. To explore these aims female mice will be placed into sedentary or voluntary exercise groups. The exercise dams will have 24 hour access to running wheels before mating and throughout pregnancy and nursing. The maturing offspring will not have access to running wheels for any portion of the study. Obesity glucose and insulin tolerance and hypertension will be monitored in the offspring fed either standard or high calorie diet. These studies will provide important information on the potential positive impact maternal exercise can have on offspring health. Obesity diabetes and cardiovascular disease are at epidemic levels and interventions targeting gestation might be an efficient way to stem the tide.    PUBLIC HEALTH RELEVANCE:  Exercise is currently used as a treatment for gestational diabetes but the long-term influence of this intervention on offspring health has been ignored. The proposed studies will provide novel information on whether maternal exercise can be used as an intervention to decrease obesity diabetes and hypertension development in offspring. Maternal exercise during pregnancy is a very realistic intervention that may provide a lifetime of benefits for the next generation.

project_terms:
Acetylation;Adult;Adult Children;Affect;Age;Behavior;Biological Assay;Blood Pressure;Body Composition;Cardiovascular Diseases;Commit;Consumption;CpG Islands;Development;Diabetes Mellitus;Diet;Discipline of Nursing;Disease;Embryo;Environment;Epidemic;Epigenetic Process;Exercise;Fasting;Female;Genes;Gestational Diabetes;Glucokinase;Glucose;Glucose Transporter;Health;Heart Diseases;Histone Acetylation;Home environment;Hour;Human;Hypertension;Incidence;Injection of therapeutic agent;Insulin;Insulin Receptor;Insulin Resistance;Insulin Signaling Pathway;Intervention;Laboratories;Lead;Liver;Longevity;Measures;Metabolic;Methylation;Modeling;Monitor;Mothers;Motor;Mus;Obese Mice;Obesity;Outcome;Parents;Partner in relationship;Pathology;Pathway interactions;Performance;Phenotype;Phosphorylation;Pilot Projects;Population;Pregnancy;Probability;Promoter Regions (Genetics);Proteins;Publishing;Research;Role;Running;Skeletal muscle structure;Termination of pregnancy;Testing;Tissues;Ursidae Family;Very Light Exercise;Western World;blood glucose regulation;design;epidemiology study;fasting glucose;feeding;glucose disposal;glucose tolerance;glucose-6-phosphatase;improved;insulin sensitivity;insulin signaling;insulin tolerance;leptin receptor;next generation;novel;offspring;pregnant;programs;protein expression;public health relevance;response;sedentary;stem;trend;unborn child

public_health_relevance:
PROJECT NARRATIVE:Exercise is currently used as a treatment for gestational diabetes but the long-term influence of thisintervention on offspring health has been ignored. The proposed studies will provide novel information onwhether maternal exercise can be used as an intervention to decrease obesity diabetes and hypertensiondevelopment in offspring. Maternal exercise during pregnancy is a very realistic intervention that may provide alifetime of benefits for the next generation.


