# projects

application_id: 8168480
project_number: 5P20RR020145-07
project_title: UKY DENTAL COBRE: BIOINFORMATICS & BIOSTATISTICS CORE
administering_ic: NCRR
award_notice_date: 2010-09-10
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2010-08-01
project_end_date: 2011-07-31
study_section: ZRR1-RI-B(01)
subproject_number: 8306
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The Biostatistics and Bioinformatics Core (BBC) will provide a centralized secure database statistical consultation on study design and data analysis and bioinformatics support during development and implementation of the projects and pilot studies in the CBBO/SD. The specific aims of this BBC are:
(1) Assist investigators in resolving issues related to experimental design sample size determinations and  the statistical / bioinformatics analysis of data 
(2) Create a centralized database to assure high quality data is collected 
(3) Maintain the integrity confidentiality and security of all data in compliance with all current regulatory statutes but at a minimum cost to the projects.
(4) Provide periodic summaries of the database in clinically oriented projects to the Center Executive Committee to monitor subject recruitment and follow-up.
(5) Participate in the training of graduate students Certificate Students postdoctoral researchers and young investigators.
(6) Develop new methodology in statistics and/or bioinformatics as needed in the CBBO/SD.
(7) Collaborate with CBBO/SD investigators in preparing papers for publication
(8) Work with investigators in developing competitive research proposals

project_terms:
Bioinformatics;Biometry;Biostatistics Core;Computer Retrieval of Information on Scientific Projects Database;Confidentiality;Consultations;Data;Data Analyses;Data Quality;Databases;Dental;Development;Experimental Designs;Funding;Grant;Institution;Methodology;Monitor;Paper;Pilot Projects;Publications;Research;Research Design;Research Personnel;Research Proposals;Resources;Sample Size;Secure;Security;Source;Students;Training;United States National Institutes of Health;Work;cost;follow-up;graduate student;statistics


application_id: 8168479
project_number: 5P20RR020145-07
project_title: UKY DENTAL COBRE: ADMINISTRATIVE AND EDUCATIONAL CORE
administering_ic: NCRR
award_notice_date: 2010-09-10
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2010-08-01
project_end_date: 2011-07-31
study_section: ZRR1-RI-B(01)
subproject_number: 8305
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The Administrative/Educational Core of the CBBO/SD has facilitated the research and training goals of the COBRE by: 
(1) To schedule and organize meetings for the CBBO/SD participants; 
(2) To organize meetings of the Scientific Advisory Committee (SAC);
(3) To provide fiscal administration and accounting; 
(4) To interface with institutional administration in new faculty recruitment;
(5) To oversee the funding of new pilot projects; 
(6) To interface and provide appropriate reporting to the NIH and other regulatory agencies; 
(7) To sponsor and organize research career development and training opportunities; and 
(8) To provide outcomes assessment of the CBBO/SD.

project_terms:
Accounting;Advisory Committees;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Dental;Faculty;Funding;Goals;Grant;Institution;Outcome Assessment (Health Care);Participant;Pilot Projects;Reporting;Research;Research Personnel;Research Training;Resources;Schedule;Source;Training;United States National Institutes of Health;career development;meetings


application_id: 8168303
project_number: 5P20RR016481-10
project_title: ACUTE EFFECTS OF ALCOHOL AND ENERGY DRINKS ON BEHAVIORAL CONTROL
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8131
contact_pi_person_id: 10253421
contact_pi: MARCZINSKI, CECILE A.
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The working hypothesis of this proposal is that the consumption of AmED may be riskier than alcohol consumption alone. Mixing alcohol with another beverage with strong stimulant properties may decrease selfperceptions of intoxication and may increase the reinforcing properties of alcohol. In addition the acute effects of alcohol impair impulse control and this impairment may not be counteracted by co-administration of a stimulant. The proposed research will examine the acute effects of alcohol energy drinks AmED or a placebo beverage in social drinkers. The effects of these beverages will be determined by performance on tasks that measure neurocognitive control mechanisms and the subjective effects of alcohol. The specific aims of the proposed research are: 1) to determine whether the consumption of AmED alters neurocognitive and subjective measures of intoxication compared to the consumption of alcohol alone and 2) to establish whether the consumption of AmED enhances priming of the motivation to drink alcohol compared with the consumption of alcohol alone. The results of these studies should elucidate whether the consumption of AmED increases alcohol consumption and may be escalating binge drinking in young people.

project_terms:
Acute;Alcohol consumption;Alcohols;Behavior Control;Beverages;Computer Retrieval of Information on Scientific Projects Database;Consumption;Funding;Grant;Impairment;Institution;Intoxication;Measures;Motivation;Neurocognitive;Performance;Placebos;Property;Research;Research Personnel;Resources;Source;United States National Institutes of Health;Work;alcohol effect;binge drinking;drinking;social


application_id: 8168302
project_number: 5P20RR016481-10
project_title: TOWARDS UNDERSTANDING THE NON-CLASSICAL SECRETION OF HUMAN INTERLEUKIN-1 ALPHA
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8130
contact_pi_person_id: 10281309
contact_pi: DAKSHINAMURTHY, RAJALINGAM
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Interleukins (IL's) are involved in a wide spectrum of biological processes associated with infection inflammation and autoimmunity. IL-1's in particular are pro-inflammatory cytokines and they assist the host in fighting infection. Deficiency in IL-1's is known to result in lethality in bacterial infections. In addition recent studies suggest that IL-1 also plays a role in wound healing carcinogenesis tumor invasion rheumatoid arthritis and Alzheimer's disease. IL-1 lacks the N-terminal signal peptide therefore unlike most other extracellular proteins it is not secreted through the classical endoplasmic recticulum  Golgi pathway. Preliminary studies have suggested that the release of IL-1 into the extracellular compartment occurs by the formation of a multi-protein complex to the calcium- binding protein S100A13 in the presence of copper. Although useful information exists on the IL-1 signaling process the exact mechanism of IL-1 secretion into the extracellular compartment is not clear. Until now structure- function data have been limited for IL-1 because of the difficulty in its overexpression in mammalian cells. In this context the purpose of the proposed research is to fully understand IL-1's non-classical release and it's binding to copper and S100A13. Specific aims of this proposal include: 1) determing the binding affinity of IL-1 for copper and S100A13; 2) characterizing the molecular interactions necessary for the non-classical secretion of IL-1. A complete understanding of the non-classical secretion of IL-1 will provide valuable information towards understanding the general principles of export of proteins without signal peptide. Furthermore over the funding period this project will engage numerous undergraduates and master's level graduate students in independent research enhancing their learning of scientific principles giving them an opportunity to make unique contributions to the study the role played by IL-1 in this devastating family of diseases and stimulating their excitement for future careers in biomedical research. Moreover the funding of this application will expand student research in protein stability structure and function and enable more students from Kentucky a state traditionally underrepresented in biomedical sciences to successfully advance into biomedical graduate programs.

project_terms:
Affinity;Alzheimer's Disease;Autoimmunity;Bacterial Infections;Binding (Molecular Function);Biological Process;Biomedical Research;Calcium-Binding Proteins;Computer Retrieval of Information on Scientific Projects Database;Copper;Data;Disease;Extracellular Protein;Family;Funding;Future;Golgi Apparatus;Grant;Human;Infection;Inflammation;Inflammatory;Institution;Interleukin-1;Interleukin-1 alpha;Interleukins;Kentucky;Learning;Mammalian Cell;N-terminal;Pathway interactions;Peptide Signal Sequences;Play;Protein Export Pathway;Proteins;Research;Research Personnel;Resources;Rheumatoid Arthritis;Role;Science;Source;Structure;Students;Tumor Cell Invasion;United States National Institutes of Health;Wound Healing;carcinogenesis;career;computerized data processing;cytokine;extracellular;fighting;graduate student;overexpression;programs;protein complex


application_id: 8168301
project_number: 5P20RR016481-10
project_title: PROTEOMIC ANALYSIS OF OXIDATIVE STRESS OF OXIDATIVELY MODIFIED GLYCOLYTIC PROTEI
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8129
contact_pi_person_id: 9835336
contact_pi: REED, TANEA TYLETTE
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.In this project I plan to first examine the amyloid beta hypothesis of Alzheimer's disease (AD) and apply it to a novel Down Syndrome (DS) model by developing a mechanism in which the p3 fragment of the DS preamyloid can possibly be equivalent to the earliest stage of Alzheimer Disease mild cognitive impairment (MCI). Secondly by specifically focusing on glycolytic protein oxidation in this model a basis for the reduced glucose metabolism observed in Alzheimer's disease may be determined and further support of the altered energy metabolism hypothesis of AD may be provided. Investigation of oxidatively modified glycolytic proteins in this novel DS model may also create a new focal point for potential biomarkers in AD and potential therapeutics. 
Down syndrome is a genetic disease in which persons have reduced mental capacity. Persons with DS have a trisomy at chromosome 21 the location of amyloid precursor protein. This trisomy causes A overproduction which could possibly be a correlate to the early development of AD in persons with DS. Enzymatic cleavage by -secretase and -secretase forms the toxic p3 fragment A(17-42) which is the major form of A peptide in Down syndrome. No correlation has yet been made between the p3 fragment and AD pathogenesis. 
Glycolysis is a metabolic pathway that converts glucose to pyruvate and generates 2 ATP molecules in the process. Many key glycolytic enzymes such as -enolase -enolase glyceraldehyde 3-phosphate phosphoglycerate mutase and triosephosphate isomerase are oxidized in AD brain confirming the inability to effectively metabolize glucose the brain's principal source of energy. In the three progressive stages of Alzheimer's disease MCI EAD and late-stage AD 70% of glycolytic enzymes undergo oxidative modification which can greatly affect their enzyme activity and subsequent protein function. All enzymes affected react after the production of fructose 16-bisphosphate (FBP). If oxidatively modified pre-FBP proteins are observed in DS this will provide further support for the altered energy metabolism of AD.

project_terms:
Affect;Alzheimer's Disease;Amyloid beta-Protein;Amyloid beta-Protein Precursor;Brain;Chromosomes Human Pair 21;Computer Retrieval of Information on Scientific Projects Database;Development;Down Syndrome;Energy Metabolism;Energy-Generating Resources;Enzymes;Fructose;Funding;Glucose;Glyceraldehyde 3-Phosphate;Glycolysis;Grant;Hereditary Disease;Institution;Investigation;Location;Metabolic Pathway;Modeling;Modification;Oxidative Stress;Pathogenesis;Peptides;Persons;Phosphoglycerate Mutase;Process;Production;Proteins;Proteomics;Proteus;Psyche structure;Pyruvate;Pyruvates;Research;Research Personnel;Resources;Source;Staging;Therapeutic;Triose-Phosphate Isomerase;Trisomy;United States National Institutes of Health;base;biomarker;enolase;enzyme activity;fructose-16-diphosphate;glucose metabolism;mild cognitive impairment;novel;oxidation;protein function;secretase


application_id: 8168300
project_number: 5P20RR016481-10
project_title: PHOTOCHEMISTRY AND PHOTOPHYSICS OF ESTROGENS
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8128
contact_pi_person_id: 9857887
contact_pi: HARE, PATRICK MICHAEL
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The overarching goal of the proposed research is to determine the mechanisms of photodegradation of the natural estrogens and the effect of solvent environment on that photodegradation. Steady-state and time resolved spectroscopy and computational chemistry will be used to elucidate the photochemistry and the underlying photophysics of the estrogens. Natural estrogens are potent endocrine disruptors in surface waters and are known to photodegrade naturally but the mechanisms are poorly understood. Understanding how they are photodegraded in the environment may also lead to better removal strategies for the estrogens in the waste stream. The effects of solvent on the excited states of estrogens will first be determined by steady-state spectroscopy and computational chemistry. The time-dependent population of these excited states will then be determined by time-resolved spectroscopy with guidance from computation of the excited state properties. Finally the solvent and wavelength depedence of the photodegradation will be carried out with product assignments being guided by infrared spectroscopy and computational modeling of likely product structures. Determining how solvent and excitation wavelength affect the population of the estrogen excited states that lead to photochemistry will allow better modeling of photodegradation in surface waters and may lead to more efficient removal strategies for the estrogens in municipal waste streams.

project_terms:
Affect;Computer Retrieval of Information on Scientific Projects Database;Computer Simulation;Endocrine Disruptors;Environment;Estrogens;Excision;Funding;Goals;Grant;Institution;Lead;Modeling;Photochemistry;Population;Property;Research;Research Personnel;Resources;Solvents;Source;Spectrum Analysis;Stream;Structure;Surface;Time;United States National Institutes of Health;Water;computational chemistry;infrared spectroscopy;wasting


application_id: 8168299
project_number: 5P20RR016481-10
project_title: SEX DEPENDENT REGULATION OF MIRNA IN CARDIAC REMODELING
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8127
contact_pi_person_id: 9528523
contact_pi: WAIKEL, REBEKAH
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Estrogen has been shown to play a protective role in cardiac hypertrophy and heart failure in both humans and rodent models. My current working hypothesis is that male/female differences in susceptibility to systolic LV dysfunction in the setting of cardiac hypertrophy is due to regulation of miRNAs by estrogens. During the first year I have completed Specific Aim 1 by characterizing pressure overload induced cardiac remodeling in female C57BL6 and 129SvImJ mice. This work was published in collaboration with my mentor Dr. Susan Smyth in the American Journal of Physiology  Heart Circulation Physiology in Sept 2009. Our work has demonstrated that female C57BL6 are relatively protected in terms of cardiac remodeling and function in response to pressure overload. Our work further showed that there is no male susceptibility gene present on the Y chromosome thus further supporting the presence of a female "factor" provides the protection from cardiac hypertrophy and heart failure. In addition during my first year of KBRIN funding I was able to establish a rodent wing of our current animal care facility including the appropriate IACUC protocol approval. I am now able to do the rat experiments at my home institution Eastern Kentucky University. During year 2 I will work to accomplish the remaining 2 aims: I have Aim 2) to establish separate miRNA profiles for males and females cardiac remodeling following pressure overload. Aim 3) to determine which miRNAs play a functional role in estrogen mediated inhibition of cardiomyocyte hypertrophy.

project_terms:
American;Cardiac;Cardiac Myocytes;Collaborations;Computer Retrieval of Information on Scientific Projects Database;Estrogens;Female;Functional disorder;Funding;Grant;Heart Hypertrophy;Heart failure;Home environment;Human;Hypertrophy;IACUC;Institution;Journals;Kentucky;Mediating;Mentors;MicroRNAs;Mus;Physiology;Play;Predisposition;Protocols documentation;Publishing;Rattus;Regulation;Research;Research Personnel;Resources;Rodent;Rodent Model;Role;Source;Susceptibility Gene;United States National Institutes of Health;Universities;Wing;Work;Y Chromosome;animal care;heart circulation;male;pressure;research study;response;sex


application_id: 8168298
project_number: 5P20RR016481-10
project_title: GENETIC SUSCEPTIBILITY TO PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8126
contact_pi_person_id: 8110072
contact_pi: CURRAN, CHRISTINE PERDAN
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) that bio-accumulate in the food supply and resist environmental degradation. In September 2008 Kentucky identified numerous waterways where PCB-contaminated fish remain a human health concern. Recently new sources of human exposure have been identified including wood treatments and construction materials used in older homes and schools. Studies of human populations near the most polluted sites have found learning memory and behavioral abnormalities in children exposed during pregnancy and breast-feeding. Not all exposed individuals experience the same level of adverse health effects indicating that genetic differences are important in determining who is at highest risk. The applicant previously used a novel mouse model to identify two genes which affect susceptibility to PCB exposure during brain development: the aryl hydrocarbon receptor (Ahr) and cytochrome P450 1A2 (Cyp1a2). PCB-treated mice with a high-affinity AHR and lacking CYP1A2 showed deficits in tests of spatial and non-spatial learning and memory and an attenuated startle response. Prenatal stress can produce a similar behavioral phenotype in conjunction with reduced expression of the glucocorticoid receptor and related genes regulated by DNA methylation. AHR activation was recently shown to increase the activity of DNA methylases. Therefore we hypothesize that persistent activation of the AHR alters normal brain development and the response to stress via epigenetic mechanisms.

project_terms:
Affect;Affinity;Aryl Hydrocarbon Receptor;Attenuated;Behavioral;Brain;Breast Feeding;CYP1A2 gene;Child;Computer Retrieval of Information on Scientific Projects Database;Construction Materials;Cytochrome P-450 CYP1A2;DNA;DNA Methylation;Development;Epigenetic Process;Fishes;Food Supply;Funding;Genes;Genetic;Genetic Predisposition to Disease;Glucocorticoid Receptor;Grant;Health;Home environment;Human;Individual;Institution;Kentucky;Learning;Memory;Methyltransferase;Mus;Phenotype;Polychlorinated Biphenyls;Predisposition;Pregnancy;Research;Research Personnel;Resources;Schools;Site;Source;Stress;Testing;United States National Institutes of Health;Wood material;developmental neurotoxicity;experience;exposed human population;high risk;human population study;mouse model;novel;pollutant;prenatal stress;response


application_id: 8168297
project_number: 5P20RR016481-10
project_title: INVESTIGATING THE ROLE OF PLUMBAGIN IN ABATING ULCERATIVE COLITIS PATHOGENESIS
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8125
contact_pi_person_id: 9861170
contact_pi: SHARMA, NILESH CHARNDRA
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Aim I: To develop a chemically-induced murine-model of ulcerative colitis: Towards this end we used three groups of 10-week-old female C57BL/6 mice each group comprising 5 replicates. Experimental groups 1 and 2 were administered 2% and 4% DSS respectively via feeding water for 8 days. Control was set up with normal feeding water. Mice body weight and symptoms of disease were monitored every alternate day. Change in body weight was noticeable by D-5 and by D-8 a decrease of 4.7% in group 1 (with 2% DSS) and more than 6% in group 2 (4% DSS) was recorded. Disease symptom such as diarrhea was manifest by 3rd day. While consistency of stool became loose by D-3 in both groups 4% DSS caused more severity by D-5. Likewise symptom of rectal bleeding was more severe by D-8 in group 2 with 4% DSS. DSS-treated mice also presented symptoms of pain by huddling. Control registered negligible increase (less than 1%) in body weight with no disease symptoms. DSS mice presented similar disease symptoms in two different sets of experiments when they were used as DSS-control against plumbagin treatments. Size of isolated large intestine was found significantly reduced in DSS mice. In this way we achieved the first goal. Aim II: To test the effects of plumbagin on UC pathogenesis in murine model: Four groups of mice (each having 5 replicates) were administered 4% DSS as before. Group 1 and group 2 were treated with plumbagin at the rate of 2mg/kg body weight and 4mg/kg body weight respectively. Group 3 was treated with plumbagin (2mg/kg) and curcumin (100mg/kg). Drugs were administered via feeding water after 8 days of DSS treatment to all mice. Group 4: DSS-control was given no drug. Plumbagin improved body weight significantly at both doses. Symptoms of diarrhea also improved with plumbagin. Plumbagin was found to be more effective singly than in combination with curcumin another anti-inflammatory polyphenol. Isolated large intestine was significantly larger than DSS- control. It is hoped that various alterations in the dosage and mode of drug administration will be required to determine the effect clearly.

project_terms:
Abate;Anti-Inflammatory Agents;Anti-inflammatory;Body Weight;C57BL/6 Mouse;Computer Retrieval of Information on Scientific Projects Database;Curcumin;Diarrhea;Disease;Dose;Feces;Female;Funding;Goals;Grant;Hemorrhage;Institution;Large Intestine;Modeling;Monitor;Mus;Pain;Pathogenesis;Pharmaceutical Preparations;Research;Research Personnel;Resources;Role;Severities;Source;Symptoms;Testing;Ulcerative Colitis;United States National Institutes of Health;Water;dosage;feeding;improved;plumbagin;polyphenol;rectal;research study


application_id: 8168296
project_number: 5P20RR016481-10
project_title: MENTORING CORE
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8124
contact_pi_person_id: 9258139
contact_pi: MATTINGLY, BRUCE A
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:
This subproject is one of many research subprojects utilizing the
resources provided by a Center grant funded by NIH/NCRR. The subproject and
investigator (PI) may have received primary funding from another NIH source
and thus could be represented in other CRISP entries. The institution listed is
for the Center which is not necessarily the institution for the investigator.
Consistent with the overall aims of the KY-INBRE program the primary goal of the mentoring core is provide an array of services to further enhance the competitiveness of our biomedical researchers at primarily undergraduate institutions (PUIs) in obtaining NIH funding.  During this first year of funding for this core three new services have been provided. First an intensive all-day grant writing workshop was developed and presented in conjunction with the annual Kentucky Academy of Science meeting. Focusing exclusively on the development of the NIH-Academic Research Enhancement Award (AREA-R15) proposals this workshop included interactive presentations and discussions led by the PI (Nigel Cooper) PC (Bruce Mattingly) and several KY-INBRE network PIs who are currently funded through the R15 mechanisms ( Mark Bardgett Patrick Schultheis Doug Dennis Rodney King Eimear Mullin and Stephan Paula). The morning session was directed primarily toward PUI researchers with little or no NIH grant writing experience .The afternoon session built upon this foundation by providing more specific information and advice related to the development of successful R15 proposals. 

In an effort to help prepare faculty for successful NIH-R15 proposal submissions we utilize R15 guidelines and forms for our internal small grant program referred to as KBRIN-AREA Fellowships grants ($25000/year). To further enhance NIH grant writing skills we are now providing extensive reviews and feedback to the PIs from steering and mentoring core members utilizing NIH review criteria. These reviews are then used by the funded PIs in preparing their NIH-R15 proposals. So far the PIs seem very appreciative of the extensive review comments and suggestions. 

The third mentoring core initiative introduced this year is our individualized consultation service. Specifically PIs who are unsuccessful in their quest for R15 funding are invited to submit their proposals and critiques to the mentoring core. The director of the mentoring core then arranges an individual consultation to help the PI revise and strengthen their proposal for resubmission. We just now receiving reviews from September/October NIH submissions and are currently working with two PIs to revise their proposals. 

It should also be noted that our mentoring core is collaborating with the Puerto Rico (PR)  INBRE leadership to provide assistance in improving their success rate in receiving NIH R15 funding. Dr. Nigel Cooper (PI) and Dr. Bruce Mattingly (PC) recently met with Dr. Sandra Pena (PR PI) to plan an NIH R15 grant writing workshop for researchers at PR PUIs in early May 2010.

project_terms:
Academic Research Enhancement Awards;Academy;Computer Retrieval of Information on Scientific Projects Database;Consultations;Critiques;Development;Educational workshop;Faculty;Feedback;Fellowship;Foundations;Funding;Goals;Grant;Guidelines;Individual;Institution;Kentucky;Leadership;Mentors;Published Comment;Puerto Rico;Research;Research Personnel;Resources;Science;Services;Source;Suggestion;United States National Institutes of Health;Work;Writing;experience;improved;meetings;member;programs;skills;success


application_id: 8168295
project_number: 5P20RR016481-10
project_title: SUMMER RESEARCH PROGRAM
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8123
contact_pi_person_id: 1956866
contact_pi: ANDERSON, DAWN J
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Participating students at University of Louisville and University of Kentucky attended a research ethics training seminar prior to beginning their research experience.  They also attended weekly research seminars. During their KBRIN SUR experience students also attended presentations given by researchers and graduate school & medical/dental school faculty about biomedical research and career options. Students attended numerous field trips and social outings arranged by their KBRIN university coordinator or research mentor as well.  At the end of their research experience students were required to prepare and present either an oral presentation or poster presentation at their respective institutions.  Participating students were also expected to present their research at the Annual Meeting of the Kentucky Academy of Science.  Meeting registration and housing are provided by the KBRIN SUR Program.  Many students also presented their KBRIN SUR results at research symposia at their home institutions.

project_terms:
Academy;Biomedical Research;Computer Retrieval of Information on Scientific Projects Database;Dental Schools;Faculty;Funding;Grant;Home environment;Housing;Institution;Kentucky;Mentors;Oral;Research;Research Ethics;Research Personnel;Resources;Science;Source;Students;Training;United States National Institutes of Health;Universities;career;experience;medical schools;meetings;posters;programs;social;symposium


application_id: 8168294
project_number: 5P20RR016481-10
project_title: DENNIS POST-DOC/TECHNICIAN SUPPORT
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8122
contact_pi_person_id: 9258111
contact_pi: DENNIS, DOUGLAS
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.This proposal accomplishes the AREA program objectives of: 1) supporting meritorious research; 2) exposing undergraduates to research; and 3) strengthening the research environment in non-research intensive universities. The goal of this research is 
to elucidate the mechanism of polyhydroxyalkanoate inclusion biogenesis. Electron microscopy studies have been unable to resolve the structure of PHA inclusions and this has inhibited movement toward a cohesive model of inclusion biogenesis. Employing atomic force microscopy we have determined that there are three layers of structure an outer envelope that is the thickness of a membrane bilayer a middle network layer and 
an underlying crystalline lamellar layer. Genetic studies have indicated that the middle network is comprised at least partially of PhaP and that PhaP is likely to be translocated to the periplasm. Thus it would appear that inclusion biogenesis may occur by 
movement of protein and/or proteins to the periplasm and budding through the cytoplasmic membrane into the cytoplasm facilitating the acquisition of the cytoplasmic membrane as an envelope. The goal of this research is to prove or disprove this supposition. The specific aims of the research are: 1) definitively prove periplasmic 
localization of PhaP via fluorescence localization and Western blot analyses of subcellular fractions 2) demonstrate that the inclusion envelope is derived from the cytoplasmic membrane by proteomic analysis and 3) characterize proteins that bind transiently and permanently to PhaP in hopes of elucidating the mechanism of inclusion biogenesis. Ultimately the goal of the research is to enlarge our knowledge of inclusion biogenesis to the point that this process can be controlled and utilized for medical applications. For instance it could be envisioned that instead of polymer being inserted into the inclusion bioactive compounds could be inserted making the inclusion into a drug delivery vehicle.

project_terms:
Atomic Force Microscopy;Biogenesis;Cell membrane;Computer Retrieval of Information on Scientific Projects Database;Cytoplasm;Drug Delivery Systems;Electron Microscopy;Environment;Fluorescence;Funding;Genetic;Goals;Grant;Institution;Knowledge;Medical;Membrane;Modeling;Movement;Polymers;Postdoctoral Fellow;Process;Protein Binding;Proteins;Proteomics;Research;Research Personnel;Resources;Source;Structure;Subcellular Fractions;Thick;United States National Institutes of Health;Universities;Western Blotting;periplasm;programs


application_id: 8168293
project_number: 5P20RR016481-10
project_title: MECHANISMS IN REGULATING DNA DAMAGE-INDUCED GENES IN A UMUC-DEFICIENT BACTERIUM
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8121
contact_pi_person_id: 9257147
contact_pi: HARE, JANELLE M
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The long term goal of this research is to understand the mechanisms by which cells respond to DNA damage. The link between DNA damage and human health is well-established: the inability to correctly repair damaged DNA can result in various forms of colon breast and ovarian cancers in humans. The existence of similar extensive DNA damage sensing and repair mechanisms in organisms ranging from humans to bacteria demonstrates this central role of DNA integrity. In the typical bacterial SOS response pathway after DNA damage the UmuD protein self-cleaves and then acts with its partner UmuC to function as a translesion synthesis DNA polymerase.

project_terms:
Bacteria;Breast;Cells;Cleaved cell;Colon;Computer Retrieval of Information on Scientific Projects Database;DNA;DNA Damage;DNA Repair;DNA-Directed DNA Polymerase;Funding;Genes;Goals;Grant;Health;Human;Institution;Link;Malignant neoplasm of ovary;Organism;Pathway interactions;Proteins;Research;Research Personnel;Resources;Role;SOS Response (Genetics);Source;United States National Institutes of Health;human DNA damage;repaired


application_id: 8168292
project_number: 5P20RR016481-10
project_title: IMMUNOMODULATION OF INFLUENZA A AND RESPIRATROY SYNCYTIAL VIRUS VIRONS
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8120
contact_pi_person_id: 9061178
contact_pi: MESTER, JOSEPH CHARLES
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Cells of the innate and adaptive immune system are capable of exerting a range of potent anti-viral effects both directly and in collaboration with other cell types. These responses are critical for protection against pathogenic respiratory viruses such as human respiratory syncytial virus (HRSV) and influenza A virus. Pathogenic viruses in turn have evolved mechanisms for escaping exacerbating or suppressing human cellular immune responses. The work completed over the previous year focused on the interaction between human immune cells of the monocyte/macrophage natural killer (NK) and T cell lineages with virion components of HRSV and influenza A virus with the goal of distinguishing between protective and pathological responses triggered by specific virion proteins. Immune cells were cultured with whole inactivated virions fractionated virion components or synthetic peptides corresponding to viral proteins to examine their effect on the immune cells. Expression of immunologically relevant inflammatory mediators cytokines and cell surface molecules by the human immune cells were characterized by real-time polymerase chain reaction (RT-PCR) following a two or four hour exposure. HRSV is known to promote an allergic-type inflammatory response by boosting interleukin (IL)-5 and IL-13 expression. The role of specific human immune cells in this inappropriate response is not well-defined. We have shown that HRSV exposure caused an upregulation of IL-5IL -6 IL-10 and IL-13 gene expression in human NK cells. These cytokines are linked to either immune suppression or an aberrant inflammatory response and the results indicate that NK cells as one of the first immune cells to reach the site of viral infection may be important mediators of a deleterious immune response. Additional results have linked regions of both the F and G virion proteins to these cytokine responses from NK cells. Exposure of NK cells to influenza A virus enhanced IL-17A expression. High expression levels of this cytokine are associated with pathological inflammation. Both HRSV and influenza A virus altered the expression of other immunologically relevant genes such as colony stimulating factor I and OX40 ligand. Altered expression of these immune response mediators in vivo would impact the course of infection and the effectiveness of innate and adaptive immune responses. Future work will continue to investigate the cause of these immune modulations with virion fractionation and testing of isolated viral glycoproteins. Signaling molecules involved in generating the NK cell response will also be investigated. Understanding the immunomodulatory potential of virion components will yield insights into viral pathogenesis and allow the design of more effective subunit vaccines.

project_terms:
Allergic;Cell Lineage;Cell surface;Cells;Collaborations;Colony-Stimulating Factors;Computer Retrieval of Information on Scientific Projects Database;Effectiveness;Fibrinogen;Fractionation;Funding;Future;Gene Expression;Genes;Glycoproteins;Goals;Grant;Hour;Human;Human respiratory syncytial virus;IL13 gene;Immune;Immune response;Immune system;Infection;Inflammation;Inflammation Mediators;Inflammatory Response;Influenza;Influenza A virus;Institution;Interleukin-10;Interleukin-13;Interleukin-5;Interleukin-6;Interleukins;Link;Mediator of activation protein;Natural Killer Cells;Natural immunosuppression;Polymerase Chain Reaction;Proteins;Research;Research Personnel;Resources;Role;Signaling Molecule;Site;Source;Subunit Vaccines;Testing;Time;United States National Institutes of Health;Up-Regulation (Physiology);Viral;Viral Pathogenesis;Viral Proteins;Virion;Virus;Virus Diseases;Work;cell type;cytokine;design;immunoregulation;in vivo;insight;killer T cell;macrophage;monocyte;respiratory virus;response;synthetic peptide;tumor necrosis factor ligand superfamily member 4;viron


application_id: 8168291
project_number: 5P20RR016481-10
project_title: MULLEN POST-DOC/TECHNICIAN SUPPORT
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8119
contact_pi_person_id: 9482332
contact_pi: MULLEN, EIMEAR M.
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Soy is known to lower cholesterol levels and this corresponds to a decrease in cardiovascular disease risk. However the mechanisms of this hypocholesterolemic effect as well as the components of soy that cause thiseffect are a source of controversy. It is also unknown whether soy protein containing endogenous isoflavones would have the same effect as soy protein containing low isoflavones with isoflavones supplemented back to the protein source. 
We have previously shown in a cell culture model that the isoflavones genistein and daidzein increase the processing of the Sterol Regulatory Element Binding Proteins (SREBPs) and the expression SREBP-regulated genes such as HMG CoA reductase HMG CoA synthase and the LDL receptor. This study will address whether isoflavones cause a similar increase in SREBP processing and SREBP-regulated gene expression in an in vivo model. We will use the C57BL/6J mouse and feed it an atherogenic diet for either 2 days 10 days or 6 weeks. The diets will contain soy protein with low endogenous amounts of isoflavones with or without 
isoflavone supplementation or soy protein with high amounts of endogenous isoflavones. The animals will be sacrificed and their plasma and liver tissue lipids will be analyzed. The processing of SREBP-2 and the protein levels of HMG CoA reductase will be measured by immunoblotting. The expression levels of SREBP regulated genes will also be investigated by quantitative real time PCR. We hypothesize that there will be a decrease in plasma cholesterol and triglyceride levels and that this will correspond to an increase in SREBP processing as well as SREBP-regulated gene expression. However we do not know if we will observe the same results for soy protein containing high amounts of endogenous isoflavones or soy protein containing low amounts of isoflavones with isoflavones supplemented back to the protein source.

project_terms:
3-hydroxy-3-methylglutaryl-coenzyme A;Address;Animals;Atherogenic Diet;Back;Binding Proteins;Cell Culture Techniques;Cholesterol;Computer Retrieval of Information on Scientific Projects Database;Diet;Funding;Gene Expression;Genes;Genistein;Grant;Hydroxymethylglutaryl-CoA reductase;Immunoblotting;Institution;Isoflavones;Lipids;Liver;Low Density Lipoprotein Receptor;Measures;Modeling;Mus;Plasma;Postdoctoral Fellow;Process;Proteins;Regulatory Element;Research;Research Personnel;Resources;SRE-2 binding protein;Source;Soy Proteins;Sterols;Supplementation;Time;Tissues;Triglycerides;United States National Institutes of Health;cardiovascular disorder risk;daidzein;feeding;in vivo Model;protein expression;soy


application_id: 8168290
project_number: 5P20RR016481-10
project_title: INVESTIGATING NANOPARTICLE INTERACTIONS WITH MODELSOF THE BLOOD BRAIN
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8118
contact_pi_person_id: 8564296
contact_pi: HAIK, KRISTI LYNN
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Glioblastomas are a subtype of the most common and aggressive group of primary brain tumors.  A major issue in treating lioblastoma is that most potential drugs cannot reach the entire tumor.  The core tends to have a weakened blood brain barrier (BBB) where drugs can enter but the extensions of the tumor are around intact BBB and cannot be treated.  The BBB is a tight seal of cells that lines the blood vessels in the brain controlling cerebral homeostasis and preventing toxins and other chemicals which ake it into the blood stream from entering the brain.  The purpose of this project is to examine a series of nanoparticles that have been shown to carry a drug to the brain for safety and toxicity and to determine their distribution within the brain when administered systemically.  Poly(butylcyanoacrylate) (PBCA) nanoparticles coated with polysorbate 80 and loaded with an anti-cancer agent doxorubicin) have been shown to treat a specific type of brain tumor in rats.  It is suggested that these NPs cross the blood brain barrier by adsorbing apolipoprotein enabling the NP to cross the BBB using LDL receptors.  Layer by layer (LbL)-technology(r) will be used to create nanocapsules (containing doxorubicin) made of layers of polyelectrolyte and apolipoprotein.  We hypothesize that the outer layer of apolipoprotein will enable the LbL nanocapsules to cross the BBB using LDL receptors similar to the PBCA.  While much research has been conducted on the above-mentioned PBCA NPs issues of toxicity and tissue distribution have not been elucidated.
Additionally no known research has investigated the proposed LbL
nanocapsules.  Specific aims of this proposal include: (1) testing the
safety and toxicity of NPs using a two-cell culture model of the BBB and rat tissues; (2) characterizing physicochemical properties of NPs and their interaction with lipid BBB models; and (3) testing the
distribution of nanoparticles through the rat BBB.  By locating markers for tight junction proteins astrocytes and degenerating neurons in the brain we will be able to narrow down NP location and gain an additional measure of toxicity.

project_terms:
Antineoplastic Agents;Apolipoproteins;Astrocytes;Blood;Blood - brain barrier anatomy;Blood Vessels;Brain;Brain Neoplasms;Cell Culture Techniques;Cell Line;Cerebrum;Chemicals;Computer Retrieval of Information on Scientific Projects Database;Doxorubicin;Drug or chemical Tissue Distribution;Funding;Glioblastoma;Grant;Homeostasis;Institution;Lipids;Location;Low Density Lipoprotein Receptor;Measures;Modeling;Neurons;Pharmaceutical Preparations;Polysorbate 80;Primary Brain Neoplasms;Property;Proteins;Rattus;Research;Research Personnel;Resources;Safety;Series;Source;Stream;Technology;Testing;Tight Junctions;Tissues;Toxic effect;Toxin;United States National Institutes of Health;mind control;nanoparticle;prevent;safety testing;seal;tumor


application_id: 8168289
project_number: 5P20RR016481-10
project_title: PROTEIN STRUCTURAL REFINEMENT USING COARSE-GRAINED MODELS OVER HIGH PERF COMPUT
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8117
contact_pi_person_id: 9259622
contact_pi: WU, DI
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator. Protein structures can be determined through either experimental methods such as X-ray crystallography and Nuclear Magnetic Resonance (NMR) technology or theoretical methods such as protein folding and homology modeling. However many of determine protein structures are usually not as accurate as desired. Therefore their applications have been severely limited in important fields and structure refinement is always important and critical. In recent decades the number of high resolution protein structures determined and deposited in PDB database is increasing which makes it possible to conduct statistical analysis in the structural database. In this project we propose a knowledge-based approach for protein structure refinement.

project_terms:
Cereals;Computer Retrieval of Information on Scientific Projects Database;Databases;Deposition;Funding;Grant;Homology Modeling;Institution;Methods;Modeling;Nuclear Magnetic Resonance;Research;Research Personnel;Resolution;Resources;Source;Structural Protein;Structure;Technology;United States National Institutes of Health;X-Ray Crystallography;knowledge base;protein folding;protein structure


application_id: 8168288
project_number: 5P20RR016481-10
project_title: RHO KINASE REGULATION OF CYTOSKELETAL REMODELING IN THE A7R5 SMOOTH MUSCLE CELL
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8116
contact_pi_person_id: 2017035
contact_pi: FULTZ, MICHAEL J
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.This investigation will focus on the role and regulation of actin and myosin remodeling in the contracting A7r5 smooth muscle cell in comparison to aortic smooth muscle tissue. We have previously provided evidence of differential remodeling of the alpha- and beta- actin as well as smooth muscle myosin II cytoskeletal structures. However the mechanism(s) regulating this differential remodeling is not understood. Data suggests that the redistribution of actin- actin to podosomes is more sensitive to phorbol stimulation than redistribution of beta-actin to the podosomes. Myosin distribution appears to follow changes in alpha-actin component of the cytoskeleton. Also preliminary evidence suggests that Rho kinase inhibition previously shown to antagonize the development and maintenance of contraction in rat aortic smooth muscle tissue blocked alpha-actin remodeling to the podosomes and re-establishment of alpha-actin stress cables. This evidence supports the hypothesis of differential remodeling and potentially different regulatory mechanisms governing the actin cytoskeleton. The major objective of the proposed project is to determine the effects of Rho kinase inhibition on actin and myosin remodeling in A7r5 cells and compare this to the effect previously observed in aortic smooth muscle tissue. Preliminary evidence suggests several Rho kinase may have a selective effect on alpha-actin and therefore support our hypothesis of differential remodeling of the alpha-actin and beta-actin cytoskeleton. This would suggest that there may be several possible biochemical pathways regulating remodeling and therefore contraction in smooth muscle. If kinase regulation of cytoskeleton is differentially regulated it would support our model of contraction which assigns different roles to alpha- and beta-actin during smooth muscle contraction. Also over the two year funding period this project will engage numerous undergraduate and graduate students in research enhancing their understanding of the scientific process and allowing them to make contributions to a poorly understood physiological mechanism.

project_terms:
Actins;Biochemical Pathway;Cells;Computer Retrieval of Information on Scientific Projects Database;Contracts;Cytoskeleton;Data;Development;Funding;Grant;Institution;Investigation;Maintenance;Modeling;Muscle Contraction;Myosin ATPase;Myosin Type II;Phorbol;Phorbols;Phosphotransferases;Physiological;Process;Rattus;Regulation;Research;Research Personnel;Resources;Rho-associated kinase;Role;Smooth Muscle Myocytes;Smooth Muscle Myosins;Smooth muscle (tissue);Source;Stress;Structure;United States National Institutes of Health;alpha Actin;beta Actin;graduate student


application_id: 8168287
project_number: 5P20RR016481-10
project_title: JACOBSHAGEN POST-DOC/TECHNICIAN SUPPORT
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8115
contact_pi_person_id: 8234056
contact_pi: JACOBSHAGEN, SIGRID
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.We were able to determine the optimal time of giving a light pulse. Greatest phase shifts can be observed 7 h into the dark phase of a 12 h light/12 h dark cycle. We have not optimized the duration of the light pulse yet. However since two of the photoreceptors we are investigating for their possible involvement in circadian entrainment by light in our model organism absorb in the blue region of the light spectrum we already tested blue light. We have preliminary evidence that blue light is indeed effective. This is contrary to previously reported findings that were based on a particular mutant of the organism and obtained under ambiguous conditions. Plant-like cryptochrome: We succeeded in identifying several of our transformants with the RNA interference construct for this particular photoreceptor as having indeed reduced amounts of the protein. They will now provide the basis for experiments that test whether these strains also show reduced abilities to phase shift upon blue light pulses. Animal-like cryptochrome: We did not succeed in cloning the coding sequence for this protein because we were not able to amplify it by PCR. We only succeeded in amplifying shorter fragments most likely due to the high GC content of the DNA. Because of our difficulties and because the protein is most likely a DNA photolyase rather than a photoreceptor as previously suggested we have abandoned this part of the project. Chlamyopsin: Experiments are currently underway to clone a marker into an RNA interference construct received by a collaborator so that strains with reduced amounts of this photoreceptor can be created. Phototropin: When testing RNA interference strains for this photoreceptor that we received from a colleague we did not succeed in detecting the protein in western blots. There is some evidence that the problem arises from degradation problems with the antibodies during shipment and subsequent storage. Our collaborator has kindly agreed to send us another sample in a more secure fashion.

project_terms:
Amino Acid Sequence;Animal Model;Animals;Antibodies;Circadian Rhythms;Cloning;Code;Computer Retrieval of Information on Scientific Projects Database;DNA;DNA Photolyase;Funding;Grant;Guanine + Cytosine Composition;Institution;Light;Organism;Peptide Sequence Determination;Phase;Photoreceptors;Physiologic pulse;Plants;Postdoctoral Fellow;Proteins;RNA Interference;Reporting;Research;Research Personnel;Resources;Sampling;Secure;Source;Testing;Time;United States National Institutes of Health;Western Blotting;base;cryptochrome;light entrainment;mutant;phototropin;research study


application_id: 8168286
project_number: 5P20RR016481-10
project_title: SERCA INHIBITION BY HYDROQUINONE DERIVATIVES
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8114
contact_pi_person_id: 8527958
contact_pi: PAULA, STEFAN FRANZ
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Inhibitors of the enzyme sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) are valuable research tools for the study of the enzyme's role in physiological processes and they also have the potential of being developed into new anti-cancer agents. A series of 25-disubstitued hydroquinones will be synthesized and their ability to inhibit SERCA will be assessed in bioassays. Based on the results computational techniques such as structure-activity relationship modeling and ligand docking will be used to develop models capable of predicting the activities of yet untested hydroquinone-based compounds. With the aid of these models compound libraries will be screened virtually for novel SERCA inhibitors that then will be obtained and tested in bioassays.

project_terms:
Antineoplastic Agents;Biological Assay;Ca(2+)-Transporting ATPase;Computational Technique;Computer Retrieval of Information on Scientific Projects Database;Docking;Endoplasmic Reticulum;Enzyme Inhibitor Drugs;Enzyme Inhibitors;Enzymes;Funding;Grant;Hydroquinones;Institution;Libraries;Ligands;Modeling;Physiological Processes;Research;Research Personnel;Resources;Role;Series;Source;Structure-Activity Relationship;Testing;United States National Institutes of Health;base;hydroquinone;inhibitor/antagonist;novel;tool


application_id: 8168285
project_number: 5P20RR016481-10
project_title: ZEBRAFISH: A POTENTIAL MODEL FOR MAMMALIAN HAIR CELL DEATH AND REGENERATION
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8113
contact_pi_person_id: 2128827
contact_pi: SMITH, MICHAEL
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Auditory hair cells are the sensory cells that transduce acoustical signals into neural ones in vertebrates thus providing the ability to hear. In mammals when these terminally-differentiated cells are damaged or lost the result is permanent loss of hearing since lost mammalian hair cells do not regenerate. In fish and birds damaged auditory sensory epithelia have the capability of regenerating new hair cells resulting in recovery of hearing. Recent studies show that goldfish exhibit both structural (hair cells) and functional (hearing) recovery following noise exposure. To fully understand what normal cellular processes lead to regeneration in fishes knowledge of how specific genes mediate hair cell growth (proliferation and transdifferentiation) is essential. The overall goal of this project is to study the process of hair cell regeneration in zebrafish since zebrafish has become a productive model for studying the gene expression of many cellular pathways. The current proposal has three aims directed at this goal: 1) to determine the time course of hair cell death and regeneration in noise-exposed zebrafish (using immunocytochemistry); 2) to determine the time course of functional recovery of hearing following noise exposure in zebrafish (using auditory brainstem response); and 3) to examine gene expression during the process of hair cell death and regeneration in the zebrafish ear using rtPCR and microarray analysis. We were initially interested in examining expression of three genes (p27Kip1 Atoh1 and Rb1). These genes have recently been shown to regulate hair cell development in mammals. We have performed a microarray experiment that examined gene expression during the process of hair cell generation and the three genes of interest above were not highly regulated but growth hormone and a number of other genes were. We recently validated our microarray experiments with real-time PCR using significantly regulated genes. These studies will provide a basis for future investigations in hair cell regeneration research and may be critical in establishing a link between hair cell proliferation and development of new therapeutics to treat deafness.

project_terms:
Auditory;Auditory Brainstem Responses;Birds;Cell Death;Cell Proliferation;Cell physiology;Computer Retrieval of Information on Scientific Projects Database;Deafness;Development;Ear structure;Epithelium;Exhibits;Fishes;Funding;Future;Gene Expression;Generations;Genes;Goals;Goldfish;Grant;Hair Cells;Hearing;Institution;Investigation;Knowledge;Lead;Link;Mammals;Mediating;Microarray Analysis;Modeling;Natural regeneration;Noise;Pathway interactions;Process;Recovery;Recovery of Function;Research;Research Personnel;Resources;Sensory;Signal Transduction;Somatotropin;Source;Study models;Time;United States National Institutes of Health;Vertebrates;Zebrafish;base;cell growth;cell injury;cellular transduction;hair cell regeneration;hearing impairment;immunocytochemistry;interest;novel therapeutics;relating to nervous system;research study;transdifferentiation


application_id: 8168284
project_number: 5P20RR016481-10
project_title: WKU LEAD FACULTY
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8112
contact_pi_person_id: 7326029
contact_pi: DAVIS, CHERYL D
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.As Western Kentucky University's Lead Faculty Representative my role in the INBRE program is primarily administrative.  During this budget year I have overseen institutional activities related to the program I have represented WKU on the KBRIN steering committee and the KBRIN AREA subcommittee I have promoted and facilitated interactions and exchange of ideas between faculty postdocs technicians and students in our biomedical research community and I have served as a liaison between the Administrative Core of the INBRE program and the faculty investigators and administrators at WKU. Between May 1 2009 and April 30 2010 the INBRE program provided support for one junior faculty investigator (Michael Smith) and three tenured faculty investigators (Sigrid Jacobshagen Rodney King and Nancy Rice).  All four investigators directed successful and productive research programs involving numerous undergraduate and masters level graduate students as well as 3 full time technicians and 1 post doc.  Three of our INBRE investigators are also currently funded by NIH-AREA grants.  Three additional junior faculty members from WKU Di Wu from the Department of Mathematics Rajalingam Dakshinamurthy from the Department of Chemistry and Nilesh Sharma from the Department of Biology participated in the INBRE program during this budget year through our KBRIN AREA initiative.  In addition the Director of our Bioinformatics and Information Science Center Claire Rinehart received funding from the INBRE program to allow the BISC to take on increasing responsibility for arranging and facilitating the annual Kentucky/Tennessee Bioinformatics Summit.  
A record number of six faculty members from Ogden College of Science and Technology at WKU submitted NIH AREA proposals during the current budget year.  We are also pleased to report that two INBRE funded students from WKU received national level scholarships/awards during this budget year.  Patrick Stewart and undergraduate research student in Michael Smith's lab was the recipient of a Morris K. Udall Scholarship and Joseph Chavarria-Smith from Nancy Rice's lab received an NSF Graduate Fellowship to pursue doctoral studies at the University of California-Berkeley.

project_terms:
Administrator;Award;Bioinformatics;Biology;Biomedical Research;Budgets;California;Chemistry;Communities;Computer Retrieval of Information on Scientific Projects Database;Faculty;Fellowship;Funding;Grant;Information Sciences;Institution;Kentucky;Lead;Mathematics;Postdoctoral Fellow;Reporting;Research;Research Personnel;Resources;Rice;Role;Scholarship;Science;Source;Students;Technology;Tennessee;Time;United States National Institutes of Health;Universities;college;graduate student;member;programs


application_id: 8168283
project_number: 5P20RR016481-10
project_title: KING POST-DOC/TECHNICIAN SUPPORT
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8111
contact_pi_person_id: 8534212
contact_pi: KING, RODNEY ALLEN
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The goal of this project is to understand a unique mechanism of transcription elongation control originally discovered in the bacteriophage HK022. Most members of the lambda phage family use phage-encoded proteins to promote early gene expression by suppressing transcription termination. HK022 does not encode an antitermination protein but relies instead on the direct interaction of sites in the nascent transcript with RNA polymerase. The specific hypothesis is that the activity of RNA-based antiterminators depends upon the recognition of sequence and structural information in the nascent transcript by RNA polymerase. This hypothesis is based upon previous studies that 1) have shown that mutations that disrupt base pairing in the RNA reduce antitermination and secondary mutations that re-establish base pairing restore terminator read through 2) interchanging segments of antiterminator RNAs drastically affects activity and 3) RNA-mediated antitermination is blocked by mutations in the beta prime subunit of E. coli RNA polymerase. The goal of this proposal is to identify the required sequence and structural elements of RNA based antiterminators. The specific aims are: 1) to identify additional examples of antiterminator RNAs in lambdoid phages; 2) to use in vivo in vitro and in silico approaches to determine the structurally and functionally important features of the newly identified antiterminator RNAs; and 3) to complete the annotation of two new phage genomes that possess RNA-based antiterminators. The antiterminator sequences discovered in HK022 provide unique examples of RNAs that control gene expression by directly modifying the transcription apparatus. Unusual modes of gene regulation are potential targets for drug design. Therefore a better understanding of antiterminator RNAs and their recognition by RNA polymerase may facilitate the discovery or development of therapeutic agents capable of altering the expression of virulence genes and thus attenuating disease processes.

project_terms:
Affect;Attenuated;Bacteriophage HK022;Bacteriophage lambda;Bacteriophages;Base Pairing;Computer Retrieval of Information on Scientific Projects Database;Computer Simulation;DNA-Directed RNA Polymerase;Development;Disease;Drug Design;Elements;Escherichia coli;Family;Funding;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genome;Goals;Grant;In Vitro;Institution;Mediating;Mutation;Postdoctoral Fellow;Process;Proteins;RNA;Reading;Research;Research Personnel;Resources;Site;Source;Therapeutic Agents;Transcript;Transcription Elongation;United States National Institutes of Health;Virulence;antitermination;base;in vivo;member;transcription termination


application_id: 8168282
project_number: 5P20RR016481-10
project_title: NKU LEAD FACULTY
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8110
contact_pi_person_id: 1893500
contact_pi: BARDGETT, MARK EDWARD
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Funds have been used to support continued coordination of research administration between INBRE faculty and administrators at NKU in addition to the timely and effective communication of information with INBRE administrators at other KY universities. Dr. Bardgett will continue to attend state and regional meetings related to INBRE. Among new faculty and students at NKU he will continue to increase awareness of the KBRIN faculty fellowship program the KBRIN Summer Student program the Bioinformatics summit and other INBRE-sponsored research and training initiatives.

project_terms:
Administrator;Awareness;Bioinformatics;Communication;Computer Retrieval of Information on Scientific Projects Database;Faculty;Fellowship Program;Funding;Grant;Institution;Lead;Research;Research Personnel;Research Training;Resources;Source;Students;United States National Institutes of Health;Universities;meetings;programs


application_id: 8168281
project_number: 5P20RR016481-10
project_title: SCHULTHEIS POST-DOC/TECHNICIAN SUPPORT
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8109
contact_pi_person_id: 6945317
contact_pi: SCHULTHEIS, PATRICK JOHN
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.P-type ATPases which transport ions across cell membranes have been grouped into five subfamilies. The P1- P2- and P3-ATPases have been well characterized and include heavy metal ATPases NaK-ATPases HK-ATPases SERCAs and other Ca2+-ATPases and bacterial Mg2+-ATPases. The P4-ATPases are found only in eukaryotes and have been implicated in the transport of aminophospholipids. Although they are present in all eukaryotes little is known about the P5-ATPases other than the observations that loss of Cod1p one of the two yeast P5-ATPases leads to defects in glycoprotein processing endoplasmic reticulum associated protein degradation (ERAD) and constitutive activation of the unfolded protein response (UPR). Thus our objective is to obtain basic information regarding the distribution and ion specificity of the mammalian P5-ATPases. In preliminary studies we have identified 5 mammalian P5-ATPases termed Atp13a1-Atp13a5 determined their sequences and mRNA tissue distribution and begun development of isoform-specific antibodies and expression constructs. In Aim 1 we will develop isoform-specific antibodies and in situ hybridization probes and determine the membrane location and cell-type distribution of mouse Atp13a1-Atp13a5 using a combination of Western blot analysis of tissues and subcellular membrane fractions immunocytochemistry and in situ hybridization. In Aim 2 the ion specificity of the murine P5-ATPases will be determined. Membrane fractions from cell lines in which histidine-tagged versions of Atp13a1-Atp13a5 are over-expressed will be prepared and subjected to detergent solubilization. The His-tagged transporters will then be purified by nickel affinity chromatography and ion specificities will be determined by measuring cation-dependent ATP hydrolysis using sensitive assays of ATPase activity and phosphoenzyme formation. Ion uptake in whole cells or isolated membrane vesicles will also be analyzed using the appropriate radioisotope to confirm ion specificity. These studies will provide basic information that will be critical for more detailed mechanistic studies of the cell biological and physiological functions of this most poorly understood subfamily of mammalian P-type ATPases.

project_terms:
ATP Hydrolysis;ATP phosphohydrolase;Affinity Chromatography;Antibodies;Biological;Biological Assay;Ca(2+) Mg(2+)-ATPase;Ca(2+)-Transporting ATPase;Cations;Cell Line;Cell membrane;Cells;Computer Retrieval of Information on Scientific Projects Database;Defect;Detergents;Development;Drug or chemical Tissue Distribution;Endoplasmic Reticulum;Eukaryota;Funding;Glycoproteins;Grant;H(+)-K(+)-Exchanging ATPase;Heavy Metals;Histidine;In Situ Hybridization;Institution;Ion Transport;Ions;Location;Measures;Membrane;Messenger RNA;Mus;Na(+)-K(+)-Exchanging ATPase;Nickel;Physiological;Postdoctoral Fellow;Process;Protein Isoforms;Proteins;Radioisotopes;Research;Research Personnel;Resources;Source;Specificity;Tissues;United States National Institutes of Health;Vesicle;Western Blotting;Yeasts;cell type;immunocytochemistry;protein degradation;response;uptake


application_id: 8168280
project_number: 5P20RR016481-10
project_title: RICE POST-DOC/TECHNICIAN SUPPORT
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8108
contact_pi_person_id: 6773495
contact_pi: RICE, NANCY AYERS
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Myofibroblasts are necessary cells for tissue remodeling and repair. The fact that under certain circumstances myofibroblasts persist and continue to secrete extracellular matrix has implicated them in interstitial fibrosis of the lung. Several studies suggest that nitric oxide (NO)-mediated signals may be important in regulating myofibroblast phenotypes. Inhibition of NO production leads to increased accumulation of myofibroblasts; NO reduces myofibroblast accumulation and collagen deposition; and transforming growth factor  (TGF) a known activator of myofibroblast differentiation blocks myofibroblast apoptosis. In vivo endothelial NOS (eNOS) knockout mice experience prolonged pulmonary fibrosis in response to the profibrotic agent bleomycin suggesting that eNOS operates in regulating myofibroblast proliferation and/or apoptosis. The fact that the eNOS gene promoter can be induced by the mechanical force of laminar flow in epithelial cells and the observation that other genes  smooth muscle actin (ASMA) in particular are mechanotranscriptionally regulated in myofibroblasts suggests a potential mechanism for regulating the expression of eNOS and thus apoptosis in myofibroblasts. Therefore we hypothesize that contraction of myofibroblasts mediates their apoptosis via eNOS signaling. In our current proposal we are investigating three specific aims to extend our knowledge of the role of mechanical stress and NO in regulating myofibroblasts. One we are evaluating the role of mechanical stress on pulmonary myofibroblast eNOS expression; two we are determining the role of NO on pulmonary myofibroblast apoptosis; and three we are assessing the deletion of sarcomeric myosin on bleomycin induced pulmonary fibrosis in vivo.

project_terms:
Apoptosis;Bleomycin;Cells;Collagen;Computer Retrieval of Information on Scientific Projects Database;Deposition;Epithelial Cells;Extracellular Matrix;Fibrosis;Funding;Genes;Grant;Institution;Knockout Mice;Knowledge;Lung;Mechanical Stress;Mechanics;Mediating;Myofibroblast;Myosin ATPase;Nitric Oxide;Phenotype;Postdoctoral Fellow;Production;Promotor (Genetics);Pulmonary Fibrosis;Research;Research Personnel;Resources;Rice;Role;Signal Transduction;Smooth Muscle Actin Staining Method;Source;Tissues;Transforming Growth Factors;United States National Institutes of Health;experience;human NOS3 protein;in vivo;interstitial;repaired;response


application_id: 8168279
project_number: 5P20RR016481-10
project_title: BARTON POST-DOC/TECHNICIAN SUPPORT
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8107
contact_pi_person_id: 7614787
contact_pi: BARTON, HAZEL A
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The goal of my project is to understand the metabolic activity that supports microbial growth under extreme starvation. In understanding the interactions and processes that sustain microbial communities in starved environments we hope to better understand one of the outstanding questions of microbial ecology: why are the majority of organisms identified in the environment unculturable in the laboratory? This unculturability is presumed to be due to the inability to reproduce the fastidious growth requirements of many of these species making them viable within the environment but unculturable under laboratory conditions. Through this proposal we aim to test our hypothesis that microbial communities subsist in extremely oligotrophic environments by establishing mutualistic interactions allowing species to more efficiently utilize the complex nutrient sources entering the system. While such interactions may promote diversity under extreme starvation obligate mutualism prevents cultivation of these species using traditional techniques. The experiments proposed are geared toward understanding the role that the amount and type of available energy entering these systems have on community diversity and mutualism. The specific aims are: 1) to determine whether microbial mutualistic interactions are occurring under extreme starvation conditions and what role they play in supporting community growth; 2) to determine whether such mutualism increases the usable energy sources and metabolic efficiency under extreme starvation driving community diversity; and 3) to increase the number of previously unculturable bacterial species from these extremely oligotrophic environments by separating previously interdependent species. By using a combination of techniques to monitor how nutrient flow affects community diversity we endeavor to understand some of the more complex metabolic interactions capable of supporting life under starvation while increasing the diversity and number of culturable microbial species.

project_terms:
Affect;Automobile Driving;Communities;Complex;Computer Retrieval of Information on Scientific Projects Database;Ecology;Energy-Generating Resources;Environment;Funding;Goals;Grant;Growth;Institution;Laboratories;Life;Metabolic;Monitor;Nutrient;Organism;Play;Postdoctoral Fellow;Process;Research;Research Personnel;Resources;Role;Source;Starvation;System;Techniques;Testing;United States National Institutes of Health;microbial;microbial community;mutualism;prevent;research study


application_id: 8168278
project_number: 5P20RR016481-10
project_title: BARDGETT POST-DOC/TECHNICIAN SUPPORT
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8106
contact_pi_person_id: 1893500
contact_pi: BARDGETT, MARK EDWARD
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The goal of the proposed research is to develop and use models of modest excitotoxic hippocampal injury to assess the cognitive enhancing ability of specific candidate compounds. Our preliminary data demonstrate that excitotoxic injury to the dorsal hippocampus produces enduring deficits in spatial working memory. We have also shown in preliminary studies that antagonists at histamine H3 receptors alleviate injury-induced deficits in spatial working memory. The specific aims of our currently-funded R15 research have been to answer the following questions: 1) Can H3 antagonists alleviate spatial working memory deficits in rats with adult-onset hippocampal injury 2) Can direct infusion of H3 antagonists into the prefrontal cortex improve memory in rats with adult-onset hippocampal injury & 3) Can H3 antagonists alleviate changes in spatial working memory prepulse inhibition and locomotor activity in rats with neonatal-onset hippocampal injury? For this application we requested INBRE supplemental support for a research associate who can advance the aims of our R15 research and supervise undergraduate research. Between May 2009 and the present we have assessed the effects of H3 antagonists on spatial memory deficits and other behavioral anomalies produced by drugs that block NMDA receptors. These studies mainly performed by Molly Griffith our research associate and several undergraduates in the lab have shown that H3 antagonists exacerbate the effects of NMDA antagonists on locomotor activity but also alleviate the spatial memory deficits produced by such drugs. We submitted an R15 to continue these studies in June 2009 and it received a priority score of 37. We will revise and resubmit this application in February 2010. Having INBRE support for our research associate has greatly facilitated the pace of our R15 research and resulted in two published papers support for award-winning undergraduate research and an R15 renewal application that received a favorable (although unfundable) score.

project_terms:
Adult;Award;Behavioral;Cognitive;Computer Retrieval of Information on Scientific Projects Database;Data;Dorsal;Funding;Goals;Grant;Hippocampus (Brain);Histamine H3 Receptors;Infusion procedures;Injury;Institution;Memory;Memory impairment;Modeling;Mollies;Motor Activity;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;Neonatal;Paper;Pharmaceutical Preparations;Postdoctoral Fellow;Prefrontal Cortex;Publishing;Rattus;Request for Applications;Research;Research Personnel;Resources;Short-Term Memory;Source;United States National Institutes of Health;improved;prepulse inhibition


application_id: 8168277
project_number: 5P20RR016481-10
project_title: UK BIOINFOMRATICS
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8105
contact_pi_person_id: 8383697
contact_pi: PETERSON, MARTHA L.
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The UK Bioinformatics Core provides bioinformatics and statistical consulting on multiple genomics projects. The facility supports the BLAST server Computational Proteomics Analysis System (CPAS) proteomics suite and other custom bioinformatics applications. Facility personnel are actively engaged in statistical consulting and program development and all are members of the Center for Biomedical Informatics of the UK Center for Clinical and Translational Sciences. The INBRE bioinformatics core particularly Dr. Stromberg continues to serve as the primary statistical consultant on transcription microarray analyses at UK serving approximately 30 investigators per year and analyzing data from approximately 1000 expression arrays. Dr. Stromberg is a co-PI on numerous grants and participates in writing the statistical parts of proposals. Of particular note Dr. Stromberg is a Co-PI with Dr. Randal Voss as the PI on a recently awarded $2000000 grant from the Department of Defense. Dr. Voss and the Salamander Genome Project had been supported in part by this core for eight years but was discontinued this year due to the great success he has had in obtaining extramural support for his work. The core also provides informatics support of proteomics and protein expression analyses. Dr. Viele is developing statistical methods to handle mass spectroscopic protein quantification. Dr. Bert Lynn the director of the University of Kentucky Mass Spectrometry Facility (UKMSF) helps direct the efforts of Mr. William Nelson in the proteomics area. They recently designed and implemented Massively Parallel Peptide Discovery methods that they have submitted for publication and which form the basis of an NIH RO1 grant application. UK is a participant in the national LabKey software development consortium and offers support that can be deployed statewide. This year Mr. Nelson provided training for the Labkey Computational Proteomics Analysis System (CPAS) at the University of Louisville for ten members of the CREAM grant and installed CPAS at the CREAM facility. Their CPAS install is integrated with the SEQUEST cluster at the UKMSF. A publication from this effort should be submitted soon. Mr. Nelson also provided a prototype and training on the Labkey Server Study Module for twelve researchers from the Markey Cancer Center and the Kentucky Cancer Registry (KCR). The Study module provides data management and statistical analysis tools for Clinical Translational Studies. As a result the Study module is being adopted by the KCR to support the Markey Cancer Center's SPORE grant. The KCR is hiring a permanent administrator to support the Labkey server. Also Dr. Andre Baron's group has adopted the Labkey for their cancer biomarker research. His project has been implemented at the UKMSF's Labkey installation. Dr. Sujin Kim is developing tools to segment pathology images to facilitate computer identification and standardization of pathology data. She has submitted several grants and publications as well as supervised multiple master's-level students in projects to develop web-based information systems. Dr. Jinze Liu has established multiple bioinformatics collaborations across campus including developing robust methods for analyzing RNA-seq data for an equine gene annotation project (with Dr. James Macleod) and a plant annotation project (with Dr. Chris Schardl). She recently received an NSF grant to develop methods to discover alternative splicing patterns from RNA-seq data. Dr. Dave Fardo a biostatistician who studies genome-wide association studies has established collaborations on campus with colleagues at U of L and internationally. Dr. Bert Lynn has recently agreed to mentor and collaborate with Dr. Darrin Smith from the EKU department of chemistry. Dr. Peter Mirabito organized and supervised the KBRIN-supported students working at UK over the summer.

project_terms:
Administrator;Adopted;Alternative Splicing;Applications Grants;Area;Award;Bioinformatics;Blast Cell;Cancer Center;Chemistry;Clinical;Collaborations;Computer Retrieval of Information on Scientific Projects Database;Computers;Consult;Cream;Custom;Data;Data Analyses;Department of Defense;Equus caballus;Extramural Activities;Funding;Genes;Genetic Transcription;Genome;Genomics;Grant;Human Resources;Image;Informatics;Information Systems;Institution;Kentucky;Malignant Neoplasms;Mass Spectrum Analysis;Mentors;Methods;Online Systems;Participant;Pathology;Pattern;Peptides;Plants;Program Development;Proteins;Proteomics;Publications;Reproduction spores;Research;Research Personnel;Resources;Salamander;Source;Standardization;Statistical Methods;Students;Systems Analysis;Training;Translational Research;United States National Institutes of Health;Universities;Work;Writing;base;biomarker;biomedical informatics;data management;design;genome wide association study;member;neoplasm registry;protein expression;prototype;software development;success;tool;translational study


application_id: 8168276
project_number: 5P20RR016481-10
project_title: EKU - LEAD FACULTY
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8104
contact_pi_person_id: 10574352
contact_pi: CALIE, PATRICK JOSEPH
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The goal of this project is to provide INBRE support at Eastern Kentucky University. The PI provides research opportunities to undergraduate students and appropriate seminar speakers.

project_terms:
Computer Retrieval of Information on Scientific Projects Database;Faculty;Funding;Goals;Grant;Institution;Kentucky;Lead;Research;Research Personnel;Resources;Source;Students;United States National Institutes of Health;Universities


application_id: 8168275
project_number: 5P20RR016481-10
project_title: MSU LEAD FACULTY
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8103
contact_pi_person_id: 9258111
contact_pi: DENNIS, DOUGLAS
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The major objective of the proposed project is to facilitate the development of faculty and student biomedical research activities with the overall goal of creating a self-sustaining biomedical research program and infrastructure at MSU independent of INBRE funding. This goal will be accomplished through two complimentary mechanisms. First faculty and student biomedical research capacity will be enhanced through participation in the state-wide INBRE program of investigator-initiated research projects student summer workshops seminars bioinformatics programs etc. Second faculty and student research will be encouraged and supported through the continuation of an MSU INBRE program that supports biomedical research and travel faculty NIH research grant proposal development and an INBRE seminar series.

project_terms:
Applications Grants;Bioinformatics;Biomedical Research;Computer Retrieval of Information on Scientific Projects Database;Development;Educational workshop;Faculty;Funding;Goals;Grant;Institution;Investigator-Initiated Research;Lead;Research;Research Activity;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Series;Source;Students;Travel;United States National Institutes of Health;programs


application_id: 8168274
project_number: 5P20RR016481-10
project_title: INBRE: UOFL: GENOMICS CORE
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8102
contact_pi_person_id: 1866398
contact_pi: COOPER, NIGEL G.F.
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The shared centralized research core facility is designed to provide sequencing and gene-micro-array services to the University of Louisville and its KBRIN/INBRE affiliated institutions. 

In September 2009 the UofL Microarray Facility moved to the new Clinical Translational Research Building (CTRB) opened in August 2009 on the same Health Science Center Campus. This building provides state-of-the-art new and expanded lab space for the Facility. The new facility is approx. 1500 square feet which includes four large lab areas with benches a separate room for processing ozone sensitive Agilent arrays and a pre-PCR room. The facility houses an Agilent Microarray Scanner G2505B Workstation and Hybridization Oven G2545A an Affymetrix Microarray System including an Affymetrix GCS 3000 Scanner 7G two Fluidics Stations 450 and a Hybridization Oven 640 a Beckman CEQ 8000 Sequencer an Agilent Bioanalyzer 2000 a Nanodrop ND-1000 and three Applied Biosystems PCR Thermocyclers 9700. This core hosts specialized training on an on going basis.  

Most importantly the move allowed to physically merge the Affymetrix and Agilent components of the Facility and their respective personnel into one centralized Facility location with ample bench space for all hardware and instrumentation work and storage space and desk areas for all personnel.

The Facility is in the process of obtaining CLIA certification for the processing of standardized CGH genetic tests on clinical patient samples using the Agilent platform.

As expansion of the services offered microRNA expression profiling on human and rodent samples using either the Agilent or Affymetrix array platforms was introduced and is now routinely performed.

Also Yinlu Chen M.S. Sr. Research Analyst was hired in Dec 2009 as addition to the Facility personnel to support client data analyses onsite.

project_terms:
Area;Arts;Certification;Client;Clinical;Computer Retrieval of Information on Scientific Projects Database;Core Facility;Data Analyses;Funding;Genes;Genetic screening method;Genomics;Grant;Health Sciences;Housing;Human;Human Resources;Institution;Location;Molecular Profiling;Ozone;Patients;Process;Research;Research Personnel;Resources;Rodent;Sampling;Services;Source;System;Training;Translational Research;United States National Institutes of Health;Universities;Work;base;design;instrumentation;square foot


application_id: 8168273
project_number: 5P20RR016481-10
project_title: UOFL BIOINFORMATICS CORE
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8101
contact_pi_person_id: 7948398
contact_pi: ROUCHKA, ERIC C
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.This is a network-distributed core with assets contributed by and shared among the KBRIN-affiliated institutions. The resources include hardware software and human resources.

Dr. Eric Rouchka a faculty member in CECS. His background and training is in computer sciences and genomics (sequencing). Dr. Rouchka serves as the KBRIN Bioinformatics Lead at the University of Louisville.

A University of Louisville Bioinformatics Research Group (CECS SOM and SPH faculty and students meet every other week; anyone interested in bioinformatics should attend). The group has developed a Web site which lists Bioinformatics Research Group personnel and projects. The BRG are developing new tools for the development of data banks for genomics data mining image analysis and for gene-array analysis. 

The Eighth Annual UT-ORNL-KBRIN Bioinformatics Summit was held at Fall Creek Falls State Park in Pikeville Tennessee from March 20-22 2009.  A total of 202 participants registered for the summit with 94 from various Tennessee institutions and 68 from various Kentucky institutions.  A number of additional participants came from universities and research institutions from other states and countries e.g. the National Institutes of Health Virginia Commonwealth University University of Cincinnati Emory University and the University of British Columbia.  Seventy-seven registrants were faculty with an additional 62 student 43 staff and 20 postdoctoral level participants.
 The conference program included three days of presentations.  The first day was devoted to workshops including two Geospiza/Digital World Biology workshops along with a bioinformatics education and a microarray analysis workshop.  The last day and a half were dedicated to scientific sessions in bioinformatics divided into three plenary sessions: Medical and Translational Informatics (plenary speakers Bruce Aronow University of Cincinnati; Ian Brooks University of Tennessee Health Science Center) Systems Biology (plenary speakers Mike Miles VCU; Greg Buck VCU; Zhongming Zhao VCU; Ping Xu VCU; Damail Bonchev VCU) and Next-Generation Sequencing and Epigenetics (plenary speakers Jarret Glasscock Cofactor Genomics; Robert Hanson NIH-NIDDK). 


The Ninth  Annual UT-ORNL-KBRIN Bioinformatics Summit that will be held March 19-21 2010 at Lake Barkley State Park Western Kentucky University was tasked with some of the responsibility to arrange and facilitate the meeting. To assist in preparing and executing the summit Donna Schulte was hired to help Dr. Claire Rinehart in this task.

project_terms:
Bioinformatics;Biology;British Columbia;Computer Retrieval of Information on Scientific Projects Database;Computer software;Country;Databases;Educational aspects;Educational workshop;Epigenetic Process;Faculty;Funding;Genes;Genomics;Grant;Health Sciences;Human Resources;Image Analysis;Informatics;Institution;Kentucky;Lead;Medical;Microarray Analysis;Participant;Research;Research Personnel;Resources;Source;Students;Systems Biology;Tennessee;Training;United States National Institutes of Health;Universities;Virginia;cofactor;computer science;data mining;digital;falls;interest;meetings;member;next generation;programs;symposium;tool development;web site


application_id: 8168272
project_number: 5P20RR016481-10
project_title: INBRE: UOFL KENTUCKY INBRE ADMINISTRATIVE CORE
administering_ic: NCRR
award_notice_date: 2010-05-26
opportunity_number: PAR-08-150
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2010-05-01
project_end_date: 2011-04-30
study_section: ZRR1-RI-4(01)
subproject_number: 8100
contact_pi_person_id: 1866398
contact_pi: COOPER, NIGEL G.F.
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Administrative Core:
The administrative core provides a leadership role in the development of the statewide network. The core is located in approximately 600 sq ft of office space on the Health Sciences campus at the University of Louisville. The office provides budget management services for the network and logistical support for KBRIN committees and their activities. The KBRIN administrative office works with the Grants Management Office at the University of Louisville for the development of subcontracts to KBRIN affiliates and the subsequent invoicing. Dr. Nigel Cooper is Director of the Administrative Core.  He is aided by Dr. Bruce Mattingly the Program Coordinator who is located at Morehead State University. In addition the Administrative Core is managed on a daily basis by 3 staff including: Ms Stephanie Dearing (budget) Ms Michelle Padgett (reconciliation) and Ms Jane Thornton (logistics). A Steering Committee comprising individuals from each affiliated institution the PD and the PC meets on a regular basis to provide guidance on programmatic activities and budget distributions.

project_terms:
Budgets;Computer Retrieval of Information on Scientific Projects Database;Development;Funding;Grant;Health Sciences;Individual;Institution;Kentucky;Leadership;Logistics;Office Management;Research;Research Personnel;Resources;Role;Services;Source;United States National Institutes of Health;Universities;Work;base;meetings;programs;square foot


application_id: 8168254
project_number: 5P20RR020171-07
project_title: MOLECULAR MECHANISM OF MAMMALIAN AUTOPHAGY
administering_ic: NCRR
award_notice_date: 2010-08-16
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2010-07-01
project_end_date: 2011-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8082
contact_pi_person_id: 8688832
contact_pi: WANG, QINGJUN
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.As a ubiquitous lysosomal pathway essential for degrading and recycling proteins and organelles autophagy has been implicated in a broad spectrum of human disease including cancer infection liver disease myopathy and neurodegeneration. However the molecular machinery comprising the mammalian autophagy pathway and the molecular mechanism of how this machinery functions are largely unknown. Our long-term goal is to understand the molecular mechanism of the mammalian autophagy pathway and its relevance to human disease for discovering much needed early diagnostic biomarkers and therapeutic targets. To achieve this goal our overall objective is to first identify novel protein-protein interactions in the mammalian autophagy pathway and subsequently to determine the functions of these novel interactors. Beclin 1 the first reported mammalian autophagy protein plays an important positive role in autophagy regulation and has been implicated in a variety of human physiology and pathology including tumor suppression neurodegeneration development and aging. Therefore for this study we will investigate Beclin 1-mediated autophagy regulation so as to begin deciphering the molecular mechanism of mammalian autophagy. Guided by strong preliminary data three specific aims will be pursued using a combination of a novel integrated mouse genetic-proteomic approach as well as biochemical and cell biological studies. In Aim 1 we will establish the framework of a context-dependent mammalian autophagy interactome through identifying Beclin 1-interacting proteins from living animals; in Aim 2 we will elucidate the molecular details of autophagy regulation by two novel Beclin 1-interacting proteins Atg14L and Rubicon; and in Aim 3 we will explore the molecular details of autophagy regulation by a third novel Beclin 1-interactor and its cancer relevance. By establishing the framework of the mammalian autophagy interactome and unraveling the molecular details of autophagy regulation by Beclin 1 and its interacting proteins this proposed work will not only provide insight into the role of autophagy in mammals but also generate novel potential targets for preventive and therapeutic interventions that may ultimately aid patients suffering from autophagy-related human disease.

project_terms:
Aging;Animals;Autophagocytosis;Biochemical;Biological;Cells;Computer Retrieval of Information on Scientific Projects Database;Data;Development;Diagnostic;Funding;Genetic;Goals;Grant;Human;Infection;Institution;Life;Liver diseases;Malignant Neoplasms;Mammals;Mediating;Molecular;Mus;Myopathy;Nerve Degeneration;Organelles;Pathology;Pathway interactions;Patients;Physiology;Play;Preventive;Proteins;Proteomics;Recycling;Regulation;Reporting;Research;Research Personnel;Resources;Role;Source;Therapeutic Intervention;Tumor Suppression;United States National Institutes of Health;Work;biomarker;human disease;insight;novel;protein protein interaction;therapeutic target


application_id: 8168253
project_number: 5P20RR020171-07
project_title: IDENTIFICATION OF QSHBC-REGULATED GENES IN NONTYPEABLE HAEMOPHILUS INFLUENZAE
administering_ic: NCRR
award_notice_date: 2010-08-16
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2010-07-01
project_end_date: 2011-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8081
contact_pi_person_id: 6714687
contact_pi: JOHNSTON, JASON W.
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.A newly described signaling pathway in Escherichia coli the QseBC two-component signal transduction (TCST) system has been proposed to be involved in both interspecies cell-cell communication and host-pathogen interaction. A homolog to the QseBC system has been identified in NTHi. This system which I have designated QshABC has a novel operon organization that includes a gene qshA that encodes for a small periplasmic protein.  A qshBC mutant exhibits severely attenuated biofilm formation and/or persistence in the chinchilla model for otitis media while it is unaffected in its ability to form a biofilm in vitro. Based on these observations I propose to further characterize the QshABC system in NTHi to assist in the exploration of its role in pathogenesis. Successful completion of the proposed work would be a crucial step in the characterization of this system and will lead to a better understanding of the signal transduction pathways that are required for the virulence of NTHi.

project_terms:
Attenuated;Cell Communication;Cells;Chinchilla (genus);Computer Retrieval of Information on Scientific Projects Database;Escherichia coli;Exhibits;Funding;Genes;Grant;Homologous Gene;In Vitro;Institution;Lead;Microbial Biofilms;Modeling;Nontypable Haemophilus influenza;Operon;Otitis Media;Pathogenesis;Periplasmic Proteins;Research;Research Personnel;Resources;Role;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Source;System;United States National Institutes of Health;Virulence;Work;base;mutant;novel;pathogen


application_id: 8168252
project_number: 5P20RR020171-07
project_title: MECHANISMS OF PERIPHERAL REGULATORY T CELL GENERATION
administering_ic: NCRR
award_notice_date: 2010-08-16
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2010-07-01
project_end_date: 2011-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8080
contact_pi_person_id: 7732443
contact_pi: MARTI, FRANCESC
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Peripherally induced Regulatory T cell (iTregs) is the predominant source of T cell suppressor activity in the human immune system. As such the possibility to control their development holds a tremendous therapeutic promise. Our lab has established a cell culture system that recapitulates the generation of functional iTregs ex vivo from primary human. Our long term goal is to identify the molecular mechanisms that control T cell activation as a prerequisite to develop therapeutic approaches to induce direct or restore the normal immunological activity. In recent years epidemiological and clinical studies have demonstrated the beneficial effects of a balanced consumption of dietary Polyunsaturated Fatty Acids (PUFAs). Currently the mechanisms underlying PUFA regulation of immune response are largely unknown. We postulate that PUFAs play a crucial role in controlling the T cell response through three different but related mechanisms: 1) changing the composition and structure of the cell membrane; 2) regulating signaling networks and gene expression through the synthesis of eicosanoids and 3) controlling cell fate decisions in different cell activities and developmental processes. In this project we will take advantage of a primary human cell culture system to elucidate the role of PUFA in the molecular regulation of T cell activity with special focus on the dynamic process to generate iTregs. To do so our experimental research plan will address these three Specific Aims: 
1)Test the hypothesis that the lipid architecture of the T cell plasma membrane is altered by PUFA treatment. We will integrate analyses of lipid rafts protein microclusters and the immune synapse (IS) formation to convey a model of T cell membrane structure function and dynamics modulated by PUFA.    
2)Test the hypothesis that PUFAs regulate the eicosanoid synthesis in T cells. We will analyze and compare the eicosanoid pathways engaged in T cells treated with PUFAs and their potential role in the regulation of gene expression induced by the nuclear receptor Peroxisome Proliferator Activator Receptor gamma (PPAR). 
3)Test the hypothesis that PUFAs control peripheral iTreg development and stability. We will analyze and compare the time-course effects of PUFAs on the generation and the stability of iTregs. 

The results ought to provide a solid foundation to support the development of rational strategies to induce direct or restore the normal immunological activity in different pathologies such as autoimmunity chronic inflammation or cancer. This project has clear and direct relevance to human health since the capacity to modulate the development and/or response of Tregs may become instrumental in controlling the dynamic plasticity of the immune response.

project_terms:
Address;Architecture;Autoimmunity;Cell Culture System;Cell Fate Control;Cell Membrane Structures;Cell membrane;Cells;Chronic;Clinical Research;Computer Retrieval of Information on Scientific Projects Database;Consumption;Development;Developmental Process;Eicosanoids;Epidemiology;Equilibrium;Foundations;Funding;Gene Expression;Gene Expression Regulation;Generations;Goals;Grant;Health;Human;Immune;Immune response;Immune system;Inflammation;Institution;Lipids;Malignant Neoplasms;Membrane Microdomains;Membrane Structure and Function;Modeling;Molecular;Nuclear Receptors;Pathology;Pathway interactions;Peripheral;Peroxisome Proliferators;Play;Polyunsaturated Fatty Acids;Process;Proteins;Regulation;Regulatory T-Lymphocyte;Research;Research Personnel;Resources;Role;Signal Transduction;Solid;Source;Suppressor-Effector T-Lymphocytes;T cell regulation;T cell response;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;Time;United States National Institutes of Health;receptor;research study;response;synaptogenesis


application_id: 8168251
project_number: 5P20RR020171-07
project_title: THE CONNECTION BETWEEN LAFORA DISEASE AND OTHER POLYGLUCOSAN BODY DISEASES
administering_ic: NCRR
award_notice_date: 2010-08-16
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2010-07-01
project_end_date: 2011-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8079
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Lafora disease (LD) is caused by mutations in the carbohydrate phosphatase laforin.  A hallmark of LD is the accumulation of insoluble carbohyrate called Lafora bodies (LBs) in the cytoplasm of cells.  While LBs accumulate in most cells apoptosis only occurs in neurons and this eventually leads to epilepsy and death of the patient.  Wolff-Parkinson-White (WPW) syndrome is a cardiac hypertrophy caused by insoluble carbohydrate accumulations resulting from mutations in the cellular energy sensor and regulator AMP-activated protein kinase (AMPK).  McArdle's disease (GSD V) is a glycogen storage disease that results in increased glycogen storage in muscle caused by mutations in  the PYGM gene that encodes muscle glycogen phosphorylase.  Andersen's disease (GSD IV) is caused by mutations in glycogen branching enzyme and results in aberrant glycogen storage especially in the liver and heart.  This proposal will define the events and determine the connection between LD and other diseases involving polyglucosan accumulations.  Specific Aim 1 will identify modification of LD proteins and interacting proteins.  In specific Aim 2 we will determine if post-translation modification affects laforin binding to known substrates the localization of laforin and/or the phosphatase of laforin.  In specific aim 3 we will determine the mechanism of carbohydrate stimulated AMPK kinase activity.  In doing so we will define the fold increase in AMPK-kinase activity the carbohydrate(s) catalyst and the substrates affected.  Finally we will translate these findings into a mouse model of LD.  The studies proposed will define connections between Lafora disease and other polyglucosan body disorders.  In addition they will better characterize carbohydrate metabolism which is at the heart of multiple metabolic disorders including diabetes and yield insights into novel treatments.

project_terms:
5'-AMP-activated protein kinase;AMP-activated protein kinase kinase;Affect;Apoptosis;Binding (Molecular Function);Carbohydrates;Cells;Cessation of life;Computer Retrieval of Information on Scientific Projects Database;Cytoplasm;Diabetes Mellitus;Disease;Epilepsy;Event;Funding;Genes;Glycogen;Glycogen Branching Enzyme;Glycogen Phosphorylase;Glycogen Storage Disease;Glycogen Storage Disease Type IV;Glycogen Storage Disease Type V;Grant;Heart;Heart Hypertrophy;Institution;Lafora Disease;Liver;Metabolic Diseases;Modification;Muscle;Mutation;Neurons;Patients;Phosphoric Monoester Hydrolases;Proteins;Research;Research Personnel;Resources;Source;Translating;Translations;United States National Institutes of Health;Wolff-Parkinson-White Syndrome;carbohydrate metabolism;catalyst;insight;mouse model;novel;polyglucosan;sensor


application_id: 8168250
project_number: 5P20RR020171-07
project_title: NEGATIVE REGULATION OF THE YEAST MRP YCF1P AND THE HUMAN MRPS BY CK2
administering_ic: NCRR
award_notice_date: 2010-08-16
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2010-07-01
project_end_date: 2011-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8078
contact_pi_person_id: 6926841
contact_pi: PAUMI, CHRISTIAN M
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The multidrug resistance-associated protein (MRP) subfamily of the ATP-binding cassette (ABC) transporters plays a key role in protecting cells from drugs and environmental toxins such as heavy metals (mercury arsenic lead and cadmium).  The MRPs (also called ABCCs) are distinguished from other ABC transporters by two striking hallmarks: 1) they contain an additional "N-terminal extension" with a conserved region called L0 and 2) they transport substrates in the form of glutathione (GSH)-conjugates.  The overall goal of this work  is to determine how MRP function is regulated in vivo.   Specifically I am interested in defining the role of MRP-protein kinase interactors in regulating MRP function.   The aims if this proposal are identifying the mechanism by which an  MRP-protein kinase interactor the yeast casein kinase 2 (CK2) alpha subunit Cka1p  negatively regulates the function of the yeast MRP Ycf1p.   Cka1p has been shown to be catalytically active as a homodimer and a heterodimer with the CK2 alpha' subunit Cka2.  Therefore this proposal will determine if Cka1p regulation  ofYcf1p function requires Cka2p.  In addition the Paumi lab will examine the role of the homologous human kinase CKalpha in regulating human MRP1 and MRP6 function.  The studies described within this proposal will provide useful insight into the role of kinases in the regulation of MRP function the role of the MRPs in "metabolic quality control" and have the potential to establish new and more effective treatments for MRP related diseases such as cystic fibrosis multidrug resistance in cancer and pseudoxanthoma elasticum.

project_terms:
ABCC1 gene;ATP-Binding Cassette Transporters;Arsenic;Cadmium;Casein Kinase 2alpha;Casein Kinase 2alpha';Cells;Computer Retrieval of Information on Scientific Projects Database;Cystic Fibrosis;Disease;Employee Strikes;Funding;Glutathione;Goals;Grant;Heavy Metals;Human;Institution;Lead;Malignant Neoplasms;Mercury;Metabolic;Multi-Drug Resistance;Multidrug Resistance-Associated Proteins;N-terminal;Pharmaceutical Preparations;Phosphotransferases;Play;Protein Kinase;Pseudoxanthoma Elasticum;Quality Control;Regulation;Research;Research Personnel;Resources;Role;S100A12 gene;Source;Toxic Environmental Substances;United States National Institutes of Health;Work;Yeasts;casein kinase II;effective therapy;in vivo;insight;interest;protein function


application_id: 8168249
project_number: 5P20RR020171-07
project_title: STRUCTURAL STUDIES OF NEUROPILIN SIGNALING
administering_ic: NCRR
award_notice_date: 2010-08-16
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2010-07-01
project_end_date: 2011-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8077
contact_pi_person_id: 9627039
contact_pi: VANDER KOOI, CRAIG
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Neuropilin is an essential bi-functional mammalian cell surface receptor functioning in both angiogenesis and axon guidance.  Neuropilin is of particular medical importance since in addition to its normal roles it also is required for VEGF dependent tumor angiogenesis facilitating neo-vascularization and growth of solid tumors.  During both normal and tumor-angiogenesis neuropilin binds members of the VEGF family of ligands and functions as a co-receptor for the VEGF-R receptor tyrosine kinases. During neural development neuropilin binds members of the semaphorin III family of ligands and functions as a co-receptor for members of the plexin family of receptors.  We seek to understand neuropilin ligand binding specificity and receptor activation. Additionally we seek to inform ongoing studies to define novel anti-angiogenesis targets.  Fundamentally our goal will be to answer the following questions: How does neuropilin activate and regulate VEGF dependent angiogenesis and semaphorin dependent axon guidance?

Structural studies of neuropilin ligand binding will allow definition of the physical basis for interaction between core neuropilin and ligand domains.  These studies will define common features of ligand binding as well as unique features that determine specificity between different protein homologues and isoforms.  Further studies will characterize the mechanism(s) by which ligand binding to neuropilin couples to activation of VEGF-R and plexin signaling receptors.  Structural studies will primarily be based on X-ray crystallography but will also employ a variety of other structural techniques including NMR EM and SAXS. The latter two techniques will be particularly employed to study large and conformationally labile protein complexes. In addition other biophysical and biochemical techniques will be employed to characterize protein-protein interactions and the effects of mutations in this system.

project_terms:
Binding (Molecular Function);Biochemical;Cell Surface Receptors;Computer Retrieval of Information on Scientific Projects Database;Couples;Family;Funding;Goals;Grant;Growth;Homologous Gene;Institution;Ligand Binding;Ligands;Mammalian Cell;Medical;Mutation;Neuropilins;Protein Isoforms;Proteins;Receptor Activation;Receptor Protein-Tyrosine Kinases;Receptor Signaling;Research;Research Personnel;Resources;Role;Signal Transduction;Solid Neoplasm;Source;Specificity;System;Techniques;Tumor Angiogenesis;United States National Institutes of Health;Vascular Endothelial Growth Factor Receptor;Vascular Endothelial Growth Factors;Vascularization;X-Ray Crystallography;angiogenesis;antiangiogenesis therapy;axon guidance;base;member;neurodevelopment;novel;plexin;protein complex;protein protein interaction;receptor;receptor function


application_id: 8168248
project_number: 5P20RR020171-07
project_title: ORGANIC SYNTHESIS CORE
administering_ic: NCRR
award_notice_date: 2010-08-16
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2010-07-01
project_end_date: 2011-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8076
contact_pi_person_id: 9175312
contact_pi: WATT, DAVID
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The organic synthesis core is designed to provide access to novel compounds not available through commercial sources. The well-trained technical staff as well as the core director will consult with investigators to understand the particular need and will design and synthesize appropriate molecules. The staff will undertake the synthesis and characterization of a novel probe for an enzymatic reaction for a biochemical process a photoactive analog of a drug a fluorescent derivative of a small-molecule probe a modified natural product that might covalently bind a receptor an unnatural peptide that would have better stability than its wild-type counterpart a polymer-bound a compound needed for a particular purification etc. The core is equipped with appropriateequipment to prepare and characterize organic compounds with molecular weights of 2 kDa or less and has access to appropriate chromatographic and analytical techniques including NMR and mass spectrometry that will be used to confirm structural assignments.

project_terms:
Binding (Molecular Function);Biochemical Process;Biochemical Reaction;Biological Factors;Computer Retrieval of Information on Scientific Projects Database;Consult;Funding;Grant;Institution;Mass Spectrum Analysis;Molecular Weight;Organic Synthesis;Peptides;Pharmaceutical Preparations;Polymers;Research;Research Personnel;Resources;Source;Techniques;Training;United States National Institutes of Health;analog;design;novel;receptor;small molecule


application_id: 8168247
project_number: 5P20RR020171-07
project_title: PROTEOMICS CORE
administering_ic: NCRR
award_notice_date: 2010-08-16
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2010-07-01
project_end_date: 2011-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8075
contact_pi_person_id: 7875249
contact_pi: ZHU, HAINING
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The proteomics core is designed to provide quantitative and qualitative protein profiling and identification analysis as well as post-translational modification and sequence analysis through a combination of 2D gel mass spectrometry and Edman sequencing analysis services. The core is equipped with Bio-Rad IPG and SDS-PAGE apparatus for 2D gel analysis a Typhoon phosphorimager/scanner system for detection and quantitation of fluorescent protein dyes (Cy-dyes) and stains (SYPRO-Ruby Pro-Q Diamond) used to analyze 1D and 2D gels a Ciphergen SELDI-TOF protein profiling system an ABI QSTAR II Q-TOF Mass Spectrometer with both MALDI and LC/ESI source capabilities Waters HPLC systems and multiple PCs for data acquisition and analysis including a site license for PDQuest software and a 5 station site license for Ciphergen software. Fully trained technical staff will assist investigators with the full range of proteomics analytical services. The staff will instruct investigators and their laboratory
staff (students post-doctoral fellows and technicians) in sample preparation 2D gel analysis and quantitation by fluorescent staining methods. Protein fragmentation mass peptide mapping and protein sequencing by both MS/MS mass spectrometry and chemical sequencing will be performed by Dr. Beach on samples provided by individual investigators. Preparation and analysis of samples with the Ciphergen system will be facilitated by automated robotic work stations. Data analysis will be performed by investigators and their colleagues through multiple distant work stations connected to the Ciphergen system via the web.

project_terms:
Amino Acid Sequence;Chemicals;Computer Retrieval of Information on Scientific Projects Database;Computer software;Data Analyses;Detection;Diamond;Distant;Dyes;Funding;Gel;Grant;High Pressure Liquid Chromatography;Individual;Institution;Internet;Laboratories;Licensing;Mass Spectrum Analysis;Peptide Mapping;Peptide Sequence Determination;Post-Translational Protein Processing;Postdoctoral Fellow;Preparation;Pro-Q aerosol foam;Proteins;Proteomics;Research;Research Personnel;Resources;Robotics;Sampling;Sequence Analysis;Services;Site;Source;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Staining method;Stains;Students;System;Training;United States National Institutes of Health;Water;Work;aerobic respiration control protein;data acquisition;design;mass spectrometer;protein profiling


application_id: 8168246
project_number: 5P20RR020171-07
project_title: IMAGING CORE
administering_ic: NCRR
award_notice_date: 2010-08-16
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2010-07-01
project_end_date: 2011-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8074
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The imaging core facility houses three epifluorescence microscopes (Nikon Eclipse 600 Zeiss Axiovert 100 and 200M) with digital image capture capability (Spot CE and Orca ER digital cameras with Metaview and Open Lab software). The Eclipse 600 will allow the high resolution imaging of cells and sub-cellular compartments. This instrument can be used for detailed analysis of various cellular structures. The core also contains two inverted epifluorescence microscopes. The Axiovert 200M is equipped with stage controllers to allow long term analysis of live cells. The Axiovert 100 can be used for analysis of cells in tissue culture dishes or fixed samples on slides. The flexibility of the instruments in the facility will enable the core users a wide range of analytical techniques with which to pursue their individual projects. The facility contains two computers for image processing. The computers have complete internet access and network access to color printers and to data storage. The core director Dr. Whiteheart will be available to offer advice on sample preparation on data analysis and on imaging procedures. In addition Dr. Whiteheart will also advise in the preparation of figures and selection of images for publication.

project_terms:
Cells;Cellular Structures;Color;Computer Retrieval of Information on Scientific Projects Database;Computer software;Computers;Core Facility;Data Analyses;Data Storage and Retrieval;Funding;Grant;Housing;Image;Imaging Techniques;Individual;Institution;Internet;Life;Microscope;Preparation;Publications;Research;Research Personnel;Resolution;Resources;Sampling;Slide;Source;Spottings;Staging;Techniques;United States National Institutes of Health;cellular imaging;digital;digital imaging;flexibility;image processing;instrument;tissue culture


application_id: 8168245
project_number: 5P20RR020171-07
project_title: PROTEIN ANALYTICAL CORE
administering_ic: NCRR
award_notice_date: 2010-08-16
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2010-07-01
project_end_date: 2011-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8073
contact_pi_person_id: 7875214
contact_pi: RODGERS, DAVID W
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The Protein Analytical Core is designed to facilitate recombinant protein production and macromolecular characterization by the COBRE investigators key components of their proposed projects. It makes available well-maintained equipment and instrumentation that would not normally be found within individual laboratories particularly those of junior investigators. The approach is to provide training and priority access to members of the investigators'' teams rather than maintaining the personnel required to accomplish the tasks on a service basis. In this way costs are kept to a minimum. The core provides instrumentation for characterizing macromolecules including dynamic light scattering spectropolarimetry fluorescence isothermal titration calorimetry high performance liquid chromatography X-ray crystallography TIRF microscopy for single molecule studies  and analytical ultracentrifugation. In addition fermenters bioreactors tissue culture facilities cell cracking equipment and chromatography instrumentation are available for production and purification of recombinant proteins. A staff member maintains the core equipment provides training to new users and oversees scheduling.

project_terms:
Bioreactors;Calorimetry;Cells;Centers of Research Excellence;Chromatography;Computer Retrieval of Information on Scientific Projects Database;Equipment;Fluorescence;Funding;Grant;High Pressure Liquid Chromatography;Human Resources;Individual;Institution;Laboratories;Production;Proteins;Recombinant Proteins;Research;Research Personnel;Resources;Schedule;Services;Source;Titrations;Total Internal Reflection Fluorescent;Training;United States National Institutes of Health;X-Ray Crystallography;analytical ultracentrifugation;base;cost;design;instrumentation;light scattering;macromolecule;member;single molecule;tissue culture


application_id: 8168244
project_number: 5P20RR020171-07
project_title: ADMINISTRATIVE CORE
administering_ic: NCRR
award_notice_date: 2010-08-16
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2010-07-01
project_end_date: 2011-06-30
study_section: ZRR1-RI-B(01)
subproject_number: 8072
contact_pi_person_id: 7875201
contact_pi: LOUIS HERSH, LOUIS HERSH LOUIS HERSH
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:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The Administrative Core is designed to facilitate and coordinate the research and training objectives of the Molecular Basis of Human Disease (MBHD)-COBRE. This core will provide the organizational and administrative structure needed to insure that the faculty members to be mentored have access to an environment that will facilitate their success in obtaining independent ROl-type research funding. This core will:
1) Provide administrative leadership and coordination of the overall research effort.
2) Provide support for grants accounting preparation of progress reports and grant writing.
3) Insure that the trainees have access to state-of-the-art training
4) Provide a mentoring environment that will enhance the ability of the junior faculty to obtain grant funding
5) Facilitate the use of modern research core facilities and provide funds to enhance and utilize the services of these research cores.
6) Fund pilot projects to expand research efforts in studying human disease at the molecular level.
7) Facilitate the hiring of new faculty to increase the critical mass of investigators conducting research on the molecular basis of human disease.
8) Oversee a website dedicated to the program.

project_terms:
Accounting;Arts;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Core Facility;Environment;Faculty;Funding;Grant;Health Services Research;Institution;Leadership;Mentors;Molecular;Pilot Projects;Preparation;Progress Reports;Research;Research Personnel;Research Training;Resources;Source;Structure;Training;United States National Institutes of Health;Writing;base;design;human disease;member;programs;success;web site


application_id: 8168214
project_number: 5P20RR024489-03
project_title: RESOLUTION OF DIABETIC VASCULAR INFLAMMATION: ROLE OF LIPID MEDIATORS PROJ5
administering_ic: NCRR
award_notice_date: 2010-07-16
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 024489
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 8043
contact_pi_person_id: 8656605
contact_pi: SPITE, MATTHEW R
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: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Project 5: Resolution of diabetic vascular inflammation: Role of lipid mediators
The overall aim of this project is to develop a better understanding of the mechanisms that support and sustain chronic low-grade vascular inflammation in diabetes and whether the resolution phase of inflammation could be stimulated to prevent vascular dysfunction in diabetes.  Our hypothesis is that chronic vascular inflammation during diabetes could be attributed in part to a loss in endogenous counter-regulatory lipid mediator pathways that promote the resolution of inflammation.  It follows that restoration of these deficits with synthetic pro-resolving lipid mediators such as the lipoxins and resolvins could facilitate the resolution of vascular inflammation associated with long-term diabetes. The following specific aims were designed to test this novel hypothesis:

1. Examine diabetic changes in the resolution of acute inflammation.   For this we will measure the intensity and duration of leukocyte infiltration in a murine model of microbial peritonitis in which we have defined specific resolution indices. The time course of inflammation will be studied in non-diabetic mice and in murine models of both type 1 and type 2 diabetes. Type 1 diabetes will be established by streptozotocin injections and for studying type 2 diabetes db/db mice will be used.  Comparisons between these models will help in assessing the contribution of hyperglycemia and hyperinsulinemia to diabetic changes in the resolution of inflammation and in understanding the mechanism by which diabetes affects the resolution of inflammation;

2. Assess the contribution of altered pro-resolution lipid mediator biosynthesis to diabetic changes in resolution.   To understand how diabetes affects resolution we will identify changes in lipid mediator biosynthesis during peritonitis using targeted liquid chromatography/mass spectrometry.  We will determine which lipid mediator pathways (pro-inflammatory vs. pro-resolution) are affected during the time course of peritonitis in models of both type 1 and type 2 diabetes.  Moreover to elucidate the mechanisms by which diabetes affects pro-resolution lipid mediator biosynthesis we will measure their biosynthetic intermediates and determine how they are affected by diabetes; and

3. Determine whether treatment with pro-resolution lipid mediators restores diabetic changes in resolution. We will determine how treatment with exogenous lipoxins and resolvins affects the resolution of peritonitis in non-diabetic and diabetic mice. To delineate the mechanisms by which these mediators affect inflammation we will examine their effects on leukocyte:endothelial interactions by intravital microscopy. To elcuidate the cellular mechanisms by which pro-resolution lipid mediators counter-act diabetic vascular inflammation we will examine how lipoxins and resolvins affect high glucose and high fatty acid-induced signaling pathways in microvascular endothelial cells.

project_terms:
Acute;Affect;Anabolism;Blood Vessels;Chronic;Computer Retrieval of Information on Scientific Projects Database;Diabetes Mellitus;Diabetic mouse;Endothelial Cells;Fatty Acids;Functional disorder;Funding;Glucose;Grant;Hyperglycemia;Hyperinsulinism;Infiltration;Inflammation;Inflammatory;Injection of therapeutic agent;Institution;Insulin-Dependent Diabetes Mellitus;Leukocytes;Lipoxins;Measures;Mediator of activation protein;Modeling;Mus;Non-Insulin-Dependent Diabetes Mellitus;Pathway interactions;Peritonitis;Phase;Research;Research Design;Research Personnel;Resolution;Resources;Role;Signal Pathway;Source;Streptozocin;Testing;Time;United States National Institutes of Health;db/db mouse;design;diabetic;indexing;intravital microscopy;lipid mediator;liquid chromatography mass spectrometry;microbial;non-diabetic;novel;prevent;restoration;type I and type II diabetes;vascular inflammation


application_id: 8168213
project_number: 5P20RR024489-03
project_title: MESENCHYMAL STEM CELL THERAPY FOR INFARCT PROJ 3 2009
administering_ic: NCRR
award_notice_date: 2010-07-16
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 024489
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 8042
contact_pi_person_id: 10217681
contact_pi: CAI, CHUANXI
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: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Nearly two-thirds of diabetics suffer from overt cardiovascular conditions including coronary artery disease myocardial infarction (MI) and cardiomyopathy. Despite the known systemic nature of diabetes therapy for MI and ischemic cardiomyopathy are often not specifically tailored for diabetics and the feasibility and efficacy of stem cell therapy for infarct repair in diabetic patients remains unclear. Although mesenchymal stem cells (MSCs) have been shown to induce infarct repair the results have been variable and mechanisms remain controversial. The variability in MSC-mediated cardiac repair might have stemmed from the fundamentally heterogeneous nature of unfractionated 'MSCs'. We hypothesize that the use of a homogenous antigenically-defined MSC subpopulation with greater endothelial and cardiomyogenic differentiation potential and greater ability to secrete cardioprotective factors will result in superior cardiac repair in diabetics. These studies will identify the best MSC to use for infarct repair specifically in diabetics and the results would have enormous therapeutic implications for diabetic patients with ischemic heart disease and post-MI heart failure.

project_terms:
Cardiac;Cardiomyopathies;Cardiovascular system;Computer Retrieval of Information on Scientific Projects Database;Coronary Arteriosclerosis;Funding;Grant;Heart failure;Infarction;Institution;Mediating;Mesenchymal Stem Cells;Myocardial Infarction;Myocardial Ischemia;Nature;Research;Research Personnel;Resources;Source;Therapeutic;United States National Institutes of Health;diabetes mellitus therapy;diabetic;diabetic patient;repaired;stem;stem cell therapy


application_id: 8168212
project_number: 5P20RR024489-03
project_title: RENOVATIONS
administering_ic: NCRR
award_notice_date: 2010-07-16
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 024489
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 8041
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Renovations are to upgrade and improve existing space to accommodate the Core facilities for the Center for Excellence in Diabetes and Obesity Research.

project_terms:
Computer Retrieval of Information on Scientific Projects Database;Core Facility;Diabetes Mellitus;Funding;Grant;Institution;Obesity;Research;Research Personnel;Resources;Source;United States National Institutes of Health;improved


application_id: 8168211
project_number: 5P20RR024489-03
project_title: STEM CELLS AND DIABETIC CARDIOMYOPATHY PROJ 2 2009
administering_ic: NCRR
award_notice_date: 2010-07-16
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 024489
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 8040
contact_pi_person_id: 8492518
contact_pi: HE, JIA-QIANG
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: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.PROJECT #2: STEM CELLS AND DIABETIC CARDIOMYOPATHY

The central hypothesis of this project is that diabetes produces negative effects on the growth reserve of cardiac stem cells (CSC) so that the enhanced cell's death cannot be counteracted by repopulating cells that preserve the architecture and function of the myocardium. To test this hypothesis the murine models of type 1 and 2 diabetes (T1D T2D) will be used in the following specific aims (SA):

1. SA1 is to examine whether CSC from normal mice will exhibit differences of stemness and pluripotency compared with CSC from diabetic mice. The whole heart of T1D and T2D mice will be used to isolate and identify CSC with c-kit positive sca1 positive MDR1 positive also Lineage negative antigens and/or frozen tissue sections from those tissues will be stained for the markers. The total number of CSC distribution in cardiac tissue stem cell proliferation and in vitro cardiac lineage differentiation will be compared between diabetic and non-diabetic groups. Flow cytometry immunocytochemistry immunohistochemistry and echocardiography techniques will be used in these experiments.  
       
2. SA2 is to investigate how diabetes and hyperglycemia impairs the stemness and cardiac lineage differentiation of CSC isolated from diabetic and non-diabetic hearts.  Gene and protein expression patterns in c-kit sca1 MDR1 AMPK P53 PI3K/Akt Nxk2.5 Glut1&4 of CSC from diabetic hearts will be compared with those from non-diabetic CSC.  Cardiac lineage markers will be checked before and after in vitro differentiation. To mimic the in vivo diabetic condition normal CSC of control hearts will also undergo in vitro hyperglycemia treatments. The underlying mechanism related with the genes and protein change under in vivo and in vitro conditions will be explored accordingly. Gene chip protein array Western blot RT-PCR technique and cell apoptosis/viability/cytotoxicity assays will be used in the analyses. 

3. SA3 is to determine whether transplantation of CSC from normal mice will result in greater improvement in cardiac structure and function in infarcted diabetic mouse heart compared with CSC isolated from diabetic mouse heart. The normal mice and diabetic mice will be used to evaluate cardiac function and structural improvements with transplanted CSC. Echocardiography histological and pathological techniques will be used in the studies.

project_terms:
ABCB1 gene;Antigens;Apoptosis;Architecture;Biological Assay;Cardiac;Cell Death;Cell Proliferation;Cells;Computer Retrieval of Information on Scientific Projects Database;Diabetes Mellitus;Diabetic mouse;Echocardiography;Exhibits;Flow Cytometry;Freezing;Funding;Gene Chips;Gene Proteins;Grant;Growth;Heart;Heart Transplantation;Hyperglycemia;Immunohistochemistry;In Vitro;Infarction;Institution;Insulin-Dependent Diabetes Mellitus;Modeling;Mus;Myocardium;Non-Insulin-Dependent Diabetes Mellitus;Pattern;Protein Array;Proto-Oncogene Protein c-kit;Research;Research Personnel;Resources;Reverse Transcriptase Polymerase Chain Reaction;Source;Staining method;Stains;Stem cells;Structure;TP53 gene;Techniques;Testing;Tissues;Transplantation;United States National Institutes of Health;Western Blotting;cytotoxicity;diabetic;diabetic cardiomyopathy;immunocytochemistry;in vivo;non-diabetic;pluripotency;protein expression;research study;stemness


application_id: 8168210
project_number: 5P20RR024489-03
project_title: CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH: PROJECT 4
administering_ic: NCRR
award_notice_date: 2010-07-16
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 024489
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 8039
contact_pi_person_id: 8759282
contact_pi: BARSKI, OLEG A
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The aims of this proposal have not changed. They are designed to address the hypothesis that under hyperglycemic conditions increased metabolism of glucose by aldose reductase (AR) exacerbates hypercholesterolemia-induced endoplasmic reticulum (ER) stress and unfolded protein response (UPR) and thereby promotes macrophage activation and atherogenesis. It has been established that accumulation of excessive cholesterol in macrophage-derived foam cells leads to ER stress and activates UPR. This pathway has recently emerged as a unifying theme in atherosclerosis and diabetes research and UPR has been suggested to be the major cause of insulin resistance. Despite these advances the mechanisms leading to the activation of ER stress and specific consequences of its activation for macrophage proinflammatory response and foam cell formation is not known. Specifically we proposed: 

1.Examine whether high glucose increases foam cell formation cytokine production and apoptosis in cholesterol-loaded macrophages. 

2.Determine whether high glucose modulates cholesterol-induced macrophage activation by triggering UPR.  

3.Delineate the contribution of UPR activation to cytokine production and atherosclerotic lesion formation in diabetic mice.

project_terms:
Address;Aldehyde Reductase;Apoptosis;Arterial Fatty Streak;Atherosclerosis;Cholesterol;Computer Retrieval of Information on Scientific Projects Database;Diabetes Mellitus;Diabetic mouse;Foam Cells;Funding;Glucose;Grant;Hyperglycemia;Institution;Insulin Resistance;Macrophage Activation;Obesity;Pathway interactions;Production;Proteins;Research;Research Personnel;Research Project Grants;Resources;Source;United States National Institutes of Health;atherogenesis;cytokine;design;endoplasmic reticulum stress;glucose metabolism;hypercholesterolemia;macrophage;response


application_id: 8168209
project_number: 5P20RR024489-03
project_title: CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH: PROJECT 1
administering_ic: NCRR
award_notice_date: 2010-07-16
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 024489
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 8038
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
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: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Project 1:  Endothelial progenitor cell (EPC) mobilization defects in diabetes

Diabetes is associated with a wide spectrum of cardiovascular diseases that are best characterized by a dysfunctional endothelium an impaired capacity for its repair. The central hypothesis of this project is that these vascular abnormalities result from a loss of circulating EPCs due to defects in their mobilization from the bone marrow. To test this hypothesis we will:      

1. Define diabetes-induced changes in EPC populations: Using murine models of Type I and/or Type II diabetes we will quantify levels of antigenically-defined EPC populations in peripheral blood spleen and bone marrow; determine if these effects are specific to early/late or non-monocytic/monocytic EPCs; and determine when these effects become prominent during disease progression. To establish specificity we will determine whether the effects of diabetes are unique to EPCs or whether mesenchymal (MSC) and hematopoietic (HSC) stem cells are also affected; and  
2. Delineate the mechanisms by which diabetes limits EPC mobilization: To assess the 
involvement of integrin-mediated adhesion we will examine the properties of alpha4 beta1 and EPC
levels in mice expressing alpha4 variants. To determine whether MMPs are deficient we will examine their levels in the bone marrow of diabetic mice and in the media of cultured cells. To establish a role for the polyol pathway we will characterize EPCs diacylglycerols (DAGs) reactive oxygen species (ROS) and PKC activity levels in diabetic wild type and aldose reductase (AR) knockout mice; and 

3. Evaluate the reparative efficacy of EPC mobilizing strategies: Based upon Aim 2 studies
 we will examine the efficacy of interventions in promoting neo-vascularization and wound
 repair in diabetes.

project_terms:
12-diacylglycerol;Adhesions;Affect;Aldehyde Reductase;Blood Vessels;Bone Marrow;Cardiovascular Diseases;Computer Retrieval of Information on Scientific Projects Database;Cultured Cells;Defect;Diabetes Mellitus;Diabetic mouse;Diglycerides;Disease Progression;Endothelium;Funding;Grant;Hematopoietic;Institution;Integrins;Knockout Mice;Matrix Metalloproteinases;Mediating;Mesenchymal;Modeling;Mus;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathway interactions;Population;Property;Reactive Oxygen Species;Research;Research Personnel;Research Project Grants;Resources;Role;Source;Specificity;Spleen;Stem cells;Testing;Treatment Efficacy;United States National Institutes of Health;Variant;Vascularization;Wound Healing;base;diabetic;impaired capacity;peripheral blood;polyol;repaired


application_id: 8168208
project_number: 5P20RR024489-03
project_title: CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH: CORE E
administering_ic: NCRR
award_notice_date: 2010-07-16
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 024489
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 8037
contact_pi_person_id: 1914941
contact_pi: PRABHU, SUMANTH D
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: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The role of the Cardiovascular Imaging and Function Core is to support the COBRE Projects and related investigations examining the effects of diabetes and obesity on cardiovascular performance. The services provided include echocardiographic imaging tail-cuff measurement of blood pressure and heart rate and left ventricular (LV) pressure-volume measurement. High-volume echocardiography is currently performed with Philips (HP) Sonos 5500 machine coupled to a ComPACS Computer WorkStation complete with Echo Analysis Software. All measurements and computed data are automatically stored in ComPACS MSDE or SQL database in DICOM SR format linked to Crystal Reports for generating customized output documents. Non-invasive measurement of blood pressure and heart rate in conscious mice is performed with a CODA-6 tail-cuff system (Kent Scientific). Aortic and LV catheterization is performed using a Millar pressure volume conductance system (MPCU-200) for mice. Hemodynamic data are acquired using Chart (ADInstruments) and analyzed using PVAN software (Millar) to generate indexes of contraction and relaxation. The Core not only provides procedural and technological support for the COBRE Projects but also extends the capabilities of new investigators as they embark on ongoing and future research projects requiring cardiovascular imaging. Thus the Core advances the career development of COBRE-supported investigators.

project_terms:
Blood Pressure;Cardiovascular system;Catheterization;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Computer Workstations;Computer software;Conscious;Coupled;Data;Databases;Diabetes Mellitus;Echocardiography;Funding;Future;Grant;Heart Rate;Image;Institution;Investigation;Left;Link;Measurement;Mus;Obesity;Output;Performance;Physiologic intraventricular pressure;Relaxation;Reporting;Research;Research Personnel;Research Project Grants;Resources;Role;Services;Source;System;Tail;United States National Institutes of Health;Ventricular;cardiovascular imaging;career development;hemodynamics;indexing;pressure


application_id: 8168207
project_number: 5P20RR024489-03
project_title: CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH: CORE D
administering_ic: NCRR
award_notice_date: 2010-07-16
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 024489
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 8036
contact_pi_person_id: 10654563
contact_pi: SRIVASATAVA, 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
budget_start_date: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Major functions of the Animal Core Facility (Core D) is to house breed genotype and provide mouse models of diabetes and obesity.

project_terms:
Animals;Breeding;Computer Retrieval of Information on Scientific Projects Database;Core Facility;Diabetes Mellitus;Diabetic mouse;Funding;Genotype;Grant;Housing;Institution;Obesity;Research;Research Personnel;Resources;Source;United States National Institutes of Health


application_id: 8168206
project_number: 5P20RR024489-03
project_title: CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH: CORE C
administering_ic: NCRR
award_notice_date: 2010-07-16
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 024489
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 8035
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The Cardiovascular Pathology Core serves as a central resource for generating and evaluating data from in vivo mouse models of cardiovascular disease particularly those that are complicated by diabetes.  This Core performs surgical occlusion and reperfusion in the intact mouse.  Such subjects can be evaluated over time in Core D via echocardiography and tissue can be harvested and evaluated by virtually all of the other Cores and individual Projects.  This Core has more than a decade of experience in the in vivo mouse infarction model.  Such experience will prove invaluable for the new investigators in each of the COBRE's Projects.  In addition to the in vivo models of cardiovascular disease this Core serves the basic histopathology needs of the individual projects.

project_terms:
Cardiovascular Diseases;Cardiovascular Pathology;Computer Retrieval of Information on Scientific Projects Database;Data;Diabetes Mellitus;Echocardiography;Funding;Grant;Harvest;Histopathology;Individual;Infarction;Institution;Modeling;Mus;Obesity;Operative Surgical Procedures;Reperfusion Therapy;Research;Research Personnel;Resources;Source;Time;Tissues;United States National Institutes of Health;experience;in vivo;in vivo Model;mouse model


application_id: 8168205
project_number: 5P20RR024489-03
project_title: CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH: CORE B
administering_ic: NCRR
award_notice_date: 2010-07-16
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 024489
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 8034
contact_pi_person_id: 7033203
contact_pi: ROKOSH, GREGG
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: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The Imaging and Flow Cytometry Core Laboratory consists of two Units: the Confocal Microscopy Unit (responsible for all confocal image acquisition and processing) and the Flow Cytometry Unit (responsible for all flow cytometric cell sorting and analysis). The core laboratory houses a confocal microscope with all necessary accessories and a cell sorter with all necessary accessories. The Imaging and Flow Cytometry Core maintains active collaborations and provides instruction to COBRE-affiliated faculty and related personnel.

project_terms:
Cell Separation;Cells;Collaborations;Computer Retrieval of Information on Scientific Projects Database;Confocal Microscopy;Diabetes Mellitus;Faculty;Flow Cytometry;Funding;Grant;Housing;Human Resources;Image;Institution;Instruction;Laboratories;Microscope;Obesity;Process;Research;Research Personnel;Resources;Source;United States National Institutes of Health


application_id: 8168204
project_number: 5P20RR024489-03
project_title: CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH
administering_ic: NCRR
award_notice_date: 2010-07-16
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 024489
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 8033
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The Administrative Core (Core A) provides scientific mentoring budgetary administrative logisitic and statistical oversight to all aspects of the Diabetes and Obesity Center of Biomedical Research Excellence (DOC-COBRE)The Core Leaders - Dr. Aruni Bhatnagar and Dr. Roberto Bolli Director and Co-Directors of the Center with assistance from Ms. Tammy Green the COBRE Administrator are resposnible for all administrative activities for the COBRE. This funding has assisted in providing the research data necessary for multiple Center members to receive fundable scores on their recent NIH applications indicated in detail in the Summary update.

project_terms:
Administrator;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Data;Diabetes Mellitus;Funding;Grant;Institution;Mentors;Obesity;Research;Research Personnel;Resources;Source;United States National Institutes of Health;Update;member


application_id: 8167784
project_number: 5P20RR018733-08
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE E: BIOPHYSICAL FACILITY
administering_ic: NCRR
award_notice_date: 2010-08-24
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 7619
contact_pi_person_id: 1863983
contact_pi: CHAIRES, JONATHAN B.
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: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The Biophysics Core Facility is located on the fourth floor of the Brown Cancer Center in a newly renovated 504 square-foot laboratory.  This state-of-the-art facility provides the capability to perform calorimetry electronic spectroscopy rapid kinetics and hydrodynamics determinations.   Expertise is provided by the director Dr. J. Brad Chaires and by Dr. Nichola Garbett the facility manager both of whom have considerable experience in this area.  In addition to the instrumentation this facility provides training in biophysical methods and data analysis and is integrated with the molecular modeling and structural biology cores at the Brown Cancer Center to enhance drug discovery efforts.  The Biophysics Core Facility provides a unique resource to all MT-COBRE investigators.

project_terms:
Area;Arts;Biophysics;Calorimetry;Cancer Center;Computer Retrieval of Information on Scientific Projects Database;Core Facility;Data Analyses;Electronics;Floor;Funding;Grant;Institution;Kinetics;Laboratories;Methods;Molecular Models;Research;Research Personnel;Resources;Source;Spectrum Analysis;Training;United States National Institutes of Health;drug discovery;experience;instrumentation;molecular modeling;square foot;structural biology


application_id: 8167783
project_number: 5P20RR018733-08
project_title: COBRE PROJ 10: VSEL AND BRAIN REGENERATION IN A MURINE MODEL OF SLEEP APNEA
administering_ic: NCRR
award_notice_date: 2010-08-24
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 7618
contact_pi_person_id: 8945910
contact_pi: KUCIA, MAGDALENA J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Magdalena Kucia PI

    Stem cells provide a novel potential source to replace dead neurons and supporting tissue in a brain damaged by chronic ischemia as seen for example in sleep apnea (SA). Some investigations of animals and short-term human bone marrow (BM) transplants have demonstrated that bone marrow cells provide a source of neurons and can repair brain damage (e.g. during stroke). The mechanisms of this functional improvement are currently the focus of intense research creating a need for new study methodologies to assess the effectiveness of such strategies. Elucidation of stem cell-related mechanisms of regeneration is crucial to developing effective stem cell-based therapies that could extend the lifespan of patients with diseases that are treatable by tissue regeneration. One such disorder is chronic brain damage due to hypoxia resulting from sleep apnea. 
     Based on preliminary data a novel hypothesis is presented that the pool of CXCR4+ epiblast-derived VSELs is deposited in the BM during early development.  These cells subsequently serve as a reserve mobile pool of stem cells that may be mobilized into peripheral blood and play an important role in brain regeneration - where they are chemoattracted by an SDF-1 gradient.  Furthermore it is hypothesized that an age-related decrease in the marrow pool of these circulating VSELs may contribute to aging of the central nervous system (CNS) resulting in less effective repair.  To investigate these issues four specific aims were proposed.
     Specific Aim 1. Neural differentiation of bone marrow-derived VSELs. We have presented evidence that BM contains a population of VSELs and that these epiblast-derived cells are deposited there early in development during rapid body growth/expansion. We will first optimize their isolation from bone marrow and neural differentiation (ability to grow neurospheres). Next we will evaluate the age-related presence of VSELs in bone marrow tissue. Once it is determined whether VSELs circulate under normal steady-state conditions in the peripheral blood (PB) at very low but detectable levels we will study their mobilization in a murine model of sleep apnea.
    Specific Aim 2. Optimize mobilization of VSELs into peripheral blood. Since mobilized peripheral blood (mPB) may be a source of VSELs for potential neural regeneration we will optimize their mobilization into PB.  We will test the effect of various mobilizing agents involving selected growth factors (G-CSF Flt3-ligand VEGF HGF) and small-molecule inhibitors (CXCR4-antagonist T140 C3aR antagonist) on the efficacy of their mobilization.  We also will investigate mobilization of these cells in response to hypoxia damage and the role of the SDF-1CXCR4 axis in this process. It is hypothesized that CXCR4+ VSELs are mobilized and subsequently chemo-attracted into a damaged brain in an SDF-1-dependent manner. 
      Specific Aim 3. Develop an approach to expand VSELs.  Since the number of VSELs that can be isolated from the BM and mPB of older individuals is relatively low an efficient ex vivo expansion system may be needed to obtain a sufficient number of these cells for neural regeneration.  It also is possible that ex vivo culture-derived VSELs will better engraft and regenerate brain cells.  We will employ selected strategies to expand these cells ex vivo involving cocktails of selected growth factors BM stroma support and our new strategy based on the expansion of stem cells in the presence of membrane-derived microvesicles isolated from embryonic stem cells (ESMV). We observed that purified VSEL cells are able to form spheres in co-cultures with C2C12 myoblastic cell line feeder layers that resemble embryoid bodies.  Cells from these spheres may again (up to 5-7 passages) grow new secondary spheres or if plated into cultures promoting tissue differentiation expand into cells from all three germ-cell layers.  We will employ this system to expand neural cells from VSEL-derived spheres.
     Specific Aim 4. Determine the efficacy of VSELs in brain regeneration in vivo in a murine model of sleep apnea (SA).  The contribution of VSELs to functional regeneration of damaged tissues will be tested in an in vivo mouse model of SA. We will compare the regeneration potential of syngeneic VSELs isolated from enhanced green immunofluorescence protein (EGFP+) transgenic mice to rescue brain cells damaged by hypoxia and the role of the SDF-1CXCR4 axis in this process.  We will employ freshly isolated VSELs from BM or mPB as well as VSEL expanded in ex vivo cultures.  As a readout of brain regeneration we will use selected behavioral tests.

project_terms:
Aging;Animals;Bone Marrow;Bone Marrow Cells;Bone Marrow Transplantation;Brain;Brain Injuries;CXCR4 gene;Cell Count;Cell Line;Cell Therapy;Cells;Chronic Brain Damage;Coculture Techniques;Computer Retrieval of Information on Scientific Projects Database;Data;Deposition;Development;Disease;Effectiveness;Epiblast;Funding;Germ Cells;Grant;Growth;Growth Factor;Human;Hypoxia;Immunofluorescence Immunologic;Individual;Institution;Investigation;Ischemia;Ligands;Longevity;Marrow;Membrane;Methodology;Modeling;Mus;Natural regeneration;Nerve Regeneration;Neuraxis;Neurons;Patients;Play;Population;Process;Research;Research Personnel;Resources;Role;Sleep Apnea Syndromes;Source;Stem cells;Stromal Cell-Derived Factor 1;System;T140 peptide;Testing;Tissue Differentiation;Tissues;Transgenic Mice;United States National Institutes of Health;Vascular Endothelial Growth Factors;age related;base;behavior test;brain cell;cell injury;embryonic stem cell;enhanced green fluorescent protein;functional improvement;in vivo;in vivo regeneration;inhibitor/antagonist;mouse model;novel;peripheral blood;relating to nervous system;repaired;response;small molecule;stroke;tissue regeneration


application_id: 8167782
project_number: 5P20RR018733-08
project_title: COBRE PROJ 9: STRUCTURE-ACTIVITY ANALYSIS OF TISSUE-SPECIFIC CARCINOGENS
administering_ic: NCRR
award_notice_date: 2010-08-24
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 7617
contact_pi_person_id: 6088353
contact_pi: CUNNINGHAM, ALBERT R
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: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Albert Cunningham PI
This project will use structure-activity relationship (SAR) modeling to define groups of tissue-specific carcinogens followed by comparative toxicogenomics and proteome analyses to identify the molecular targets they interact with or influence.

This subproject has three specific aims:
1. Model Development:  Update existing SAR models for rodent carcinogenicity that will serve as "control" models and a set of "experimental" SAR models based on target tissue-specific chemical carcinogenesis. The control models will be based on the traditional SAR approach of contrasting carcinogens to noncarcinogens and the experimental models will be based on a new approach of contrasting chemical carcinogens from one site to those of all other sites. In essence the control models will handle the question of "What makes a chemical a carcinogen?" and the experimental models will tackle the problem of "What makes a carcinogen target a specific tissue?" This aim will use the Core C facility (Molecular Modeling) to carry out this approach.
2. Toxicophore Identification:  Based on information developed in Aim 1 we will identify toxicophore-defined sets of compounds (i.e. with similar structure and biological activity) associated with tissue-specific carcinogenesis. Then we will refine toxicophores from these models with ligand-based 3D SAR methods and develop small libraries of suitable compounds for in vitro testing. This aim will use Core C (Molecular Modeling).
3. Genome/Proteome Target Identification:  Using the compounds from the toxicophore libraries developed in Aim 2 as chemical probes we will assay site-matched cell lines in order to identify the molecular targets with which they interact. Comparative toxicogenomics and proteomics will be used to identify the specific molecular targets associated with tissue-specific carcinogenicity. This aim will use Cores B (Microarray facility).

project_terms:
Biological;Biological Assay;Carcinogens;Cell Line;Chemicals;Computer Retrieval of Information on Scientific Projects Database;Experimental Models;Funding;Genome;Grant;Institution;Libraries;Ligands;Methods;Modeling;Molecular Models;Molecular Target;Proteome;Proteomics;Research;Research Personnel;Resources;Rodent Model;Site;Source;Structure;Structure-Activity Relationship;Tissues;Toxicogenomics;United States National Institutes of Health;Update;base;carcinogenesis;carcinogenicity;chemical carcinogen;chemical carcinogenesis;comparative;in vitro testing;model development;molecular modeling;novel strategies;three dimensional structure


application_id: 8167781
project_number: 5P20RR018733-08
project_title: COBRE PROJ 8: ROLES OF IKK ?LPHA IN SKIN DEVELOPMENT AND DYSPLASIA
administering_ic: NCRR
award_notice_date: 2010-08-24
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 7616
contact_pi_person_id: 8891723
contact_pi: LI, QIUTANG
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: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Qiutang Li PI

      The long-term goal of this project is to elucidate the cellular and molecular mechanism by which IKKalpha exerts its effects on epidermal homeostasis. IKKalpha is a subunit of IKK complexes in the NF-kappa B signaling pathway. IKKalpha knockout mice die at birth from the skin defects associated with increased proliferation and impaired terminal differentiation in keratinocytes.  The function of IKKalpha in keratinocytes is independent from its kinase activity and NF-kappa B signaling pathway.  The mechanism by which the IKKalpha regulates keratinocyte proliferation and differentiation remains unclear.  In the present studies we will test the hypothesis that IKKalpha regulates keratinocyte cell cycle and functions as a tumor suppressor gene in skin. 
     Specifically the following questions will be addressed:  (1) What are the roles of the IKKalpha in regulation of the keratinocyte cell cycle and cell cycle checkpoint?  (2) What are the IKKalpha-interacting proteins in keratinocyte?  (3) How do those interacting proteins participate in the IKKalpha signaling in the keratinocytes?  (4) Does IKKalpha function as a tumor suppressor in skin? 
     Cell cycle analysis and functional studies will be performed in the primary keratinocytes isolated from either wild-type or the IKKalpha deficient embryos at embryonic day 18.5 using a combination of genetics cytological and biochemical approaches.  The data that have been generated from IKKalpha immunoprecipitation and mass spectrometry will be further validated and characterized to understand the IKKalpha function at a molecular level.  We will examine skin tumor susceptibility and metastatic potential in IKKalpha+/- mice exposed to mutagenic carcinogen and check the loss of heterozygosity frequency at the IKKalpha locus in IKKalpha+/- mouse tumors.  The knowledge will be important for elucidating clinically relevant problems such as skin cancers.

project_terms:
Address;Biochemical;Birth;Carcinogens;Cell Cycle;Cell Cycle Checkpoint;Complex;Computer Retrieval of Information on Scientific Projects Database;Data;Defect;Development;Dysplasia;Embryo;Frequencies (time pattern);Funding;Genetic;Goals;Grant;Homeostasis;Immunoprecipitation;Institution;Knockout Mice;Knowledge;Loss of Heterozygosity;Mass Spectrum Analysis;Molecular;Mus;NF-kappa B;Phosphotransferases;Predisposition;Proteins;Regulation;Research;Research Personnel;Resources;Role;Signal Pathway;Signal Transduction;Skin;Skin Cancer;Skin Neoplasms;Source;Testing;Tumor Suppressor Genes;Tumor Suppressor Proteins;United States National Institutes of Health;clinically relevant;keratinocyte;tumor


application_id: 8167780
project_number: 5P20RR018733-08
project_title: COBRE PROJ 7: CONTROL OF TUMOR GROWTH BY RAS-RELATED PROTEINS
administering_ic: NCRR
award_notice_date: 2010-08-24
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 7615
contact_pi_person_id: 8801334
contact_pi: CLARK, GEOFFREY J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Geoffrey Clark PI

Specific Aim 1:  Investigation of the RASSF family of Ras effectors in transformation
      The Ras oncogene has been implicated as a key player in the development of more than a third of human cancers.  Ras appears to function by activating multiple heterologous effector proteins that regulate synergistic signaling pathways controlling growth and development.  Experimentally excess Ras activation leads to vigorous transformation and the best characterized Ras effector proteins are themselves oncoproteins.  However excessive activation of Ras can also cause cells to undergo growth arrest and apoptosis.  This suggests that Ras proteins may activate a sub-set of effectors that rather than promoting transformation mediate growth inhibition.  It would seem reasonable to suppose that such effector systems would have to be subverted during the transformation process to allow progression to tumorigenicity. 

Specific Aim 2:  Development of novel small molecule inhibitors of Ras action
       Ras has been identified as a prime candidate for targeted anti-cancer therapy for more than two decades but attempts to develop specific inhibitors of Ras have so far proved ineffective.  The best known attempt involved a series of Farnesyl transferase inhibitors that actually do work well on H-Ras but are ineffective against the most important member of the family K-Ras.  Recent work has shown that the most important Ras effector for transformation in human systems is the RalGDS group of effectors.  This contrasts with results in murine systems which have implicated Rafs as the key effectors.  No inhibitors of RalGDS function have been described.

project_terms:
Apoptosis;Cells;Computer Retrieval of Information on Scientific Projects Database;Development;Family;Family member;Farnesyl Transferase Inhibitor;Funding;Grant;Growth;Growth and Development function;HRAS gene;Human;Institution;Investigation;Malignant Neoplasms;Mediating;Mus;Oncogene Proteins;Process;Proteins;RALGDS gene;RAS Superfamily Proteins;Ras Inhibitor;Research;Research Personnel;Resources;Series;Signal Pathway;Source;System;Tumorigenicity;United States National Institutes of Health;Work;cancer therapy;inhibitor/antagonist;novel;ras Oncogene;ras Proteins;small molecule;tumor growth


application_id: 8167779
project_number: 5P20RR018733-08
project_title: COBRE PROJ 6: PROGRAMMED DEATH PATHWAY INITIATED FROM THE ENDOPLASMIC RETICULUM
administering_ic: NCRR
award_notice_date: 2010-08-24
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 7614
contact_pi_person_id: 6950638
contact_pi: LI, CHI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Chi Li PI Project 6

      The aims of this proposal have not changed. They are designed to examine the molecular mechanisms that regulate programmed cell death initiated from the endoplasmic reticulum (ER).  Programmed cell death plays an important role in cancer development and one of the hallmarks of cancer is the inhibition of programmed cell death.  Upon a variety of death signals cells can initiate death pathways from different subcellular compartments.  Although much attention has been focused on the death pathway initiated from mitochondria relatively little is known about the involvement of the ER during programmed cell death.  It remains unclear how signals from ER stress are transduced to induce cell death.  To address this question three specific aims are envisioned:

     1. Study the mechanisms of releasing death-inducing factors from the ER lumen during ER stress-induced cell death.
     2. Investigate the signaling pathway activated by death-inducing factors from the ER.
    3. Determine how the ER-specific death pathway communicates with the death pathway initiated from mitochondria.

project_terms:
Address;Apoptosis;Attention;Cell Death;Cell Death Signaling Process;Cessation of life;Computer Retrieval of Information on Scientific Projects Database;Development;Endoplasmic Reticulum;Funding;Grant;Institution;Malignant Neoplasms;Mitochondria;Molecular;Pathway interactions;Play;Research;Research Personnel;Resources;Role;Signal Pathway;Signal Transduction;Source;United States National Institutes of Health;design;endoplasmic reticulum stress;programs


application_id: 8167778
project_number: 5P20RR018733-08
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE D: NMR & PROTEIN PURIFICATION FACILITIES
administering_ic: NCRR
award_notice_date: 2010-08-24
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 7613
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
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: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Andrew Lane Core D Director

      The primary aims of the core are to provide infrastructure for and support to structural analysis and metabolomics of cancer cells and tissue and for producing proteins in high yield suitable for NMR analysis. This includes stable isotope labeling strategies including N-15 and C-13 precursors. Our goals continue to be to streamline both data collection and analysis as well as introduce new labeling strategies to provide more detailed information about specific metabolic pathways. 
      Established researchers and new recruits to the program are realizing the benefits of the core facility for their research. This includes both protein production for biophysical analyses by X-ray crystallography NMR and Biophysics as well as extensive use of the metabolomics capabilities of the Core (see below). Efforts are being made to ensure that new recruits are fully cognizant of the core facilities and will be actively encouraged to use the unique capabilities.
     Dr. Chi Li (Project 6) is beginning to use metabolomics approaches for understanding metabolic consequences of apoptotic proteins on isolated mitochondria. 
     Dr. Geoffrey Clark (Project 7) is using the Protein Expression core to produce human DNMT3b (DNA (cytosine-5-)-methyltransferase 3 beta) as a GST fusion that will be used for characterization and biological experiments.
     Dr. Magda Kucia (Project 10) is working on stem cells for regenerative therapy. In addition to characterizing the gene expression profile of such cells during expansion she is interested in determining the metabolic phenotype of such cells to learn about the precise requirements for growth and differentiation in terms of energy and anabolic metabolism.
     Dr. Hong Ye (COBRE graduate) makes use of the expression core facilities for protein production advice and analysis and will need the NMR capabilities for some functional analyses of the proteins whose structures she has solved by X-ray diffraction methods.
     Dr. Jason Chesney (COBRE graduate) has continued to make extensive use of the facility and has been analyzing the metabolic consequences of expression of iPFK2 and ras (and effects of RNAi knockdowns) as well as the effects of immortalization via hTERT and large T antigen expression in a number of cell types including Jurkat cells MCF-7 bronchial epithelia and fibroblasts. Metabolite profiles and isotopomer analyses using the NMR facility have been instrumental in discovering consequences of cellular perturbations on the road to transformation (with sometimes surprising results) as well as validating (or otherwise) potential anticancer target enzymes. Some of this work has now been published and other manuscripts are in preparation.
      Dr. Binks Wattenberg (COBRE graduate) is expressing sphingosine kinase using transient expression in insect cells and also in bacteria (E. coli). The enzyme in the latter case enters inclusion bodies and has to be refolded after purification. The protein expression laboratory is working on purification schemes based on hexahis affinity chromatography as well as calmodulin affinity chromatography which has been shown to separate folded SK from unfolded enzyme. This will be used for biophysical studies including crystallography ligand binding and NMR analyses. In addition he has been analyzing the solution properties of targeting peptides using the NMR facility.

project_terms:
Affinity Chromatography;Apoptotic;Bacteria;Biological;Biophysics;Calmodulin;Cells;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Core Facility;Crystallography;Cytosine;DNMT3B gene;Data Collection;Differentiation and Growth;Ensure;Enzymes;Escherichia coli;Fibroblasts;Funding;Gene Expression Profile;Goals;Grant;Human;Inclusion Bodies;Insecta;Institution;Jurkat Cells;Label;Laboratories;Large T Antigen;Learning;Ligand Binding;Manuscripts;Metabolic;Metabolic Pathway;Metabolism;Methods;Methyltransferase;Mitochondria;Peptides;Phenotype;Preparation;Production;Property;Proteins;Publishing;RNA Interference;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Resources;Scheme;Solutions;Source;Stable Isotope Labeling;Stem cells;Structure;Tissues;United States National Institutes of Health;Work;X ray diffraction analysis;X-Ray Crystallography;X-Ray Diffraction;base;bronchial epithelium;cancer cell;cell type;interest;metabolomics;programs;protein expression;protein purification;regenerative therapy;research study;sphingosine kinase


application_id: 8167777
project_number: 5P20RR018733-08
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE C: MOLECULAR MODELING FACILITY
administering_ic: NCRR
award_notice_date: 2010-08-24
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 7612
contact_pi_person_id: 7821204
contact_pi: TRENT, JOHN O
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: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.       The goals of the COBRE in Molecular Targets Molecular Modeling Core Facility have not changed. The Molecular Modeling Core Facility operated by Dr. John Trent is a state-of-the-art molecular modeling facility that has the capability of providing models based on structural data obtained from either X-ray crystallographic or NMR studies.  In particular this facility has provided important molecular modeling services for Projects 1 2 3 and 4.  Using homology modeling and virtual screening of potential inhibitors Dr. Trent has made very important contributions on a collaborative basis to members of each COBRE-MT project.  This facility is located within the Brown Cancer Center.  The capabilities of the facility include techniques such as explicitly solvated molecular dynamics homology modeling docking virtual screening ESP calculations and conformational searching.
        For Dr. Geoffrey Clark's project (7) the Core C is performing virtual screens on two targets. Finding new drug templates for two projects demonstrates excellent progress and represents a relatively unique hit rate.

project_terms:
Arts;Cancer Center;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Core Facility;Data;Docking;Funding;Goals;Grant;Homology Modeling;Institution;Modeling;Molecular Models;Molecular Target;Pharmaceutical Preparations;Research;Research Personnel;Resources;Roentgen Rays;Screening procedure;Services;Source;Techniques;United States National Institutes of Health;base;inhibitor/antagonist;member;molecular dynamics;molecular modeling;virtual


application_id: 8167776
project_number: 5P20RR018733-08
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE B: MICROARRAY FACILITY
administering_ic: NCRR
award_notice_date: 2010-08-24
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 7611
contact_pi_person_id: 1969307
contact_pi: ZACHARIAS, WOLFGANG
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: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.  The Microarray Facility is located in the Baxter II Biomedical Research Building one block from the Brown Cancer Center. This facility contains both Affymetrix and Agilent microarray instrument systems which are available to all MT-COBRE members. The Facility is under the direction of Dr. Wolfgang Zacharias and has been fully operational for the past eight years since Spring 2001. It includes a full-time Facility Manager Sabine Waigel and two research technologists Vennila Arumugam and Xiaohong Li. They provide administrative support project logistics and management technical assistance in platform-specific sample processing and hybridization as well as data collection analysis and storage. Dr. Zacharias is available for assistance with experimental design data analysis and collaborative or consultant support for grant applications.

The Microarray Facility has close interactions with other Core Facilities and Bioinformatics personnel. Also the close relationship with the Tissue Biorepository in the J.G. Brown Cancer Center allows the preparation of samples with known pathologic characteristics and appropriate control specimens. Plans are underway for the development of a tissue array component of this facility as well. The high-resolution Affymetrix Scanner 3000 upgrade allows all COBRE investigators to use the newest generation of high-density whole genome v2.0 arrays and SNP 6.0 arrays for human or mouse. The Facility continues to organize and hold software/data analysis workshops on campus to train microarray technology users.

project_terms:
Applications Grants;Bioinformatics;Biomedical Research;Cancer Center;Centers of Research Excellence;Characteristics;Computer Retrieval of Information on Scientific Projects Database;Computer software;Core Facility;Data Analyses;Data Collection;Development;Educational workshop;Experimental Designs;Funding;Generations;Genome;Grant;Human;Human Resources;Institution;Logistics;Microarray Analysis;Mus;Pathologic;Preparation;Process;Research;Research Personnel;Resolution;Resources;Sampling;Source;Specimen;System;Time;Tissue Microarray;Tissues;Training;United States National Institutes of Health;biobank;density;instrument;member


application_id: 8167775
project_number: 5P20RR018733-08
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE A:ADMINISTRATIVE CORE
administering_ic: NCRR
award_notice_date: 2010-08-24
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 7610
contact_pi_person_id: 1898718
contact_pi: MILLER, DONALD M.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Core A the Administrative Core is responsible for the day-to-day operations of the Molecular Targets Center of Biomedical Research Excellence (MT-COBRE).  Core A manages the scientific and administrative aspects of the COBRE.  In collaboration with Diane Konzen the COBRE Administrator Drs. Miller and Eaton are responsible for oversight of all administrative aspects of the COBRE.  This funding has provided an opportunity to recruit five additional faculty to the MT-COBRE as the original faculty have received new funding and left the COBRE.  Four of the five original project directors are faculty at the UofL Brown Cancer Center and serve as members of the Executive Committee.

project_terms:
Administrator;Cancer Center;Centers of Research Excellence;Collaborations;Computer Retrieval of Information on Scientific Projects Database;Faculty;Funding;Grant;Institution;Left;Molecular Target;Recruitment Activity;Research;Research Personnel;Resources;Source;United States National Institutes of Health;member;operation


application_id: 8167657
project_number: 5P20RR017702-08
project_title: BIOMARKERS OF NEUROTOXICITY ASSOCIATED WITH FETAL TOBACCO SMOKE EXPOSURE?
administering_ic: NCRR
award_notice_date: 2010-06-11
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2010-06-01
project_end_date: 2011-05-31
subproject_number: 7496
contact_pi_person_id: 8531285
contact_pi: NEAL, RACHEL ELIZABETH
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: 2010-06-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Approximately 45 million U.S adults are active smokers. Cigarette smoke consists of more than 4000 chemical compounds including polycylic aromatic hydrocarbons carbon monoxide hydrogen cyanide and arsenic. Nicotine the primary addictive component of cigarettes is rapidly metabolized to cotinine with a systemic clearance by day 3 post-withdrawal. Biomarkers of cigarette smoke exposure which are present post-nicotine clearance and which are peripheral markers of sustained neurotoxicity are lacking. The emphasis of the first study (April-December 2009) was upon identification of abnormalities in tissue protein and metabolite homeostasis which are mirrored by serum markers of toxicity. 
 
In the current proposal (Jan-March 2010) we are establishing whether alcohol exposure induced IUGR is mediated by uterine/placental phosphatide availability.  Fetal Alcohol Spectrum Disorders (FASD) affect approximately 1 per 100 live births of which low birth weight (LBW) and developmental delays are most common. In rodent models of FASD gestational exposure to ethanol induces increased embryo resorption and intrauterine growth restriction (IUGR); persistent neurocognitive and behavioral deficits; as well as a variety of craniofacial malformations including microphthalmia and microcephaly .  In FASD models supplementation with phosphatide precursors [choline or omega-3 long-chain polyunsaturated fatty acids (omega-3 LC-PUFAs; fish oil supplement)] during decidualization/placentation alleviates IUGR.  Arachidonic acid availabilityan established mediator of successful implantation decidualization and fetal growth--is mediated by phosphatide transport/metabolism.  In the coming year we will probe whether maternal alcohol consumption modifies the uterine/placental lipid environment leading to IUGR and LBW.  Further we will examine whether maternal nutrient supplementation with LC-PUFAs or choline which is reported to alleviate LBW will modify the uterine/placental lipid profiles.

project_terms:
Adult;Affect;Alcohol consumption;Arachidonic Acids;Aromatic Hydrocarbons;Arsenic;Behavioral;Carbon Monoxide;Chemicals;Choline;Cigarette;Computer Retrieval of Information on Scientific Projects Database;Cotinine;Decidual Cell Reactions;Developmental Delay Disorders;Disease model;Embryo Resorption;Environment;Ethanol;Exposure to;Fetal Alcohol Spectrum Disorder;Fetal Growth;Fetal Growth Retardation;Fish Oils;Funding;Grant;Homeostasis;Hydrogen Cyanide;Institution;Lipids;Live Birth;Low Birth Weight Infant;Mediating;Mediator of activation protein;Metabolism;Microcephaly;Microphthalmos;Neurocognitive;Nicotine;Nutrient;Omega-3 Fatty Acids;Peripheral;Phospholipids;Placentation;Reporting;Research;Research Personnel;Resources;Rodent Model;Serum Markers;Smoker;Source;Supplementation;Tissues;Tobacco smoke;Toxic effect;United States National Institutes of Health;Withdrawal;alcohol exposure;biomarker;cigarette smoke;craniofacial;fetal;implantation;malformation;neurotoxicity;protein metabolite


application_id: 8167656
project_number: 5P20RR017702-08
project_title: PHAGOCYTOSIS AND MERTK FAMILY OF THE RECEPTOR TYROSINE KINASE
administering_ic: NCRR
award_notice_date: 2010-06-11
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2010-06-01
project_end_date: 2011-05-31
subproject_number: 7495
contact_pi_person_id: 8875628
contact_pi: LU, QINGXIAN
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: 2010-06-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The TAM family of receptor tyrosine kinases participates in both innate and adaptive immune response. Mice lacking all three receptors exhibit defective clearance of apoptotic cells or spent cellular organelles by the professional or non-professional phagocytes. Apoptotic cells are a major source of autoantigens and impaired clearance leads to the development of autoimmunity. Furthermore Axl and Mertk two members of TAM family are expressed by macrophage and dendritic cells (DC) and play a negatively regulatory role during the antigen-presenting cell (APC) activation. Overpresentation of autoantigens in the mutant APCs causes autoimmune disorders. We have previously shown that TAM triple (as well as AM double) mutants produce elevated levels of circulating autoantibodies overreactive ocular antigen-specific syngeneic T-cell population. In this period of study we further demonstrated that AM double (also triple) mutant mice developed ocular autoimmune disorder through overwhelmingly hyperactivation of Th1 subtype of T cells. This study brings us even closer to understanding of the molecular etiology for human uveitis.

project_terms:
Antigen-Presenting Cells;Antigens;Apoptotic;Autoantibodies;Autoantigens;Autoimmune Diseases;Autoimmunity;Cells;Computer Retrieval of Information on Scientific Projects Database;Dendritic Cells;Development;Etiology;Exhibits;Family;Funding;Grant;Human;Immune response;Institution;Molecular;Mus;Mutant Strains Mice;Organelles;Pb clearance;Phagocytes;Phagocytosis;Play;Population;Receptor Protein-Tyrosine Kinases;Research;Research Personnel;Resources;Role;Source;T-Lymphocyte;United States National Institutes of Health;Uveitis;macrophage;member;mutant;receptor


application_id: 8167655
project_number: 5P20RR017702-08
project_title: REGULATION OF NEURAL CREST CELL MIGRATION BY SDF1-CXCR4 SIGNALING
administering_ic: NCRR
award_notice_date: 2010-06-11
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2010-06-01
project_end_date: 2011-05-31
subproject_number: 7494
contact_pi_person_id: 8634532
contact_pi: SEELAN, RATNAM SATHIAGANA
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: 2010-06-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Project #1: The overall goal of the project is to examine the role of SDF1/CXCR4 signaling in the migration of trunk neural crest cells (NCCs) to the Dorsal Root Ganglion (DRG) and to identify factors that regulate this process. Defective migration of trunk NCCs can cause perinatal lethality and affect the development and formation of the peripheral nervous system. Towards this end we constructed riboprobes for chicken SDF1 and CXCR4 and utilized them in in situ hybridization (ISH) analyses to determine the spatiotemporal expression of the two genes during embryonic development. The hypothesis being addressed is that trunk NCCs express CXCR4 and migrate towards mesodermal regions of high SDF-1 concentration where they differentiate into the DRG. Chicken embryos (Hamilton-Hamburger (HH) stages ~7-22) were used for the study as their developmental stages have been well defined and are more amenable to analysis and manipulation. Gene expression profiling of SDF1 and CXCR4 expression spanning these developmental stages in the chick embryo has largely been accomplished. Ongoing studies are determining if the expression patterns of CXCR4 and SDF-1 correspond to the developmental paths undertaken by migrating NCCs to become DRG using specific antibodies --  anti-HNK-1 for NCCs and anti-Islet-1 for the DRG. In a parallel study PC12 cells (derived from the adrenal gland; neural crest origin) are being used in experiments involving transwells and chemotaxis chambers to address possible roles for upstream factors (e.g. TGF1 and BMP4) in regulating NCC migration via SDF1/ CXCR4 signaling and the effect of this signaling on putative downstream targets such as IP3 kinase. 

Project #2: (new): 
Orofacial clefts such as cleft palate (CP) and cleft lip with or without cleft palate (CL/P) are amongst the most prevalent birth defects in the United States. CP is caused by defects in the development of the secondary palate which in mice occurs during gestational days (gd) 12-14. Genetic and environmental factors have been implicated in the etiology of CP. Environmentally-induced epigenetic alterations provide a mechanism by which environmental insults could trigger abnormal DNA methylation without a change in DNA sequence. Previous analyses of mRNA profiling during secondary palate development using Affymetrix GeneChips coupled with bioinformatic analyses identified Sox4 as a gene that is potentially regulated by DNA methylation during palate development and therefore relevant to the study of orofacial clefting. Sox4 mRNA was found to decrease two-fold from gd12 to gd13/14 indicative of increased methylation during this period. An extensive CpG methylation profile was developed for mouse Sox4 in the 5' upstream region in gd12-14 secondary palates. The resulting analyses  indicated a strong association between DNA methylation in the 5' flanking region and decreased mRNA levels seen during gd12-14. Specifically two CpG residues residing in a Differentially Methylated Region (DMR) which are 60%-70% methylated at gd12 become fully methylated by gd13. Increased methylation of these residues correlates with the decrease in Sox4 mRNA levels during this developmental time-frame. Current studies seek to validate the functionality of these CpG residues using methylation-dependent luciferase expression vectors.

project_terms:
5' Flanking Region;Address;Adrenal Glands;Affect;Antibodies;BMP4;Bioinformatics;CXCL12 gene;CXCR4 gene;Chemotaxis;Chick Embryo;Chickens;Cleaved cell;Cleft Palate;Cleft lip with or without cleft palate;Computer Retrieval of Information on Scientific Projects Database;Congenital Abnormality;Coupled;DNA Methylation;DNA Sequence;Defect;Development;Embryo;Embryonic Development;Environmental Risk Factor;Epigenetic Process;Etiology;Funding;Gene Expression Profiling;Genes;Genetic;Goals;Grant;In Situ Hybridization;In-Migration;Institution;Luciferases;Messenger RNA;Methylation;Mus;Neural Crest;Neural Crest Cell;PC12 Cells;Palate;Pattern;Perinatal;Peripheral Nervous System;Phosphotransferases;Process;Regulation;Research;Research Personnel;Resources;Role;Secondary Palate;Signal Transduction;Source;Spinal Ganglia;Staging;Stromal Cell-Derived Factor 1;Time;United States;United States National Institutes of Health;cell motility;expression vector;islet;migration;orofacial;research study;spatiotemporal


application_id: 8167654
project_number: 5P20RR017702-08
project_title: PRE- AND POSTNATAL TOBACCO SMOKE EXPOSURE:EFFECTS ON NEUROCOGNITIVE DEVELOPMENT
administering_ic: NCRR
award_notice_date: 2010-06-11
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2010-06-01
project_end_date: 2011-05-31
subproject_number: 7493
contact_pi_person_id: 1866555
contact_pi: PISANO, M. MICHELE
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: 2010-06-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Maternal cigarette smoking has been associated with a variety of adverse fetal infant and childhood developmental outcomes.  In the United States alone approximately one million infants are exposed prenatally to cigarette smoke each year! Although maternal cigarette smoking during pregnancy is a well documented risk factor for low birth weight with its attendant complications for infant/childhood development a direct linkage between prenatal cigarette smoke exposure and postnatal neurobehavioral/cognitive impairment remains poorly defined.  The global objective of the present research program is to establish mouse-human experimental correlates to mechanistically investigate the neuroanatomical cellular and molecular substrates underlying maternal cigarette smoking-induced defects in neuro/cognitive development. Since the hippocampus subserves a central role  across species   in neuro/cognition especially in the information processing involved in learning and memory the central hypothesis under investigation is that maternal tobacco use during pregnancy interferes with the cellular and molecular ontogenesis of the hippocampus resulting in altered hippocampus-dependent learning and memory in the offspring. The animal studies conducted under this research program employ a mouse model established in our laboratory in which developmental (gestational and early postnatal) inhalation exposure to cigarette smoke simulates human maternal smoking during pregnancy. Preliminary examination of functional (behavioral) deficits in hippocampus-dependent learning/memory in animals developmentally exposed (gestational day 1-18 and postnatal days 1-21) to cigarette smoke or ambient air demonstrated that such cigarette smoke exposure affects neurodevelopment and results in spatial learning and cognitive deficits.  Moreover developmental cigarette smoke exposure results in increased anxiety- and depression-like behavior the these animals. Although no alterations in the gross or cellular morphology of the hippocampus from developmentally cigarette smoke-exposed offspring are apparent from our preliminary analyses gene expression profiling of the isolated hippocampus from the exposed animals indicates significant alterations in the expression of various genes involved in neuronal signaling learning and memory among others. Both the assessments of hippocampal dependent behavioral functions proposed in Specific Aim #1 and the assessments of hippocampal gross and cellular morphology proposed in Specific Aim #2 are targeted for completion in the coming 6 months. Successful completion of the these studies along with those proposed in Specific Aims #3 and #4 of the Research Program will aid in understanding the effects of and mechanisms underlying in utero tobacco smoke exposure on neuro/cognitive development in infants and children and  long-term   will facilitate the diagnosis of and intervention into learning disabilities and other cognitive impairments in children affected by prenatal maternal tobacco abuse.

project_terms:
Affect;Air;Animal Behavior;Animals;Anxiety;Behavioral;Cellular Morphology;Child;Childhood;Cigarette;Cognition;Cognitive;Cognitive deficits;Computer Retrieval of Information on Scientific Projects Database;Defect;Development;Diagnosis;Exposure to;Funding;Gene Expression Profiling;Genes;Grant;Hippocampus (Brain);Human;Impaired cognition;Infant;Inhalation Exposure;Institution;Intervention;Investigation;Laboratories;Learning;Learning Disabilities;Low Birth Weight Infant;Memory;Mental Depression;Molecular;Mus;Neurocognitive;Neurons;Outcome;Pregnancy;Research;Research Personnel;Resources;Risk Factors;Role;Signal Transduction;Simulate;Smoke;Source;Tobacco smoke;United States;United States National Institutes of Health;cigarette smoke;cigarette smoke-induced;fetal;fetal tobacco exposure;in utero;information processing;maternal cigarette smoking;maternal tobacco abuse;maternal tobacco use;mouse model;neurobehavioral;neurodevelopment;offspring;postnatal;prenatal;prenatal exposure;programs


application_id: 8167653
project_number: 5P20RR017702-08
project_title: INTERMITTENT HYPOXIA-MEDIATED OLIGO DEFECTS:A MODEL OF GESTATIONAL SLEEP APNEA
administering_ic: NCRR
award_notice_date: 2010-06-11
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2010-06-01
project_end_date: 2011-05-31
subproject_number: 7492
contact_pi_person_id: 9256836
contact_pi: CAI, JUN
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: 2010-06-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.      The goal of this subproject is to identify the impact of maternal sleep apnea-associated intermittent hypoxia on oligodendrocyte and axon development in offspring CNS. The study will focus on investigating oligodendroglial defects elicited by maternal intermittent hypoxia exposure during gestational period tracing the destiny of insulted oligodendrocytes and exploring the long-term consequences in mouse embryos and neonates. Three aims are proposed to characterize the molecular and cellular mechanisms underlying IH-mediated OL injury due to maternal OSA-related IH exposure: aim 1: to examine OL generation proliferation and differentiation in mouse forebrain and spinal cord at different embryonic stages following IH exposure during gestation (1st-2nd year); aim 2: to determine consequences of maternal IH exposure on myelin-forming process and myelin architecture in developing and adult mice as well as local effects on axonal development that maybe induced or deteriorated by myelin deficit (2nd-3rd year); aim 3: to explore signaling molecules invovled in IH-mediated OL injury occurring in maternal sleep apnea during pregnancy (2nd -4th year).  

      Our previous study showed that oligodendrocyte progenitor cells (OPCs) in neural tube decline after 3-day maternal IH exposure during the window of oligodendrogenesis. After the IH insult withdrawn more Olig2+ progenitors appear in the ventricular zone but less in both gray and white matter suggesting an increased proliferation or restraint in migration of progenitors. Oligodendrocyte differentiation as well as transcripts of mbp and MAG is inhibited at perinatal stages. These findings indicate that oligodendrogenesis is vulnerable to gestational IH insults as occurs in OSA during pregnancy.

      Although early gestational IH exposure leads to 10%~20% decrease of mbp and MAG transcripts in newborns myelin proteins appear to be normal in the developing offspring. Recently clinical retrospective studies reported that most of OSA occurring in pregnancy is diagnosed in the last trimester and 90% showed severe symptoms. Since oligodendrocyte maturation myelination axon sprouting and synapse formation initiate from the late second and early third trimesters of pregnancy maternal OSA in the 3rd trimester may result in much severe sequelae in offspring white matter. Thereby we duplicated a mouse neonatal model of IH insult during the time window that is equivalent to the human 3rd trimester. Based on this model we explored the differentiation of oligodendrocyte expression of myelin-related proteins axonal cytoskeleton and white matter development. A few CC1+/MAG+ mature oligodendrocytes were found in IH-treated spinal cords. The synthesis of myelin-related proteins were dramatically inhibited (40% in brain). In addition all transcripts of neurofilament subunits (NF-L M and H) were significantly decreased with high percentage of NF-L/M components indicating immaturity of axons.  Consistent with these findings less phosphorylated NFs were detected in IH-exposed developing mice. Furthermore IH insult resulted in hypoplasia of white matter following IH-induced oligodendroglial-axonal injury.

project_terms:
Adult;Architecture;Axon;Brain;Clinical;Computer Retrieval of Information on Scientific Projects Database;Cytoskeleton;Defect;Development;Diagnosis;Embryo;Funding;Generations;Goals;Grant;Gray unit of radiation dose;Human;Hypoxia;In-Migration;Injury;Institution;Mediating;Modeling;Molecular;Mus;Myelin;Myelin Proteins;Myeloma Proteins;Neonatal;Neural tube;Neurofilament-L;Newborn Infant;Oligodendroglia;Oligonucleotides;Perinatal;Pregnancy;Process;Prosencephalon;Proteins;Reporting;Research;Research Personnel;Resources;Retrospective Studies;Signaling Molecule;Sleep Apnea Syndromes;Source;Spinal Cord;Staging;Stem cells;Symptoms;Third Pregnancy Trimester;Time;Transcript;United States National Institutes of Health;Ventricular;base;myelination;neonate;neurofilament;offspring;progenitor;restraint;synaptogenesis;white matter


application_id: 8167652
project_number: 5P20RR017702-08
project_title: TGF-? SIGNALING DURING MOUSE SECONDARY PALATE ELEVATION AND FUSION
administering_ic: NCRR
award_notice_date: 2010-06-11
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2010-06-01
project_end_date: 2011-05-31
subproject_number: 7491
contact_pi_person_id: 7594575
contact_pi: DING, JIXIANG
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: 2010-06-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Cleft palate is a common birth defect caused by malformation in secondary palate development. Palate formation requires signaling pathways to function interactively rather than in isolation. However our understanding of the signaling networks during palate fusion growth and elevation remains poor. The proposed research will focus on the interactions among major signaling pathways during palate development. TGF-3 is an essential signaling molecule mediating palate fusion but the mechanism of action is unknown. We found that TGF-3 is required for the down-regulation of Jag2 expression during fusion suggesting TGF- and Notch pathways function synergistically during fusion. Jag2 IRF6 and IKKa are key regulator factors in preventing pathogenic palate fusion with the tongue and other tissues and recent studies have revealed the integration of these factors in controlling palate adhesion and fusion. We will pursue two specific aims: 

I) Interactions between TGF-3 Notch1/Jag2 during normal and pathogenic palate fusion. We will 1) take a genetic approach to test the hypothesis that TGF-3 mediates palate fusion by down-regulating Jag2 expression in the MEE; 

2) investigate the functional significance of Jag2 down-regulation in MEE during wild type palate fusion.

II) Investigation of TGF- signaling and its interaction with Wnt5a during palate elevation. We will 1) investigate the downstream target genes of Zfhx1a during palate elevation focusing on the genes involving cell migration; 2) investigation of the function of TGF-12 during palate by generating TGF-12 double mutants; 3) examine the effects of TGF-s on Wnt5a mediated non-canonical signaling.

project_terms:
Adhesions;Cleft Palate;Computer Retrieval of Information on Scientific Projects Database;Congenital Abnormality;Development;Down-Regulation;Funding;Gene Targeting;Genes;Genetic;Grant;Growth;Institution;Investigation;Mediating;Mus;Palate;Pathway interactions;Research;Research Personnel;Resources;Secondary Palate;Signal Pathway;Signal Transduction;Signaling Molecule;Source;Testing;Tissues;Tongue;United States National Institutes of Health;cell motility;malformation;mutant;notch protein;prevent


application_id: 8167651
project_number: 5P20RR017702-08
project_title: FGF SIGNALING AND ZINC FINGER PROTEINS IN GONAD DEVELOPMENT AND REPRODUCTION
administering_ic: NCRR
award_notice_date: 2010-06-11
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2010-06-01
project_end_date: 2011-05-31
subproject_number: 7490
contact_pi_person_id: 6574851
contact_pi: LAN, ZI-JIAN
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: 2010-06-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Our research interest is to identify factors contributing to male and female subfertility and infertility. Our original project is to characterize the potential role of hedgehog signaling molecules patched 1 and suppressor of fused using Ptcmes/mes and Sufu+/-;Ptc1mes/mes in the ovarian development. Due to minor ovarian defects in those mutant mice we have shifted our focus on the studies of other molecules including FGFRs and male germ cell-expressing zinc finger proteins in reproduction using mutant mouse models. Generation and functional analyses of these mutant mice will provide insight into the pathogenesis of human subfertility or infertility.

project_terms:
Computer Retrieval of Information on Scientific Projects Database;Defect;Development;Female;Funding;Generations;Germ Cells;Gonadal structure;Grant;Human;Infertility;Institution;Minor;Mutant Strains Mice;Ovarian;Pathogenesis;Proteins;Reproduction;Research;Research Personnel;Resources;Role;Signal Transduction;Signaling Molecule;Source;United States National Institutes of Health;Zinc Fingers;insight;interest;male;mutant mouse model;smoothened signaling pathway


application_id: 8167650
project_number: 5P20RR017702-08
project_title: COBRE: UL: ADMIN CORE: MOLECULAR DETERMINANTS OF DEVELOPMENTAL DEFECTS
administering_ic: NCRR
award_notice_date: 2010-06-11
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
project_start_date: 2010-06-01
project_end_date: 2011-05-31
subproject_number: 7489
contact_pi_person_id: 1861667
contact_pi: GREENE, ROBERT M
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: 2010-06-01
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.DESCRIPTION (provided by applicant): The purpose of this application for a Center of Biomedical Research Excellence (COBRE) is to foster health-related research and increase the competitiveness of junior unfunded investigators at the Birth Defects Center at the UL School of Dentistry for independent funding. This COBRE augments and strengthens the biomedical research capacity at the Birth Defects Center through provision of flexible support to expand and develop biomedical faculty research capability. The program is led by an established biomedical research scientist well recognized for his extensive expertise central to the research theme of the proposal. The COBRE supports junior investigators from several complementary disciplines each of whom is mentored by an established well-funded senior biomedical research faculty member recognized for his/her scientific expertise in the area of the junior investigator's research proposal. This approach is a critical assurance of success of this initiative. This COBRE represents an integrated series of studies focusing on two common themes - molecular mechanisms of birth defects and cellular signal transduction - that encompass a number of diverse scientific disciplines.  Faculty from the Schools of Dentistry Medicine and Public Health representing a multiplicity of scientific disciplines present a multifunctional approach to questions of the molecular basis of developmental anomalies. The COBRE substantially enhances the development of eight young investigators with outstanding potential to develop into competitive independent and collaborative investigators. A detailed plan for their research career development has been formulated expectations and goals for achieving extramural support is outlined the extent of departmental and university support provided to these junior faculty is substantial clear and tangible evidence of institutional commitment has been documented and sufficient and adequate space and equipment resources for the conduct of the proposed studies exists.

project_terms:
Area;Biomedical Research;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Congenital Abnormality;Defect;Development;Discipline;Equipment;Extramural Activities;Faculty;Fostering;Funding;Goals;Grant;Institution;Medicine;Mentors;Molecular;Research;Research Personnel;Research Proposals;Resources;School Dentistry;Scientist;Series;Signal Transduction;Source;United States National Institutes of Health;Universities;base;career development;expectation;flexibility;member;programs;public health medicine (field);success


application_id: 8166442
project_number: 1R03NS075694-01
project_title: Mitochondrial protection of a GDNF propeptide
administering_ic: NINDS
award_notice_date: 2011-04-20
opportunity_number: PA-10-064
application_type: 1
activity_code: R03
ic: NS
serial_number: 075694
program_official: SIEBER, BETH-ANNE
project_start_date: 2011-07-01
project_end_date: 2013-04-30
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 9077753
contact_pi: BRADLEY, LUKE H
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Mitochondrial dysfunction has been identified as one of the key players in Parkinson's disease (PD) pathogenesis. While the etiology is unknown in most cases the development of progressive parkinsonian symptoms has been shown in patients following exposure to various environmental and occupational toxins. Numerous studies demonstrate that these neurotoxins specifically inhibit the mitochondrial respiratory chain complexes of dopaminergic neurons which initiates a cascade of events ultimately leading to cell death. Furthermore the susceptibility to environmental neurotoxins is increased in the aged nervous system. Thus for the long-term treatment of PD and parkinsonian symptoms therapeutic strategies are needed that not only restore dopaminergic neuron function but also provide mitochondrial protection and restoration from various stresses including environmental toxin exposure.  In the past neurotrophic growth factors have received considerable attention as potential therapeutic agents for neurological disorders. However the clinical application of these native molecules has not advanced primarily due to pharmacological disadvantages and challenges associated with directly delivering large protein molecules to the brain. The emergence of physiologically functional propeptides from the neurotrophic factor family provides a wealth of novel smaller sequences for biotherapeutic exploration and evaluation. Examination of the glial cell line-derived neurotrophic factor (GDNF) prosequence predicts internal dibasic endopeptidase sites that would yield a smaller amidated eleven amino acid residue peptide named dopamine neuron stimulating peptide-11 (DNSP-11). Recent evaluation of DNSP-11 has shown that it exhibits similar GDNF-like neurotrophic responses in normal and parkinsonian rat models. However cell culture and proteomic pull-down data suggest that DNSP-11 functions differently than mature GDNF; leading to our hypothesis that DNSP-11's neurobiological actions are through the mitochondria. The research outlined in the current proposal will measure DNSP-11's bioenergetic and protective effects in the MN9D dopaminergic cell line from toxins that specifically target the mitochondrial respiratory complexes. The information obtained in this study will further our understanding of this propeptide's neurobiological activity and provide the basis for future evaluation and biotherapeutic development of DNSP-11.  
  
PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) a chronic neurological disorder that affects over 1 million Americans is characterized by stooped posture balance impairments rigidity resting hand tremors and bradykinesia. While the cause of PD is largely unknown parkinsonian symptoms have been shown to develop following long-term exposure to common environmental toxins that specifically target the mitochondria of dopamine neurons. The goal of this pilot project is to investigate the neuroprotective properties of a novel neurotrophic propeptide DNSP-11 from mitochondrial-specific toxins to pave the way for its downstream evaluation as a potential PD therapeutic.

project_terms:
Affect;Agriculture;American;Amino Acids;Attention;Bioenergetics;Biological Response Modifier Therapy;Bradykinesia;Brain;Cell Culture Techniques;Cell Death;Cell Line;Cells;Chronic;Complex;Data;Development;Disadvantaged;Dopaminergic Cell;Endopeptidases;Etiology;Evaluation;Event;Exhibits;Exposure to;Family;Future;Goals;Growth Factor;Hand;Individual;Measures;Mitochondria;Modeling;Names;Nervous system structure;Neurobiology;Neurotoxins;Occupational;Parkinson Disease;Parkinsonian Disorders;Pathogenesis;Patients;Peptides;Pilot Projects;Posture;Predisposition;Property;Proteins;Proteomics;Rattus;Research;Respiration;Respiratory Chain;Rest;Site;Stress;Symptoms;Testing;Therapeutic;Therapeutic Agents;Toxic Environmental Substances;Toxin;Tremor;aged;base;clinical application;dopaminergic neuron;equilibration disorder;glial cell-line derived neurotrophic factor;mitochondrial dysfunction;nervous system disorder;neurotrophic factor;novel;protective effect;respiratory;response;restoration

public_health_relevance:
Parkinson's disease (PD) a chronic neurological disorder that affects over 1 million Americans is characterized by stooped posture balance impairments rigidity resting hand tremors and bradykinesia. While the cause of PD is largely unknown parkinsonian symptoms have been shown to develop following long-term exposure to common environmental toxins that specifically target the mitochondria of dopamine neurons. The goal of this pilot project is to investigate the neuroprotective properties of a novel neurotrophic propeptide DNSP-11 from mitochondrial-specific toxins to pave the way for its downstream evaluation as a potential PD therapeutic.


application_id: 8165806
project_number: 1K08EY021757-01
project_title: Endothelial Cell Dysregulation in Neovascular AMD
administering_ic: NEI
award_notice_date: 2011-08-08
opportunity_number: PA-10-059
application_type: 1
activity_code: K08
ic: EY
serial_number: 021757
program_official: SHEN, GRACE L
project_start_date: 2011-09-01
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZEY1 VSN (11)]
contact_pi_person_id: 8784086
contact_pi: KLEINMAN, MARK E
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 candidate is applying for a Mentored Clinical Scientist Research Career Development Award (K08) to  support a 5 year research career training program that will significantly bolster his transition to faculty  independence as a fellowship trained clinician-scientist specializing in vitreoretinal and macular diseases. The  rigorous training program has been designed with extensive input and unyielding support from the candidate's  mentor co-mentor chairman and advisory committee. All training will take place in the excellent scientific and  academic environment of the University of Kentucky Department of Ophthalmology and Visual Sciences which  includes an ocular angiogenesis research consortium consisting of four independent investigators. The  applicant will spend the first 3 years of the program as a Research Assistant Professor and Clinical Fellow. The  specific design of the fellowship is precisely detailed in the Career Development section and accompanied by a  very strong institutional commitment that allows the candidate at least 80% effort performing research and 20%  performing clinical duties. After completion of the fellowship the candidate will transition to a full-time faculty  position as Assistant Professor at University of Kentucky with the same institutional commitment of 80%  research and 20% clinical effort. The long-term goal of the award is to offer the candidate the critical career  development support to establish a pathway to faculty independence that will extensively train him as a  biomedical researcher confident and masterful specialist in the diagnosis and treatment of vitreoretinal and  macular diseases and leading academician. The candidate aims to have an independent laboratory up and  running within the initial 12-18 months of the award period in order to gain early independence with his  research project and develop critical principal investigator skills with guidance from his established mentors  and advisory committee. The research plan has been devised by the candidate and his mentors and aims to  extend his scientific expertise beyond basic vascular biology with a rich experience to develop new techniques  and to utilize such methods in experimental designs to obtain critical data that expand his current fund of  knowledge in order to yield fundamental insights on endothelial cell dysregulation immuno-modulation in  vascular growth and therapeutic targets in neovascular age-related macular degeneration (AMD).  AMD is a devastating blinding disease that affects as many as 10 million Americans a number that rivals the  prevalence of all cancers combined and is unfortunately expected to double by 2020. The overwhelming cause  of severe vision loss in AMD is choroidal neovascularization (CNV) the growth of abnormal blood vessels  beneath the retina. Despite the use of recently approved molecular therapeutics targeting vascular endothelial  growth factor (VEGF)-A the majority of patients do not regain functional vision and a significant fraction  progress to legal blindness. This treatment failure is attributed to the frequent clinical situation in which patients  present to eye physicians after vision is already lost and irreversible structural and functional tissue damage  has already occurred. Moreover while patients with AMD often undergo at least one or more dilated eye  examinations per year the physician is often not able to detect CNV before it grows beneath the retina and  wreaks havoc. Fortunately there is an exciting development that may provide the first available technique for  detecting incipient CNV in patients with AMD thereby allowing for earlier detection and treatment to prevent  loss of vision and quality of life. This discovery was recently reported in the journal Nature and described as  the first molecular marker that is specific for human CNV (Takeda et al. Nature 2009). It is an immune receptor  called chemokine receptor 3 (CCR3) that is involved in allergic response and recruitment of white blood cells  but may also be found on inflamed and growing blood vessels.  The identification of CCR3 as a molecular signature has opened a gateway to a new understanding in vascular  disease in AMD. CCR3 expression is found on the surface of the specialized endothelial cells that line the  abnormal blood vessels. In this proposal rigorous basic science investigations of the cellular circuitry that  mediates this pathogenic switch will be explored in conjunction with the biological relationships between  endothelial cell dysregulation aging immune activation and oxidative stress. The initial aim of the study is to  decipher how these established AMD risk factors regulate the progression of disease through chemokine and  other immune signaling pathways in order to develop appropriately targeted diagnostics and therapeutics that  will enable clinicians to offer improved care of patients suffering from AMD. A second aim focuses specifically  on CCR3 biology with scientific exploration of its pathogenetic induction expression patterns and signaling  effects during endothelial cell dysregulation in neovascular AMD. In a final aim optimized fluorescent CCR3-  targeting probes will be engineered and applied to pre-clinical animal models of CNV and human cellular  toxicology studies in order to obtain necessary data to proceed with future clinical studies. These specific  experimental aims will provide fundamental insights into the modulatory function of the immune system  chemokine signaling and the role of CCR3 as a molecular switch during the endothelial cell dysregulation that  heralds vision loss in neovascular AMD.  
  
PUBLIC HEALTH RELEVANCE: The abnormal growth of blood vessels beneath the retina results in devastating vision loss in  age-related macular degeneration (AMD) yet the specific molecular and cellular mechanisms  by which this process occurs are an area of active scientific investigation. The proposal aims to  provide fundamental insights into the dysregulation of the specialized endothelial cells that line  the abnormal blood vessels during AMD progression. Importantly this award will grant the  candidate a critical opportunity to gain essential research training while greatly enhancing  career development and a confident transition to faculty independence.

project_terms:
Ablation;Accounting;Advisory Committees;Affect;Age related macular degeneration;Aging;American;Animal Model;Architecture;Area;Automobile Driving;Award;Basic Science;Biological;Biology;Biomedical Research;Blindness;Blood;Blood Vessels;Bone Marrow Transplantation;Cell Line;Cells;Chairperson;Choroidal Neovascularization;Chromatin Remodeling Factor;Clinical;Clinical Research;Complement Activation;Coupled;Data;Detection;Development;Diagnosis;Diagnostic;Disease;Disease Progression;Drusen;Dyes;Early Diagnosis;Early treatment;Endothelial Cells;Engineering;Environment;Experimental Designs;Exudative age-related macular degeneration;Eye;Faculty;Fellowship;Fluorescein Angiography;Funding;Future;Gene Expression;Genetic;Goals;Grant;Growth;Human;Hypersensitivity;Image;Imaging Techniques;Immune;Immune system;Immunoglobulin Fragments;Immunologic Receptors;In Vitro;Inflammation;Interleukins;Invaded;Investigation;Journals;K-Series Research Career Programs;Kentucky;Knowledge;Laboratories;Lead;Legal;Legal Blindness;Lesion;Leukocytes;Ligands;Malignant Neoplasms;Maps;Mediating;Medicine;Mentors;Methods;Molecular;Molecular Profiling;Molecular Target;Mus;Nature;Nonexudative age-related macular degeneration;Ophthalmic examination and evaluation;Ophthalmology;Outcome;Oxidative Stress;Pathogenesis;Pathologic Processes;Pathway interactions;Patient Care;Patients;Pattern;Physicians;Positioning Attribute;Prevalence;Principal Investigator;Process;Progressive Disease;Quality of life;Regulation;Relative (related person);Reporting;Research;Research Personnel;Research Project Grants;Research Training;Retina;Retinal Diseases;Risk Factors;Role;Running;Safety;Scientist;Sensitivity and Specificity;Signal Pathway;Signal Transduction;Signaling Molecule;Specialist;Specimen;Staging;Structure of retinal pigment epithelium;Sum;Surface;Symptoms;Techniques;Testing;Therapeutic;Therapeutic Uses;Time;Tissues;Toxicology;Training;Training Programs;Transgenic Mice;Treatment Efficacy;Treatment Failure;United States;Universities;Uveal Melanoma;Vascular Diseases;Vascular Endothelial Growth Factor A;Vision;Visual;Work;allergic response;base;biomarker;career;career development;cell type;chemokine;chemokine receptor;cost;cytokine;cytotoxicity;design;disorder of macula of retina;experience;imaging probe;immune activation;improved;in vivo;insight;molecular marker;mouse model;nanocrystal;neutralizing antibody;next generation;normal aging;ocular angiogenesis;pre-clinical;prevent;professor;programs;research study;response;skills;small molecule;therapeutic development;therapeutic target;vision science


application_id: 8165604
project_number: 1K02DA031766-01
project_title: Medications Development for Cannabis-Use Disorders: Clinical Studies
administering_ic: NIDA
award_notice_date: 2011-06-13
opportunity_number: PA-10-057
application_type: 1
activity_code: K02
ic: DA
serial_number: 031766
program_official: BOUGH, KRISTOPHER J
project_start_date: 2011-07-01
project_end_date: 2016-06-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Cannabis is the most commonly used illicit drug in the United States and its use is associated with rates of development of abuse and dependence treatment admission and relapse that are comparable to other illicit drugs. Currently there is no effective pharmacological treatment for cannabis-use disorders. The overarching goal of my career is to develop a clinical research program in which I am able to screen potential medications for cannabis-use disorders using an efficient evidence-based progression of laboratory procedures followed by an evaluation of the efficacy of promising leads in dependent treatment-seeking individuals. My graduate and post-doctoral training and K01 and R01 support have enabled me to build an independent research program in which rational targets for medications development are identified based on the neuropharmacology of 9-THC. My research has identified compounds that could represent major breakthroughs in cannabis-use treatment. The goal of this K02 award is to continue my career development trajectory by acquiring the additional skills and experience needed to move my research into the next steps of the screening process. In order to achieve this goal I have formulated a career development plan that includes additional coursework training with expert preceptors relevant research and data publication/presentation activities further grant development and the receipt and delivery of training in the responsible conduct of research. The research to be conducted during the funding period consists of a three-step screening process to 1) identify targets and/or specific compounds for subsequent screening; 2) test the safety and tolerability of cannabis administration during maintenance on candidate medications; and 3) test the ability of maintenance on putative pharmacotherapies to attenuate the reinforcing effects of cannabis under controlled laboratory conditions while simultaneously monitoring changes in cannabis use in the natural ecology. Importantly this last step represents an innovative approach that will enhance the efficiency of early phase clinical trial research direct the choice of candidate medications for full scale clinical efficacy testing and facilitate my eventual transition to clinical trials research. This research will be carried out in the Department of Behavioral Science at the University of Kentucky which is an exceptional environment having the necessary physical and intellectual resources for successful completion of the proposed career development plan. Moreover this institution is committed to my scientific development and has acknowledged that my research program is an integral part of its scientific community. I have a solid foundation of training and research experience have established a strong record of productivity and independent funding and have demonstrated a commitment to mentoring the next generation of scholars interested in the treatment of cannabis-use disorders. The career development activities supported by the K02 award will allow me to sustain and expand these efforts and thus meet my career goals which will directly impact the field of cannabis-use treatment.  
  
PUBLIC HEALTH RELEVANCE:  Cannabis is the most commonly used illicit drug in the United States and its use is associated with rates of development of abuse and dependence treatment admission and relapse that are comparable to other illicit drugs. Currently there is no effective pharmacological treatment for cannabis-use disorders. Five years of funding is requested to support full-time (100% effort) research and training to support the development of an efficient evidence-based medication screening process.

project_terms:
Abstinence;Address;Admission activity;Adopted;Adverse effects;Agonist;Area;Attenuated;Baclofen;Behavioral Sciences;Biological Assay;Brain;Cannabinoids;Cannabis;Cannabis Smoking;Clinical;Clinical Data;Clinical Research;Clinical Treatment;Clinical Trials;Commit;Communities;Controlled Clinical Trials;Data;Dependence;Development;Development Plans;Diagnostic;Disease;Dose;Drug Combinations;Drug usage;Ecology;Environment;Foundations;Funding;Future;Goals;Gold;Grant;Hybrids;Illicit Drugs;Independent Scientist Award;Individual;Inpatients;Institution;Kentucky;Knowledge;Laboratories;Laboratory Procedures;Laboratory Research;Link;Maintenance;Measures;Mediating;Mentors;Methods;Monitor;Nabilone;Neurons;Neuropharmacology;Outpatients;Persons;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacotherapy;Phase;Population;Procedures;Process;Productivity;Publications;Receptor Cannabinoid CB1;Relapse;Reporting;Research;Research Training;Resistance;Resources;Risk;Safety;Sampling;Screening procedure;Self Administration;Series;Solid;Stimulus;System;Testing;Therapeutic;Time;Toxicology;Training;Treatment Efficacy;Treatment outcome;United States;Universities;Urine;Withdrawal;absorption;base;career;career development;clinical efficacy;clinical practice;cost effective;drug discrimination;drug of abuse;efficacy evaluation;efficacy testing;endogenous cannabinoid system;evidence base;experience;gabapentin;gamma-Aminobutyric Acid;improved;innovation;interest;meetings;next generation;post-doctoral training;post-market research;programs;public health medicine (field);responsible research conduct;safety testing;skills;tiagabine


application_id: 8163679
project_number: 261201000031C-1-0-2
project_title: TAS::75 0849::TAS SURVEILLANCE EPIDEMIOLOGY AND END RESULTS (SEER) PROGRAM
administering_ic: NCI
project_start_date: 2010-08-01
project_end_date: 2011-09-29
contact_pi_person_id: 11064694
contact_pi: TUCKER, THOMAS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_terms:
Cancer Burden;Cancer Control;Cancer Control Research Program;Cancer Etiology;Cancer Patient;Data;Diagnosis;Disease;Incidence;Lead;Medical Surveillance;Monitor;National Cancer Institute;National Cancer Program;Procedures;SEER Program;Subgroup;base;improved;trend


application_id: 8155329
project_number: 5F31AA019853-02
project_title: Role of Anandamide in a Rodent Model of an Alcohol Use Disorder
administering_ic: NIAAA
award_notice_date: 2011-08-15
opportunity_number: PA-09-208
application_type: 5
activity_code: F31
ic: AA
serial_number: 019853
program_official: LIU, QI-YING
project_start_date: 2010-09-30
project_end_date: 2012-09-29
study_section: Neuroscience and Behavior Study Section[AA-4]
contact_pi_person_id: 10296753
contact_pi: LIPUT, DANIEL JAMES
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): Alcohol Use Disorders (AUDs) represent a major public health problem in the United States with over 8% of Americans meeting the DSM-IV criteria for an AUD. Excessive alcohol intake causes progressive neurodegeneration that often leads to cognitive and behavioral deficits and subsequently alcoholism. To date there are no approved therapies for alcohol-induced neurodegeneration thus warranting investigation into novel mechanisms of neuroprotection. The endocannabinoid system has been implicated as a novel neuroprotective system in a variety brain injury models. Studies suggest that the endocannabinoid anandamide (AEA) is elevated after ischemic and traumatic brain injuries which affords endogenous neuroprotection. However it is not know if AEA affords similar neuroprotection for alcohol-induced neurodegeneration. Therefore the guiding hypothesis for this present proposal is that AEA tone is amplified by alcohol-induced brain damage as a neuroprotective mechanism and therefore potentiating AEA tone by inhibiting AEA degradation affords additional neuroprotection. Specific Aim 1 will utilize HPLC/MS/MS techniques to assess levels of AEA in the entorhinal/perirhinal cortex and hippocampus two regions susceptible to alcohol-induced neurodegeneration in a binge model of an AUD. Additionally immunoblotting will be used to elucidate the mechanism of altered AEA tone. Specific Aim 2 will utilize receptor autoradiography to assess cannabinoid 1 (CB1) receptor expression during a binge-alcohol exposure paradigm in the brain regions mentioned above. This will allow us to gain insight to the relationship between CB1 receptors and elevations of AEA in context of neuroprotection as AEA may cause CB1 down-regulation. Aim 3 will consist of two experiments to evaluate the efficacy of enhancing AEA tone by inhibiting fatty acid amide hydrolase (FAAH) to attenuate alcohol- induced neurodegeneration. Experiment 1 will determine an optimum dose of URB-595 a FAAH inhibitor to attenuate alcohol-induced neurodegeneration in the entorhinal/perirhinal cortex and ventral dentate gyrus of the hippocampus using fluoro-jade b stain. The second experiment will test whether AEA neuroprotection is mediated through the CB1 receptor using the CB1 receptor antagonist SR-141716. These studies will provide important insight into the effects of binge alcohol administration on the endocannabinoid system as well as neuroprotective properties of the endocannabinoid system in alcohol-induced brain damage. These studies will lead to future investigation into the specific mechanisms linking the endocannabinoid system to alcohol- induced neurodegeneration. Additionally these results will lead to novel approaches and/or novel pharmaceutical agents for the treatment of neurodegeneration linked to AUD's.  
  
PUBLIC HEALTH RELEVANCE: Current treatments for alcohol use disorders commonly referred to as alcoholism although effective for some are less than adequate.  With over 8% percent of the population currently suffering from an alcohol use disorder it is essential that new therapies become available for these individuals. The proposed studies will give insight into novel treatment strategies for the treatment of alcohol use disorders specifically for the treatment of alcoholic brain damage.

project_terms:
2-arachidonylglycerol;Address;Agonist;Alcoholism;Alcohols;American;Attenuated;Autoradiography;Behavioral;Brain;Brain Injuries;Brain region;Cannabinoids;Cells;Characteristics;Chronic;Cognitive;DSM-IV;Dose;Down-Regulation;Endocannabinoids;Enzymes;Functional disorder;Future;Glutamates;Goals;Heavy Drinking;High Pressure Liquid Chromatography;Hippocampus (Brain);Immunoblotting;Impairment;Individual;Inflammation;Investigation;Ischemia;Knockout Mice;Lead;Link;Literature;Measures;Mediating;Modeling;Nerve Degeneration;Oxidative Stress;Parahippocampal Gyrus;Parkinson Disease;Pathologic;Pathology;Pharmacologic Substance;Play;Population;Property;Proteins;Research;Research Design;Rodent Model;Role;Signal Transduction;Staining method;Stains;Structure;System;Techniques;Testing;Tissues;Traumatic Brain Injury;United States;addiction;alcohol abuse therapy;alcohol exposure;alcohol response;alcohol use disorder;anandamide;cannabinoid receptor;dentate gyrus;excitotoxicity;executive function;fatty acid amide hydrolase;fluoro jade;inhibitor/antagonist;insight;meetings;neuroprotection;neurotoxicity;novel;novel strategies;phosphoric diester hydrolase;prevent;problem drinker;progressive neurodegeneration;public health medicine (field);public health relevance;receptor;receptor density;receptor expression;research study;response;treatment strategy

public_health_relevance:
7. Project Narrative Current treatments for alcohol use disorders commonly referred to as alcoholism although effective for some are less than adequate.  With over 8% percent of the population currently suffering from an alcohol use disorder it is essential that new therapies become available for these individuals. The proposed studies will give insight into novel treatment strategies for the treatment of alcohol use disorders specifically for the treatment of alcoholic brain damage.


application_id: 8150958
project_number: 5R44CA136017-03
project_title: SapC-DOPS nanovesicles for Treating Glioblastoma Multiforme
administering_ic: NCI
award_notice_date: 2011-08-15
opportunity_number: PA-10-050
application_type: 5
activity_code: R44
ic: CA
serial_number: 136017
program_official: HAIM, TODD E
project_start_date: 2008-09-25
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZRG1-ETTN-C(11)B]
contact_pi_person_id: 8717940
contact_pi: XU, KEVIN
other_pis: QI, XIAOYANG
congressional_district: 04
department: Unavailable
primary_duns: 782233501
primary_uei: HJPDQTK95NS8
duns_number: 782233501
uei: HJPDQTK95NS8
fips: US
organization_id: 10010035
organization_name: BEXION PHARMACEUTICALS, INC.
organization_city: COVINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 410112312
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
Our goal is to develop a new molecular entity with a novel mechanism of action for targeting and eliminating glioblastoma multiforme (GBM high grade glioma) a deadly and invasive brain tumor with no effective treatment. Of the 12000 patients expected to be diagnosed with GBM this year most will succumb within the first year. Clearly there is an urgent demand for an efficacious anti-glioma drug. To address this need we are developing a new class of therapeutic proteolipid nanovesicle that can target and destroy glioma tumors. Composed of the small lysosomal sphingolipid activator protein saposin C (SapC 80 aa) and the phospholipid dioleoylphosphatidylserine (DOPS); the stable 200 nm SapC-DOPS nanovesicles have unusually high affinity for phosphatidylserine-enriched membrane surfaces that occur widely in many types of tumor cells and tumor neovasculature. In a mechanism consistent with activation of sphingolipid protein function SapC- DOPS also appears to selectively induce tumor cells to undergo apoptosis. In Phase I of this proposal we demonstrated the feasibility of using SapC-DOPS nanovesicles to target and kill intracranial gliomas in mouse models. Injections of SapC-DOPS in mice with orthotopically implanted gliomas resulted in dose-dependent improvement in survival. Specific targeting of SapC-DOPS to the tumor mass was demonstrated using fluorescently-tagged nanovesicles in live animal imaging experiments. We also showed that saposin C protein in specific association with DOPS is essential for targeting. Anticancer activity of SapC-DOPS was confirmed in a second orthotopic glioma model derived from an aggressive and invasive glioma line. Pilot toxicity data indicated SapC-DOPS to be relatively nontoxic with no evidence of behavioral abnormalities or pathological lesions. Our objective in Phase II proposal is to identify and select optimized SapC-DOPS formulations and treatment methods suitable for advancing toward planned human testing. The specific aims of Phase II are: (1) optimize protein expression and purification and develop clinically suitable formulation; (2) conduct preclinical pharmacokinetics stability and brain and tissue distribution analysis in animal models to determine in vivo disposition of the nanovesicles; and (3) carry out toxicity studies in two animal models to assess safety towards filing of the IND. Upon the completion of these studies we expect to have compelling evidence to progress clinical development of SapC-DOPS nanovesicles as a potent new anti-cancer therapeutic (during SBIR Phase III). This research is innovative because SapC-DOPS nanovesicles offer a unique approach for slowing tumor growth and eliminating deep-seated brain tumors. Ultimately we expect to adapt our technology for targeting different types of tumors and for developing tumor-targeted diagnostics.  
  
PUBLIC HEALTH RELEVANCE:   
We are developing a new molecular entitity for treating glioblastoma multiforme a deadly form of brain tumor that kills over 90% of afflicted patients. Current standards of treatment consisting of surgery radiation and chemotherapy have not been effective in significantly reducing morbidity. Our strategy involves using new proteolipid nanovesicles that can penetrate the tumors and selectively destroy malignant cells without harming normal cells. Success in the proposed animal models will enable us to test the product in humans.

project_terms:
Address;Affinity;Amino Acid Sequence;Animal Model;Animals;Antibodies;Antineoplastic Agents;Apoptosis;Behavioral;Biodistribution;Biological Assay;Blood;Brain;Brain Neoplasms;Cardiotoxicity;Catabolism;Clinical;Clinical Research;Data;Development;Diagnosis;Diagnostic;Dose;Drug Formulations;Drug Kinetics;Drug or chemical Tissue Distribution;Endotoxins;Epitopes;Escherichia coli;Excretory function;Fermentation;Freeze Drying;Future;Glioblastoma;Glioma;Glucosylceramides;Goals;High Pressure Liquid Chromatography;Human;Image;Immune response;Implant;Inflammation;Injection of therapeutic agent;Killings;Lead;Lesion;Life;Macaca fascicularis;Maximum Tolerated Dose;Measures;Membrane;Metabolism;Methods;Modeling;Molecular;Monitor;Monkeys;Morbidity - disease rate;Mus;Normal Cell;Nude Mice;Pathology;Patients;Peptide Sequence Determination;Pharmaceutical Preparations;Phase;Phosphatidylserines;Phospholipids;Plan B;Preparation;Primates;Procedures;Process;Production;Property;Proteins;Proteolipids;Protocols documentation;Radiolabeled;Radiosurgery;Rattus;Research;Rodent;Safety;Small Business Innovation Research Grant;Sphingolipid Activator Proteins;Sphingolipids;Surface;System;Technology;Testing;Therapeutic;Tissues;Toxic effect;Toxicokinetics;Xenograft Model;anti-cancer therapeutic;anticancer activity;base;beta-Glucosidase Stimulating Protein;brain tissue;cancer cell;chemotherapy;citrate carrier;clinical efficacy;effective therapy;expectation;glioma cell line;immunogenic;immunogenicity;immunotoxicity;improved;in vivo;innovation;lysosomal proteins;meetings;mouse model;neoplastic cell;neovasculature;nonhuman primate;novel;pre-clinical;preclinical study;protein expression;protein function;protein purification;public health relevance;radiotracer;research study;response;scale up;standard care;success;tumor;tumor growth

public_health_relevance:
We are developing a new molecular entitity for treating glioblastoma multiforme a deadly form of brain tumorthat kills over 90% of afflicted patients. Current standards of treatment consisting of surgery radiation andchemotherapy have not been effective in significantly reducing morbidity. Our strategy involves using newproteolipid nanovesicles that can penetrate the tumors and selectively destroy malignant cells without harmingnormal cells. Success in the proposed animal models will enable us to test the product in humans.


application_id: 8150759
project_number: 1T32CA160003-01
project_title: Oncology Research Training for Surgeon-Scientists
project_terms: Research Training;Scientist;Surgeon;oncology
administering_ic: NCI
award_notice_date: 2011-07-01
opportunity_number: PA-10-036
application_type: 1
activity_code: T32
ic: CA
serial_number: 160003
program_official: PERKINS, SUSAN N
project_start_date: 2011-07-01
project_end_date: 2016-06-30
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The primary focus of our training program at the University of Kentucky (UK) is to provide intensive and interdisciplinary basic science research training for a minimal period of two years for qualified individuals who are committed to pursuing a career in academic oncologic surgery. Our training program is specifically designed to focus on the research training of academic surgeons so that they will be prepared to become independent scientists and incorporate the new and state-of-the-art techniques learned during their training period into a successful academic career. Also these trainees will be prepared to be active participants in multidisciplinary teams which are required for the optional treatment of the complex cancer patient. Our training program represents a collaboration between the Markey Cancer Center and the Department of Surgery and benefits greatly from the experience and collegiality of the program and associate directors who have worked together for many years and have led other successful training programs for clinician-scientists and basic researchers. The primary training faculty is composed of both basic and clinical-scientists who are collegial collaborative and multidisciplinary; each primary faculty mentor is a recognized expert in his or her field and has a long record of research productivity in the training of young investigators from the US and abroad. In the past 10 years our 15 primary faculty mentors have trained over 100 predoctoral students and more than 130 postdoctoral fellows. The diversity of our training program is further enhanced by the inclusion of seasoned adjunct faculty mentors who will provide additional clinical and biostatistical expertise. Also we have designed a "pipeline" mechanism to provide the time and instruction for promising junior faculty members to further hone their mentoring skills so that they can become effective primary mentors in the future. The breadth and depth of the basic research available in the laboratories of the various faculty mentors will allow the trainees to become familiar with and adept at the application of state-of-the-art techniques for the comprehensive care of the cancer patient. In addition to an intensive research experience the trainees will take formal courses (eg grant writing skills ethics and biostatistics). Furthermore the trainees will participate in regularly scheduled Cancer Center and Department of Surgery seminars and lectures. All of our trainees will be required to complete coursework for a Master's degree in Clinical and Translational Science (CTS). This requirement will further add depth to the program and increase interactions with other scientists on campus through the required supervisory committee. Trainees will also be mentored in the fine points of preparing abstracts scientific papers and presentations and writing successful grant proposals. We are concerned with the alarming decrease in the number of clinician-scientists; this decrease is most apparent in the diminishing number of surgeon-scientists. We are passionate motivated and committed to the training of future academic surgeons.  
  
PUBLIC HEALTH RELEVANCE: The number of clinician-scientists and in particular surgeon-scientists is decreasing at an alarming rate; this reduction will negatively impact the ability and rapidity to "translate" basic discoveries made in cancer research to the patient. Our training program representing a collaboration between the Markey Cancer Center and the Department of Surgery at the University of Kentucky is focused on the interdisciplinary training of future academic surgeons. Of the more than 150 training programs funded by the NCI we are aware of only 2 others that are specifically training surgeon-scientists; we feel that this is an inadequate number to prepare surgeon- investigators to be competitive in the academic arena and to be active participants in multidisciplinary cancer teams which are required for the care of the complex cancer patient.


application_id: 8147698
project_number: 5R01HD061617-02
project_title: Function of RUNX transcription factors in COCs
administering_ic: NICHD
award_notice_date: 2011-08-30
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HD
serial_number: 061617
program_official: TAYMANS, SUSAN
project_start_date: 2010-09-24
project_end_date: 2014-05-31
study_section: Cellular, Molecular and Integrative Reproduction Study Section[CMIR]
contact_pi_person_id: 8244639
contact_pi: JO, MISUNG
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of the present proposal is to determine the molecular/cellular mechanism(s) involved in the maturation process of cumulus oocyte complexes (COCs). Proper maturation of the COC is critical to reproductive success in vivo and in vitro. Our lack of a complete understanding of this maturation process restricts our ability to manage fertility in vivo and hinders implementation of ART such as in vitro fertilization and in vitro maturation. Recent studies by our laboratory and others have begun to shed light on a small family of nuclear transcription factors RUNX1 and RUNX2 as key transcriptional regulators involved in COC expansion. Our preliminary data demonstrated that Runx1 and Runx2 expression is highly induced in cumulus cells of periovulatory follicles. We also found that RUNX1 and RUNX2 regulate the expression of Ptgs2 (a rate-limiting enzyme in the biosynthesis of prostaglandins) and Hapln1 (a stabilizer of cumulus matrix) in mural granulosa cells and/or cumulus cells. Both gene products are known to play crucial roles in COC expansion. Most importantly our pilot study demonstrated that over-expression of dominant negative RUNX in cumulus cells blocked COC expansion. Based on these novel findings we hypothesized that RUNX1/2 are essential transcriptional regulators necessary for the gonadotropin surge-induced COC expansion. This hypothesis will be tested by first demonstrating the functional significance of Runx1/2 expression in cumulus cells (Aim #1). Secondly we will determine the regulation action(s) of RUNX1 and RUNX2 on their target genes (Aim #2). Next we will determine the regulatory mechanism(s) of Runx1 and Runx2 expression in cumulus cells (Aim #3). These 3 Aims will be studied using rat COCs. To insure that the data obtained from rat studies is translatable to humans RUNX1/2 and their target gene expression profile will be also verified using human cumulus cells collected throughout the periovulatory period. We will also examine the correlation of the cumulus expression of RUNX1/2 and their target genes to oocyte quality fertilization and embryo development using COCs obtained from women undergoing IVF (Aim #4). These human studies will serve as a foundation for future translational/clinical application. The information obtained from the proposed studies will not only advance our understanding of the mechanism involved in COC maturation but also be instrumental for future translational/clinical application(s) thus leading to improved management of fertility in vivo and in vitro.  
  
PUBLIC HEALTH RELEVANCE: Proper maturation of COCs is requisite for successful ovulation and fertilization. Appropriate COC expansion induced by the preovulatory gonadotropin surge is directly linked to oocyte quality and developmental competence. There are still huge gaps in our understanding of how the preovulatory gonadotropin surge induces the maturation process in COCs. Previous studies and our preliminary data suggest that RUNX transcription factor(s) plays a critical role in cumulus expansion by regulating the transcription of specific periovulatory cumulus genes. Building upon these findings the present proposal will determine the molecular/cellular mechanism(s) involved in COC expansion by elucidating the functional role(s) of RUNX transcription factors during maturation of COCs. Information derived from the present proposal will provide new insight into the mechanisms involved in COC maturation. Such knowledge can be applied for promoting and inhibiting this critical facet of ovarian physiology thereby allowing us to better manage fertility in vivo and in vitro.

project_terms:
Adenoviruses;Anabolism;Animal Model;Cells;Collecting Cell;Competence;Complex;Data;Development;Dominant-Negative Mutation;Embryonic Development;Enzymes;Female;Fertility;Fertilization;Fertilization in Vitro;Foundations;Future;GDF9 gene;Gene Expression;Gene Expression Profile;Gene Targeting;Genes;Genetic Transcription;Goals;Gonadotropins;Hormonal;Human;In Vitro;Knowledge;Laboratories;Light;Link;Mediating;Mediator of activation protein;Molecular;Molecular Profiling;Mus;Nuclear Family;Oocytes;Ovarian;Ovulation;Peptides;Physiology;Pilot Projects;Play;Process;Promotor (Genetics);Prostaglandins;Proteins;RUNX1 gene;Rattus;Regulation;Role;Signal Transduction;Small Interfering RNA;Testing;Woman;base;clinical application;combinatorial;cytokine;granulosa cell;implantation;improved;in vivo;insight;novel;public health relevance;reproductive success;success;time interval;transcription factor

public_health_relevance:
Project Narrative Proper maturation of COCs is requisite for successful ovulation and fertilization. Appropriate COCexpansion induced by the preovulatory gonadotropin surge is directly linked to oocyte quality anddevelopmental competence. There are still huge gaps in our understanding of how the preovulatorygonadotropin surge induces the maturation process in COCs. Previous studies and our preliminary datasuggest that RUNX transcription factor(s) plays a critical role in cumulus expansion by regulating thetranscription of specific periovulatory cumulus genes. Building upon these findings the present proposal willdetermine the molecular/cellular mechanism(s) involved in COC expansion by elucidating the functional role(s)of RUNX transcription factors during maturation of COCs. Information derived from the present proposal willprovide new insight into the mechanisms involved in COC maturation. Such knowledge can be applied forpromoting and inhibiting this critical facet of ovarian physiology thereby allowing us to better manage fertility invivo and in vitro.


application_id: 8146941
project_number: 5R21ES020123-02
project_title: Repair of Airway Epithelium Following Chlorine Lung Injury
administering_ic: NIEHS
award_notice_date: 2011-08-22
opportunity_number: PAR-10-019
application_type: 5
activity_code: R21
ic: ES
serial_number: 020123
program_official: NADADUR, SRIKANTH
project_start_date: 2010-09-23
project_end_date: 2013-08-31
study_section: Special Emphasis Panel[ZRG1-MDCN-J(50)R]
contact_pi_person_id: 2736750
contact_pi: HOYLE, GARY W.
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Acute high-level exposures to chemicals that damage the respiratory tract can cause life-threatening lung injury. Chlorine gas is a highly toxic respiratory irritant that is considered a chemical threat agent because of the possibility that it could be released in industrial accidents or terrorist attacks. Chlorine like many pulmonary toxicants produces injury to epithelial cells lining the respiratory tract. Loss of the respiratory epithelial cell barrier contributes to other sequelae observed in acute lung injury including pulmonary edema airway obstruction inflammation and respiratory infections. Efficient repair of respiratory epithelium and restoration of barrier function are essential for resolution of chlorine-induced lung injury. The epithelium of the respiratory tract is repaired following injury through the proliferation and differentiation of stem cells. One type of cell involved in the repair of airway epithelium is the basal cell. The low-affinity nerve growth factor receptor (NGFR) has been identified as a marker for basal cells as well as for epithelial stem cells in other tissues but the role of this protein in stem cell function is unknown. NGFR binds multiple neurotrophin ligands including nerve growth factor (NGF) brain-derived neurotrophic factor and neurotrophin 3. The hypothesis to be tested in the proposed studies is that NGFR controls the proliferation survival and differentiation of lung epithelial stem cells following chlorine-induced lung injury. In Specific Aim 1 basal cells will be purified from the trachea of normal mice and from mutant mice lacking functional NGFR. The ability of the cultured cells to survive proliferate and differentiate into other types of epithelial cells (ciliated cells and Clara cells) will be measured in the presence or absence of NGFR ligands. In Specific Aim 2 wild-type NGFR knockout and NGF transgenic mice will be exposed to chlorine gas according to a protocol established in the Principal Investigator's laboratory. Effects of neurotrophins will be tested by delivering ligands intranasally or by using NGF-overexpressing transgenic mice previously developed in the Principal Investigator's laboratory. The extent of tracheal epithelial repair will be measured at various times after chlorine exposure. In Specific Aim 3 the effect of neurotrophins on epithelial repair following chlorine exposure in rabbits will be investigated. Rabbits will be used for these studies because of the wider distribution of basal cells in the airways in this species which is more similar to that in humans. The proposed experiments will not only investigate mechanisms of epithelial repair but will also foster the development of therapeutic agents that could be used to stimulate resolution of lung injury following inhalation of toxic chemicals.  
PUBLIC HEALTH RELEVANCE:  This application is submitted in response to PAR-10-019 CounterACT Exploratory/Developmental Projects in Translational Research (R21). The proposed experiments are designed to understand how the lung repairs itself after inhalation of a toxic gas with the goal of developing therapy for lung injury based on stimulating lungs cells to accelerate repair. This type of research is sought through the Funding Opportunity Announcement because of concerns that U. S. civilians could be adversely affected by highly toxic chemicals released intentionally in terrorist attacks or unintentionally in industrial accidents or natural disasters.

project_terms:
Acute;Affect;Airway Obstruction;Basal Cell;Binding (Molecular Function);Brain-Derived Neurotrophic Factor;Breathing;Cell Differentiation process;Cell Line;Cell physiology;Cells;Characteristics;Chemicals;Chlorine;Clara cell;Clinical;Coughing;Cultured Cells;Development;Distal;Dyspnea;Epithelial;Epithelial Cells;Epithelium;Exposure to;Fostering;Funding Opportunities;Gases;Goals;Health;Human;Industrial Accidents;Inflammation;Injury;Irritants;Knock-out;Knockout Mice;Laboratories;Life;Ligands;Lung;Lung Injury Acute;Measures;Microarray Analysis;Mus;Mutant Strains Mice;NGFR Protein;Natural Disasters;Natural regeneration;Nerve Growth Factors;Neurotrophin 3;Oryctolagus cuniculus;Peptides;Poisons;Population;Principal Investigator;Proliferating;Proteins;Protocols documentation;Pseudostratified Epithelium;Pulmonary Edema;Recording of previous events;Research;Resolution;Respiratory System;Respiratory Tract Infections;Respiratory tract structure;Role;Signal Transduction;Stem cells;Structure of respiratory epithelium;Symptoms;Testing;Therapeutic Agents;Time;Tissues;Toxic effect;Trachea;Tracheal Epithelium;Transgenic Mice;Translational Research;Unconscious State;United States;Wild Type Mouse;airway epithelium;base;cell type;chemical release;chlorine gas;design;embryonic stem cell;injured;injured airway;lung injury;neurotrophic factor;novel strategies;overexpression;repaired;research study;respiratory;response;restoration;small molecule;stem cell differentiation;therapy development;toxicant;treatment strategy

public_health_relevance:
This application is submitted in response to PAR-10-019 CounterACT Exploratory/DevelopmentalProjects in Translational Research (R21). The proposed experiments are designed to understand howthe lung repairs itself after inhalation of a toxic gas with the goal of developing therapy for lung injurybased on stimulating lungs cells to accelerate repair. This type of research is sought through theFunding Opportunity Announcement because of concerns that U. S. civilians could be adverselyaffected by highly toxic chemicals released intentionally in terrorist attacks or unintentionally inindustrial accidents or natural disasters.


application_id: 8146894
project_number: 5F31DA029374-02
project_title: Clinical Evaluation of Novel Methods for Extending Microneedle Pore Lifetime
administering_ic: NIDA
award_notice_date: 2011-06-13
opportunity_number: PA-09-208
application_type: 5
activity_code: F31
ic: DA
serial_number: 029374
program_official: LAO, GUIFANG
project_start_date: 2010-07-01
project_end_date: 2012-06-30
study_section: Special Emphasis Panel[ZRG1-F10A-S(20)L]
contact_pi_person_id: 10105185
contact_pi: BROGDEN, NICOLE K
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term objective of the proposed research project entitled "Clinical evaluation of novel methods for extending microneedle pore lifetime" is to improve current methods of transdermal drug delivery by increasing the lifetime of pores created from inserting microneedles into the skin. Improvement of transdermal drug delivery techniques (via the use of microneedles) would have important clinical implications by providing a less invasive means to deliver drugs systemically which would lead to greater patient safety and compliance. This could also have strong implications in developing better treatments for alcoholism and opiate addiction as this proposal examines the delivery of naltrexone (an opiate antagonist used for the treatment of opioid and alcohol abuse) following microneedle insertion. Effective transdermal delivery would be an excellent alternative to the current oral and parenteral formulations of naltrexone. The specific aims of the proposal include 1) inhibition of the cyclooxygenase (COX) pathway as a means to inhibit pore closure 2) pharmacokinetic analysis of naltrexone to characterize pore lifetime following COX inhibition and 3) employing small-interfering RNA (siRNA) methods to inhibit pore closure. The research methods will involve the use of in vitro and in vivo models (cell culture qRT-PCR ELISAs) animal models (hairless guinea pigs and Yucatan miniature pigs) and human studies. Many of the methods described in the proposal involve novel applications of commercially available products or development of innovative means to improve transdermal drug delivery with the use of microneedles. Studying these compounds and delivery methods makes it feasible to do translational bioengineering and biopharmaceutical training research in human proof-of-concept studies.

project_terms:
Alcohol abuse;Alcoholism;Animal Model;Biological Products;Biomedical Engineering;Cavia;Cell Culture Techniques;Clinical;Compliance behavior;Development;Diclofenac;Drug Formulations;Drug Kinetics;Family suidae;Goals;Healed;Heroin Abuse;Human;In Vitro;Knowledge;Lead;Medical;Methods;Modeling;Naltrexone;Narcotic Antagonists;Opiate Addiction;Oral;Pain;Pathway interactions;Pharmaceutical Preparations;Process;Prostaglandin-Endoperoxide Synthase;Research;Research Methodology;Research Project Grants;Research Training;Skin;Small Interfering RNA;Solid;Stainless Steel;Techniques;Time;Topical application;Transdermal substance administration;Vascular Endothelial Growth Factors;Work;Wound Healing;alcoholism therapy;celecoxib;clinical application;clinically relevant;healing;improved;in vivo Model;innovation;novel;opioid abuse;patient safety;public health medicine (field);public health relevance;research clinical testing

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Project Narrative This research will lead to a better understanding of new methods for delivering drugs through the skin. This will help to improve public health by leading to less painful and potentially safer ways of treating many different medical conditions including heroin abuse and alcoholism.


application_id: 8146451
project_number: 3P30ES014443-04S1
project_title: Center for Environmental Genomics and Integrative Biology
administering_ic: NIEHS
award_notice_date: 2010-09-23
opportunity_number: RFA-ES-05-008
application_type: 3
activity_code: P30
ic: ES
serial_number: 014443
suffix: S1
program_official: QUINN, ASHLINN KO
project_start_date: 2007-06-04
project_end_date: 2012-03-31
study_section: Environmental Health Sciences Review Committee[EHS]
contact_pi_person_id: 6221833
contact_pi: RAMOS, KENNETH S.
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
The main goal of the Center for Environmental Genomics and Integrative Biology (CEGIB) is to support outstanding basic and translational investigations into the etiology of environmental disease and the development of new approaches to manage these conditions.   Center investigators with diverse disciplinary backgrounds and research interests will combine their efforts to: 1) study genetic molecular and cellular mechanisms of environmental injury 2) evaluate the ethical legal and social implications of genomics research and 3) advance the emerging fields of environmental genomics and intergrative biology.   CEGIB will provide scientific leadership and administrative support for creation of a synergistic inter- and trans-disciplinary network structure that brings together University of Louisville investigators to focus on the study of environmental disease.   The Center will support facility cores in Bioinformatics Biostatistics and Computational Biology and Integrative Health Sciences.  These cores will provide expertise and facilities to advance research efforts in the areas of environmental cardiology environmental carcinogenesis and developmental origins of health and disease.  The Center structure also includes programs in Career Development for Junior Investigators and a Pilot Project Program to encourage development of novel research approaches and data collection that enable pursuit of other funding mechanisms.   A Community Outreach and Education Core has been included to facilitate translation of scientific information into knowledge that can use be used to reduce health disparities of underserved Hispanic populations in the greater Louisville area.   CEGIB is in a unique position to meet its objectives given the depth of expertise and talent in environmental health molecular biology bioinformatics and computational biology and ELSI research and strong institutional emphasis on bench-to-bedside and bench-to-community investigations.   The focus on environmental  genomics and integrative biology reflects the interests of its members in advancing molecular investigations and ELSI research of environmentally related diseases.   The creation of a Center with a resolute focus on environmental genomics and integrative biology will further NIEHS' goal to understand the etiology of environmental disease at its most fundamental levels and provide a visible infrastructure for advancement of the Institute's agenda in the post-genomic era.

project_terms:
Area;Bioinformatics;Biology;Biometry;Cardiology;Communities;Community Outreach;Computational Biology;Core Facility;Data Collection;Development;Disease;Educational aspects;Environmental Health;Etiology;Funding Mechanisms;Genomics;Goals;Health;Health Sciences;Hispanics;Injury;Institutes;Investigation;Knowledge;Leadership;Molecular;Molecular Biology;Molecular Genetics;National Institute of Environmental Health Sciences;Pilot Projects;Positioning Attribute;Research;Research Infrastructure;Research Personnel;Structure;Talents;Translations;Universities;bench to bedside;career development;environmental carcinogenesis;ethical legal social implication;health disparity;interest;meetings;member;novel;novel strategies;programs


application_id: 8146162
project_number: 5R43DK089892-02
project_title: Biomarker for Early Detection of Chronic Kidney Disease
administering_ic: NIDDK
award_notice_date: 2011-09-13
opportunity_number: PA-09-080
application_type: 5
activity_code: R43
ic: DK
serial_number: 089892
program_official: GOSSETT, DANIEL ROBERT
project_start_date: 2010-09-20
project_end_date: 2012-05-31
study_section: Special Emphasis Panel[ZRG1-DKUS-G(11)B]
contact_pi_person_id: 1897474
contact_pi: CARRITHERS, STEPHEN L
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 189577070
primary_uei: DJ6WUEKKFBM8
duns_number: 189577070
uei: DJ6WUEKKFBM8
fips: US
organization_id: 10001287
organization_name: SEQUELA
organization_city: PEWEE VALLEY
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400569116
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal is submitted in response to the program announcement PA-09-080 "Omnibus Solicitation of the NIH CDC and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44])" and intended to be directed to the NIDDK with a potential dual assignment to the NHLBI. There are an estimated 14 million Americans with early chronic kidney disease (CKD). Early diagnosis and treatment of CKD are the only cost-effective means to reverse this growing problem. Current methods and biomarkers that are used to assess CKD are effective once the disease is well established but none thus far are reliable for the detection of early renal disease. Existing tests used by physicians today are all essentially markers of kidney filtration function. NIH recognizes the challenge to diagnose CKD early during its initiation and development phases in order to prevent further renal damage reduce cardiovascular risk and minimize the economic impact of CKD through program announcements such as PA-09-204 (Development and Validation of Disease Biomarkers) and PA-09-181 (Non-Invasive Methods for Diagnosis and Progression of Diabetes Kidney Urological Hematological and Digestive Diseases). We will produce a new ELISA for CKD based upon the use of a novel biomarker that reflects in part the pathophysiology of kidney disease. Detection of this biomarker for CKD will give laboratory results and clinical insight that is complementary to creatinine-based GFR estimates (eGFR) as well as tests for urine albumin. Development of this test should result in a more reliable identification and detection of early CKD patients. In addition our CKD ELISA would give physicians the ability to evaluate patients that have been recently diagnosed with hypertension or diabetes the two leading causes of CKD. In turn this Phase I proposal will evaluate the prototype assay in both populations. We will look for the influence of comorbid conditions and medications on assay performance. Lastly we will evaluate whether patient characteristics such as age gender BMI ethnicity and other factors impact on assay performance. The information gained from this test will also lead to a better basic understanding of the biological mechanisms underlying CKD. Sequela requests Phase I support so that we can evaluate a prototype assay and test its feasibility to help identify at-risk patients for early kidney disease and monitor therapy with the ultimate goal of obtaining FDA approval.  
  
PUBLIC HEALTH RELEVANCE: Chronic Kidney Disease affects nearly 26 million people in the United States which places them at higher risk of renal failure and hemodialysis. We will develop an ELISA to aid in the diagnosis of early kidney disease to aid physicians in earlier treatment and better assessment of chronic kidney disease.

project_terms:
Affect;Age;Albumins;American;Antihypertensive Agents;Award;Biochemical Markers;Biological;Biological Assay;Blood Circulation;Cardiovascular Diseases;Cardiovascular system;Centers for Disease Control and Prevention (U.S.);Cessation of life;Characteristics;Chronic Kidney Failure;Clinical;Clinical Trials;Collaborations;Collection;Complement;Confusion;Creatinine;Data;Detection;Development;Diabetes Mellitus;Diagnosis;Diagnostic;Diagnostic tests;Dialysis procedure;Diet;Digestive System Disorders;Disease;Disease Outcome;Early Diagnosis;Early treatment;Effectiveness;End stage renal failure;Endocrinology;Enzyme-Linked Immunosorbent Assay;Erythrocytes;Essential Hypertension;Ethnicity aspects;Evaluation;Exclusion Criteria;Excretory function;Filtration;Freezing;Functional disorder;Gender;Glomerular Filtration Rate;Goals;Gold;Health;Hematological Disease;Hemodialysis;Homeostasis;Hormonal;Hospitals;Human;Hypertension;Impairment;Indiana;Institutes;Institutional Review Boards;Intervention;Iothalamate;Israel;Kidney;Kidney Diseases;Kidney Failure;Kidney Transplantation;Laboratories;Lead;Letters;Life;Location;Measurement;Measures;Metabolism;Methods;Microalbuminuria;Modeling;Monitor;NIH Program Announcements;National Heart Lung and Blood Institute;National Institute of Diabetes and Digestive and Kidney Diseases;Nephrology;Nephrons;Parents;Participant;Patients;Performance;Pharmaceutical Preparations;Phase;Physicians;Plasma;Play;Population;Population Control;Prevention;Production;Proteins;Protocols documentation;Receiver Operating Characteristics;Recording of previous events;Renal Glycosuria;Renal function;Risk;Risk Factors;Role;Sampling;Series;Serum;Site;Small Business Innovation Research Grant;Sodium;Sodium Chloride;Staging;Technology;Testing;Therapeutic Intervention;Transplant Recipients;Transplantation;Transport Process;Tube;United States;United States National Institutes of Health;Universities;Urine;Urologic Diseases;Validation;Waiting Lists;Water;Weight;Work;base;biomarker;cardiovascular disorder risk;cardiovascular risk factor;cost;cost effective;diabetic;diabetic patient;economic impact;high risk;improved;inorganic phosphate;insight;medical schools;novel;novel diagnostics;post gamma-globulins;prevent;prohormone;prototype;prouroguanylin;public health medicine (field);public health relevance;receptor;response;tool

public_health_relevance:
PROJECT NARRATIVE Chronic Kidney Disease affects nearly 26 million people in the United States which places them athigher risk of renal failure and hemodialysis. We will develop an ELISA to aid in the diagnosis of early kidneydisease to aid physicians in earlier treatment and better assessment of chronic kidney disease.


application_id: 8145754
project_number: 3R01EY018350-04S1
project_title: Pro-and anti-angiogenic effects of vascular endothelial growth factor-A
administering_ic: NEI
award_notice_date: 2010-09-20
application_type: 3
activity_code: R01
ic: EY
serial_number: 018350
suffix: S1
program_official: SHEN, GRACE L
project_start_date: 2007-08-01
project_end_date: 2012-07-31
study_section: Biology and Diseases of the Posterior Eye Study Section[BDPE]
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): Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. The overwhelming cause of severe vision loss in these patients is choroidal neovascularization (CNV) the growth of abnormal blood vessels beneath the retina. The mechanisms responsible for this process have been deduced to angiogenesis the sprouting of new blood vessels from pre-existing vasculature and vasculogenesis the recruitment proliferation and incorporation of bone marrow-derived progenitor cells into nascent vasculature. Vascular endothelial growth factor-A (VEGF-A) is a critical mediator in both these pathways and is the target for many FDA approved therapies for CNV. Using the mouse model of laser-induced CNV we recently discovered a paradoxical effect whereby both endogenous and exogenous VEGF-A suppressed CNV during the acute phase after laser-injury whereas before injury they enhanced CNV consistent with dogma. We determined that the matricellular protein SPARC/osteonectin constitutively interacts with VEGF-A and prevents it from activating VEGF receptor (VEGFR)-1. Because SPARC levels decline transiently after injury VEGF-A activates an anti-angiogenic pathway through VEGFR-1 binding and subsequent dephosphorylation of VEGFR-2 the principal signaling receptor that promotes neovascularization. VEGF-A also downregulated the expression of monocyte chemoattractant protein-1 (Ccl-2) which suppressed cell-mediated inflammation and subsequent CNV. The molecular basis of the vexing macular predilection for CNV in humans is unknown; however the spatial confinement of SPARC in the macula of monkey retina is intriguing as a potential underpinning for this phenomenon. The specific aims of this proposal are to further define the interaction of SPARC and VEGF-A in experimental CNV determine the precise anti-angiogenic and anti-vasculogenic mechanisms of VEGF-A induced CNV suppression evaluate the efficacy of modulating SPARC in a non-human primate model of CNV and define the expression and activity profiles of SPARC and VEGF-A and its receptors in human retina and choroid. Our long term goal is to fully characterize the SPARC-VEGF-A pathway in CNV and identify novel targets for the treatment of this blinding condition which constitutes nothing short of a public health epidemic.

project_terms:
Acute;Affect;Age related macular degeneration;Animal Model;Binding (Molecular Function);Biochemical;Biology;Blindness;Blood Vessels;Bone Marrow;Breast;Cells;Choroid;Choroidal Neovascularization;Clinical;Complex;Data;Development;Disease;Elderly;Endothelial Cells;Environment;Epidemic;Extracellular Matrix;Extracellular Protein;FDA approved;Genes;Goals;Growth;Human;In Situ;In Vitro;Incidence;Inflammation;Inflammatory;Injury;Laser injury;Lasers;Leukocytes;Ligands;Link;Malignant neoplasm of prostate;Mediating;Mediator of activation protein;Membrane;Methods;Modality;Modeling;Molecular;Monkeys;Monocyte Chemoattractant Protein-1;Operative Surgical Procedures;Osteonectin;PTPN6 gene;Pathologic Neovascularization;Pathway interactions;Patients;Phase;Prevalence;Process;Promotor (Genetics);Protein Dephosphorylation;Proteins;Receptor Activation;Receptor Protein-Tyrosine Kinases;Receptor Signaling;Relative (related person);Reporting;Research Personnel;Retina;Role;Route;Signal Transduction;Specimen;Stem cells;Structure of retinal pigment epithelium;Testing;Therapeutic;Tissues;United States;Vascular Endothelial Growth Factor A;Vascular Endothelial Growth Factor Receptor;Vascular Endothelial Growth Factor Receptor-1;angiogenesis;base;bone;cytokine;driving force;drug development;in vivo;injured;insight;macula;mouse model;neovascularization;nonhuman primate;novel;prevent;programs;public health medicine (field);receptor;receptor binding;response;stem;therapy development;vasculogenesis


application_id: 8145584
project_number: 5R01AR060701-02
project_title: The role of satellite cells in adult skeletal muscle growth and maintenance
administering_ic: NIAMS
award_notice_date: 2011-08-09
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AR
serial_number: 060701
program_official: BOYCE, AMANDA T
project_start_date: 2010-09-17
project_end_date: 2015-08-31
study_section: Special Emphasis Panel[ZRG1-MOSS-R(02)M]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: MCCARTHY, JOHN JOSEPH
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): The loss of skeletal muscle mass is of clinical importance because it is associated with increased morbidity and mortality as well as a marked deterioration in the quality of life. A broad patient population is affected by significant losses in muscle mass including those afflicted by various systemic diseases (cancer sepsis HIV- AIDS) chronic physical inactivity as a result of long term bed rest rheumatoid arthritis and limb immobilization and sarcopenia the age associated loss in muscle mass and strength. Satellite cells are currently an attractive therapeutic target given their stem cell characteristics and essential role in post-natal muscle growth and regeneration. What remains controversial is the necessity of satellite cells in other aspects of muscle plasticity such as hypertrophy re-growth following atrophy and muscle maintenance with aging. In an effort to resolve this fundamental issue a novel mouse line was created which enables the specific ablation of satellite cells in mature skeletal muscle. The Pax7-DTA mouse will be used to investigate the physiological function of satellite cells in skeletal muscle hypertrophy (Aim 1) and re-growth following muscle atrophy (Aim 2). The results from the proposed experiments are expected to provide fundamental knowledge on the function of satellite cells in adult skeletal muscle plasticity which will help define the therapeutic value of satellite cells in treating the loss of muscle mass in various clinical conditions.  
  
PUBLIC HEALTH RELEVANCE: Loss of muscle a common symptom associated with many chronic diseases physical inactivity or aging negatively impacts a person's quality of life increases the susceptibility to other complications of disease and can even lead to death. Treatments designed to restore or prevent muscle loss have in part focused on using muscle stem cells referred to as satellite cells. The goal of the proposed research is to determine if satellite cells are necessary for adult muscle growth and thus are an appropriate target for therapy for skeletal muscle loss.

public_health_relevance:
RelevanceLoss of muscle a common symptom associated with many chronic diseases physical inactivity or agingnegatively impacts a person's quality of life increases the susceptibility to other complications of disease andcan even lead to death. Treatments designed to restore or prevent muscle loss have in part focused on usingmuscle stem cells referred to as satellite cells. The goal of the proposed research is to determine if satellitecells are necessary for adult muscle growth and thus are an approprioate target for therapy for skeletal muscleloss.


application_id: 8144562
project_number: 2U01ES015673-07
project_title: Novel Therapies for Chlorine-Induced Lung Injury
administering_ic: NIEHS
award_notice_date: 2011-08-22
opportunity_number: PAR-10-180
application_type: 2
activity_code: U01
ic: ES
serial_number: 015673
program_official: NADADUR, SRIKANTH
project_start_date: 2006-09-29
project_end_date: 2016-05-31
study_section: Special Emphasis Panel[ZRG1 MDCN-J (50)]
contact_pi_person_id: 2736750
contact_pi: HOYLE, GARY W.
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Chlorine gas is a highly toxic respiratory irritant that is considered a chemical threat agent. The goal of the research proposed in this renewal application is to develop a medical countermeasure to treat lung injury induced by chlorine inhalation. During the previous U01 award a mouse model of chlorine gas inhalation was developed a detailed characterization of lung injury following chlorine exposure was performed signaling pathways representing possible targets for therapeutic intervention were investigated strategies for manipulating signaling pathways of interest were tested and compounds that significantly inhibited lung injury or inflammation in chlorine-exposed mice were identified. Rolipram a type 4 phosphodiesterase inhibitor was shown to stimulate alveolar fluid transport decrease pulmonary edema and inhibit airway hyperreactivity. Triptolide a diterpenoid anti-inflammatory compound inhibited chlorine-induced lung inflammation. In the present application formulations of rolipram and triptolide will be developed for intramuscular (i.m.) injection a preferred delivery route for potential mass casualty situations. In addition methylprednisolone an FDA-approved anti-inflammatory compound will be evaluated as an alternative to triptolide. The overall hypothesis to be tested is that i.m. injection of an encapsulated formulation of rolipram in combination with an anti-inflammatory compound will represent the most effective countermeasure for chlorine-induced lung injury. Countermeasure formulations will be tested in mice to determine efficacy against chlorine-induced acute lung injury to assess longer term effects on airway remodeling and airway hyperreactivity and to measure the length of effective post-exposure treatment window. The most effective countermeasure formulation will be evaluated in rabbits to demonstrate efficacy in a non-rodent animal model. An optimized countermeasure formulation with efficacy against chlorine-induced lung injury in mice and rabbits will be subject to additional studies necessary for progression toward regulatory approval including collection of pharmacokinetic/pharmacodynamic and toxicity data and production of the countermeasure using current good manufacturing practices.   
Public Health Relevance: The goal of the proposed experiments is to develop novel ways to treat acute lung injury caused by chlorine gas inhalation. The research will focus on medical countermeasures that can be easily and rapidly administered in a mass casualty situation. This type of research is important because of concerns that U.S. civilians could be adversely affected by the accidental or intentional release of highly toxic chemicals.

project_terms:
Affect;Alveolar;Animal Model;Anti-Inflammatory Agents;Anti-inflammatory;Award;Breathing;Chemicals;Chlorine;Collection;Data;Development;Diterpenes;Drug Formulations;Drug Kinetics;Encapsulated;FDA approved;Gases;Goals;Human;Inflammation;Intramuscular Injections;Irritants;Length;Liquid substance;Long-Term Effects;Lung Inflammation;Lung Injury Acute;Maximum Tolerated Dose;Measures;Medical;Methylprednisolone;Mus;No-Observed-Adverse-Effect Level;Oryctolagus cuniculus;Pathway interactions;Pharmacodynamics;Phosphodiesterase Inhibitors;Poisons;Principal Investigator;Production;Pulmonary Edema;Research;Research Institute;Rodent;Rolipram;Route;Signal Pathway;Testing;Therapeutic Intervention;Toxic effect;Universities;airway hyperresponsiveness;airway remodeling;chemokine;chlorine gas;efficacy testing;interest;lung injury;mouse model;neutrophil;novel;pre-clinical;prevent;public health relevance;research study;respiratory;triptolide


application_id: 8143019
project_number: 3R01NS039774-07S1
project_title: Sympathetic Function in Diabetes
administering_ic: NINDS
award_notice_date: 2010-09-15
application_type: 3
activity_code: R01
ic: NS
serial_number: 039774
suffix: S1
program_official: MITLER, MERRILL
project_start_date: 2000-09-30
project_end_date: 2011-08-31
study_section: Special Emphasis Panel[ZRG1-CICS(01)Q]
contact_pi_person_id: 1887495
contact_pi: RANDALL, DAVID C
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): Autonomic neuropathy is a serious complication of both Types 1 and 2 diabetes mellitus. We identified 2 promising indices of sympathetic neuropathy during the initial years of this grant. The first is a cross- correlation between arterial blood pressure (BP) and heart rate; the second is a mathematical (wavelet) analysis sensitive to a specific rhythm in arterial BP that is uniquely driven by the sympathetic nervous system. We now propose in Aim 1 to analyze changes in our indices as diabetic dysautonomia develops in the diabetes prone (DP) rat and to identify characteristics of the indices that coincide with the development of moderate (Stage 1) and severe (Stage 2) autonomic neuropathy. We will accomplish this by recording BP via telemetry for >10 months in the DP rat vs. a non-diabetic control; recording commences before the DP rat converts to the diabetic state allowing us to follow progressive changes in function during the development of AN. Objective features of the indices will be assessed relative to quantitative histological characteristics of the autonomic nerves harvested from the rats at each of the stages. In Aim 2 we compare in human diabetic patients our new indices to standard clinical tests of autonomic neuropathy. We will assess our indices in our patients against state-of-the-art evaluations of the autonomic control of cardiovascular function. Tests will be conducted during rest and during a passive tilt intended to challenge sympathetic and parasympathetic systems. Our ultimate goal is to develop a practical assessment of autonomic neuropathy that relative to those currently in use is more sensitive (detect and track the initial stages of the disease process more reliably) more selective (distinguish between sympathetic vs. parasympathetic dysfunction) and easier and less expensive to obtain. The results of these experiments will thereby help develop better clinical approaches to the control and management of diabetic autonomic neuropathy.

project_terms:
Age;Anatomy;Appearance;Area;Arts;Autonomic Dysfunction;Blood Glucose;Blood Pressure;Breathing;Cardiovascular Physiology;Cardiovascular system;Characteristics;Clinical;Complication;Data;Development;Diabetes Mellitus;Diabetic Autonomic Neuropathy;Disease;Disease Progression;Dysautonomias;Evaluation;Frequencies (time pattern);Functional disorder;Goals;Grant;Harvest;Head;Heart Rate;Human;Hyperglycemia;Individual;Measures;Methods;Nerve;Neural Conduction;Neurons;Neuropathy;Non-Insulin-Dependent Diabetes Mellitus;Pathway interactions;Patients;Peripheral Nerves;Persons;Process;Property;Rattus;Records Controls;Relative (related person);Research Personnel;Rest;Signal Transduction;Specific qualifier value;Staging;Sympathetic Nervous System;System;Telemetry;Testing;Time;Work;autonomic nerve;autonomic neuropathy;blood pressure regulation;clinical practice;diabetic;diabetic patient;digital;indexing;nerve supply;non-diabetic;programs;research study;response;type I and type II diabetes;visceral afferent nerve


application_id: 8142242
project_number: 5U48DP001932-03
project_title: THE RURAL CANCER PREVENTION CENTER: CATEGORY 1 PROPOSAL
administering_ic: NCCDPHP
award_notice_date: 2011-09-21
opportunity_number: RFA-DP-09-001
application_type: 5
activity_code: U48
ic: DP
serial_number: 001932
program_official: SIMS, JOYNER
project_start_date: 2009-09-30
project_end_date: 2014-09-29
study_section: ZCD1-ZDQ(15)
contact_pi_person_id: 8234905
contact_pi: CROSBY, RICHARD A
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Rural health disparities are common in the US. Rural Appalachia is widely recognized as a geographic region that is vastly overburdened by chronic disease including cancers. This health disparity is concentrated in Southeastern KY. The mission of the UK PRC is to reduce cancer incidence and mortality rates among underserved rural residents of an eight-county health district located in the heart of SE KY. The strength and commitment of our existing community advisory board coupled with an enduring investment in. the PRC by the University of Kentucky provides an important opportunity to achieve this mission using community-based participatory research. Previous accomplishments by the PRC have laid a solid foundation for the proposed activities that occur in the next funding cycle. The PRC will be strategically located in the center of the Kentucky River Area Development District (KR-ADD). Guided by thee distinct advisory boards the director (Dr. Crosby) and deputy director (Dr. Casey) will oversee plans designed to enhance community engagement in cancer prevention activities and research throughout the KR-ADD. Augmented by the state and local health departments planned engagements will provide a model for rural Appalachian communities to use in their efforts to prevent invasive cancers. The UK PRC will continue to expand its sponsorship of cancer prevention research. Drs. Crosby and Casey will direct local state and national dissemination efforts elative to the community-based activities and research of the PRC. Local dissemination will promote cancer- protective behaviors of KR-ADD residents. Drs. Crosby and Casey will also direct ongoing training efforts for capacity building in the KR-ADD. Working closely with the College of Public Health at UK the PRC- sponsored training efforts will provide foundational and advanced experiences to local professionals public health graduate students and preventive medicine residents. Ongoing process evaluation of these coordinated activities will occur through periodic assessment of 33 indicators. Evaluation feedback will inform subsequent refinements in PRC activities. Ultimately the outcomes of the combined PRC activities will be increased cancer screening in the KR-ADD and population-level increases in cancer protective behaviors.   
RELEVANCE (See instructions): The proposed Rural Center for Cancer Prevention will provide a cancer prevention research infrastructure in an under-served area of rural Appalachia. The Center will engage the communities of this area in ongoing efforts directed toward reducing cancer incidence and mortality rates.


application_id: 8141916
project_number: 1R43ES020135-01
project_title: First Responders e-Training Curricula for Mass Screening After a Nuclear Event
administering_ic: NIEHS
award_notice_date: 2011-08-20
opportunity_number: RFA-ES-10-003
application_type: 1
activity_code: R43
ic: ES
serial_number: 020135
program_official: REMINGTON, JAMES W
project_start_date: 2011-09-01
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZES1 JAB-J (DJ)]
contact_pi_person_id: 11064605
contact_pi: REA, MICHAEL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 963949107
primary_uei: VKSAV1S1KC77
duns_number: 963949107
uei: VKSAV1S1KC77
fips: US
organization_id: 10027501
organization_name: NICOLALDE R AND D, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40509
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Most training curricula for first responders and Skilled Service Personnel (SSP) has been focused on chemical biological natural disaster (hurricane flood) and pandemic response. However training curricula regarding response to radiological events has been limited. Although some basic training exists for small radiological events training that focuses on the screening and triaging of large numbers of potential victims seeking medical services after a catastrophic nuclear event i.e. the detonation of an Improvised Nuclear Device and even an Explosive Dispersal Device is nonexistent. First responders are ill prepared to deal with an overwhelming large number of victims and worried-well resulting from such a catastrophic event and current guidelines and training curricula from federal sources such as the REMM and the REAC/TS focus only on small events i.e. nuclear power plant accidents. Nicolalde R&D LLC in collaboration with Dartmouth College proposes to develop (in Phase 1) an e-training curricula for First Responders Skilled Service Personnel (SSP) and volunteers to respond to a catastrophic nuclear event that requires the screening and medical triage of larger numbers of potential victims following our proprietary methodology for developing implementing and evaluating new operating procedures and technologies for emergency response. The current literature regarding Standard Operating Procedures and federal guidelines for responding and mitigating the effects of radiation exposures for any size of radiological event relies on unreliable and poorly tested methods for measuring radiation exposure at the individual level i.e. time to emesis and serial lymphocyte count over a period of several days and assumes that the medical system will have the capacity to admit every potential victim. These guidelines will not provide the needed capabilities to screen large numbers of potential victims which will most likely overwhelm the medical system. The federal government has been spending significant amounts of money on grants (U19 CMCR) and contracts (BARDAs) to support the development and implementation of high throughput and rapid biodosimetry technologies that can be available through the national stockpile. We propose to include in our training curricula the use of these novel biodosimetry technologies that can screen and triage potential victims efficiently and reliably. Electron Paramagnetic Resonance dosimetry (EPR) is one of such technologies capable of providing the needed capability. Another example of such technologies is a blood assay based on genetic markers that can be used rapidly in the field. Curricula for the use of any of these fast dosimetry techniques is not existent. In phase 1 we will develop the training curricula (content) in two languages English and Spanish. We will also explore the feasibility to deliver the content using some of the currently available methods to deliver e-training such as the Just-In-Time Training for Emergency Incidents System (JITTEIS) or through interactive DVD format or through interactive video games. We will explore these alternatives and make the appropriate contacts to potentially test the training program using the selected alternative in Phase 2.  
  
The application is rated at a priority score level of 49.

project_terms:
Acute;Biological;Biological Assay;Blood;Chemicals;Collaborations;Communication;Communities;Contracts;Development;Devices;Disasters;Dose;Educational Curriculum;Electron Spin Resonance Spectroscopy;Electronics;Emergency Situation;English Language;Evaluation;Event;Exercise;Federal Government;Feedback;Floods;Focus Groups;Funding;General Population;Genetic Markers;Goals;Government;Grant;Guidelines;Human Resources;Hurricane;Individual;Learning;Literature;Lymphocyte Count;Maintenance;Mass Screening;Measures;Medical;Methodology;Methods;Natural Disasters;Nuclear;Nuclear power plant accident;Performance;Phase;Population;Procedures;Process;Radiation;Radiation Syndromes;Screening procedure;Services;Site;Small Business Innovation Research Grant;Source;System;Techniques;Technology;Testing;Time;Training;Training Programs;Triage;Video Games;Vomiting;base;biodosimetry;college;design;dosimetry;emergency service/first responder;novel;operation;pandemic disease;population based;programs;radiation effect;research and development;response;simulation;volunteer

public_health_relevance:
Project Narrative:The availability of e-training curricula for First Responders Skilled Service Personnel and volunteers for theprocesses of setting-up operating maintaining and troubleshooting mass screening centers for triagingpotential victims after as catastrophic nuclear event represents a major improvement in the capabilities of theemergency response community to responding to these kind of events. There is currently a significant gap inthe training curricula and standard operating procedures for accomplishing mass casualty triage after a nuclearevent that involves large numbers of potential victims and an even larger number of worried-well.


application_id: 8141790
project_number: 1R01ES019217-01A1
project_title: Endothelial Progenitor Cells and Particulate Air Pollution
administering_ic: NIEHS
award_notice_date: 2011-09-23
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: ES
serial_number: 019217
suffix: A1
program_official: NADADUR, SRIKANTH
project_start_date: 2011-09-23
project_end_date: 2016-05-31
study_section: Special Emphasis Panel[ZRG1 CVRS-C (02)]
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: BHATNAGAR, ARUNI ;POPE, ARDEN
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): Multiple epidemiological and experimental studies report that acute or chronic exposure to air pollution is associated with adverse cardiovascular events including myocardial ischemia stroke arrhythmias heart failure sudden cardiac arrest and atherogenesis. These effects of air pollution are most strongly correlated with fine and ultrafine particulate matter (PM) fractions which are generated directly from the combustion of fossil fuels and are found in automobile exhaust wood or coal smoke and industrial emission from smelters paper or steel mills or cement plants. A common feature of PM-associated cardiovascular disorders is the establishment and maintenance of a dysfunctional endothelium. Because endothelial dysfunction is an early symptom of cardiovascular disease and an important factor in acute thrombotic complications of atherosclerosis such as stable and unstable angina myocardial infarction and ischemic stroke it could be a key mediator of the cardiovascular toxicity associated with PM exposure. The adult endothelium is a differentiated cell layer that provides a non-thrombotic interface between parenchymal cells and peripheral blood. Damages due to normal "wear-and-tear" in this layer are repaired by the mobilization and homing of bone-marrow resident pluripotent cells or endothelial progenitor cells (EPCs) which also promote angiogenesis and wound healing. We have recently identified a negative correlation between PM exposure and circulating EPC level. Here we hypothesize that defects in EPC mobilization or function are a consequence of PM-induced systemic inflammation induced by oxidative stress. We will test this hypothesis in three aims. First we will examine PM-induced changes in EPC populations in the peripheral blood and bone marrow of mice exposed to concentrated ambient air particles (CAPS) or filtered air. We will determine the time course of these effects whether there is a mobilization defect per se whether specific populations and locations of EPC are affected and whether this response is selective to EPCs or other stem cells such as the hematopoietic stem cells and mesenchymal stem cells are affected as well. In addition we will measure circulating levels of EPC-derived microparticles to test whether exposure to PM increases EPC activation or cell death. The second aim is to delineate the mechanisms by which PM exposure affects EPC function. For this we will assess how exposure to CAPs affects the ability of EPCs to grow differentiate migrate and promote wound healing. We will examine whether these changes in EPC are accompanied by an increase in systemic inflammation and oxidative stress and whether antioxidant interventions or strategies to increase NO availability would prevent PM-induced deficits in EPC number and function. Finally Aim 3 is to examine whether PM-induced changes in human peripheral blood EPC number and function are accompanied by an increase in systemic inflammation oxidative stress and microparticle or miRNA biomarkers and whether anti-oxidant intervention could reverse such changes. Successful completion of this project will provide novel insights into the cardiovascular toxicity of PM and how it affects the abundance and the reparative capacity of stem cells. Findings of this project could also form the basis for the development of new biomarkers of PM exposure or new strategies to mitigate PM toxicity.  
  
PUBLIC HEALTH RELEVANCE: Exposure to particulate matter (PM) air pollution is strongly correlated with the initiation and progression of atherosclerosis increased thrombosis myocardial infarction and stroke. These cardiovascular pathologies are characterized by a dysfunctional endothelium and its inefficient repair by pluripotent cells or endothelial progenitor cells (EPCs). Thus in this proposal we test the hypothesis that the cardiotoxicity resulting from PM exposure is a consequence of PM-induced deficits in EPC number or function.

project_terms:
Acetylcholine;Acute;Admission activity;Adult;Affect;Air;Air Pollution;Animals;Antioxidants;Aorta;Arrhythmia;Atherosclerosis;Automobile Exhaust;Blood Cells;Blood Pressure;Blood Vessels;Bone Marrow;Breathing;Cardiotoxicity;Cardiovascular Diseases;Cardiovascular Pathology;Cardiovascular system;Cell Count;Cell Death;Cell Survival;Cell physiology;Cells;Cessation of life;Chronic;Coagulation Process;Coal;Defect;Deposition;Development;Endothelium;Epidemiologic Studies;Event;Exposure to;Flow Cytometry;Fossil Fuels;Free Radicals;Functional disorder;Generations;Goals;Health;Heart Arrest;Heart failure;Hematopoietic;Hematopoietic stem cells;Homing;Hospitals;Human;Inflammation;Inflammatory Response;Injury;Intervention;Ischemic Stroke;Lead;Location;Maintenance;Measures;Mediator of activation protein;Mesenchymal Stem Cells;MicroRNAs;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Oxidation-Reduction;Oxidative Stress;Paper;Particulate;Particulate Matter;Plants;Plasma;Population;Reaction;Relaxation;Reporting;Risk;Smoke;Steel;Stem cells;Symptoms;Testing;Thrombosis;Time;Toxic effect;Ultrafine;Unstable angina;Wood material;Wound Healing;air filter;angiogenesis;atherogenesis;base;biomarker;cardiovascular disorder risk;cardiovascular risk factor;cell growth;human tissue;insight;novel;particle;peripheral blood;prevent;repaired;research study;response;stroke;young adult


application_id: 8141663
project_number: 3R43AA018226-01A2S1
project_title: Selection-driven plant metabolites for treatment of CNS diseases
administering_ic: NIAAA
award_notice_date: 2010-09-17
opportunity_number: PA-08-071
application_type: 3
activity_code: R43
ic: AA
serial_number: 018226
suffix: A2S1
program_official: EGLI, MARK
project_start_date: 2010-08-20
project_end_date: 2012-07-31
study_section: Special Emphasis Panel[ZRG1-ETTN-C(11)B]
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The primary aim is to transfer a biotechnology platform for plant drug discovery from the academic laboratory to industry use (i.e. this application is directly responsive to the "lab to marketplace" roadmap program). Many "defensive" metabolites in plants are targeted on key proteins in the insect CNS and homology between these and human proteins makes such metabolites potentially valuable as CNS drugs. These plant metabolites evolved in response to natural selection and so an imposed selection pressure should direct plant secondary metabolism toward more effective drugs. One way this could be achieved is by the expression of a human target protein linked to a toxic mechanism in plant cells. Now cells which are producing inhibitors of this protein are more likely to survive and repeated mutagenesis and selection should direct "evolution" toward increasingly effective inhibitors. For example the human dopamine transporter (hDAT) is a molecular target in drug dependence and neurodegenerative disease. Expression of the functional hDAT in plant cells (Preliminary studies) makes these susceptible to neurotoxins (MPTP 6hydroxydopamine) which are transported by the hDAT. Conversely the selective DAT inhibitor GBR12909 protects these cells. Therefore in a mutant population transgenic hDAT plant cells that survive these toxins should be "enriched" in clones which over-produce metabolites that inhibit the hDAT or protect against the neurotoxins in some other way. Both would be of potential therapeutic value. To identify a species for this approach extracts from ~1000 native plants were screened for relevant activity. This identified Lobelia cardinalis as the best candidate and this species is also easy to culture and transform making it ideal for proof of application. A population of transgenic hDAT L. cardinalis hairy roots mutagenized by activation tagging has now been subjected to MPTP selection. The proposal for phase 1 is to screen the resistant mutant sub-population for the presence of metabolites which inhibit the DAT in rat brain synaptosomes or protect a human dopaminergic cell line against neurotoxins. Positive clones (phase 1 deliverables) will be used in phase 2 for compound identification assessment of potential therapeutic value in complex models and for regeneration into mutant medicinal plant lines. All of these products have potential commercial value but it is the illustration of the general value of the technology and its transfer from lab to marketplace which is of most commercial value to the company.    PUBLIC HEALTH RELEVANCE: Plants remain a very valuable source of complex bioactive compounds but current methods of plant drug discovery do not compete with the pharmaceutical industry techniques of combinatorial chemistry and high throughput pharmacological screening. This proposal uses a novel biotechnology approach to the directed evolution and discovery of plant metabolites with potential value in human CNS diseases. These are among the most devastating and economically important diseases in the USA and world wide. The proposal focuses on potential medications for drug dependence and alcoholism as well as for neurodegenerative conditions including psychostimulant-induced neurotoxicity and diseases associated with aging including parkinsonism and Parkinson's Disease (the second most common neurodegenerative disease in the US). The technology to be used combines plant molecular biology and molecular pharmacology and its support will accelerate the introduction of this academic research into the commercial sector. Its simplicity and rapidity suggests that it may compete with the existing synthetic chemistry approaches and might even revitalize the use of plants as a source of medicines for CNS disease.

project_terms:
Age;Aging;Agonist;Agrobacterium;Alcoholism;Animal Model;Biological Factors;Biotechnology;Brain;Businesses;Carrier Proteins;Cell Death;Cell Line;Cells;Central Nervous System Diseases;Combinatorial Chemistry Techniques;Commercial Sectors;Complex;Contracts;Disease;Dopaminergic Cell;Drug Addiction;Drug Industry;Enzymes;Exposure to;Foundations;Free Radical Scavengers;Human;Ilex vomitoria;Individual;Industry;Insecta;Intellectual Property;Investigation;Killings;Laboratories;Licensing;Link;Lobelia;Mediating;Medicinal Plants;Medicine;Metabolism;Methods;Modeling;Molecular;Molecular Biology;Molecular Target;Mutagenesis;N-Methyl-D-Aspartate Receptors;Natural Selections;Natural regeneration;Nerve Degeneration;Neuroblastoma;Neurodegenerative Disorders;Neurons;Neurotoxins;Nicotinic Receptors;Parkinson Disease;Parkinsonian Disorders;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Phase;Phenotype;Plant Roots;Plants;Population;Production;Proteins;Rattus;Research;Resistance;Screening procedure;Small Business Innovation Research Grant;Source;Synaptosomes;Synthesis Chemistry;Technology;Therapeutic;Therapeutic Agents;Toxic effect;Toxin;Transfection;Transgenic Organisms;Transgenic Plants;design;directed evolution;dopamine transporter;dopaminergic neuron;drug discovery;gain of function mutation;inhibitor/antagonist;link protein;mutant;neurotoxicity;novel;pressure;prevent;programs;protein activation;psychostimulant;public health relevance;receptor;research and development;response;stimulant abuse;success;uptake

public_health_relevance:
Project narrative (unchanged)Plants remain a very valuable source of complex bioactive compounds but current methods of plant drugdiscovery do not compete with the pharmaceutical industry techniques of combinatorial chemistry and highthroughput pharmacological screening. This proposal uses a novel biotechnology approach to the directedevolution and discovery of plant metabolites with potential value in human CNS diseases. These are amongthe most devastating and economically important diseases in the USA and world wide. The proposal focuseson potential medications for drug dependence and alcoholism as well as for neurodegenerative conditionsincluding psychostimulant-induced neurotoxicity and diseases associated with aging including parkinsonismand Parkinson's Disease (the second most common neurodegenerative disease in the US). The technology tobe used combines plant molecular biology and molecular pharmacology and its support will accelerate theintroduction of this academic research into the commercial sector. Its simplicity and rapidity suggests that itmay compete with the existing synthetic chemistry approaches and might even revitalize the use of plants as asource of medicines for CNS disease.


application_id: 8139497
project_number: 1R01MH092226-01A1
project_title: A Brief Clinic-Based Safer Sex Program for Young African American Men Who Have
administering_ic: NIMH
award_notice_date: 2011-08-01
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: MH
serial_number: 092226
suffix: A1
program_official: KAMATH, SUSANNAH M A
project_start_date: 2011-08-01
project_end_date: 2016-05-31
study_section: Behavioral and Social Science Approaches to Preventing HIV/AIDS Study Section[BSPH]
contact_pi_person_id: 8234905
contact_pi: CROSBY, RICHARD A
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The Centers for Disease Control and Prevention (CDC) has termed AIDS a "health crisis" for African Americans and has called for a heightened national response. The crisis is especially dramatic in the South and it is now apparent that young African American men who have sex with men (MSM) are exceedingly likely to be infected. Unfortunately the ever-expanding HIV epidemic experienced by this population has not been matched by equal attention to the development of efficacious prevention programs. The proposed project expands upon an NIMH-funded study (R21 MH066682-01A1) conducted by Dr. Crosby. His study of young African American males found that a brief clinic-based intervention reduced incidence of subsequent STDs by about 50%. This brief one-on-one intervention program known as Focus on the Future (FOF) is a practical alternative to group-based safer sex programs that can be difficult to translate from science into practice. The program is now classified as a "Best Practice" intervention by CDC. This project will begin with an extensive formative phase designed to adapt FOF to MSM. The adapted program will seek to "sexualize" condoms to promote their consistent and correct use to better prevent STD/HIV. The program is uniquely flexible in that it can be applied to MSM regardless of their HIV serostatus. The adapted program will be tested by a two-arm efficacy trail. We will recruit 750 MSM (15-29 years of age) from a publicly-funded STD clinic in Jackson MS. Men in the treatment condition will be compared to men receiving the control condition comprised of standard of care counseling from the clinic plus a free ditty bag of supplies from the "condom and lube buffet" (condom/lube distribution). The trial will test five hypotheses. Men randomized to receive the intervention will: 1) have a lower incidence rate of laboratory-confirmed STDs (by urine assay and rectal swab) at each of three follow-up assessments (3 6 and 12 months) compared to controls; 2) report significantly fewer acts of unprotected penetrative sex (penile-vaginal or penile-anal) between follow-up assessments compared to controls; 3) report having significantly fewer unprotected penetrative (penile-vaginal or penile-anal) sex partners between follow-up assessments compared to controls; 4) report having significantly fewer negative experiences with condom use between follow-up assessments compared to controls; and 5) demonstrate significantly greater improvement in condom application skills throughout the 12-month study compared to those receiving the control condition. Given the dearth of evidence-based options for intervening with this vulnerable population in clinical settings demonstrated efficacy of the adapted program has important implications for public health efforts to prevent STD/HIV. The adapted FOF is also directly responsive to the President's National HIV/AIDS strategy particularly with regards to the target population of this proposal.  
  
PUBLIC HEALTH RELEVANCE: The proposed efficacy trial will occur in Jackson MS and it tests a brief clinic-based HIV/STD prevention program adapted specifically for young African American MSM. This program is based on a CDC-classified Evidenced-Based Intervention known as Focus on the Future. The randomized trial is designed with 3 follow-up assessments and it uses biomarker outcomes as well as a novel method of collecting self-reported outcomes.

project_terms:
Acquired Immunodeficiency Syndrome;African American;Age-Years;Anal Sex;Anus;Attention;Behavior;Biological Assay;Centers for Disease Control and Prevention (U.S.);Chlamydia;Clinic;Clinical;Counseling;Development;Enrollment;Epidemic;Evidence based intervention;Funding;Future;Gays;Glare;Gonorrhea;HIV;Health;Heart;Hispanics;Incidence;Intervention;Laboratories;Methods;Modeling;National Institute of Mental Health (U.S.);Outcome;Patient Self-Report;Phase;Population;Prevention program;Randomized;Randomized Controlled Trials;Recruitment Activity;Relative (related person);Reporting;Research;Research Design;Risk;Sampling;Science;Sexual Partners;Swab;Syphilis;Target Populations;Testing;Translating;Trichomonas Infections;Urine;Vagina;Vulnerable Populations;arm;base;biomarker;clinical practice;condoms;design;disorder prevention;effective intervention;efficacy testing;efficacy trial;evidence base;experience;flexibility;follow-up;high risk men;inclusion criteria;intervention effect;intervention program;male;men;men who have sex with men;novel;post intervention;prevent;programs;public health medicine (field);randomized trial;rectal;response;safer sex;sex;skills;standard of care;theories;therapy design;transmission process;two-arm study


application_id: 8139300
project_number: 5R01DK082426-03
project_title: Prognosis of Nonalcoholic Fatty Liver Disease
administering_ic: NIDDK
award_notice_date: 2011-07-28
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 082426
program_official: DOO, EDWARD
project_start_date: 2009-09-30
project_end_date: 2013-08-31
study_section: Special Emphasis Panel[ZRG1-DIG-F(90)S]
contact_pi_person_id: 8258682
contact_pi: ANGULO, PAUL
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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): About 60 million Americans suffer from nonalcoholic fatty liver disease (NAFLD). As the long-term prognosis of patients with NAFLD remains poorly defined one of the research goals of the NIDDK Action Plan in fatty liver disease is the need to establish a cohort study to determine the natural history of NAFLD. The cohort study would have to be followed-up for a long period of time to have enough events (deaths liver transplantations development of cirrhosis' complications) to be able to determine prognosis. Our proposal can reach this research goal as we have a very large and well characterized patient population with more than 3 decades of follow-up. A recent community-based study conducted in the United States demonstrated that mortality in patients with NAFLD is significantly higher than the expected mortality in the general population of same age and sex. However as the prevalence of overweight/obesity is significantly higher among patients with NAFLD than in the general population it remains uncertain whether the higher mortality seen in patients with NAFLD is because of this higher prevalence of overweight/obesity or NAFLD itself. The Rochester Epidemiology Project (REP) had indexed all medical diagnoses made by health care providers in Olmsted County Minnesota since 1966 allowing evaluation of the health status of what is effectively the entire county. Aim 1 consists of a nested case-control population-based cohort study using the REP resources to determine the overall and cause- specific mortality of 554 (cases) individuals from the community with overweight or obesity who developed NAFLD in comparison to appropriately matched 1108 (controls) individuals (1:2 marching) who did not develop NAFLD. This cohort of 1662 individuals has been followed for up to 33 years. This will allow us to accurately determine to what extent developing NAFLD increases mortality in community individuals who suffer from overweight/obesity. It remains unknown whether long-term prognosis differs among the major NAFLD categories namely simple steatosis and NASH and what prognostic implications can be derived from grading and staging the different histological features of NAFLD. Aim 2 consists of a longitudinal cohort study to determine the overall and cause specific mortality and liver-related morbidity among patients with simple steatosis definitive NASH and borderline NASH as well as to determine the prognostic significance of the major individual histological features of NAFLD namely fibrosis inflammation hepatocyte ballooning and severity of steatosis. A total of 1050 patients with the whole spectrum of NAFLD confirmed by liver biopsy that had been followed for up to 32 years will be included in this study. This will allow us to determine whether any of the three subtypes of NAFLD is associated with a higher mortality and to compare the long-term mortality of each one of these three NAFLD categories with mortality of the general United States population of same age and gender. In addition this study will allow us to determine whether presence and/or severity of a particular histological feature can accurately predict long-term morbidity and mortality in patients with NAFLD. PUBLIC HEALTH RELEVANCE: The data generated with this research will substantially advance our current knowledge on prognosis of nonalcoholic fatty liver disease (NAFLD) and will provide a scientific compelling basis for counseling and monitoring of the several million of individuals with NAFLD in the general population in the United States. Specifically our investigation will create the bases to select the overweight or obese individuals with NAFLD from the general population who will benefit the most from intensive diagnostic and therapeutic interventions. In addition our investigation will provide strong data to determine whether a liver biopsy is necessary to determine long-term prognosis in an individual patient with NAFLD and what long-term prognostic implications can be derived by grading and scoring the histological features of NAFLD.

project_terms:
Age;American;Categories;Cessation of life;Cirrhosis;Clinical;Cohort Studies;Communities;Counseling;County;Data;Development;Diagnosis;Diagnostic;Epidemiology;Evaluation;Event;Fatty Liver;Fibrosis;Gender;General Population;Goals;Health Personnel;Health Status;Hepatocyte;High Prevalence;Individual;Inflammation;Investigation;Knowledge;Liver;Liver diseases;Medical;Minnesota;Monitor;Morbidity - disease rate;Mortality Vital Statistics;National Institute of Diabetes and Digestive and Kidney Diseases;Natural History;Obesity;Overweight;Patients;Population;Prevalence;Research;Resources;Severities;Staging;Therapeutic Intervention;Time;United States;base;case control;cohort;follow-up;indexing;liver biopsy;liver transplantation;non-alcoholic;non-alcoholic fatty liver;nonalcoholic steatohepatitis;outcome forecast;patient population;population based;prognostic;public health relevance;sex

public_health_relevance:
The data generated with this research will substantially advance our current knowledge on prognosis ofnonalcoholic fatty liver disease (NAFLD) and will provide a scientific compelling basis for counseling andmonitoring of the several million of individuals with NAFLD in the general population in the United States.Specifically our investigation will create the bases to select the overweight or obese individuals with NAFLDfrom the general population who will benefit the most from intensive diagnostic and therapeutic interventions.In addition our investigation will provide strong data to determine whether a liver biopsy is necessary todetermine long-term prognosis in an individual patient with NAFLD and what long-term prognostic implicationscan be derived by grading and scoring the histological features of NAFLD.


application_id: 8139285
project_number: 5R43HG005799-02
project_title: Generation of Site-Specific Recombinase-Expressing Transgenic Rats using an Enhan
administering_ic: NHGRI
award_notice_date: 2011-09-15
opportunity_number: PA-09-080
application_type: 5
activity_code: R43
ic: HG
serial_number: 005799
program_official: FLETCHER, COLIN F
project_start_date: 2010-09-09
project_end_date: 2012-12-31
study_section: Special Emphasis Panel[ZRG1-IMST-E(15)B]
contact_pi_person_id: 3075176
contact_pi: OSTERTAG, ERIC M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 145182338
duns_number: 145182338
fips: US
organization_id: 10004431
organization_name: TRANSPOSAGEN BIOPHARMACEUTICALS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405071112
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-06-01
budget_end_date: 2012-12-31
project_abstract:
DESCRIPTION (provided by applicant):   
The goal is to create site-specific recombinase (SSR)-expressing transgenic rats in an efficient and unbiased manner through a transposon-mediated in vivo gene trap. Rats are very relevant for modeling human biology and disease because rats unlike mice possess key biological similarities to humans. While in vitro gene trap mutagenesis is useful for gene discovery a rapid and efficient in vivo method is preferable for two key reasons: 1) an in vivo gene trap will reveal an authentic spatio-temporal expression pattern and 2) these genetic resources of can then be immediately employed for genome manipulations in the rat. Piecemeal promoter analysis in transgenic animals is clearly not sufficient for rapidly and economically generating effective tools for SSR-mediated tissue-specific genome manipulation. The generation of transgenic rats is simply too expensive and is performed at only a few institutions. Mouse promoter elements could be used to generate SSR-expressing transgenic rats but most promoter elements lack key regulatory sequences are sensitive to position effects at genomic insertion sites or will not necessarily produce identical expression patterns across species. Considering that tens of thousands of transcribed elements likely exist in the mammalian genome an efficient in vivo method is needed to authentically and rapidly recapitulate endogenous expression patterns to generate a diverse and effective set of transgenic tools. Furthermore a method to identify new transcribed elements would accelerate a comprehensive understanding of mammalian genomics.  Gene trap mutagenesis is a standard approach for identifying and exploiting new transcription units but traditional strategies such as those targeting embryonic stem cells are simply untenable for a rapid and efficient in vivo screen. By using a PiggyBac (PB) transposon system that we have enhanced at Transposagen we will pursue an in vivo promoter trap in rats. Promoter traps will be visualized in live embryos and animals using bright fluorescent proteins (FPs). The primary reporter in this promoter trap is a Cre-EGFP fusion protein in which both Cre recombinase activity and EGFP fluorescence marks the expression domain of each trapped element. The Cre-EGFP cassette trap is delivered by a PB transposon that originates as a transgene concatemer in one transgenic line called the "donor." Another transgenic line the "driver" provides expression of the PB transposase in the germ line. Transposon mobilization is simply initiated by interbreeding driver and donor lines such that the PB transposase mobilizes the Cre-EGFP gene trap transposon within germ cells in double transgenic animals designated as "seed" rats. PB is the most efficient transposon yet described for gene mutagenesis in mammalian cells and by using an enhanced PB transposase we expect an insertion rate that should yield at least one gene trap event per gamete. As a result each G1 offspring bred from seed rats will display a unique expression pattern of the Cre-EGFP reporter. Because it is an insertional mutagen the integration site of the PB transposon is easily determined by simple PCR cloning techniques. EGFP fluorescence will be documented in E13.5 and E16.5 embryos and the identification of insertion sites will enable one to link a specific expression pattern with specific genomic locations.  As noted above tools are needed for expanding the genetic resources of the rat. A strategy to accelerate the tools for genetic manipulations in the rat is integral to our approach here. By using a Cre-EGFP reporter we will be creating recombinase-mediated tools for conditional mutagenesis. To monitor Cre activity we will create transgenic rats that express a tdTomato fluorescent protein in cells following a Cre recombination event. The tdTomato protein exhibits very bright fluorescence and has proven useful for in vivo expression analysis. Using the rat ROSA26 promoter that drives ubiquitous expression tdTomato expression will be activated only following Cre-mediated removal of an intervening sequence. These transgenic rats will be mated to the G1 offspring described above that are obtained from seed rats. We will analyze live G2 embryos for EGFP and tdTomato fluorescence. By using these FPs each gene trap can be monitored in real-time; this will create the opportunity for a further in depth analyses in future investigations. We will identify at least 25 unique Cre- expressing elements in this screen in live embryos as a proof of concept.  In addition to tdTomato Cre recombinase activity will also trigger FlpERT2 expression which is linked to the tdTomato open reading frame via an internal ribosomal expression sequence. FlpERT2 activity is dependent on 4-hydroxytamoxifen (4-OHT) and thus provides inducible Flp recombinase activity. Our design enables two key Flp-mediated manipulations: 1) Flp recombinase induction (via 4-OHT) removes the Cre-EGFP gene trap through flanking Flp recombinase target sites and 2) FlpERT2 expression will enable Flp-dependent conditional modification of FRT-containing alleles (generated through other efforts).  The tools and resources generated here will provide great advances for rat genetics. This screen will identify at least 25 transcribed elements exhibiting a unique in vivo expression pattern of Cre-EGFP. Our strategy will provide the opportunity to easily generate hundreds of additional gene trap lines. Our investigation will generate valuable rat transgenic lines for recombinase-mediated conditional mutagenesis in future studies.  
  
PUBLIC HEALTH RELEVANCE:   
This proposal describes a rapid method to discover and harness the power of tissue-specific expression patterns (where genes are turned "on") of a wide variety of genes in the rat genome in live animals. Using a mobile DNA element or "jumping gene" called piggyBac we will tag hundreds of genes in live rat embryos. The unique expression patterns that are revealed will then be exploited as tools for tissue-specific mutagenesis in future studies. The rat is highly suitable for seeking a better understanding of human genetics and biology because the rat in many ways better resembles human pathology physiology neurology and cancer biology than other popular animal models such as the mouse. The results from this study will generate valuable genetic tools for refined and subtle investigations of gene function in specific tissues.

project_terms:
4-Hydroxy-Tamoxifen;Adult;Alkaline Phosphatase;Alleles;Animal Model;Animals;Biological;Breeding;Cancer Biology;Cells;Chimeric Proteins;Cloning;Communities;DNA Transposons;Development;Drug Industry;Elements;Embryo;Event;Excision;Exhibits;Fluorescence;Future;Gene Delivery;Generations;Genes;Genetic;Genetic Recombination;Genetic Transcription;Genome;Genomics;Germ Cells;Germ Lines;Germ-Line Mutation;Goals;Human;Human Biology;Human Genetics;Human Pathology;Humulus;In Vitro;Indium;Individual;Inherited;Institution;Introns;Investigation;Jumping Genes;Knock-out;Lead;Life;Link;Location;Mammalian Cell;Mediating;Methods;Modeling;Modification;Monitor;Mus;Mutagenesis;Mutagens;Mutation;Neurology;Open Reading Frames;Organism;Partner in relationship;Pattern;Phase;Physiology;Positioning Attribute;Production;Promotor (Genetics);Proteins;Rattus;Reporter;Resources;Seeds;Site;Sleeping Beauty;Stem cells;System;Techniques;Technology;Time;Tissues;Toxicology;Transgenes;Transgenic Animals;Transgenic Organisms;Transposase;Validation;design;embryonic stem cell;falls;fusion gene;gene discovery;gene function;genetic manipulation;genetic resource;homologous recombination;human disease;in vivo;mammalian genome;mouse model;mutant;offspring;public health relevance;rapid technique;rat genome;recombinase;red fluorescent protein;retroviral transduction;sperm cell;success;tool;transposon/insertion element;vertebrate genome

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This proposal describes a rapid method to discover and harness the power of tissue-specific expression patterns (where genes are turned "on") of a wide variety of genes in the rat genome in live animals. Using a mobile DNA element or "jumping gene" called piggyBac we will tag hundreds of genes in live rat embryos. The unique expression patterns that are revealed will then be exploited as tools for tissue-specific mutagenesis in future studies. The rat is highly suitable for seeking a better understanding of human genetics and biology because the rat in many ways better resembles human pathology physiology neurology and cancer biology than other popular animal models such as the mouse. The results from this study will generate valuable genetic tools for refined and subtle investigations of gene function in specific tissues.


application_id: 8139014
project_number: 5R41DK081296-02
project_title: ApoFasL as a novel treatment for Type 1 Diabetes in Nonhuman Primates
administering_ic: NIDDK
award_notice_date: 2011-09-05
opportunity_number: PA-08-051
application_type: 5
activity_code: R41
ic: DK
serial_number: 081296
program_official: ARREAZA-RUBIN, GUILLERMO
project_start_date: 2010-09-05
project_end_date: 2013-08-31
study_section: Special Emphasis Panel[ZRG1-IMM-G(10)B]
contact_pi_person_id: 8392573
contact_pi: MACLEOD, KATHRYN J
other_pis: ECKHOFF, DEVIN E;SHIRWAN, HAVAL
congressional_district: 03
department: Unavailable
primary_duns: 140646345
duns_number: 140646345
fips: US
organization_id: 4350801
organization_name: APOVAX, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-09-01
budget_end_date: 2013-08-31
project_abstract:
DESCRIPTION (provided by applicant):  Pancreatic islet transplantation is a viable approach for the treatment of type 1 diabetes (T1D). However this therapeutic approach suffers from graft rejection. Dr. Shirwan founder of ApoImmune has developed a novel immunotherapeutic approach aimed at tolerance induction to alloantigens without chronic use of general immunosuppression. This approach termed ApoFasL involves engineering pancreatic islets ex vivo using the Company's platform ProtEx(tm) technology in a rapid practical and nontoxic manner to efficiently display a novel form of Fas ligand (FasL) on the islet surface. Engineered islets transplanted into diabetic allogeneic mice recipients treated with a short course (15 days) of rapamycin resulted in 100% survival over an observation period of >200 days without any sign of rejection. Moreover since the last submission of this grant we have now followed these animals long-term. Recipients of FasL-engineered islet grafts enjoyed rejection-free survival unless their Treg cells were depleted. Some of these animals are over 500 (n=8) and 400 (n=12) days with functioning islets in the absence of any immunosuppression. These data demonstrate that tolerance induction is sufficient for long-term drug free survival.  
Building on this and other strong data obtained in rodent models the primary objective of this proposal is to test the efficacy of this novel therapeutic approach ApoFasL for tolerance induction to allogeneic pancreatic islets in rhesus macaques. FasL will be displayed on rhesus macaque donor islets using ProtEx(tm) technology prior to transplantation into chemically-induced diabetic macaques. Transplants will be done under transient cover of rapamycin a pharmaceutical agent used in the clinic for the prevention of graft rejection. The rationale for using rapamycin in these experiments is two-fold. First it will face fewer regulatory hurdles and ease translation of the ApoFasL protocol into the clinic. And second it works in synergy with FasL to eliminate pathogenic T effector cells and generate/expand protective T regulatory cells thereby enhancing ApoFasL's efficacy. We hypothesize that islets engineered to display FasL on their surface will induce tolerance by physically eliminating alloreactive pathogenic lymphocytes responding to the transplanted islets through Fas/FasL interaction. Rapamycin is expected to further augment this response by eliminating T effector cells and/or expanding T regulatory cells thereby creating donor- specific immune tolerance leading to the survival of transplanted islets. Proof-of-principle in a nonhuman primate model will be followed by a Phase II SBIR application to further develop ApoFasL into a lead product. Tolerance to allogeneic islets in a nonhuman primate model will serve as the first step towards translation of this novel immunotherapy to the clinic for the treatment of T1D. If proven effective ApoFasL may improve the quality of life for millions of individuals worldwide with an economic impact in the billions of dollars.  
PUBLIC HEALTH RELEVANCE: ApoFasL is a novel immunotherapy being developed for the treatment of Type 1 Diabetes (T1D). Successful completion of this proposal testing ApoFasL in a diabetic nonhuman primate model will be a significant step toward developing ApoFasL for clinical trials. This novel therapy has the potential to break new grounds for the clinical treatment of T1D.

project_terms:
Acute;Alloantigen;Allogenic;Animals;Apoptosis;Apoptotic;Architecture;Autoantigens;Biotin;CD95 Antigens;Cell Maintenance;Cell surface;Cells;Chimeric Proteins;Chronic;Clinic;Clinical;Clinical Treatment;Clinical Trials;Critiques;Data;Diabetes Mellitus;Disease;Effector Cell;Engineering;Event;Extracellular Domain;Face;Freedom;Generations;Gold;Graft Rejection;Graft Survival;Grant;Harvest;Health;Homeostasis;Human;IL2RA gene;Immune;Immune Tolerance;Immunosuppressive Agents;Immunotherapeutic agent;Immunotherapy;Implant;Individual;Insulin;Insulin-Dependent Diabetes Mellitus;Islet Cell;Islets of Langerhans;Islets of Langerhans Transplantation;Lead;Licensing;Lymphocyte;Macaca;Macaca mulatta;Metabolic;Modeling;Modification;Mus;Natural immunosuppression;Outcome;Peripheral;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Physiology;Play;Pre-Clinical Model;Prevention;Primates;Procedures;Proteins;Protocols documentation;Publishing;Quality of life;Recovery;Regulatory T-Lymphocyte;Replacement Therapy;Rodent;Rodent Model;Role;Series;Sirolimus;Small Business Innovation Research Grant;Streptavidin;Streptozocin;Surface;T-Lymphocyte;Technology;Testing;Therapeutic;Therapy Clinical Trials;Translating;Translations;Transplantation;Treatment Efficacy;Tumor Necrosis Factor Ligand Superfamily Member 6;Work;base;commercialization;diabetic;economic impact;efficacy testing;immunogenicity;immunoregulation;improved;insulin secretion;islet;nonhuman primate;novel;novel therapeutic intervention;research study;response

public_health_relevance:
PROJECT NARRATIVE ApoFasL is a novel immunotherapy being developed for the treatment of Type 1Diabetes (T1D). Successful completion of this proposal testing ApoFasL in a diabeticnonhuman primate model will be a significant step toward developing ApoFasL forclinical trials. This novel therapy has the potential to break new grounds for the clinicaltreatment of T1D.


