# projects

application_id: 8055392
project_number: 5R01DE017680-05
project_title: P. gingivalis: Role of GSK3 in Host Inflammation
administering_ic: NIDCR
award_notice_date: 2011-02-17
application_type: 5
activity_code: R01
ic: DE
serial_number: 017680
program_official: BURGOON, PENNY W
project_start_date: 2007-04-25
project_end_date: 2012-03-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7338645
contact_pi: SCOTT, DAVID A
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
budget_start_date: 2011-04-01
project_abstract:
DESCRIPTION (provided by applicant):  The host immune response to periodontal-associated pathogens has been shown to be a key determinant involved in periodontal disease by regulating the production of pro- and anti-inflammatory cytokines that regulate the severity of this disease. An inability to regulate the nature or duration of the host's inflammatory response can often mediate detrimental host effects as observed in chronic inflammatory diseases. Our laboratory has identified the kinase glycogen synthase kinase 3 (GSK3) as a central regulator of the inflammatory process by its ability to differentially regulate the levels of pro- and anti-inflammatory cytokines upon TLR activation. Our specific hypothesis is that the ability of P. gingivalis to interact with TLR2 and TLR4 expressed on immune cells and the subsequent differential regulation of GSK3 activity mediated by these TLRs are major mechanisms responsible for the pathogenesis of this organism by regulating the nature and magnitude of the host's inflammatory response. This hypothesis is based on: 1) stimulation of immune cells from TLR2- or TLR4-deficient mice with P. gingivalis resulted in pronounced differences in the inhibition of GSK3; 2) inhibition of GSK3 in macrophages or dendritic cells stimulated with P. gingivalis resulted in the severe reduction in the levels of pro-inflammatory cytokines i.e. IL-12 while concurrently augmenting the levels of the anti-inflammatory cytokine IL-10; 3) a direct comparison of TLR2- and TLR4- deficient cells stimulated with P. gingivalis demonstrated that the levels of pro-inflammatory cytokines such as IL-12 were largely mediated by TLR4 whereas the levels of the anti-inflammatory cytokine IL-10 were predominantly mediated by TLR2; 4) analysis of the two major isoforms of GSK3 in innate immune cells revealed that dendritic cells contain only detectable levels of GSKS-p whereas macrophages contain both isoforms of GSK3 GSK3-a and GSK3-p; 5) in vivo administration of a GSK3 inhibitor resulted in a potent reduction in the levels of IL-1b IL-6 IL-12 and IFN-y whereas the levels of the anti-inflammatory cytokine IL-10 were potently augmented in response to P. gingivalis; and 6) inhibition of GSK3 in mice resulted in a predominant Th2-assoicated immune response to P. gingivalis. These observations provide a strong rationale and focus concerning the reported differences of TLR2 and TLR4 to mediate pro- and anti- inflammatory cytokine responses and elucidate a critical role for the GSK3 cell-signaling pathway in modulating the host's inflammatory response to P. gingivalis. The specific aims are designed to characterize how host-microbial interactions are involved in the regulation of the host inflammatory response to P. gingivalis. to elucidate and characterize the involvement of GSK3 in regulating these immune responses and to evaluate the efficacy of a therapeutic target (GSK3) that could attenuate the disease process in vivo.

project_terms:
Abscess;Affect;Alveolar Bone Loss;Anti-Inflammatory Agents;Anti-inflammatory;Attenuated;Cell Nucleus;Cell surface;Cells;Chronic;Dendritic Cells;Disease;Event;Foundations;Gene Expression;Glycogen Synthase Kinase 3;Host Defense;Immune;Immune response;Immune system;Immunity;Inflammation;Inflammatory;Inflammatory Response;Interferons;Interleukin-1;Interleukin-10;Interleukin-12;Interleukin-6;Invaded;Laboratories;Mediating;Microbe;Modeling;Mus;Nature;Organism;Pathogenesis;Pathway interactions;Periodontal Diseases;Phosphotransferases;Play;Porphyromonas gingivalis;Principal Investigator;Process;Production;Property;Protein Isoforms;Receptor Activation;Receptor Signaling;Regulation;Reporting;Role;Severity of illness;Signal Pathway;Signal Transduction;Signaling Molecule;Solid;TLR2 gene;TLR4 gene;Toll-like receptors;base;cytokine;design;in vivo;inhibitor/antagonist;macrophage;microorganism interaction;mouse model;pathogen;programs;response;therapeutic target


application_id: 8055351
project_number: 5R01EY018836-04
project_title: Intrinsic anti-angiogenic activity of siRNA
administering_ic: NEI
award_notice_date: 2011-05-18
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 018836
program_official: SHEN, GRACE L
project_start_date: 2008-04-01
project_end_date: 2013-03-30
study_section: Special Emphasis Panel[ZRG1-CB-G(90)S]
contact_pi_person_id: 2446639
contact_pi: AMBATI, JAYAKRISHNA
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The discovery of RNA interference (RNAi) and its potential to silence any gene of interest via the RNA-induced silencing complex (RISC) has revolutionized modern genetics and launched a new class of therapeutics termed short interfering RNA (siRNA). The first clinical trials of siRNA were initiated in patients with choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) which is the leading cause of blindness among the elderly in industrialized world and afflicts more people in the United States than all cancers combined. In new and exciting recent work we made the surprising discovery that siRNAs uniformly suppress experimental CNV in mice independent of RNAi. We found that that siRNAs against non- mammalian genes genes not expressed in the eye or random sequences without homology to any known gene all suppressed CNV as did a modified siRNA incapable of RISC incorporation. This novel class effect was mediated via activation of toll like receptor-3 (TLR3) and its adaptor protein TRIF and induction of interferon-3 and interleukin-12. Interestingly siRNAs targeting vascular endothelial growth factor (VEGF)-A or its receptor VEGFR-1 which are in Phase II clinical trials also suppressed CNV via TLR3 activation and not cognate transcript knockdown. We will test the hypothesis that both targeted and non-targeted siRNAs activate TLR3 by direct interaction and trigger a cellular program of vascular growth suppression. The specific aims of this proposal are to further define the interaction between siRNA and TLR3 determine the precise anti-angiogenic mechanisms of siRNA-induced CNV suppression in mice and test the efficacy of non-targeted siRNA in a non-human primate model of CNV. These studies will provide clarifying insights into the mechanisms underlying unanticipated siRNA activities in vivo define the molecular architecture governing this intersection of vascular biology and innate immunity provide pharmacogenetic data that will enable personalized medicine in patients with TLR3 mutations and propel the development of new more affordable anti-angiogenic therapeutics for the public health epidemic that is AMD.Angiogenesis (the growth of abnormal blood vessels) is responsible for the majority of blindness in patients with age-related macular degeneration (AMD) which accounts for a lion's share of the annual $51 billion cost of blindness in the United States. The Nobel Prize winning discovery of RNA interference led to the development of short interfering RNA (siRNA) as a new class of targeted drugs which were first launched in clinical trials in AMD.   
  
Public Health Relevance: Our surprising discovery that all siRNAs have intrinsic anti-angiogenic activity has immediate and profound implications both for ongoing clinical trials and for treating the estimated 500 million people with diseases driven by angiogenesis.

project_terms:
2-thiouridine;Accounting;Adaptor Signaling Protein;Adopted;Affect;Age related macular degeneration;Angiogenesis Modulating Agents;Apoptosis;Architecture;Ascaridil;Biology;Blindness;Blood Vessels;Cell Proliferation;Cell surface;Cells;Chemicals;Choroidal Neovascularization;Cleaved cell;Clinical Trials;Complex;Data;Development;Disease;Double Stranded RNA Virus;Double-Stranded RNA;Drug Delivery Systems;Elderly;Endothelial Cells;Epidemic;Exudative age-related macular degeneration;Eye;Gene Mutation;Genes;Genetic;Goals;Growth;Immune;Immune response;Immune system;Incidence;Individual;Infiltration;Inhibition of Cell Proliferation;Interferons;Interleukin-12;Investigation;Kinetics;Laser injury;Lasers;Lead;Length;Leukocytes;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Mediator of activation protein;Medicine;Messenger RNA;Modeling;Modification;Molecular;Molecular Profiling;Mus;Mutation;Natural Immunity;Nature;Nobel Prize;Ophthalmology;Pathway interactions;Patients;Pharmacogenetics;Phase II Clinical Trials;Positioning Attribute;Prevalence;Process;Property;RNA;RNA Interference;RNA-Induced Silencing Complex;Retina;Role;Signal Pathway;Signal Transduction;Surface;System;Techniques;Testing;Therapeutic;Thrombospondin 1;Toxic effect;Transcript;United States;Vascular Endothelial Growth Factor A;Vascular Endothelial Growth Factor Receptor-1;Work;angiogenesis;chemokine;cost;design;efficacy testing;gene therapy;human DICER1 protein;human TLR3 protein;in vivo;insight;interest;mRNA Transcript Degradation;malignant breast neoplasm;mouse model;neovascular;nonhuman primate;novel;novel strategies;pigment epithelium-derived factor;programs;public health medicine (field);public health relevance;receptor;response;thrombospondin 2;tool


application_id: 8054787
project_number: 5R01HD023333-19
project_title: Listening Skills in children with and without cochlear implants
administering_ic: NICHD
award_notice_date: 2011-03-23
application_type: 5
activity_code: R01
ic: HD
serial_number: 023333
program_official: KAU, ALICE S
project_start_date: 1989-04-01
project_end_date: 2011-08-31
study_section: Auditory System Study Section[AUD]
contact_pi_person_id: 1963999
contact_pi: WIGHTMAN, FREDERIC L
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
budget_start_date: 2011-04-01
project_abstract:
DESCRIPTION (provided by applicant): The long term goal of this program is a complete understanding of the capabilities and limitations of auditory information processing in children the development of auditory processing skills and how that developmental course may be affected by hearing impairment deafness and the use of a cochlear mplant. The current focus of the project is on the strategies used by children to segregate desired auditory signals from interfering sounds. Results to date suggest that most young children display a remarkable nability to perform this segregation in simple detection tasks and in tasks requiring attention to a target speech message in the presence of other speech distracters. The data also reveal large individual differences in source segregation ability with some teenagers demonstrating child-like performance and some young school-aged children demonstrating adult-like performance. The adult-child differences are argely consistent with what iresults. The new work also addresses the special selective attention problems faced by children and adults with cochlear implants and evaluates strategies by which selective attention can be enhanced. Auditory selective attention is quantified in four kinds of tasks: 1) simple signal detection in which the target signal is masked by random multicomponent tonal complexes; 2) a speech fundamental frequency discrimination task; 3) speech recognition tasks both with and without a visual representation of the speaker; 4) spatial segregation tasks in which the target message and the distracter are spatially separated. The aim of the first task is to quantify auditory selective attention within the constraints of a simple one-parameter model. The second task will produce a scale of talker similarity which will then be used to predict the impact of talker similarity in the selective attention tasks. The third and fourth tasks explore means by which selective attention can be enhanced eithssessed. The overall importance of this project lies in its study of communication situations common in everyday life. Speech communication in noisy environments is an especially important issue for children who are developing speech and language and the results of this project will add important new knowledge about how children and adults are able to address this issue.

project_terms:
3 year old;Acoustics;Address;Adolescence;Adopted;Adult;Affect;Age;Algorithms;Attention;Auditory;Child;Child Development;Cochlear Implants;Communication;Complex;Cues;Data;Deafness;Dependence;Detection;Development;Discrimination (Psychology);Ear structure;Environment;External auditory canal structure;Failure (biologic function);Frequencies (time pattern);Funding;Goals;Hearing;Hearing Impaired Persons;Implant;Individual;Individual Differences;Knowledge;Laboratories;Language;Life;Lipreading;Masks;Measurable;Measurement;Measures;Modeling;Noise;Participant;Performance;Peripheral;Population;Positioning Attribute;Principal Investigator;Process;Publishing;Reading;Rehabilitation therapy;Relative (related person);Research;Resolution;School-Age Population;Signal Transduction;Simulate;Source;Speech;Stimulus;Techniques;Teenagers;Testing;Training;Uncertainty;Visual;Weight;Work;age effect;age related;base;expectation;hearing impairment;information processing;programs;research study;segregation;selective attention;simulation;skills;sound;speech recognition;stimulus processing;virtual


application_id: 8054187
project_number: 5F31MH089867-02
project_title: GABAergic Modulation of Pulvinar Projection Cells
administering_ic: NIMH
award_notice_date: 2011-03-18
opportunity_number: PA-09-208
application_type: 5
activity_code: F31
ic: MH
serial_number: 089867
program_official: PINARD, COURTNEY ROSE
project_start_date: 2010-04-01
project_end_date: 2012-01-01
study_section: Special Emphasis Panel[ZRG1-F02B-Y(20)L]
contact_pi_person_id: 9419270
contact_pi: DAY-BROWN, JONATHAN DAVID
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:
The function of the pulvinar nucleus is largely unexplored although it is thought to play a key role in visual attention and visual motion perception. Recently the pulvinar nucleus has gained attention because it has been found to be significantly smaller in schizophrenic brains when compared to controls and studies of patients with restricted lesions of the pulvinar nucleus exhibit some of the same visual deficits experienced by schizophrenic patients. Therefore further study of the pulvinar nucleus could shed light on brain circuits affected by schizophrenia. The proposed experiments focus on the physiological response properties and synaptic organization of the pulvinar nucleus and its projections to the striatum and amygdala with the goal of elucidating how these circuits are modulated by the neurotransmitter gamma amino butyric acid (GABA). Anatomical experiments will determine whether separate cell types project to the striatum and amygdala using tract tracing and confocal microscopy. Immunocytochemistry and electron microscopy will be used to compare the GABAergic innervation of pulvinar neurons that project to the striatum or amygdala and physiological experiments will compare the responses of these two cell types to moving visual stimuli in the presence or absence of the GABA receptor antagonist bicuculline. The proposed studies will use the tree shrew (Tupaia belangeri) which is considered to represent a prototype of early prosimian primates. Therefore our results should be easily related to primate brain organization and could shed light on human disorders such as schizophrenia.

project_terms:
Affect;Amygdaloid structure;Attention;Bicuculline;Binding (Molecular Function);Brain;Butyric Acids;Cell Nucleus;Cells;Cholera Toxin;Confocal Microscopy;Controlled Study;Corpus striatum structure;Disease;Dorsal;Electron Microscopy;Exhibits;Facial Expression;Goals;Human;Image;Infusion procedures;Injection of therapeutic agent;Label;Lesion;Light;Modeling;Motion Perception;Neurons;Neurotransmitters;Pathway interactions;Patients;Pattern;Physiological;Play;Primates;Property;Prosimii;Pulvinar structure;Saccades;Scandentia;Schizophrenia;Signal Transduction;Speed (motion);Staining method;Stains;Symptoms;Synapses;Techniques;Tracer;Tupaia;Tupaiidae;Visual;Visual Motion;Visual attention;cell type;experience;extracellular;immunocytochemistry;in vivo;nerve supply;prototype;receptive field;receptor;research study;response;retrograde transport;visual stimulus

public_health_relevance:
Studies of patients with restricted pulvinar lesions have revealed a wide array of visual deficits including the diminished ability to filter distracting signals difficulty in binding image features or difficulty in recognizing facial expressions. Because schizophrenic patients exhibit similar deficits and the pulvinar nucleus of schizophrenic patients has been shown to be smaller than that of control subjects our proposed studies could shed light on potential pulvinar pathways involved in symptoms of this disease.


application_id: 8053929
project_number: 5P42ES007380-14
project_title: Core E: Superfund Inter-Disciplinary Training Core
administering_ic: NIEHS
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 9008
contact_pi_person_id: 8534462
contact_pi: BACHAS, LEONIDAS G
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: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The environmental challenge posed by Superfund chemicals is of high magnitude and affects severalaspects of human life. The aim of the University of Kentucky Superfund Program is studying the effects ofnutrition on the toxicity of Superfund chemicals detection of these chemicals and their remediation. To solveany environmental problems the emerging researchers should have specific scientific training broadknowledge of different disciplines and be effective communicators. The Training Core plans to address thisneed through cross-disciplinary graduate education and a training program in environmental sciences. Thecollaboration of the Training Core with the individual projects and the other Cores of the UK-SBRP willexpose our trainees to both basic and applied research. In addition to their involvement in individualprojects trainees will be introduced to (a) proteomics EPA methods and Bioinformatics and SystemsBiology in Toxicology though workshops organized by the Research Support Core (Core B); (b) ResearchTranslation strategies through workshops and participation in the activities of the Research Translation Core(Core C); and (c) real environmental problems through participation in the activities of the CommunityOutreach Core in communities residing close to Superfund sites. The goals of the Training Core are (i) toprovide thorough training of students in their specific field (ii) to instill basic knowledge about socioeconomiclaw engineering and science aspects (iii) to enhance the ability of students to communicate with scientistsas well as non-scientists. In addition to providing student stipents the Training Core will make availabletravel funds to student trainees and postdoctoral scholars to present their Superfund-related research atscientific conferences. Emphasis will be placed on identifying and recruiting motivated individuals andstudents from underrepresented groups through brochures web page and presentations at minorityinstitutions. The Training Core program will be evaluated on a regular basis to assess the progress inmeeting the goals of the program. This will be accomplished by first evaluating the progress of the traineestoward their educational goals and second in terms of how the trainees view and value the program.

project_terms:
Address;Affect;Applied Research;Basic Science;Bioinformatics;Chemicals;Collaborations;Collection;Communication;Communities;Community Outreach;Community Participation;Complex;Detection;Dimensions;Discipline;Ecology;Economics;Educational Activities;Educational workshop;Effectiveness;Engineering;Environment;Ethics;Evaluation;Evaluation Methodology;Faculty;Funding;Generations;Goals;Graduate Education;Human;Individual;Institution;Interdisciplinary Study;Interview;Kentucky;Knowledge;Laws;Learning;Legal;Life;Mentors;Methods;Minority;Monitor;Nutritional;Pamphlets;Postdoctoral Fellow;Principal Investigator;Problem Solving;Process;Proteomics;Published Comment;Recruitment Activity;Research;Research Activity;Research Personnel;Research Project Grants;Research Support;Science;Scientist;Series;Societies;Students;Superfund;System;Systems Biology;Toxic effect;Toxicology;Training;Training Programs;Translational Research;Travel;Universities;base;college;environmental toxicology;interest;knowledge base;meetings;member;next generation;nutrition;outreach;programs;remediation;research and development;skills;social;socioeconomics;superfund chemical;superfund site;symposium;web page


application_id: 8053928
project_number: 5P42ES007380-14
project_title: Core D: Community Outreach Core (SCAN)
administering_ic: NIEHS
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 9007
contact_pi_person_id: 8535399
contact_pi: GAETKE, LISA M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Since 2000 UK's SBRP's Community Outreach Core has provided support and guidance through criticalinformation on nutrition and health-related issues to meet the needs of individuals and communities affectedby environmental contaminants. This purpose is underscored through its title Superfund Community Actionthrough Nutrition (SCAN). During previous funding SCAN established a close collaboration with communitygroups in eastern and western Kentucky and SCAN programs endorsed by these two communitiesprovided a new service resource for nutrition and scientific information. The aim of SCAN is to empoweraffected individuals and communities to take proactive steps toward their own health by drawing on thestrength of the nutrition-related research from UK's SBRP. The specific aims of SCAN include: 1) furtherdevelop and present SCAN nutrition and environmental health education programs for a new third site incentral Kentucky and the previously established community constituents; 2) further define SCAN's nutritioneducation message and enhanced recommendations that diets low in fat and high in phytonutrients mayreduce the toxicity of RGB's and related compounds as reported by UK SBRP's biomedical researchers; 3)develop new tangible qualitative outcome measures of SCAN programs as to improved knowledge andattitudes of health risks associated with exposure to environmental contaminants and the influence ofnutrition on these risks with consideration of sensitive issues such as community characteristics andpending litigation that may impede quantitative measures; 4) further establish trust with identified communityconstituents in order to provide advanced SCAN programs which show changes in nutrition and healthrelatedbehaviors. Results of SCAN programs will be used to assess the differences that diet and geo-socialcharacteristics play on nutrition and health issues and to design new diet strategies for individuals familiesand communities to enable them to optimize their health in the face of exposure to Superfund contaminants.Exposure to Superfund chemicals has been shown to affect public health by contributing to an increasedrisk for chronic diseases especially in combination with poor diet. UK's nutrition education programsdesigned with input from participants empower affected individuals to make more informed decisions abouttheir diet and health and are an important community service for Kentuckians in proximity to Superfund sites.

project_terms:
Affect;Anthropometry;Attitude to Health;Behavior;Body Composition;Characteristics;Chronic Disease;Collaborations;Communities;Community Actions;Community Outreach;Community Services;Diet;Diet Records;Dietitian;Educational aspects;Environmental Health;Environmental Pollution;Exercise;Exposure to;Face;Family;Fatty acid glycerol esters;Fiber;Food;Funding;Hazardous Waste Sites;Health;Health Knowledge Attitudes Practice;Health Professional;Health education;Individual;Intake;Kentucky;Knowledge;Litigation;Measures;Metabolic;Nutrition Assessment;Nutritional status;Outcome Measure;Participant;Pharmacists;Physicians;Play;Quality of life;Questionnaires;Recommendation;Reporting;Research;Research Personnel;Research Project Grants;Resources;Risk;Scanning;Services;Site;Social Characteristics;Superfund;Testing;Toxic effect;Trust;design;empowered;improved;insight;interest;meetings;nutrition;nutrition education;programs;public health medicine (field);superfund chemical;superfund site


application_id: 8053927
project_number: 5P42ES007380-14
project_title: Core B: Research Support Core
administering_ic: NIEHS
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 9005
contact_pi_person_id: 8260644
contact_pi: TOBOREK, MICHAL
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: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The Research Support Core (Core B) of the Superfund Basic Research Program at the Universityof Kentucky (UK-SBRP) will perform the vital role of supporting the research activities of all biomedicaland non-biomedical projects. The main objective of Core B is to provide a central facility that willenhance and develop the research capabilities of the University of Kentucky SBRP (UK SBRP)particularly in the areas of systems biology bioinformatics/biostatistics proteomics and PCBanalysis. Creation of a central facility in these research areas is critical to study the impact of nutritionon the toxicity of environmental pollutants (primarily PCBs). Establishment of a coordinated effort in theform of one Research Support Core will maximize both the research and cost effectiveness of UKSBRP.Core B consists of four entities (namely Systems Biology Bioinformatics/Biostatistical AnalysisProteomics and Analytical Components) directed by an expert in each area. The Aims of Core B are:1. Cross-link the individual research projects by developing a unified data managementinfrastructure and by providing feedback information to guide the process of discoveringcommon pathways and mechanisms of modulatory effects of diets on vascular pathology ofPCBs.2 Integrate diverse biological data from the individual research projects in order to generate acomprehensive systems biology model of the effects of nutrition on PCB-induced vasculartoxicity.3. Develop and provide analytical services expertise and technical support in the areas ofbioinformatics proteomics and PCB analysis.4. Provide training and support on using bioinformatics and systems biology tools as well asanalytical chemistry approaches for toxicology research to all investigators involved in theUK-SBRP.Core B will bind together critical research activities of individual projects to enhance the overallresearch potential and success of UK-SBRP. Thus it will not only offer research services but will alsobe critical for integration of individual research projects into a unified entity. In addition to providing auniform platform for generation and computational analysis of high-throughput data (microarrays andproteomics) the Core will employ the systems biology approaches to create predictive models to betteranticipate the effects of nutrition on toxicity of superfund chemicals.

project_terms:
Address;Analytical Chemistry;Area;Arts;Basic Science;Binding (Molecular Function);Bioinformatics;Biological;Biometry;Blood Vessels;Computer Analysis;Consultations;Data;Data Analyses;Databases;Diet;Disease;Educational workshop;Ensure;Environmental Pollutants;Equipment;Experimental Designs;Feedback;Generations;Genomics;Human Resources;Individual;Kentucky;Mediating;Modeling;National Institute of Environmental Health Sciences;Pathology;Pathway interactions;Polychlorinated Biphenyls;Procedures;Process;Proteomics;Quality Control;Research;Research Activity;Research Infrastructure;Research Personnel;Research Project Grants;Research Proposals;Research Support;Role;Sampling;Services;Software Tools;Structure;Superfund;Surveys;Systems Biology;Technical Expertise;Technology;Toxic effect;Toxicology;Training;Training Support;Universities;cost effectiveness;crosslink;data management;innovative technologies;new technology;nutrition;predictive modeling;programs;success;superfund chemical;tool


application_id: 8053926
project_number: 5P42ES007380-14
project_title: Core C: Research Translation Core
administering_ic: NIEHS
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 9004
contact_pi_person_id: 8535916
contact_pi: ORMSBEE, LINDELL E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The University of Kentucky Superfund Basic Research Program will focus on the environmental healthimpacts of chlorinated organics with a more specific focus on RGBs and TCE. The Program will include fiveseparate biomedical research projects that seek to better understand the biochemical and cellularmechanisms associated with exposure to such chemicals as well as the associated impacts on suchdiseases as cancer diabetes hypertension and cardiovascular disease i.e. diseases common in Kentucky.One of the unique aspects of the research program will be the investigation of the role of nutrition inmitigating the impacts associated with such exposures. In addition separate projects will examine the use ofnanotechnologies and biosensors in detecting such chemicals in the environment and will explore noveltechniques for remediation with a particular focus on groundwater contaminated by TCE. The latter projectwill have specific potential for application as a result of ongoing remediation studies associated with theGaseous Diffusion Plant in Paducah Kentucky. The Research Translation Core will translate Programresearch to five targeted audiences: Government Industry Broad Audiences Health Professionals andAcademia. Consistent with the guidelines of the RFA the specific aims of the Research Translation Core aresummarized as follows:1. Communicate important research outcomes to specific targeted audiences to ensure the accurate andtimely use of the knowledge and technologies generated by individual research projects thus contributing tothe reduction of environmental contamination and the improvement of public health. Specific targetaudiences include: a) government b) academia industry and health professionals and c) broad audiences(including the general public and impacted communities).2. Leverage research translation activities and targeted research translation projects through effectivepartnerships and other communication tools. Specific partnerships include: 1) The Kentucky WaterResources Research Institute 2) The Kentucky Research Consortium for Energy and Environment 3) TheKentucky Cooperative Extension Service 4) UK College of Communications and Information Studies 5) UKCenter for Clinical and Translational Science and 6) Other SBRP Research Translation Cores (seeattached letters of support)3. Develop and implement a mechanism for tracking and evaluating the effectiveness of the translatedresearch to confirm the utility and appropriateness of the communication tools selected.These efforts promoted through eight specific translation projects will contribute to a reduction inenvironmental contamination an increase in target audiences' knowledge about the relationship betweenSuperund chemical exposure and health outcomes and a subsequent improvement in human health.

project_terms:
Academia;Basic Science;Biochemical;Biomedical Research;Biosensor;Cardiovascular Diseases;Chemical Exposure;Chemicals;Clinical;Communication;Communication Tools;Communities;Diabetes Mellitus;Diffusion;Disease;Effectiveness;Ensure;Environment;Environmental Health;Environmental Pollution;Exposure to;General Population;Government;Guidelines;Health;Health Professional;Human;Hypertension;Individual;Industry;Investigation;Kentucky;Knowledge;Letters;Malignant Neoplasms;Nanotechnology;Outcome;Outcomes Research;Plants;Research;Research Institute;Research Project Grants;Role;Services;Superfund;Targeted Research;Techniques;Technology;Translating;Translational Research;Translations;Universities;Water;college;novel;nutrition;programs;public health medicine (field);remediation


application_id: 8053925
project_number: 5P42ES007380-14
project_title: Project 7: Chloro-Organic Degradation by Nanosized Metallic Systems and by Chelat
administering_ic: NIEHS
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 0010
contact_pi_person_id: 8534525
contact_pi: BHATTACHARYYA, DIBAKAR
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: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Chlorinated organics bring toxicity from water soil and sediment phases and exert a cumulativedeleterious effect on the environment. Various Superfund sites contain mixtures of RGBs chloroethylenesand other compounds. The degradation of of chloro-organics to nontoxic non-chlorinated and easilybiodegradable products will require integrated approaches involving "combined" (reductive and oxidative)remediation technologies. Our proposed approach to use combined technologies should lead to significantimprovement over current remediation practices by the elimination of the production of chloro-organicintermediates. Our research will focus on the degradation of selected RGBs TCE and RGB mixtures. Athorough understanding of the reaction kinetics for both steps (reductive and oxidative) the potential role ofsurfactants and material (such as doping catalyst metals chelates) characteristics will be important for theintegration of the steps. The approaches taken for reductive dechlorination by bimetallic nanoparticles inpolymer media and nanotubes will allow the development of highly controlled structures for high reactivityand stability. The proposed technology will have a significant impact on the role of nanostructured materialsand hydroxyl radical /superoxide radical anion reaction pathway in the environmental field for current andfuture needs. The technique for potential on-site generation of hydrogen peroxide and gluconic acid (ironchelate) provides enzyme (glucose oxidase) immobilization using an innovative approach of layer- by-layerassembled membranes and this should enhance application opportunities in various Superfund sites.Kinetic modeling of both oxidative and reductive systems should establish an excellent foundation forfundamental understanding of bimetallic nanotechnology-based systems and for chelate-modifiedhydroxyl/superoxide radical-based reactions. Another important aspect of this proposal is that pollutanttoxicity will be reduced significantly for both the dechlorination step and the combined reaction systems.Relevance: The proposed research is expected to have significant positive impact on pollution remediationthrough flexible dechlorination technology developments with significant reduction of material usage andhighly improved health benefits through toxicity reduction.

project_terms:
Advanced Development;Anions;Carbon;Characteristics;Chelating Agents;Chemicals;Chlorine;Development;Educational workshop;Effectiveness;Environment;Enzymes;Equilibrium;Flushing;Foundations;Free Radicals;Future;Generations;Glucose;Health Benefit;Hydrogen;Hydrogen Peroxide;Hydroxyl Radical;Immobilization;In Situ;Iron;Iron Chelating Agents;Kinetics;Lead;Life;Maps;Membrane;Metals;Methods;Modeling;Monitor;Morphology;Nanostructures;Nanotechnology;Nanotubes;Natural regeneration;Parents;Pathway interactions;Phase;Phenols;Pollution;Polychlorinated Biphenyls;Polymers;Production;Property;Reaction;Reagent;Research;Roentgen Rays;Role;Salts;Sampling;Site;Soil;Solvents;Spectrum Analysis;Structure;Superoxides;Surface;System;Techniques;Technology;Testing;Toxic effect;Trichloroethylene;Vascular Endothelial Cell;Vinyl Chloride;Water;Work;base;biodegradable product;catalyst;cost;dechlorination;diphenyl;enzyme immobilization;flexibility;gluconate;glucose oxidase;improved;innovation;membrane assembly;nanoparticle;nanosized;nanostructured;novel strategies;operation;organic acid;oxidation;particle;pollutant;reaction rate;remediation;superfund site;surfactant;technology development


application_id: 8053923
project_number: 5P42ES007380-14
project_title: Project 4: The Impact of Obesity on PCB Toxicity
administering_ic: NIEHS
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 0008
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Obesity predisposes to cardiovascular disease which is the primary cause of death in the obese population.During the current period of support results demonstrate that coplanar PCB ligands of the arylhydrocarbonreceptor (AhR) which accumulate markedly in adipose tissue increase adipocyte differentiation andproinflammatory gene expression. Administration of PCB77 to apolipoprotein E (apoE)-/- mice resulted in anincrease in body weight adipose mass and macrophage imrnunostaining in adipose tissue. Importantlymice administered PCB77 exhibited a marked increase in their susceptibility to angiotensin II (Angll)-inducedabdominal aortic aneurysm (AAA) formation. We have previously demonstrated that Angll-induced AAAsare associated with marked inflammation in vascular and surrounding peri-aortic adipose tissue and thatobesity increases the susceptibilty to Angll-induced AAAs. The working hypothesis of this proposal is thatadiposity and proinflammatory adipokine expression in response to coplanar PCBs promotes Angll-inducedAAAs. Moreover we hypothesize that dietary manipulation of fat content will modulate the adverse effects ofcoplanar PCBs on Angll-induced AAAs. In aim 1 we will identify mechanisms for coplanar PCB-inducedregulation of proinflammatory gene expression in adipocytes focusing on oxidative stress and NFkappaB assignaling intermediates. Given that adipocytes store fatty acids we will examine the interplay betweenpolyunsaturated fatty acids (PUFA) of the n-6 versus n-3 family in their ability to promote or abrogate theeffects of coplanar PCBs. In aim 2 we will define the role of the adipocyte AhR in the effects of PCB77 onproinflammatory adipokine expression body weight and Angll-induced AAAs. In aim 3 we will determinethe effect of diets enriched with linoleic acid (n-6) or linolenic acid (n-3) on PCB77-induced regulation of bodyweight ectopic lipid deposition and the formation and progression of Angll-induced AAAs. Results fromthese studies will directly relate to all projects of this superfund through elaboration of mechanisms wherebydietary intervention through fatty acids can mitigate or augment the toxicity of PCBs on the vascular systemon the ability to measure and detect PCBs in biological samples and on the pathophysiologic effects of PCBremediation products on adipocyte and vascular function. The long-term health benefits of this researchrelate to definition of contribution of PCBs to obesity and to obesity-associated cardiovascular disease.

project_terms:
Abdominal Aortic Aneurysm;Acute-Phase Proteins;Adipocytes;Adipose tissue;Adverse effects;Agonist;Angiotensin II;Apolipoprotein E;Biological;Blood Vessels;Body Weight;Cardiovascular Diseases;Cause of Death;Chronic;Data;Deposition;Diet;Dietary Intervention;Disease;Employee Strikes;Exhibits;Experimental Models;Family;Fatty Acids;Fatty acid glycerol esters;Figs - dietary;Gene Expression;Greater sac of peritoneum;Health Benefit;In Vitro;Incidence;Infiltration;Inflammation;Inflammatory;Laboratories;Ligands;Linoleic Acids;Linolenic Acids;Lipids;Measures;Mortality Vital Statistics;Mus;Obesity;Obesity associated cardiovascular disease;Obesity associated disease;Omega-3 Fatty Acids;Oxidative Stress;Polychlorinated Biphenyls;Polyunsaturated Fatty Acids;Predisposition;Production;Regulation;Research;Role;Sampling;Severities;Signal Pathway;Signal Transduction;Superfund;Toxic effect;Translating;Vascular Diseases;Vascular System;Weight Gain;Work;abdominal aorta;adipocyte differentiation;adipokines;base;cytokine;in vivo;lipophilicity;macrophage;male;receptor;remediation;response


application_id: 8053922
project_number: 5P42ES007380-14
project_title: Project 6: Sensing Superfund Chemicals with Recombinant Systems
administering_ic: NIEHS
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1
subproject_number: 0004
contact_pi_person_id: 1964876
contact_pi: DAUNERT, SYLVIA
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: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
There is an on-going need for simple rapid and cost-effective analytical methods capable of detecting toxicsubstances in the environment and in biological samples. Among these toxic compounds polychlorinatedbiphenyls (PCBs) have been extensively studied and proven to be harmful to humans and the environmentand consequently classified as Superfund chemicals. More recently hydroxylated PCBs (OH-PCBs) havealso been more closely examined as potentially exhibiting significant toxic health effects. Due to the toxicityand environmental and biological persistence of PCBs and OH-PCBs it is necessary to have efficient andeconomical methods to detect and quantify them. Currently employed traditional analytical methods arecostly time- and labor-consuming not amenable to field analyis and not appropriate for extensivemonitoring of target analytes in biological samples. To that end the long-term objective of this proposal is todesign and develop molecular biosensors employing genetic engineering tools which are selectivesensitive portable and inexpensive and propose them as a viable alternative to traditional analyticalmethods for the detection of PCBs and OH-PCBs in biological and environmental samples. Specificallywhole-cell biosensors will be constructed that are based on bacteria engineered to harbor a plasmidcontaining the genes encoding for the proteins involved in the catabolic pathways of Superfund chemicalscoupled to those of a signal-producing reporter protein. Additionally the regulatory proteins of bacterialresistance operons will be redesigned to improve their binding selectivity to target analytes and will beincorporated as the recognition elements in a new biosensing format. These redesigned proteins should beable to act like molecular switches to detect the presence of the target compounds in samples. Furthermorethe newly developed biosensing systems will be miniaturized and integrated into enabling technologies for insitu detection and field studies. As part of the enabling technologies the transformation of bacterial wholecellsensors into spores as long-term highly rugged storage and transport elements will be explored.These spore-based biosensors as well as the molecular switches will then be incorporated into portableminiaturized microfluidic platforms for field sensing. These biosensing systems provide with new tools formonitoring of human health and the environment therefore they are of high relevance for public health.

project_terms:
Bacteria;Bacterial Transformation;Binding (Molecular Function);Biological;Biosensing Techniques;Biosensor;Cells;Chemicals;Coupled;Detection;Development;Ecology;Elements;Emerging Technologies;Engineering;Environment;Environmental Monitoring;Exhibits;Funding;Genes;Genetic Engineering;Goals;Health;Human;In Situ;Indium;Methods;Microfluidic Analytical Techniques;Microfluidics;Molecular;Molecular Biology;Monitor;Nanotechnology;Nature;Operon;Pathway interactions;Plasmids;Poisons;Polychlorinated Biphenyls;Proteins;Recombinants;Reporter;Reproduction spores;Research Personnel;Sampling;Signal Transduction;System;Technology;Time;Toxic effect;Trademark;Work;analytical method;bacterial resistance;base;cost;design;field study;genetic regulatory protein;improved;miniaturize;pollutant;public health relevance;sensor;success;superfund chemical;tool


application_id: 8053921
project_number: 5P42ES007380-14
project_title: Project 1: Superfund Chemicals Nutrition and Endothelial Cell Dysfunction
administering_ic: NIEHS
opportunity_number: RFA-ES-06-003
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 2010-04-01
project_end_date: 2013-03-31
study_section: ZES1
subproject_number: 0002
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
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: 2010-04-01
project_abstract:
Atherosclerosis a chronic inflammatory disease is still the number one cause of death in the United States.Numerous risk factors for the development of atherosclerosis have been identified including obesityhypertriglyceridemia and exposure to Superfund chemicals such as persistent organic pollutants (e.g.RGBs). Plant-based bioactive food components are reported to have antioxidant and anti-inflammatoryproperties. Our preliminary data suggest that endothelial cell dysfunction and inflammatory events inducedby exposure to coplanar PCBs can be markedly down-regulated by bioactive compounds such as flavonoidsevents which also can be modified by the cellular lipid milieu. Little is known about mechanisms of nutritionalmodulation of environmental toxicity. Membrane lipid domains such as caveolae are particularly abundant inendothelial cells where they are believed to play a major role in the regulation of endothelial vesiculartrafficking. More recently caveolae have also been implicated in the regulation of cell signal transductions.Thus we hypothesize that caveolae are critical in the cellular responses to Superfund pollutants lipids andlipophilic bioactive compounds such as flavonoids. We also hypothesize that the anti-inflammatoryproperties of flavonoids against chemical insults may be enhanced by omega-3 fatty acids and antagonizedor lessened by omega-6 fatty acids. These hypotheses will be tested in vitro as well as in vivo by studyingthe interactions of PCBs with dietary components such as fatty acids and flavonoids. Importantly we willuse cell and mouse models lacking the caveolin gene to determine the involvement of caveolae ininflammatory outcome. We propose to explore novel mechanisms of nutrient-mediated modulation ofSuperfund chemical toxicity and the outcome of our proposed study will lead to novel nutritionalrecommendations and therapeutic interventions in populations exposed to Superfund chemicals. Superfundchemical exposure specifically persistent organic pollutants like PCBs has been linked to a heightened riskof cardiovascular disease to the public. Project 1 intends to investigate the mechanisms used by thesechemicals resulting in disease specifically signaling pathways controlled by the membrane domainscaveolae. Project 1 will focus on means of nutritional intervention by blocking these targets and thusproposing means of protecting the public from the harmful effects of Superfund chemical exposure.

project_terms:
Anti-Inflammatory Agents;Anti-inflammatory;Antiatherogenic;Antioxidants;Atherosclerosis;Blood Vessels;CAV1 gene;Cardiovascular Diseases;Cause of Death;Caveolae;Caveolins;Cells;Chemical Exposure;Chemicals;Chronic;Critical Pathways;Data;Development;Diet;Dietary Component;Dietary Fats;Dietary Fatty Acid;Dietary Intervention;Disease;Endothelial Cells;Event;Exposure to;Fatty Acids;Flavonoids;Functional disorder;Genes;Health;Hypertriglyceridemia;Incidence;Inflammatory;Inflammatory Response;Intervention;Lead;Link;Lipids;Mediating;Membrane;Membrane Lipids;Mus;Nutrient;Nutritional;Obesity;Omega-3 Fatty Acids;Omega-6 Fatty Acids;Outcome;Pathology;Plants;Play;Polychlorinated Biphenyls;Population;Process;Property;Recommendation;Regulation;Reporting;Risk;Risk Factors;Role;Signal Pathway;Signal Transduction;Superfund;Testing;Therapeutic Intervention;Toxic effect;United States;base;bioactive food component;cardiovascular disorder risk;in vitro testing;in vivo;mouse model;novel;nutrition;pollutant;prevent;response;superfund chemical;trafficking;uptake


application_id: 8053845
project_number: 5K23AA018399-02
project_title: Zinc supplementation in alcoholic cirrhosis
administering_ic: NIAAA
award_notice_date: 2011-03-30
opportunity_number: PA-09-043
application_type: 5
activity_code: K23
ic: AA
serial_number: 018399
program_official: GENTRY, THOMAS
project_start_date: 2010-04-01
project_end_date: 2015-03-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This K23 application will enable Matthew Cave M.D. to achieve his goal of becoming an independent investigator focusing on clinical and translational research in alcoholic liver disease (ALD) and nutrition. Dr. Cave will conduct a mechanistic study evaluating the effects of zinc sulfate therapy in patients with alcoholic cirrhosis (AC). Highlights of Dr. Cave's career development plan include: (i) obtaining a Master of Science degree in Interdisciplinary Studies (I-MS) focusing on toxicology clinical trial design and biostatistics and (ii) board certification in nutrition (ABPNS). These activities will occur in the setting of the recently funded University of Louisville Alcohol Research Center (P01) and will be monitored quarterly by an advisory committee. An estimated two million Americans have ALD and there are no FDA approved medications for any stage of ALD. Our preliminary data document (i) zinc deficiency in human subjects with AC and (ii) improvement in liver injury and in postulated mechanisms of liver injury with zinc supplementation in murine models. Our hypothesis is that zinc sulfate therapy will result in improvement in mechanisms postulated to play a role in the development and progression of human AC. To test this hypothesis we will perform a randomized double blind placebo-controlled "drop in" mechanistic study of zinc sulfate 220 mg daily in 30 subjects with Child-Pugh A-B AC for 24 months. The primary endpoints are reduction in (i) serum endotoxemia and (ii) ex vivo basal and endotoxin-stimulated TNF1 production. Secondary endpoints are (i) improved serum zinc status (ii) increased intestinal tight junctions with decreased permeability (iii) improved serum pro-inflammatory cytokine profile (iv) reduced oxidative stress and improved serum antioxidant status (v) reduced hepatocyte death (vi) decreased fibrosis and (vii) improved clinical status. These studies utilize state- of-the art techniques in a translational approach to develop an enhanced understanding of a potential new therapy for AC.  
  
PUBLIC HEALTH RELEVANCE: This K23 application will enable Matthew Cave M.D. to achieve his goal of becoming an independent investigator focusing on clinical and translational research in alcoholic liver disease (ALD) and nutrition. We will perform a randomized double blind placebo-controlled "drop in" mechanistic study of zinc sulfate 220 mg daily in 30 subjects with Child-Pugh A-B AC for 24 months.

project_terms:
Accounting;Advisory Committees;Alcohol consumption;Alcoholic Liver Cirrhosis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcoholism;American;Animal Model;Antioxidants;Attenuated;Biometry;Blood Circulation;Board Certification;Cell Death;Cell Wall;Cessation of life;Child;Chronic;Cirrhosis;Clinical;Clinical Research;Clinical Trials Design;Data;Development;Development Plans;Disease;Doctor of Medicine;Double-Blind Method;Drops;Endotoxemia;Endotoxins;Epithelial;FDA approved;Fibrosis;Funding;Generations;Goals;Gram-Negative Bacteria;Health Benefit;Hepatocyte;Human;Immune system;Inflammatory;Injury;Interdisciplinary Study;Intestines;Kupffer Cells;Liver;Master of Science;Mediator of activation protein;Modeling;Monitor;Morbidity - disease rate;Mortality Vital Statistics;Mus;Oral;Oxidative Stress;Pathway interactions;Patients;Permeability;Pharmaceutical Preparations;Placebo Control;Play;Primary carcinoma of the liver cells;Principal Investigator;Production;Publishing;Randomized;Reactive Oxygen Species;Reporting;Research;Research Personnel;Research Proposals;Role;Safety;Serum;Staging;Structure;Supplementation;TNF gene;Techniques;Testing;Tight Junctions;Toxicology;Translational Research;United States;Universities;Venous;Work;Zinc;Zinc Sulfate;Zinc deficiency;alcohol research;animal data;base;career development;clinical practice;cytokine;human subject;improved;nutrition;prevent;problem drinker;programs;public health relevance;translational approach

public_health_relevance:
This K23 proposal will enable Matthew Cave MD to achieve his goal of becoming an independent investigator focusing on clinical and translational research in alcoholic liver disease (ALD) and nutrition.  We will perform a randomized double blind placebo-controlled "drop in" mechanistic study of zinc sulfate 220 mg daily in 30 subjects with Child-Pugh A-B AC for 24 months.


application_id: 8053458
project_number: 5R21AI088605-02
project_title: Chylomicrons promote intestinal absorption and systemic dissemination of dietary
administering_ic: NIAID
award_notice_date: 2011-03-17
opportunity_number: RFA-AI-09-011
application_type: 5
activity_code: R21
ic: AI
serial_number: 088605
program_official: DAVIDSON, WENDY F
project_start_date: 2010-04-01
project_end_date: 2013-03-31
study_section: ZAI1-SV-I(J1)
contact_pi_person_id: 1863468
contact_pi: WOODWARD, JEROLD G
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 incidence of food allergies is on the rise in Western societies. Common food allergies include milk- egg- soy and peanut allergy and especially the latter can be fatal. An allergic response occurs when the dietary allergen gains access to IgE molecules on the surface of Mast cells in the intestine or in other tissues. It is therefore reasonable to assume that intestinal absorption of the allergens is detrimental. However intestinal absorption of the allergen and of dietary antigens in general is also required for the induction of broad systemic immunological tolerance ("oral tolerance") which prevents food allergies and may even be used to treat food allergies. It appears thus that the mechanism of antigen absorption plays a crucial role in the pathogenesis of food allergies. Unfortunately relatively little is currently known on the mechanism by which food antigens cross the intestinal epithelium and how they are subsequently transported through the body. Most dietary proteins including most known allergens have emulsifying properties which predicts that they show affinity for lipoprotein particles such as chylomicrons. These large emulsion particles transport dietary long-chain triglycerides (LCT "fat") through mesenteric lymph and blood. If dietary antigens are bound to chylomicrons they would then be transported to chylomicron target tissues such as mesenteric lymph nodes (MLN). Transport of dietary antigens to MLN could promote oral tolerance to the antigen since this is the common immune response in these lymph nodes. Thus chylomicron-dependent antigen absorption is hypothesized to promote oral tolerance. Most food staples including those with allergens such as milk eggs soybeans and peanuts also contain significant amounts of LCT meaning that antigen ingestion is followed by chylomicron secretion. We hypothesize that intestinal absorption and systemic transport of dietary antigens occurs through association with chylomicron secretion. More specifically we hypothesize that 1.) dietary antigens associate with newly formed chylomicron particles within intestinal epithelial cells (IEC) and are secreted into mesenteric lymph in association with nascent chylomicrons 2.) dietary antigens are transported in association with chylomicrons through mesenteric lymph via MLN into blood 3.) chylomicron-dependent antigen absorption promotes oral tolerance.These hypotheses are supported by preliminary data obtained with a prototypical food allergen ovalbumin (OVA) in mice but future experiments will also study peanut allergens. We propose to study the absorption mechanism in detail in this R21 grant application and to explore immune modulating effects of the novel chylomicron pathway. These studies are expected to significantly impact food allergy research since they define the underlying mechanism of dietary antigen absorption and provide the mechanistic framework for optimization of antigen delivery to the intestinal and peripheral immune system.

project_terms:
Address;Affect;Affinity;All-Trans-Retinol;Allergens;Allergic;Allergic Reaction;Allergy to peanuts;Antibodies;Antibody Formation;Antigen Presentation;Antigen-Presenting Cells;Antigens;Applications Grants;Binding (Molecular Function);Biological Models;Blood;Blood Circulation;Cell Differentiation process;Cell Line;Chylomicrons;Data;Defect;Development;Dietary Fats;Dietary Fatty Acid;Dietary Proteins;Emulsions;Epithelial Cells;Extravasation;Fatty acid glycerol esters;Food;Food Hypersensitivity;Fractionation;Future;IgE;Immune;Immune response;Immune system;In Vitro;Incidence;Individual;Ingestion;Intestinal Absorption;Intestinal Secretions;Intestines;Lamina Propria;Lipoproteins;Lymph;Maintenance;Measures;Medium chain triglycerides;Mesentery;Milk;Morbidity - disease rate;Mortality Vital Statistics;Mus;Oils;Ovalbumin;Pathogenesis;Pathway interactions;Peanuts - dietary;Peripheral;Phagocytosis;Plasma;Play;Production;Property;Regulatory T-Lymphocyte;Research;Role;Sampling;Societies;Source;Soybeans;Surface;T-Cell Proliferation;T-Lymphocyte;Testing;Tight Junctions;Tissues;Transgenic Organisms;Triglycerides;Vitamins;Water;absorption;allergic response;antigen binding;antigen challenge;egg;fast protein liquid chromatography;feeding;food allergen;food antigen;in vivo;in vivo Model;inhibitor/antagonist;intestinal epithelium;lymph nodes;mast cell;monolayer;novel;oral tolerance;particle;prevent;research study;soy

public_health_relevance:
There is an increase in the incidence of food allergies such as peanut allergy. Little is known on themechanism by which dietary proteins including allergens are absorbed across the intestinal epithelium andsubsequently transported through lymph and blood. We propose an entirely novel mechanism in which dietaryantigens are taken up by intestinal epithelial cells loaded onto chylomicron particles (which transport dietaryfat) and secreted together with chylomicrons into mesenteric lymph. This is hypothesized to promote oraltolerance. Unraveling this mechanism will strongly impact food allergy research.


application_id: 8052858
project_number: 5R01DA027981-02
project_title: Victimization and Women in the Criminal Justice System
administering_ic: NIDA
award_notice_date: 2011-02-03
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: 8052309
project_number: 1S10RR026827-01A1
project_title: Cell Sorter Upgrade for Flow Cytometry Service Facility
administering_ic: NCRR
award_notice_date: 2011-03-15
opportunity_number: PAR-10-082
application_type: 1
activity_code: S10
ic: RR
serial_number: 026827
suffix: A1
program_official: LEVY, ABRAHAM
project_start_date: 2011-04-01
project_end_date: 2012-03-31
study_section: Special Emphasis Panel[ZRG1 CB-J (30)]
contact_pi_person_id: 1878476
contact_pi: COHEN, DONALD A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Funding through this NCRR Shared Instrument Grant application is requested for the purchase of an iCyt Reflection high speed parallel cell sorter for the Flow Cytometry Service Facility at the University of Kentucky College of Medicine. The Flow Cytometry Service Facility is a university-subsidized core which was established over 25 years ago. It is currently staffed by two experienced instrument operators under the direction of the principal investigator. The facility provides flow cytometric analysis and sorting on a fee-for-service basis to over 100 laboratories in 5 different colleges 22 different departments 14 divisions and 6 centers at the University of Kentucky. Among these labs are 68 NIH-funded investigators who utilize the services of the facility to provide flow cytometric data and sorted cells for their research programs. The Flow Cytometry Service Facility currently has one cell sorter a MoFlo system which is now 11 years old. Over the last three years this instrument has become unreliable requiring the facility to cancel scheduled sorts for a number of investigators. In addition the number of requests for sorting of live human cells and/or infected cells has increased significantly over the last several years. However since the MoFlo system is not designed for BSL2 biocontainment requests by investigators had to be denied. The inability to perform cell sorting and analysis under BSL2 containment has severely restricted the ability of NIH-funded investigators at our university to carry out the aims of their grants. For these reasons we will purchase the iCyt Reflection parallel sorter which is integrated within a Baker Sterigard III BSL2 biosafety hood as a replacement for our aging MoFlo sorter. The university has agreed to provide new laboratory space for the Flow Cytometry Service Facility which will be renovated so as to have a restricted-access room for all biohazardous sorting and analysis that is separated from our other cell analyzers. This facility upgrade will establish the only cell sorter at the university that is equipped for analysis and sorting of live infected cells under conditions that fully protect facility personnel. With this important upgrade the facility will be able to assist investigators who need to sort potentially hazardous samples for their research programs. Moreover the iCyt sorter will offer NIH- funded investigators the opportunity to expand their research efforts in new directions that were not otherwise available with the existing instrumentation. In turn the availability of this instrumentation will spawn new opportunities for collaborations and research grants.

project_terms:
11 year old;Aging;Applications Grants;Cell Separation;Cells;Collaborations;Containment;Data;Fee-for-Service Plans;Flow Cytometry;Funding;Funding Applicant;Grant;Human;Human Resources;Kentucky;Laboratories;Life;Medicine;National Center for Research Resources;Principal Investigator;Research;Research Personnel;Research Project Grants;Sampling;Schedule;Services;Sorting - Cell Movement;Speed (motion);System;United States National Institutes of Health;Universities;base;cell analyzer;college;design;experience;instrument;instrumentation;programs


application_id: 8052002
project_number: 3R01GM066152-07S1
project_title: Synthetic Probes of Protein Prenylation
administering_ic: NIGMS
award_notice_date: 2010-05-10
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: GM
serial_number: 066152
suffix: S1
program_official: FABIAN, MILES
project_start_date: 2010-05-15
project_end_date: 2011-04-30
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 7875230
contact_pi: SPIELMANN, H PETER
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Covalent modification by isoprenoid lipids (prenylation) is a critical post-translational event for many proteinsinvolved in cellular signaling and cancer. The primary goal of this research program is to design and test prenylfunction inhibitors and to identify and characterize proteins that are farnesylated in vivo. The studies outlined inthis proposal will result in the preparation of new tools to probe the specificity of the prenyltransferases protein-farnesyltransferase (FTase) and protein-geranylgeranyltransferase (GGTase-I) enable further development ofprenyl function inhibitors and identify new prenylated proteins as potential targets for therapeutic intervention.By varying the chemical structure of the prenyl lipid we are developing reagents to probe the biologicalfunction of the posttranslational modification. Taking advantage of the fact that the prenyl group forms asubstantial part of the peptide substrate binding site in the prenyltransferases has allowed us to developpeptide selective inhibitors of prenyl function. These unnatural analogues may allow for the selectiveinterference with specific prenylation targets and may provide lead compounds to alleviate the potential toxicityassociated with complete inhibition of protein prenylation. In particular the unnatural analogues may be usefulto obtain a more complete understanding of the role that alternative prenylation plays in Farnesyl transferaseinhibitor (FTI) evasion by oncogenes such as K-Ras. Critical to understanding the clinical effects of existingand future FTIs and geranylgeranyl transferase inhibitors (GGTIs) is the identification of in vivo substrates ofFTase and GGTase-I. Our innovative strategy of using unnatural transferable prenyl analogues and analoguespecific monoclonal antibodies to identify prenylated cellular proteins will provide valuable information on thecellular targets of inhibitors of prenylation. We expect these studies to result in the identification of previouslyunknown prenylated proteins. The specific aims of this project are: 1) Synthesis of farnesyl and geranylgeranyldiphosphate analogues to study protein prenylation. 2) Screening these compounds for ubstrate specificity ofFTase and GGTase-I and development of prenyl function inhibitors. 3) Identification of prenylated proteins incells. The results from these studies may provide leads to new molecules to treat cancer and also identify newmolecular targets to develop anti-cancer therapies. Substantial evidence points to the central role of proteins normally modified by a prenyl group in cancerprogression. We propose to design and test prenyl function inhibitors and to identify and characterize proteinsthat are modified with prenyl groups. The results from these studies may provide leads to new molecules totreat cancer and also identify new molecular targets to develop future anti-cancer therapies.

project_terms:
Active Sites;Antibodies;Binding Sites;Biochemical;Biological;Biological Assay;Biological Process;Biology;Cells;Chemical Structure;Dependence;Development;Dimethylallyltranstransferase;Discrimination (Psychology);Drug Design;Enzymes;Event;Exhibits;Farnesyl Transferase Inhibitor;Funding;Future;Goals;Growth;Immunoprecipitation;Lead;Lipids;Malignant Neoplasms;Methods;Modification;Molecular Target;Monoclonal Antibodies;Oncogenes;Pathway interactions;Peptides;Play;Post-Translational Protein Processing;Preparation;Process;Protein Isoprenylation;Proteins;Proteomics;Reagent;Research;Role;Screening procedure;Signal Transduction;Site-Directed Mutagenesis;Specificity;Substrate Specificity;Techniques;Testing;Therapeutic Intervention;Toxic effect;Transformed Cell Line;analog;cancer therapy;cellular targeting;chemical synthesis;clinical effect;cytotoxicity;design;enzyme substrate;geranylgeranyl diphosphate;in vivo;inhibitor/antagonist;innovation;isoprenoid;lipophilicity;novel;prenyl;prenylation;programs;protein farnesyltransferase;protein function;protein geranylgeranyltransferase;tool;tumor progression


application_id: 8051964
project_number: 1S10RR026489-01A1
project_title: Aperio ScanScope XT Digital Slide Scanner System
administering_ic: NCRR
award_notice_date: 2011-03-14
opportunity_number: PAR-10-082
application_type: 1
activity_code: S10
ic: RR
serial_number: 026489
suffix: A1
program_official: LEVY, ABRAHAM
project_start_date: 2011-04-01
project_end_date: 2012-03-31
study_section: Special Emphasis Panel[ZRG1 CB-J (31)]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The University of Kentucky proposes to acquire an Aperio ScanScope(R) XT digital slide scanner including the ImageScope"/Genie" and Webscope" viewing software. This instrument will be housed in the University of Kentucky Alzheimer's Disease Center Neuropathology Core laboratory. The location is safe and secure but open to all the Major and Minor Users with outstanding Institutional Support. 11 Major Users and 3 Minor Users representing ten different academic departments within the University strongly desire the instrument. There is no analogous instrument currently available within or nearby the University of Kentucky; however this scientific advancement dovetails very well with existing medical expertise technical infrastructure and research facilities at the University of Kentucky. The Aperio ScanScope XT scans and analyzes microscope slides in a digitized format that will enable optimized and detailed archiving and data mining of histopathological data. The instrument represents a significant technological step forward for the field of quantitative neuropathology by facilitating the digitized identification and analysis of histopathological hallmarks of ND in addition to normal structures. In addition the slide scanner is ideal for improving quantitative measures of surviving cell counts in stereology in situ hybridization signal quantification animal model assessments (including brain trauma and prion disease models) and other cutting edge applications that will directly facilitate NIH-funded research projects by Major Users at the University of Kentucky. This instrument will provide a unique opportunity to introduce validate and publish methods in digital microscopy and bioinformatics for the purpose of quantifying brain pathology. The instrument will have an Advisory Panel that is broad-based with representation by eight different academic departments from the University of Kentucky. Finally due to its web-based functionality the purchase of the Aperio ScanScope XT will allow for the exchange of data throughout Kentucky's remote regions and through the network of Alzheimer's Disease Centers nationally.

project_terms:
Alzheimer's Disease;Animal Model;Archives;Bioinformatics;Brain Pathology;Cell Count;Computer software;Data;Disease model;Funding;Genie;Housing;In Situ Hybridization;Kentucky;Laboratories;Location;Measures;Medical;Methods;Microscope;Microscopy;Minor;Online Systems;Prion Diseases;Publishing;Research Infrastructure;Research Project Grants;Scanning;Secure;Signal Transduction;Slide;Structure;System;Technical Expertise;Traumatic Brain Injury;United States National Institutes of Health;Universities;base;data exchange;data mining;digital;improved;instrument;neuropathology;research facility


application_id: 8051376
project_number: 1R01AG037868-01A1
project_title: Psychosocial stress interactions with electrophysiology and brain aging
administering_ic: NIA
award_notice_date: 2011-02-17
opportunity_number: PA-09-216
application_type: 1
activity_code: R01
ic: AG
serial_number: 037868
suffix: A1
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
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;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 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.


application_id: 8051194
project_number: 1S10RR026884-01A1
project_title: Advion Triversa Nanomate/ABSciex Nanospray III Ion Source for Targeted Lipidomics
administering_ic: NCRR
award_notice_date: 2011-04-20
opportunity_number: PAR-10-082
application_type: 1
activity_code: S10
ic: RR
serial_number: 026884
suffix: A1
program_official: LEVY, ABRAHAM
project_start_date: 2011-05-01
project_end_date: 2012-04-30
study_section: Special Emphasis Panel[ZRG1 BST-F (30)]
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Lipids are intermediates in energy metabolism structural components of biological membranes and as intra- and extra- cellular signals. Aberrant lipid metabolism plays a central role human pathophysiologies including cardiovascular disease obesity diabetes and cancer Systems-level analysis of lipids has lagged behind rapid progress in genomics and proteomics. Newly developed analytical approaches using tandem liquid chromatography and multi- dimensional mass spectrometry have spawned the field of "lipidomics"- a focused area of metabolomics that concerns the systems-level analysis of lipids and lipid-dependent processes. As a component of a core laboratory of our Center for Research on Obesity and Cardiovascular Disease the University of Kentucky operates an ABSciex 4000 Q-Trap hybrid triple quadrupole linear ion trap mass spectrometer which is used primarily for analysis of lipids and lipid-related molecules including glycero and sphingo phospholipids fatty acids ceramides sphingomyelins sterols and cholesterol esters di and tri glycerides acyl carnitines oxidized lipids and their reaction products peptide hormones arachidonic acid derived signaling molecules and their metabolites by HPLC electospray ionization (ESI) selective reaction monitoring mode tandem mass spectrometry. In addition to its ability to operate as a component of a triple quadrupole mass spectrometer the Q3 mass analyzer of this instrument can function as a linear ion trap conferring significant additional capabilities to the instrument that make it an extremely powerful tool for metabolite identification. While the HPLC configuration for sample separation and introduction using a high flow Turbo V ESI ion source is ideal for analyte quantitation by selective reaction monitoring this arrangement is not compatible with newly developed powerful strategies for lipid profiling. This is because it is often difficult (or not possible) to separate the sometimes greater than 30-50 distinct lipid molecular species within a given class by column chromatography so narrow peak widths limit the time the instrument has to conduct scans to identify components of closely eluting lipid species. Methods that address this limitation mandate direct sample infusion allowing the instrument to identify lipid species conducting a series of lipid class specific precursor ion or neutral loss scans. Because of issues of sensitivity sample availability and analyte abundance detection of lipids in these experiments is greatly enhanced by low flow (10-200 nl/min) infusion of small volumes of concentrated samples. The purpose of the present application is to request funds to upgrade the instrument with an Advion Nanomate Triversa automated chip infusion system and an ABI Nanospray III ion source. This upgrade will allow us to use our instrument for lipid profiling studies by automated nanospray ESI mass spectrometry using these newly developed platforms for instrument operation and data analysis.

project_terms:
Address;Arachidonic Acids;Area;Biological;Cardiovascular Diseases;Carnitine;Ceramides;Cholesterol Esters;Column Chromatography;Data Analyses;Detection;Diabetes Mellitus;Energy Metabolism;Fatty Acids;Functional disorder;Funding;Genomics;Glycerides;High Pressure Liquid Chromatography;Human;Hybrids;Infusion procedures;Ions;Kentucky;Laboratories;Lipids;Liquid Chromatography;Malignant Neoplasms;Mass Spectrum Analysis;Membrane;Methods;Molecular;Monitor;Obesity;Phospholipids;Play;Process;Proteomics;Reaction;Research;Role;Sampling;Scanning;Series;Signal Transduction;Signaling Molecule;Sphingomyelins;Sterols;System;Time;Universities;Width;instrument;ion source;ionization;lipid metabolism;mass analyzer;mass spectrometer;metabolomics;operation;oxidized lipid;peptide hormone;research study;tandem mass spectrometry;tool


application_id: 8051024
project_number: 3R01HD052724-03S2
project_title: Functional neuroanatomy of developmental changes in face processing
administering_ic: NICHD
award_notice_date: 2010-05-03
application_type: 3
activity_code: R01
ic: HD
serial_number: 052724
suffix: S2
program_official: FREUND, LISA S
project_start_date: 2010-05-01
project_end_date: 2010-09-30
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 1911365
contact_pi: JOSEPH, JANE E
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: Y
project_abstract:
DESCRIPTION (provided by applicant):  The remarkable capacity that humans have to recognize countless faces over a lifetime has captured the attention of scientists for years. Even newborn infants are tuned into and attend to the human face. However adults appear to be more skilled than children in both remembering and differentiating faces indicating that there is a certain degree of plasticity in face recognition that may be affected by experience. One aspect of face processing that appears to undergo developmental change is perceiving subtle differences in the configuration of the features of a face a property that is integral to uniquely identifying a person. This type of processing improves with age and continues to develop well into adolescence whereas other aspects of face recognition appear to develop much earlier even in infancy. Previous research has focused on the development of these capacities from a behavioral perspective but little research has examined the brain bases efface recognition mechanisms. Understanding the brain basis efface recognition during normal development is of utmost importance in understanding why the brain is not influenced by similar exposure to faces in some developmental disorders such as autism or congenital prosopagnosia. In the present proposal functional magnetic resonance imaging (fMRI) will be used as a brain imaging tool to study the development efface recognition capacities from age 6 to adulthood in normal healthy human volunteers. This proposal focuses on several aspects of face recognition to determine which mechanisms improve with age and which mechanisms are relatively stable across development. fMRI is ideal for answering such developmental questions due to its non-invasive nature and minimal risks. The findings from this proposal will be integral in establishing the normal pattern of brain development for face recognition given that few studies have done so to date. Moreover fMRI can reveal large-scale functional connectivity patterns among brain regions involved in face processing and the present proposal will investigate whether connectivity patterns undergo developmental reorganization. This line of inquiry is important for establishing a baseline to interpret brain connectivity patterns in individuals with difficulties in face recognition. Ultimately such data can then inform potential treatments or interventions for developmental disorders efface processing and help restore an important aspect of social behavior to these individuals.

project_terms:
Adolescence;Adult;Affect;Age;Attention;Autistic Disorder;Base of the Brain;Behavioral;Brain;Brain imaging;Brain region;Child;Cognitive;Data;Development;Event-Related Potentials;Exposure to;Face;Face Processing;Functional Magnetic Resonance Imaging;Human;Human Volunteers;Imaging Device;Imaging Techniques;Individual;Intervention;Lead;Literature;Nature;Neuroanatomy;Neurobiology;Newborn Infant;Pattern;Persons;Process;Property;Prosopagnosia;Research;Research Personnel;School-Age Population;Scientist;Shapes;Social Behavior;Techniques;cognitive function;developmental disease/disorder;experience;improved;infancy;interest;minimal risk


application_id: 8050626
project_number: 5P01HL080100-05
project_title: CORE--Mouse
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 080100
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: 2010-04-01
budget_end_date: 2011-03-31
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 measurement. 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. Perform bone marrow transplantation.
3. Measure arterial blood pressure in a standardized manner.
4. Prepare and implant Alzet pumps for the infusion of Angll or saline.
5. Harvest DNA by tail clipping for the purpose of genotyping.
6. In vivo ultrasound. Non-invasively quantify lumen diameter during the evolution of AAAs.
Centralization of these facilities will permit an efficient use of resources for the Program coupled with optimal
quality control and standardization across Projects.

project_terms:
Blood Pressure;Bone Marrow Transplantation;Caliber;Caring;Clip;Coupled;DNA;Evolution;Generations;Genotype;Harvest;Implant;Infusion Pumps;Location;Maintenance;Measurement;Measures;Mus;Quality Control;Resources;Saline;Services;Standardization;Tail;Ultrasonography;in vivo;programs


application_id: 8050625
project_number: 5P01HL080100-05
project_title: CORE--Human Studies
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 080100
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 9001
contact_pi_person_id: 7332137
contact_pi: MUKHERJEE, DEBABRATA
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: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The purposesof this Core is to begin to translate findings from experimental studies in the individual projects
examining Angll-induced AAAs to human AAAs. Specifically this Core will offer the following services:
1. A tissue bank of human AAAs for immunohistochemical analysis of mediators under study in the
individual projects.
2. Sera plasma and DNA samples from the AAA Cohort and the Health In Men Study from the Western
Australia Abdominal Aortic Aneurysm Study (WA AAAS). These samples will be used to examine the
relationship between plasma concentrations of molecules of interest genotypes and aortic diameter.
3. Statistical analysis of serum concentrations and aortic diameter odds ratios and 95% confidence intervals
to estimate the relative risk of either aortic diameter or rate of expansion with concentration of the mediator.
4. Cardiovascular imaging to noninvasively examine AAAs and their relationship to proposed plasma
measurements.
Establishment of this Core with recognized Clinician Scientists to supervise translational studies as well as
samples from an NIH funded study focused on a unique AAA population will permit translation of
experimental studies to human AAAs.

project_terms:
Abdominal Aortic Aneurysm;Caliber;Confidence Intervals;DNA;Funding;Genotype;Health;Human;Individual;Measurement;Mediator of activation protein;Odds Ratio;Plasma;Population;Relative Risks;Sampling;Scientist;Serum;Services;Tissue Banking;Tissue Banks;Translating;Translations;United States National Institutes of Health;Western Australia;cardiovascular imaging;cohort;interest;men;research study;translational study


application_id: 8050624
project_number: 5P01HL080100-05
project_title: Specific Secretory Phospholipase A2 Isozymes Promote Aneurysm Formation
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 080100
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: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Secretory phospholipase A2 enzymes (sPLA2's) in particular the Group HA Group V and Group X
subtypes have been implicated in a wide variety of inflammatory diseases. We provide evidence that
sPLA2s play a role in promoting abdominal aortic aneurysm (AAA) formation in a mouse model of this
vascular disease. An sPLA2 inhibitor of broad specificity profoundly reduces both the incidence and severity
of Angiotensin II (Angll)-induced AAAs in apoE-/- mice. Additionallly transgenic mice expressing human
Group IIA sPLA2 have increased susceptibility to Angll-induced AAAs compared to non-transgenic mice.
The central hypothesis of this proposal is that Group IIA Group V and/or Group X sPLA2 expressed by
macrophages infiltrating into the vessel wall accelerate AAA formation by promoting the localized release of
inflammatory prostanoids. This hypothesis is based on published data and our own preliminary findings that:
a) macrophage infiltration into the medial layer of the abdominal aorta is an early event in AAAs; b) Group V
and Group X sPLA2 protein are present in AAAs in apoE-/- mice c) the aortic expression of Group V and
Group X sPLA2 mRNA is increased in apoE-/- mice infused with Angll; d) these isozymes are expressed by
macrophages; e) these isozymes have been implicated in cyclooxygenase 2 (COX-2)-dependent prostanoid
production; and f) mice treated with a COX-2-selective inhibitor have significantly reduced AAAs in response
to chronic Angll infusion. To test this hypothesis we propose to identitify specific sPLA2(s) mediating AAA
progression and define the relative contribution of leukocyte expression of these sPLA2 isozymes in its
pathogenic effect (Specific Aim 1); define the relative contribution of systemic versus leukocyte-expressed
Group IIA sPLA2 in mediating Angll-induced AAAs (Specific Aim 2); and determine whether the pathogenic
effect of sPLA2 is dependent on COX-2 activity (Specific Aim 3). These studies hold the potential to identify
a new target for AAA intervention.

project_terms:
Abdominal Aortic Aneurysm;Affect;Aneurysm;Angiotensin II;Animal Model;Aorta;Apolipoprotein E;Arachidonic Acids;Blood Circulation;Blood Vessels;Bone Marrow Transplantation;Cardiovascular system;Cells;Chronic;Coronary Arteriosclerosis;Coupling;Data;Deposition;Development;Disease;Eicosanoids;Elastin Fiber;Enzymes;Event;Extracellular Matrix;Gene Targeting;Generations;Human;Incidence;Infiltration;Inflammation;Inflammatory;Infusion procedures;Intervention;Isoenzymes;Lead;Leukocytes;Medial;Mediating;Messenger RNA;Mus;Pathology;Phospholipase A2;Plasma;Play;Predisposition;Process;Production;Program Research Project Grants;Prostaglandin Production;Prostaglandins;Proteins;Publishing;Relative (related person);Research Personnel;Risk Factors;Role;Serum;Severities;Site;Specificity;Testing;Tissues;Transgenes;Transgenic Mice;Transgenic Organisms;Vascular Diseases;abdominal aorta;base;cell type;cyclooxygenase 1;cyclooxygenase 2;group V secretory phospholipase A2;group X secretory phospholipase A(2);in vivo;inhibitor/antagonist;interest;macrophage;mouse model;programs;response;sPLA2 enzyme


application_id: 8050623
project_number: 5P01HL080100-05
project_title: Smooth Muscle Cell AT1a Receptor in Initiating Events in AAAs
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 080100
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0002
contact_pi_person_id: 8378256
contact_pi: DAUGHERTY, ALAN
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: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
We propose a central hypothesis that Angll initiates AAA formation through smooth muscle cell AT1 receptor
activation regulating the LRP-uPAR axis to promote medial macrophage accumulation. To test this
hypothesis we propose the following specific aims: Aim>1: Determine the contribution of smooth muscle
cell-specific AT1a receptors to AAA production and cellular changes in the aorta. The effects of smooth
muscle cell specific AT1a receptor deficiency on AAA development will be determined in Angll-infused LDL
receptor -/- mice. We will use AT1a receptor floxed mice in which smooth muscle cell deficiency will be
accomplished with Cre expressed under the control of SM22. The effect of smooth muscle cell AT1a
receptor deficiency will be determined on the cellular changes that occur in the initiating phase of AAA
development. Aim 2: Determine the role of Angll on regulation of LRP in smooth muscle cells and the effect
of reduced LRP on susceptibility to AAA development. We will determine the mechanisms by which Angll
downregulates LRP. This will be performed in cultured smooth muscle cells derived from specific aortic
regions. We will determine if mice that are hypomorphic for LRP are more susceptible to Angll-induced
AAAs. This will be performed in mice that are deficient in RAP the molecular chaperone of LRP. Aim 3:
Determine the contribution of uPAR to the development of Angll-induced AAAs. We will use uPAR -/- mice
to determine its role in development of Angll-induced AAAs. "Forward" and "reverse" bone marrow
transplantation studies will determine the tissue loci of uPAR involved in Angll-induced AAAs. Aim 4:
Determine the origin of medial macrophages accumulated in the aorta during Angll-infusion. Bone marrow
transfer studies with mice expressing allelic variants of CD45 will be used to define whether Angll-induced
accumulation of macrophages in the aortic layers originate from blood-borne monocytes or resident
macrophages in the adventitia of the aorta.

project_terms:
Abdomen;Abdominal Aortic Aneurysm;Aneurysm;Angiotensin II;Aorta;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Blood;Blood Vessels;Bone Marrow;Bone Marrow Transplantation;Cell surface;Cells;Characteristics;Chest;Development;Disease;Dissection;Event;Genotype;Infiltration;Infusion procedures;LDL-Receptor Related Protein 1;Link;Lipoprotein Receptor;Low Density Lipoprotein Receptor;Medial;Molecular Chaperones;Mus;PTPRC gene;Pathology;Phase;Plasminogen Activator;Predisposition;Production;Protein Deficiency;Proteins;Proteolysis;Receptor Activation;Regulation;Research Personnel;Role;Smooth Muscle Myocytes;Stimulus;Testing;Thick;Tissues;Tunica Adventitia;Urokinase;Variation (Genetics);base;cell type;macrophage;migration;monocyte;programs;receptor


application_id: 8050622
project_number: 5P01HL080100-05
project_title: Androgen Regulation of Angiotensin Responses in Aneurysms
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 080100
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0001
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Male gender is one of the strongest risk factors in the development of abdominal aortic aneurysms (AAAs).
Our results demonstrate a 3-fold greater incidence of angiotensin II (Angll)-induced AAAs in male ApoE-/-
mice compared to females. Ovariectomy did not influence Angll-induced AAAs. In contrast orchiectomy
reduced AAA incidence to the level observed in females. These results demonstrate that male sex
hormones mediate gender differences in Angll-induced AAAs. Additional data demonstrate greater Angll
receptor density and responsiveness in the abdominal aorta of male than female mice. We hypothesize that
during development androgen localizes the AT1a receptor to vascular smooth muscle cells of the abdominal
aorta of male mice and continues to increase AT1a receptor expression in cell types critical to the formation
of AAAs in adult male mice. In Specific Aim 1 we will determine the temporal effect of exogenous
testosterone administration on AAA formation and localization. The effect of exogenous testosterone in
orchiectomized male and in female mice on Angll-induced AAAs will be determined. A focus will be on
regulation of the AT1a receptor in the abdominal aorta of male1 and female mice administered testosterone.
In Specific Aim 2 we will determine the cell type mediating androgen receptor effects on AAA formation.
The effect of whole body androgen receptor deficiency on Angll-induced AAAs will be examined in male
mice. Since macrophages and smooth muscle are involved early in Angll-induced AAAs we will determine
the effect of deficiency of androgen receptors on bone marrow-derived cells and on smooth muscle on Angllinduced
AAAs. Additional studies will define mechanisms for androgen regulation of the AT1a receptor
promoter. In Specific Aim 3 we hypothesize that in utero developmental effects of androgen on the
mesenchyme give rise to AT1a receptors on vascular smooth muscle cells of the abdominal aorta in adult
male mice thereby localizing AAAs to this region. We will determine the effect of androgen ablation in utero
in males and testosterone administration to neonatal female mice on Angll-induced AAAs in adult offspring.
Results from these studies will identify mechanisms for gender differences in AAA formation.

project_terms:
Abdomen;Abdominal Aortic Aneurysm;Ablation;Adult;Adult Children;Age;Androgen Receptor;Androgens;Aneurysm;Angiotensin II;Angiotensins;Aorta;Apolipoprotein E;Area;Atherosclerosis;Blood Vessels;Bone Marrow;Cardiovascular Diseases;Cells;Chest;Chronic;Clinical;Data;Development;Dissection;Event;Exhibits;Female;Gender;Genes;Genetic;Gonadal Steroid Hormones;Human;Incidence;Infusion procedures;Length;Low Density Lipoprotein Receptor;Medial;Mediating;Mesenchymal;Mesenchyme;Molecular;Mus;Neonatal;Orchiectomy;Ovariectomy;Promotor (Genetics);Regulation;Research;Research Personnel;Risk Factors;Role;Series;Sex Characteristics;Smooth Muscle Myocytes;Smooth muscle (tissue);Stem cells;Testicular Hormones;Testosterone;abdominal aorta;cell type;density;in utero;macrophage;male;offspring;programs;receptor;receptor binding;receptor density;receptor expression;response


application_id: 8050553
project_number: 5R01EY020672-02
project_title: Endogenous Specific Inhibitor of Corneal Lymphangiogenesis
administering_ic: NEI
award_notice_date: 2011-05-18
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 020672
program_official: SHEN, GRACE L
project_start_date: 2010-04-01
project_end_date: 2014-03-31
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 2446639
contact_pi: AMBATI, JAYAKRISHNA
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Absence of blood and lymphatic vessels in the normal cornea is essential for optical clarity and optimal vision. Numerous pathological disorders result in corneal neovascularization that is responsible for blindness in hundreds of millions of individuals worldwide. The vascular endothelial growth factor (VEGF) family and their receptors (VEGFR) are critical elements of the tightly regulated balance of endogenous angiogenesis stimulators and inhibitors which when disrupted results in neovascularization. The principal positive regulators of blood (hemangiogenesis) and lymphatic (lymphangiogenesis) in the cornea are VEGF-A and VEGF-C respectively. Among the many inhibitors of hemangiogenesis that reside in the cornea we have shown that soluble VEGFR-1 (sVEGFR-1) by acting as a trap for VEGF-A is essential for corneal avascularity (Ambati et al. Nature 2006). In contrast the molecular basis of the alymphatic cornea has not been resolved; indeed no endogenous specific inhibitor of lymphangiogenesis in any tissue has yet been reported. In new and exciting studies we identified the existence of a novel secreted splice variant of VEGFR-2 in mouse and human (sVEGFR-2) (Albuquerque et al. Nature Medicine 2009). Surprisingly loss of sVEGFR-2 resulted in spontaneous invasion of lymphatic but not blood vessels into the mouse cornea at birth. sVEGFR-2 also specifically inhibited injury-induced corneal lymphangiogenesis and dramatically reduced corneal allograft rejection. This proposal will test the hypothesis that the lymphatic specificity of sVEGFR-2 is due to its existence as a monomer that interacts with and antagonizes VEGF-C but not VEGF-A. The Specific Aims of this proposal are to define the expression and function of sVEGFR-2 during mouse and human corneal development decipher the molecular mechanisms by which mouse and human sVEGFR-2 inhibit lymphangiogenesis but not hemangiogenesis and resolve the spatial and temporal expression and function of sVEGFR-2 in the mouse cornea following injury and allograft rejection. By providing clarifying insights into a critical endogenous regulator of lymphangiogenesis and identifying mechanisms that might serve as potential targets for advancing novel therapies for corneal neovascularization and transplant rejection these studies directly address the 5-year goals of the NEI Corneal Diseases program. The impact of these studies also extends to pathological states such as tumor metastasis lymphedema and lymphangioma which can be better studied and possibly treated by modulating the endogenous uncoupler of lymphatic and blood vessels we have discovered.  
  
PUBLIC HEALTH RELEVANCE: Corneal neovascularization and transplant rejection which involve abnormal blood and lymphatic vessels lead to blindness in millions worldwide. We discovered a naturally occurring molecule (sVEGFR-2) that selectively blocks lymphatic but not blood vessels. By molecularly uncoupling these intertwined processes we introduce a new research tool that can be used to specifically study lymphatic vascular biology and a new target that can lead to novel therapies for corneal blindness.

project_terms:
Accounting;Address;Adult;Allografting;Angiogenesis Inducing Agents;Angiogenesis Inhibitors;Binding (Molecular Function);Biochemical;Biology;Birth;Blindness;Blood;Blood Vessels;Cell surface;Cornea;Corneal Diseases;Corneal Neovascularization;Data;Dendritic Cells;Development;Disease;Elements;Equilibrium;Extracellular Domain;Family;Family member;Goals;Graft Rejection;Growth;Heterodimerization;Human;Immune;Individual;Inflammatory;Injury;Keratoplasty;Lead;Lymphangiogenesis;Lymphangioma;Lymphatic;Lymphatic Endothelial Cells;Lymphatic vessel;Lymphedema;Mediating;Medicine;Membrane;Modeling;Molecular;Mus;Nature;Neoplasm Metastasis;Optics;Organ;Pathology;Pharmaceutical Preparations;Process;RNA Interference;RNA Splicing;Recombinants;Regulation;Relative (related person);Reporting;Research;Risk;Signal Transduction;Source;Specificity;Surgical sutures;Testing;Tissues;Transplantation;Variant;Vascular Endothelial Growth Factor A;Vascular Endothelial Growth Factor C;Vascular Endothelial Growth Factor D;Vascular Endothelial Growth Factor Receptor-2;Vascular Endothelial Growth Factors;Vision;World Health;allograft rejection;angiogenesis;base;cell motility;corneal allograft;high risk;inhibitor/antagonist;insight;lymph nodes;monomer;neovascularization;novel;novel strategies;prevent;programs;public health relevance;receptor;tool;tumor


application_id: 8050219
project_number: 7R01AT004294-04
project_title: Curcumin reverses tumor exosomes-mediated inhibition of myeloid differentiation
administering_ic: NCCIH
award_notice_date: 2010-05-11
opportunity_number: RFA-AT-06-004
application_type: 7
activity_code: R01
ic: AT
serial_number: 004294
program_official: PONTZER, CAROL H
project_start_date: 2007-09-30
project_end_date: 2011-09-29
study_section: ZAT1-SM(06)
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The naturally occurring polyphenol curcumin has been shown to be a potent chemotherapeutic agent in a variety of tumor models; however its effects on tumor-associated immunosuppression have not been investigated to any great extent. The accumulation of immature myeloid cells is a hallmark of cancer and our data indicate that exosomes produced by tumors can suppress the differentiation of immature myeloid cells (iMCs). We have now found that curcumin treatment inhibits the tumor exosome-mediated suppression of differentiation of IMCs in mice preventing their accumulation in the spleen and delaying tumor growth. Analysis of the composition of the tumor exosomes using a proteomics approach identified CSN5 as a candidate regulatory molecule and siRNA knockdown of CSN5 resulted in attenuation of the tumor exosome- mediated induction of IMCs in the spleen suggesting that exosomal CSN5 plays a key role in tumor exosome-mediated immune suppression. We have now found that curcumin treatment destabilizes exosomal CSN5. The exosomal CSN5 is stable when associated with phosphorylated STAM1. Curcumin treatment leads to the dephosphorylation of STAM1 permitting the recruitment of an E3 ligase BARD1/BRCA1 to the CSN5 complex resulting in CSN5 degradation. Our in vitro kinase assay results indicate that the curcumin- mediated disassociation of STAM1 from CSN5 complex is most likely due to the inhibition of CSN5- associated kinase activity. The clinical relevance of these studies is supported by our recent data that indicate that CSN5 is packed in exosomes isolated from the peripheral blood of breast cancer patients but not healthy subjects. We propose: (1) To use siRNA technology to determine if tumor exosomal CSN5 is a primary target of curcumin in its prevention of breast tumor exosome-mediated immunosuppression; (2) To determine whether CSN5-associated kinase activity prevents BARD1/BRCA1 E3 complex degradation of CSN5 in TS/A tumor cells; and (3) To determine whether curcumin treatment of human tumor cells results in degradation of CSN5 and prevents blocking of differentiation of CD33 (equivalent to mouse GDI lb+) Grl+ cells. We will further determine if exosomes packed with CSN5 circulate in the peripheral blood of patients with breast cancer and if overproduction of exosomes is correlated with the accumulation of iMCs in patients with breast cancer. RELEVANCE: The data generated should identify a novel mechanism for the actions of curcumin and identify its molecular targets in preventing CSN5/tumor exosome-mediated blockade of myeloid cell differentiation.

project_terms:
Address;Antineoplastic Agents;BARD1 gene;Biological Assay;Cancer Patient;Cell Differentiation process;Cells;Chemopreventive Agent;Co-Immunoprecipitations;Complex;Curcuma longa;Curcumin;Data;Doctor of Medicine;Doctor of Philosophy;Growth;Guanine Nucleotide Dissociation Inhibitors;Human;ITGAM gene;Immune;In Vitro;Knock-out;Malignant Neoplasms;Mammary Neoplasms;Mediating;Modeling;Molecular;Molecular Target;Mus;Myelogenous;Myeloid Cells;Natural immunosuppression;Nude Mice;Pathway interactions;Patients;Phosphorylation;Phosphorylation Inhibition;Phosphotransferases;Play;Prevention;Production;Protein Dephosphorylation;Proteomics;RCA1 gene;Research Personnel;Rhizome;Role;Screening procedure;Site;Small Interfering RNA;Spleen;T-Lymphocyte;Technology;Treatment Efficacy;Tumor Cell Line;Tumor Suppressor Genes;Ubiquitination;Yeasts;attenuation;chemotherapeutic agent;clinically relevant;equilibration disorder;in vitro testing;in vivo;malignant breast neoplasm;mouse model;neoplastic cell;novel;overexpression;peripheral blood;polyphenol;prevent;programs;tumor;tumor growth;ubiquitin-protein ligase;yeast two hybrid system


application_id: 8050040
project_number: 5P01AG005119-22
project_title: ANIMAL CORE
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 005119
study_section: ZAG1
subproject_number: 9005
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
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: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
This program project will primarily use genetic modified mice. The Animal Core will provide essential
genetically modified mice and control wild-type mice to support the research of all four projects. To
accomplish this objective the Animal Core will be responsible for: 1) establishing maintaining and breeding
the required numbers and ages of knock-in knockout and transgenic mice; 2) characterizing gene altered
mice using molecular biochemical and pathological methods to ensure genotype and phenotypes; 3)
performing the complex genetic crosses required to obtain mice with the desired combinations of mutations;
and 4) providing pups at the desired gestation stages and ages to establish primary culture cells. By
coordinating and standardizing animal and cell use among projects animals money and time will be saved.
Providing every project with animals and cells derived in the same manner will make it possible to crosscorrelate
information from the projects which will result in synergistic use of the animals and the data
generated. The Animal Core will also work closely with the Administrative Core and Core B to help the
project leaders plan and/or define their studies.

project_terms:
APP-PS1;Age;Age-Months;Alzheimer's Disease;Amyloid;Amyloid beta-Protein;Animal Model;Animals;Biochemical;Brain;Breeding;Cell Culture Techniques;Cells;Clinical;Complex;Consultations;Deposition;Development;Disease;Embryo;Ensure;Excision;Funding;Generations;Genes;Genetic;Genetic Crosses;Genotype;Histologic;Histopathology;In Vitro;Individual;Knock-in Mouse;Knock-out;Leucine;Mediating;Methionine;Methods;Microglia;Molecular;Monitor;Mus;Mutate;Mutation;NADP;NADPH Oxidase;Neurons;Newborn Infant;Oxidative Stress;Pathologic;Phenotype;Pregnancy;Primary Cell Cultures;Rattus;Research Design;Research Personnel;Research Support;Rodent;Role;Schedule;Source;Southern Blotting;Staging;Techniques;Time;Transgenic Mice;Transgenic Organisms;Wild Type Mouse;Work;animal data;base;brain cell;postnatal;prevent;programs;pup;research study;success


application_id: 8050039
project_number: 5P01AG005119-22
project_title: BETA-AMYLOID CORE
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 005119
study_section: ZAG1
subproject_number: 9004
contact_pi_person_id: 8425703
contact_pi: MURPHY, PAUL M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
A major problem in amyloid-p peptide (A(3) related research is the inconsistency introduced by the
multiple and varied protocols employed by different laboratories for isolating analyzing quantifying
preparing and handling Af3; the centralization of procedures within this Core will circumvent these
inconsistencies. This Core thus has two specific aims: to provide an A(3 index to each project and to supply
A(3 to each project.
Ap index: Different aspects of Ap (concentration physiological properties deposition etc.) are often
measured in isolation. To date a comprehensive assessment of these aspects has not been performed in
the same tissue. For each project Core B will collect and collate from both human and rodent tissues the
following data: (a) the amounts of Ap (including AP40 and A042) and its solubility (b) the amounts of
oligomeric and fibrillar Ap and (c) the number of neuritic and non-neuritic plaques. These data will allow the
determination of the relationship(s) between individual changes in Ap and the various neurochemical end
point measures studied in the different projects.
Supply Ap: Evaluation of the physiological properties and toxicity of Ap has been hampered by
inconsistencies caused by variability in every possible aspect of Ap handling. Core B will maintain
consistency between projects by controlling each of these different variables (peptide acquisition and
storage preparation and quantification of oligomers and fibrils quantification of toxicity) through adherence
to established standardized protocols and through maintenance of rigid quality control. The novelty of this
Core is its thoroughness. We have assembled a unique group of investigators who together possess
proven expertise for each function of Core B. Utilizing methods that are well characterized and established in
their respective laboratories this team-oriented approach will allow the first comprehensive multifaceted
analysis of Ap in vivo and in vitro. Ultimately this will provide an unprecedented level of thoroughness and
rigor to Ap analysis imparting much needed fidelity and continuity to project data. First and foremost the
data and materials generated in Core B will allow the individual projects to correlate each of their individual
neurochemical alterations to different aspects of Ap assembly deposition and toxicity.

project_terms:
AP40;Adherence (attribute);Amyloid;Amyloid beta-Protein;Data;Deposition;Evaluation;Human;In Vitro;Individual;Laboratories;Maintenance;Measures;Methodology;Methods;Peptides;Physiological;Preparation;Procedures;Property;Protocols documentation;Quality Control;Research;Research Personnel;Rodent;Senile Plaques;Solubility;Tissues;Toxic effect;in vivo;indexing;neurochemistry;peptide A


application_id: 8050037
project_number: 5P01AG005119-22
project_title: AB AND NADPH OXIDASE IN MILD COGNITIVE IMPAIRMENT AND ALZHEIMER'S DISEASE
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 005119
study_section: ZAG1
subproject_number: 0012
contact_pi_person_id: 2306174
contact_pi: BRUCE-KELLER, ANNADORA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Alzheimer's disease (AD) is the major age-related dementia and is expected to take an increasing toll on
society as the population ages. Histopathologically while the diagnostic criterion for AD is the presence of
amyloid-containing plaques and neurofibrilliary tangles AD brains are typified by increased oxidative stress
and focal neuronal death. While the exact relationship between beta amyloid (AP) deposition oxidative
stress and neuronal injury is still unresolved increasing evidence suggests that the NADPH oxidase system
may be altered in AD and in response to Ap. NADPH oxidase (NOX) originally described as the main
component of the leukocyte oxidative burst produces reactive oxygen species (ROS) that are involved in
both intracellular signaling and oxidative stress. NOX expression has been established in neurons thus
raising the possibility that aberrant activation of neuronal NOX by toxic forms of A(3 could contribute to ADrelated
neuronal alterations. The focus of this project is to test the hypothesis that sustained activation of
NOX by Ap triggers a pernicious cascade linking increases in ROS production to altered intracellular redoxbased
signaling and oxidative stress culminating in neuron degeneration and death. The specific aims to
test this hypothesis are as follows: 1) To test the hypothesis that NOX activity is increased during the
progression of AD; 2) To test the hypothesis that NOX activity is increased in response to increasing Ap
deposition in a specific APP/PS1 knock-in mouse model of amyloidogenesis; 3) To test the hypothesis that
toxic forms of Ap increase neuronal oxidative stress and cell death via NOX; 4) To test the hypothesis that
microglial NOX activation exacerbates neuronal responses to AP; and 5) To test the hypothesis that genetic
or pharmacologic ablation of NOX in the APP/PS1 transgenic mice attenuates oxidative stress and Ap
pathogenesis in vivo. The proposed experiments will make use of our extensive and well-characterized
tissue bank of human brain specimens as well as a novel and highly relevant mouse model of beta amyloid
pathogenesis. Finally studies will determine the specific effects of distinct physiological forms of AP(1-40/1-
42/oligomer/fibrillar) on NOX activation both in vitro and in vivo. Completion of these studies will result in a
more thorough understanding of the relationship between Ap deposition and AD-related neuronal pathology
and could highlight an innovative and highly promising target for therapeutic intervention in AD.

project_terms:
4 hydroxynonenal;APP-PS1;Ablation;Affect;Age;Age-Months;Alzheimer's Disease;Amyloid;Amyloid beta-Protein;Amyloid deposition;Attenuated;Automobile Driving;Biochemical;Brain;Brain region;Cell Death;Cerebellum;Cessation of life;Characteristics;Clinical;Data;Dementia;Deposition;Diagnostic;Dose;Free Radicals;Frontotemporal Dementia;Future;Genetic;Genetic Techniques;Hippocampus (Brain);Histological Techniques;Human;Impairment;In Vitro;Inferior;Inflammation;Inflammatory;Injury;Knock-in Mouse;Link;Lobule;Measures;Mediating;Methods;Microglia;Mitochondria;Modeling;Monitor;Mus;NADPH Oxidase;Nerve Degeneration;Neurofibrillary Tangles;Neuroglia;Neuronal Injury;Neurons;Oxidases;Oxidation-Reduction;Oxidative Stress;Parietal;Pathogenesis;Pathology;Patients;Physiological;Population;Production;Proteins;RNA;Reactive Oxygen Species;Regulation;Respiratory Burst;Role;Senile Plaques;Signal Transduction;Societies;Specimen;Staging;Structure of middle temporal gyrus;Sum;System;Testing;Therapeutic Intervention;Time;Tissue Banking;Tissue Banks;Tissues;Transgenic Mice;acetovanillone;age related;amyloidogenesis;attenuation;base;disorder control;in vivo;indexing;inhibitor/antagonist;innovation;mild cognitive impairment;mind control;mouse model;neuron loss;neuropsychological;neurotoxic;neurotoxicity;nitration;novel;novel strategies;oxidation;pre-clinical;research study;response


application_id: 8050036
project_number: 5P01AG005119-22
project_title: AB AND RAGE INTERACTIONS IN ALZHEIMER'S DIESEASE
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 005119
study_section: ZAG1
subproject_number: 0011
contact_pi_person_id: 7875104
contact_pi: KELLER, JEFFREY NEIL
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: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The receptor for advanced glycosylation end products (RAGE) has been implicated in mediating beta
amyloid (A(3) toxicity and contributing to Alzheimer's disease (AD) pathogenesis although the specifics on
many aspects of RAGE biology and toxicity remain to be elucidated. Recent reports have demonstrated
that in contrast to the transmembrane RAGE receptor the secreted or soluble forms of RAGE (sRAGE) are
capable of suppressing several aspects of Ap pathogenesis in vivo. Pilot studies from our laboratory
demonstrate that sRAGE suppresses the formation of assembled A(3 species and Ap -induced neurotoxicity
with sRAGE interacting with the oligomeric forms of Ap at higher apparent affinity than monomeric Ap.
However it is currently not known which regions of sRAGE are responsible for mediating each of these
observations. The goal of this proposal is to test two related hypotheses. The first hypothesis is that
increases in RAGE-ligand interactions occur during the progression of AD and in a transgenic
mouse model of Ap pathogenesis with oligomeric Ap representing a significant portion of the overall
RAGE-ligand interactions. The second hypothesis is that sRAGE inhibits the formation of pathogenic
p and the effects of pathogenic Ap via specific and related domains within the sRAGE protein. The
specific aims to test each of these hypotheses are as follows: 1) To define the alterations in RAGE-ligand
interactions in AD and APP/PS-1 mice 2) To elucidate the functional domains responsible for RAGE- Ap
interactions 3) To determine the mechanism by which sRAGE suppresses Ap-induced neurotoxicity and 4)
To determine the mechanism by which sRAGE suppresses Ap assembly and Ap deposition. Cumulatively
these data will advance the field by potentially identifying novel therapeutic strategies that could lead to
eventual treatments for AD. Additionally these findings will be critical in clarifying the current gaps that exist
in our understanding of RAGE with Ap-assembly Ap-deposition and Ap-induced neurotoxicity.

project_terms:
Advanced Glycosylation End Products;Affinity;Alzheimer's Disease;Amyloid beta-Protein;Biology;Data;Deposition;Goals;Laboratories;Lead;Ligands;Mediating;Mus;Pathogenesis;Pilot Projects;Proteins;Reporting;Testing;Toxic effect;Transgenic Mice;amyloidogenesis;in vivo;mouse model;neurotoxicity;novel therapeutics;receptor;receptor for advanced glycation endproducts


application_id: 8050035
project_number: 5P01AG005119-22
project_title: BRAIN PROTEIN OXIDATION IN AD MCI AND PCAD: ROLES OF AB AND PIN1
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 005119
study_section: ZAG1
subproject_number: 0010
contact_pi_person_id: 8329002
contact_pi: BUTTERFIELD, D. ALLAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Oxidative stress is present in Alzheimer's disease (AD) brain and we recently provided evidence that protein
oxidation and lipid peroxidation are also present in brains of persons with mild cognitive impairment (MCI).
Our lab first used redox proteomics to identify oxidatively modified proteins in AD and MCI brain. One
protein that is oxidatively modified and dysfunctional in both AD and MCI is Pin1 a regulatory protein of
many functions relevant to neurodegeneration. One source of oxidative stress in AD is amyloid beta-peptide
(AP). The single methionine (Met) of Ap appears to be critical to the oxidative stress induced by Ap. Our
overall hypothesis is A(3-mediated oxidative modification of brain Pin1 is fundamental to the progression of
AD and occurs via mechanisms involving the single Met of AfJ. To test this overall hypothesis a series of
Specific Aims are proposed. In Specific Aim 1 oxidative stress indices and redox proteomics of preclinical
AD (PCAD) brain will be undertaken to test the hypothesis that Pin 1 is oxidatively modified and must be
important in the progression of AD. In Specific Aim 2 to determine the temporal role of toxic aggregated AP
in the in vivo oxidative modification of Pin 1 we will use redox proteomics to test the hypothesis that in
human mutant APP/PS-1 knock in mice oxidative modification and dysfunction of Pin1 will occur. In Specific
Aim 3 we will test the hypothesis that Pin 1 in neuronal cultures will be oxidatively dysfunctional by
aggregated toxic forms of Ap. In Specific Aim 4 we will test the hypothesis that in vivo elevation of Pin 1 will
result in decreased levels of phospho-tau and Ap in brain of APP/PS-1 mice. In Specific Aim 5 we will test
the hypothesis that mechanisms involving the single Met residue of Ap are paramount in the in vivo toxic
properties of Ap including the oxidative modification of Pin1. In each Aim correlation of the status of Ap
(type solubility oligomerization etc. determined by Core B) will be made. This proposal reflects a set of
comprehensive and integrated studies that utilizes a variety of novel methodologies and that takes
advantage of our expertise in oxidative stress Ap and redox proteomics applied to AD. Dr. K.P. Lu
(Harvard) an acknowledged leader in Pin 1 research will serve as a Senior Investigator and provide
additional expertise. New insights into the oxidative stress neurodegeneration and progression of AD are
envisaged as are insights into a potential treatment to slow or disrupt progression of MCI to AD.

project_terms:
Abeta synthesis;Accounting;Affect;Affinity;Age-Months;Alanine;Alzheimer's Disease;Alzheimer's disease model;Amyloid beta-Protein;Amyloid beta-Protein Precursor;Autopsy;Binding (Molecular Function);Binding Sites;Biological Assay;Brain;Brain region;Caenorhabditis elegans;Cerebellum;Cerebral cortex;Cessation of life;Codon Nucleotides;Collaborations;Cysteine;Data;Dementia;Dependovirus;Depressed mood;Digestion;Disease;Electrospray Ionization;Ensure;Environment;Event;Free Radicals;Functional disorder;Human;Hydrophobicity;In Vitro;Individual;Institutes;Isomerase;Knock-in Mouse;Laboratories;Lead;Length;Leucine;Lipid Peroxidation;Measures;Mediating;Mediator of activation protein;Methionine;Methodology;Methods;Microtubules;Modeling;Modification;Mus;Mutate;N-terminal;NADPH Oxidase;Nerve Degeneration;Neurofibrillary Tangles;Neurons;Norleucine;Oxidation-Reduction;Oxidative Stress;Pathogenesis;Pathology;Peptides;Peptidylprolyl Isomerase;Persons;Play;Positioning Attribute;Process;Progress Reports;Proline;Property;Protein Binding;Protein Biosynthesis;Protein Dephosphorylation;Proteins;Proteomics;RNA;Recombinants;Research;Research Personnel;Role;Senile Plaques;Series;Serine;Side;Site;Small Interfering RNA;Solubility;Source;Specificity;Staging;Tauopathies;Testing;Therapeutic Intervention;Threonine;Time;Transgenic Mice;Transgenic Organisms;Triose-Phosphate Isomerase;Western Blotting;Wild Type Mouse;abeta deposition;abeta toxicity;aging brain;base;disorder control;genetic regulatory protein;human DNA;in vivo;in vivo Model;indexing;insight;knock-down;mild cognitive impairment;mind control;mutant;nervous system disorder;neurotoxic;neurotoxicity;novel;numb protein;oxidation;oxidative damage;pre-clinical;protein aminoacid sequence;success;tandem mass spectrometry;tau Proteins;tau phosphorylation;therapeutic target


application_id: 8050034
project_number: 5P01AG005119-22
project_title: BETA AMYLOID-INDUCED RNA OXIDATION AS A MEDIATOR OF AD PATHOGENESIS
administering_ic: NIA
application_type: 5
activity_code: P01
ic: AG
serial_number: 005119
study_section: ZAG1
subproject_number: 0009
contact_pi_person_id: 1894359
contact_pi: MARKESBERY, WILLIAM 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: 2010-04-01
budget_end_date: 2011-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Alzheimer's disease (AD) is one of the major health problems in the United States and as our population
ages it will become more prominent unless measures to treat or prevent it are found. Understanding the
pathogenesis of selective neuron degeneration in AD is the key to defining preventive or therapeutic
measures. There is a rapidly increasing body of knowledge that indicates free radical-mediated oxidative
damage is involved in the pathogenesis of AD. Our recent studies have demonstrated significant oxidative
damage to brain lipids proteins DMA and RNA in amnestic mild cognitive impairment the earliest
detectable phase of AD indicating that oxidative damage is an early event in AD and not secondary to
neurodegeneration. The major hypothesis of this proposal is that RNA oxidation in early AD is mediated in
part by amyloid-beta peptide (AP) that promotes impairment of protein synthesis and neuron dysfunction. In
Specific Aims 1 and 2 we will quantify RNA oxidation and aldehydic modifications in neurons in the
progression of AD from normal to MCI to late AD (LAD) and in the APP/PS1 knock-in transgenic mice over
time using immunohistochemistry confocal microscopy and antibodies against 8-OHG acrolein/guanine
adducts and MC-1. In the same brain regions of normal controls disease controls (frontotemporal
dementia) MCI and LAD and brain specimens from APP/PS-1 mice we will quantify RNA oxidation in
purified pools of rRNA tRNA and mRNA by GC-MS-SIM and acrolein-modified guanine in these pools using
LC-MS-MS. In Specific Aim 3 we will determine the ability of toxic and non-toxic Ap from Core B to define
RNA oxidation and acrolein/guanine adducts in cultured neurons and compare this with the RNA oxidation
observed in vivo in Specific Aims 1 and 2. In Specific Aim 4 we will determine if the individual mRNAs
oxidized in response to Ap in vitro are also oxidized in the brains of control subjects and MCI LAD and
frontotemporal dementia patients. We will then determine whether the predicted proteins encoded by the
oxidized mRNAs exhibit decreased expression and function in the progression from normal to MCI to LAD.
Specific Aim 5 will define the ability of histone deacetylase inhibitors to ameliorate Ap-induced neurotoxicity
in vitro and in the APP/PS1 transgenic mice. We have preliminary data in all specific aims indicating the
feasibility of these studies. By conducting these studies in an unbiased manner and allowing the neurons
and brain specimens to guide us we will define how Ap promotes neuron dysfunction in AD. This study has
the potential of identifying molecular targets for development of therapeutic agents aimed at reducing neuron
injury and slowing the progression of or potentially preventing AD.

project_terms:
APP-PS1;Acrolein;Affect;Age;Age-Months;Alzheimer's Disease;Amino Acid Substitution;Amyloid beta-Protein;Antibodies;Antioxidants;Attenuated;Autopsy;Brain;Brain region;Cerebellum;Cerebral cortex;Confocal Microscopy;DNA;Data;Deposition;Development;Enzymes;Event;Exhibits;Feasibility Studies;Free Radicals;Frontotemporal Dementia;Functional disorder;Guanine;Health;Hippocampus (Brain);Histone Deacetylase Inhibitor;Human;Immunohistochemistry;Impairment;In Vitro;Individual;Inferior;Injury;Ions;Knock-in Mouse;Knowledge;L-Selenomethionine;Link;Lipid Peroxidation;Lipids;Lobule;Manganese Superoxide Dismutase;Mass Fragmentography;Measures;Mediating;Mediator of activation protein;Messenger RNA;Methods;Mitochondria;Modification;Molecular Target;Monitor;Motor Cortex;Mus;Mutant Strains Mice;NADPH Oxidase;Nerve Degeneration;Neuronal Injury;Neurons;Nuclear;Oxidative Stress;Parietal;Pathogenesis;Pathology;Patients;Pattern;Peptides;Phase;Play;Population;Preventive;Property;Protein Biosynthesis;Proteins;RNA;Relative (related person);Ribosomal RNA;Rodent;Role;Rotenone;Secondary to;Selenomethionine;Specificity;Specimen;Staging;Structure of middle temporal gyrus;Study Section;Testing;Therapeutic;Therapeutic Agents;Time;Toxin;Transfer RNA;Transgenic Mice;Translations;United States;Wild Type Mouse;Yeasts;adduct;amyloidogenesis;base;biomarker;copper zinc superoxide dismutase;disorder control;enzyme activity;glutathione peroxidase;in vivo;in vivo Model;indexing;inhibitor/antagonist;male;mild cognitive impairment;mind control;mouse model;neurotoxicity;novel therapeutics;oxidation;oxidative DNA damage;oxidative damage;pre-clinical;prevent;programs;response;stressor;time use;usability


application_id: 8049664
project_number: 5P01HL086670-05
project_title: HDL Function and Metabolism During Inflammation
administering_ic: NHLBI
award_notice_date: 2011-03-07
application_type: 5
activity_code: P01
ic: HL
serial_number: 086670
program_official: HASAN, AHMED A K
project_start_date: 2007-04-01
project_end_date: 2013-03-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
contact_pi_person_id: 7875298
contact_pi: VAN DER WESTHUYZEN, DENEYS REM
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: 2011-04-01
project_abstract:
DESCRIPTION (provided by applicant)    Atherosclerosis is the leading cause of mortality in the western world. Unlike LDL HDL levels are inversely correlated with the risk of atherosclerosis. HDL exerts its protective effect through several putative mechanisms in large part through its ability to promote the so-called reverse cholesterol transport pathway.  Atherosclerosis and inflammation share intimate associations and the atherosclerotic process exhibits features of a chronic inflammation. Inflammation is known to significantly alter HDL structure and composition as well as plasma levels of HDL cholesterol and apolipoproteins but the underlying mechanisms and the consequences of such changes on atherosclerotic disease are not understood. In studying the impact of HDL on atherosclerosis it is therefore critical to understand how HDL may be modified as a result of inflammation both systemically and within the inflammatory microenvironment of the atherosclerotic lesion. The Central Unifying Theme of this program project is an understanding of how inflammation alters HDL structure and metabolism and how such changes influence the development of atherosclerosis. The program comprises three inter-dependent and synergistic projects to address these questions: Project 1 "HDL structure and metabolism during inflammation" (PI Frederick C. de Beer) will address how inflammation alters HDL remodeling through the actions of secreted phospholipases SAA and CETP; Project 2 "Inflammation HDL and Class B Scavenger Receptors" (PI van der Westhuyzen) will determine how inflammation and SAA impact cellular lipid trafficking by Class B scavenger receptors; Project 3 "Macrophage cholesterol efflux during inflammation" (PI Nancy R. Webb) will investigate the effect of inflammatory modifications of HDL on macrophage cholesterol efflux and atherosclerotic risk. The major goals of the program are to understand how HDL structure and metabolism are altered during inflammation and to determine how such changes influence HDL's function particularly its roles in cellular cholesterol efflux and plasma cholesterol transport and its influence on atherosclerosis. The program is expected to make significant contributions towards elucidating how the inflammatory process affects HDL and cholesterol metabolism and the extent to which such effects impact atherosclerotic disease.


application_id: 8049663
project_number: 5P01HL086670-04
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: 2010-04-01
budget_end_date: 2011-03-31
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;Human Resources;Hygiene;Location;Progress Reports;Radioactivity;Resources;Services;Travel;animal care;human subject;meetings;programs;web site


application_id: 8049662
project_number: 5P01HL086670-04
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: 2010-04-01
budget_end_date: 2011-03-31
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;Housing;Infusion procedures;Kinetics;Ligands;Lipoproteins;Location;Maintenance;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: 8049661
project_number: 5P01HL086670-04
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: 2010-04-01
budget_end_date: 2011-03-31
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;Ampholine;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;Dialysis procedure;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;Hydrolysis;Imagery;In Vitro;Incubated;Individual;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;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: 8049660
project_number: 5P01HL086670-04
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: 2010-04-01
budget_end_date: 2011-03-31
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;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: 8049620
project_number: 5R01DK071349-07
project_title: Mechanisms Underlying Metabolic Syndrome in Obesity
administering_ic: NIDDK
award_notice_date: 2011-03-17
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 071349
program_official: ABRAHAM, KRISTIN M
project_start_date: 2005-06-01
project_end_date: 2014-03-31
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: KERN, PHILIP A
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Resident macrophages in adipose tissue account for much of the cytokine expression with obesity. We described the expression of thrombospondin (TSP1) a pleiotropic adipokine in insulin resistant subjects. Through its anti-angiogenic properties and its ability to activate TGF2 TSP1 may be an important part of the adipocyte/macrophage interaction that results in simultaneous impairment of angiogenesis and increased TGF- 2-mediated fibrosis and inflammation. We recently demonstrated that macrophages also infiltrate skeletal muscle with obesity that is strongly correlated with insulin resistance. Furthermore the presence of macrophages in co-culture with muscle cells in the presence of palmitic acid to mimic an obese environment results in a synergistic increase in the expression and secretion of inflammatory cytokines from muscle cells all of which impair insulin action. We hypothesize that macrophages in both muscle and adipose tissues promote the development of metabolic syndrome during obesity. To test this hypothesis adipose (Aim 1) and muscle tissue (Aim 2) from obese insulin resistant compared to normal human subjects will be characterized. Macrophage number the proportion of macrophages that are classically versus alternatively activated and the proportion of macrophages in crown-like structures (in adipose) will be quantified along with markers of the TGF2 pathway fibrosis hypoxia tissue remodeling and vascularity. To specifically determine the role of TSP1 and the TGF2 pathway in insulin resistance adipose and muscle tissue fibrosis hypoxia and macrophage function will be analyzed in high fat fed TSP1 null mice in Aim 3. A peptide that specifically blocks TSP1- mediated TGF2 activation will also be used in wild type high fat fed mice to test the hypothesis that macrophage infiltration and fibrosis in adipose and muscle will be ameliorated in the absence of TSP1 resulting in improved insulin sensitivity. Aim 4 is the intervention aim in which the mechanisms underlying the beneficial effects of aerobic exercise training on insulin sensitivity will be determined. Following 12 weeks of training in obese and lean subjects changes in muscle and adipose macrophage number activation state the TSP1/TGF2 pathway and inflammation in response to a single bout of eccentric exercise will be quantified relative to insulin sensitivity. Finally in Aim 5 the effects of different macrophage populations on adipocytes and muscle cells will be studied in vitro. The expression of genes involved in adipogenesis extracellular matrix and the TGF2 pathway will be monitored in adipocytes following macrophage co-culture. These will also be quantified in muscle cells as well as the response to insulin. We will determine whether mechanical stimulation of myotubes to mimic exercise will alter the muscle cell response to macrophages.  
  
PUBLIC HEALTH RELEVANCE:  The American population is experiencing an explosion in obesity metabolic syndrome and diabetes and this national trend is magnified in Kentucky and the Southeast. The cost of caring for diabetes and its complications is enormous. Impaired glucose tolerance and metabolic syndrome are preludes to the development of type 2 diabetes represent a risk factor for coronary artery disease and are more prevalent than diabetes itself. These studies are intended to examine fundamental mechanisms of insulin resistance and inflammation and involve studies in humans mice and cell culture. New insight into these fundamental mechanisms may form the basis for new treatments.

project_terms:
Accounting;Adipocytes;Adipose tissue;Aerobic Exercise;American;Anti-Inflammatory Agents;Anti-inflammatory;Area;Arkansas;Award;Budgets;Caring;Cell Culture Techniques;Chronic;Clinical;Coculture Techniques;Collaborations;Coronary Arteriosclerosis;Data;Dental crowns;Development;Diabetes Mellitus;Doctor of Philosophy;Environment;Etiology;Exercise;Explosion;Extracellular Matrix;Fatty acid glycerol esters;Fibrosis;Functional disorder;Funding;Funding Mechanisms;Gene Expression;Goals;Grant;Human;Hypoxia;Impairment;In Vitro;Individual;Infiltration;Inflammation;Inflammatory;Insulin;Insulin Resistance;Interleukin-1;Interleukin-6;Intervention;Kentucky;Knockout Mice;Link;Mechanical Stimulation;Mediating;Medical;Metabolic syndrome;Monitor;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscle function;Necrosis;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Palmitic Acids;Pathway interactions;Phenotype;Population;Process;Property;Relative (related person);Research Personnel;Risk Factors;Role;Science;Signal Pathway;Skeletal muscle structure;Stretching;Structure;System;TNF gene;Talents;Testing;Thrombospondin 1;Time;Tissues;Training;United States National Institutes of Health;Universities;Update;Vascularization;Work;adipokines;adiponectin;angiogenesis;base;cost;cytokine;experience;feeding;human subject;impaired glucose tolerance;improved;in vitro Model;innovation;insight;insulin sensitivity;insulin signaling;lipid biosynthesis;lipid metabolism;macrophage;peptide A;programs;public health relevance;repaired;response;stem;trend

public_health_relevance:
Project NarrativeThe American population is experiencing an explosion in obesity metabolic syndrome and diabetes and thisnational trend is magnified in Kentucky and the Southeast. The cost of caring for diabetes and itscomplications is enormous. Impaired glucose tolerance and metabolic syndrome are preludes to thedevelopment of type 2 diabetes represent a risk factor for coronary artery disease and are more prevalentthan diabetes itself. These studies are intended to examine fundamental mechanisms of insulin resistance andinflammation and involve studies in humans mice and cell culture. New insight into these fundamentalmechanisms may form the basis for new treatments.


application_id: 8049608
project_number: 5R21AR053967-02
project_title: The role of endonuclease G in nuclear apoptosis of atrophying skeletal muscle
administering_ic: NIAMS
award_notice_date: 2011-03-14
opportunity_number: PA-09-164
application_type: 5
activity_code: R21
ic: AR
serial_number: 053967
program_official: NUCKOLLS, GLEN H
project_start_date: 2010-04-01
project_end_date: 2013-03-31
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1884084
contact_pi: DUPONT-VERSTEEGDEN, ESTHER E
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Skeletal muscle atrophy is an important determinant in the loss of independence in elderly and is associated with poor prognosis in chronic disease states. Identifying mechanisms of atrophy will enable us to develop therapeutic strategies to prevent or treat the loss of muscle mass. We have shown previously that myofiber nuclear apoptosis occurs in muscles undergoing disuse-induced or age-associated muscle atrophy and that the caspase-independent mitochondrial enzyme endonuclease G (EndoG) is translocated to nuclei during atrophy possibly inducing DNA fragmentation in a subset of nuclei. Therefore we hypothesize that nuclear apoptosis which occurs in atrophying skeletal muscle is mediated by EndoG. In Specific Aim 1 we will determine whether EndoG is required for the apoptotic response in skeletal muscle during disuse atrophy using EndoG knockout (KO) mice. Mice will be hind limb suspended (HS) and nuclear loss apoptosis and atrophy will be assayed. In addition we hypothesize that increased permeability of the nuclear membrane due to elevated oxidative stress with atrophy is necessary for EndoG to enter the nucleus. Wild type (WT) mice will be treated with an iron-chelator and translocation of EndoG oxidative damage nuclear endonuclease activity and nuclear apoptosis will be measured. In Specific Aim 2 we will study the consequences of nuclear changes on skeletal muscle atrophy. First permeability changes of nuclei of WT mice after (HS) will be studied in vitro and correlated to oxidative stress to determine whether this is directly responsible for the entry of molecules into the nucleus. Additionally we will test directly whether the loss of nuclei induces atrophy by eliminating muscle nuclei by laser ablation and assaying for muscle atrophy and protein loss. Lastly we propose to develop an in vitro model of disuse atrophy by mechanical stimulus withdrawal and compare this to an in vitro atrophy model of oxidative stress. The role of EndoG in nuclear apoptosis in these models will be tested. In summary the proposed experiments will enable us to determine the role of EndoG-mediated nuclear apoptosis in skeletal muscle atrophy. These results may be not only be used to develop strategies to combat muscle atrophy but may also yield novel insight into mechanisms of apoptosis in other tissues. Relevance to public health: Muscle atrophy is associated diseases such as cancer AIDS and congestive heart failure and has been suggested as a main contributor to the loss of independence in elderly. We showed that apoptosis is an important event in the process of muscle atrophy. Identifying underlying mechanisms may lead to therapeutic interventions not just in decreasing atrophy but in preventing it. Additionally identifying pathways and molecules underlying the process of nuclear apoptosis in muscle will increase our knowledge about apoptosis in other tissues as well likely leading to interventions and treatments in fields such as cancer.  
  
PUBLIC HEALTH RELEVANCE: Skeletal muscle atrophy is associated diseases such as cancer AIDS and congestive heart failure and has been suggested as a main contributor to the loss of independence in elderly. We have shown that nuclear apoptosis is an important event in the process of muscle atrophy. Identifying underlying mechanisms may lead to new therapeutic interventions not just in decreasing atrophy but particularly in preventing it. Additionally identifying pathways and molecules underlying the process of nuclear apoptosis in muscle will increase our knowledge about apoptosis in other tissues as well possibly leading to new interventions and treatments in fields such as cancer.

project_terms:
Ablation;Acquired Immunodeficiency Syndrome;Age;Animals;Apoptosis;Apoptotic;Atrophic;Attenuated;Biological Assay;Biological Models;Cell Membrane Permeability;Cell Nucleus;Cessation of life;Chelating Agents;Chronic Disease;Congestive Heart Failure;DNA Fragmentation;Data;Deferoxamine;Development;Disease;Disuse Atrophy;Elderly;Enzymes;Event;Exhibits;Exploratory/Developmental Grant for Diagnostic Cancer Imaging;GTP-Binding Proteins;Gastrocnemius muscle structure;Goals;In Vitro;Intervention;Iron;Knockout Mice;Knowledge;Lasers;Lead;Limb structure;Location;Malignant Neoplasms;Measures;Mechanics;Mediating;Mitochondria;Mitochondrial Proteins;Modeling;Molecular;Mus;Muscle;Muscle Fibers;Muscle Proteins;Muscular Atrophy;NIH Program Announcements;Nuclear;Nuclear Envelope;Oxidative Stress;Pathway interactions;Permeability;Process;Protein Biosynthesis;Regulation;Research;Research Project Grants;Research Proposals;Role;Skeletal muscle structure;Soleus muscle structure;Stimulus;Structure;Study models;Suspension substance;Suspensions;System;Testing;Therapeutic;Therapeutic Intervention;Time;Tissues;United States National Institutes of Health;Wild Type Mouse;Withdrawal;Work;age related;base;caspase;combat;endonuclease;endonuclease G;in vitro Model;innovation;insight;interstitial cell;muscle form;novel;novel therapeutic intervention;outcome forecast;oxidative damage;prevent;protein degradation;public health medicine (field);public health relevance;research study;response;sarcopenia

public_health_relevance:
NarrativeSkeletal muscle atrophy is associated diseases such as cancer AIDS and congestive heart failure and hasbeen suggested as a main contributor to the loss of independence in elderly. We have shown that nuclearapoptosis is an important event in the process of muscle atrophy. Identifying underlying mechanisms may leadto new therapeutic interventions not just in decreasing atrophy but particularly in preventing it. Additionallyidentifying pathways and molecules underlying the process of nuclear apoptosis in muscle will increase ourknowledge about apoptosis in other tissues as well possibly leading to new interventions and treatments infields such as cancer.


application_id: 8049179
project_number: 5R01DK078175-04
project_title: A Prevascularized Islet Immunoisolation Device
administering_ic: NIDDK
award_notice_date: 2011-03-17
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 078175
program_official: APPEL, MICHAEL C
project_start_date: 2008-04-01
project_end_date: 2013-03-31
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 7715841
contact_pi: WILLIAMS, STUART K
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: ORGANIZED RESEARCH UNITS
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Beta-cell replacement therapy via islet transplantation remains a promising technology for the reversal of type 1 diabetes. A significant barrier to the clinical utilization of beta cell transplants has been the lack of a host-derived blood supply to maintain the viability and thus the function of transplanted cells. We have developed a new cell-based therapy for the generation of pre-vascularized tissue engineered constructs. We have also developed a new generation of biomaterials that support extensive neovascularization. The combined cell and material construct to be evaluated is termed a Prevascularized Immuno-Isolation Device or PVID. We propose to use these materials in the development of a new beta-cell immuno-isolation device to prolong beta cell viability and function. These constructs represent a pre-formed microcirculation that can be constructed from a patient's own fat-derived microvascular endothelial cells avoiding the use of immuno- suppressive drugs. Specific aim 1 will evaluate the maturation of the microcirculation within a prevascularized construct following implantation in an animal model. Specific aim 2 will evaluate novel porous biomaterials and material surface modification to support the neovascularization of the porous material to assure perfusion of encapsulated islets. The biomaterial developed is a two component hybrid system that also provides immunoisolation for the encapsulated islets. Specific aim 3 will evaluate the viability and function of islets encapsulated in the prevascularized immunoisolation devices in an animal model of diabetes.

project_terms:
Address;Animal Model;Autologous;Beta Cell;Biocompatible Materials;Blood Circulation;Cell Survival;Cell Therapy;Cell Transplantation;Cell Transplants;Cell physiology;Cells;Chronic;Clinical;Clinical Trials;Collagen;Development;Devices;Diabetes Mellitus;Encapsulated;Endothelial Cells;Environment;Evaluation;Failure (biologic function);Fatty acid glycerol esters;Gel;Generations;Goals;Graft Survival;Healed;Hybrids;Hyperglycemia;Insulin;Insulin-Dependent Diabetes Mellitus;Islet Cell;Islets of Langerhans;Islets of Langerhans Transplantation;Knowledge;Laboratories;Lead;Measurement;Metabolic;Methods;Microcirculation;Modification;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Natural immunosuppression;Nutrient;Organ;Organ Transplantation;Patients;Perfusion;Pharmaceutical Preparations;Physiological;Postoperative Period;Recruitment Activity;Regional Perfusion;Replacement Therapy;Research;Research Personnel;Risk;Staging;Structure;Supporting Cell;Surface;System;Technology;Testing;Time;Tissue Engineering;Tissues;Transplantation;Vascular blood supply;Work;angiogenesis;base;beta cell replacement;design;diabetic;healing;implantation;improved;islet;mouse model;neovascularization;new technology;novel;pancreas allograft;response;yeast two hybrid system


application_id: 8046185
project_number: 1R03DE020839-01A1
project_title: Rank tests for clustered data with potentially informative cluster size: Novel st
administering_ic: NIDCR
award_notice_date: 2011-08-17
opportunity_number: PAR-09-182
application_type: 1
activity_code: R03
ic: DE
serial_number: 020839
suffix: A1
program_official: HARRIS, EMILY L
project_start_date: 2011-09-01
project_end_date: 2013-08-31
study_section: Special Emphasis Panel[ZDE1 LK (25)]
contact_pi_person_id: 9020729
contact_pi: DATTA, SOMNATH
other_pis: Not Applicable
congressional_district: 03
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop appropriate rank based tests for clustered data when the cluster size is potentially informative and apply the resulting methods for various marginal comparisons (e.g. average condition of teeth before and after treatment) using existing dental database resources specifically as obtained from the Piedmont 65 + Dental Study and Iowa Fluoride Study. Informative cluster size arises when the number of units in a cluster is non-constant/random and in correlation with the outcome of interest. In the context of dental data all teeth belonging to an individual will form a cluster. Since tooth loss (in adult) is correlated with two of the diseases we are planning to study namely periodontal disease and dental caries we have potentially informative cluster sizes in the Piedmont data sets. It is a methodological challenge to adapt a classical rank test to such situations. As for example the two sample Wilcoxon rank sum test has difficulty maintaining the correct size/significance level under informative clustering even if it is adjusted for cluster dependence through appropriate variance estimate.  This proposal has a goal of developing proper classes of rank based tests (and related R estimators) and studying their statistical properties for three classical problems adapted to marginal inference under cluster dependence with informative cluster size. These are the so called one sample location problem (Aim 1) the regression problem (Aim 2) and the association problem (Aim 3). In each of these problems we will obtain a class of test statistics using general score functions that maintain proper asymptotic size under the informative cluster size scenario. We will also study the properties of the related R estimates of marginal parameters. Multivariate extensions of the first two problems will also be considered (Aim 4). Another signification component of the proposed research will be to extend these procedures to handle missing data where the missingness mechanism can be modeled using observable covariates (Aim 5). Finally when the cluster size is not informative as in the case of Iowa Study which comprises of children only we will be able to increase the power of our tests by incorporating cluster specific weights in the construction of our test statistics (Aim 6).  
  
PUBLIC HEALTH RELEVANCE: The proposed research will lead to novel methodological and theoretical development in nonparametric/rank tests and estimators for clustered data that will have direct impact on the analyses of a dental data. The results from the proposed research have the potential to transform the way clustered data are handled in practice. Dental researchers and practitioners will be more aware of the informative cluster size issue and employ robust methods such as the ones developed here that accounts for the non-ignorability of the cluster size.  
  
-cluster exchangeability remains an issue.

project_terms:
Accounting;Adult;Aftercare;Data;Data Analyses;Data Set;Databases;Dental;Dental Hygiene;Dental Research;Dental caries;Dependence;Development;Disease;Environment;Fluorides;Goals;Individual;Iowa;Lead;Literature;Location;Measurement;Methods;Modeling;Only Child;Oral health;Outcome;Outcome Measure;Paired Comparison;Patients;Periodontal Diseases;Physiological;Population;Procedures;Property;Rank-Sum Tests;Research;Research Personnel;Resources;Sampling;Statistical Methods;Sum;Testing;Tooth Loss;Tooth structure;Weight;Work;base;improved;interest;novel;statistics

public_health_relevance:
The proposed research will lead to novel methodological and theoretical development in nonparametric/rank tests and estimators for clustered data that will have direct impact on the analyses of a dental data. The results from the proposed research have the potential to transform the way clustered data are handled in practice. Dental researchers and practitioners will be more aware of the informative cluster size issue and employ robust methods such as the ones developed here that accounts for the non-ignorability of the cluster size.  
  
-cluster exchangeability remains an issue.


application_id: 8045927
project_number: 3R01DA022967-03S1
project_title: African American Female Drug Users: HIV Health Disparities & Criminality
administering_ic: NIDA
award_notice_date: 2010-03-18
opportunity_number: PA-07-114
application_type: 3
activity_code: R01
ic: DA
serial_number: 022967
suffix: S1
program_official: JONES, DIONNE
project_start_date: 2008-04-01
project_end_date: 2013-01-31
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
project_abstract:
The overall goal of this study is to understand how drug use and criminality are related to health disparitiesparticularly HIV and service utilization among African American drug using and non-drug using women acrosscriminal justice status. While drug use is similar across racial groups in the US African Americans aredisproportionately more likely to experience severe health consequences and criminal involvemement as aresult of drug misuse. Adequate health care may not be received by African American female offendersbecause they experience the burden of their race class gender and criminal offender status. There is limitedscientific data to help understand the linkages between health disparities such as HIV untreated drug abusebarriers to service utilization and status as a criminial offender among African American females. This study issignificant because of its potential to identify differences in health disparities and service utilization amongAfrican American drug using and non-drug using women in selected levels of criminal justice status (intensivecorrectional supervision-prison (n=200) moderate correctional supervision-jail (n=200) communitysupervision-probation (n=200) and no criminal justice involvement (n=200)). All 800 African American femaleswill be followed logitudinally for three 6-month intervals to examine health status and the use of health servicesacross time. The specific aims are: (1) To describe the prevalence of health problems among AfricanAmerican women across criminal justice status and drug use status; (2) To determine the culturalpredisposing historical health and potential enabling factors that are predictors of health problems amongAfrican American drug using and non-drug using women across criminal justice status over 18 months; (3) Todescribe the prevalence of untreated health problems the patterns of health services utilization and thecultural barriers to service utilization among African American women across criminal justice status and druguse status; and (4) To examine the factors that predict the likelihood of using health services among AfricanAmerican drug using and non-drug using women across criminal justice status over 18 months. Thesignificance of this study includes the potential to provide criminal justice systems-level data for health planningand 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 healthdisparities among African American women across criminal justice status and drug use status and to predicthealth status and the use of health services over time. This knowledge of African American females can beused as a foundation for future criminal justice systems-level interventions to increase the use of preventativehealth care and subsequently reduce the need for expensive medical services as well as to decrease HIV riskbehaviors 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;public health medicine (field);racism;recidivism;service utilization;substance abuse treatment;time use


application_id: 8045368
project_number: 5R01EY014701-06
project_title: Ganglion Cell Function in Retinal Disease
administering_ic: NEI
award_notice_date: 2011-03-29
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 014701
program_official: GREENWELL, THOMAS
project_start_date: 2004-02-01
project_end_date: 2015-03-31
study_section: Biology and Diseases of the Posterior Eye Study Section[BDPE]
contact_pi_person_id: 1905800
contact_pi: MCCALL, MAUREEN A
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The goals of this research are focused on understanding signaling mechanisms that regulate the development of visual function and spatial organization of retinal ganglion cells and how they are altered in retinal disease. Normal vision begins in the retina and is initiated by photoreceptor detection of light. Parallel pathways of information flow are initiated at the first synapse between photoreceptors and depolarizing and hyperpolarizing bipolar cells which detect luminance increases and decreases and/or vision under dark- and light-adapted conditions. As a result the pathways extend the dynamic range of information processing in the intensity domain and increase specialization of information processing for salient environmental features e.g. motion direction and size. Signaling within these circuits is refined by inhibitory inputs in the outer and inner retina and these interactions culminate in and define the receptive field organization of the retinal ganglion cells. The receptive field is a basic property shared across all sensory neurons in all species. It defines the types and range of environmental stimuli that each cell encodes. Thus understanding how receptive field properties develop is key to understanding visual function in the retina and the ganglion cells are a vital part because they represent both the culmination of all retinal processing and the scaffold for the rest of visual processing. Because basic RF spatial organization is already present at the onset of visual responses in ganglion cells the processes underlying their development have been relatively intractable to investigation. That normal vision requires signaling through the depolarizing and hyperpolarizing pathways is amply indicated by the visual defects that occur in patients with and mouse models of congenital stationary night blindness (CSNB) where depolarizing bipolar cell processing is eliminated. We have three unique mouse models of CSNB1 that we will continue to use to probe the synaptic circuitry underlying CSNB in which normal photoreceptor function is retained. The nature of the changes in spontaneous and visually-evoked responses across GCs in the three mutants provides a unique opening to study the development of receptive field organization and ganglion cell signaling. The phylogenetic conservation of receptive field organization suggests that our findings in the mouse will be relevant to primate peripheral retinal processing. We suggest that the characterization of these mouse models represents a significant opportunity not afforded by other mouse or vertebrate models and represents a critical step in our understanding both the disease mechanisms in CSNB1 and normal retinal development and function.   
  
PUBLIC HEALTH RELEVANCE: This proposal seeks to understand the mechanisms that govern the development of vision in the retina and to investigate the changes in the downstream synaptic mechanisms when signaling is eliminated from one of the parallel pathways of information processing in the retina. One focus is to understand the exact changes that occur in complete congenital stationary night blindness a retinal disease that does not involve photoreceptor dysfunction or morphological defects. A second focus is to understand the fundamental processes that regulate the development of normal retinal function particularly in the ganglion cells. We believe that our results will guide diagnosis and therapeutic approaches to restore or rescue CSNB and also will be relevant to other blinding diseases in people of all ages.

project_terms:
Address;Affect;Afferent Neurons;Age;Amacrine Cells;Cations;Cell physiology;Cells;Data;Defect;Detection;Development;Developmental Delay Disorders;Diagnosis;Disease;Electroretinography;Eye;Functional disorder;Funding;Genes;Glutamate Receptor;Glutamates;Goals;Human;Individual;Investigation;Lead;Light;Masks;Mediating;Modeling;Motion;Mus;Mutant Strains Mice;Mutation;Nature;Nervous system structure;Night Blindness;Pathway interactions;Patients;Pattern;Peripheral;Phenotype;Photoreceptors;Phylogenetic Analysis;Play;Primates;Principal Investigator;Process;Property;Research;Rest;Retina;Retinal;Retinal Diseases;Retinal Ganglion Cells;Role;Sensory;Signal Transduction;Stimulus;Synapses;Testing;Therapeutic;Vision;Visual;Visuospatial;Work;disease phenotype;ganglion cell;information processing;luminance;mouse model;mutant;neural circuit;programs;public health relevance;receptive field;receptor;research study;response;scaffold;vision development;visual process;visual processing


application_id: 8044768
project_number: 5R44MH078437-05
project_title: Genomic Biomarkers for Neuropsychiatric Illnesses
administering_ic: NIMH
award_notice_date: 2011-02-28
opportunity_number: PA-06-016
application_type: 5
activity_code: R44
ic: MH
serial_number: 078437
program_official: GRABB, MARGARET CHRISTINE
project_start_date: 2006-09-26
project_end_date: 2012-09-30
study_section: Special Emphasis Panel[ZRG1-GGG-J(10)B]
contact_pi_person_id: 8483374
contact_pi: BRENNAN, MARK DAVID
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 609831222
duns_number: 609831222
fips: US
organization_id: 10007145
organization_name: SUREGENE, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402992882
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-04-01
budget_end_date: 2012-09-30
project_abstract:
DESCRIPTION (provided by applicant):  The long-term objective of this project is to develop validated genetic biomarkers to aid in more accurate diagnosis and targeted treatment of schizophrenia and related neuropsychiatric illnesses including bipolar disorder. In Phase I SureGene demonstrated the feasibility of using specific dimensions of mental illness to discover novel genes and genetic variants that influence risk and impact the clinical presentation of these diseases. This project will build on first-generation genetic biomarkers in the form of single nucleotide polymorphisms (SNPs) and chromosomally-related associations of these polymorphisms called haplotypes. The Phase II project will further develop biomarkers for neuropsychiatric illnesses using a set of genes that meet stringent criteria for genetic replication. The project will develop products for research and clinical applications that combine biomarkers in these genes. The aims are 1) Develop a prototype AssureGeneTM array and data set for schizophrenia-spectrum disorders. SureGene will develop a flexible SNP genotyping product incorporating a high density of SNPs in approximately 200 genes and generate a detailed data set relating genotypes to phenotypes based on 2000 NIMH schizophrenia bipolar and control samples. A first-generation array and data set will be made available to the research community by the middle of Grant Year 2. A refined array and data set for prospective clinical applications will be completed by the end of Phase II. 2) Evaluate the utility of the AssureGeneTM test for differential diagnosis and for predicting progression to clinically defined psychosis. SureGene will develop genetic algorithms for the array for use in predicting dichotomous clinical outcomes. This Aim should provide a collective set of predictive models that can be evaluated on the basis of their sensitivity specificity and overall classification accuracy. 3) Develop and implement a flexible medical resequencing platform (ExonReadTM) for high priority genes. SureGene will develop a cost-effective "next generation" medical resequencing platform that can be used by the research community to evaluate the contribution of rare or spontaneous mutations in key genes contributing to psychopathology and clinical outcomes for neuropsychiatric illnesses. A prototype sequencing platform for research use will be completed in Grant Year 2. SureGene will apply ExonReadTM to a sample of African Americans and Caucasians with a family history of schizophrenia or bipolar disorder to establish baseline expectations and limitations of the product. The commercial potential for these products is significant. By targeting common variants the AssureGeneTM array should have broad applicability in research and clinical settings with both diagnostic and pharmacogenetic applications. The ExonReadTM platform will be a valuable cost-effective tool for identifying rare or unique high penetrance mutations expected in familial cases of neuropsychiatric illnesses and will have applications for genetic counseling and for differential diagnosis.   
  
PUBLIC HEALTH RELEVANCE: The long term objective of this project is to develop validated gene-related tests (genetic biomarkers) to aid in more accurate diagnosis and customized treatment of schizophrenia and related "schizophrenia spectrum" disorders including bipolar disorder. SureGene's goals for this research are to refine existing genetic biomarkers and to discover and refine additional novel genetic biomarkers. Products based on these biomarkers should be helpful to individuals suffering from schizophrenia and related disorders their families and health care providers and researchers seeking to improve diagnosis and treatment.

project_terms:
African American;Algorithms;Basic Science;Biological;Bipolar Disorder;Caucasians;Caucasoid Race;Classification;Clinical;Communities;Complex;DNA Resequencing;Data;Data Set;Diagnosis;Diagnostic;Differential Diagnosis;Dimensions;Disease;Family;Family health status;Family history of;Generations;Genes;Genetic;Genetic Counseling;Genetic Markers;Genetic Models;Genetic Polymorphism;Genetic Programming;Genetic screening method;Genome;Genomics;Genotype;Goals;Grant;Haplotypes;Health;Health Personnel;Individual;Legal patent;Medical;Mental disorders;Mutation;National Institute of Mental Health (U.S.);Outcome;Patients;Penetrance;Pharmacogenetics;Phase;Phenotype;Positioning Attribute;Psychopathology;Psychotic Disorders;Public Domains;Research;Research Personnel;Resources;Risk;Sampling;Schizophrenia;Sensitivity and Specificity;Single Nucleotide Polymorphism;Technology;Testing;Variant;Work;Youth;base;biomarker;case control;clinical application;cohort;cost effective;density;design;disorder control;disorder risk;disorder subtype;expectation;flexibility;genetic variant;high risk;improved;meetings;neuropsychiatry;next generation;novel;predictive modeling;proband;prospective;prototype;public health relevance;tool

public_health_relevance:
The long term objective of this project is to develop validated gene-related tests (genetic biomarkers) to aid inmore accurate diagnosis and customized treatment of schizophrenia and related "schizophrenia spectrum"disorders including bipolar disorder. SureGene's goals for this research are to refine existing geneticbiomarkers and to discover and refine additional novel genetic biomarkers. Products based on thesebiomarkers should be helpful to individuals suffering from schizophrenia and related disorders their familiesand health care providers and researchers seeking to improve diagnosis and treatment.


application_id: 8044758
project_number: 5R01AG026711-05
project_title: Role of Neutral Sphingomyelinase-2 in aging
administering_ic: NIA
award_notice_date: 2011-02-03
application_type: 5
activity_code: R01
ic: AG
serial_number: 026711
program_official: FRANKOWSKI, DAVID WITT
project_start_date: 2007-02-15
project_end_date: 2013-01-31
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 6730250
contact_pi: NIKOLOVA-KARAKASHIAN, MARIANA N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-02-15
project_abstract:
DESCRIPTION (provided by applicant): Aging is characterized by an altered immune function and stress response. It becomes increasingly clear that at least in part this is due to alterations in ability of the cells to respond to different stress inducers. The hypothesis to be tested in this proposal is that aging-induced up-regulation of neutral sphingomyelianse-2 (NSMase-2) activity underlies the exaggerated response of hepatocytes IL-1beta during aging. We further hypothesized that aging-associated increases in NSMase-2 activity are consequence of the decreases in the cellular glutathione level. Therefore the long-term objective of our study is to understand the relation between aging the altered cellular response to inflammation and the state of oxidative stress. The following specific aims are proposed: Specific aim 1. To test the role of NSMase-2 as a mediator of aging-induced hyperresponsiveness to IL-1b. Studies in this specific aim will decipher the contribution of NSMase-2 to the IL-1b hyperresponsiveness of aged animals. Gene silencing approach will be used in vitro in hepatocytes isolated from old rats and in vivo in aged animals. Specific aim 2. To study the IL-1b hyperresponsiveness in calorie-restricted aged rats. Calorie-restriction (CR) is known to increase the life span of experimental animals and to attenuate the onset of oxidative stress including preventing aging-induced GSH/GSSH decline. Thus we hypothesized that CR attenuates IL-1B hyperresponsiveness of liver. This will be tested in vivo and in vitro. If NSMase-2 mediates IL-1b hyperresponsiveness by acting down-stream of GSH/GSSH changes then NSMase-2 overexpression in aged CR should restore the aging-associated IL-1b hyperresponsiveness. This will be tested by adenoviral-mediated expression of NSMase-2 in isolated hepatocytes and intact liver from aged CR rats. Specific aim 3: To study the role of GSH in aging-associated NSMase-2 activation and IL-1b hyperresponsiveness. These studies will ask whether GSH depletion in aging and NSMase-2 activation are causatively linked and will establish a link between the onset of oxidative stress and the IL-1b hyperesponsivness in aged animals. The proposed studies will provide novel understanding on the cellular mechanisms involved in the onset of aging and may have practical application in the development of new anti-inflammatory drugs for the elderly.

project_terms:
Acute-Phase Proteins;Acute-Phase Reaction;Adenoviruses;Affect;Age;Age of Onset;Aging;Aging-Related Process;Animal Model;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Attenuated;Bypass;CCAAT-Enhancer-Binding Proteins;Caloric Restriction;Cell Aging;Cell Line;Cell model;Cells;Cellular Stress Response;Ceramides;Characteristics;Cytokine Signaling;Defect;Development;Doctor of Philosophy;Dose;Elderly;Endocrine;Exhibits;Gene Silencing;Genes;Glutathione;Glutathione Disulfide;Goals;Hepatocyte;IRAK1 gene;Immune system;In Vitro;Incidence;Inflammation;Inflammatory;Injection of therapeutic agent;Interleukin-1;Interleukin-10;Interleukins;Link;Liver;Longevity;MAPK8 gene;Measures;Mediating;Mediator of activation protein;Molecular;Mortality Vital Statistics;Neuroglia;Oligonucleotides;Organism;Oxidative Stress;Pattern;Peritoneal Macrophages;Pharmaceutical Preparations;Phenotype;Play;Process;Protein Dephosphorylation;Protein Phosphatase 2A Regulatory Subunit PR53;Rattus;Research Personnel;Role;Signal Pathway;Sphingomyelinase;Stream;Stress;Testing;Ubiquitination;Up-Regulation (Physiology);adenoviral-mediated;aged;biological adaptation to stress;feeding;functional decline;human IRAK1 protein;immune function;in vivo;induced pluripotent stem cell;inhibitor/antagonist;juvenile animal;novel;overexpression;practical application;prevent;programs;receptor;research study;response;scyphostatin


application_id: 8043973
project_number: 1R21ES019249-01A1
project_title: Quercitrin functions as an antioxidant and protects UV-induced carcinogenesis
administering_ic: NIEHS
award_notice_date: 2011-02-11
opportunity_number: PA-10-069
application_type: 1
activity_code: R21
ic: ES
serial_number: 019249
suffix: A1
program_official: HUMBLE, MICHAEL C
project_start_date: 2011-02-15
project_end_date: 2013-01-31
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
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;reaction rate;research study;silibinin;tumorigenesis;ultraviolet irradiation

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.


application_id: 8043382
project_number: 3R01DK080770-01A1S1
project_title: Renal Osteodystrophy: A Fresh Approach
administering_ic: NIDDK
award_notice_date: 2010-04-09
opportunity_number: PA-07-070
application_type: 3
activity_code: R01
ic: DK
serial_number: 080770
suffix: A1S1
program_official: KIMMEL, PAUL
project_start_date: 2010-04-09
project_end_date: 2011-03-31
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
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;Awareness;Biochemical;Biochemical Markers;Biopsy;Blood;Blood Tests;Blood specimen;Bone Diseases;Bone Resorption;Cardiovascular system;Caring;Chronic Kidney Failure;Clinical;Clinical Research;Clinical and Translational Science Awards;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;Work;X-Ray Computed Tomography;base;bone;bone loss;bone mass;bone metabolism;bone turnover;burden of illness;calcification;cancer type;cerebrovascular;cohort;cost;diagnosis standard;experience;follow-up;imaging modality;improved;inorganic phosphate;mineralization;novel;patient population;prevent;public health relevance;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: 8043360
project_number: 1RC4DE021580-01
project_title: Aging and novel therapeutic interventions in periodontal disease
administering_ic: NIDCR
award_notice_date: 2010-09-27
opportunity_number: RFA-OD-10-005
application_type: 1
activity_code: RC4
ic: DE
serial_number: 021580
program_official: LUNSFORD, DWAYNE
project_start_date: 2010-09-27
project_end_date: 2011-12-31
study_section: Special Emphasis Panel[ZRG1 MOSS-G (55)]
contact_pi_person_id: 6712964
contact_pi: HAJISHENGALLIS, GEORGIOS
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 DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
DESCRIPTION (provided by applicant):  This proposal is based on a novel mechanism linking advanced age to destructive periodontal inflammation which is targeted for new therapeutic intervention against periodontitis. The application therefore addresses the second thematic area of RFA-OD-10-005 Translating Basic Science Discoveries into New and Better Treatments. Old age is associated with increased prevalence and severity of certain chronic inflammatory diseases including periodontitis. This oral inflammatory disease can lead to tooth loss and moreover exerts a systemic impact on the patients. However current clinical periodontal treatment is often not sufficient on its own to control destructive inflammation. This necessitates improved therapeutic approaches especially in the elderly who are more susceptible to periodontitis. In this regard preliminary studies have identified a major mechanism linking advanced age to uncontrolled periodontal inflammation attributed to age-associated deficiency of a molecule (termed Del-1 for developmental endothelial locus-1) that regulates the accumulation of neutrophils and associated inflammatory activity in the periodontal tissue. This regulatory homeostatic function involves the ability of Del-1 to bind and block the leukocyte-associated antigen-1 (LFA-1). Importantly Del-1 deficiency leads to dramatic periodontal bone loss in a preclinical animal model. The destructive effects of neutrophils in periodontitis can be mediated either directly or indirectly via their ability to chemotactically recruit T-helper 17 (Th17) cells which can cause chronic bone immunopathology mainly via interleukin-(IL)-17 production. This study was designed to provide proof-of-concept evidence that Del-1 treatment (as a fusion protein with the IgG Fc fragment; Del-1-Fc) in advanced age can reduce the excessive accumulation of neutrophils to the periodontium and inhibit destructive periodontal inflammation. At a first stage this interventional study necessitates the use of an appropriate preclinical animal model. The specific aims are to show that (1) treatment of old mice with Del-1-Fc inhibits excessive neutrophil recruitment to periodontal tissues and leads to reduced inflammation and Th17-like activity; (2) treatment with Del-1-Fc inhibits periodontal disease in old mice; and (3) to compare Del-1-Fc with antagonists of LFA-1 and IL-17 for therapeutic treatment of periodontitis. The latter will help determine whether Del-1-Fc is sufficient on its own or whether it needs to be supplemented with antagonists of LFA-1 and/or IL-17A for maximum protection against periodontitis. This is probably the first time that an age-associated deficiency in periodontal innate immune regulation has been identified and a promising therapeutic intervention has been proposed. The long-term goal is to therapeutically exploit Del-1 to effectively complement current periodontal treatment and revolutionize the way elderly periodontal patients are managed. Moreover Del-1-Fc may have wider applications given the destructive effects of uncontrolled leukocyte trafficking in various inflammatory and autoimmune conditions.  
  
PUBLIC HEALTH RELEVANCE:  Conventional periodontal treatment is often not sufficient by itself to control destructive inflammation. We have discovered a major mechanism linking advanced age to uncontrolled periodontal inflammation attributed to age-associated deficiency of a molecule (termed Del-1 for developmental endothelial locus-1) that regulates the accumulation of neutrophils and associated inflammatory activity in the periodontal tissue. Our objective is to therapeutically exploit Del-1 to correct age-associated Del-1 deficiency and thereby prevent destructive periodontal inflammation.

project_terms:
Address;Adult;Age;Aging;Alveolar Bone Loss;Animal Model;Antigens;Area;Aspiration Pneumonia;Atherosclerosis;Autoimmune Process;Bacteria;Basic Science;Binding (Molecular Function);Cells;Chimeric Proteins;Chronic;Clinical;Clinical Treatment;Complement;Data;Development;Diabetes Mellitus;Disease;Elderly;Endothelial Cells;Ethics;Experimental Designs;Extravasation;Fc Immunoglobulins;Gingiva;Glycoproteins;Goals;Human;Immune;Immune response;Immunoglobulin G;Individual;Inflammation;Inflammatory;Interleukin-17;Interleukins;Investigation;Knockout Mice;Knowledge;Lead;Leukocyte Trafficking;Leukocytes;Link;Mediating;Modeling;Mus;Natural Immunity;Neutrophil Infiltration;Oral;Pathogenesis;Patients;Periodontal Diseases;Periodontitis;Periodontium;Population;Positioning Attribute;Predisposition;Prevalence;Production;Recruitment Activity;Recurrent disease;Regulation;Relative (related person);Research;Research Design;Risk Factors;Severities;Site;Staging;Therapeutic;Therapeutic Intervention;Time;Tissues;Tooth Loss;Tooth structure;Topical application;Translating;age related;base;bone;bone loss;chromosome 1 loss;design;immunopathology;improved;in vivo;insight;interest;neutrophil;novel;novel therapeutic intervention;oral infection;pre-clinical;prevent;public health relevance;receptor;research study

public_health_relevance:
Project NarrativeConventional periodontal treatment is often not sufficient by itself to control destructive inflammation. We havediscovered a major mechanism linking advanced age to uncontrolled periodontal inflammation attributed toage-associated deficiency of a molecule (termed Del-1 for developmental endothelial locus-1) that regulatesthe accumulation of neutrophils and associated inflammatory activity in the periodontal tissue. Our objective isto therapeutically exploit Del-1 to correct age-associated Del-1 deficiency and thereby prevent destructiveperiodontal inflammation.


application_id: 8040975
project_number: 5R01HL086450-05
project_title: An Intervention for Promoting Smoke-free Policy in Rural Kentucky
administering_ic: NHLBI
award_notice_date: 2011-03-01
opportunity_number: PAR-06-039
application_type: 5
activity_code: R01
ic: HL
serial_number: 086450
program_official: RILEY, WILLIAM T
project_start_date: 2007-04-01
project_end_date: 2013-02-28
study_section: Special Emphasis Panel[ZRG1-HOP-S(50)R]
contact_pi_person_id: 1906116
contact_pi: HAHN, ELLEN J
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The purpose of this study is to test the effects of a community intervention on smoke-free policy outcomes in rural underserved communities. The intervention combines assessment of community readiness with tailored evidence-based dissemination and implementation strategies. Rural residents are more likely to be exposed to secondhand smoke than those living in urban areas reflecting a major rural-urban disparity in smoke-free laws. The overall goal of the study is to accelerate the 'diffusion-of-innovations curve' in rural communities through tailored evidence-based dissemination and implementation efforts. The long-term goal is to develop a best practices framework for disseminating scientific knowledge about the effects of secondhand smoke and smoke-free laws and implementing effective community policy change and maintenance strategies in rural underserved communities. A pretest posttest three-group quasi- experimental design will be used to test the primary hypotheses: Controlling for contextual factors (a) the overall change in stage of readiness for smoke-free policy will be greater for Treatment than Control communities; (b) media coverage will be more favorable toward smoke-free environments in Treatment than Control communities; and (c) Treatment communities will be more likely than Control communities to demonstrate smoke-free policy outcomes. Guided by a community readiness model the Intervention will have two components: (1) assessment of community stage of readiness; and (2) stage-specific tailored dissemination and implementation strategies. The main elements of Component II of the Intervention include translating and disseminating knowledge and building capacity and demand for smoke-free policy. The Treatment communities (n = 20) will participate in both components of the Intervention. Control I communities (n = 10) will participate in the community assessment of readiness at baseline and annually. The Control II communities (n = 10) will participate in community assessment of stage of readiness at the end of the study only. Community stakeholders will participate in key informant telephone interviews to assess community readiness for smoke-free policy. Print media clippings from all 51 daily and non-daily newspapers in study counties will be evaluated for pro/con slant related to smoke-free environments. Initial intermediate and final smoke-free policy outcomes will be measured. The potential influence of secular trends on the impact of this community intervention will be analyzed. The proposal is directly relevant to public health in that it has the potential to protect residents in rural underserved communities from premature death and disease from exposure to secondhand smoke.

project_terms:
Affect;Air;Cessation of life;Clip;Communities;Controlled Study;County;Diffusion of Innovation;Disease;Elements;Environment;Environmental Tobacco Smoke;Experimental Designs;Exposure to;Goals;Health;Intervention;Kentucky;Knowledge;Laws;Life;Maintenance;Measures;Modeling;NIH Program Announcements;Newspapers;Outcome;Policies;Population;Printed Media;Public Health Practice;Readiness;Research;Resources;Rural;Rural Community;Science;Smoke;Staging;Telephone Interviews;Testing;Time;Tobacco use;Translating;community intervention;contextual factors;dissemination research;evidence base;implementation research;informant;innovation;outreach;population based;premature;public education;public health medicine (field);public policy on tobacco;smoke-free policy;tobacco control;tobacco exposure;trend;urban area


application_id: 8040936
project_number: 5R24RR016344-11
project_title: Genome resources for model amphibians
administering_ic: NCRR
award_notice_date: 2011-04-08
application_type: 5
activity_code: R24
ic: RR
serial_number: 016344
program_official: O'NEILL, RAYMOND R
project_start_date: 2001-10-01
project_end_date: 2012-07-22
study_section: Comparative Medicine Review Committee[RIRG-C]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-04-01
project_abstract:
DESCRIPTION (provided by applicant): Salamanders are important vertebrate model organisms in several areas of human health and disease research including spinal cord and limb regeneration post-embryonic development toxicology vision olfaction heart development renal function and neural transmission. We initiated the Salamander Genome Project (SGP) to develop the first genomic and bioinformatic resources for research using ambystomatid salamanders. During the last grant period we created the first comprehensive amphibian genetic map several annotated molecular databases a community web-portal (www.ambystoma.org) and identified a large number of unique sequences that correspond to different genes in the Ambystoma genome. We propose three Specific Aims to further increase the utility of salamanders in biomedical research. First we will increase the number of genes identified from Ambystoma mexicanum whose functions are known in humans. This will increase the number of probes for molecular studies microarray analysis and gene mapping. More generally it will allow a greater amount of genetic and genomic information to be cross- referenced from salamander to other vertebrate model organisms (Zebrafish Xenopus Chick Mouse Rat Human etc). Second we will design a microarray gene chip and use it to identify genes that are differentially expressed during natural spinal cord regeneration and thyroid hormone induced metamorphosis. To better enable the research community we will make the microarray design freely available. This aim will provide a powerful new tool for salamander researchers and a means for non-salamander researchers to rapidly screen the salamander for candidate genes and gene networks. Third we will develop a large interspecific mapping panel and use it to identify markers and candidate genes for important A. mexicanum mutants and the sex- determining locus. Gene markers will increase the efficiency of managing a federally funded laboratory stock that provides salamander material to researchers from around the world. With respect to longer-term goals the proposed project will spur development of additional resources that will facilitate identification of salamander genes of biomedical significance.

project_terms:
3' Untranslated Regions;Acids;Ambystoma;Ambystoma mexicanum;Amphibia;Animal Model;Animals;Area;Base Sequence;Bioinformatics;Biological Metamorphosis;Biology;Biomedical Research;Candidate Disease Gene;Chromosome Mapping;Code;Communities;Custom;DNA;DNA Sequence;Data;Databases;Development;Diagnostic;Disease;Embryonic Development;Endocrine disruption;Expressed Sequence Tags;Failure (biologic function);Funding;Future;Genbank;Gene Chips;Generations;Genes;Genetic;Genome;Genomics;Genotype;Goals;Grant;Health;Human;Hypothyroidism;In Situ Hybridization;Internet;Investigation;Laboratories;Maps;Methods;Microarray Analysis;Modeling;Molecular;Molecular Probes;Mus;Nucleotides;Orthologous Gene;Phenotype;Pigments;Proteins;Quantitative Trait Loci;Rattus;Renal function;Research;Research Personnel;Resources;Robotics;Salamander;Signal Transduction;Smell Perception;Spinal Cord;Synaptic Transmission;System;Thyroid Hormones;Tigers;Time;Toxicology;Vision;Xenopus;Zebrafish;base;cardiogenesis;design;developmental toxicology;limb regeneration;meetings;molecular marker;mutant;novel;programs;regenerative;research study;sex;spinal cord regeneration;tool


application_id: 8040126
project_number: 1R01AI087849-01A1
project_title: ???Biosynthesis of nucleoside antibiotics targeting bacterial translocase I???
administering_ic: NIAID
award_notice_date: 2011-06-14
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: AI
serial_number: 087849
suffix: A1
program_official: XU, ZUOYU
project_start_date: 2011-06-15
project_end_date: 2015-05-31
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 9509796
contact_pi: VAN LANEN, STEVEN GARY
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The emergence of multiple drug resistant pathogens is becoming problematic worldwide and the discovery of new antibiotics continues to decline. The broad long-term objective of this proposal is to discover characterize and develop a new structural class of antibiotics-nucleoside antibiotics-that target bacterial translocase I involved in peptidoglycan cell wall biosynthesis. The specific aims of this proposal are (I) to characterize the assembly and incorporation of the aminoribosyl moiety found within the family of lipopeptidyl-nucleoside antibiotics and (II) to functionally and mechanistically characterize enzymes catalyzing novel or unusual biochemical reactions represented herein by a new family of serine hydroxymethyltransferase-like enzymes that are hypothesized to catalyze an aldol-type condensation to form unusual nonproteinogenic amino acids. Specific Aim I and II will be achieved by using the robust genetic system developed for the lipopeptidyl nucleoside A-90289-producing strain for in vivo studies employing gene inactivation and cross-complementation and recombinant proteins will be exploited for functional and mechanistic studies in vitro. The results will establish a new mechanism for incorporating ribosyl units into natural product scaffolds and will establish a paradigm for the entry into high-carbon nucleoside antibiotics. The results will be essential for our long-term goals of searching for new nucleoside antibiotics using genetic information (a genotype-to-chemotype approach) will allow for the structural diversification of the parent scaffolds using combinatorial biosynthesis and total synthesis and will provide the basis for the design of second generation antibiotics with improved biocompatibility and pharmacological properties.  
  
PUBLIC HEALTH RELEVANCE: Diseases caused by multidrug resistant bacteria are becoming a significant threat to human health worldwide. The goal of this proposal is to study nucleoside antibiotics that represent a new structural class of antibiotics have a different mode of action than clinically used antibacterial drugs and are in general not toxic to animals.


application_id: 8040122
project_number: 1R01CA149438-01A1
project_title: Activation of Cyclin-Dependent Kinases by Fructose-26-Bisphosphate
administering_ic: NCI
award_notice_date: 2011-04-01
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: CA
serial_number: 149438
suffix: A1
program_official: SPALHOLZ, BARBARA A
project_start_date: 2011-04-01
project_end_date: 2016-03-31
study_section: Tumor Cell Biology Study Section[TCB]
contact_pi_person_id: 1923745
contact_pi: CHESNEY, JASON 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
project_abstract:
DESCRIPTION (provided by applicant): The 6-phosphofructo-2-kinase/fructose-26-bisphosphatases (PFKFB) phosphorylate fructose-6-phosphate (F6P) to fructose-26-bisphosphate (F26BP) which is an allosteric activator of 6-phosphofructo-1-kinase a rate-limiting enzyme in the glycolytic pathway. Although there are four PFKFB enzymes PFKFB3 and PFKFB4 are of particular interest since these enzymes have been found to be activated in human cancers to be increased by hypoxic exposure via HIF-1? and in the case of PFKFB3 to be required for the growth of Ras-transformed tumors. In order to better understand the relative contributions of PFKFB2-4 to glycolysis we examined the subcellular localization of these enzymes and were surprised to find that whereas PFKFB2 and PFKFB4 localized to the cytoplasm (the site of glycolysis) PFKFB3 localized to the nucleus. We then over-expressed PFKFB3 in HeLa cells and observed no change in glucose uptake but rather an increase in proliferation. Eukaryotic cell division is controlled by cyclin dependent kinases (CDKs) that bind to regulatory cyclins and phosphorylate hundreds of substrates that control DNA replication transcription and mitosis. We found that over-expression of PFKFB3 stimulated CDK1 activity in HeLa cells and that purified F26BP stimulated recombinant monomeric CDK1 in vitro. We then confirmed the requirement of CDK1 for the pro-proliferative effects of PFKFB3 by demonstrating that CDK1 siRNA but not CDK2 CDK4 or CDK6 siRNA reversed the increased proliferation caused by over-expression of PFKFB3. Importantly transfection of HeLa cells with PFKFB3-specific siRNA decreased endogenous PFKFB3 which in turn reduced CDK1 activity increased p27 expression suppressed G1/S transition induced apoptosis but had no impact on glucose uptake. These data support a distinct role for PFKFB3 in the regulation of cell cycle progression and apoptosis and not glucose metabolism. We propose to test the hypothesis that nuclear F26BP generated by PFKFB3 activates CDKs and promotes cell cycle progression. We anticipate that nuclear F26BP may serve unique roles in regulating CDK1 and other CDKs and that inhibition of PFKFB3 will suppress CDK activities without significantly affecting glucose metabolism in transformed but not in normal cells.  
  
PUBLIC HEALTH RELEVANCE: The research proposed in this application may enable the identification of a novel molecular target - the CDK1 F26BP-binding domain - that is required for the regulation of the cell cycle and cancer progression. This binding pocket then can be used for receptor-based virtual screening to identify novel anti-neoplastic agents.

project_terms:
6-Phosphofructo-2-kinase;6-Phosphofructokinase;Affect;Amino Acids;Apoptosis;Binding (Molecular Function);CDC2 Protein Kinase;CDK2 gene;CDK4 gene;Cancer cell line;Cell Cycle;Cell Cycle Progression;Cell Cycle Regulation;Cell Nucleus;Cell division;Cells;Cyclin-Dependent Kinases;Cyclins;Cytoplasm;Cytostatics;DNA biosynthesis;Data;Enzymes;Epithelial;Epithelial Cells;Eukaryotic Cell;Family;Family member;Fructose;G1/S Transition;Genes;Genetic Transcription;Genomics;Glycolysis;Growth;Hela Cells;Hematopoietic;Human;Human Development;Hypoxia;In Vitro;Liver;Malignant Neoplasms;Mitosis;Molecular Target;Mus;Mutation;Normal Cell;Normal tissue morphology;Nuclear;Oncogenes;Pathway interactions;Phosphoric Monoester Hydrolases;Phosphotransferases;Protein p53;Recombinants;Regulation;Relative (related person);Research;Role;Screening procedure;Signal Pathway;Site;Small Interfering RNA;Testing;Tissues;Transfection;Transformed Cell Line;Transgenic Organisms;base;cancer cell;chemotherapeutic agent;clinically significant;fructose-6-phosphate;glucose metabolism;glucose uptake;in vitro activity;interest;mutant;neoplastic;novel;receptor;small molecule;tumor;tumor growth;tumor progression;virtual

public_health_relevance:
The research proposed in this application may enable the identification of a novel molecular target - the CDK1 F26BP-binding domain - that is required for the regulation of the cell cycle and cancer progression. This binding pocket then can be used for receptor-based virtual screening to identify novel anti-neoplastic agents.


application_id: 8040017
project_number: 5R01NS058382-05
project_title: Cellular Nucleic Acid Binding Protein (CNBP) in Aging and Disease
administering_ic: NINDS
award_notice_date: 2011-02-07
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 058382
program_official: CORRIVEAU, RODERICK A
project_start_date: 2007-09-30
project_end_date: 2014-03-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 8535896
contact_pi: MURPHY, MICHAEL PAUL
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): Investigation into the genetic causes of the muscular dystrophies has provided unique insights into the mechanisms of several disease processes. Type II Myotonic Dystrophy is caused by a large expansion in the ZNF9 gene which encodes the single strand RNA binding protein CNBP (Cellular Nucleic Acid Binding Protein). Remarkably we recently discovered that CNBP is involved in regulating the activity of -secretase the enzyme that produces the first cleavage event in the generation of the amyloid- peptide (A). The progressive fibrillization and deposition of A is widely believed to be the primary causal factor in the development of Alzheimer's disease. Importantly the activity and protein levels of the major -secretase enzyme in the brain (BACE1) increase in both Alzheimer's disease and in normal aging. This implicates regulators of BACE1 as potentially critical for the development of Alzheimer's disease and our preliminary data suggest that CNBP may be one of these regulatory factors. Further both BACE1 and the related peripheral enzyme BACE2 are both increased in Inclusion Body Myositis an age-related degenerative disease of the skeletal musculature considered by some to be a pathological cousin of Alzheimer's disease. Therefore -secretase activity itself is linked to at least two age-related diseases making the question of understanding its regulation potentially important for human health. This proposal is designed to determine the role of CNBP as a critical protein for RNA regulation and as a potential mediator of degenerative disease via the regulation of -secretase activity. This project focuses on three specific aims designed to (1) determine the mechanism through which CNBP regulates its targets (2) determine what the normal function of CNBP is in the cell and (3) determine what the role of CNBP is in disease. The project will advance through parallel stages of in vitro studies in biochemical and cell culture based model systems up to studies in animal models of degenerative pathology. Understanding the mechanism through which CNBP operates will inform us about both basic processes in RNA regulation and how they might go awry. These studies will lay the foundation for future advances into therapeutics to treat these diseases.

project_terms:
Aging;Alzheimer's Disease;Amyloid;Amyloid beta-Protein Precursor;Amyloid deposition;Animal Model;Automobile Driving;Binding Proteins;Binding Sites;Biochemical;Biological;Biological Models;Brain;Cell Culture System;Cell Culture Techniques;Cell physiology;Cells;Data;Degenerative Disorder;Deposition;Development;Disease;Drug Industry;Enzymes;Event;Foundations;Future;Generations;Genes;Genetic;Health;Human;In Vitro;Inclusion Body Myositis;Introns;Investigation;Knowledge;Lead;Link;Mediator of activation protein;Messenger RNA;Muscular Dystrophies;Myopathy;Myotonic Dystrophy;Nucleotides;Pathogenesis;Pathology;Peptides;Peripheral;Process;Protein Binding;Proteins;RNA;RNA-Binding Proteins;Regulation;Role;Site;Staging;Testing;Therapeutic;age related;base;beta-site APP cleaving enzyme 1;beta-site APP cleaving enzyme 2;design;human ZNF9 protein;improved;in vivo;inhibitor/antagonist;insight;knock-down;mouse model;normal aging;novel;overexpression;secretase;skeletal


application_id: 8040008
project_number: 5R01HL095593-02
project_title: Atherogenic mechanism of lipid peroxidation-derived aldehydes
administering_ic: NHLBI
award_notice_date: 2011-02-28
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: 8039082
project_number: 5R01NS060784-03
project_title: Reconstruction of the Nigrostriatal pathway
administering_ic: NINDS
award_notice_date: 2011-02-24
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 060784
program_official: SIEBER, BETH-ANNE
project_start_date: 2009-04-15
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZRG1-BDCN-N(93)S]
contact_pi_person_id: 1882501
contact_pi: SMITH, GEORGE M
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Neuronal replacement strategies using stem cells or fetal transplants are potential treatments for neurological disorders caused by damage or degeneration of specific neural circuits in the central nervous system (CNS). Parkinson's disease (PD) is one such disorder caused by the degeneration of dopaminergic neurons in the substantia nigra. Many investigators have already explored neural transplantation as therapy for PD both in the lab and in the clinic but in most cases dopaminergic neurons are transplanted directly into their target - the striatum - rather than into their site of origin the substantia nigra (SN). This leads to incomplete recovery of function both in animal models and in human PD patients because the transplanted neurons provide a dopamine source to the striatum but do not reestablish the degenerated neural circuit. This proposal shall examine the hypothesis that a growth-supportive pathway created between the SN and the striatum can guide the growth of axons from dopaminergic neurons transplanted into the SN of the parkinsonian brain resulting in an anatomically and physiologically correct reestablishment of the nigrostriatal pathway and an amelioration of parkinsonian symptoms. Preliminary data is presented showing that a combination of glial cell line-derived neurotrophic factor (GDNF) and its alpha-1co-receptor (GFR-11) or netrin-1 support long distance axon growth from dopaminergic transplants in the SN to the striatum. In this study a series of experiments are proposed to further enhance the growth along the pathway and targeting within the striatum. The specific aims are to: 1) examine these and other potential growth factor candidates either individually and in combination for their ability to support long distance growth of dopaminergic axons within the adult brain; 2) examine the ability BDNF and chondroitinase to enhance axon branching and synaptogenesis within the adult striatum; 3) reconstruct the nigrostriatal pathway using data acquired from Aims 1 and 2 and examine functional recovery; 4) examine the release of dopamine cell type specificity (A9/A10 neurons) and synaptic connectivity of dopaminergic axons re-innervating the striatum. The outcome of these studies will demonstrate the feasibility of targeting the growth of axons using neuronal replacement to ameliorate the symptoms of Parkinson's disease. These studies will also provide a model for developing neuronal replacement strategies for other neurological disorders. PUBLIC HEALTH RELEVANCE Parkinson's disease is a widespread neurodegenerative disease that manifests severe motor dysfunction ultimately leading to death. Present cell replacement therapies and drug treatments have either failed in clinical trials or induce long term side effect and loss of efficacy over time. Neuronal replacement strategies that rebuild the damage circuit have a high probability of reducing or reversing motor deficits associated with Parkinson's disease as well as numerous other neurological disorders.

project_terms:
Address;Adult;Adverse effects;Animal Model;Axon;Behavior;Behavioral;Brain;Brain-Derived Neurotrophic Factor;Cells;Cessation of life;Cholera Toxin;Chondroitin Sulfate Proteoglycan;Chondroitinases;Clinic;Clinical Trials;Contralateral;Corpus Callosum;Corpus striatum structure;Data;Dendritic Spines;Disease;Dopamine;Electron Microscopy;Embryo;Ensure;FGF2 gene;Functional disorder;Growth;Growth Factor;Health;Human;Hyaluronidase;Image;Injection of therapeutic agent;Label;Laboratories;Left;Maps;Measures;Microelectrodes;Modeling;Motor;Neuraxis;Neurodegenerative Disorders;Neurons;Outcome Study;Oxidopamine;Parkinson Disease;Parkinsonian Disorders;Pathway interactions;Patients;Pharmaceutical Preparations;Probability;Rattus;Recombinants;Recovery of Function;Replacement Therapy;Research Personnel;Series;Site;Source;Specificity;Stem cells;Subfamily lentivirinae;Substantia nigra structure;Symptoms;Synapses;Time;Transplantation;axon growth;cell body (neuron);cell type;density;dopaminergic neuron;fetal;functional restoration;glial cell-line derived neurotrophic factor;human NTN1 protein;improved;in vivo;motor deficit;nervous system disorder;netrin-1;neural circuit;neuronal replacement;nigrostriatal pathway;overexpression;receptor;reconstruction;relating to nervous system;research study;restoration;synaptogenesis

public_health_relevance:
Parkinson's disease is a widespread neurodegenerative disease that manifests severemotor dysfunction ultimately leading to death. Present cell replacement therapies anddrug treatments have either failed in clinical trials or induce longterm side effect and lossof efficacy over time. Neuronal replacement strategies that rebuild the damage circuithave a high probability of reducing or reversing motor deficits associated withParkinson's disease as well as numerous other neurological disorders.


application_id: 8038393
project_number: 5R21CA143456-02
project_title: Targeting Signaling to Prevent Colon Cancer
administering_ic: NCI
award_notice_date: 2011-03-25
opportunity_number: PA-08-185
application_type: 5
activity_code: R21
ic: CA
serial_number: 143456
program_official: FU, YALI
project_start_date: 2010-03-04
project_end_date: 2011-05-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 7649061
contact_pi: DAMODARAN, CHENDIL
other_pis: Not Applicable
congressional_district: 06
department: OTHER CLINICAL 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: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Our research focuses on complementary and alternative medicines (CAM) that possess anti- cancer properties. In the proposed study we will analyze the mechanism of action of Withaferin-A (WA) a CAM based herbal used extensively in African and Asian countries for the treatment of various ailments including cancer. Our preliminary in vitro data suggest WA targets colon cancer cells by down-regulating cleaved NOTCH1 pAkt pS6K p4E-BP1 and Bcl- 2 and simultaneously promoting caspase-3 activation and PARP cleavage. Based on these results we hypothesize WA will effectively inhibit colon cancer growth due to its ability to inactivate Notch-1/Akt/mTOR-mediated pro-survival signaling and induce apoptosis in colon cancer cells. To address our hypothesis we propose: study the mechanism(s) of WA-mediated Notch-1/Akt/mTOR inhibition in colon cancer (Aim 1) and determine the in vivo efficacy of WA and its chemosensitization effect on colon cancer xenografts that over-express either Akt or mTOR (Aim 2). For our in vitro studies we will use RT-PCR Western Blotting SiRNA strategies immunoprecipitation cell viability assays apoptotic assays kinase assays transient transfection gene transcription assays pharmacological blocking and immunocytochemistry to clarify the impact of WA on the Notch-1/Akt/mTOR signaling axis. For our in vivo studies colon cancer cells will be stably transfected with either constitutively active Akt or mTOR. Using these transfectants xenografts will be formed in nude mice and the effect of WA on the tumor bearing animal models will be studied. Additionally to determine the chemosensitization effect of WA on tumor bearing animal models we will treat mice with WA and a sub-lethal dose of 5-Fluorouracil (5-FU). Necroscopy histopathology and immunohistochemical (Notch-1 Akt mTOR cyclin D1 Par-4 and Bid) analyses will be performed on the tumor sections following the termination of the study. Additionally HPLC will be performed to determine serum concentrations of WA in the nude mice models. Our long term goal is to encourage the use of CAMs in a clinical environment where these agents can be best used for their chemopreventive and chemotherapeutic properties. Our preliminary data indicate WA is one such compound and is a viable candidate for investigating its clinical potency against colon cancer cells.  
  
PUBLIC HEALTH RELEVANCE: Colorectal cancer is the third most frequently diagnosed cancer in men and women in the United States and although its mortality rates have decreased due to early detection and adjuvant therapies the disease is incurable once metastases develop. Complementary and alternative systems of medicine (CAM) may offer novel and effective therapies not yet explored by conventional medicine. The proposed study of the dietary supplement Withaferin-A (WA) the major bioactive compound from Withania somnifera) will provide molecular level insight into the mechanism of action of Withaferin-A against colon cancer and clarify the clinical potential of WA with respect to the chemoprevention and/ or chemotherapy of colon cancer.

project_terms:
Address;Adjuvant Therapy;African;Animal Model;Animals;Apoptosis;Apoptotic;Asians;Biological Assay;Blood;Cancer Model;Cell Death;Cell Proliferation;Cell Survival;Cells;Chemoprevention;Chemopreventive Agent;Chemosensitization;Cleaved cell;Clinical;Colon;Colon Carcinoma;Colorectal Cancer;Complementary and alternative medicine;Country;Cyclin D1;Data;Diet;Dietary Supplements;Disease;Dose;Down-Regulation;Early Diagnosis;Environment;Exhibits;Fluorouracil;Foundations;Future;Genetic Transcription;Goals;Growth;Herbal Medicine;High Pressure Liquid Chromatography;Histopathology;Human;Immunoprecipitation;In Vitro;Induction of Apoptosis;Lead;Malignant Neoplasms;Mediating;Medicinal Plants;Medicine;Mitosis;Mitotic;Molecular;Molecular Target;Monitor;Mortality Vital Statistics;Mus;NOTCH1 gene;Neoplasm Metastasis;Nude Mice;PAWR gene;Pathogenesis;Pattern;Phosphotransferases;Play;Property;Reporting;Research;Resistance;Reverse Transcriptase Polymerase Chain Reaction;Role;Serum;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Signaling Molecule;System;TAN-1 protein;Toxic effect;Transfection;Tumor Tissue;United States;Western Blotting;Withania somnifera;Woman;Xenograft Model;Xenograft procedure;base;biomarker;cancer cell;cancer diagnosis;caspase-3;chemotherapy;colon cancer cell line;effective therapy;feeding;immunocytochemistry;in vivo;insight;mTOR protein;men;mouse model;notch protein;novel;prevent;pro-apoptotic protein;public health relevance;tumor;tumorigenesis

public_health_relevance:
Project NarrativeColorectal cancer is the third most frequently diagnosed cancer in men and women in the United States andalthough its mortality rates have decreased due to early detection and adjuvant therapies the disease isincurable once metastases develop. Complementary and alternative systems of medicine (CAM) may offernovel and effective therapies not yet explored by conventional medicine. The proposed study of the dietarysupplement Withaferin-A (WA) the major bioactive compound from Withania somnifera) will provide molecularlevel insight into the mechanism of action of Withaferin-A against colon cancer and clarify the clinical potentialof WA with respect to the chemoprevention and/ or chemotherapy of colon cancer.


application_id: 8038268
project_number: 5R01NS061933-04
project_title: A specific microRNA (Mir-107) is a potential therapeutic target in Alzheimer's di
administering_ic: NINDS
award_notice_date: 2011-02-03
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 061933
program_official: CORRIVEAU, RODERICK A
project_start_date: 2008-09-30
project_end_date: 2012-08-28
study_section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Abstract MicroRNAs (miRNAs) are recently-discovered small regulatory RNAs that play fundamental roles in neurobiology. Preliminary results indicate that decreased expression of a particular miRNA miR-107 may contribute to Alzheimer's disease (AD) pathogenesis through a metabolic pathway. These are the first published data pertaining to miRNAs in a specific pathway that may contribute to AD. We will test a specific strategy to target this pathway for AD therapy. Hypothesis #1:  MiR-107 expression is decreased very early in AD which increases BACE1 expression and hence increases the amount of neurotoxic Abeta peptides in AD patients' brains. Hypothesis #2:  Bezafibrate treatment decreases AD-type pathology by increasing levels of miR-107. Specific Aim #1:  Characterize fully the regulation of BACE1 by miRNAs. Sub-Aim a. A novel technique will test directly whether BACE1 mRNA is a miRNA target. This biochemical approach involves co- immunoprecipitation using our monoclonal anti-Argonaute antibody. Sub-Aim b. Tissue culture studies will be performed to evaluate exactly which parts of the BACE1 mRNA 3'UTR constitute miRNA targets. Sub-Aim c. `Knock-in' and `knock-down' techniques will be used to alter miR-107 levels specifically in human cultured cells to determine the effects of miR-107 expression changes on the levels of BACE1 protein C99 polypeptide and A2 peptide. Experiments will be performed initially on H4 and SH-SY5Y cells. Specific Aim #2:  Characterize the impact of miR-107 on glucose metabolism and correlate the expression of miR-107 and other miRNAs with AD pathology in situ Sub-Aim a. Tissue culture studies will be performed to assess how pharmacological treatments that alter metabolism affect miR-107 expression and to evaluate how cellular changes in miR-107 influence the levels of specific metabolic intermediaries. Sub-Aim b. Human brain in situ hybridization will be used to understand how miR-107 expression relates to pathological hallmarks of AD and non-AD dementia. Specific Aim #3:  Evaluate bezafibrate for increasing miR-107 levels and decreasing BACE1 protein and A2 peptide(s) formation in vitro and in vivo. Bezafibrate is an orally-administered well-tolerated medication. Sub-Aim a. Preliminary results in cultured cells demonstrated that bezafibrate causes increased miR-107 expression and also induced down-regulation of BACE1 protein. The specific mechanism of bezafibrate action will be characterized using experiments in which the levels of miR-107 are manipulated. Sub-Aim b. Bezafibrate will be administered to mice - APPNLh/NLh x PS1P264L/P264L humanized APP knock-in mutants - that are an excellent model of AD-type amyloidogenesis (1) to demonstrate in vivo the efficacy of bezafibrate in modulating miR-107 BACE1 A2 levels and AD-type neuropathology. PUBLIC HEALTH RELEVANCE:  MicroRNAs are recently-discovered molecules that serve fundamental functions in the human brain. This research demonstrates for the first time that a particular microRNA may play an important role in Alzheimer's disease. A research program is proposed which exploits this new discovery in order to develop and evaluate a novel therapy for patients at risk for Alzheimer's disease.

project_terms:
3' Untranslated Regions;Affect;Alzheimer's Disease;Alzheimer's Disease Pathway;Alzheimer's disease model;Alzheimer's disease risk;Amyloid beta-Protein;Antibodies;Bezafibrate;Biochemical;Biological Assay;Brain;Cells;Clinical Trials;Co-Immunoprecipitations;Cultured Cells;Data;Dementia;Development;Down-Regulation;Glucose;Health;Human;In Situ;In Situ Hybridization;In Vitro;Knock-in Mouse;Lipids;MK-886;Messenger RNA;Metabolic;Metabolic Pathway;Metabolism;MicroRNAs;Mus;Neurobiology;Pathogenesis;Pathologic Processes;Pathology;Pathway interactions;Patients;Peptides;Pharmaceutical Preparations;Pharmacological Treatment;Play;Proteins;Publishing;Regulation;Research;Research Personnel;Role;Stimulus;Techniques;Testing;Time;Translations;abstracting;amyloidogenesis;base;beta-site APP cleaving enzyme 1;brain tissue;glucose metabolism;in vivo;knock-down;mutant;neuroblastoma cell;neuropathology;neurotoxic;novel;polypeptide;programs;relating to nervous system;research study;therapeutic target;tissue culture

public_health_relevance:
Project Narrative MicroRNAs are recently-discovered molecules that serve fundamentalfunctions in the human brain. This research demonstrates for the first time that aparticular microRNA may play an important role in Alzheimer's disease. Aresearch program is proposed which exploits this new discovery in order todevelop and evaluate a novel therapy for patients at risk for Alzheimer's disease.


application_id: 8037087
project_number: 5R01HL080394-05
project_title: Fibrinogen-Induced Vasoconstriction during Hypertension
administering_ic: NHLBI
award_notice_date: 2011-02-28
application_type: 5
activity_code: R01
ic: HL
serial_number: 080394
program_official: THRASHER, TERRY N
project_start_date: 2007-03-01
project_end_date: 2013-02-28
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 6869069
contact_pi: LOMINADZE, DAVID
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
arra_indicator: N
budget_start_date: 2011-03-01
project_abstract:
DESCRIPTION (provided by applicant): Hypertension is accompanied by an increased content of plasma fibrinogen (Fg). We reported that binding of Fg to the arterial wall causes vasoconstriction which is mediated by intercellular adhesion molecule-1 (ICAM-1). In addition blockade of the endothelin type A receptors attenuated Fg-induced vasoconstriction. In our preliminary studies endothelial binding of Fg enhanced production of endothelin-1 (ET-1). Furthermore Fg binding to endothelial cells (ECs) resulted in phosphorylation of extracellular signal regulated kinase (ERK). Activation of ICAM-1 and another Fg endothelial receptor alpha5beta1 integrin leads to phosphorylation of ERK and c-Jun-NH2-terminal kinase (JNK). Fg-induced vasoconstriction is increased during hypertension and regulated production of ET-1 results from exocytosis of Weibel-Palade bodies (WPb). We hypothesize that during hypertension increased Fg binding to endothelial ICAM-1 (and possibly alpha5beta1) induces enhanced exocytosis of WPbs through ERK (and possibly JNK) signaling and results in increased production of ET-1 leading to enhanced vasoconstriction. Based on our finding that Fg binding to ECs changes EC proteome which may be associated with WPb exocytosis we will determine if these Fg-induced cellular changes are associated with ET-1 release and therefore with vasoconstriction. The specific aims of the proposed study are: 1) To evaluate Fg binding to ICAM-1 the resultant production of ET-1 and subsequent vasoconstriction during hypertension; 2) To determine the signaling pathway (ERK- and/or JNK-involved) for Fg-induced ET-1 production and the elevated vasoconstriction during hypertension; and 3) To determine the functional role of EC proteins altered by Fg binding in Fg-induced exocytosis of WPbs during hypertension. Hypertension-induced enhanced Fg binding to endothelial ICAM-1 (and alpha5beta1) the role of ERK (and JNK) signaling and the role of proteins altered by Fg binding to ECs in increased exocytosis of WPbs and production of ET-1 which causes enhanced vasoconstriction will be determined. Genetic (SHR) and non-genetic (DOCA-salt) rat hypertension models will be studied at early and established stages of hypertension to identify changes associated with the development and maintenance of hypertension. This study will delineate mechanisms of Fg-regulated production of ET-1 and the resultant increased vasoconstriction that exacerbates microcirculatory complications during hypertension.

project_terms:
Acetates;Age;Animals;Attenuated;Big Endothelin;Binding (Molecular Function);Blood;Blood Pressure;Cardiovascular Diseases;Cerebrovascular Disorders;Confocal Microscopy;Control Animal;Deoxycorticosterone;Development;Dose;Endothelial Cells;Endothelin;Endothelin-1;Endothelium;Enzymes;Exocytosis;Extracellular Signal Regulated Kinases;F-Actin;Fibrinogen;Fibrinogen Receptors;Flow Cytometry;Genetic;Genetic Models;Hypertension;Inbred SHR Rats;Inbred WKY Rats;Integrin alpha5beta1;Integrins;Intercellular adhesion molecule 1;JUN gene;MALDI-TOF Mass Spectrometry;Maintenance;Mediating;Mitogen-Activated Protein Kinases;Mitogens;Modeling;Operative Surgical Procedures;Phosphorylation;Plasma;Production;Protein Kinase;Proteins;Proteome;Proteomics;Rattus;Reporting;Research Personnel;Resolution;Risk Factors;Role;SP600125;Signal Pathway;Signal Transduction;Small Interfering RNA;Sodium Chloride;Sprague-Dawley Rats;Staging;Surface;Time;Transfection;Two-Dimensional Polyacrylamide Gel Electrophoresis;Vascular Endothelium;Vascular constriction (function);Weibel-Palade Bodies;animal data;arteriole;base;high risk;inflammatory marker;inhibitor/antagonist;non-genetic;novel;programs;receptor;research study;response;stress-activated protein kinase 1


application_id: 8037033
project_number: 5R01AG031764-03
project_title: Beta-Amyloid Immunization in a Canine Model of Aging
administering_ic: NIA
award_notice_date: 2011-03-02
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AG
serial_number: 031764
program_official: RYAN, LAURIE M
project_start_date: 2009-03-01
project_end_date: 2014-02-28
study_section: Clinical Neuroimmunology and Brain Tumors Study Section[CNBT]
contact_pi_person_id: 8662513
contact_pi: HEAD, ELIZABETH
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) is associated with progressive cognitive decline and the accumulation of senile plaques and neurofibrillary tangles. Senile plaques contain the beta-amyloid peptide (A) which is thought to play a causative role in the disease. Thus a number of therapeutics are being developed that may reduce the production deposition or enhance clearance of A in the brains of patients with AD. In transgenic mouse models of AD deposition of A may be prevented or reduced after immunization with fibrillar A1-42. Further learning and memory is improved by either active or passive immunization with anti-A antibodies. On the basis of work in transgenic mice a clinical trial (AN1792) was initiated in AD patients who were administered fibrillar A42. Cognitive benefits were reported in this study and autopsy studies show a reduction in brain A. We extended immunotherapy studies into the canine model of human brain aging that naturally develop human-type A and cognitive decline. Aged animals were actively immunized for over 2 years (25 injections in total). Our results in immunized aged beagles showed decreased brain A and improved executive function. We hypothesize that we can improve cognition to a greater extent and extend cognitive improvements to include multiple domains by combined treatment with an intervention that may restore neuron health after A removal. Thus we propose to combine immunotherapy with behavioral enrichment in aged dogs and target two molecular pathways that may converge to provide additive benefits. We predict aged dogs will show significant cognitive improvements maintenance of cognition and reduced neuropathology when we combine immunotherapy with behavioral enrichment. Further the combination treatment will provide larger benefits to cognition and neuropathology than either treatment alone. The canine provides a unique model system in which to develop combinatorial treatment approaches involving immunotherapy for reducing AD pathology and improving cognition that may be more directly translated into human clinical trials. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is associated with progressive cognitive decline and the accumulation of brain pathology. We will use a combination treatment approach to improve cognition and reduce neuropathology in the canine model of aging through immunotherapy and behavioral enrichment which is an approach that may be directly translated into human clinical trials.

project_terms:
12 year old;AN-1792;Active Immunization;Adjuvant;Adverse event;Affect;Aftercare;Age;Aging;Alzheimer's Disease;Amyloid;Amyloid beta-Protein;Animal Model;Animals;Antibodies;Antigens;Attenuated;Autopsy;B-Lymphocytes;Behavioral;Biological Models;Brain;Brain Pathology;Brain-Derived Neurotrophic Factor;Bromodeoxyuridine;Canis familiaris;Cerebral Amyloid Angiopathy;Clinical Trials;Cognition;Cognitive;Combined Modality Therapy;Congo Red;Data;Deposition;Discrimination (Psychology);Discrimination Learning;Disease;Dot Immunoblotting;Dynamin I;Enzyme-Linked Immunosorbent Assay;Excision;Exercise;Experimental Designs;Female;Future;GDNF gene;Growth Factor;Head;Health;Hippocampus (Brain);Housing;Human;Immune response;Immunization;Immunotherapy;Impaired cognition;Individual;Infiltration;Injection of therapeutic agent;Intervention;Lead;Learning;Maintenance;Matched Group;Measures;Mediating;Memory;Memory impairment;Methods;Modeling;Molecular;NR2B NMDA receptor;Neurofibrillary Tangles;Neurons;Neuropsychological Tests;Outcome;Outcome Measure;Outcome Study;Passive Immunization;Pathogenesis;Pathology;Pathway interactions;Patients;Phase;Play;Polysorbate 80;Procedures;Production;Proteins;Prussian blue;Publishing;Reagent;Relative (related person);Reporting;Reversal Learning;Role;S-nitro-N-acetylpenicillamine;Sampling;Senile Plaques;Synapses;Synaptophysin;T-Lymphocyte;Techniques;Testing;Therapeutic;Time;Tissues;Toy;Transgenic Mice;Translating;Visual;Walking;Western Blotting;Work;aged;aging brain;aluminum sulfate;base;cognitive function;cognitive training;combinatorial;design;disability;drebrins;environmental enrichment for laboratory animals;executive function;improved;improved functioning;male;mild cognitive impairment;mouse model;neurogenesis;neuron loss;neuropathology;neurotrophic factor;normal aging;novel;prevent;research study;response;sex;social

public_health_relevance:
Project Narrative Alzheimer's disease (AD) is associated with progressive cognitive decline an the accumulation of brain pathology. We will use a combination treatment approach to improve cognition and reduce neuropathology in the canine model of aging through immunotherapy and behavioral enrichment which is an approach that may be directly translated into human clinical trials.


application_id: 8035981
project_number: 5R01ES015518-04
project_title: Reactive oxygen species in Ni(II) carcinogenesis
administering_ic: NIEHS
award_notice_date: 2011-02-28
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: 2013-02-28
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:
DESCRIPTION (provided by applicant): Nickel-containing compounds are human carcinogens. The mechanisms of their carcinogenic actions remain to be investigated. Recent studies have indicated that reactive oxygen species (ROS) may play an important role. We hypothesize that nickel induces generation of ROS which activate nuclear transcription factors leading to cell transformation and tumorigenesis. Specific Aim 1 will detect and identify ROS generated in human bronchial epithelial cells (BEAS-2B) and mouse embryo fibroblast cells exposed to nickel compounds and investigate the mechanism involved. We hypothesize that nickel (Ni3S2 and NiCl2) can stimulate the cells to activate NADPH oxidase via cdc42 and p47phox to produce superoxide radical which is then converted to hydrogen peroxide and hydroxyl radical. Specific Aim 2 will test the hypothesis that ROS are required for activation of NFAT and NFkappaB in cells and in vivo in response to nickel compounds. The role of ROS in nickel-induced activation of NFAT and NFkappaB in cells will be evaluated by co-transfection of NFkappaB-luciferase or NFAT-luciferase reporter plasmids and specific ROS scavenger enzymes. For in vivo study BALB/c transgenic mice with alternation of antioxidant enzymes or NADPH oxidase (ROS generating enzyme) will be employed. Specific Aim 3 will investigate the role of ROS NFAT and NFkappaB in nickel-induced cell transformation and tumorigenesis. We hypothesize that ROS activate transcription factors and cause cell transformation and tumorigenesis. We will use overexpression of DN-NFAT DN-IkappaBalpha and DN- IKKbeta to investigate the involvement of NFAT and NFkappaB in nickel-cell transformation and induced tumorigenesis. The role of ROS will be investigated using specific antioxidant enzyme expressions and NADPH oxidase alternation. We anticipate that nickel causes activation of NFAT and NFkappaB through ROS reactions leading to cell transformation and tumorigenesis. We attempt to link the cell transformation and tumorigenesis with specific transcription factors and specific reactive oxygen species. The results obtained from this proposal will elucidate the role of ROS and NFAT/NFkappaB signaling in Ni compounds-induced carcinogenesis. The long term goals are to provide a fundamental understanding concerning the mechanism of carcinogenic actions of Ni; to fill a need for the mechanistic information of cancer risk assessment for exposure; to propose methods for early detection; and to develop intervention and prevention strategies. Nickel-containing compounds are human carcinogens. This project will investigate the mechanism of Ni-induced carcinogenesis by testing the hypothesis that nickel induces generation of ROS which activate nuclear transcription factors leading to cell transformation and tumorigenesis. The long term goals are to understand the mechanism of Ni-carcinogenesis; to propose methods for early detection; and to develop intervention 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: 8035902
project_number: 5R01AR055246-04
project_title: Circadian rhythms and skeletal muscle
administering_ic: NIAMS
award_notice_date: 2011-03-01
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:
DESCRIPTION (provided by applicant): Circadian rhythms have long been known to influence behavioral and biological processes such as physical activity and feeding behavior. The fundamental importance of this system which works to link physiology with the day/night cycle is underscored by its presence in every known species and the growing evidence linking alterations 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 and Bmal1 dramatically disrupt muscle function. This is the first genetic evidence linking skeletal muscle function to circadian rhythms. Expression profiling studies of skeletal muscle over 48 hours identified that MyoD is a circadian gene. Molecular experiments went on to demonstrate that the MyoD promoter is directly bound and regulated by the core clock factors CLOCK and BMAL1.   
  
The studies outlined in this proposal combine molecular cell biological and biophysical approaches to understand the mechanisms by which the core clock mechanism is regulated in skeletal muscle and how loss of this rhythm leads to altered MyoD expression and loss of muscle function. The hypotheses for this proposal are 1) Synchronization of core clock gene expression in skeletal muscle requires intact innervation 2) Muscle specific mutations of Bmal1 or Clock will be sufficient to cause arrhythmic MyoD expression and muscle 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 sarcomeric structure and/or altered stoichiometry of myofilament proteins.   
  
The results of the experiments outlined in this proposal have significant implications for maintenance of muscle with an impact on our understanding and treatment of sarcopenia muscle wasting/cachexia and problems associated with metabolic diseases such as insulin resistance. In addition our understanding of circadian regulation of skeletal muscle will have likely applications for rehabilitation therapies for spinal cord injury patients and people that are exposed to prolonged periods of bed rest. PUBLIC HEALTH RELEVANCE. The results of the proposed work will determine the role of the biological clock in maintaining normal skeletal muscle structure and function. The findings have significant implications for maintenance of muscle with an impact on our understanding and treatment of sarcopenia muscle wasting/cachexia and problems associated with metabolic diseases such as insulin resistance. In addition our understanding of circadian regulation of skeletal muscle will have likely applications for rehabilitation therapies for spinal cord injury patients and people that are exposed to prolonged periods of bed rest.

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;Health;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: 8035837
project_number: 1R15NS067548-01A1
project_title: Nanotechnology: Advancing Toxicity Testing
administering_ic: NINDS
award_notice_date: 2011-02-14
opportunity_number: PA-10-070
application_type: 1
activity_code: R15
ic: NS
serial_number: 067548
suffix: A1
program_official: KOENIG, JAMES I
project_start_date: 2011-02-15
project_end_date: 2015-07-31
study_section: Nanotechnology Study Section[NANO]
contact_pi_person_id: 8564296
contact_pi: HAIK, KRISTI LYNN
other_pis: MORRIS, CELESTE ANN
congressional_district: 04
department: BIOLOGY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Nanotechnology provides an opportunity to develop drug delivery systems that cross the blood brain barrier (BBB). However as the production and discovery of new nanomaterials increases identification of the toxic effects of nanomaterials is essential. Factors affecting toxicity include size of the nanoparticle (NP) as well as core material drugs within the core external functional groups and surfactants. A standardized procedure to assess the toxicity of newly created nano-drug vehicles is highly desirable. This work will utilize an interdisciplinary approach to in vitro studies providing a more comprehensive and accurate screening tool for toxicity. Specifically the studies proposed will compare cellular toxicity measures specific genes related to toxicity and biophysical characteristics of NP interactions with model BBB membranes. This will enable the development of a standard panel of toxicity tests that can be conducted in a timely and relatively inexpensive fashion to investigate the toxicity of any type and number of NPs. In this work we will utilize the toxicity panel to characterize the effects of different charged surfactants on the toxicity of poly (butylcyanoacrylate) (PBCA) NPs which have been shown to deliver drugs to the brain in animal models. While much research has been conducted on PBCA NPs issues of toxicity have not been fully elucidated. Specific aims of this application include: (1) testing the toxicity of NPs using a two-cell culture model of the BBB; (2) examining a subset of genes related to (a) apoptosis and (b) stress and toxicity using PCR arrays; and (3) evaluating the biophysical characterization of NP-BBB model membrane interactions. This project fits well with the Academic Research Enhancement Award (AREA) R15 mechanism. Northern Kentucky University (NKU) is a primarily undergraduate institution but has not been a major recipient of NIH funding. The investigators and project faculty have strong active undergraduate research programs where students have the opportunity to present and publish their research.  
  
PUBLIC HEALTH RELEVANCE:  More than one billion people across the world suffer with brain diseases disorders or injuries. To combat these maladies researchers have been working hard to develop potential therapies a majority of which may only be administered by injecting them directly into the brain. Nanotechnology has shown promise in delivering drugs to the brain that previously had not had access. The purpose of this application is to compare cellular toxicity measures specific genes related to toxicity and biophysical characteristics of model BBB membranes that have been exposed to a variety of nanoparticles. This will enable the development of a much needed standard panel of toxicity tests that can be conducted in a timely and relatively inexpensive fashion to investigate the toxicity of any type and number of nanoparticles.

project_terms:
Academic Research Enhancement Awards;Accounting;Affect;Animal Model;Antineoplastic Agents;Apoptosis;Apoptotic;Area;Astrocytes;Biological Assay;Blood;Blood - brain barrier anatomy;Brain;Brain Diseases;Bromides;Cell Culture Techniques;Cell Line;Cell membrane;Cells;Cerebrum;Characteristics;Charge;Chemicals;Chemistry;Development;Disease;Doxorubicin;Drug Carriers;Drug Delivery Systems;Drug vehicle;Endothelial Cells;Exhibits;Faculty;Funding;Gene Expression;Genes;Glioblastoma;Homeostasis;In Vitro;Injury;Institution;Kentucky;Lactate Dehydrogenase;Lipids;Measures;Membrane;Membrane Lipids;Methods;Mitochondria;Modeling;Molecular;Molecular Profiling;Molecular and Cellular Biology;Nanotechnology;Outcome;Oxidative Stress;Pathway interactions;Penetration;Pharmaceutical Preparations;Phase;Polysorbate 80;Procedures;Production;Property;Publishing;Reporting;Research;Research Personnel;Screening procedure;Stream;Stress;Students;Surface;Testing;Tissues;Toxic effect;Toxicity Tests;Toxin;United States National Institutes of Health;Universities;Up-Regulation (Physiology);Work;base;combat;cytotoxicity;functional group;gene repression;interdisciplinary approach;membrane model;monolayer;nanodrug;nanomaterials;nanoparticle;nervous system disorder;pressure;prevent;programs;surfactant;tool

public_health_relevance:
More than one billion people across the world suffer with brain diseases disorders or injuries. To combat these maladies researchers have been working hard to develop potential therapies a majority of which may only be administered by injecting them directly into the brain. Nanotechnology has shown promise in delivering drugs to the brain that previously had not had access. The purpose of this application is to compare cellular toxicity measures specific genes related to toxicity and biophysical characteristics of model BBB membranes that have been exposed to a variety of nanoparticles. This will enable the development of a much needed standard panel of toxicity tests that can be conducted in a timely and relatively inexpensive fashion to investigate the toxicity of any type and number of nanoparticles.


application_id: 8035633
project_number: 1R15CA156601-01
project_title: Targeting the immunoproteasome as a novel colorectal cancer therapy
administering_ic: NCI
award_notice_date: 2010-12-20
opportunity_number: PA-10-070
application_type: 1
activity_code: R15
ic: CA
serial_number: 156601
program_official: FORRY, SUZANNE L
project_start_date: 2011-01-01
project_end_date: 2013-12-31
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 9659382
contact_pi: LEE, WOOIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second most frequent cause of cancer-related death in the United States. When detected early CRC is readily curable with surgery and in some cases with the addition of chemotherapy. However approximately 25% of CRC patients are diagnosed with incurable metastatic disease and their predicted 5-year survival is less than 10%. Thus novel approaches are urgently needed to improve clinical outcomes of CRC patients. Several recent studies have shown that the immunoproteasome an alternative form of the constitutive proteasome plays a role in a number of diseases including cancer and inflammatory diseases. In our preliminary studies we found that LMP2 a major catalytic subunit of the immunoproteasome is highly expressed in primary CRC tissues and cell lines compared to nonmalignant colorectal tissues. In addition the treatment of CRC cells with 'UK-101' a small molecule that selectively inhibits LMP2 induces cell death. Interestingly the human LMP2 has naturally occurring genetic variations including a common LMP2 polymorphism (p.60R>H allelic frequency of 17~35%) which was previously associated with decreased proteasomal activity. However the functional impact of LMP2 polymorphisms in CRC has never been investigated. In this proposal we will assess the potential of the immunoproteasome-targeting approach as a novel CRC therapy using UK-101. Our hypothesis is that the antitumor effect of UK-101 is mediated by LMP2 inhibition and the therapeutic efficacy of UK-101 may be influenced by the expression level and genetic variations of LMP2 in CRC. The following specific aims are proposed; 1) To determine the frequency of LMP2 expression in CRC tissues and investigate the molecular mechanisms of UK-101-induced CRC cell death 2) To determine the impact of LMP2 polymorphisms on the proteasomal activity and sensitivity of CRC to UK-101. We expect that the results from the proposed studies will provide crucial information in evaluating the therapeutic potential of the immunoproteasome as a novel target in CRC therapy and identifying genetic and molecular factors affecting the tumor response to the immunoproteasome-targeting approach. The proposed study is the first one to explore the immunoproteasome-targeting approach in solid tumor therapy. The results from the proposed study will provide crucial data for further investigations of the in vitro and in vivo efficacy of the immunoproteasome-targeting approaches in treating CRC.  
  
PUBLIC HEALTH RELEVANCE: Although the effectiveness of bortezomib a broadly acting proteasome inhibitor in multiple myeloma has validated the proteasome as a cancer drug target the broad application of bortezomib is limited due to its side effects and development of resistance. The immunoproteasome may be an alternative target in cancer therapy. Using an immunoproteasome-specific inhibitor developed in these laboratories we will validate the immunoproteasome as a potential target for colorectal cancer treatment.

project_terms:
Adverse effects;Affect;Antineoplastic Agents;Apoptosis;Apoptotic;Attention;Bortezomib;Cancer Etiology;Cancer Patient;Cancer cell line;Catalytic Domain;Cell Death;Cell Line;Cell Survival;Cell physiology;Cells;Cessation of life;Clinical;Codon Nucleotides;Colonic Neoplasms;Colorectal;Colorectal Cancer;Colorectal Neoplasms;Complex;DNA;Data;Diagnosis;Disease;Drug Delivery Systems;Effectiveness;Ethnic group;FDA approved;Frequencies (time pattern);Gene Frequency;Generations;Genetic Polymorphism;Genotype;Goals;Human;In Vitro;Inflammatory;Interferons;Investigation;Laboratories;Malignant Neoplasms;Malignant lymphoma lymphocytic intermediate differentiation diffuse;Malignant neoplasm of prostate;Mediating;Mind;Molecular;Molecular Genetics;Multiple Myeloma;Non-Malignant;Operative Surgical Procedures;Outcome;Peptides;Play;Proteasome Inhibitor;Resistance;Resistance development;Role;Sampling;Signal Pathway;Small Interfering RNA;Solid Neoplasm;Staging;Staining method;Stains;System;TNF gene;Therapeutic;Tissue Microarray;Tissues;Toxic effect;Treatment Efficacy;Tumor Tissue;Ubiquitin;United States;Up-Regulation (Physiology);Variant;Variation (Genetics);cancer cell;cancer therapy;chemotherapy;improved;in vivo;inhibitor/antagonist;multicatalytic endopeptidase complex;new therapeutic target;novel;novel strategies;response;small molecule;therapeutic target;tumor

public_health_relevance:
Although the effectiveness of bortezomib a broadly acting proteasome inhibitor in multiple myeloma has validated the proteasome as a cancer drug target the broad application of bortezomib is limited due to its side effects and development of resistance. The immunoproteasome may be an alternative target in cancer therapy. Using an immunoproteasome-specific inhibitor developed in these laboratories we will validate the immunoproteasome as a potential target for colorectal cancer treatment.


application_id: 8035430
project_number: 5R01DC009418-03
project_title: Neurotrophin receptor regulation of taste development
administering_ic: NIDCD
award_notice_date: 2011-03-22
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DC
serial_number: 009418
program_official: SULLIVAN, SUSAN L
project_start_date: 2009-04-01
project_end_date: 2013-03-31
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: MINICHIELLO, LILIANA
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Description (provided by applicant): During development sensory innervation to taste buds is tightly regulated by the actions of two neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4). Although both of these factors regulate gustatory innervation their specific functions are different from one another. BDNF is expressed in gustatory epithelium and determines whether gustatory neurons will locate and innervate taste placodes during development while NT4 does not. Both BDNF and NT4 regulate gustatory neuron and taste bud number but they have their influences at different times during development. The long range goal of this research is to understand the cellular and molecular mechanisms that regulate the neural innervation to and the maintenance of taste buds during development. The proposed studies focus on mechanisms by which these two neurotrophins BDNF and NT4 can influence various aspects of neural innervation through the same receptors TrkB and p75. The proposed studies use cell counting tract tracing immunohistochemistry and scanning electron microscopy in gene knockout mice to determine when TrkB and p75 are required for specific aspects of gustatory development including axonal extension into the tongue target selection and geniculate neuron/taste bud survival. Furthermore these studies combine these anatomical approaches with sophisticated genetic tools allowing the function of single phosphorylation sites on the TrkB receptor protein to be blocked in vivo. These experiments will determine which TrkB intracellular signaling pathways are required for axonal extension into the tongue target selection and geniculate neuron/taste bud survival. Together these studies test the hypotheses that TrkB mediates the effects of both BDNF and NT4 but that each function of these neurotrophins requires a different intracellular signaling pathway. While p75's more subtle role is to modulate the regulation of gustatory development by neurotrophins. Because these experiments examine the fundamental mechanisms of how neurotrophins regulate neuronal survival and axon targeting via Trk receptors this project has important implications for the therapeutic use of these signaling mechanisms in controlling neuron survival and axon targeting during regeneration. PUBLIC HEALTH RELEVANCE: The taste system is an ideal and commonly used system for examining axon regeneration following injury. We are examining the signaling mechanisms for two factors (neurotrophins) that influence axon targeting and neuron survival during development. By understanding of how these signaling mechanisms normally function techniques can be developed to manipulate these important signaling factors during nerve regeneration which will improve reinnervation and function following nervous system injury.

project_terms:
Adult;Afferent Neurons;Axon;Binding (Molecular Function);Birth;Brain-Derived Neurotrophic Factor;Cell Count;Cell Cycle;Data;Development;Developmental Process;Docking;Embryonic Development;Epithelium;Fiber;Fungiform Papilla;Genes;Genetic;Goals;Growth;Growth Factor;Health;Immunohistochemistry;Injury;Intracellular Signaling Proteins;Knockout Mice;Maintenance;Mediating;Microscopy Electron Scanning;Molecular;Mus;Mutate;NTF3 gene;Natural regeneration;Nerve;Nerve Growth Factor Receptors;Nerve Regeneration;Nervous System Trauma;Neurites;Neuronal Differentiation;Neurons;Neurotrophic Tyrosine Kinase Receptor Type 2;Palate;Pathway interactions;Pattern;Peripheral;Phospholipase;Phosphorylation Site;Receptor Protein-Tyrosine Kinases;Receptor Signaling;Regulation;Research;Role;Sensory;Sensory Ganglia;Signal Pathway;Signal Transduction;Site;System;Systems Development;Taste Buds;Taste Perception;Techniques;Testing;Therapeutic Uses;Time;Tongue;Tyrosine;Wild Type Mouse;adapter protein;axon regeneration;improved;in vivo;nerve supply;neuron development;neuron loss;neuronal survival;neurotrophic factor;neurotrophin 4;postnatal;receptor;reinnervation;relating to nervous system;research study;response;somatosensory;synaptogenesis;tool;transcriptional coactivator p75

public_health_relevance:
The taste system is an ideal and commonly used system for examining axonregeneration following injury. We are examining the signaling mechanisms for twofactors (neurotrophins) that influence axon targeting and neuron survival duringdevelopment. By understanding of how these signaling mechanisms normally functiontechniques can be developed to manipulate these important signaling factors duringnerve regeneration which will improve reinnervation and function following nervoussystem injury.


application_id: 8035281
project_number: 5F32HL095281-03
project_title: ACE2 in Hypercholesterolemia and Angiotensin II-Induced Vascular Diseases
administering_ic: NHLBI
award_notice_date: 2011-01-27
application_type: 5
activity_code: F32
ic: HL
serial_number: 095281
program_official: MEADOWS, TAWANNA
project_start_date: 2009-02-01
project_end_date: 2012-01-31
study_section: Special Emphasis Panel[ZRG1-F10-H(21)L]
contact_pi_person_id: 9412060
contact_pi: THATCHER, SEAN ERIC
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
budget_start_date: 2011-02-01
project_abstract:
DESCRIPTION (provided by applicant): Angiotensin converting enzyme-2 (ACE-2) catabolizes angiotensin II (Angll) to form the vasodilator Angiotensin1-7 (Ang1-7). The sponsor's laboratory has demonstrated that Angll increases atherosclerotic lesions and induces formation of abdominal aortic aneurysms (AAAs) in hyperlipidemic mice. Preliminary data generated by the applicant demonstrates ACE2 expression in macrophages and localization to atherosclerotic and AAA lesions. ACE2 has been implicated in blood pressure regulation however it is unclear whether dysregulated ACE2 contributes to Angll-induced vascular diseases. The long term objective of this study is to understand the role of ACE-2 in the development of atherosclerotic lesions and in Angll-induced AAA formation. Since macrophages are key mediators in developing atherosclerotic lesions and AAAs we will focus on macrophage ACE2 as a regulator of Angll-induced vascular diseases. The following specific aims will address our goal: 1) determine the effect of whole-body and/or bone marrow-derived ACE2 deficiency on hypercholesterolemia-induced atherosclerosis in low density lipoprotein receptor (LDLr) -/- mice; 2) determine the effect of whole body and/or bone marrow-derivedACE2 deficiency on Angll-induced AAAs in LDLr-/- mice. In aim 1 we will first examine the effect of ACE2 deficiency in LDLr-/- mice on high fat diet-induced atherosclerosis. Additional studies will use chimeric LDLr-/- mice repopulated with bone marrow from ACE2-/y mice to define the role of leukocytes in hypercholesterolemia-induced atherosclerosis. Mechanisms for ACE2 regulation by hypercholesterolemia will be examined using mouse peritoneal macrophages. In aim 2 we will define effects of ACE2 deficiency in LDLr-/- mice on Angll-induced AAAs and in follow up studies determine effects of ACE2 deficiency in bone marrow-derived cells on AAA formation. The relevance of the proposed research is to define mechanisms contributing to the development of two different types of common vascular diseases that negatively impact the health of millions of Americans. Identification of a regulatory role of the enzymeACE2 in Angll-induced atherosclerosis and AAAs may lead to novel medical therapies for these cardiovascular diseases.

project_terms:
Abdominal Aortic Aneurysm;Address;American;Angiotensin II;Angiotensinogen;Angiotensins;Arterial Fatty Streak;Atherosclerosis;Blood Pressure;Blood Vessels;Bone Marrow;Bone Marrow Transplantation;C57BL/6 Mouse;Cardiovascular Diseases;Cells;Data;Development;Diet;Fatty acid glycerol esters;Follow-Up Studies;Goals;Health;Homologous Gene;Infusion procedures;Laboratories;Lead;Lesion;Leukocytes;Low Density Lipoprotein Receptor;Mediator of activation protein;Medical;Mus;Pathology;Peptides;Peptidyl-Dipeptidase A;Peritoneal Macrophages;Play;Regulation;Renin;Research;Role;Signal Transduction;Source;Vascular Diseases;Vasodilator Agents;Work;blood pressure regulation;cardiovascular disorder therapy;cell type;hypercholesterolemia;macrophage;novel;response


application_id: 8035164
project_number: 1R03DC011360-01
project_title: Clinical measurement of vocal fold impact stress in children
administering_ic: NIDCD
award_notice_date: 2010-10-29
opportunity_number: PAR-10-055
application_type: 1
activity_code: R03
ic: DC
serial_number: 011360
program_official: SHEKIM, LANA O
project_start_date: 2010-12-01
project_end_date: 2013-11-30
study_section: Special Emphasis Panel[ZDC1 SRB-Y (55)]
contact_pi_person_id: 9635662
contact_pi: PATEL, RITA R
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Nationwide over one million or 6-9%1 of all children suffer from dysphonia. Dysphonia can be detrimental to children both psychologically and academically hence early identification and restoration of optimal vocal health is critical. Direct visualization of vocal fold vibratory patterns is fundamental to appropriate diagnosis and treatment of vocal fold pathology. Objective assessments of vocal fold physiology are non-existent in the field of pediatric voice care leading to delayed diagnosis and deferred development of effective treatments. The long term goal of the proposed research is to improve treatment outcomes and early identification in children with hoarseness by establishing age appropriate quantitative measurements of immature vocal fold function that contribute to voice disorders. To accomplish this goal it is necessary to quantify vocal fold vibrations resulting from differences in the multilayered vocal fold structure of children compared with adults. Most voice problems in children are thought to be caused by mechanical trauma to the vocal folds manifested as high impact stress leading to the development of vocal nodules. The specific goal of this project is to identify the impact of growth and development of the layered structure of the vocal folds on vocal physiology and the relationship of these factors to the development of vocal fold nodules in children. This research proposes 1 milestone-driven aim and 2 hypotheses-driven aims. Therefore the specific aims of this application are: 1) to optimize a 2-point laser projection system developed in our laboratory for precision and to compute expected measurement variability to fully translate use of this system to children 2) to quantify the relationship between short vocal fold length and increased vibratory amplitude during the developmental process in children with and without nodules and 3) to quantify spatiotemporal features of vocal fold impact stress in children as a function of age and pathology. A total of 80 children will be recruited to participate (ages: 5-12) 40 with and 40 without nodules. Forty adults (21-45 years) will be recruited to obtain the developmental end point for maturation of vibratory motion because adults have a well-defined layered structure of the vocal folds. The following spatiotemporal features of vocal fold vibrations will be measured using a novel 2-point pediatric laser high speed digital imaging system to identify impact stress: mid membranous amplitude-to-length ratio peak vocal fold acceleration(mm/sec2) peak closing velocity (mm/sec) open quotient and vibratory stiffness (ratio of maximum velocity by maximum displacement) and closed quotient. The proposed research is significant in filling a gap in knowledge concerning the most effective methods for assessing vibratory function and identifying predisposing factors in children with hoarseness. The fundamental knowledge of vibratory function obtained from this work will directly translate to the clinic by producing meaningful findings and measures that can be applied to pediatric vocal health outcomes and will thus reduce the burden of illness and disability caused by voice disorders in children.  
  
PUBLIC HEALTH RELEVANCE: It has been estimated that over one million1 children suffer from voice disorders nationwide with potentially detrimental psychological effects. Knowledge of vocal fold vibratory motion is fundamental for measuring treatment outcomes in children but has been slow to emerge due to technical challenges. This work is the first to examine spatiotemporal measurements of vocal fold motion that lead to the development of impact stress and voice disorders in children and to use a novel custom-built pediatric imaging system to examine the relationship of the immature vocal system and the formation of vocal fold nodules.

project_terms:
12 year old;Acceleration;Adult;Aftercare;Age;Biomechanics;Caring;Child;Childhood;Chronic;Clinic;Clinical;Clinical assessments;Coupled;Custom;Development;Developmental Process;Diagnosis;Disease;Dysphonia;Early identification;Endoscopes;Ensure;Foundations;Goals;Growth;Growth and Development function;Health;Hoarseness;Image;Imagery;Individual;Investigation;Knowledge;Laboratories;Larynx;Lasers;Lead;Length;Lesion;Loudness;Measurement;Measures;Mechanics;Methodology;Methods;Modeling;Motion;Movement;Nodule;Outcome;Pathology;Pattern;Phonation;Physiology;Population;Predisposing Factor;Production;Recruitment Activity;Relative (related person);Research;Risk;Shapes;Speed (motion);Stress;Structure;System;Therapeutic;Translating;Trauma;Traumatic Stress Disorders;Treatment outcome;Voice;Voice Disorders;Work;base;burden of illness;clinical application;digital imaging;disability;effective therapy;glottis;high standard;imaging modality;improved;innovation;insight;kinematics;novel;programs;prototype;psychologic;restoration;spatiotemporal;theories;tool;trend;vibration;vocal cord

public_health_relevance:
It has been estimated that over one million1 children suffer from voice disorders nationwide with potentially detrimental psychological effects. Knowledge of vocal fold vibratory motion is fundamental for measuring treatment outcomes in children but has been slow to emerge due to technical challenges. This work is the first to examine spatiotemporal measurements of vocal fold motion that lead to the development of impact stress and voice disorders in children and to use a novel custom-built pediatric imaging system to examine the relationship of the immature vocal system and the formation of vocal fold nodules.


application_id: 8034944
project_number: 3R01DK081324-02S1
project_title: An Intergenerational CBPR Intervention to Reduce Appalachian Health Disparities
administering_ic: NIDDK
award_notice_date: 2010-04-06
opportunity_number: PAR-07-379
application_type: 3
activity_code: R01
ic: DK
serial_number: 081324
suffix: S1
program_official: HUNTER, CHRISTINE
project_start_date: 2010-04-10
project_end_date: 2012-03-31
study_section: Special Emphasis Panel[ZRG1-RPHB-K(50)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
project_abstract:
DESCRIPTION (provided by applicant): Appalachian communities are disproportionately affected by the leading causes of morbidity and mortality. Specifically cancer and diabetes mortality rates are 17 percent and 33 percent above national rates. The Appalachian region also has the nation's highest cardiovascular death rates with 328.9 to 405.9 deaths per 100000 population. A leading risk factor implicated in all of these health disparities is problematic energy balance; BRFSS data indicate that only 22 percent of Appalachian Kentuckians receive the RDI for fruit and vegetable intake between 62-76 percent are overweight or obese and between 45-62 percent report sedentary lives. Nationally Kentucky ranks third in not meeting fruit and vegetable intake #3 in overweight #9 in obesity and #3 for sedentary behavior. Of particularly elevated concern the obesity rate has doubled since 1990 and Kentucky youth rank #1 in overweight and significantly lower than their national counterparts in fruit/vegetable intake and physical activity. Despite the pervasiveness of these risk factors and disease burdens Appalachian culture contains many characteristics and structures that offer locally based solutions including strong intergenerational ties faith-based activism and healthy traditional activities. Drawing on epidemiologic evidence and informed by our current successful faith-based trained lay health advisor tailored intervention (R01CA108696) we propose to administer and evaluate an intergenerational culturally appropriate CBPR energy balance intervention that has the potential of greatly preventing and reducing cancer CVD and diabetes morbidity and mortality by increasing fruit and vegetable intake lowering BMI and increasing physical activity. Working in partnership with 70 faith-based institutions in Appalachian Kentucky the proposed project has three phases: Phase I (Developmental phase) will use ethnographic methods (socio-ecological inventories key informant interviews participant observation) to assess the barriers to and facilitators of healthy diet weight and physical activity; develop culturally appropriate instruments; and modify existing interventions (Healthy Body/ Healthy Spirit and We Can!) to be responsive to local culture. During Phase II we will administer the group randomized staggered CBPR intervention based on Healthy Body/ Healthy Spirit and NHLBI's We Can! Theoretically informed by the SCT TTM and socio-ecological determinants of health the intervention will include culturally appropriate workshops (with locally relevant activities like square dance community gardening story telling and cooking classes) tailored lay health adviser visits and motivational interviewing. Throughout the project the RE-AIM model will inform our evaluation. During Phase III we will undertake qualitative process evaluation interviews and evaluate consistency with CBPR principles. PUBLIC HEALTH RELEVANCE: Rural Appalachian communities suffer some of the highest rates of the most common causes of death; cancer heart disease and diabetes. These conditions are strongly associated with being overweight and having a substandard diet and inadequate physical activity risk factors that are pervasive in Appalachia. The proposed project works in partnership with 70 faith-based institutions in Appalachian Kentucky to develop administer and evaluate an intergenerational intervention that uses culturally appropriate activities and workshops to reduce overweight and increase physical activity and fruit and vegetable intake.

project_terms:
Affect;Appalachian Region;Behavior;Behavioral Risk Factor Surveillance System;Body Weight decreased;Cardiovascular system;Cause of Death;Cessation of life;Characteristics;Chronic Disease;Communities;Dancing;Data;Death Rate;Development;Diabetes Mellitus;Diet;Diet good;Dietary intake;Educational workshop;Effectiveness of Interventions;Ensure;Epidemiology;Equipment and supply inventories;Evaluation;Exercise;Goals;Health;Health care facility;Heart Diseases;Institution;Intake;Intervention;Interview;Kentucky;Life;Linguistics;Malignant Neoplasms;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Nutritionist;Obesity;Overweight;Participant;Phase;Physical activity;Population;Process;Protocols documentation;Psychologist;Questionnaires;Randomized;Regimen;Reporting;Research;Research Personnel;Research Project Grants;Risk Factors;Rural;Solutions;Structure;Testing;Training;Translational Research;Visit;Weight;Work;Youth;base;burden of illness;community based participatory research;cooking;design;energy balance;ethnographic method;fruits and vegetables;health disparity;improved;informant;innovation;instrument;intergenerational;meetings;member;motivational enhancement therapy;prevent;public health relevance;sedentary


application_id: 8034778
project_number: 5R01DK074720-05
project_title: Novel hematopoietic effects of C3 cleavage fragments
administering_ic: NIDDK
award_notice_date: 2011-02-28
application_type: 5
activity_code: R01
ic: DK
serial_number: 074720
program_official: WRIGHT, DANIEL G
project_start_date: 2007-03-01
project_end_date: 2013-02-28
study_section: Hematopoiesis Study Section[HP]
contact_pi_person_id: 2265592
contact_pi: RATAJCZAK, MARIUSZ Z
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-03-01
project_abstract:
DESCRIPTION (provided by applicant): The preliminary data from our laboratory established a novel and previously underappreciated role of the complement (C) system in modulating SDF-1-CXCR4 axis-dependent homing/retention/mobilization of hematopoietic stem/progenitor cells (HSPC) in bone marrow (BM). We found that C proteins are synthesized in BM and C activation provides one of the earliest signals of BM injury e.g. during conditioning for transplant by irradiation/chemotherapy or G-CSF-induced mobilization. We reported that HSPC express functional C3aR and the iC3b-receptor CR3 and while C3a and desArgCSa stimulation of HSPC enhances/sensitizes responsiveness of HSPC to SDF-1 gradients deposition of iC3b on BM stroma tethers early CR3-positive hematopoietic progenitors causing retention in the BM. Four aims are proposed to better elucidate the role of C3 in hematopoiesis during stress situations: 1. The molecular aspects of the C3a-C3aR axis in homing/engraftment of HSPC in bone marrow. Preliminary research points to a crucial role for the C3a-C3aR axis in homing/retention of HSPC in the bone marrow. We will focus on determining the molecular mechanisms of C3aR signaling in HSPC crucial for these processes and test whether priming of HSPC before transplantation with C3 cleavage fragments enhances engraftment of long-term repopulating HSPC in wt mice and human cord blood HSPC engraftment in NOD/SCID mice. 2. Blockade of the C3a-C3aR axis as a new strategy to mobilize stem cells. We reported that the small molecular C3aR antagonist SB2900157 enhances and accelerates G-CSF-induced mobilization. As a continuation of this work we will study the phenotype of mobilized cells and test whether they engraft efficiently after transplantation into syngeneic mice. 3. C3 fragments as modulators of the SDF-1-CXCR4 axis. C3a desArgCSa and iC3b prime chemotaxis of HSPC to SDF-1. This aim will define the molecular mechanism of this phenomenon and explore the hypothesis that C3 cleavage fragments promote a shift of CXCR4 into membrane lipid rafts which increases their responsiveness to SDF-1. 4. C3 and impaired mobilization in immunodeficient mice. We have observed that immunodeficient RAG2-/- and SCID mice show impaired mobilization of HSPC which is restored after infusion of immunoglobulins. We will test the hypothesis that this defect is related to the lack of naturally occurring C cascade-activating IgM antibodies.

project_terms:
Address;Adhesions;Animals;Antibodies;Apoptosis;B-Lymphocytes;Binding (Molecular Function);Biological;Blood;Bone Marrow;Bone Marrow Cells;C3bi;CD34 gene;CSF3 gene;CXCR4 gene;Cell Adhesion Molecules;Cells;Chemotaxis;Cleaved cell;Clinic;Complement;Complement 3 Convertase;Complement 3a;Complement 3b;Complement Activation;Cytostatics;Data;Defect;Deposition;Dose;Engraftment;Exhibits;Exposure to;Generations;Half-Life;Hematopoiesis;Hematopoietic;Hematopoietic stem cells;Homing;Human;Hypoxia;Immunodeficient Mouse;Immunoglobulin M;Immunoglobulins;In Vitro;Inflammation;Infusion procedures;Injury;Laboratories;Lead;Ligands;Link;Liquid substance;Macrophage-1 Antigen;Marrow;Mediating;Membrane Lipids;Membrane Microdomains;Molecular;Mus;NOD/SCID mouse;Organ;Pathway interactions;Patient Care;Patients;Peptides;Phase;Phenotype;Play;Process;Progenitor Cell Engraftment;Radiation therapy;Radio;Recovery;Reporting;Research;Research Personnel;Role;SCID Mice;Serum;Signal Transduction;Site;Solid;Staging;Stem cells;Stress;Stromal Cell-Derived Factor 1;Stromal Cells;Supplementation;System;Testing;Tissues;Transplantation;Transplantation Conditioning;Umbilical Cord Blood;Work;Zymosan;base;cell motility;chemotherapy;citrate carrier;conditioning;in vivo;in vivo Model;injured;insight;irradiation;mouse model;novel;prevent;progenitor;programs;stem;trafficking


application_id: 8034238
project_number: 5R01AR045617-10
project_title: Intracellular signaling during skeletal muscle hypertrophy
administering_ic: NIAMS
award_notice_date: 2011-02-22
application_type: 5
activity_code: R01
ic: AR
serial_number: 045617
program_official: BOYCE, AMANDA T
project_start_date: 1999-02-05
project_end_date: 2013-02-28
study_section: Special Emphasis Panel[ZRG1-MOSS-H(02)S]
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
budget_start_date: 2011-03-01
project_abstract:
DESCRIPTION (provided by applicant):  Growth and maintenance of skeletal muscle mass is critical for long-term health and quality of life. Muscle is important for mobility but it is also crucial for metabolic health because of its contribution to glucose uptake and fat metabolism. Our lab and others have demonstrated that signaling through the mammalian target of rapamycin (mTOR) is necessary for skeletal muscle growth but the molecular links between signal input and downstream function are far from understood. In our previous studies we showed that a) prolonged activation of mTOR signaling is specific to growth inducing contractions b) mechanical strain activates mTOR signaling in skeletal muscle but not in non-muscle cells c) strain-induced mTOR signaling is independent of the IGFl/insulin/PI3 kinase signaling pathways and d) cell cycle genes such as cyclin D1 and c-myc are induced during mTOR dependent growth and they likely function in the differentiated muscle cell to induce ribosomal biogenesis/protein synthesis. The overall goal of this research is to use in vitro and in vivo models of skeletal muscle growth with molecular tools to identify the necessary upstream regulators and downstream effectors of mTOR. I) mechanical strain acts synergistically with IGF1 to prolong activation of mTOR signaling and II) mTOR kinase activity is necessary for translational-regulation of critical growth mRNAs including cyclin D1 and c- myc. These hypotheses will be tested by the following specific aims: Specific Aim 1. To determine the molecular signals by which mechanical strain regulates mTOR signaling. Specific Aim 2. To demonstrate whether mechanical signaling acts synergistically with IGF1 to regulate growth-related mTOR function. Specific Aim 3. Specific Aim 3. To determine whether the kinase activity of mTOR is necessary for growth protein synthesis and increased c-myc and cyclin D1 protein levels in response to mechanical overload in vivo. The results of these studies will provide novel insight for the field of mTOR regulation and the role of mechanical strain in the growth process of skeletal muscle. The clinical implications of this work are also significant and will contribute to development of strategies to attenuate or ameliorate muscle atrophy associated with disuse aging bed rest and cachexia.

project_terms:
1-Phosphatidylinositol 3-Kinase;Ablation;Aging;Amino Acids;Area;Attenuated;Bed rest;Biogenesis;Cachexia;Cells;Clinical;Complex;Cyclin D1;Cyclins;Development;Event;Fiber;Funding;Genetic;Goals;Growth;Growth Factor;Health;IGF1 gene;In Vitro;Incubated;Insulin;Link;Maintenance;Measures;Mechanics;Messenger RNA;Metabolic;Modeling;Molecular;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscular Atrophy;Outcome;Phosphorylation;Phosphotransferases;Process;Protein Biosynthesis;Proteins;Proto-Oncogene Proteins c-myc;Quality of life;Raptors;Regulation;Research;Research Personnel;Resistance;Ribosomal RNA;Role;Signal Pathway;Signal Transduction;Signaling Protein;Sirolimus;Skeletal muscle structure;Stretching;TSC1 gene;TSC2 gene;Testing;Transfection;Transgenic Mice;Translational Regulation;Work;c-myc Genes;cdc Genes;glucose uptake;in vivo;in vivo Model;insight;insulin receptor substrate 1 protein;knock-down;lipid metabolism;mTOR protein;muscle form;muscle hypertrophy;novel;programs;research study;response;skeletal muscle growth;tool


application_id: 8033177
project_number: 5R01MH063022-09
project_title: Implications of caveolae in Tat signaling and integrity of brain endothelium
administering_ic: NIMH
award_notice_date: 2011-02-08
opportunity_number: PA-07-089
application_type: 5
activity_code: R01
ic: MH
serial_number: 063022
program_official: RAO, VASUDEV RAMACHANDRA
project_start_date: 2001-08-01
project_end_date: 2012-03-31
study_section: NeuroAIDS and other End-Organ Diseases Study Section[NAED]
contact_pi_person_id: 8260644
contact_pi: TOBOREK, MICHAL
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): CNS complications of HIV infection remain a serious risk in HIV-1 infection despite significant advances in highly active antiretroviral therapy. Our research is based on a general hypothesis that specific HIV proteins such as Tat contribute to the dysfunction of brain microvascular endothelial cells (BMEC) and the disruption of the blood-brain barrier (BBB) facilitating virus entry into the brain. The present grant application is designed to study the signaling mechanisms that can be responsible for these effects. Our recent preliminary data indicate that exposure of endothelial cells to Tat results in immediate localization of Tat to caveolae the subset of lipid rafts characterized by the presence of proteins termed caveolins. The importance of this observation is related to the fact that a variety of cell surface receptors and signaling pathways activated by Tat are also localized in these membrane domains. In addition we demonstrate that silencing of caveolin-1 protein can protect against Tat-mediated toxicity to BMEC. Based on our preliminary data we propose that caveolae provide the signaling platform detrimental for vascular toxicity of Tat. We hypothesize that Tat-induced alterations of caveolae-associated pathways such as the Ras and Rho signaling cascades are the underlying mechanisms of Tat-induced injury to BMEC and disruption of the BBB. Mechanistically we propose that Tat-induced alterations of the Ras and Rho signaling pathways result in disturbances in tight junction protein expression leading to increased transendothelial passage of inflammatory cells and HIV entry into the brain. We also propose that statins can regulate caveolae-associated signaling and protect against Tat- mediated vascular toxicity. This project is interdisciplinary and combines molecular and vascular biology with pro- clinical approaches. It is based on the newly developed co-cultures of human brain microvascular endothelial cells (HBMEC) with genetically altered human astrocyte cell lines that produce Tat (SVGA-Tat cells). This proposal is the first attempt to study the role of functional caveolae in the regulation of the BBB in relationship to HIV-1 infection. Data arising from this proposal will be critical for a better understanding of the development of the BBB dysfunction in neuroAIDS. The long term goals of this proposal are to determine therapeutic strategies to prevent neurological complications of HIV infection. RELEVANCE Dysfunction of the blood-brain barrier and brain endothelial cells contribute to HIV-1 trafficking into the brain and the development of HIV-1-associated neurotoxicity. We hypothesize that HIV-1 protein Tat can contribute to this pathology through stimulation of caveolae-associated pathways. This proposal is the first attempt to study the role of functional caveolae in the regulation of the blood-brain barrier in relationship to HIV-1 infection.

project_terms:
1-Phosphatidylinositol 3-Kinase;AIDS neuropathy;Abbreviations;Address;Affect;Animal Model;Anti-HIV Agents;Applications Grants;Astrocytes;Attenuated;Basic Science;Biology;Blood - brain barrier anatomy;Blood Vessels;Brain;Caveolae;Caveolins;Cell Line;Cell Surface Receptors;Cells;Cellular Structures;Central Nervous System Infections;Characteristics;Clinical;Coculture Techniques;Cytoskeleton;DNA Sequence Rearrangement;Data;Development;Disease;Down-Regulation;Elements;Endothelial Cells;Endothelium;Event;Functional disorder;GTP-Binding Proteins;Goals;HIV;HIV Infections;HIV drug resistance;HIV-1;Heterotrimeric GTP-Binding Proteins;Highly Active Antiretroviral Therapy;Homeostasis;Human;Infection;Infiltration;Inflammatory;Injury;Intercellular Junctions;Lead;Mediating;Membrane;Membrane Microdomains;Molecular;Mus;Nervous System Physiology;Neuraxis;Neuroglia;Neurologic;Neurons;Pathology;Pathway interactions;Play;Prevention;Process;Proteins;Receptor Signaling;Regulation;Research;Research Proposals;Risk;Role;Signal Pathway;Signal Transduction;Structure;Therapeutic;Tight Junctions;Tissues;Toxic effect;Vascular Endothelial Growth Factor Receptor-2;Virus;base;caveolin 1;cell injury;design;genetic regulatory protein;innovation;interest;neglect;neuropathology;neurotoxicity;neurovascular unit;novel;prevent;protective effect;protein expression;receptor;rho;sarcoma;tat Protein;trafficking;uptake


application_id: 8033091
project_number: 5R01NS050242-05
project_title: Relationship between BOLD effects on DA degeneration
administering_ic: NINDS
award_notice_date: 2011-01-21
application_type: 5
activity_code: R01
ic: NS
serial_number: 050242
program_official: SIEBER, BETH-ANNE
project_start_date: 2007-02-16
project_end_date: 2013-01-31
study_section: Clinical Neuroscience and Disease Study Section[CND]
contact_pi_person_id: 2154561
contact_pi: ZHANG, ZHIMING
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
budget_start_date: 2011-02-01
project_abstract:
DESCRIPTION (provided by applicant):  The hallmark of Parkinson's disease (PD) is the loss of dopamine neurons in the substantia nigra. However clinical symptoms of PD do not manifest until the loss of dopamine neurons exceeds a critical threshold. Thus for the early detection of PD there is particular interest in using an objective noninvasive sensitive and cost-effective imaging method to supplement existing clincal measures and response to treatments. The primary goal of this project is to determine whether BOLD-phMRI can meet these aforementioned criteria as an imaging biomarker of PD. Recently we.have demonstrated that the blood oxygenation level dependent (BOLD) response to dopaminergic stimulation as measured by pharmacological MRI (phMRI) correlated with specific histological and behavioral features of the parkinsonian state. For example d-amphetamine-evoked activations correlated with the number of surviving dopamine neurons and stronger apomorphine-induced activations were seen in more severely motor impaired parkinsonian rhesus macaques (see preliminary studies). In addtion apomorphine-induced activations in the dopamine denervated putamen were attenuated by a neurorestorative therapy (chronic intraputamenal infusion of GDNF). Therefore by using the imaging proctocol developed by our group over several years we are now proposing a large scale study in groups of rhesus monkeys that are: 1) normal animals 2) MPTP-lesioned but asymptomatic 3) MPTP-lesioned but mild unilateral symptoms and 4) MPTP-lesioned with severe unilateral symptoms in order to address the following specific aims: 1) whether BOLD-phMRI can be used to monitor the progression of the disease namely to determine if the BOLD effects will correlate with severity of PD features assessed behaivorally and also with pathological stages of the disease; and 2) whether BOLD-phMRI can be used to assess responses to therapy such as L-dopa treatment. If proven predictive of changes in dopamine functions BOLD-phMRI could be used in the future as an imaging biomarker to supplement existing clinical measures and to provide valuable information about the disease process or intervention. In addition because of the noninvasive highly sensitive highly reproducible and cost-effective features of BOLD-phMRI this technique may be used to screen the general population to investigate pathogenesis of the disease.

project_terms:
Address;Amphetamines;Animal Model;Animals;Apomorphine;Appearance;Attenuated;Basal Ganglia;Behavioral;Biological Process;Chronic;Clinical;Corpus striatum structure;Deterioration;Development;Dextroamphetamine;Disease;Disease Progression;Dopamine;Dopamine Agonists;Dopamine Receptor;Dopaminergic Cell;Early Diagnosis;Fiber;Future;General Population;Geographic Locations;Goals;Image;Imaging Techniques;Infusion procedures;Intervention;Kentucky;Lesion;Levodopa;MPTP Poisoning;MRI Scans;Macaca mulatta;Magnetic Resonance Imaging;Measures;Modeling;Monitor;Motor;Outcome;Parkinson Disease;Parkinsonian Disorders;Pathogenesis;Pathological Staging;Patients;Positron-Emission Tomography;Process;Protocols documentation;Published Comment;Recovery of Function;Research;Research Personnel;Research Proposals;Rest;Severities;Signal Transduction;Signs and Symptoms;Specificity;Staging;Substantia nigra structure;Suggestion;Symptoms;System;Techniques;Testing;Therapeutic Agents;Universities;base;biomarker;blood oxygen level dependent;blood oxygenation level dependent response;cost effective;dopamine system;dopaminergic neuron;functional restoration;glial cell-line derived neurotrophic factor;imaging modality;interest;meetings;motor impairment;neurorestoration;nigrostriatal system;novel therapeutics;programs;putamen;response;treatment center


application_id: 8032454
project_number: 5R01AG029623-06
project_title: Role of TWEAK in Skeletal Muscle Metabolism
administering_ic: NIA
award_notice_date: 2011-02-02
application_type: 5
activity_code: R01
ic: AG
serial_number: 029623
program_official: WILLIAMS, JOHN
project_start_date: 2007-02-01
project_end_date: 2012-08-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 1917770
contact_pi: KUMAR, ASHOK
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-02-15
project_abstract:
DESCRIPTION (provided by applicant): Skeletal muscle atrophy/wasting is a devastating complication of a number of chronic diseases including aging cancer diabetes sepsis AIDS chronic obstructive pulmonary disease chronic heart failure and cystic fibrosis. Beyond a reduced survival rate muscle atrophy is also related to poor functional status and health-related quality of life in these and many other conditions such as starvation immobilization and disuse. However effective treatments require insight into the etiology of skeletal muscle atrophy. In our search to identify potential regulatory molecules that play an important role in the acquisition and maintenance of skeletal muscle mass we have accumulated several lines of evidence that support a key role for TNF-related weak-inducer of apoptosis (TWEAK) in regulation of skeletal muscle mass. These findings include: 1) Exogenous addition of recombinant TWEAK protein inhibits myoblast differentiation; 2) Inhibition of TWEAK activity using a blocking peptide promotes differentiated functions of myoblasts; 3) TWEAK accelerates degradation of specific muscle proteins in differentiated myoblasts; and 4) Chronic administration of TWEAK in mice reduces body and skeletal muscle weights and induces degradation of muscle proteins suggesting that TWEAK is a powerful muscle wasting molecule. Based on our strong preliminary data we hypothesize that: a) Deletion of TWEAK in mice will cause accretion of skeletal muscle mass and prevent muscle loss in response to aging tumor growth and diabetes; and b) TWEAK effects on myogenic cells are mediated through activation of signaling pathways independent of the Fn14 receptor. In this grant using TWEAK-knockout and transgenic mice we will evaluate the role and mechanisms of action of TWEAK in skeletal muscle. Our specific aims are to investigate: I) The consequence of disruption of TWEAK gene on the acquisition and maintenance of skeletal muscle mass under normal and pathological conditions; II) The key cellular processes that TWEAK affects in skeletal muscles; and III) The molecular pathways through which TWEAK regulates acquisition and maintenance of skeletal muscle mass. The successful completion of the propsoed work should provide the first experimental proof for involvement of TWEAK in the regulation of skeletal muscle mass and could lead to identification of TWEAK as a novel molecular target for future development of therapies to prevent muscle loss.

project_terms:
Ablation;Acquired Immunodeficiency Syndrome;Actins;Adverse effects;Affect;Aging;Anabolism;Apoptosis;Apoptosis Promoter;Area;Attenuated;Bacteria;Binding (Molecular Function);Biological;Body Weight;Cachexia;Catabolism;Cell Culture Techniques;Cell physiology;Cells;Chronic;Chronic Disease;Chronic Obstructive Airway Disease;Complementary DNA;Complication;Cystic Fibrosis;Cytoplasmic Tail;Data;Dexamethasone;Diabetes Mellitus;Differentiation Antigens;Disease;Dominant-Negative Mutation;Endotoxins;Equilibrium;Etiology;Event;Exhibits;Family;Fiber;Fibroblast Growth Factor;Future;Genes;Grant;Growth;HIV;Heart failure;Hypersensitivity;Immobilization;In Vitro;Inflammation;Inflammatory;Interferons;Interleukin-6;Knock-out;Knockout Mice;Lead;Ligand Binding;Ligand Binding Domain;Maintenance;Malignant Neoplasms;Mediating;Medical;Modeling;Molecular;Molecular Target;Morbidity - disease rate;Mortality Vital Statistics;Mus;Muscle;Muscle Cells;Muscle Development;Muscle Fibers;Muscle Proteins;Muscle function;Muscular Atrophy;Myoblasts;Myogenic Regulatory Factors;Myogenin;Natural Killer Cells;Natural regeneration;Outcome;Pathway interactions;Peptides;Phenotype;Physiological;Play;Prevention;Principal Investigator;Process;Production;Proteins;Publishing;Recombinants;Regulation;Reporting;Research Personnel;Role;Screening procedure;Sepsis;Signal Pathway;Skeletal muscle structure;Small Interfering RNA;Somatomedins;Space Flight;Starvation;Stimulus;Study Section;Survival Rate;Syndrome;TNF gene;Techniques;Testing;Transgenic Mice;Transgenic Organisms;Tropomyosin;Troponin;Tumor Necrosis Factor Receptor;Tumor Necrosis Factor-Beta;Two-Hybrid System Techniques;Weight;Work;Yeasts;angiogenesis;base;cDNA Library;caspase;cell growth;common treatment;cytokine;effective therapy;functional status;gene function;health related quality of life;in vivo;induced pluripotent stem cell;insight;knockout animal;mouse model;muscle form;muscle metabolism;neutralizing antibody;novel;overexpression;prevent;programs;protein degradation;receptor;research study;response;skeletal muscle wasting;success;therapeutic development;therapy development;tumor growth;wasting;yeast two hybrid system


application_id: 8032155
project_number: 1R36AG038547-01
project_title: The role of adipokines in age-related sensitivity to sepsis
administering_ic: NIA
award_notice_date: 2011-02-14
opportunity_number: PAR-08-250
application_type: 1
activity_code: R36
ic: AG
serial_number: 038547
program_official: FLORES, ROBERTO L
project_start_date: 2011-02-15
project_end_date: 2011-05-07
study_section: Biological Aging Study Section[NIA-B]
contact_pi_person_id: 10399494
contact_pi: STARR, MARLENE ELENA
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The role of adipokines in age-related sensitivity to sepsis Abstract Aging is characterized by a deteriorated stress response that underlies compromised resistance to such physiological stresses as systemic inflammatory response syndrome and sepsis clinical conditions in which the inflammatory and coagulant pathways are pervasively activated. Recent evidence suggests that adipokines adipose tissue-derived signaling proteins including cytokines coagulation factors and hormones may play an important role in the inflammatory response. My long term goals are to identify the mechanisms by which adipokines contribute to age-related alterations in inflammatory response and to use this information in the development of therapeutic tools. For these studies I propose to use two widely accepted mouse models of sepsis: (1) acute endotoxemia by injection with bacterial endotoxin lipopolysaccharides (LPS) and (2) acute peritonitis by cecal ligation and puncture (CLP). My central hypothesis is that expression patterns of cytokines and coagulation factors from the adipose tissue are significantly altered with age and that this alteration contributes to age-related sensitivity to sepsis. I intend to achieve these goals in the pursuit of the following three specific aims. In Aim 1 I will determine which adipokines are involved in age-associated differences during systemic inflammation by analyzing mRNA and protein expression in adipose tissues from young and aged mice after LPS injection. In Aim 2 I will use in vitro organ culture techniques and adipose tissue transplantation to understand the mechanisms by which adipokines contribute to this age-associated difference in systemic inflammation. In Aim 3 I will test interventions for improving age-related vulnerability to systemic inflammation through decreases in adipose tissue by surgical removal or dietary restriction. These studies will provide significant insight into the association of the previously neglected adipose organ in inflammatory disorders.  
  
PUBLIC HEALTH RELEVANCE: This project is relevant to public health because it will provide information for the development of treatments and preventative therapies that will decrease incidence rates and deaths related to sepsis and systemic inflammation in the aged and it will also potentially identify new biomarkers for the early detection of sepsis. Preventative therapies will likely result in reduced patient visits and health care costs. This research will also provide more understanding into the importance of adipose tissue and obesity in health and disease.

project_terms:
Abdomen;Acute;Adipose tissue;Age;Aging;Blood Coagulation Factor;Blood coagulation;Body Weight;Body fat;Clinical;Coagulants;Coagulation Process;Data Analyses;Death Rate;Disease;Disseminated Intravascular Coagulation;Early Diagnosis;Elderly;Endotoxemia;Endotoxins;Environment;Excision;Functional disorder;Gene Expression;Goals;Growth Factor;Health;Health Care Costs;Hormones;Human;Immune response;Incidence;Individual;Infection;Inflammation;Inflammatory;Inflammatory Response;Injection of therapeutic agent;Intervention;Life;Ligation;Link;Lipopolysaccharides;Medical;Medicine;Methods;Microarray Analysis;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mus;Obesity;Organ;Organ Culture Techniques;Pathway interactions;Patients;Pattern;Peritonitis;Physiological;Play;Population;Predisposition;Process;Puncture procedure;Research;Resistance;Reverse Transcriptase Polymerase Chain Reaction;Role;Sepsis;Sepsis Syndrome;Series;Shock;Signaling Protein;Staging;Stress;Survival Rate;Symptoms;System;TNF gene;Techniques;Testing;Time;Tissue Transplantation;Transcript;Transplantation;Visceral;Visit;Western Blotting;Youth;abstracting;adipokines;age related;aged;biological adaptation to stress;biomarker;cDNA Arrays;chemokine;cytokine;dietary restriction;improved;inflammatory marker;insight;interest;mRNA Expression;mRNA Stability;mouse model;neglect;older patient;protein expression;public health medicine (field);research study;therapeutic development;therapy development;tool

public_health_relevance:
This project is relevant to public health because it will provide information for the development of treatments and preventative therapies that will decrease incidence rates and deaths related to sepsis and systemic inflammation in the aged and it will also potentially identify new biomarkers for the early detection of sepsis. Preventative therapies will likely result in reduced patient visits and health care costs. This research will also provide more understanding into the importance of adipose tissue and obesity in health and disease.


application_id: 8031205
project_number: 1R21AI092074-01
project_title: Transgenic mouse models of HCV infection and replication
administering_ic: NIAID
award_notice_date: 2010-12-03
opportunity_number: PA-10-069
application_type: 1
activity_code: R21
ic: AI
serial_number: 092074
program_official: KOSHY, RAJEN
project_start_date: 2010-12-03
project_end_date: 2012-11-30
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): Hepatitis C virus (HCV) is the leading cause of chronic hepatitis cirrhosis and hepatocellular carcinoma (HCC). HCV chronically infects approximately 4 million people in the U.S. and 170 million people worldwide. HCV co-infection with HIV is very common with overall 25-30% of HIV-positive persons particularly among drug abusers with up to 70% co-infection (2). HCV infection is a major risk factor for HCC development. HCV- associated end-stage of liver diseases is the leading indication for liver transplantation. Advances on HCV research have been significantly hampered by the lack of a robust cell culture HCV propagation system and reliable small animal models of HCV infection and replication. Recent breakthroughs have been the development of robust cell culture systems for replication of HCV replicon RNAs and production of infectious HCV which allows genetic studies of the entire HCV life cycle. However development of small animal models of HCV infection and replication is challenging and that the lack of a reliable small animal model represents a major barrier to HCV research. Recently we have demonstrated that genotype 2a HCV RNA replicated efficiently in mouse embryonic fibroblasts (MEF) albeit inefficiently in mouse hepatocytes. More importantly we have demonstrated that the cDNA-derived HCV RNA inside the cell resulted in robust production of infectious HCV. A recent study by Charlie Rice's group has demonstrated that the expression of human CD81 and occludin in mouse hepatocytes is essential and sufficient for infection of HCV pseudotyped particles. These remarkable advances provide a firm foundation to develop novel transgenic mouse models of HCV infection and replication. We hypothesize that cell type-specific cellular proteins are important for efficient HCV RNA replication and that transgenic mice expressing human CD81 and occludin in hepatocytes are susceptible to HCV infection. The overall goal of this exploratory research proposal is to develop novel transgenic HCV mouse models. Specifically we will 1) identify cellular proteins important for efficient HCV RNA replication in mouse cells using proteomics biochemical and genetic complementation approaches (Specific Aim 1); 2) develop novel transgenic mice that either contain full-length cDNAs of luciferase-expressing JFH1 HCV RNAs or express both human CD81 and occludin under the control of a liver-specific promoter (Specific Aim 2); and 3) determine HCV infection and replication in transgenic mice using luciferase-expressing HCV in conjunction with the administration of mouse interferon and HCV NS3 protease- and NS5B polymerase-specific inhibitors (Specific Aim 3). The successful development of transgenic HCV mouse models will represent a paradigm shift in the field of HCV research and will allow us to determine the roles and mechanisms of action of viral and cellular proteins in HCV infection replication pathogenesis and carcinogenesis as well as the effects of illicit drugs and alcohol on HCV replication and pathogenesis. Additionally transgenic HCV mouse models will facilitate the anti-HCV drug discovery and HCV vaccine development to eventually control HCV infection.  
  
PUBLIC HEALTH RELEVANCE: Hepatitis C virus (HCV) infection remains a major global health problem affecting approximately 170 million people worldwide and 4 million Americans. Our overall goal of this research proposal is to develop novel transgenic HCV mouse models for the determination of the molecular mechanisms of HCV replication pathogenesis carcinogenesis and the effects of illicit drugs and alcohol on HCV replication and pathogenesis. Additionally transgenic HCV mouse models will facilitate the antiviral drug discovery and vaccine development to eventually control HCV infection.

project_terms:
Affect;Albumins;Alcohols;American;Animal Model;Antiviral Agents;Biochemical Genetics;CD81 gene;Catalytic RNA;Cell Culture System;Cell Culture Techniques;Cell Line;Cells;Chronic Hepatitis;Cirrhosis;Complementary DNA;DNA Polymerase II;Development;Drug abuser;Embryo;Fibroblasts;Foundations;Genetic;Genetic Transcription;Genome;Genomics;Genotype;Goals;HCV Vaccine;HIV;HIV Seropositivity;Hepatitis C;Hepatitis C virus;Hepatitis Delta Virus;Hepatocyte;Human;Illicit Drugs;Infection;Infectious hepatitides;Interferons;Knowledge;Laboratories;Length;Life Cycle Stages;Liver;Liver diseases;Luciferases;Measures;Molecular;Mouse Cell Line;Mus;Pathogenesis;Peptide Hydrolases;Persons;Polymerase;Primary carcinoma of the liver cells;Production;Promotor (Genetics);Proteins;Proteomics;RNA;RNA Sequences;RNA replication;Replicon;Research;Research Proposals;Rice;Risk Factors;Role;Staging;Structure;System;Transgenic Mice;Transgenic Organisms;Variant;Viral;Viral Proteins;Virion;Virus;Virus Receptors;Virus Replication;Work;anti-hepatitis C;base;carcinogenesis;cell type;drug development;drug discovery;global health;hepatitis C virus NS3 protein;hepatoma cell;in vivo;inhibitor/antagonist;innovation;interdisciplinary approach;liver transplantation;mouse model;novel;occludin;particle;receptor;vaccine development;viral RNA

public_health_relevance:
Hepatitis C virus (HCV) infection remains a major global health problem affecting approximately 170 million people worldwide and 4 million Americans. Our overall goal of this research proposal is to develop novel transgenic HCV mouse models for the determination of the molecular mechanisms of HCV replication pathogenesis carcinogenesis and the effects of illicit drugs and alcohol on HCV replication and pathogenesis. Additionally transgenic HCV mouse models will facilitate the antiviral drug discovery and vaccine development to eventually control HCV infection.


application_id: 8030355
project_number: 1R03DE021438-01
project_title: Genetic Markers Associated with Epithelial Ovarian Cancer and Hypodontia
administering_ic: NIDCR
award_notice_date: 2011-08-01
opportunity_number: PAR-07-418
application_type: 1
activity_code: R03
ic: DE
serial_number: 021438
program_official: HARRIS, EMILY L
project_start_date: 2011-08-01
project_end_date: 2013-07-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 9768371
contact_pi: MORFORD, LORRI A.
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Epithelial ovarian cancer (EOC) known as the silent killer in women is difficult to diagnosis due to a lack of effective early screening markers for the disease. Without improvements in the current early detection protocols over 70% of women diagnosed with EOC will be identified in late stage disease with a significantly reduced chance of survival. Interestingly recent work at the University of Kentucky has demonstrated that subjects diagnosed with EOC were 8.1 times more likely to also have hypodontia the lack of formation of 1 to 6 permanent teeth when compared to age-matched control subjects without EOC. Hypodontia which can be diagnosed as early as age 9 by radiograph in the dental clinic may be the earliest known marker of EOC- risk today. If hypodontia alone was utilized as a risk marker in the medical or dental clinic however many women could undergo increased testing for EOC with great cost and anxiety and may not truly be at risk. If specific markers (changes in a person's genetic code) could be identified which more frequently associate with EOC patients who have hypodontia (compared to healthy controls) these markers could be utilized for the early screening of young women with hypodontia to identify women at the highest risk for developing EOC in their lifetime. This could lead to earlier screening protocols for women at highest risk of developing EOC increased numbers of early stage diagnoses and the saving of countless numbers of lives. This study will create a DNA (genetic code) resource bank from the saliva of a population of Caucasian women in Central Kentucky who have either been diagnosed with EOC or are healthy control subjects. Every subject's DNA sample will be accompanied with the subject's complete dental history and an extensive family medical/cancer history covering three generations. Markers (small changes in the DNA code) will be studies using a process called Taqman genotyping to identify markers which most frequently associate with the subjects having EOC and hypodontia but not the control subjects. The markers to be studies are found within genes (DNA code) of the Activin/Inhibin and RUNX cell-to-cell signaling pathways. These two pathways have important roles for tooth development and reproductive tissue development and/or maintenance. In summary this study will identify specific markers which when combined with the observation of hypodontia in women could result in earlier screenings for highest EOC risk individuals an increase number of early stage diagnoses and the saving of many lives.  
  
PUBLIC HEALTH RELEVANCE: Epithelial Ovarian Cancer (EOC) accounts for 3% of all cancers in women. As the deadliest reproductive system cancer that afflicts women and the fifth leading cause of death due to cancer in women it is an important health issue. Less than 20% of all EOC cases are diagnosed in stage I when the cancer is confined to the ovaries and the 5 year survival rate is 93%. Without improvements in the current screening methods for early detection over 70% of women diagnosed with EOC will be diagnosed after the cancer has metastasized (i.e. in Stages III and IV) with 5 year survival rates of only 34% and 18% respectively. This project will explore the novel observation that missing teeth (teeth that never properly formed) and EOC appear to be associated. We will identify genetic markers which when combined with the presence of missing teeth will identify women at greatest risk of developing EOC in their lifetime at much younger ages than previously possible. Identification of these high risk individuals should result in earlier screening regiments for the individuals an increased number of early stages diagnoses and the saving of many lives.

project_terms:
Accounting;Activins;Affect;Age;Alleles;Anxiety;Cancer Patient;Caucasians;Caucasoid Race;Cause of Death;Cells;Cessation of life;Code;Collection;DNA;Dental;Dental Clinics;Development;Diagnosis;Disease;Disease Marker;Early Diagnosis;Eligibility Determination;Epithelial ovarian cancer;Family;Female;Foundations;Future;Generations;Genes;Genetic Code;Genetic Markers;Genotype;Health;High Risk Woman;Hypodontia;Individual;Kentucky;Lead;Maintenance;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;Medical;Methods;Nature;Neoplasm Metastasis;Oral health;Ovarian Tissue;Ovary;Pathway interactions;Persons;Population;Process;Protocols documentation;Recording of previous events;Reproductive system;Research;Resources;Risk;Risk Marker;Role;Saliva;Sampling;Screening procedure;Shapes;Signal Pathway;Signal Transduction;Single Nucleotide Polymorphism;Staging;Survival Rate;Symptoms;Testing;Time;Tissues;Tooth structure;Universities;Variant;Woman;Women's Health;Work;aged;base;cancer risk;cost;genetic association;high risk;inhibin;novel;outcome forecast;permanent tooth;reproductive development

public_health_relevance:
Epithelial Ovarian Cancer (EOC) accounts for 3% of all cancers in women. As the deadliest reproductive system cancer that afflicts women and the fifth leading cause of death due to cancer in women it is an important health issue. Less than 20% of all EOC cases are diagnosed in stage I when the cancer is confined to the ovaries and the 5 year survival rate is 93%. Without improvements in the current screening methods for early detection over 70% of women diagnosed with EOC will be diagnosed after the cancer has metastasized (i.e. in Stages III and IV) with 5 year survival rates of only 34% and 18% respectively. This project will explore the novel observation that missing teeth (teeth that never properly formed) and EOC appear to be associated. We will identify genetic markers which when combined with the presence of missing teeth will identify women at greatest risk of developing EOC in their lifetime at much younger ages than previously possible. Identification of these high risk individuals should result in earlier screening regiments for the individuals an increased number of early stages diagnoses and the saving of many lives.


application_id: 8029051
project_number: 1R03AI092170-01
project_title: Novel activities and the T. gondii vacuolar membrane
administering_ic: NIAID
award_notice_date: 2010-11-29
opportunity_number: PA-10-064
application_type: 1
activity_code: R03
ic: AI
serial_number: 092170
program_official: MCGUGAN, GLEN C
project_start_date: 2010-12-01
project_end_date: 2012-11-30
study_section: Special Emphasis Panel[ZRG1 IDM-B (02)]
contact_pi_person_id: 6624897
contact_pi: SINAI, ANTHONY P.
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 protozoan parasite Toxoplasma gondii is an important opportunistic parasite causing life threatening infections in the immune compromised and severe birth defects when acquired in utero. The parasite grows within a specialized compartment the parasitophorous vacuole (PV) within the infected host cell. The boundary defining this niche is the PV membrane (PVM) that serves as the interface between the parasite and host. Despite its importance investigation of the PVM has been limited. We have recently completed a proteomic analysis of the T. gondii PVM resulting in the identification of 123 proteins of which 70 appear to be novel. Of these novel proteins 26 are annotated as "hypothetical ORF's" precluding any assignment of function. As hypothetical ORF's these loci lack any identifiable motif indicating they are truly novel. While several appear unique to Toxoplasma others have similarly annotated homologs in other less tractable Apicomplexa including Plasmodium and Cryptosporidium spp. suggesting conserved function. As novel proteins that are potentially localized to the PVM an organelle found only in the context of parasite infection these hypothetical ORF's represent potentially unique activities that may serve as drug targets. In this study we exploit recently developed technologies to epitope tag and localize the hypothetical ORF's as a prelude to cloning the validated genes and attempting the gene knockouts. Together these studies represent a secondary analysis of an existing data set as a limited short term project with a high potential of revealing novel activities. As such it is ideally suited to the RO3 funding mechanism. With this proposal we aim to perform the initial characterization of these orphan genes toward establishing their functions in parasite biology.  
  
PUBLIC HEALTH RELEVANCE: Toxoplasma gondii causes serious illness in immune compromised individuals and is a model organism for several less experimentally tractable parasites. This study aims to investigate truly novel proteins that were identified as being components of the parasitophorous vacuole membrane a unique and essential parasite organelle. We expect with the completion of this work to open new areas of investigation in parasite biology.

project_terms:
Acute;Address;Affinity;Animal Model;Antigens;Apicomplexa;Area;Biochemical;Bioinformatics;Biological;Biological Process;Biology;Cells;Cellular biology;Cloning;Complex;Congenital Abnormality;Coupled;Cryptosporidium;Cyst;Cytoskeleton;Data Set;Development;Drug Delivery Systems;Employment;Endoplasmic Reticulum;Epitopes;Expression Library;Fibroblasts;Funding Mechanisms;Gene Targeting;Genes;Genome;Grant;Heart;Homologous Gene;Immune;Immune Sera;In Situ;Individual;Infection;Investigation;Length;Life;Manuscripts;Membrane;Methods;Mitochondria;Molecular;Molecular Biology;Nutrient;Open Reading Frames;Organelles;Orphan;Oryctolagus cuniculus;Parasites;Plasmodium;Preparation;Proteins;Proteome;Proteomics;Reagent;Resources;Rewards;Risk;Role;Screening procedure;Signal Transduction;System;Technology;Toxoplasma;Toxoplasma gondii;Vacuole;Work;base;biological systems;cDNA Expression;gene function;genome-wide;in utero;insight;interest;knockout gene;novel;parasite genome;pathogen;stem

public_health_relevance:
Toxoplasma gondii causes serious illness in immune compromised individuals and is a model organism for several less experimentally tractable parasites. This study aims to investigate truly novel proteins that were identified as being components of the parasitophorous vacuole membrane a unique and essential parasite organelle. We expect with the completion of this work to open new areas of investigation in parasite biology.


application_id: 8028495
project_number: 1R01CA143428-01A1
project_title: Rel B mediated-redox regulation of radiation therapy
administering_ic: NCI
award_notice_date: 2010-12-15
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: CA
serial_number: 143428
suffix: A1
program_official: BERNHARD, ERIC J
project_start_date: 2011-01-01
project_end_date: 2015-11-30
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: ST CLAIR, WILLIAM H
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Accumulating data suggest that prostate cancers exist in an elevated state of oxidative stress and that reactive oxygen species (ROS) contribute importantly to the cytotoxic effect of ionizing radiation (IR). However ROS also participate in cellular signaling processes leading to adaptive responses that reduce the effectiveness of radiation therapy. Thus despite rapid advances in treatment techniques the outcome of radiation therapy especially for patients with tumors with unfavorable prognoses remains to be improved. The goal of this project is to identify novel mechanisms that could lead to the development of specific measures for effective treatment of aggressive prostate cancers. We have identified the alternative pathway of the redox sensitive nuclear factor kappa beta (NF-?B) as a major contributor to prostate cancer growth and progression. Preliminary data indicate that: 1) aggressive prostate cancers have high nuclear RelB a member of the alternative pathway of NF-:B and manganese superoxide dismutase (MnSOD) a critical antioxidant enzyme levels; 2) suppression of RelB in androgen independent-aggressive prostate cancer cells results in reduction of interleukin 8 (IL8) levels in tumor cells and reduced tumor growth in vivo; 3) overexpression of RelB in androgen responsive prostate cancer cells results in enhanced tumor growth and production of IL8 but reduced prostate specific androgen (PSA) production; and 4) suppression of RelB nuclear translocation enhances radiation sensitivity of prostate cancer. Based on these novel and important preliminary findings we hypothesize that RelB regulates prostate cancer response to radiation via a MnSOD dependent NF-?B switch to activate expression of IL8 and suppress expression of PSA in prostate cancer cells. We propose that clinical testing for recurrent tumor growth should involve measuring levels of IL8 in addition to employing the standard PSA test. Combining these tests will enhance accurate cancer detection and prognosis. To test this hypothesis and validate the proof-of-concept for the combined use of IL8 and PSA as prognostic factors three interrelated specific aims will be addressed. Aim 1 will elucidate the mechanism by which MnSOD modulates the effect of RelB on the transcription of IL8 and PSA in prostate cancer cells using biochemical and molecular biology approaches. Aim 2 will examine the role of IL8 in the protection against the effects of radiation therapy of prostate cancer. Aim 3 will determine whether serum IL8 level is a predictive marker of prostate cancer response to radiation therapy using samples from cancer patients.  These mechanistic based bench to bedside approaches should provide novel insights into the mechanisms of prostate cancer resistant to radiation therapy and may provide practical predictive measures for prostate cancer diagnostic treatment planning and surveillance.  
  
PUBLIC HEALTH RELEVANCE: Prostate cancer is the most frequently diagnosed cancer in men and the number of men who die from prostate cancer is unacceptably high. The results obtained from this study will provide insights into the novel mechanisms by which interleukin 8 (IL8) and prostate specific antigen (PSA) are differentially regulated and will test a proof-of-concept for using their relationship to predict the efficacy of radiation therapy for treating prostate cancer. Thus this study will enable physicians to tailor risk-adjusted strategies for treatment of prostate cancer.

project_terms:
Address;Affinity Chromatography;Androgens;Animal Model;Antioxidants;Basic Science;Binding (Molecular Function);Biochemical;Biological Assay;Cancer Center;Cancer Detection;Cancer Diagnostics;Cancer Etiology;Cancer Patient;Cancer Prognosis;Cessation of life;Clinical;Clinical Research;Cultured Cells;Data;Development;Diagnosis;Diagnostic Neoplasm Staging;Effectiveness;Enzymes;Family;Gene Expression;Genes;Genetic Transcription;Goals;Growth;Human;Immunoprecipitation;Interleukin-8;Ionizing radiation;Kentucky;Lead;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Manganese Superoxide Dismutase;Measures;Mediating;Modeling;Molecular Biology;NF-kappa B;Nuclear;Nuclear Translocation;Outcome;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Patients;Physicians;Play;Predictive Factor;Production;Prognostic Factor;Prostate;Prostate-Specific Antigen;Proteomics;Radiation;Radiation Tolerance;Radiation therapy;Reactive Oxygen Species;Recurrent tumor;Regulation;Resistance;Risk;Role;Sampling;Serum;Site-Directed Mutagenesis;Small Interfering RNA;Techniques;Testing;Time;Transcriptional Regulation;Translating;Tumorigenicity;Universities;Visit;base;bench to bedside;cancer cell;cancer diagnosis;cancer type;computerized data processing;cytotoxic;cytotoxicity;effective therapy;follow-up;improved;in vivo;inflammatory marker;insight;member;men;neoplastic cell;novel;outcome forecast;overexpression;research clinical testing;research study;response;treatment planning;treatment strategy;tumor;tumor growth

public_health_relevance:
Prostate cancer is the most frequently diagnosed cancer in men and the number of men who die from prostate cancer is unacceptably high. The results obtained from this study will provide insights into the novel mechanisms by which interleukin 8 (IL8) and prostate specific antigen (PSA) are differentially regulated and will test a proof-of-concept for using their relationship to predict the efficacy of radiation therapy for treating prostate cancer. Thus this study will enable physicians to tailor risk-adjusted strategies for treatment of prostate cancer.


application_id: 8026913
project_number: 1U54CA153604-01
project_title: Administrative Core
administering_ic: NCI
opportunity_number: RFA-CA-09-032
application_type: 1
activity_code: U54
ic: CA
serial_number: 153604
project_start_date: 2010-07-01
project_end_date: 2015-06-30
study_section: Special Emphasis Panel[ZCA1 PCRB-G (M1)]
subproject_number: 7552
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
project_terms:
Address;Advisory Committees;Appalachian Region;Budgets;Communication;Communities;Community Outreach;Electronic Mail;Ensure;Faculty;Fostering;Goals;Grant;Information Dissemination;Information Services;Institutes;Kentucky;Leadership;Location;Monitor;Ohio;Program Research Project Grants;Regional Cancer;Research;Research Personnel;Research Training;Services;Strategic Planning;Structure;Students;Time;Universities;Virginia;West Virginia;Work;cancer health disparity;community based participatory research;computerized data processing;experience;falls;health disparity;meetings;programs;symposium


application_id: 8026911
project_number: 1U54CA153604-01
project_title: Training Program
administering_ic: NCI
opportunity_number: RFA-CA-09-032
application_type: 1
activity_code: U54
ic: CA
serial_number: 153604
project_start_date: 2010-07-01
project_end_date: 2015-06-30
study_section: Special Emphasis Panel[ZCA1 PCRB-G (M1)]
subproject_number: 7550
contact_pi_person_id: 6192172
contact_pi: LENGERICH, EUGENE J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
project_terms:
Adoption;Adult;Advisory Committees;Affect;Appalachian Region;Applications Grants;Arts;Award;Awareness;Behavioral;Body Image;Cancer Burden;Cancer Research Network;Colon;Colorado;Communication;Communities;Community Outreach;Community Participation;Computer software;Consumption;Data;Development;Doctor of Philosophy;Eating;Educational aspects;Endometrium;Environment;Environmental Risk Factor;Esophagus;Evaluation;Faculty;Family;Family member;Feedback;Female;Foundations;Funding;Gallbladder;Generations;Habits;Hand;Health;High Prevalence;Individual;Institution;Investigation;Kentucky;Kidney;Lead;Life;Link;Malignant Neoplasms;Mentors;Methods;Minority;NCI Scholars Program;National Cancer Institute;Obesity;Ohio;Outcome;Ovary;Pancreas;Physical activity;Physician-Patient Relations;Pilot Projects;Policy Maker;Positioning Attribute;Postdoctoral Fellow;Postmenopause;Preventive Intervention;Primary Cancer Prevention;Principal Investigator;Process;Recording of previous events;Recruitment Activity;Religion and Spirituality;Reporting;Research;Research Personnel;Research Training;Risk;Risk Factors;Screening for cancer;Screening procedure;Self Perception;Site;Social Discrimination;Solid;Structure;Technology;Testing;Time;Training;Training Programs;Training and Education;United States National Institutes of Health;Universities;West Virginia;Woman;Work;anticancer research;base;biobehavior;burden of illness;cancer health disparity;cancer prevention;cancer risk;evidence base;experience;fruits and vegetables;improved;innovation;intervention program;investigator training;lifestyle factors;male;malignant breast neoplasm;medically underserved population;meetings;member;men;outreach program;professor;public health medicine (field);self reliance;social;success;surveillance strategy;trend


application_id: 8026910
project_number: 1U54CA153604-01
project_title: Pilot Project
administering_ic: NCI
opportunity_number: RFA-CA-09-032
application_type: 1
activity_code: U54
ic: CA
serial_number: 153604
project_start_date: 2010-07-01
project_end_date: 2015-06-30
study_section: Special Emphasis Panel[ZCA1 PCRB-G (M1)]
subproject_number: 7549
contact_pi_person_id: 9323351
contact_pi: RAUP-KRIEGER, JANICE L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
project_terms:
Address;Affect;Anthropology;Appalachian Region;Award;Calendar;Cancer Patient;Clinical Treatment;Clinical Trials;Communication;Communities;Community Networks;County;Data Collection;Decision Making;Development;Doctor of Philosophy;Educational Materials;Educational workshop;Enrollment;Epidemiology;Family;Family member;Future;General Population;Goals;Grant;Health;Health Communication;Human Resources;Intervention;Interview;Kentucky;Life;Malignant Neoplasms;Medical;Mentors;Mississippi;Mortality Vital Statistics;New York;Newly Diagnosed;Ohio;Patients;Phase III Clinical Trials;Pilot Projects;Relative (related person);Research;Research Methodology;Rural;Source;Stretching;Testing;Training;Treatment Efficacy;Universities;base;burden of illness;community based participatory research;efficacy testing;experience;improved;medically underserved;medically underserved population;meetings;member;programs;skills;social group;theories;therapy development;treatment trial


application_id: 8025067
project_number: 1R01AI091953-01
project_title: Viral and Cellular Determinants of HCV Assembly
administering_ic: NIAID
award_notice_date: 2011-06-14
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: AI
serial_number: 091953
program_official: KOSHY, RAJEN
project_start_date: 2011-06-15
project_end_date: 2015-05-31
study_section: Virology - A Study Section[VIRA]
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): Hepatitis C virus (HCV) infection continues to be a major burden on public health affecting approximately 170 million people worldwide and 3-4 million Americans. HCV-associated end-stage liver disease is the leading indicator of liver transplantation. Current standard therapy with pegylated interferon-? in combination with ribavirin only achieves limited (<50%) antiviral response and causes severe side effects. The HCV protease- and polymerase-specific inhibitors currently in clinical trials are promising but are undermined by rapid emergence of drug-resistant HCV mutants. Future antiviral therapy for hepatitis C likely requires a combination of several drugs targeting different steps of the HCV life cycle. The lack of knowledge about the molecular details of the HCV life cycle has significantly impeded the discovery and development of antiviral drugs against HCV infection. A more complete understanding of the roles of viral and cellular proteins in the HCV life cycle will provide additional novel targets for anti-HCV drug discovery. Our recent studies have demonstrated that human apolipoprotein E (apoE) is an important determinant for the outcomes of HCV infection and assembly. ApoE was also found to interact with the HCV NS5A in our preliminary studies. In Specific Aim 1 we will dissect apoE domains and amino acid residues important for its dual functions in HCV infection and assembly. We will also determine the importance and the underlying molecular mechanisms of apoE and its interaction with NS5A in HCV infection and assembly respectively. In preliminary studies we have demonstrated that adaptive mutations in the HCV non-structural (NS) proteins greatly enhanced HCV production and cytopathogenicity in cell culture. We have also found that HCV NS proteins interact with viral structural proteins as demonstrated by experiments with the mammalian two-hybrid system and co-immunoprecipitation assay. Consistent with our findings recent genetic studies done by others suggest that HCV NS proteins play important roles in HCV assembly and/or production. However the underlying molecular mechanisms of the HCV NS proteins in the HCV life cycle have not been defined. In Specific Aim 2 we will decipher the roles and mechanisms of action of cell culture adaptive mutations in HCV assembly and induction of cytopathogenicity. In Specific Aim 3 we will determine the importance of viral NS proteins and their interactions with structural proteins in HCV assembly. We will accomplish these specific aims using a robust HCV reverse genetics system recently developed in our lab in conjunction with mutagenesis studies and the use of biochemical immunological and cell biological approaches. New knowledge derived from these studies will lead to a paradigm shift in virology with respect to the roles of viral NS proteins in HCV assembly. Our studies will also provide novel targets for discovery of antiviral drugs to effectively treat hepatitis C.  
  
PUBLIC HEALTH RELEVANCE: Hepatitis C virus (HCV) infection continues to be a major burden on public heath affecting approximately 170 million people worldwide and 4 million Americans. Our overall objective is to determine the roles and mechanisms of action of viral and cellular proteins that determine the outcomes of HCV infection and production. Our proposed studies will provide new knowledge and novel targets for discovery and development of antiviral drugs for treatment of HCV infection.

project_terms:
Address;Adverse effects;Affect;American;Amino Acids;Antiviral Agents;Antiviral Response;Antiviral Therapy;Apolipoprotein E;Binding (Molecular Function);Biochemical;Biological;Biological Assay;Cell Culture System;Cell Culture Techniques;Cells;Cessation of life;Cirrhosis;Clinical Trials;Co-Immunoprecipitations;Combined Modality Therapy;Development;Drug Delivery Systems;Drug resistance;Ectopic Expression;Future;Genetic;Genome;Genotype;Goals;HCV Vaccine;Hepatitis;Hepatitis C;Hepatitis C Therapy;Hepatitis C virus;Human;Infectious hepatitides;Interferons;Knowledge;Lead;Life Cycle Stages;Liver diseases;Molecular;Mutagenesis;Mutation;Outcome;Peptide Hydrolases;Play;Polymerase;Primary carcinoma of the liver cells;Production;Protein Isoforms;Proteins;RNA Sequences;RNA replication;Research;Research Design;Ribavirin;Role;Sequence Analysis;Staging;Structural Protein;Structure;System;United States;Variant;Viral;Viral Nonstructural Proteins;Viral Proteins;Viral Structural Proteins;Virion;Virus;Virus Assembly;anti-hepatitis C;base;drug development;drug discovery;inhibitor/antagonist;liver transplantation;mutant;novel;positional cloning;public health medicine (field);research study;viral RNA;virology;yeast two hybrid system

public_health_relevance:
Hepatitis C virus (HCV) infection continues to be a major burden on public heath affecting approximately 170 million people worldwide and 4 million Americans. Our overall objective is to determine the roles and mechanisms of action of viral and cellular proteins that determine the outcomes of HCV infection and production. Our proposed studies will provide new knowledge and novel targets for discovery and development of antiviral drugs for treatment of HCV infection.


application_id: 8024556
project_number: 5R01DE018292-05
project_title: Oral Pathogen Exploitation of Innate Recognition as a Function of Age
administering_ic: NIDCR
award_notice_date: 2011-01-26
opportunity_number: RFA-DE-07-004
application_type: 5
activity_code: R01
ic: DE
serial_number: 018292
program_official: BURGOON, PENNY W
project_start_date: 2007-03-06
project_end_date: 2011-12-31
study_section: ZDE1-YL(20)
contact_pi_person_id: 6712964
contact_pi: HAJISHENGALLIS, GEORGIOS
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):  Innate immunity is present from birth and represents the inherited resistance to infection. Microbial infection is detected by pattern-recognition receptors (PRRs) through recognition of microbe-associated molecular patterns (MAMPs). Since MAMPs are conserved in a wide range of pathogenic or commensal organisms it is not clear how PRR-MAMP interactions per se lead to differential host responses to pathogens and commensals. This application proposes that pathogens exploit selective pattern recognition pathways in ways that perturb the otherwise homeostatic PRR-MAMP interactions leading to chronic persistence of the pathogen and nonproductive inflammation. This outcome is detrimental especially to the elderly host due to age-related alterations in pattern-recognition mechanisms. In this regard it is proposed that pathway-specific alterations in innate recognition render the aging innate immune system more amenable to exploitation by pathogens than its younger counterpart. Taking advantage of the accessibility and relevance of the oral cavity in host-microbial interactions these concepts will be investigated in the context of periodontitis and the model pathogen Porphyromonas gingivalis. P. gingivalis interacts via its surface fimbriae with the CD14/Toll-like receptor 2 recognition complex and induces phosphatidylinositol-3-kinase signaling for activating the adhesive capacity of CR3 a monocytic beta2 integrin with PRR capabilities. Although this proadhesive pathway promotes the migratory activity of monocytes it has surprisingly been co-opted by P. gingivalis for exploiting CR3. By means of immunological genetic and biophysical techniques as well as a mouse periodontitis model these studies will test the hypothesis that the interaction of P. gingivalis with activated CR3 leads to pathogen internalization suppression of normal defense clearing mechanisms inhibition of apoptosis and promotion of intracellular persistence. Moreover it is hypothesized that the inducibility of this co-opted pathway becomes higher with age leading to enhanced immune evasion by P. gingivalis and potentially increased periodontal disease activity. This study has been designed not only for answering fundamental questions in innate immunity but also for facilitating the development of novel immunomodulatory concepts at a translational level. Indeed only by knowing how the innate response is deregulated by pathogens could effective immunomodulatory strategies be implemented for redirecting the oral mucosal immune defense to the benefit of the elderly host. While the proposed experimental model focuses on a periodontal pathogen the fundamental concept of immune evasion by corruption of PRR function and how this process changes with advancing age may be applicable to infections of less accessible mucosal tracts such as the respiratory gastrointestinal and genitourinary tracts.

project_terms:
1-Phosphatidylinositol 3-Kinase;16p;Adhesives;Age;Aging;Bacteroides thetaiotaomicron;Binding (Molecular Function);Biochemical;Birth;Bone Resorption;CD14 gene;CD18 Antigens;Chronic;Clinical;Complex;Data;Development;Dominant-Negative Mutation;Down-Regulation;Elderly;Event;Experimental Models;Genetic;Genitourinary system;Human;Immune;Immune response;Immune system;Infection;Inflammation;Inherited;Inhibition of Apoptosis;Integrins;Interleukin-12;Killings;Lead;Ligand Binding;Literature;Macrophage-1 Antigen;Mediating;Microbe;Modeling;Molecular;Mus;Natural Immunity;Oral cavity;Oral mucous membrane structure;Organism;Outcome;Pathway interactions;Pattern;Pattern Recognition;Pattern recognition receptor;Periodontal Diseases;Periodontitis;Peritonitis;Porphyromonas gingivalis;Predisposition;Process;Receptor Signaling;Research Personnel;Resistance to infection;Role;Severities;Signal Pathway;Signal Transduction;Study models;Surface;TLR2 gene;Techniques;Testing;Toll-Like Receptor 2;Virulence;Virulence Factors;age related;aged;base;design;fimbria;gastrointestinal;in vivo;inhibitor/antagonist;macrophage;microbial;microorganism interaction;monocyte;mutant;novel;oral pathogen;pathogen;receptor;receptor function;respiratory;response


