# projects

application_id: 7644675
project_number: 3R01DA013425-05S1
project_title: Naltrexone Prodrugs for Transdermal Delivery
administering_ic: NIDA
award_notice_date: 2008-08-20
application_type: 3
activity_code: R01
ic: DA
serial_number: 013425
suffix: S1
program_official: PARK, MOO KWANG
project_start_date: 2002-04-01
project_end_date: 2011-03-31
study_section: Medication Development Research Study Section[NIDA-L]
contact_pi_person_id: 1866585
contact_pi: STINCHCOMB, AUDRA L.
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alcoholism and opiate addiction lead to major health-related problems and societal costs for people in the United States and the rest of the world as well. Therefore research and development for improved pharmacologic treatments for drug and alcohol abuse are very important. Naltrexone an opioid antagonist is currently used in oral tablet form to help maintain opioid addicts in a drug-free state. Most recently naltrexone has been indicated as an adjunct in the treatment of alcohol dependence as well as reported to reduce alcohol craving in certain alcoholic populations. Transdermal delivery of naltrexone is desirable for opioid addicts and alcoholics in order to help reduce side effects associated with oral therapy and improve compliance. Naltrexone itself does not have the essential physicochemical properties that would allow a therapeutic dose of the drug to cross the human skin barrier. We plan to continue designing and synthesizing prodrugs which are more skin permeable than naltrexone in order to make a therapeutically successful drug delivery system. We hypothesize that prodrugs of naltrexone and prodrugs in combination with microneedle treatment will improve the transdermal delivery rate of naltrexone and that these prodrugs will make excellent research tools for investigating quantitative structure-permeability relationships (QSPR) for transdermal flux and optimization of flux in combination with microneedle enhancement. These prodrugs/microneedles should improve naltrexone delivery rates across the skin because of optimized physicochemical properties for faster diffusion. The specific aims of this project include: (1) to synthesize a series of naltrexone and naltrexol (active metabolite) prodrugs designed to elucidate fundamental QSPRs for transdermal flux optimization with and without microneedle use (2) to characterize the physicochemical parameters of the drugs including molecular weight molecular volume lipophilicity hydrogen-bonding potentials melting points heats of fusion and solubilities in select solvents (3) to measure the drugs' penetration and concurrent bioconversion through human skin in vitro with and without microneedle use and (4) to characterize the pharmacokinetics of the drugs in guinea pigs in vivo with and without microneedle use. Correlation of our in vitro data with the in vivo model will aid in the creation of a reliable QSPR database for transdermal prodrugs with and without microneedle use as well as help to identify the most promising prodrug/microneedle system for eventual human use.

project_terms:
6 beta-hydroxynaltrexone;Addiction Opiate;Adverse effects;Alcohol abuse;Alcohol dependence;Alcoholism;Cavia;Data;Databases;Diffusion;Dosage Forms;Dose;Drug Delivery Systems;Drug Kinetics;Goals;Heating;Human;Hydrogen Bonding;In Vitro;Knowledge;Lead;Measures;Molecular;Molecular Weight;Naltrexone;Narcotic Antagonists;Opioid;Oral;Penetration;Permeability;Pharmaceutical Preparations;Pharmacotherapy;Plasma;Population;Prodrugs;Property;Rate;Recovery;Reporting;Research;Rest;Series;Skin;Solubility;Solvents;Structure;System;Tablets;Therapeutic;United States;alcohol craving;clinical application;cost;craving;design;improved;in vivo;in vivo Model;lipophilicity;melting;problem drinker;research and development;tool


application_id: 7644554
project_number: 5R01HL065660-07
project_title: Role of the JAK-STAT Pathway in Ischemic Preconditioning
administering_ic: NHLBI
award_notice_date: 2009-06-29
application_type: 5
activity_code: R01
ic: HL
serial_number: 065660
program_official: SCHWARTZ, LISA
project_start_date: 2001-05-08
project_end_date: 2010-01-11
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 1964532
contact_pi: XUAN, YU-TING
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: 2009-07-01
project_abstract:
DESCRIPTION (provided by applicant): The overall objective of this continuation of our ongoing project is to investigate the signaling and molecular mechanisms underlying the sustained infarct-sparing and anti-apoptotic effects observed during the late phase of ischemic preconditioning (PC). Although apoptosis has been shown to play a crucial role in cell death after ischemia/reperfusion injury it remains largely unknown whether late PC protects against cardiac apoptosis and what signaling/molecular mechanisms underlie these protective actions. Building upon our previous works we propose that brief episodes of mvocardial ischemia (ischemic PC protocol) protect against apoptotic cardiomyocyte death. Our fundamental hypothesis is that ischemic PC induces a sustained cardioprotected phenotype by activating pro-survival signaling pathways via the recruitment of stress-responsive transcription factors (STAT1 and STATS) leading to the upregulation of anti-apoptotic proteins that inhibit both the death receptor- and the mitochondria-dependent pathways of apoptosis. All studies will be conducted in an established murine model of ischemic PC. In Ajrn 1 we will determine whether ischemic PC inhibits cardiomyocyte apoptosis contributed to the delayed cardioprotective effects. Cardiac apoptosis will be evaluated by in situ hairpin-1-biotin ligation assay DNA laddering TUNEL assays and immunohistochemistry of active caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP). The influence of ischemic PC on the death receptor-mediated and the mitochondria-mediated pathways of apoptosis will be elucidated by examining their effects on the release of cytochrome c and Smac from mitochondria on the activation of caspases (caspase-3 8 and 9) and the cleavage of PARP and on the expression of pro- and anti-apoptotic proteins. In Aims 2 and 3 we will establish whether the delayed anti- apoptotic actions afforded by late PC are mediated by STAT1 and/or STATS. The individual roles of STAT1 and STATS in mediating apoptotic cell death (the mitochondria-mediated vs. the death receptor-mediated apoptosis) will be conclusively established by targeted knockout of the STAT1 gene and by genetic inhibition of STATS via an inducible cardiac-specific STATS knockout mouse model. In Aim 4 we will identify whether the delayed cardioprotective effects conferred by late PC require both Tyr-705 and Ser-727 phosphorylation of STATS by using a Tyr-705 dominant negative mutant of STATS and a Ser-727 mutant of STAT3 respectively. This proposal will provide important new insights into the signaling and molecular mechanisms whereby the late phase of ischemic PC reprograms the heart in the intact animal.

project_terms:
Abbreviations;Animals;Apoptosis;Apoptotic;BIRC4 gene;Biological Assay;CASP8 and FADD-like apoptosis regulating protein;Cardiac;Cardiac Myocytes;Cell Death;Cessation of life;Cleaved cell;Complex;DNA;Doctor of Philosophy;Dominant-Negative Mutation;Formates;Funding;Gene Targeting;Genetic;Genetic Programming;Genetic Techniques;Genetically Engineered Mouse;Heart;Immunohistochemistry;In Situ;Individual;Infarction;Interferon Type II;Investigation;Ischemia;Ischemic Preconditioning;Knock-out;Knockout Mice;Late Effects;Ligation;Measurement;Measures;Mediating;Microscopic;Mitochondria;Modeling;Molecular;Molecular Genetics;Mus;Myocardial;Myocardial Infarction;Pathway interactions;Phase;Phenotype;Phosphorylation;Physiology;Play;Poly(ADP-ribose) Polymerases;Protein Chemistry;Protein Isoforms;Proteins;Protocols documentation;Regulation;Relative (related person);Reperfusion Injury;Research Personnel;Role;STAT protein;STAT1 gene;STAT3 gene;Signal Pathway;Signal Transduction;Site;Somatomedins;Stress;TdT-Mediated dUTP Nick End Labeling Assay;Techniques;Testing;Up-Regulation (Physiology);Work;biotin 1;caspase;caspase-3;caspase-8;caspase-9;cytochrome c;in vivo;insight;interdisciplinary approach;mouse model;mutant;preconditioning;pro-apoptotic protein;programs;protective effect;receptor;response;transcription factor


application_id: 7644324
project_number: 5R37HL055757-15
project_title: OXYGEN RADICALS AND CARDIAC ADAPTATIONS TO ISCHEMIA
administering_ic: NHLBI
award_notice_date: 2009-06-23
application_type: 5
activity_code: R37
ic: HL
serial_number: 055757
program_official: WONG, RENEE P
project_start_date: 1995-05-01
project_end_date: 2012-12-31
study_section: NSS-H
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
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: 2009-07-01
project_abstract:
ecent evidence demonstrates that exercise induces delayed cardioprotection similar to that of ischemic preconditioning (PC) ia mechanisms that are presently unknown. Unlike ischemic or pharmacologic PC exercise PC is triggered by a physiologic itimulus and thus would appear to be a natural means for achieving cardioprotection. The overall objective of this proposal is.0 elucidate the molecular mechanisms .underlying the newly-discovered phenomenon of exercise PC. Our fundamentallypothesis is that exercise-induced release of NO (via eNOS) activates a signal transduction cascade that includes PKCeSrc/Lck and multiple transcription factors and culminates in the upregulation of iNOS which then mediates the protectioneither singularly or in conjunction with eNOS. A broad multidisciplinary approach will be used that will combine diverseechniques (integrative physiology protein chemistry mass spectrometry biochemistry cell biology molecular biology gene.argeting and transgenesis) and will integrate genetic information at the molecular level with biochemical information at thejrotein structure level and physiological information at the whole animal level. Unequivocal evidence for or against anDbligatory role of three specific kinases (PKCe Src.Lck) in exercise PC will be provided by the use of a novel dominantnegative PKCe transgenic mouse line and Src and Lck knockout mice this will enable us to achieve for the first time(inase-specific modulation of PKCe. Src.and Lck during exercise. The role of PKCs in initiating exercise PC will be onclusivelv established by determining the effects of specific transgenic inhibition of this isozyme. The kinase-specificactivity of all seven Src PTKs expressed in the mouse heart (Fyn Fgr Yes Src Lyn Lck and Blk) will be directly measuredat serial times after exercise PC. The role of Src PTKs in triggering versus mediating exercise PC'will be discerned bycomparing inhibition of these kinases on days 1 and 2 (during the exercise stimulus) versus day 3 (during coronary occlusion).Targeted disruption of the Src and Lck gene will be employed to conclusively establish the specific function of individualPTKs in the PC protection. The transcription factors responsible for exercise PC will be systematically interrogated by usingmice with targeted genetic ablation of each of the main factors known to bind to the iNOS gene (IRF-1 TNF-a STAT1 CREBAP-1 IL-2 and IL-6). The specific NOS isoforms responsible for initiating as well as mediating exercise PC will beconclusively identified by targeted gene disruption of eNOS iNOS and nNOS. The post-translational modulation ofiNOS 24 h after exercise will be elucidated by identifying the precise phosphorylation site(s) on iNOS with HPLC coupled-electrospray ionization mass spectrometry. Finally the role of Src PTKs in the post-translational modulation of iNOS will beestablished by measuring iNOS activity and tyrosine phosphorylation in the absence and presence of Src PTK inhibitors. Thisproposal should produce important new insights into the molecular mechanisms whereby the heart adapts not only to physicalstress but also to stress in general. Elucidation of the mechanism of exercise PC may have important therapeutic implications.

project_terms:
Ablation;Acute;Animals;Arginine;Atrial Natriuretic Factor;Binding (Molecular Function);Binding Sites;Biochemical;Biochemistry;Biological Assay;CREB1 gene;Cardiac;Cellular biology;Chloride Ion;Chlorides;Complex;Coronary Arteriosclerosis;Coronary Occlusions;Coupled;Cyclic AMP-Responsive DNA-Binding Protein;Data;Development;Diethyldithiocarbamate;Doctor of Medicine;Dominant-Negative Mutation;EGF gene;EMSA;Electrophoretic Mobility Shift Assay;Electrospray Ionization;Elements;Engineering;Epidermal Growth Factor;Event;Exercise;Exposure to;FOS gene;Family;Gene Targeting;Gene Transfer Techniques;Genes;Genetic;Genetic Techniques;Genetic Transcription;Genetically Engineered Mouse;Glyceraldehyde-3-Phosphate Dehydrogenases;Heart;Heat shock proteins;High Pressure Liquid Chromatography;Hypoxia-Responsive Elements;IRF1 gene;IRF2 gene;Immunoprecipitation;Individual;Interferon Regulatory Factor 2;Interferon Type II;Interferons;Interleukin-2;Interleukin-6;Investigation;Ischemia;Ischemic Preconditioning;Isoenzymes;Janus kinase;Knockout Mice;Laboratories;Lavendustin A;Left;Lymphocyte Specific Protein Tyrosine Kinase p56(lck);MAP Kinase Gene;Manganese Superoxide Dismutase;Mass Spectrum Analysis;Measures;Mediating;Mediator of activation protein;Mitogens;Modeling;Molecular;Molecular Biology;Molecular Genetics;Mus;Mutation;Myocardial Infarction;Nitrates;Nitric Oxide Synthase;Nitric Oxide Synthase Type I;Nitrites;Nitroglycerin;Nuclear;Patients;Peroxonitrite;Phosphorylation Site;Phosphotransferases;Physiological;Physiology;Play;Positioning Attribute;Promotor (Genetics);Protein Chemistry;Protein Isoforms;Protein Kinase;Protein Kinase C;Protein Tyrosine Kinase;Proteins;Pyrazolones;Reactive Oxygen Species;Recruitment Activity;Reperfusion Injury;Reperfusion Therapy;Resistance;Response Elements;Role;S-nitro-N-acetylpenicillamine;STAT1 gene;Signal Pathway;Signal Transduction;Site;Spectrometry Mass Electrospray Ionization;Stimulus;Stress;Structure;Techniques;Therapeutic;Thiopronine;Time;Transcription Factor AP-1;Transducers;Transgenic Mice;Transgenic Organisms;Tumor Necrosis Factor-alpha;Tyrosine;Tyrosine Kinase Inhibitor;Tyrosine Phosphorylation;Up-Regulation (Physiology);Ventricular;Western Blotting;clinically relevant;diethylenetriamine;human NOS3 protein;hypoxia inducible factor 1;inhibitor/antagonist;insight;interdisciplinary approach;interest;knockout gene;novel;preconditioning;programs;protein kinase C epsilon;protein structure;protein-tyrosine kinase c-src;transcription factor


application_id: 7643547
project_number: 2R56DK056132-07A1
project_title: Neural circuitry in the dorsal vagal complex
administering_ic: NIDDK
award_notice_date: 2008-07-08
opportunity_number: PA-07-070
application_type: 2
activity_code: R56
ic: DK
serial_number: 056132
suffix: A1
program_official: SATO, SHERYL M
project_start_date: 2001-06-01
project_end_date: 2009-06-30
study_section: Neuroendocrinology, Neuroimmunology, and Behavior Study Section[NNB]
contact_pi_person_id: 1911523
contact_pi: SMITH, BRET N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Neuronal communication in the dorsal vagal complex (DVC) is critical for integrating visceral afferent and otherinputs and translating that integrated signal into a coordinated motor output via the vagus nerve. In particularGABAergic inhibition is a dominant regulator of neuronal function in the area. Despite the recognizedimportance of this circuitry to control of feeding and digestion relatively little is known about local connectionswithin the DVC. The general hypothesis of this proposal is that activity of neurons in the dorsal motor nucleusof the vagus (DMV) that control gastric function is prominently controlled by inhibitory GABAergic inputs arisingfrom neurons in the nucleus tractus solitarius (NTS). The activity of NTS GABA neurons is tightly regulated byboth glutamatergic excitatory and GABAergic inhibitory synaptic inputs. We propose that GABAergic control ofmotor output to the stomach is accomplished by both phasic and tonic postsynaptic GABAA receptor-mediatedinhibition and that specific cellular interactions in the DVC are organized in a manner that consistent with theconcept well developed in other sensory-motor systems that local inhibitory circuitry coordinates responsesbetween functional areas of the solitary complex. Gastrointestinal dysfunction effects people with diabetesmellitus and is attributed to altered vagal control of the stomach. We propose that GABAA receptor-mediatedcurrents in gastric-related DMV neurons are functionally altered in a model of type 1 diabetes mellitus. We willuse a multidisciplinary approach to examine GABA-mediated synaptic transmission between neurons in theDVC focusing particularly on inhibitory synaptic control of identified GABAergic neurons in the NTS as well ason neurons in the DMV in the context of gastrointestinal control. Electrophysiological experiments will be donein vitro using brain slice preparations from mature male mice in which DMV and NTS neurons can be identifiedby their anatomical connection with the stomach their GABA content or both. With whole-cell patch-clamprecordings we will use photoactivation of caged glutamate to stimulate selectively the soma-dendritic regionsof local neurons in order to analyze GABA-mediated connections within the solitary complex. We aim todetermine: 1) the contribution of tonic GABAergic currents to neuronal activity in the DMV; 2) how identifiedgastric-related GABAergic neurons in the NTS are regulated by GABA input; and 3) effects of hyperglycemiaon GABA currents in a model of type 1 diabetes. We will correlate electrophysiological results withpharmacological and molecular biological analyses to construct a cellular model of local GABAergic control ofDMV neuron activity.

project_terms:
Amino Acids;Area;Binding (Molecular Function);Biological;Brain;Cell model;Cells;Characteristics;Chromosome Pairing;Chronic;Communication;Complex;Condition;Data;Diabetes Mellitus;Diabetes Mellitus Insulin-Dependent;Digestion;Dorsal;Event;Functional disorder;Glutamates;Hyperglycemia;In Vitro;Label;Mediating;Membrane Potentials;Methods;Mice Transgenic;Modeling;Molecular;Motor Neurons;Motor output;Mus;Neurons;Noise;Nucleus solitarius;Preparation;Proteins;RNA Messenger;Regulation;Rest;Signal Transduction;Slice;Stomach;Streptozocin;Synapses;Synaptic Transmission;Testing;Translating;Vagus nerve structure;Viscera;Visceral Afferents;base;cell body (neuron);concept;dorsal motor nucleus;feeding;gamma-Aminobutyric Acid;gastrointestinal;interdisciplinary approach;male;neural circuit;patch clamp;photoactivation;photolysis;postsynaptic;receptor;research study;response;sensorimotor system


application_id: 7643424
project_number: 5K01DA021309-03
project_title: Rural Drug Abuse Treatment: Organizations Counselors and Client Outcomes
administering_ic: NIDA
award_notice_date: 2009-06-25
opportunity_number: PA-06-001
application_type: 5
activity_code: K01
ic: DA
serial_number: 021309
program_official: JONES, DIONNE
project_start_date: 2007-07-15
project_end_date: 2012-06-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 6264981
contact_pi: OSER, CARRIE BETH
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): The primary goal of this revised K01 application is to further develop a productive independent research career in substance abuse treatment. The major changes in this revised application include the addition of an ecological theoretical framework supplementary didactic and experiential qualitative training as well as improved recruitment and analytic strategies. Additional training will enhance Dr. Carrie Oser's experience in organizational-level models to encompass a multi-level perspective and broaden her research focus to rural areas. The proposed training goals will provide additional instruction in: (1) the cultural nuances of rural communities (2) qualitative research methods (3) advanced statistical training specific to multi-level modeling (e.g. HLM SEM) and (4) the conduct of ethical research. Dr. Carrie Oser will be sponsored by Dr. Carl Leukefeld who has experience in rural substance abuse research. The overall goal of this revised research plan is to better understand counselor contextual and organizational contributions to rural treatment outcomes in public treatment facilities. The specific aims are: (1) to describe the characteristics of rural clients as compared to urban clients; (2) to examine the characteristics and treatment practices of rural counselors as compared to those employed in urban facilities; (3) to identify the organizational characteristics of state-funded treatment facilities in rural counties as compared to urban utilizing a PDA-based data collection methodology; (4) to develop two-level hierarchical linear models from an ecological perspective to predict rural treatment outcomes and urban treatment outcomes; (5) to separately examine the proportional contributions of client-level factors counselor contextual factors and organizational factors to rural treatment outcomes and urban treatment outcomes using an ecological theoretical framework. This project will significantly contribute to understanding community treatment and client outcomes in rural and urban counties. The focus on treatment outcomes within rural public treatment facilities is a logical transition from Dr. Oser's graduate work on the adoption of innovative pharmacological treatments within privately funded treatment organizations. This proposed project will allow for a practical application of the substantive knowledge and analytical skills acquired from the K01 training activities and will ultimately culminate in the development of future investigator initiated NIDA grant applications.

project_terms:
Administrator;Adoption;Age;Alcohol or Other Drugs use;Applications Grants;Area;Attention;Belief;Censuses;Characteristics;Client;Climate;Clinical;Commit;Communities;County;Criminal Justice;Development;Drug abuse;Educational aspects;Emotional;Employment;Employment Status;Environment;Ethics;Evaluation Studies;Funding;Future;Goals;Instruction;Intention;Knowledge;Lateral;Linear Models;Literature;Mental Health;Modeling;Motivation;National Institute of Drug Abuse;Organizational Change;Outcome;Patient Self-Report;Perception;Pharmaceutical Preparations;Pharmacological Treatment;Principal Investigator;Professional Education;Professional counselor;Qualitative Research;Recording of previous events;Recovery;Reporting;Research;Research Methodology;Research Personnel;Resources;Rural;Rural Community;Services;Site;Structure;Substance abuse problem;Substance of Abuse;System;Techniques;Therapeutic;Training;Training Activity;Training and Education;Treatment outcome;Work;base;career;contextual factors;data collection methodology;demographics;exhaustion;experience;follow-up;health care service utilization;improved;innovation;metropolitan;organizational climate;organizational structure;practical application;pressure;programs;psychologic;rural area;skills;treatment as usual;treatment organization;treatment program;urban area


application_id: 7643400
project_number: 5R21CA131688-02
project_title: Predicting Non-Sentinel Node Metastasis in Breast Cancer Patients
administering_ic: NCI
award_notice_date: 2009-04-24
opportunity_number: PA-07-022
application_type: 5
activity_code: R21
ic: CA
serial_number: 131688
program_official: LIVELY, TRACY LUGO
project_start_date: 2008-07-01
project_end_date: 2010-09-08
study_section: Cancer Biomarkers Study Section[CBSS]
contact_pi_person_id: 7874100
contact_pi: CHAGPAR, ANEES B
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Sentinel lymph node (SLN) biopsy is a minimally invasive means of accurately staging the axilla in breast cancer patients. While finding negative SLNs avoids axillary lymph node dissection (ALND) the finding of micrometastasis in the SLN mandates a completion ALND. Up to 80% of all SLN-positive patients will have no further disease in the axilla. There is a significant gap in our current knowledge in predicting which SLN- positive patients have a low likelihood of non-SLN metastasis and can therefore avoid ALND. A novel intra- operative RT-PCR based assay (GeneSearch(r)) for detecting SLN micrometastases has been shown to correlate with SLN tumor burden in breast cancer patients. The potential utility of this new technology in predicting which patients will not have further disease in their non-SLNs has not been investigated. Developing a robust clinical prediction rule for non-SLN status using these data will fill this gap in our knowledge and provide timely conclusions which will have a direct impact on patient care. In order to achieve this over-arching objective we propose the following specific aims: (1) To determine the impact of quantitative cycle time values of the GeneSearch(r) assay on non-SLN status using both bivariate and multivariable logistic regression analyses and (2) to create and validate (using bootstrap techniques) a clinical prediction rule to predict non-SLN status in SLN-positive patients using preoperatively- and intraoperatively-available clinicopathologic factors including data obtained from the GeneSearch(r) assay. We hypothesize that the quantitative RT-PCR cycle time for both mammoglobin (MMG) and cytokeratin 19 (CK19) as evaluated as continuous values using the GeneSearch(r) assay will be significantly associated with non-SLN metastasis on bivariate analyses. In addition the cycle time for these markers will predict non-SLN metastasis independent of other factors. We hypothesize that a valid clinical prediction rule can be created using preoperatively- and intraoperatively-available clinicopathologic factors including data obtained from the GeneSearch(r) assay that will identify a subset of patients in whom the likelihood of non-SLN metastasis is = 5%. It is anticipated that the addition of data from the GeneSearch(r) assay will significantly improve the ability to predict this group of patients over the use of clinicopathologic factors alone. The creation and validation of a robust clinical prediction rule that incorporates novel molecular data to identify a subgroup of patients at low risk of having non-SLN metastasis will fill a significant gap in our current knowledge and will reduce unnecessary morbidity of ALND helping to meet the NCI's Challenge of eliminating suffering due to cancer by 2015. PUBLIC HEALTH RELEVANCE: Up to 80% of breast cancer patients who have minimal disease in their first draining (sentinel) lymph nodes will have no further disease in their axilla. However currently there is no accurate means of predicting which patients will not have residual disease and therefore all patients who have a tumor deposit = 0.2 mm in their sentinel lymph nodes will have the remaining lymph nodes removed -- a procedure that is associated with considerable morbidity. We seek to create and validate a clinical prediction rule incorporating novel molecular data to identify a subgroup of patients at low risk of having non-SLN metastasis thereby filling a significant gap in our current knowledge and reducing unnecessary morbidity for breast cancer patients.

project_terms:
Axilla;Axillary Lymph Node Dissection;Biological Assay;Breast;Cancer Patient;Clinical;Clinical Trials;Data;Decision Making;Deposition;Disease;Excision;Keratin-19;Knowledge;Logistic Regressions;Malignant Neoplasms;Micrometastasis;Molecular;Morbidity - disease rate;Negative Finding;Neoplasm Metastasis;Nomograms;Pathology;Patient Care;Patients;Procedures;Regression Analysis;Residual Tumors;Reverse Transcriptase Polymerase Chain Reaction;Risk;Sentinel Lymph Node;Sentinel Lymph Node Biopsy;Staging;Subgroup;Surgical Management;Techniques;Technology;Time;Translating;Tumor Burden;Validation;base;improved;lymph nodes;malignant breast neoplasm;meetings;minimally invasive;new technology;novel;public health relevance;standard of care;success;tumor


application_id: 7643179
project_number: 5R01MH074865-03
project_title: BE-ACTIV: Treating Depression in Nursing Homes
administering_ic: NIMH
award_notice_date: 2009-06-16
application_type: 5
activity_code: R01
ic: MH
serial_number: 074865
program_official: ROWLAND, LAURA
project_start_date: 2007-07-14
project_end_date: 2012-06-30
study_section: Interventions Committee for Disorders Related to Schizophrenia, Late Life, or Personality[ITSP]
contact_pi_person_id: 1908020
contact_pi: MEEKS, SUZANNE
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
project_abstract:
DESCRIPTION (provided by applicant): The purpose of this proposal is to test the efficacy of a behavioral intervention for depression in nursing homes. The program BE-ACTIV has been adapted and piloted in nursing homes and shows promise of reducing depression in residents with major and minor depression. The intervention is conceptually based on Lewinsohn's behavioral theory of depression and derived from Teri's effective outpatient intervention for elders with dementia. It involves collaboration between a mental health therapist and nursing home Activities Department staff and is tailored to the individual resident. The goal is to increase opportunities for pleasant events thus increasing activity and positive affect. There are 2 specific aims: (1) using a randomized controlled two-group design to compare outcomes for depressed residents receiving the BE-ACTIV program with those receiving treatment as usual in their nursing homes; and (2) to evaluate the treatment mechanisms including staff attention increased activity levels and increased positive affect related to improvement following participation in BE-ACTIV. The latter aim employs both within-subject process measures and between-subject comparisons. Measures include diagnostic evaluation depression and mood rating scales general functioning observed affect and activity participation behavior problems resident satisfaction and staff burden. Analyses will make use of random effects modeling to analyze within- and between-subject variability in intervention process and treatment response.   
Public Health Relevance: Nursing home residents are at a significantly higher risk for depression than community-residing elders; up to 50% of nursing home residents are affected by significant depressive symptoms. The health and cognitive multiple comorbidity of this population makes treatment and treatment research extremely challenging. Although we have a good understanding of the epidemiology and manifestations of depression in late life and are beginning to apply effective treatments to some groups of elders the benefits of the past decade of research have yet to reach these frailest elders.

project_terms:
Affect;Aftercare;Attention;Behavior Therapy;Behavioral;Cognitive;Collaborations;Communities;Comorbidity;Data;Dementia;Depressive disorder;Diagnosis;Diagnostic;Discipline of Nursing;Elderly;Epidemiology;Evaluation;Event;Face;Foundations;Goals;Health;Individual;Institution;Intervention;Interview;Interviewer;Link;Manuals;Measures;Mediating;Mental Health;Modeling;Moods;Nurses;Nursing Homes;Outcome;Outcome Measure;Outpatients;Participant;Patient Self-Report;Phase;Population;Positive Reinforcements;Problem behavior;Process;Process Measure;Randomized;Recovery;Research;Research Personnel;Risk;Social Functioning;Structure;Symptoms;Testing;Theoretical model;base;blind;depressed;depression;depressive symptoms;design;effective therapy;efficacy testing;follow-up;health practice;high risk;intervention program;member;minor depressive disorder;programs;public health medicine (field);public health relevance;satisfaction;social;symptomatic improvement;theories;treatment as usual;treatment response


application_id: 7642385
project_number: 5R01AG028925-04
project_title: INTEGRATED STUDY OF MUSCULOSKELETAL LOSS AND RESTORATION
administering_ic: NIA
award_notice_date: 2009-06-22
opportunity_number: PA-03-147
application_type: 5
activity_code: R01
ic: AG
serial_number: 028925
program_official: WILLIAMS, JOHN
project_start_date: 2006-09-15
project_end_date: 2011-06-30
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 1884084
contact_pi: DUPONT-VERSTEEGDEN, ESTHER E
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Mechanisms controlling musculoskeletal recovery following disuse are poorly understood. However there is evidence that the restoration of lost tissue is impaired with aging. Precursor cell function in both muscle and bone is altered with advancing age which may contribute to the decreased recovery. The goal of this proposal is to investigate the role of tissue-specific precursor cells during the recovery from bone loss and muscle atrophy in response to hind-limb suspension (HS) in rats and to determine whether there are age- associated differences in this process. We hypothesize that changes in the function of tissue-specific precursor cells impair the restoration of musculoskeletal mass with advancing age. The strength of our approach is that both muscle and skeletal components will be studied in the same animals facilitating evaluation of the interaction between the two systems and the integration of common mechanisms. In Aim 1 we will investigate whether advancing age decreases the capacity to recover (by reambulation) the musculoskeletal atrophy induced by HS. The temporal correlation between loss of muscle and bone and their capacity for restoration will be investigated. Aim 2 addresses whether the underlying mechanisms of precursor cell function and apoptosis in bone and muscle are changed with aging and contribute to the impaired recovery from lost tissue in vivo. In Aim 3 bone marrow stem cells and myoblasts will be isolated and proliferation differentiation and apoptotic responses in vitro determined to investigate whether age- associated changes in these processes contribute to atrophy and impaired restoration of musculoskeletal mass. Our preliminary data suggest an age-dependent role for altered BMP signaling that may account for diminished restorative capacity in bone. Whether BMP is a common target underlying the mechanistic basis of bone and muscle regulation during aging and disuse will be determined. Finally in Aim 4 we will investigate in vitro and in vivo whether changes in the insulin-like growth factor (IGF)-1 pathway are involved in the impaired restoration of musculoskeletal mass with aging. Together these studies will provide important insight into the cellular mechanisms underlying the impaired ability of older animals to recover musculoskeletal integrity after disuse. Our proven integrative approach for studying muscle and bone will enable us to elucidate common mechanisms underlying the responsiveness of the musculoskeletal system during aging. Relevance to public health: Advancing age is associated with a loss of muscle as well as bone mass and it is unknown whether the musculoskeletal system in older individuals differs in its restorative capacity after periods of disuse. In this study we will identify common mechanisms underlying age-related changes in progenitor cell function. Identifying these common pathways influencing muscle and bone integrity could lead to putative targets for pharmacologic or therapeutic interventions.

project_terms:
Accounting;Address;Age;Aging;Animals;Apoptosis;Apoptotic;Atrophic;Bed rest;Bone Density;Bone Marrow;Bone Marrow Stem Cell;Cell Nucleus;Cell physiology;Cells;Data;Disease;Elderly;Evaluation;Event;Face;Goals;In Vitro;Individual;Insulin-Like Growth Factor I;Lead;Life;Limb structure;Longevity;Maintenance;Marrow;Mechanics;Molecular;Muscle;Muscle Fibers;Muscular Atrophy;Musculoskeletal;Musculoskeletal System;Myoblasts;NIH Program Announcements;Nuclear;Operative Surgical Procedures;Osteocytes;Pathway interactions;Process;Rattus;Recovery;Regulation;Role;Signal Transduction;Skeletal muscle structure;Stem cells;Suspension substance;Suspensions;Systems Integration;Testing;Therapeutic Intervention;Time;Tissues;Workload;age related;base;bone;bone loss;bone mass;in vivo;insight;juvenile animal;muscle form;osteoblast differentiation;paracrine;precursor cell;public health medicine (field);response;restoration;sarcopenia;satellite cell


application_id: 7641104
project_number: 5R21AI078111-02
project_title: Leptospira interrogans Len adhesins
administering_ic: NIAID
award_notice_date: 2009-07-21
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: AI
serial_number: 078111
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2008-06-19
project_end_date: 2011-05-31
study_section: Special Emphasis Panel[ZRG1-IDM-A(90)S]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Leptospirosis caused by the spirochete Leptospira interrogans and close relatives of that genus is a significant zoonotic disease affecting humans throughout the United Sates and many other parts of the world. These bacteria infect humans and other animals by penetrating mucous membranes or conjunctiva or through breaks in the skin. Bacteria then disseminate throughout the host via the bloodstream followed by invasion of other tissues. Leptospirosis in humans can lead to a range of debilitating symptoms and not infrequently death. Understanding the mechanisms by which leptospires are able to initiate and establish infection can direct development of improved diagnostics and preventative/treatment therapies.   
  
Infectious leptospires are very resistant to their hosts' alternative pathway of complement-mediated killing. Our studies found that L. interrogans can bind the host complement regulator factor H to its outer surface a strategy adopted by many other pathogens to avoid killing by host complement. During infection L. interrogans invades and colonizes kidneys and other host organs apparently facilitated by the spirochete's abilities to interact with host extracellular matrix (ECM) components. We discovered that L. interrogans carries six separate but similar genes each of which encodes a protein that can bind factor H and/or ECM proteins. All six leptospiral proteins share predicted structural and some functional similarities with mammalian endostatin and have been designated LenA LenB LenC LenD LenE and LenF (Len = Leptospiral ENdostatin-like protein). We hypothesize that Len proteins enable L. interrogans to both resist killing by host complement and to interact with host ECM. As a corollary to our central hypothesis we predict that all infectious leptospires produce one or more Len proteins to facilitate mammalian infection and that infected humans and other animals produce antibodies against those Len proteins. To test our hypothesis we will (1) perform functional characterization of interactions between Len proteins and their host ligands and (2) evaluate the practicality of using Len proteins for serological diagnosis of leptospirosis patients.   
  
PUBLIC HEALTH RELEVANCE: The causative agents of leptospirosis Leptospira interrogans and closely-related members of that genus are highly invasive pathogens that can establish persistent infections of immunocompetent individuals. The aim of this project is to characterize a family of six leptospiral proteins we found to interact with human immune system regulators and extracellular matrix components and may therefore play important roles in human leptospirosis.

project_terms:
Adopted;Affect;Alternative Complement Pathway;Amino Acids;Animals;Antibodies;Arts;Bacteria;Bacterial Adhesins;Binding (Molecular Function);Blood Circulation;Cessation of life;Clinic;Complement;Complement Factor H;Data;Development;Diagnosis;Diagnostic;Disease;Endostatins;Evaluation;Extracellular Matrix;Extracellular Matrix Proteins;Family;Fibronectins;Genes;Genetic;Human;Immune response;Immune system;Immunocompetent;In Situ;In Vitro;Individual;Infection;Invaded;Kidney;Killings;Laboratories;Laminin;Lead;Leptospira;Leptospira interrogans;Leptospirosis;Ligand Binding;Ligands;Mediating;Methods;Mucous Membrane;Mutate;Order Spirochaetales;Organ;Patients;Play;Procedures;Property;Proteins;Recombinants;Relative (related person);Resistance;Role;Sampling;Serodiagnoses;Serological;Serum;Site-Directed Mutagenesis;Skin;Surface;Symptoms;Testing;Tissues;Travel;Zoonoses;conjunctiva;improved;member;pathogen;protein function;public health relevance;serological marker;tool


application_id: 7640703
project_number: 5R21AI076956-02
project_title: Importance of CD5 for the function of regulatory T cells
administering_ic: NIAID
award_notice_date: 2009-07-21
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: AI
serial_number: 076956
program_official: LAPHAM, CHERYL K
project_start_date: 2008-06-17
project_end_date: 2010-05-31
study_section: Gastrointestinal Mucosal Pathobiology Study Section[GMPB]
contact_pi_person_id: 7739669
contact_pi: BONDADA, SUBBARAO
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Studies in animal models have shown that both the adaptive and the innate immune system have a definite role in inducing intestinal inflammation a hallmark of inflammatory bowel diseases (IBD). The Th-1 and Th-17 type T cells have a dominant role in Crohn's disease while the Th-2 type T cells appear to be more important for ulcerative colitis. Studies in the past decade have established the unequivocal role of regulatory T cells (T-Reg) in controlling the development of IBD. The T-regs are a recently discovered subset of CD4+ T cells that have a profound ability to suppress the effector function of helper T cells. They are characterized by expression of a transcription factor Foxp3 and CD25 while being quiescent. In cell transfer models T-Regs have been shown to potently suppress IBD. Yet there have not been any methods to augment the function of regulatory T cells in vivo which could have therapeutic potential. T-Regs express CD5 a cell surface marker present primarily on T cells and a minor subset of B- cells called B-1 cells. Based on our previous work about the negative signaling role of CD5 in B-1 cells we hypothesized that CD5 might negatively regulate TCR signaling in T-reg cells. This predicted that the regulatory function of T-Regs can be augmented in the absence of CD5. Accordingly we have shown that T-Regs from CD5 knockout mice are more effective in suppressing proliferation of CD4+CD25- effector T cells. Moreover our preliminary studies showed that in the dextran sulfate (DSS) induced model of colitis CD5 knockout mice have a milder form of the disease which we hypothesize is due to more effective nTreg function. Our specific aims are:  1. Our goal is to first to demonstrate the increased effectiveness of CD5 deficient T- Regs in an adoptive transfer model that consists in transferring CD45RB+ CD4+ CD25- T-cells into Rag1-/- mice with wild type or CD5 knockout T-Regs. 2. To develop a wild type animal model in which nTreg function can be enhanced. Here we will determine if development of IBD is reduced by inhibiting interaction of CD5 with its ligand using a CD5-Ig fusion protein and/or anti-CD5 antibodies. Since dendritic cells (DC) are known to modulate the development and function of T-Regs and since CD5 has been shown by us to regulate TCR mediated calcium signaling we will test the hypothesis that interaction of DC with T-Regs via CD5 and its ligand CD5L affects T-reg function. 3. To develop an alternate model of colitis to evaluate the role of non T cells in the inreased resistance of CD5-/- mice to colitis induction. PUBLIC HEALTH RELEVACE We have found that CD5 a molecule generally expressed on all T cells decreases regulatory T cell (T-reg) function and that T-Regs from mice in which CD5 is genetically deleted are more potent regulators of immune response. Here we plan to demonstrate that in an in vivo animal model of colitis induced by disease causing T cells the function of T-Regs is regulated by CD5 expression.

project_terms:
Adoptive Transfer;Affect;Animal Model;Antibodies;Antigen-Presenting Cells;B-Lymphocyte Subsets;B-Lymphocytes;CD4 Positive T Lymphocytes;Calcium Signaling;Cell physiology;Cell surface;Cells;Characteristics;Chimeric Proteins;Colitis;Colon;Crohn's disease;Dendritic Cells;Development;Dextran Sulfate;Disease;Effectiveness;Goals;Helper-Inducer T-Lymphocyte;Human;IL2RA gene;Immune;Immune response;Immune system;Inflammatory;Inflammatory Bowel Diseases;Inflammatory disease of the intestine;Investigation;Knock-out;Knockout Mice;Label;Ligands;Mediating;Methods;Minor;Modeling;Molecular Target;Mus;Rag1 Mouse;Receptor Signaling;Resistance;Role;Signal Transduction;Sulfonic Acids;T-Cell Receptor;T-Lymphocyte;TCR Activation;Testing;Therapeutic;Trinitrobenzenes;Ulcerative Colitis;Work;base;combat;in vivo;novel therapeutic intervention;public health medicine (field);transcription factor


application_id: 7640625
project_number: 5P50DA005312-18
project_title: CORE
administering_ic: NIDA
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
study_section: ZDA1
subproject_number: 9001
contact_pi_person_id: 1884463
contact_pi: BARDO, MICHAEL T
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
budget_end_date: 2009-06-30
funding_mechanism: Research Centers
project_terms:
Adolescence;Advocate;Basic Science;Cell physiology;Commit;Communities;Drug abuse;Drug usage;Educational workshop;Electroencephalography;Environment;Esthesia;Faculty;Funding;Goals;Human Resources;Illicit Drugs;Individual;Individual Differences;Institution;International;Laboratories;Leadership;Link;Magnetic Resonance Imaging Functional;Measures;Modeling;Neurophysiology - biologic function;Organizations Professional;Personality;Pharmaceutical Preparations;Positioning Attribute;Prevention;Prevention intervention;Process;Publications;Publishing;Range;Rat Laboratory;Research;Research Personnel;Resources;Rewards;Risk;Role;Science;Scientist;Self Administration;Series;Services;Structure;Students;Testing;Thinking function;Training;Translating;Translations;Volunteers Human;Work;base;cohort;college;design;drug abuse prevention;drug reward;high school;implementation science;interdisciplinary collaboration;neurobehavioral;next generation;outreach;programs;psychologic;psychosocial;relating to nervous system;research study;research to practice;response;social;symposium;trait;young adult


application_id: 7640624
project_number: 5P50DA005312-18
project_title: IMPROVING EFFECTIVE DESIGN AND TARGETING OF SUBSTANCE AUBSE PREVENT MESSAGES
administering_ic: NIDA
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
study_section: ZDA1
subproject_number: 0014
contact_pi_person_id: 1963601
contact_pi: ZIMMERMAN, RICK S.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
budget_end_date: 2009-06-30
funding_mechanism: Research Centers
project_terms:
Accounting;Address;Affective;Alcohol or Other Drugs use;Alcohols;Anxiety;Attention;Attitude;Behavior;Characteristics;Complex;Data;Development;Dimensions;Drug abuse;Effectiveness;Elements;Emotions;Esthesia;Failure (biologic function);Fright;Impulsivity;Individual;Individual Differences;Intervention;Knowledge;Lead;Literature;Marihuana;Modeling;Outcome;Personality;Predisposition;Prevention;Prevention intervention;Prevention program;Preventive Intervention;Probability;Process;Reaction;Reading;Recording of previous events;Research;Research Personnel;Review Literature;Rewards;Risk;Risk Behaviors;Risk-Taking;Schools;Services;Simplexvirus;Specific qualifier value;Substance abuse problem;Teenagers;Testing;Work;base;design;experience;gallium alloy GF;high risk behavior;high risk sexual behavior;improved;member;novel;prevent;programs;research study;sex;success;trait;willingness;young adult


application_id: 7640623
project_number: 5P50DA005312-18
project_title: MEDIATING PROCESSES IN THE PERSONALITY SUBSTANCE USE RELATION
administering_ic: NIDA
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
study_section: ZDA1
subproject_number: 0013
contact_pi_person_id: 3122080
contact_pi: LYNAM, DONALD R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
budget_end_date: 2009-06-30
funding_mechanism: Research Centers
project_terms:
Acute;Alcohol consumption;Alcohol or Other Drugs use;Alcohols;Behavior;Behavioral inhibition;Biological;Cardiac;Characteristics;Complex;Computer information processing;Cues;Drug Exposure;Drug usage;Elements;Esthesia;Expectancy;Failure (biologic function);Incentives;Intervention;Lead;Left;Link;Longitudinal Studies;Measures;Mediating;Mediator of activation protein;Memory Short-Term;Motivation;Names;Numbers;Outcome;Personality;Pharmaceutical Preparations;Process;Psychophysiology;Punishment;Range;Reaction Time;Research;Research Personnel;Rewards;Risk;Risk Factors;Signal Transduction;Skin;System;Thinking function;Time;Withdrawal;analog;approach behavior;cognitive system;cohort;design;discounting;experience;peer;programs;response;social;substance abuser;trait


application_id: 7640622
project_number: 5P50DA005312-18
project_title: INDIVIDUAL DIFFERENCES IN DRUG ABUSE LIABILITY
administering_ic: NIDA
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
study_section: ZDA1
subproject_number: 0012
contact_pi_person_id: 1901822
contact_pi: KELLY, THOMAS H.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
budget_end_date: 2009-06-30
funding_mechanism: Research Centers
project_terms:
Accounting;Address;Alcohols;Behavior;Behavioral;Brain;Brain imaging;Brain region;Characteristics;Clinical;Communication;Complex;Data;Detection;Development;Dextroamphetamine;Diazepam;Dimensions;Dopamine;Dopamine Agonists;Drug abuse;Drug usage;Educational aspects;Emotional;Esthesia;Event-Related Potentials;Exhibits;Funding;Human;Image;Individual;Individual Differences;Investigation;Laboratories;Laboratory Study;Link;Magnetic Resonance Imaging Functional;Measures;Methodology;Methylphenidate;Modeling;Neurobiology;Nicotine;Novelty-Seeking Behaviors;Numbers;Pattern;Personality;Personality Traits;Pharmaceutical Preparations;Play;Prevention;Prevention intervention;Probability;Process;Rattus;Research;Research Personnel;Rewards;Risk-Taking;Role;Score;Stimulus;Substance abuse problem;Translations;base;biobehavior;drug abuse prevention;drug of abuse;drug sensitivity;emotional stimulus;experience;improved;neurobehavioral;novel;programs;psychostimulant;response;trait;willingness


application_id: 7640621
project_number: 5P50DA005312-18
project_title: INDIVIDUAL DIFFERENCES IN RESPONSE TO AMPHETAMINE
administering_ic: NIDA
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
study_section: ZDA1
subproject_number: 0011
contact_pi_person_id: 1884463
contact_pi: BARDO, MICHAEL T
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-07-01
budget_end_date: 2009-06-30
funding_mechanism: Research Centers
project_terms:
Address;Adolescent;Affect;Amphetamines;Animal Model;Behavioral;Clinical;Complex;Corpus striatum structure;Disease;Dopamine;Drug abuse;Drug usage;Esthesia;Exposure to;Formulations Drug;Human;Incentives;Individual Differences;Intervention;Investigation;Knowledge;Medial;Mediating;Models Laboratory Animal;Motivation;Neurons;Neurophysiology - biologic function;Nucleus Accumbens;Pattern;Pharmaceutical Preparations;Play;Population;Prefrontal Cortex;Prevention intervention;Rattus;Rewards;Risk;Role;Serotonin;Signal Transduction;System;Work;behavior test;behavioral pharmacology;design;dopamine system;drug abuse prevention;drug reward;human subject;in vivo;monoamine;neural circuit;neuroimaging;neuromechanism;pre-clinical;reinforcer;relating to nervous system;response;theories;trait;young adult


application_id: 7637568
project_number: 1R56DK078742-01A1
project_title: The roles of integrin receptors in adipocyte differentiation
administering_ic: NIDDK
award_notice_date: 2008-09-02
opportunity_number: PA-07-070
application_type: 1
activity_code: R56
ic: DK
serial_number: 078742
suffix: A1
program_official: HAFT, CAROL R
project_start_date: 2008-09-02
project_end_date: 2009-08-31
study_section: Cellular Aspects of Diabetes and Obesity Study Section[CADO]
contact_pi_person_id: 8794215
contact_pi: LIU, JUN
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
The hypothesis to be tested is that two proteins integrin a5 and integrin a6 work together to control theformation of fat cells. Obesity is a major health care problem in the United States and is closed associatedwith many health problems such as cancer cardiovascular disease hypertension and especially diabetes.Obesity occurs when energy input exceeds energy expenditure resulting in more fat cells and larger fat cells.The first step in fat production involves proliferation of mesenchymal stem cells followed by differentiation intofat cell precursors called preadipocytes. Preadipocytes then migrate and proliferate at the site of fat productionwhere they differentiate further to become spherical adipocytes. This multi-step process is regulated bynumerous hormones and is accompanied by dramatic changes in cell shape and gene expression. We haverecently identified a critical switch in gene activity from integrin alpha5 to integrin alpha6. That switch allowspreadipocytes to cease dividing and cluster forming bona fide fat cells. Integrins are cell surface proteins thatare involved in binding to a meshwork of proteins outside of cells that can influence their behavior. Manythings happen in the generation of fat cells and we believe that the transition from one integrin to another is acrucial step. Here we propose experiments to manipulate those two integrins and examine the effects on theformation of fat cells. The fuller understanding of what happens in fat formation opens new avenues fortreatment of obesity and diabetes.

project_terms:
Address;Adhesions;Adipocytes;Adipose tissue;Basement membrane;Behavior;Binding (Molecular Function);Biological Assay;CNTNAP1 gene;Cardiovascular Diseases;Cell Cycle;Cell Shape;Cells;Cytoplasmic Tail;Cytoskeleton;Data;Development;Diabetes Mellitus;Diet;Dominant-Negative Mutation;Down-Regulation;ECM receptor;Ectopic Expression;Embryo;Energy Metabolism;Event;Extracellular Matrix;Fatty acid glycerol esters;Fibroblasts;Fibronectins;Gene Expression;Generations;Genes;Goals;Growth;Guanosine Triphosphate Phosphohydrolases;Health;Healthcare;Hormones;Hypertension;Insulin-Like-Growth Factor I Receptor;Integrin alpha5;Integrin alpha6;Integrins;Laminin;Laminin Receptor;Ligation;Link;Malignant Neoplasms;Mediating;Mesenchymal Stem Cells;Mice Knockout;Mice Transgenic;Modeling;Molecular;Mus;Obesity;Pathway interactions;Play;Process;Production;Proliferating;Protein Overexpression;Proteins;Proteins Cell Surface;RNA Small Interfering;Receptors Fibronectin;Regulation;Relative (related person);Research;Role;Series;Signal Transduction;Site;Somatomedins;Specificity;System;Techniques;Testing;Tyrosine Phosphorylation;United States;Withdrawal;Work;adipocyte differentiation;base;cell growth;in vivo;knock-down;lentiviral-mediated;lipid biosynthesis;mutant;obesity treatment;receptor;research study;rho;rho GTPase-activating protein


application_id: 7634400
project_number: 5P20RR015576-10
project_title: Mechanisms of plasticity and repair after SCI
administering_ic: NCRR
award_notice_date: 2009-04-24
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015576
program_official: GOROSPE, RAFAEL
project_start_date: 2000-09-15
project_end_date: 2011-05-31
study_section: ZRR1-RI-8(02)
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
EXCEED THE SPACEPROVIDED.This COBRE renewal brings together 5 junior or just recently funded Principal Investigators whose researchfocuses on spinal cord injury (SCI) and repair. They will be mentored by 3 senior Investigators with strongtrack records in SCI research. Five Cores will be extensively used by all of these Projects. This COBRErepresents a true Research Center and not a collection of individual Projects as the expertise of theseInvestigators is broad based and the success of individual Projects will depend on strong collaborations withother Projects and Cores. The Specific Aims of this COBRE are:1. To develop new therapeutic approaches to the treatment of SCI that can be utilized clinically.2. To further strengthen the independent research programs of each Principal Investigator that will ultimatelylead to additional R01 or P01 support.3. To continue to develop and support the KSCIRC infrastructure through its Core facilities.4. To facilitate collaborative research projects between the COBRE Principal Investigators as well as otherUniversity of Louisville faculty that will lead to significant scientific findings that are unlikely to be achieved byindividual research activities.5. To continue to be a leading SCI Research Center recognized both nationally and internationally anddevelop a reputation that will attract outstanding graduate students postdoctoral! fellows and faculty.The five Projects are: 1) Heat shock proteins in spinal cord neural survival 2) GSK3B as a target for pro-neuronal survival in CMS neurons 3) Remyelination as a mechanism for spinal cord repair 4) PKCregulation of sensory regeneration across CSPG after SCI and 5) Gender differences in chronic SCI pain.The 5 Cores are: Administrative and Research Support Cell Culture and Molecular Biology Surgery andVeterinary Care Electrophysiology and Behavior and Microscopy.


application_id: 7633167
project_number: 5K01DA018772-05
project_title: A Pharmacological Analysis of Delta 9-THC in Humans
administering_ic: NIDA
award_notice_date: 2009-05-28
opportunity_number: PA-95-049
application_type: 5
activity_code: K01
ic: DA
serial_number: 018772
program_official: LYNCH, MINDA
project_start_date: 2005-06-01
project_end_date: 2011-05-31
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):    Dr. Lile's graduate and post-doctoral research focused on the neuropharmacological basis of stimulant addiction and how the neurotransmitter systems that mediate the effects of stimulants could be targeted for medications development. The career development and research plan proposed in this application outlines the training that will enable him to apply his previous experience along with new methodolgies to an emerging area of research the treatment of cannabis-related disorders. Despite the fact that cannabis use is more prevalent than for any other illicit drug and can progress to abuse and dependence there are no pharmacotherapies for these disorders and little clinical research has been conducted to this end. The experiments described here were designed to identify the neurotransmitter systems that are involved in the effects of the primary active constituent of cannabis delta 9-THC in humans. The primary outcome variable for these experiments is the interoceptive cue produced by delta 9-THC. The interoceptive effects of delta 9- THC will be measured using the drug-discrimination procedure which is a pharmacologically specific and sensitive means to characterize the profile of a drug. Because cannabis-related disorders are associated with maladaptive changes in behavior and cognition additional experimental measures to assess reinforcement subjective ratings impulsivity psychomotor performance learning and memory will also be taken. The role of the cannabinoid opioid GABA and dopamine systems will be investigated which will reveal targets for future research efforts. Dr. Lile will be sponsored by Dr. Kelly an expert in cannabis research in humans. The conduct of these experiments and the training described in this proposal will occur at the University of Kentucky which has an extensive community of scientists engaged in basic and clinical research related to drug addiction. This award will allow Dr. Lile to develop as an independent investigator and to establish a program of human research concentrated on cannabis-related disorders.

project_terms:
Agonist;Aminobutyric Acids;Area;Attenuated;Award;Behavior;Behavioral;Cannabinoids;Cannabis;Cannabis-Related Disorder;Chronic;Clinical Research;Cognition;Cognitive;Communities;Cues;Dependence;Development;Disease;Dopamine;Drug Addiction;Drug Combinations;Ensure;Future;Goals;Human;Hydromorphone;Illicit Drugs;Impulsivity;Kentucky;Learning;Measures;Mediating;Memory;Methylphenidate;Nabilone;National Institute of Drug Abuse;Neurotransmitters;Opioid;Oral;Outcome;Pharmaceutical Preparations;Pharmacotherapy;Postdoctoral Fellow;Prevention;Procedures;Psychological reinforcement;Psychomotor Performance;Psychostimulant dependence;Research;Research Personnel;Role;Scientist;Stimulus;System;Techniques;Testing;Tetrahydrocannabinol;Training;Triazolam;Universities;base;cannabinoid receptor;career development;design;dopamine system;drug discrimination;drug of abuse;experience;gamma-Aminobutyric Acid;novel;primary outcome;programs;reinforcer;research study


application_id: 7632915
project_number: 3R01DA013930-06S2
project_title: Redesign of Butyrylcholinesterase for Cocaine Metabolism
administering_ic: NIDA
award_notice_date: 2008-06-09
application_type: 3
activity_code: R01
ic: DA
serial_number: 013930
suffix: S2
program_official: SHIH, MING L
project_start_date: 2003-08-20
project_end_date: 2011-05-31
study_section: Medication Development Research Study Section[NIDA-L]
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
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:
This project focuses on the rational redesign of human butyrylcholinesterase (BChE) in order to acceleratecocaine metabolism in human. Enhancing cocaine metabolism by administration of BChE has beenrecognized as a promising treatment strategy for cocaine abuse. However the catalytic activity of thisplasma enzyme is three orders-of-magnitude lower against the naturally occurring (-)-cocaine than thatagainst the relatively biologically inactive (+)-cocaine isomer. The primary goal of this project in the previousfunding cycle was to understand the mechanistic difference between BChE-catalyzed hydrolyses of (-)-cocaine and (+)-cocaine and to test whether a computational approach works or not for rational design ofBChE mutants with an improved catalytic efficiency against (-)-cocaine. Progress on the project has revealedthe fundamental catalytic pathways for BChE-catalyzed hydrolyses of (-)-cocaine and (+)-cocaine. We havefurther developed a novel computational design strategy based on transition state simulation leading todiscovery of several BChE mutants with significantly improved catalytic efficiency against (-)-cocainecompared to all BChE mutants reported in literature. Taking advantage of this promising design strategy andprotocol in the next phase of the project we propose an integrated computational-experimental effort tofurther improve the catalytic efficiency of BChE against (-)-cocaine. The proposed integrated computational-experimental approach will include a large-scale virtual screening of a variety of hypothetical BChE mutantsbased on the transition-state modeling and simulation followed by more sophisticated computationalevaluation and wet experimental tests. The Specific Aims include: 1. To determine the detailed reactioncoordinates and the corresponding free energy profiles for (-)-cocaine hydrolysis catalyzed by the knownhigh-activity mutants of BChE discovered in the previous funding cycle. 2. To design and discover new BChEmutants with further improved catalytic efficiency against (-)-cocaine by using an extended computationaldesign approach based on the transition state modeling and simulation to evaluate a large number ofhypothetical BChE mutants followed by wet experimental tests including site-directed mutagenesis proteinexpression and catalytic activity assay. The long-term objective of this investigation will be to eventuallydevelop an efficient anti-cocaine medication using a high-activity BChE mutant.

project_terms:
Abuse Cocaine;Binding (Molecular Function);Biological Assay;Butyrylcholinesterase;Clinic;Cocaine;Coupled;Dependences Cocaine;Enzymes;Evaluation;Facility Construction Funding Category;Free Energy;Funding;Goals;Human;Hybrids;Hydrolysis;Investigation;Isomerism;Literature;Mechanics;Metabolism;Microscopic;Modeling;Molecular;Mutagenesis Site-Directed;Mutation;Neuraxis;Numbers;Overdose;Pathway interactions;Pharmaceutical Preparations;Phase;Plasma;Process;Protocols documentation;Rate;Reaction;Relative (related person);Reporting;Screening procedure;Simulate;Structure;Testing;Work;addiction;base;computer studies;design;enantiomer;enzyme substrate;improved;models and simulation;mutant;novel;protein expression;quantum;simulation;three dimensional structure;virtual


application_id: 7632129
project_number: 5R01CA106281-05
project_title: The CXCR4-SDF-1 Axis in Metastatic Rhabdomyosarcoma
administering_ic: NCI
award_notice_date: 2009-06-10
application_type: 5
activity_code: R01
ic: CA
serial_number: 106281
program_official: TRICOLI, JAMES
project_start_date: 2005-09-20
project_end_date: 2010-09-30
study_section: Tumor Microenvironment Study Section[TME]
contact_pi_person_id: 2265592
contact_pi: RATAJCZAK, MARIUSZ Z
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
project_abstract:
DESCRIPTION (provided by applicant):  Rhabdomyosarcoma (RMS) is the most common sarcoma in children and very often infiltrates the bone marrow (BM).  Our recently published data show that stromal derived factor-1 (SDF-1) which is secreted within the BM microenvironment may play a crucial role in directing to the BM the RMS cells that express the receptor for SDF-1 CXCR4.  To investigate the mechanisms operating in the metastasis of RMS and develop a new therapeutic approach to blocking the SDF-1-CXCR4 axis in RMS we propose three aims.  Aim #1. To elucidate the molecular mechanisms of CXCR4 priming.  Since we observed that scatter factor (SF) increases/primes the chemotactic response of CXCR4+ RMS cells to an SDF-1 gradient we will focus on molecular mechanisms of crosstalk between the SDF-1-CXCR4 and SF-c-Met axes in RMS metastasis.  We will investigate which SDF-1-mediated steps in metastasis are influenced by SF and based on our preliminary data we will test the hypothesis that SF by increasing inclusion of CXCR4 into membrane lipid rafts modulates the responsiveness of RMS cells to SDF-1 gradient.  Aim #2. To determine whether PAX genes regulate the expression of CXCR4.  Since in RMS cell lines the expression of CXCR4 correlates with alveolar RMS and expression of the PAX3-FKHR and PAX7-FKHR genes we will investigate whether PAX genes directly regulate CXCR4 expression in RMS cells.  We will test whether CXCR4 expression in cells isolated from RMS patients also correlates with the alveolar type of RMS and with PAX3- and PAX7-FKHR fusion and/or overexpression of PAX-3 and PAX-7 wild-type genes.  Aim # 3. To assess therapeutic strategies to block the metastatic behavior of RMS cells by targeting the SDF-1-CXCR4 axis.  We noticed that radio-/chemotherapy induces SDF-1 secretion in various organs and creates a "metastasis-permissive" environment.  Thus we hypothesize that the SDF-1-CXCR4 axis may play a role in the spread of tumor cells that have escaped therapy.  To control the spontaneous and radio-/chemotherapy-induced metastatic behavior of RMS cells in vivo we will employ the newly synthesized small-molecular inhibitor of the CXCR4 receptor (TE14013) in a human RMS xenotransplant-immunodeficient mouse model.  This work will be of relevance for designing strategies to block the SDF-1-CXCR4 axis to treat CXCR4-positive cancers.

project_terms:
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole;Acute leukemia;Adhesions;Affect;Alveolar;Alveolar Rhabdomyosarcoma;Amides;Amphotericin B;Antibiotics;Autologous Bone Marrow Transplantation;Behavior;Binding Sites;Blast Cell;Bone Marrow;CXCR4 Receptors;CXCR4 gene;Cell Line;Cells;Chemicals;Chemotaxis;Child;Data;Dose;Drug usage;Embryonal Rhabdomyosarcoma;Environment;Fibroblasts;Filipin;Genes;Growth;Guidelines;Hepatocyte Growth Factor;Human;Immunodeficient Mouse;In Vitro;Ligands;Malignant Neoplasms;Marrow;Mediating;Membrane Lipids;Membrane Microdomains;Modeling;Modification;Molecular;Neoplasm Metastasis;Nystatin;Organ;Osteoblasts;PAX3 gene;Patients;Peptides;Play;Polyenes;Prognostic Factor;Prognostic Marker;Promotor (Genetics);Publishing;Radio;Rhabdomyosarcoma;Role;T140 peptide;Testing;Therapeutic;Work;Xiphosura;angiogenesis;base;chemokine;chemokine receptor;chemotherapy;design;experience;fusion gene;immunodeficient mouse model;in vivo;inhibitor/antagonist;insight;meetings;migration;neoplastic cell;novel therapeutic intervention;novel therapeutics;overexpression;programs;receptor;response;sarcoma;soft tissue;tumor


application_id: 7631269
project_number: 5R01OH009197-03
project_title: Refinement and Enhancement of Agricultural Safety Curricula for Children (REACCH)
administering_ic: NIOSH
award_notice_date: 2009-06-08
opportunity_number: RFA-OH-07-002
application_type: 5
activity_code: R01
ic: OH
serial_number: 009197
program_official: POTULA, VIJI
project_start_date: 2007-08-01
project_end_date: 2012-07-31
study_section: ZOH1-SBO(50)R
contact_pi_person_id: 8431098
contact_pi: REED, DEBORAH BAKER
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Recent studies demonstrated the positive impact of farm safety day camps on the safety attitudes and behaviors of participants and their families. These effects are somewhat modest and tend to diminish over time. This project proposes to design and test the efficacy of enhanced curriculum materials and their de- livery methods to children attending farm safety days in an attempt to strengthen and extend the positive effects of these programs. A four-group quasi-experimental community trial will measure immediate and long-term effects on children's and their parents' farm safety knowledge attitude and behaviors. The trial is led by the Pis of two completed NIOSH-funded R01 independent evaluation studies of farm safety day camps in partnership with the Progressive Agriculture Foundation (PAF). Specific aims are: 1. Develop enhanced safety day curricula for three high risk activities for children who live on work on or visit farms and develop supplemental materials to be delivered as boosters after the safety day. 2. Strengthen the training of instructors for the targeted activities. 3. Test the efficacy of the enhanced curriculum and strengthened training by comparing safety-related outcomes for children and their parents and comparing ratings by instructors in enhanced versus usual safety days. 4. Test the efficacy of the supplemental boosters by comparing safety-related outcomes for children and their parents who receive boosters versus those who do not receive boosters. 5. Incorporate refined curricula and programming into the PAF Safety Day Manual; share findings with other children's safety organizations. In Phase 1 findings from the previous studies will be used to strengthen the current curriculum and instructors' delivery of safety education in three targeted content areas. Materials will be developed for the safety day instructors for classroom teachers of the safety day participants and for boosters mailed to participants several months after the safety day. In Phase 2 a 2 (enhanced curriculum vs. standard) x 2 (boosters vs. no boosters) x 4 (repeated measures) design will be used to assess changes in safety knowledge attitudes and behaviors. Eight communities that hold annual safety days for children in local schools grades 4-5 will participate. A balanced design with 200 children in each block (total N = 800) will be used. Data will consist of pre and post-tests for children and telephone surveys at 6 and 12 months for children and their parents. Quality of instruction will be assessed through observation and analysis of videotapes made of the sessions and assessment by instructors. This community trial will assist in strengthening the positive effects of an existing intervention that has been readily accepted in local communities. It has the potential to improve the health and safety of all children who attend a safety day. Children's injury rates may be reduced through their participation in tested community-based developmentally appropriate interventions that are grounded in local values.


application_id: 7631207
project_number: 5R01NS039254-10
project_title: Tat-mediated brain endothelial cell dysfunction
administering_ic: NINDS
award_notice_date: 2009-06-15
opportunity_number: PAS-03-165
application_type: 5
activity_code: R01
ic: NS
serial_number: 039254
program_official: DALEY, WILLIAM PATRICK
project_start_date: 2000-04-01
project_end_date: 2010-09-01
study_section: Special Emphasis Panel[ZRG1-AARR-A(07)M]
contact_pi_person_id: 8260644
contact_pi: TOBOREK, MICHAL
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Impaired function of the brain vasculature can contribute to HIV trafficking into the CNS and the development of neurodegenerative changes associated with HIV infection. Indeed activation or dysfunction of brain microvascular endothelial cells (BMEC) can lead to the breakdown of the blood-brain barrier (BBB) induction of inflammatory responses and provide an entry route for the HIV into the CNS. The leading hypothesis of our research is that the viral gene product HIV Tat protein can be responsible for BMEC injury and impaired function of the BBB. Furthermore we hypothesize that alterations of redox balance may be the common denominator of Tat-induced activation and dysfunction of BMEC. In support of these hypotheses we obtained strong evidence that Tat treatment can dramatically downregulate peroxisome proliferator activated receptor (PPAR) activation and thus suppress physiological functions of these critical anti-inflammatory nuclear receptors. This research proposal will focus on the consequences of Tat-induced alterations of PPAR activation namely overexpression of proinflammatory genes dysregulation of junctional protein expression and disturbances of endothelial barrier function. In addition we hypothesize that Tat-induced alterations of BMEC redox status can lead to upregulation of the efflux transport systems on the brain endothelium and thus prevent an effective anti-HIV therapy in the CNS. The proposed research combines elements of clinical approaches such as disruption of the BBB and the development of drug resistance with molecular and vascular biology. It is based on the unique and innovative co-cultures of human brain endothelial cells with astrocytic cell lines which produce Tat (the SVGA-Tat cells). In addition part of the project involves animal studies. The long-term goals of this proposal are to determine the mechanisms responsible for Tat-induced injury to BMEC disruption of the BBB and HIV entry into the CNS. In a broader aspect this proposal will contribute to better knowledge of how injury to brain endothelium can contribute to the development of neuroAIDS.

project_terms:
1-Phosphatidylinositol 3-Kinase;AIDS Dementia Complex;AIDS neuropathy;Abbreviations;Affect;Animal Model;Animals;Anti-HIV Agents;Anti-HIV Therapy;Anti-Inflammatory Agents;Anti-inflammatory;Applications Grants;Astrocytes;Attenuated;Biological Models;Biology;Blood - brain barrier anatomy;Blood Vessels;Brain;Calcium;Cell Death;Cell Line;Cell physiology;Cells;Clinical;Coculture Techniques;Data;Development;Disease;Down-Regulation;Drug resistance;Drug usage;Elements;Endothelial Cells;Endothelium;Equilibrium;Equus caballus;Excision;Exposure to;Functional disorder;Funding;Genes;Goals;HIV;HIV Infections;HIV drug resistance;HIV tat Protein;HIV-1;Highly Active Antiretroviral Therapy;Human;Inflammatory;Inflammatory Response;Injury;Ink;Inositol;Intercellular Junctions;Knowledge;Lead;Manuscripts;Mediating;Mitogen-Activated Protein Kinase 3;Mitogen-Activated Protein Kinases;Molecular;Multidrug Resistance-Associated Proteins;NIH Program Announcements;Nerve Degeneration;Neuroglia;Neurologic;Neurons;Nuclear;Nuclear Receptors;Oxidation-Reduction;Oxidative Stress;P-Glycoprotein;P-Glycoproteins;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Physiological;Play;Process;Protein Kinase C;Proteins;Publishing;Reaction;Receptor Activation;Receptor Signaling;Research;Research Personnel;Research Proposals;Resistance;Role;Route;Signal Pathway;Signal Transduction;Staging;Stream;System;Therapeutic;Tight Junctions;Tissues;Up-Regulation (Physiology);Vascular Endothelial Growth Factor Receptor-2;Vascular Endothelium;Viral;Viral Proteins;Virus;abstracting;base;cell injury;cell type;innovation;monocyte;multidrug resistance-associated protein 2;neglect;novel;overexpression;prevent;protein expression;stress-activated protein kinase 1;tat Protein;trafficking;transcription factor;transcytosis;tripolyphosphate


application_id: 7631067
project_number: 2R56HL074091-05A1
project_title: Mechanisms of Long-term Cardiac Ion Channel Regulation
administering_ic: NHLBI
award_notice_date: 2008-06-05
opportunity_number: PA-07-070
application_type: 2
activity_code: R56
ic: HL
serial_number: 074091
suffix: A1
program_official: PRZYWARA, DENNIS
project_start_date: 2003-07-15
project_end_date: 2009-05-30
study_section: Electrical Signaling, Ion Transport, and Arrhythmias Study Section[ESTA]
contact_pi_person_id: 7875430
contact_pi: SATIN, JONATHAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Ca dysregulation in cardiac myocytes contributes to heart development defects and diseases of theaging heart. The long-term objective of this proposal is to provide a molecular mechanism that explains howcardiac L-type Ca channels (LTCC) sense and transduce signals that homeostatically regulate cardiacmyocytes. Cardiac myocytes present a conundrum with respect to Ca signaling to the nucleus. Cytosolic Caamplitude varies >10-fold during each cardiac cycle yet alterations of Ca somehow are differentially decodedfor longer-term transcriptional signaling. In this funding period we will test whether Ca channel activity and thecardiac L-type Ca channel itself encodes Ca signaling for long-term regulation. In the past funding period wediscovered that RGK chronically inhibited ICaL (LTCC current) and this RGK inhibition of ICaL resulted in acompensatory up-regulation of CaV1.2 mRNA. This suggests that ICaL block may signal transcriptional eventsin the nucleus. In new studies we confirmed and extended this notion by showing that LTCC-pharmacologicalblockbut not internal Ca in general is responsible for perturbing heart development. Along the same lines inmature heart long-term blockade of LTCC also causes a compensatory up-regulation of LTCC and ICaL. Ourdriving hypothesis is that signaling is not simply determined by Ca but by active Ca channels. The discoverythat mobile segment of LTCC is localized to the nucleus or t-tubules coupled with the recent report that thispeptide is a transcription factor drives the exciting new hypothesis that this segment of the LTCC regulatesLTCC expression. We will study this aspect of long-term channel regulation in three aims: 1. We will assessnuclear translocation of a domain of the LTCC and determine the interaction between LTCC activity and subcellularlocalization; 2. We will determine the ability of LTCC to auto-regulate itself transcriptionally; and 3. Wewill determine the compensatory changes of SL Ca handling proteins in response to LTCC blockade. This workmay provide a missing molecular link between LTCC function and downstream signaling events.

project_terms:
Abbreviations;Acute;Adrenergic Agents;Adult;Aging;Automobile Driving;C-terminal;Calcium Channel;Cardiac;Cell Nucleus;Chronic;Class;Condition;Coupled;Data;Defect;Disease;Down-Regulation;Elements;Event;Funding;Growth and Development function;Heart;Homeostasis;Ion Channel;Link;Localized;Molecular;Monomeric GTP-Binding Proteins;Muscle Cells;Myocytes Cardiac;Nuclear;Nuclear Translocation;Pathway interactions;Peptides;Pharmaceutical Preparations;Protein Phosphatase 2A Regulatory Subunit PR53;Protein phosphatase;Proteins;RNA Messenger;Regulation;Reporting;Signal Transduction;Structure;Testing;Transcriptional Activation;Transducers;Up-Regulation (Physiology);Ventricular;Work;adrenergic;cardiogenesis;chromatin immunoprecipitation;clinically relevant;in vitro Model;in vivo;novel;protein expression;response;sensor;trafficking;transcription factor


application_id: 7629810
project_number: 5R42AA014554-04
project_title: Transgenic plant cells as a source of hepatoprotective drugs
administering_ic: NIAAA
award_notice_date: 2009-07-01
opportunity_number: RFA-AA-06-007
application_type: 5
activity_code: R42
ic: AA
serial_number: 014554
program_official: OROSZ, ANDRAS
project_start_date: 2003-09-30
project_end_date: 2010-05-31
study_section: ZAA1-DD(74)
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alcoholic liver damage (ALD) is among the top ten causes of death in the USA but existing therapeutic interventions are relatively ineffective. Hepatocytes are susceptible to damage probably because they have a high level of alcohol dehydrogenase (ADH) which metabolizes alcohol to form acetaldehyde and reactive oxygen species (ROS) which are both cytotoxic. Close similarities between eukaryotic cells suggest that alcohol-resistant plant cells are a potential source of hepatoprotective compounds particularly if these plant cells have been "engineered" to metabolize alcohol rapidly by ADH. In the preceding phase 1 research transgenic tobacco cells expressing rat liver ADH and a cellular screen for hepatoprotection were developed. In this phase 2 proposal mutant cultures from this transgenic plant will be selected for resistance to alcohol-induced toxicity. Extracts from this resistant sub-population will then be screened for the presence of cytoprotective metabolites against alcohol-induced toxicity in hepatocytes. Greater genetic diversity can be introduced by investigation of protective metabolites that have been evolved "naturally" by plants. In aquatic plant species fermentation reactions become important energy sources particularly in root tissue when oxygen tension is low. This induces ADH with prolonged very high rates of alcohol metabolism to acetaldehyde (Vartapetian & Jackson 1997). Some of these species should have evolved metabolites that protect against intracellular generation of ROS and acetaldehyde and some of these might also protect hepatocytes from alcohol. Extracts from ~75 native aquatic plant species were immediately available to the project and ~30 have now been screened. Several of these extracts are highly protective to hepatocytes. In phase 2 this screening will continue and the two approaches will be combined by culturing and selecting mutant populations of those aquatic plant species with greatest hepatoprotective activity. Subsequently the protective activity in these transgenic plants will be optimized and extracts and semi-purified compounds evaluated in animal models of ALD in vivo. Several patentable therapeutic products are predicted which will be commercialized with a partner in phase 3. The development of the technology also extends existing intellectual property licensed exclusively to Naprogenix by the University of Kentucky Research Foundation.

project_terms:
Acetaldehyde;Acute;Alcohol Hepatotoxicity;Alcohol dehydrogenase;Alcohol-Induced Disorders;Alcoholic liver damage;Alcohols;Animal Model;Antioxidants;Biological Factors;Cause of Death;Cell Line;Cells;Chronic;Daughter;Development;Economics;Energy-Generating Resources;Engineering;Ethanol;Ethanol Metabolism;Ethanol toxicity;Eukaryotic Cell;Fermentation;Foundations;Fractionation;Generations;Genes;Genomics;Geographic Locations;Hepatocyte;Hepatoprotective Agent;High Pressure Liquid Chromatography;Human;In Vitro;Intellectual Property;Investigation;Kentucky;Killings;Libraries;Licensing;Liver;Modeling;Mus;Mutagenesis;Mutation;Oxygen measurement partial pressure arterial;Pathology;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Plant Extracts;Plant Genome;Plant Leaves;Plant Roots;Plants;Population;Production;Proteins;Protoplasts;Rattus;Reaction;Reactive Oxygen Species;Research;Resistance;Resources;Screening procedure;Small Business Technology Transfer Research;Source;Staging;Technology;Testing;Therapeutic;Therapeutic Intervention;Tissues;Tobacco;Toxic effect;Transgenic Organisms;Transgenic Plants;Universities;Variation (Genetics);cell injury;commercialization;cytotoxic;high throughput screening;in vivo;in vivo Model;innovation;mutant;novel;problem drinker;technology development


application_id: 7628384
project_number: 5R01NS040919-09
project_title: Male Urogenital Function and Chronic Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2009-05-21
application_type: 5
activity_code: R01
ic: NS
serial_number: 040919
program_official: KLEITMAN, NAOMI
project_start_date: 2000-09-28
project_end_date: 2011-06-30
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 6490947
contact_pi: HUBSCHER, CHARLES H.
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
project_abstract:
DESCRIPTION (provided by applicant): Deficits in ejaculation urination and defecation are among of the most devastating outcomes of spinal cord injury (SCI) severely affecting quality of life. The neural mechanisms are poorly understood making restoration of function following traumatic SCI a difficult task. In humans SCI occurs predominantly in young males and compromises sexual function leaving most patients infertile. Moreover bladder dysfunction is common due to the loss of synergy between the bladder and its outlet for voiding urine. In many patients conscious control of defecation is also lost resulting in fecal incontinence and chronic constipation. Since normal ejaculation micturition and defecation require sequential contraction of perineal muscles that depend upon an intact segmental reflex arc and brainstem integration we have developed and characterized an in vivo brainstem-spinal cord electrophysiological animal model to study the neurological causes of ejaculatory and eliminative dysfunctions following severe mid-thoracic SCI. Our previous studies with this model have shown that chronic bilateral lesions of the dorsal 3/5 of T8 spinal cord is correlated with (i) impaired bladder/sexual reflexes (ii) changes in lumbosacral neural circuits mediating perineal muscle function and (iii) loss of ascending and descending connections between the genitalia/pelvic organs and the medullary reticular formation. Studies in our current grant (NS40919) address important questions regarding the neural control/coordination of smooth and striated muscles sub-serving sexual bladder and bowel functions in male rats using specific chronic lesions restricted to the dorsal 3/5 of the T8 cord. Results from our current data have raised new questions regarding injury-induced plasticity in these neural circuitries. The overall aim for this renewal grant is to use our model to investigate these injury-induced changes in order to allow us to more specifically ascertain the spinal cord regions and specific neural circuitry which should be targeted for therapeutic interventions designed to improve the control/coordination of sexual bladder and bowel functions following chronic SCI. The knowledge gained from these studies will help direct future experiments that will be geared toward the development of therapeutic interventions that will promote functional recovery following SCI. Parallel electrophysiological neuroanatomical and behavioral studies are once again proposed.

project_terms:
24-Dinitrophenol;Accidental Injury;Acute;Address;Affect;Animal Model;Animals;Anus;Area;Axon;Behavioral;Bilateral;Bladder;Bladder Dysfunction;Brain Stem;Caliber;Catheters;Cell Nucleus;Cells;Chest;Chronic;Clinical;Collaborations;Colon;Complement;Conscious;Constipation;Cutaneous;Data;Defecation;Development;Distal;Dorsal;Ejaculation;Electric Stimulation;Electrophysiology (science);Epithelium;Fecal Incontinence;Feces;Felis catus;Female;Fiber;Florida;Functional Imaging;Functional disorder;Funding;Future;Genitalia;Genitourinary system;Glans penis;Grant;Harvest;Healthy People 2000;Human;Immunohistochemistry;Infertility;Infusion procedures;Injection of therapeutic agent;Injury;Interneurons;Intestines;Knowledge;Label;Lateral;Left;Lesion;Location;Medial;Mediating;Modeling;Monitor;Motor Neurons;Movement;Muscle;Muscle function;Nerve;Neurologic;Neurons;Organ;Outcome;Pathway interactions;Patients;Pelvic Cancer;Pelvis;Phase;Phenotype;Process;Quality of life;Rattus;Reading;Recovery of Function;Reflex action;Reporting;Research Personnel;Research Priority;Reticular Formation;Sensory;Sex Functioning;Sexual Dysfunction;Side;Site;Skeletal muscle structure of perineum;Spinal;Spinal Cord;Spinal cord injury;Staining method;Stains;Stimulus;Striated Muscles;Study Section;Suid Herpesvirus 1;Surgical incisions;Synapses;Techniques;Therapeutic Intervention;Thoracic spinal cord structure;Tracer;Universities;Urethra;Urethral sphincter;Urination;Urine;Viral;Viscera;Visceral;Work;base;cancer pain;cryostat;dorsal column;implantation;improved;in vivo;injured;interest;male;microstimulation;neural circuit;neuromechanism;neuroregulation;penis;prepuce;pressure;radiofrequency;reproductive;research study;response;restoration;spinal pathway;stroke;therapy design;urinary;white matter;white matter damage


application_id: 7628057
project_number: 5R21NS060033-02
project_title: Role of Olig3 in cerebellar and precerebellar development
administering_ic: NINDS
award_notice_date: 2009-06-22
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: NS
serial_number: 060033
program_official: RIDDLE, ROBERT D
project_start_date: 2008-07-01
project_end_date: 2011-06-30
study_section: Neurogenesis and Cell Fate Study Section[NCF]
contact_pi_person_id: 1906514
contact_pi: QIU, MENGSHENG
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this application is to understand the molecular control of neuronal specification and differentiation in the cerebellum. The cerebellum is a midbrain-hindbrain structure that participates in coordination of motor function and higher cognition function. Abnormal cerebellar development can lead to neurological diseases such as autism and medulloblastoma. Although the morphogenesis of cerebellum has been well studied in the past century little is known about the molecular mechanisms that control the fate specification and differentiation of the cerebellar neurons and their associated precerebellar neurons located in the brainstem. Recent studies have demonstrated that transcription factors of the bHLH family are important regulators of the proliferation fate specification and differentiation of cerebellar neurons and precerebellar neurons. In this application we propose to study the functional role of Olig3 bHLH factor in the development of cerebellar and precerebellar neurons. During early neural development Olig3 is highly expressed in the rhombic lips of the hindbrain the dorsal neural progenitor cells that give rise to both cerebellar neurons and precerebellar neurons. The pattern of Olig3 expression leads us to hypothesize that it functions to regulate the development of cerebellar system. In this pilot application two specific aims are proposed to test this hypothesis and further define its role in the fate specification proliferation migration or differentiation of cerebellar and precerebellar neurons. The first aim of the proposal is to characterize the mutational effects of Olig3 on the specification and differentiation of cerebellar nd precerebellar neurons. The second aim is to investigate possible changes in the identity and migration of rhombic lips cells in Olig3 mutant embryos using the Cre-loxP mediated genetic labeling methods.   
PUBLIC HEALTH RELEVANCE: The proposed studies will provide important insights into the molecular regulation of neuronal specification proliferation and differentiation in the developing cerebellar system. Knowledge obtained from this study can help us understand the molecular mechanisms underlying cerebellum disorders and medulloblastoma and provide cues for therapeutic treatment of these neurological diseases.

project_terms:
Affect;Animals;Autistic Disorder;Brain Stem;Cell Nucleus;Cells;Cerebellum;Cognition;Cues;Development;Disease;Dorsal;Embryo;Family;Fiber;Genes;Genetic;Goals;Immunohistochemistry;In Situ;Inferior;Knowledge;Label;Lead;Lip structure;Maps;Mediating;Methods;Midbrain structure;Molecular;Morphogenesis;Motor;Movement;Mutation;Neurons;Olives - dietary;Pattern;Phenotype;Principal Investigator;RNA;Regulation;Role;Structure;System;Testing;Therapeutic;hindbrain;insight;medulloblastoma;migration;mossy fiber;mutant;nerve stem cell;nervous system disorder;neurodevelopment;programs;public health relevance;transcription factor


application_id: 7627994
project_number: 5R21CA127052-02
project_title: Coleus forskohlii extract: melanization and UV protection by a natural product
administering_ic: NCI
award_notice_date: 2009-04-30
opportunity_number: PA-06-400
application_type: 5
activity_code: R21
ic: CA
serial_number: 127052
program_official: UMAR, ASAD
project_start_date: 2008-07-01
project_end_date: 2010-06-30
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 8508402
contact_pi: D'ORAZIO, JOHN A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
  
Fairness of skin correlates with diminished epidermal expression of eumelanin the brown/black pigment responsible for dark complexion. Instead there is preferential expression of pheomelanin a sulfated blonde/red melanin species that is soluble and has poor UV-blocking abilities. Persons with high levels of pheomelanin and low levels of eumelanin in the skin have little basal protection from UV radiation and therefore suffer the highest incidence of UV-mediated skin damage and skin cancer. To delineate the relationship between UV exposure and pigmentation and develop novel pigment-based UV protective strategies we have developed a mouse model of "humanized skin" with inducible pigmentation. Like in humans the fair-skinned phenotype in our animal model is caused by defective signaling in melanocytes by the melanocortin-1 receptor (MC1R) a protein that mediates adenylate cyclase activation and cAMP generation when bound by its natural ligand melanocyte stimulating hormone (MSH). Similar to fair- skinned humans who tend to burn rather than tan after sunlight exposure our fair-skinned animals demonstrate heightened UV sensitivity and failure to tan adaptively. Using this novel mouse model we study melanin induction by forskolin a labdane diterpenoid that directly activates adenylate cyclase and promotes intracellular accumulation of cAMP. By topically applying root extract from the C. forskohlii plant (the natural source of forskolin) to the skin we can induce the production of UV-protective eumelanin by chemically circumventing the defective cAMP signaling associated with the mutant MC1R. Using our animal model we will directly modulate cAMP signaling and melanin levels to clarify the protective effects of C. forskohlii extract against UV-mediated skin damage. We hypothesize that pharmacologic up- regulation of cAMP in the skin will protect against UV-mediated damage by promoting eumelanin synthesis and by enhancing the repair of UV-induced DNA photolesions. To address our hypothesis we propose three specific aims: i) Characterize the role of MC1R function in UV-mediated oxidative damage and determine whether pharmacologic replacement of MC1R function protects against oxidative UV injury; ii) Delineate the impact of MC1R function in the repair of UV-induced DNA lesions; and iii) Determine whether molecular bypass of MC1R function by cAMP up-regulation enhances repair following UV exposure. Our goal is to develop the novel approach of UV protection by sunless tanning based on topical administration of this root extract or small molecule derivatives. Our research strategy will provide a substantial foundation on which we can develop UV-protective strategies to prevent rather than treat skin cancer. PUBLIC HEALTH RELEVANCE: Our goals are to (1) understand how UV irradiation damages skin of different pigment types; (2) devise natural pigment-based strategies that protect against UV-mediated skin damage; and (3) effectively prevent skin cancer. Using unique transgenic mice that mimic human skin we will measure DNA damage and repair in UV- exposed skin and explore mitigation of this damage and enhancement of repair. Our proposed research includes both in vivo and in vitro analyses of UV effects in whole skin and in melanocytes derived from our animal model respectively.

project_terms:
Address;Adenylate Cyclase;Affect;Anatomy;Animal Model;Animals;Base Excision Repairs;Binding (Molecular Function);Biological Factors;Biological Models;Biology;Breeding;Burn injury;Bypass;Coleus forskohli;Congenic Animals;Cyclic AMP;DNA;DNA Repair;DNA lesion;Data;Diterpenes;Failure (biologic function);Forskolin;Foundations;Free Radical Formation;Functional disorder;Generations;Genetic Polymorphism;Goals;Human;In Vitro;Incidence;Individual;Injury;Inorganic Sulfates;Investigation;Labdanes;Ligands;Location;Measures;Mediating;Melanins;Melanocyte stimulating hormone;Modeling;Molecular;Mus;Nucleotides;Pathway interactions;Persons;Phenotype;Pigmentation physiologic function;Pigments;Plant Roots;Plants;Production;Proteins;Receptor Signaling;Receptor Melanocortin Type 1;Relative (related person);Reporting;Research;Role;Signal Transduction;Skin;Skin Cancer;Skin tanning;Source;Sun Exposure;System;Testing;The Sun;Thymine Dimers;Topical application;Transgenic Mice;UV Radiation Exposure;UV induced;UV induced DNA damage;UV injury;UV protection;UV sensitive;Ultraviolet Rays;Unspecified or Sulfate Ion Sulfates;Up-Regulation (Physiology);Variant;Wild Type Mouse;alpha-Melanocyte stimulating hormone;base;eumelanin;in vivo;loss of function;melanocyte;melanoma;mimicry;mouse model;mutant;novel;novel strategies;oxidative damage;pheomelanin;photolesion;prevent;protective effect;public health relevance;receptor function;repaired;response;skin cancer prevention;small molecule;ultraviolet damage;ultraviolet irradiation;ultraviolet lesions


application_id: 7627843
project_number: 1R56AI075212-01A1
project_title: Modulation of Neutrophil Apoptosis by Akt-Hsp27 Signalosome
administering_ic: NIAID
award_notice_date: 2008-06-05
opportunity_number: PA-07-070
application_type: 1
activity_code: R56
ic: AI
serial_number: 075212
suffix: A1
program_official: DONG, GANG
project_start_date: 2008-06-10
project_end_date: 2008-08-07
study_section: Erythrocyte and Leukocyte Biology Study Section[ELB]
contact_pi_person_id: 6799635
contact_pi: RANE, MADHAVI 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
project_abstract:
Activated neutrophils (PMNs) play a critical role in sepsis ischemia-reperfusion injury and immunecomplex-mediated diseases. The broad long-term objective of our laboratory is to elucidate the role ofAkt in regulating PMN functions. This proposal will test the hypothesis: Hsp27 regulates neutrophil cellsurvival/death responses by modulating critical protein-protein interactions within the Akt signalosomeby acting as a scaffolding protein. The specific aims of this proposal are: Specific Aim 1- To determinewhether Akt associated/dissociated proteins regulate Akt activation and neutrophil apoptosis in theabsence of Akt-Hsp27 interaction. Specific Aim 2- To determine signaling pathways that underlie Akt-Hsp27 disruption induced neutrophil apoptosis. Specific Aim 3- To determine whether induction ofneutrophil apoptosis by disruption of Akt-Hsp27 interaction results from changes in JNK or p38 MAPKmediatedprotein phosphorylation ubiquitination or subcellular redistribution of Akt-candidate proteins.In specific aim 1 we will generate TAT-fusion proteins to 6 Akt-associating and 6 Akt-dissociatingproteins identified by our proteomic studies and determine effects of transducing these proteins on Aktactivation and neutrophil apoptosis. cDNA subclonning site-directed mutagenesis proteintransductions cDNA transfections in vitro kinase assays and apoptosis assays will be performed toaccomplish this aim. Specific aim 2 experiments will be focused on determining mechanisms thatunderlie activation of p38 MAPK and JNK pathways after disruption of Akt-Hsp27 interaction. We willalso investigate the impact of Akt-Hsp27 disruption on the regulation of proteasomal activation. In vitroJNK and p38 MAPK kinase assays proteasome activity assays transduction of relevant TATpeptides/TAT-proteins into PMNs will be performed to accomplish this aim. In specific aim 3. we willfocus our work on those Akt-associated or Akt-dissociated proteins shown to regulate Akt activationand neutrophil apoptosis in specific aim 1. We will then determine if these relevant proteins regulateAkt activation and neutrophil apoptosis by undergoing a post-translational modification such asphosphorylation and/or ubiquitination as a consequence of disruption of Akt-Hsp27 interaction. We willalso determine if these protein modifications would result in change in localization of these proteinsand/or alter their function. TAT-peptide transduction cell fractionation studies western blotting sitedirectedmutagenesis studies and confocal microscopic studies will be performed to accomplish thisspecific aim. These studies will lead us to new targets for disrupting neutrophil-mediated tissuedamage in inflammatory diseases.

project_terms:
Address;Antigen-Antibody Complex;Apoptosis;Apoptotic;Bacteria;Binding (Molecular Function);Biological Assay;Blotting Western;Cell Fractionation;Cell Survival;Cessation of life;Chimeric Proteins;Complex;DNA Complementary;Data;Disease;Disruption;Excision;Goals;Granulocyte-Macrophage Colony-Stimulating Factor;Heat Shock Protein 27;IL8 gene;Immune system;In Vitro;Infection;Infection Control;Infectious Agent;Inflammatory;Injury;Killings;Laboratories;Lead;Leukotriene B4;Lipopolysaccharides;MAP Kinase Gene;MAPK14 gene;MAPK8 gene;Mediating;Microscopic;Mitogen-Activated Protein Kinase Kinases;Molecular;Mutagenesis;Mutagenesis Site-Directed;Neutrophil Activation;Organ failure;Pathway interactions;Peptides;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Play;Protein Kinase;Protein Processing Post-Translational;Protein-Serine-Threonine Kinases;Proteins;Proteomics;Rate;Regulation;Reperfusion Injury;Reporting;Role;Scaffolding Protein;Sepsis;Signal Pathway;Signal Transduction;Site;System;Testing;Time;Tissues;Transfection;Ubiquitination;Work;base;chemokine;cytokine;fighting;intracellular protein transport;member;multicatalytic endopeptidase complex;neutrophil;novel;novel strategies;novel therapeutics;pathogen;prevent;protein localization location;protein protein interaction;research study;response


application_id: 7626369
project_number: 5R01AG026147-04
project_title: LDLR Genetics Splicing and AD Risk
administering_ic: NIA
award_notice_date: 2009-08-12
opportunity_number: PAS-03-128
application_type: 5
activity_code: R01
ic: AG
serial_number: 026147
program_official: MILLER, MARILYN
project_start_date: 2006-08-15
project_end_date: 2011-01-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 1859637
contact_pi: ESTUS, STEVEN
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): Identifying genetic variants that significantly alter the function of critical proteins provides insights into related disease processes and possible therapies. The low density lipoprotein receptor (LDLR) is remarkable in this regard because LDLR mutations are a primary cause of familial hypercholesterolemia i.e. loss of a single LDLR allele causes an approximately 100% increase in LDL-cholesterol levels. Although LDLR SNPs and their haplotypes have been associated with altered cholesterol levels specific SNPs that alter LDLR function have not been identified. Functional LDLR variants may provide insights into diseases that may be associated with increased cholesterol e.g. Alzheimer's Disease (AD). Indeed a robust genetic factor for both cholesterol and AD is the apoE4 allele of the apoE gene. Although apoE is implicated in amyloid-beta (Abeta) deposition in Alzheimer's disease apoE is known more widely for its role in cholesterol delivery and homeostasis; apoE4 is associated with increased LDL-cholesterol via its role as a ligand for the LDL family of cell surface receptors that mediate lipoprotein uptake. This proposal focuses on the global hypothesis that SNPs that modulate LDLR splicing or expression and the haplotypes defined by these functional SNPs are associated with altered cholesterol homeostasis and Alzheimer's disease. Hence we propose the following Specific Aims: 1. Evaluate LDLR SNPs to identify those that alter LDLR splicing and /or expression 2. Evaluate the expression and function of LDLR proteins resulting from alternative LDLR splicing. 3. Evaluate LDLR genotypes and haplotypes for their association with cholesterol homeostasis and Alzheimer's disease. Overall this focused approach will directly evaluate the hypothesis that LDLR polymorphisms modulate LDLR splicing and expression to increase LDL-cholesterol and Alzheimer's disease odds.

project_terms:
3' Untranslated Regions;Accounting;Alleles;Alternative Splicing;Alzheimer's Disease;Alzheimer's disease risk;Amino Acids;Amyloid beta-Protein;Antibodies;Apolipoprotein E;Binding (Molecular Function);Biological;Blood Vessels;Brain;Cell Surface Receptors;Cell model;Cell surface;Cells;Cholesterol;Cholesterol Homeostasis;Collaborations;Conditioned Culture Media;DNA;Deposition;Disease;Disease Association;Disease susceptibility;Dominant-Negative Mutation;Endosomes;Enhancers;Event;Exons;Extracellular Space;Familial Hypercholesterolemia;Family;Frequencies (time pattern);Gender;Gene Fusion;Genes;Genetic;Genetic Polymorphism;Genotype;Golgi Apparatus;Gonadal Steroid Hormones;Haplotypes;Homeostasis;Human;Immune Sera;Immunoprecipitation;In Vitro;Individual;Kentucky;LDL Cholesterol Lipoproteins;LDL-Receptor Related Protein 1;Label;Life;Ligand Binding;Ligands;Link;Lipids;Lipoproteins;Liver;Low Density Lipoprotein Receptor;Low-Density Lipoproteins;Mediating;Mutation;Neurons;Nobel Prize;Nonsense Codon;Pattern;Phenotype;Physiologic pulse;Plasma;Population;Principal Investigator;Process;Protein Binding;Protein Isoforms;Proteins;Publishing;RNA Splicing;Reading;Relative (related person);Religion and Spirituality;Reporter Genes;Reporting;Research Personnel;Risk Factors;Role;Sampling;Series;Sex Characteristics;Site;Transmembrane Domain;Universities;Variant;Vesicle;Western Blotting;Woman;Work;apolipoprotein E-3;apolipoprotein E-4;base;case control;disease phenotype;extracellular;gain of function;genetic variant;human tissue;in vivo;insight;mRNA Stability;member;novel;offspring;programs;protein function;receptor;receptor binding;receptor expression;receptor function;sugar;trend;uptake


application_id: 7626248
project_number: 5R24MD002757-02
project_title: Faith Moves Mountains: A CBPR Appalachian Wellness & Cancer Prevention Program
administering_ic: NIMHD
award_notice_date: 2009-01-12
opportunity_number: RFA-MD-07-003
application_type: 5
activity_code: R24
ic: MD
serial_number: 002757
program_official: GOODWIN, PAULA
project_start_date: 2008-05-22
project_end_date: 2013-01-31
study_section: ZMD1-RN(01)R
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Appalachian communities are disproportionately affected by many of the leading risk factors associated with cancer incidence and mortality factors amenable to primary and secondary prevention. Extensive involvement with our community partners has demonstrated strong community preference for a holistic approach toward cancer prevention; The proposed intervention extends our successful faith-based trained lay health advisor tailored intervention "Faith Moves Mountains" (R01CA108696) initiated three years ago to administer a culturally appropriate CBPR intervention. Working in partnership with 70 faith based institutions in rural Southeastern Kentucky we propose to administer evaluate and disseminate a tailored wellness and cancer prevention program focused on four of the most common prevention activities that have the potential of greatly preventing and reducing cancer morbidity and mortality. These prevention activities include smoking cessation (targeting all chronic diseases cervical and lung cancer); energy balance including dietary modification and physical activity promotion (targeting all chronic diseases and colorectal cancer (CRC)) and cancer screenings (targeting CRC cervical and breast cancer).  
  
Consistent with our Faith Moves Mountains and cancer control approach faith-based organizations will sponsor a "kick off event" or health fair in which participants will undergo a health risk appraisal (baseline). Participants will then select one or more wellness activities (smoking cessation energy balance cancer screening); then trained lay health advisors will offer modules on each of these wellness activities. Smoking cessation will include the culturally relevant Cooper-Clayton method (outcome: smoking abstinence). For those targeting dietary modification and physical activity a rural Appalachian modified Healthy Body/Healthy Spirit program will be administered (outcome: dietary change and physical activity participation). Tailored cancer screening promotion will be based on our current Faith Moves Mountains design (outcome: receipt of any recommended CRC screening test Pap test for cervical cancer and/or mammogram). To assess the intervention but remain consistent with community norms we will employ a staggered intervention design. Throughout the project the RE-AIM model will inform our evaluation. During phase three this CBPR wellness approach to cancer prevention will undertake qualitative process evaluation interviews and disseminate the intervention to medically underserved Appalachian Ohio in collaboration with partners at Ohio State University. This collaboration will facilitate dissemination of successful intervention to additional rural Appalachian populations with high rates of cancer health disparities.

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


application_id: 7625332
project_number: 2R56NS045103-05A1
project_title: Regulation of Neuronal Survival by the Rit GTPase
administering_ic: NINDS
award_notice_date: 2008-05-20
opportunity_number: PA-07-070
application_type: 2
activity_code: R56
ic: NS
serial_number: 045103
suffix: A1
program_official: MAMOUNAS, LAURA
project_start_date: 2002-12-01
project_end_date: 2010-05-31
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 7875195
contact_pi: ANDRES, DOUGLAS ALLEN
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Signaling pathways that contribute to cell death/survival influence diseases including cancer and manyneurodegenerative conditions. Elaborating signal transduction mechanisms that regulate these processes arethus important for understanding both basic biology and for therapeutic intervention. Neurotrophins potentlystimulate neuronal survival in part by activating the small GTP-binding protein Ras which functions bytranslating neurotrophin-initiated signals into multiple signaling pathways including PI-3 kinase/Akt andMEK/ERK to promote survival. In the initial funding period it was proposed that a novel and evolutionarilyconserved group of Ras-related GTPases including two mammalian proteins (Rit and Rin) and a singleDrosophila ortholog (Ric) play critical roles in regulating apoptotic signaling. From this work it is now clear thatboth Rit and Ric promote neuronal survival in a manner distinct from that of Ras. The original hypothesis isnow expanded to address how these anti-apoptotic signaling cascades are regulated. The central hypothesisof this proposal is that the Rit GTPase functions as a molecular switch in neurons responding to bothapoptotic stresses and neurotrophin-initiated signals to activate a distinct pro-survival signalingcascade that relies upon p38 MAP kinase signaling. Three specific aims are proposed: Aim 1 willcharacterize the ability of activated Rit to promote neuronal survival. In particular we will assess the ability ofRit signaling to protect neurons from trophic factor-withdrawal mediated apoptosis. Using primary neuronsfrom a transgenic mouse model expressing activated Rit specifically in neurons (developed during the previousperiod) it is now possible to analyze these critical issues. In addition microarray analysis will be used tocatalog the neuronal transcriptional program regulated by Rit signaling. Aim 2 will determine the regulatorymechanism that couples NGF-stimulated TrkA to Rit activation and the nature of Rit-dependent regulation ofthe p38 MAP kinase cascade. Aim 3 will explore the critical signaling pathways utilized for Rit anti-apoptoticsignaling. In particular Rit-mediated activation of both the p38-MSK1/2 kinase cascade and CREBtranscriptional pathways appear to play central roles and will be tested using a combination of both cell modelsystems and primary neurons. Importantly data developed since the previous review suggests that a secondnovel Rit-p38-HSP27-MK2 pathway may stimulate AKT signaling to afford neuronal protection. In summarythese studies will establish a role for Rit in neuronal survival. Regulation of this novel Ras-related G-proteinmay have a pronounced impact on neuronal physiology and would make Rit and its effectors potential targetsfor the development of new therapeutic strategies.

project_terms:
1-Phosphatidylinositol 3-Kinase;Address;Apoptosis;Apoptotic;Biochemical;Biological;Biological Models;Biology;CREB1 gene;Cataloging;Catalogs;Cell Death;Cell Survival;Cell model;Cells;Complex;Condition;Couples;Coupling;DNA Microarray Chip;DNA Microarray format;Data;Development;Disease;Disruption;Dominant-Negative Mutation;Drosophila genus;Epilepsy;Family;Family member;Funding;GTP-Binding Proteins;Gene Expression;Genes;Genetic;Guanosine Triphosphate Phosphohydrolases;Human;Injury;Ligands;MAP Kinase Modules;MAPK14 gene;MAPK14 protein human;MAPK8 gene;MEKs;Malignant Neoplasms;Mediating;Microarray Analysis;Molecular;Nature;Nerve Degeneration;Nerve Growth Factor 1;Nerve Growth Factor Pathway;Nervous system structure;Neurodegenerative Disorders;Neuronal Differentiation;Neurons;Orthologous Gene;Pathway interactions;Pheochromocytoma;Phosphotransferases;Physiological;Physiology;Play;Process;Proteins;Proto-Oncogene Proteins c-akt;Recovery;Recruitment Activity;Regulation;Role;Signal Pathway;Signal Transduction;Site;Son of Sevenless Proteins;Stimulus;Stress;Structure of superior cervical ganglion;Testing;Therapeutic Intervention;Transcription Genetic;Transducers;Transgenic Organisms;Translating;Withdrawal;Work;biological adaptation to stress;cell growth regulation;extracellular;in vivo;inhibitor/antagonist;insight;mitogen-activated protein kinase p38;mouse model;neuronal survival;neurotrophic factor;novel;novel therapeutics;programs;ras-Related G-Proteins;repaired;response;stroke;therapy development


application_id: 7625156
project_number: 5R21CA129881-02
project_title: Increasing Colorectal Cancer Screening for Patients with Multiple Morbidities
administering_ic: NCI
award_notice_date: 2009-04-06
opportunity_number: PA-06-351
application_type: 5
activity_code: R21
ic: CA
serial_number: 129881
program_official: BRESLAU, ERICA S
project_start_date: 2008-05-21
project_end_date: 2012-04-30
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Appalachian and rural underserved residents in general experience higher rates of multiple morbidities (MM) with fewer resources to prevent and manage disease. Some researchers have speculated that the well-documented cancer health disparities affecting Appalachians may be attributable to multiple morbidity management demands which may deprioritize essential and efficacious cancer screenings. In this pilot study we examine whether and how multiple morbidities affect colorectal cancer screening rates. Our long-term goal is to turn this disadvantageous situation of competing time and resource pressure into an advantage by increasing cancer screening services during the more frequent medical interactions of those with multiple morbidities. Addressing the nearly three-quarters of middle aged and older adults with MM is essential due to skyrocketing rates of MM higher rates of cancer mortality among those with MM and competing demands of disease prevention and management. We aim to expand our limited understanding of the association between MM and colorectal cancer (CRC) screening through three research activities. First to obtain rich insights into the factors and circumstances that affect patterns of CRC screening behavior among those with multiple morbidities in-depth interviews will be conducted with 5 health care providers representing diverse practices in Appalachia and with 40 patients who have two or more chronic diseases. These interviews will provide locally grounded perspectives from the two most salient health decision makers providers and patients. Second to insure generalizability we will assess the impact of factors germane to both MM and CRC screening behavior by conducting a stratified representative survey of Appalachians. Finally after identifying factors circumstances and patterns that prevent CRC screening in the context of multiple morbidities we will hold focus groups to validate our findings and discuss optimal direction for interventions. Ultimately these findings will lead to the development of a community-based participatory intervention R01 that will capitalize on the relatively frequent medical care visits of those with multiple morbidities and ultimately will increase CRC screening improve practice coordination and decrease cancer-associated deaths. PUBLIC HEALTH RELEVANCE: In the US the majority of the ever-growing middle aged and older population has multiple morbidities or several chronic diseases. Having multiple morbidities generally decreases the likelihood of receiving highly effective cancer prevention like colorectal cancer screening. This project uses innovative methods to determine the reasons why those with multiple morbidities may be less likely to get colorectal cancer screening and will eventually develop a culturally consistent intervention for the underserved rural health disparities population of Appalachia to increase early detection of this deadly cancer.

project_terms:
Address;Affect;Age;Appalachian Region;Area;Attention;Behavior;Caring;Cessation of life;Chronic;Chronic Disease;Colorectal Cancer;Communities;Computers;Consultations;Data;Development;Disease;Early Diagnosis;Elderly;Evaluation;Focus Groups;Foundations;Future;Gender;Goals;Health;Health Personnel;Healthcare;Home environment;Incidence;Intervention;Interview;Investigation;Lead;Malignant Neoplasms;Mass Media;Media Campaign;Medical;Methods;Morbidity - disease rate;Mortality Vital Statistics;Office Visits;Older Population;Outcome;Patients;Pattern;Persons;Physicians;Pilot Projects;Population;Preventive;Primary Health Care;Provider;Research;Research Activity;Research Personnel;Resources;Rural;Rural Community;Rural Health;Screening for cancer;Screening procedure;Secondary Cancer Prevention;Services;Socioeconomic Status;Surveys;Testing;Time;Visit;Work;base;cancer diagnosis;cancer health disparity;cancer prevention;colorectal cancer screening;design;disorder prevention;experience;health disparity;improved;indexing;innovation;insight;middle age;outreach;pressure;prevent;public health relevance;routine provider;successful intervention;therapy development;underserved rural area


application_id: 7624978
project_number: 5R01DC002736-12
project_title: Functional Domains and Expression of Olfactory Receptors
administering_ic: NIDCD
award_notice_date: 2009-06-10
application_type: 5
activity_code: R01
ic: DC
serial_number: 002736
program_official: DAVIS, BARRY
project_start_date: 1995-08-01
project_end_date: 2011-06-30
study_section: Special Emphasis Panel[ZRG1-IFCN-K(03)M]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-07-01
project_abstract:
DESCRIPTION (provided by applicant): The mammalian olfactory epithelium does two remarkable things with its olfactory sensory neurons. These neurons detect odorants translating the structure of volatile chemicals into a neural information code and the epithelium can replace these neurons even if they are completely eliminated. These properties are of significant interest for both basic and applied neuroscience research. The goal of this project is to generate a finely detailed description of the phenotypes of the mature olfactory sensory neurons and their immediate progenitor cells then use this description to predict critical steps in the molecular mechanisms that lead to the genesis of these neurons their ability to detect certain odors and their ability to survive in their exposed position. The first aim of this project combines a system-wide view of gene expression with our ability to purify certain cell types so that we can assign gene expression patterns and the biological processes they represent to their correct homes in the cells of the epithelium. The second aim takes advantage of predictions about genes whose products regulate the activity of other genes made by our preliminary data. We will test whether targeted knockout of six of these regulator genes all expressed by immature olfactory sensory neurons causes deficits in either the production of mature neurons or in critical functions of these neurons. The third aim is based on our belief that within the expression patterns we observe in olfactory sensory neurons are sets of genes responsible for survival of the neurons. We will use odor stimulation which is known to enhance survival to increase the activity of pro-survival genes (or suppress anti-survival genes) so that they can be detected. This project is an integrated approach to understanding the genes whose activity is important for generating the phenotype of mature olfactory sensory neurons and then maintaining these cells in the face of significant challenges.

project_terms:
Afferent Neurons;Belief;Biological Process;Cell Adhesion;Cells;Chemicals;Cilia;Code;Data;Defect;Energy Metabolism;Environment;Epithelium;Event;Face;Flagella;Gel;Gene Expression;Gene Silencing;Gene Targeting;Genes;Genetic Transcription;Goals;Home environment;Individual;Ion Transport;Knock-out;Lead;Link;Maintenance;Measures;Messenger RNA;Molecular;Mus;Neurons;Neurosciences Research;Odors;Olfactory Epithelium;Pattern;Phenotype;Population;Positioning Attribute;Production;Property;Regulation;Regulator Genes;Signal Transduction;Sorting - Cell Movement;Spermatogenesis;Stem cells;Structure;Synaptic Transmission;System;Testing;Tissues;Translating;base;cell injury;cell type;chromatin remodeling;cilium biogenesis;deprivation;experience;interest;knockout gene;neurogenesis;olfactory receptor;precursor cell;progenitor;relating to nervous system;tool;transcription factor


application_id: 7624853
project_number: 3U01CA114622-04S1
project_title: Appalachia Community Cancer Network
administering_ic: NCI
award_notice_date: 2008-07-21
opportunity_number: RFA-CA-05-012
application_type: 3
activity_code: U01
ic: CA
serial_number: 114622
suffix: S1
program_official: OGUNBIYI, PETER
project_start_date: 2005-05-06
project_end_date: 2010-04-30
study_section: ZCA1-SRRB-Y(J1)
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
A multidisciplinary team of collaboratorsfrom academic institutions and communities in Appalachian regionsof Kentucky West Virginia Ohio Pennsylvania New York Maryland and Virginia are proposing to build on astrong foundation of previous activity of the Appalachia Cancer Network (ACN) an NCI-funded SpecialPopulations Network and develop the Appalachia Community Cancer Network (ACCN). The proposedACCN will expand the previous ACN and expand to address cancer health disparities in seven areas inAppalachia areas that include some of the most medically underserved distressed and economicallydisadvantaged areas in the US. Cancer mortality rates are elevated in each of these areas as are theincidence rates for lung cervical and colorectal cancers suggesting that factors such as late stage diagnosisand barriers to cancer care must be addressed if disparities are to be reduced. The long-term goal of theACCN is to contribute to the reduction of cancer health disparities in Appalachia by developingimplementing and evaluating community-based participatory research and providing training. The specificaims of the AACN are to: 1) Build on a foundation established by the ACN and develop and maintaincommunity partnerships to facilitate research and action to reduce cancer health disparities; 2) Conductcommunity based participatory research ranging from focused needs assessments to intervention researchto policy assessments; 3) Develop pilot research projects that focus on primary and secondary prevention oflung cervical and colorectal cancers in Appalachia; 4) Train researchers in community-based participatoryresearch; and 5) Conduct evaluation of the ACCN including attention to processes short term impact andachievement of outcomes. The ACCN will build on the ACN and develop programs in cancer educationcommunity based participatory research and training. Proposals for two pilot project are also included. Thepilot projects address cervical and colorectal cancer two cancers targeted by the ACCN.

project_terms:
Achievement;Address;Appalachian Region;Area;Attention;Cervical;Clinical Trials;Colorectal Cancer;Communities;Diagnosis;Disadvantaged;Distress;Evaluation;Foundations;Funding;Goals;Incidence;Institution;Intervention Studies;Kentucky;Lung;Malignant Neoplasms;Maryland;Mortality Vital Statistics;Needs Assessment;New York;Ohio;Outcome;Pennsylvania;Pilot Projects;Policies;Process;Range;Rate;Research;Research Personnel;Research Project Grants;Research Training;Research Action;Secondary Prevention;Special Populations Networks;Staging;Training;Virginia;West Virginia;cancer care;cancer education;cancer health disparity;community based participatory research;medically underserved;multidisciplinary;programs


application_id: 7624575
project_number: 5R03AR053641-03
project_title: Circadian Regulation of Myod1 Transcription
administering_ic: NIAMS
award_notice_date: 2009-05-18
opportunity_number: PAR-06-111
application_type: 5
activity_code: R03
ic: AR
serial_number: 053641
program_official: BOYCE, AMANDA T
project_start_date: 2007-06-01
project_end_date: 2010-11-30
study_section: ZAR1-EHB-M(O1)
contact_pi_person_id: 1873134
contact_pi: MCCARTHY, JOHN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    
The myogenic differentiation 1 (Myodl) gene encodes a basic helix-loop-helix transcription factor that is a master regulator of skeletal muscle lineage determination during embryonic development. The post-natal function of Myodl is not well understood but a deficit in the specific tension of Myodl (-/-) mice in addition to their impaired regenerative ability intimate a significant role in adult skeletal muscle. We recently identified the Myodl transcript in adult skeletal muscle as having a robust circadian pattern of expression and this pattern of expression was absent in muscle of homozygous Clock mutant mice suggesting Myodl is a clockcontrolled gene. The long-range goal of the project is to understand the circadian function of Myodl in adult skeletal muscle. As a first step toward this goal the objective of this proposal will be to determine if the coreclock transcription factors Clock and Email are directly involved in the regulation of Myodl transcription. The primary hypothesis of this application is that Myodl is a direct transcriptional target of the CLOCK:BMAL1 heterodimer. The hypothesis will be tested by pursuing the following three specific aims: 1) use the Myodl DRRIoxP and CEIoxP mice to determine the role of the distal regulatory region (DRR) and the core enhancer (CE) of the Myodl promoter in the circadian regulation of Myodl transcription 2) determine the ability of core-clock transcription factors CLOCK and BMAL1 to transactivate Myodl reporter genes and 3) determine if CLOCK and BMAL1 are bound to the endogenous Myodl promoter by chromatin immunoprecipitation (ChIP) assay. The discovery of Myodl as a circadianly expressed gene is an exciting discovery because it provides a completely novel paradigm for thinking about the post-natal function of Myodl and establishes a potential link between master regulators of circadian rhythms and tissue-specific expression. A better understanding of how Myodl transcription is regulated in the adult is expected to provide a foundation for understanding the mechanisms underlying the altered expression of Myodl in such diseases as muscular dystrophy and sarcopenia.

project_terms:
Adult;Antibodies;BHLH Protein;Binding (Molecular Function);Binding Sites;Biological Assay;Circadian Rhythms;Creatine Kinase;Disease;Distal;Down-Regulation;Electronic Mail;Electrophoretic Mobility Shift Assay;Embryonic Development;Enhancers;Exhibits;Foundations;Gene Targeting;Genes;Genetic Transcription;Goals;In Vitro;Knockout Mice;Link;Maintenance;Metabolic;Modeling;Molecular;Mus;Muscle;Muscular Dystrophies;Mutant Strains Mice;Mutate;Natural regeneration;Nucleic Acid Regulatory Sequences;Pattern;Phenotype;Promotor (Genetics);Proteins;Regulation;Regulatory Element;Reporter Genes;Role;Skeletal muscle structure;Testing;Thinking function;Tissues;Transcript;Transfection;Transgenic Organisms;base;chromatin immunoprecipitation;design;functional disability;in vivo;insight;mature animal;mutant;myogenesis;novel;regenerative;research study;sarcopenia;transcription factor


application_id: 7623961
project_number: 5K02DE016845-05
project_title: Regulation of Nodal Signaling in Holoprosencephaly
administering_ic: NIDCR
award_notice_date: 2009-05-29
opportunity_number: PA-00-020
application_type: 5
activity_code: K02
ic: DE
serial_number: 016845
program_official: HARDWICK, KEVIN S
project_start_date: 2005-07-01
project_end_date: 2010-06-30
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
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
project_abstract:
DESCRIPTION (provided by applicant):  Holoprosencephaly represents a common birth defect (1:16000 in live births and 1:250 in stillbirths) with a broad spectrum of craniofacial malformations ranging from distressful cyclopia to mild symptom of a single central incisor. It is caused by defects in the specification of the ventral forebrain (a part of the anterior axial midline) which subsequently lead to incomplete separation of the brain into the left and right hemispheres. Recent studies indicated that Nodal signaling plays a central role in controlling midline development we therefore will focus on the regulation of Nodal signaling in mouse embryogenesis with a special interest in anterior axial midline formation. Nodal is a member of the transforming growth factor beta (TGF-beta) superfamily that utilizes a signaling pathway defined by Activin type I and II receptors Smad2 and 4 and FoxH1(FAST). Importantly members of the EGF-CFC family of extracellular proteins such as mouse Cripto are essential co-factors for Nodal. We previously reported a Cripto null allele and recently we generated a Cripto hypomorphic allele Cripto3-loxP by genetic manipulation. Approximately 50% of the Cripto3-loxP/CriptoNull mice displayed a wide range of axial midline defects resembling holoprosencephaly. In contrast TGIF is a homeobox gene encoding a nuclear protein that antagonizes TGF-beta signaling by blocking Smad2 function. Interestingly mutations in human TGIF gene are associated with holoprosencephaly suggesting its function in axial midline formation presumably through regulating Nodal/Smad2 signaling pathway. Based on these results we will pursue the following specific aims in the proposed research: I) Analysis of the Cripto3-loxP/CriptoNull mice as a model system for ventral forebrain defects and HPE by detailed analysis of the defects in Cripto3-loxP/CriptoNull mice at morphology and molecular levels; II) Investigation of mechanisms underlying Cripto function in mouse axial midline formation by identifying the tissues and cells where Cripto is functioning and downstream target genes of Cripto; III) Investigation of TGIF function in mouse axial midline development by generating TGIF null embryos and examining the modulation of Nodal signaling by TGIF. These studies should improve our understanding of mammalian axial midline formation and human holoprosencephaly.

project_terms:
Activins;Alleles;Anterior;Biological Assay;Biological Models;Brain;CFC1 gene;Cell Culture Techniques;Cells;Cleft Lip;Congenital Abnormality;Cultured Cells;Defect;Development;Dorsal;Ectoderm;Embryo;Embryonic Development;Endoderm;Extracellular Protein;Eye;Family;Figs - dietary;Floor;Gene Targeting;Genes;Genetic;Head;Holoprosencephaly;Homeobox Genes;Homeodomain Proteins;Human;IL10 gene;In Vitro;Incisor;Investigation;Lead;Left;Live Birth;Mediating;Mesoderm;Midbrain structure;Molecular;Morphology;Mus;Mutant Strains Mice;Mutation;Nodal;Nuclear Protein;Nuclear Proteins;Pattern;Phenotype;Play;Process;Prosencephalon;Proteins;Regulation;Reporting;Research;Role;Series;Signal Pathway;Signal Transduction;Stillbirth;Symptoms;System;Tissues;Transforming Growth Factor beta;Zebrafish;base;craniofacial;density;genetic manipulation;improved;in vivo;insight;interest;malformation;member;notochord;precursor cell;receptor;relating to nervous system


application_id: 7623053
project_number: 5R01DC006698-06
project_title: NEURAL MODULATION OF CENTRAL TASTE PROCESSING
administering_ic: NIDCD
award_notice_date: 2009-06-02
opportunity_number: PA-03-115
application_type: 5
activity_code: R01
ic: DC
serial_number: 006698
program_official: SULLIVAN, SUSAN L
project_start_date: 2005-07-01
project_end_date: 2011-06-30
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 2239737
contact_pi: LUNDY, ROBERT 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:
DESCRIPTION (provided by applicant): Food intake is not only regulated by homeostatic processes as is evidenced by eating beyond homeostatic needs if presented with highly palatable food. The palatability of taste i.e. hedonic tone is unquestionably a key factor in guiding food intake. A positive hedonic tone stimulates feeding and is one of many dietary factors associated with excess energy intake and in the long term may lead to obesity diabetes and hypertension. The object of this project is to understand how neural activity in the cortex and limbic system control taste processing in subcortical gustatory nuclei. The long-term objective is to elucidate how the brain assigns hedonic value to taste stimuli that reinforce or weaken their consumption. There must be neural circuitry by which gustatory hedonic value can be modified. For example an unpleasant experience with food-learned taste aversion-can result in the rejection of a previously accepted taste while a mineral imbalance--Na+ appetite-can transform a normally rejected Na+ solution into a highly preferred one. In normal animals changes in the motivational qualities of taste stimuli are coincident with selective alterations in the responses of brainstem taste cells. Although the isolated brainstem contains the sensory and motor apparatus necessary to produce feeding behavior ventral forebrain mechanisms are necessary for motivational states to modify these behaviors. One interpretation is that feedback from rostral structures normally modulates the afferent neural activity that conveys the hedonic value of a taste stimulus. Using electrophysiological neuroanatomical neurochemical and lesion analysis this project will test hypotheses about the centrifugal control of taste processing in the brainstem. Specific experiments examine (1) differences between the influence of forebrain activity on NST and PBN taste neurons (2) the route through which descending cortical and limbic projections modulate PBN taste neurons and (3) the neurochemicals released in the PBN by activation of cortical and limbic system nuclei.

project_terms:
Amygdaloid structure;Animals;Behavior;Brain;Brain Stem;Cell Nucleus;Cells;Chemicals;Chronic;Consumption;Corticotropin-Releasing Hormone;Desire for food;Diabetes Mellitus;Dietary Factors;Dopamine;Eating;Electric Stimulation;Energy Intake;Feedback;Feeding behaviors;Food;Glutamates;High Pressure Liquid Chromatography;Hypertension;Hypothalamic structure;Lateral;Lead;Learning;Lesion;Limbic System;Liquid substance;Measures;Medial;Mediating;Microdialysis;Minerals;Motor;Neurons;Neuropeptides;Neurotensin;Neurotransmitters;Norepinephrine;Nucleus solitarius;Obesity;Oral;Process;Prosencephalon;Radioimmunoassay;Rattus;Research Personnel;Route;Sensory;Serotonin;Solutions;Somatostatin;Specificity;Stimulus;Structure;Substance P;Taste Perception;Testing;experience;feeding;hedonic;immunoreactivity;neural circuit;neurochemistry;parabrachial nucleus;programs;relating to nervous system;research study;response


application_id: 7622162
project_number: 5R03AA015964-02
project_title: Drugged Driving in Alcohol-restricted Rural Appalachia
administering_ic: NIAAA
award_notice_date: 2009-05-01
opportunity_number: PA-06-180
application_type: 5
activity_code: R03
ic: AA
serial_number: 015964
program_official: BLOSS, GREGORY
project_start_date: 2008-05-10
project_end_date: 2011-04-30
study_section: Special Emphasis Panel[ZRG1-HOP-X(04)M]
contact_pi_person_id: 8335129
contact_pi: WEBSTER, JOHN MATTHEW
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): The literature on drug-impaired driving has not experienced the same growth as the alcohol-related DUI literature despite the early and continued recognition that drug-impaired driving is a major public health concern. This application proposes a study to examine alcohol-impaired and drug-impaired driving in rural Appalachia a group of DUI offenders who are virtually unstudied. Although some counties in rural Appalachia allow alcohol sales (wet counties) several do not allow alcohol to be sold (dry counties) or limit alcohol sales to certain towns (moist counties). DUI remains a frequent crime in rural Appalachia despite these differing levels of alcohol availability. The high rates of prescription drug abuse in rural Appalachia may contribute to the incidence of DUI in these areas. In this pilot study a sample of 120 rural Appalachian DUI offenders stratified by level of alcohol sales restriction (wet dry or moist county) will be interviewed. The specific aims for this project are to: (1) Describe individual characteristics of rural Appalachian DUI offenders including socio-demographic information alcohol and drug use histories attitudes and beliefs about alcohol and drug use and history of impaired driving; (2) Identify similarities and differences between individuals from rural Appalachian DUI offenders who have driven under the influence of drugs and rural Appalachian DUI offenders who have driven under the influence of alcohol but not drugs; and (3) Identify similarities and differences between rural Appalachian DUI offenders convicted in counties with varying levels of alcohol sales restriction. The overall aim of this project is to add to our understanding of alcohol- and drug-impaired driving in rural Appalachia. The long term objective of this project is to collect data to be used by this new investigator to develop a competitive R01 application to design and test a tailored intervention for rural Appalachian DUI offenders that equally addresses alcohol- and drug-impaired driving. More than 35 million Americans drive under the influence of alcohol or drugs per year. This project will collect information to compare alcohol-impaired drivers to drug-impaired drivers from rural Appalachia an understudied area yet known to have high levels of alcohol and prescription drug abuse. The long term objective of the project is to develop an intervention to reduce impaired driving in this area.

project_terms:
Address;Age;Alcohol consumption;Alcohols;American;Analgesics;Appalachian Region;Area;Attitude;Automobile Driving;Belief;Characteristics;Communities;County;Coupled;Crime;Data;Dependence;Diet;Drug abuser;Drug usage;Drunk driving;Educational aspects;Employment;Ethnicity aspects;Failure (biologic function);Gender;Growth;Health;Health Personnel;Health Services Accessibility;Health behavior;Incidence;Individual;Intervention;Interview;Kentucky;Knowledge;Literature;Marital Status;National Institute of Drug Abuse;Participant;Patient Self-Report;Pharmaceutical Preparations;Pilot Projects;Policies;Population;Population Density;Prevalence;Preventive;Publishing;Race;Readiness;Recording of previous events;Recruitment Activity;Reporting;Research;Research Personnel;Rural;Rural Population;Safety;Sales;Sampling;Services;Substance abuse problem;Testing;Travel;United States Substance Abuse and Mental Health Services Administration;World Health Organization;alcohol abuse therapy;alcohol availability;alcohol measurement;base;convict;depressed;design;driving under influence;drug driving;effective intervention;experience;impaired driving performance;innovation;male;offender;prescription drug abuse;public health medicine (field);trafficking


application_id: 7620146
project_number: 2R56AI048850-06
project_title: Fatty acid binding proteins in macrophage function
administering_ic: NIAID
award_notice_date: 2008-05-16
opportunity_number: PA-07-070
application_type: 2
activity_code: R56
ic: AI
serial_number: 048850
program_official: PEYMAN, JOHN A
project_start_date: 2000-12-01
project_end_date: 2010-02-28
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 1882106
contact_pi: SUTTLES, JILL
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Fatty acid binding proteins FABPs have been identified as central regulators of both metabolic andinflammatory pathways. FABPs act as intracellular receptors for a variety of hydrophobiccompounds enabling their diffusion within the cytoplasmic compartment. We have shown thatadipocyte FABP (A-FABP) and epithelial FABP (E-FABP) regulate macrophage cholesteroltrafficking and inflammatory function in part via regulation of the activity of the peroxisomeproliferator-activated receptor ( (PPAR(). Macrophages and dendritic cells (DC) from FABPdeficientmice are defective in expression of proinflammatory cytokines and are inefficient in thepromotion of proinflammatory T cells responses during antigen presentation. FABP-deficient miceare protected from development of experimental autoimmune encephalomyelitis (EAE). Overallthe results of our research suggest that FABPs regulate a molecular switch between metabolic andinflammatory pathways in macrophages and DC and as a consequence regulate both innate andadaptive immune responses. We will continue our studies of these proteins through the pursuit ofthe following specific aims: Specific Aim 1 is to identify the molecular mechanism(s) by which FABPsaffect inflammatory cytokine gene expression in macrophages and DC. We have found that FABPdeficiencyis accompanied by elevated activity of AMP-activated protein kinase (AMPK) and thatAMPK is a negative regulator of macrophage inflammatory function. Experiments will be performedto determine the link between FABPs AMPK and PPAR( testing the hypothesis that FABPregulation of energy stores regulates AMPK activity which in turn modulates inflammatory activity.Specific Aim 2 is to further delineate the impact of FABP-deficiency on autoimmune disease usingEAE as a model. This aim will include an evaluation of the specific contributions of T cell primingand of the tissue environment towards the protection from EAE displayed by FABP-deficient mice.Specific Aim 3 is to test the hypothesis that the expression of FABPs links dietary fat intake withexacerbated inflammatory disease. We will evaluate the effects of fat intake on FABP expression inleukocyte population and the association of diet-induced FABP expression with inflammatoryresponsiveness. FABPs are considered potential therapeutic targets for a number of diseases. Thisproposal is designed to gain a more complete understanding of how these proteins regulate immuneand inflammatory responses.

project_terms:
5'-AMP-activated protein kinase;Adipocytes;Adipose tissue;Affect;Antigen Presentation;Autoimmune Diseases;Autoimmune Process;Automobile Driving;Brain;Cells;Chronic;Condition;Cytokine Gene;Data;Dendritic Cells;Development;Diet;Dietary Fats;Diffusion;Disease;Encephalomyelitis;Environment;Epithelial;Evaluation;Exhibits;Experimental Autoimmune Encephalomyelitis;Fatty acid glycerol esters;Gene Expression;Genes;Glycogen Synthase Kinases;Immune;Immune response;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Intake;Interferons;Interleukin-17;Leukocytes;Link;Lipids;Metabolic;Modeling;Molecular;Mus;Nuclear;Numbers;Obesity;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Population;Proteins;Regulation;Research;Sirolimus;Spinal Cord;T-Lymphocyte;Testing;Tissues;Transcriptional Activation;Wild Type Mouse;Work;cholesterol trafficking;cytokine;design;disorder risk;fatty acid binding protein;fatty acid-binding proteins;feeding;in vivo;macrophage;peroxisome;receptor;research study;response;therapeutic target;transcription factor


application_id: 7620145
project_number: 3R01CA104333-04S1
project_title: DNA Mismatch Repair Deficiency and Leukemia Relapse
administering_ic: NCI
award_notice_date: 2008-05-07
application_type: 3
activity_code: R01
ic: CA
serial_number: 104333
suffix: S1
program_official: OGUNBIYI, PETER
project_start_date: 2005-04-01
project_end_date: 2010-02-28
study_section: Cancer Genetics Study Section[CG]
contact_pi_person_id: 7956619
contact_pi: GU, LIYA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The long term goal of this project is to understand the molecular mechanisms underlying leukemia relapse.There are more than 21000 deaths to relapsed leukemia each year in the United States but the molecularbasis of this deadly disease is still unknown. Since leukemia relapse is always associated withchemotherapy and since cells exposed to therapeutic agents usually acquire a mismatch repair (MMR)deficient phenotype we hypothesize that leukemia relapse in many cases is caused by a small fraction ofleukemic cells that have adopted an MMR deficient phenotype during the course of chemotherapy. Ourpreliminary studies have showed that defects in MMR are indeed associated with cell lines derived fromrelapsed leukemia and patients with relapsed leukemia. To further test our hypothesis this applicationproposes both genetic and biochemical approaches to analyze the relationship between relapsed leukemiaand MMR proficiency. First real-time PCR will be used to analyze the status of microsatellite sequences inadult acute leukemia patient samples at presentation remission and relapse to dynamically andquantitatively determine how leukemic cells transform from a microsatellite stable form to a microsatelliteinstable form during the development of relapse. Second leukemic cells from relapsed patients will beanalyzed for genetic alterations and epigenetic modifications in key MMR genes such as hMSH2 and hMLH1using combination technologies of PCR-based single strand conformation polymorphism DNA sequencingand methylation-specific PCR. Third individual alterations identified in leukemia patients will be introducedinto MMR genes to express recombinant mutant proteins. To determine the actual impact of these alterationson MMR function individual recombinant mutant proteins will be examined for their ability to restore MMR tothe corresponding MMR mutant extracts using an in vitro functional MMR assay. This study will providesignificant insight into the mechanism underlying leukemia relapse as well as vital information for designingtherapeutic regimens for the disease.

project_terms:
Acute leukemia;Adopted;Adult;Biochemical Genetics;Biological Assay;Cell Line;Cells;Cessation of life;Characteristics;Complement;DNA;DNA Sequence;Data;Defect;Detection;Detection of Minimal Residual Disease;Development;Diagnostic;Disease;Disease remission;Epigenetic Process;Evolution;Genes;Goals;In Vitro;In complete remission;Individual;Leukemia Myelocytic Acute;Leukemic Cell;MLH1 gene;Methylation;Microsatellite Instability;Microsatellite Repeats;Mismatch Repair;Modification;Molecular;Mutagenesis Site-Directed;Mutation;Nuclear Extract;Pathogenesis;Patients;Phenotype;Polymerase Chain Reaction;Proteins;Protocols Treatment;Publishing;Rate;Recombinants;Relapse;Research;Research Personnel;Residual state;Sampling;Single-Stranded Conformational Polymorphism;Staging;Technology;Testing;Therapeutic;Therapeutic Agents;Time;United States;Work;base;chemotherapy;design;expectation;expression vector;insight;leukemia;mutant;prevent;programs;tool


application_id: 7620138
project_number: 2R56AI033481-15
project_title: Yersiniabactin and plague pathogenesis
administering_ic: NIAID
award_notice_date: 2008-05-29
opportunity_number: PA-07-070
application_type: 2
activity_code: R56
ic: AI
serial_number: 033481
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 1993-07-01
project_end_date: 2008-12-09
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 1864186
contact_pi: PERRY, ROBERT DONALD
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Yersinia pestis causes a zoonotic disease plague with well established reservoirs on everyinhabited continent except Australia. Although humans are an accidental dead-end hostbubonic and pneumonic plague has caused widespread loss of human life during recurrentpandemics. Nearly 2000 human plague cases occur yearly and outbreaks in Africa SouthAmerica and Southeast Asia are common. In addition Y. pestis is a category A select agentwith potential use for bioterrorism. The ability of pathogens to acquire iron from their hosts is acritical requirement for the development of nearly all infectious disease processes. Y. pestisencodes a large number of proven or putative iron transport systems but the siderophoredependentyersiniabactin (Ybt) and Yfe systems are the most important for causing bubonic andpneumonic plague. In a mouse model of bubonic plague the Ybt system is essential in the earlyphases of disease while the Yfe system plays an important role in the later stages of plague.Mutations in ybt but not yfe alone affect the pathogenesis of pneumonic plague. Our studiesindicate that Yfe and Feo (a ferrous iron transporter) play somewhat redundant roles in ironuptake  mutants lacking both systems show more severe phenotypes for in vitro growthintracellular growth and pathogenesis in bubonic and pneumonic plague. All these genes areregulated by Fur and iron availability. In addition the Ybt system is activated by the AraC-typeregulator YbtA and the Ybt siderophore. The ultimate goals of my laboratory are to 1) geneticallyand biochemically characterize the iron transport systems of Y. pestis; 2) determine themechanisms regulating expression of these systems; 3) assess the relative importance of thesesystems in bubonic and pneumonic plague; and 4) explore the potential for new antimicrobialtherapies and vaccine components based on these transport systems. In this proposal we willfocus on the Ybt system. The specific aims of this proposal are to 1) characterize Ybt regulation2) analyze Ybt biosynthesis 3) investigate Ybt transport and iron utilization and 4) examine Ybtroles in bubonic and pneumonic plague pathogenesis.

project_terms:
Affect;Africa;Anabolism;Asia Southeastern;Australia;Bioterrorism;Categories;Cells;Communicable Diseases;Complex;Development;Disease;Disease Outbreaks;Enzymes;Genes;Goals;Growth;Human;In Vitro;Injections Subcutaneous;Investigation;Iron;Laboratories;Life;Manganese;Microarray Analysis;Multienzyme Complexes;Mutation;Numbers;Pathogenesis;Periplasmic Binding Proteins;Phase;Phenotype;Plague;Play;Pneumonic Plague;Process;Proteins;Reaction;Recurrence;Regulation;Regulon;Relative (related person);Role;Scheme;Siderophores;South America;Staging;System;Techniques;Testing;Therapy Vaccine;Tissues;Transcription Genetic;Transcriptional Activation;Virulence;Yersinia pestis;antimicrobial;base;member;mouse model;mutant;pandemic disease;pathogen;permease;receptor;uptake;yersiniabactin


application_id: 7620055
project_number: 5P20RR015592-10
project_title: Center of Biomedical Research Excellence- Women's Health
administering_ic: NCRR
award_notice_date: 2009-04-17
opportunity_number: RFA-RR-04-008
application_type: 5
activity_code: P20
ic: RR
serial_number: 015592
program_official: SAYRE, MICHAEL
project_start_date: 2000-09-15
project_end_date: 2012-02-28
study_section: ZRR1-RI-8(02)
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
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:
EXCEED THE SPACEPROVIDED.Gonadal neurosteroids are important modulators of behavior and have been shown to impact a range of clinicallysignificant conditions including sexual behavior sleep cognition drug and alcohol abuse affective disorderspain sensitivity epileptic seizure disorders and stress reactivity. Recent molecular and cellular studies as well asdata from whole animal behavioral models indicate that gonadal neurosteroids influence behavior through thedirect regulation of neuronal activity as well as the modulation of classical neurotransmitter function through avariety of both genonic and nongenomic mechanisms. To date the effects of estrogen and progesterone onneurotransmitter function in humans have received almost no attention. We and others have successfully useddrug discriminationand functional neuroimaging methodologies to examine the manner in which psychoactivedrugs alter classical neurotransmitter function (i.e. clinical neuropharmacological effects of drugs) as well as theneuroanatomical locations of these effects. This basic science project will be among the first to apply thesemethodologies within the same individuals to examine the manner and anatomical locations in which estrogen andprogesterone modulate clinical neurotransmitter function in humans. One series of studies will examine the effectsof estradiol on dopaminergic activity. It is hypothesized that estradiol will enhance dopamine function selectivelyin women. A second series of studies will examine the neuropharmacological effects of progesterone. It ishypothesized that progesterone and its metabolites will engender direct interoceptive effects via modulation ofmultiple receptor sites includingGABAA sigma and NMDA in both men and women. This information will beinvaluable for expanding our understanding of the neurobiologicalbasis of gender differences in mood andbehavior regulation. These studies will have important applied significance in helping future development ofgender-specific medications having selective effects at steroidal receptor sites and/or tailored to work incombination with endogenous neurosteroids. It is also likely that these studies will inform and enhance ongoingefforts to develop and evaluate steroid-based medications. Finally this project will promote the mentoringdevelopment and promotion of our junior and early career colleagues' academic interests in the clinicalneurobiology of women's health.


application_id: 7619180
project_number: 5F31DA023853-02
project_title: Reinforcing and neurochemical effects of cocaine in a rodent model of ADHD
administering_ic: NIDA
award_notice_date: 2009-04-01
opportunity_number: PA-07-002
application_type: 5
activity_code: F31
ic: DA
serial_number: 023853
program_official: AVILA, ALBERT
project_start_date: 2008-03-24
project_end_date: 2010-03-23
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 8780703
contact_pi: WOOTERS, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   The use of methylphenidate (MPH) for the treatment of attention-deficit/hyperactivity disorder (ADHD) has increased in recent years. However MPH has abuse potential and is typically administered during early development prompting some concern that early MPH exposure may increase the risk for substance abuse later in life. Despite of this there is a notable lack of experimental data directly examining the influence of oral MPH exposure on subsequent cocaine (COC) abuse. This is critical because MPH and COC produce similar behavioral and neurochemical effects and because COC abuse is prevalent in the ADHD population. In the present application experiments are proposed to examine the role of developmental exposure to oral MPH on vulnerability for COC abuse in early adulthood in the spontaneously-hypertensive rat (SHR) model of ADHD; Sprague-Dawley rats will be used as controls. Specific Aim 1 will determine whether repeated oral MPH administration during postnatal days (PND) 28-42 (i.e. periadolescence) alters the locomotor effect of COC on PND 75 (i.e. early adulthood). Specific Aim 2 will test for MPH-induced alterations in COC self administration. MPH-treated rats will be trained to self-administer COC under a fixed ratio (FR) 1 schedule during a single training session on PND 75. Then over the next 14 days COC infusions will be available under a progressive ratio (PR) schedule to assess motivational aspects of COC self-administration following developmental MPH exposure. This protocol has been shown previously to produce progressive increases ('sensitization') of PR breakpoints and should therefore be more sensitive than FR schedules for detecting potential enduring MPH-induced alterations in the reinforcing efficacy of COC. Food-maintained responding will also be assessed to determine whether MPH selectively alters motivation for COC reinforcement. Specific Aim 3 will assess the effect of COC on dopamine transporter (DAT) function in the nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC) of MPH-treated rats in early adulthood. The NAcc and mPFC are implicated in COC abuse as well as ADHD; thus the effect of systemic COC on clearance of locally-applied dopamine in these regions will be monitored with in vivo voltammetry (high-speed chronoamperometry) in order to determine whether DAT is a substrate for potential MPH-induced alterations n COC self-administration. Collectively these preclinical results should provide clinically-relevant information on the association between oral MPH exposure during adolescence and subsequent COC abuse in early adulthood.   
  
PUBLIC HEALTH RELEVANCE:  These results may also aid the development of safer ADHD medications and should enhance our understanding of the etiology of COC abuse in the vulnerable ADHD population.

project_terms:
Adolescence;Amphetamines;Attention deficit hyperactivity disorder;Behavioral;Brain region;Catheters;Clinical;Cocaine;Cocaine Abuse;Data;Development;Dopamine;Dose;Drug abuser;Etiology;Exhibits;Exposure to;Food;Human;Implant;Inbred SHR Rats;Infusion procedures;Life;Medial;Methylphenidate;Modeling;Monitor;Motivation;Nucleus Accumbens;Oral;Oral Administration;Pharmaceutical Preparations;Population;Prefrontal Cortex;Protocols documentation;Psychological reinforcement;Rat Strains;Rattus;Relative (related person);Risk;Rodent Model;Role;Route;Schedule;Self Administration;Self-Administered;Specificity;Speed (motion);Sprague-Dawley Rats;Substance abuse problem;Techniques;Testing;Therapeutic;Time;Training;Work;clinically relevant;density;dopamine transporter;emerging adult;in vivo;neurochemistry;non-drug;postnatal;pre-clinical;public health relevance;reinforced behavior;reinforcer;relating to nervous system;research study;response


application_id: 7618860
project_number: 5F31EY017275-02
project_title: Minority Predoctoral Fellowship Program
administering_ic: NEI
award_notice_date: 2008-06-04
opportunity_number: PA-00-069
application_type: 5
activity_code: F31
ic: EY
serial_number: 017275
program_official: SHEN, GRACE L
project_start_date: 2007-03-01
project_end_date: 2011-02-28
study_section: Special Emphasis Panel[ZRG1-GGG-T(29)L]
contact_pi_person_id: 8320211
contact_pi: IMBERT-FERNANDEZ, YOANNIS
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Dry eye disease is due to tear deficiency or excessive tear evaporation and results in inflammation and damage to the ocular surface. Mucins are highly O-glycosylated proteins that lubricate and protect the ocular surface. Recent findings indicate that the mucin MUC1 has anti-inflammatory properties and also can interact with estrogen receptor-alpha thereby modulating gene transcription. Androgens are key to maintaining homeostasis of the ocular surface. A potential interaction between MUC1 and androgen receptor (AR) could confer additional protection: My long term goal is to elucidate the molecular mechanisms involved in the pathogenesis of dry eye. My hypothesis is that MUC1 and androgen receptor (AR) are key factors that can act together to protect the ocular surface. The hypothesis will be tested by three specific aims: Aim 1- Determine the interaction between MUC1 and AR in human ocular surface epithelial cell lines; Aim 2- Elucidate the anti-inflammatory role of MUC1 and AR in those cells; and Aim 3- We have found that persons expressing the MUC1/A splice variant rather than MUC1/B are less susceptible to dry eye. We will determine if MUC1/A and MUC1/B splice variants differ in their signal transduction capabilities.

project_terms:
Androgen Receptor;Androgens;Anti-Inflammatory Agents;Anti-inflammatory;Breast Cancer Cell;Cell Communication;Cell Line;Cell Survival;Cell physiology;Cells;Chronic;Complex;Country;Defense Mechanisms;Disease;Dry Eye Syndromes;Dryness of eye;Epithelial;Epithelial Cells;Estrogen Receptor alpha;Estrogen Receptors;Etiology;Excessive tearing;Eye diseases;Fellowship Program;Female;Figs - dietary;Film;Gender;Goals;Growth;Homeostasis;Human;Inflammation;Keratoconjunctivitis Sicca;Laboratories;Lacrimal gland structure;MCF7 cell;Maintenance;Mediating;Minority;Molecular;Mucin-1 Staining Method;Mucins;Pathogenesis;Persons;Play;Population;Postmenopause;Production;Property;Proteins;RNA Splicing;Role;Signal Transduction;Stress;System;Testing;Thinking function;Tissues;Transcription Genetic;Variant;Woman;aqueous;biological adaptation to stress;evaporation;hormone regulation;novel;ocular surface;pre-doctoral;protective effect


application_id: 7618432
project_number: 5R44AR049941-03
project_title: Durable Muscle-Prosthetic Bond for Artificial Tendons
administering_ic: NIAMS
award_notice_date: 2009-04-28
opportunity_number: PA-07-280
application_type: 5
activity_code: R44
ic: AR
serial_number: 049941
program_official: PANAGIS, JAMES S
project_start_date: 2005-09-15
project_end_date: 2011-04-30
study_section: Special Emphasis Panel[ZRG1-MOSS-L(10)B]
contact_pi_person_id: 9182453
contact_pi: JUNCOSA-MELVIN, NATALIA
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 969951859
duns_number: 969951859
fips: US
organization_id: 4007401
organization_name: CARDIOENERGETICS, INC.
organization_city: COVINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 410112312
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-05-01
budget_end_date: 2011-04-30
project_abstract:
DESCRIPTION (provided by applicant):  A coupling mechanism with the strength to fix a forcefully contracting muscle to a totally inert prosthesis or to bone would meet a serious and common need in clinical orthopaedics.  We have explored a new approach to such a coupling. The hypothesis was that a coupling prosthesis with a low-mass high-surface configuration designed to transfer force by shear would transfer greater loads without pressure-damage to tissue than can be transferred by the interlocking mechanism of sutures or staples. The resulting device is the OrthoCouplerTM. The Phase I feasibility study results exceeded expectations. This was a 60 day assessment reattaching 8 goat semitendinosus (hamstring) muscles; 7 completed all testing - 6 with paired experimental/control data one with experimental alone. Each proposed Aim was met:--devices were built validated for cyclic fatigue life implanted and succeeded clinically. Excised specimens were 2.5 times the strength of an expertly applied state-of-the art-control (Krackow stitches under close direction of a senior orthopaedic oncologic surgeon). The proposed work applies the OrthoCoupler in goats to the most demanding setting imaginable - restablishing the knee extensor mechanism after complete excision of quadriceps tendon patella and patellar tendon securing the cut quadriceps muscle stump to a tibial bone plate. This succeeded in four pilot animals - (servohydraulic testing to over 1000 N with femur fracturing without pullout). Specific Aim (1) assesses in a random block study the efficacy of two plausible improvements each intended to facilitate ease of operative use compatible with minimally invasive placement (2) standardizes design and fabrication with a contracted 'GMP' manufacturer and (3) rigorously reprises preclinical testing in a 'GLP' facility. Achieving these three specific aims would place the device at a decisive competitive advantage relative to any present alternative and ensure our overriding long-term objective - commercialization of OrthoCoupler in a range of specific configurations for a market of over 20000 muscle-to-prosthetic applications annually including but by no means limited to orthopaedic oncology revision arthroplasty expanded tendon transfer and sports-injury reconstruction.  PUBLIC HEALTH RELEVANCE:  We have developed and patented a new technology for durable strong connections with tissue not having sufficient strength for conventional sutures or staples. A dominant need for this is in several orthopaedic dilemmas - sports injury reconstruction orthopaedic oncology revision joint replacement and tendon transfers. Pilot studies have succeeded in the most demanding application possible reattachment of the body's most powerful muscle the quadriceps femoris and the proposal will expand that work in an extended term goat model.

project_terms:
Acute;Animals;Arthroplasty;Arts;Athletic Injuries;Autopsy;Biological Assay;Biomechanics;Bone plates;Clinical;Collaborations;Collagen;Confounding Factors (Epidemiology);Contracts;Counseling;Coupling;Data;Development;Device Designs;Devices;Documentation;Ensure;Excision;Failure (biologic function);Fatigue;Feasibility Studies;Femoral Fractures;Fiber;Filament;Filler;Fright;Funding;Goals;Goat;Grant;Hand;Histologic;Implant;In Vitro;International;Joint Revision;Joints;Knee;Knee bone;Laboratories;Legal patent;Life;Malignant Neoplasms;Manufacturer Name;Marketing;Medical Device;Microencapsulations;Modeling;Modification;Muscle;Needles;Operative Surgical Procedures;Orthopedics;Performance;Phase;Pilot Projects;Plant Roots;Plants;Polymers;Postoperative Period;Preclinical Testing;Procedures;Process;Prosthesis;Protocols documentation;Qualifying;Randomized;Rehabilitation therapy;Relative (related person);Replacement Arthroplasty;Reporting;Sampling;Schedule;Secure;Simulate;Site;Soil;Solid;Specimen;Sports Medicine;Suggestion;Surface;Surgeon;Surgical Oncologist;Surgical sutures;Tendon Transfer;Tendon structure;Testing;Time;Tissues;Validation;Variant;Weight-Bearing state;Work;Wound Healing;base;bone;clinical application;commercialization;design;expectation;experience;good laboratory practice;implantation;improved;manufacturing process;meetings;minimally invasive;new technology;novel strategies;oncology;pilot trial;pressure;prospective;public health relevance;reconstruction;research study;response;sample fixation;success;tibia


application_id: 7618282
project_number: 5P01HL078825-05
project_title: Protection of Ischemic Myocardium
administering_ic: NHLBI
award_notice_date: 2009-03-30
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: LIANG, ISABELLA Y
project_start_date: 2005-04-15
project_end_date: 2011-06-30
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
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: 2009-04-01
project_abstract:
DESCRIPTION (provided by applicant):   The heart has evolved an adaptive response to stress termed late preconditioning (PC) that confers powerful and sustained protection against ischemia/reperfusion injury. Previous work by us and others has shown that late PC is mediated by the upregulation of a cluster of stress-responsive proteins namely iNOS HO-1 and ecSOD which mitigate tissue injury via the combined regulation of the myocardial levels of NO and CO. Our preliminary data indicate that these proteins are organized hierarchically and interact with one another to effect cytoprotection thereby forming a functional module. The central theme of this Program Project is to elucidate the molecular mechanisms responsible for the powerful cardioprotective effects of the iNOS-HO-1-ecSOD module and to explore the feasibility of upregulating this module with genetic or pharmacologic approaches in order to achieve chronic prophylactic cardioprotection. The Program will consist of four Projects and four Cores. Project 1 (Bolli) will determine whether gene therapy strategies that increase myocardial NO and CO levels (iNOS HO-1 or ecSOD gene therapy) result in a chronically-protected phenotype and will elucidate how these three-stress responsive genes interact in modulating NO and CO levels. This Project will test the novel idea that gene therapy can be used to achieve a permanent preconditioned-like state. Project 2 (Prabhu) will determine whether the same three genes (iNOS HO-1 and ecSOD) mitigate chronic post-infarction myocardial remodeling and the resulting heart failure and will investigate the mechanisms for these beneficial effects. The same gene therapy strategies tested in Project 1 in the setting of acute ischemia/reperfusion injury will be tested in Project 2 in the setting of post-infarction LV remodeling. This Project will test the novel idea that the iNOS-HO-1-ecSOD module is a critical protective mechanism against heart failure. Project 3 (Xuan) will investigate the signaling and molecular mechanisms Whereby NO and CO induce delayed protection focusing on the remarkable ability of these molecules to suppress apoptosis. The central hypothesis of this Project is that the NO-CO axis plays a critical role in the cardiac adaptation to stress by virtue of its ability to genetically reprogram the heart in a manner that promotes cell survival. Project 4 (Bhatnagar) will test the hypothesis that in the preconditioned heart iNOS and HO-1 inhibit mitochondrial respiration which decreases free radical generation inhibits mitochondrial permeability transition and prevents cell death. These four projects will be supported by four Cores that will provide services in mouse surgery cardiac gene-transfer transgenic and knockout mouse generation viral vector production and pathology. This Program Project is the natural evolution of our previous work on late PC - having identified NO and CO as key mediators of this adaptation we will investigate the mechanism of protection and the therapeutic utility of the NO-CO axis. Because of the ubiquitous role of NO and CO the results will have broad pathophysiological implications for numerous biological processes in which NO and CO are known to serve and important regulatory function. In addition the results may provide a framework for translating cardioprotective therapies to the clinical arena.


application_id: 7618281
project_number: 5P01HL078825-04
project_title: CORE--Pathology Core
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 9003
contact_pi_person_id: 1880936
contact_pi: ANVERSA, PIERO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The Pathology Core (Core D) will perform all microscopic analyses needed for the four Projects of this PPG. The Core has state-of-the-art facilities and extensive experiences with virtually all pathologic analyses of cardiac tissues. This Core represents the continuation of the ongoing collaboration between Dr. Anversa's team at the New York Medical College and the Cardiology team at the University of Louisville which have worked together for the past two years. The logistics of this arrangement have been extensively tested and do not pose any problem. Following perfusion fixation tissue samples will be obtained in each of the four Projectsat the University of Louisville and sent to the Pathology Core at New York Medical College for analysis. The Core will perform several functions that can be summarized as follows. 1. Morphometric analysis of infarct size myocyte volume and number and length density of resistance arterioles and capillary network within the myocardium. Myocyte volume will be assessed both in situ and in enzymatically dissociated cells. Myocyte classes and distribution will be analyzed with confocal microscopy both in situ and in isolated myocytes. Thesemeasurements will enable us to calculate the total number of myocytes lost during  post-infarction LV remodeling (Project 2) and to compare the number of lost myocytes with conventional measurements of infarct size by tetrazolium staining at 24 h of reperfusion. 2. Two-photon microscopy to perform simultaneous detection of multiple antigens without the limitations imposed by photobleaching of fluorophores. Two-photon microscopy will also be used to measure pyridine nucleotides in Project 4. 3. Confocal microscopic analysis of tissuesections obtained from perfusion-fixed hearts. The combination of two-photon and confocal microscopy will enable us to quantitate the expression of multiple antigens (e.g. iNOS HO-1 ecSOD nitrotyrosines protein-HNE adducts protein-MDA adducts protein carbonyls) simultaneously in the same tissue section. Two-photon and confocal microscopy will be employed for quantitative analysis of fluorescence intensity of iNOS HO-1 ecSOD protein-HNE adducts protein-MDA adducts nitrotyrosines and 8-hydroxy-deoxyguanosine. Allimmunocytochemistry will be done by using primary antibodies labeled directly with the fluorochromes recognized by our two-photon microscope and confocal microscope which will avoid the complications of nonspecific staining and cross-reactivity between antibodies. 4. Quantitative measurement of apoptotic and necrotic cells with our newly-developed dual-labeling technique (hairpin-1 in situ ligation coupled with immunohistochemistry for active caspase-3 hairpin-2 ligation coupled with immunohistochemistry for active caspase-3) along with TUNEL. The dual hairpin-1/active caspase-3 labeling and hairpin-2/active caspase-3 labeling will afford a very high degree of specificity in assigning a cell to apoptosis vs. necrosis. 5. Routinehistologic examination to assess inflammation fibrosis or any other morphologic changes.

project_terms:
3-nitrotyrosine;Antibodies;Antigens;Apoptosis;Apoptotic;Arts;Blood capillaries;Capillary Unspecified;Cardiac;Cardiology;Cells;Class;Collaborations;Coupled;Deoxyguanosine;Detection;Fibrosis;Fluorescence;Fluorochrome;Heart;Histologic;Immunohistochemistry;In Situ;In Situ Nick-End Labeling;Infarction;Inflammation;Label;Left Ventricular Remodeling;Length;Ligation;Logistics;Measurement;Measures;Medical;Microscope;Microscopic;Microscopy;Microscopy Confocal;Muscle Cells;Myocardium;Necrosis;New York;Numbers;Pathologic;Pathology;Perfusion;Photobleaching;Physiological reperfusion;Proteins;Reperfusion Therapy;Resistance;Specificity;Staining method;Stains;Structure of arteriole;Techniques;Testing;Tetrazolium Salts;Tissue Sample;Tissues;Universities;Work;adduct;caspase-3;college;cross reactivity;density;experience;fluorophore;immunocytochemistry;pyridine nucleotide;sample fixation;size;two-photon


application_id: 7618280
project_number: 5P01HL078825-04
project_title: CORE--Vector Core
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 9002
contact_pi_person_id: 8307878
contact_pi: LI, QIANHONG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Core C (Vector Core) will provide access to a wide array of gene transfer technology. The Core has assembled a comprehensive inventory of DNA plasmids cell lines and viruses useful for the development of vectors. The Core will provide services in terms of vector creation amplification purification and analysis for Projects 1 2 and 4. This dedicated facility will be run by Dr. Qianhong Li who has extensive experience with recombinant viruses and has studied virus-mediated gene therapy for myocardial ischemia/reperfusion injury for eight years. We have developed an rAAV vector system that is helper adenovirus free thereby eliminating the problem of adenovirus contamination in the final preparation. We have already created and successfully used rAAV/LacZ rAAV/iNOS and rAAV/ecSOD for in vivo cardiac gene transfer in mice. rAAV vectors currently available in the Vector Core include rAAV/LacZ rAAV/hrGFP "empty" rAAV rAAV/ecSOD and rAAV/iNOS. The primary responsibility of the Vector Core will be to design create produce and analyze rAAV vectors for long-term in vivo gene transfer. Specific responsibilities include: (i) cloning the gene of interest into an AAV DNA plasmid containing ITR sequences (ii) cloning the mitochondrial leader sequence into an AAVDNA plasmid containing the ITR and the therapeutic gene (iii) amplifying and maintaining purified stocks of AAV DNA plasmid containing the therapeutic gene (iv) amplifying and maintaining purified stocks of an AAV DNA plasmid containing the rep and cap genes as well as a helper DNA plasmid encoding the Ad5 E2a and E4 gene regions (v) constructing rAAV vectors in 293 cells (vi) purifying titrating and analyzing rAAV vectors (vii) long-term storage of rAAV vectors and (viii) developing mitochondrially-targeted rAAV vectors (mt-rAAV) which will be used in Project 4 to study the effects of targeting iNOS and HO-1 specifically to the mitochondria.

project_terms:
Adenoviruses;Cardiac;Cell Line;Cells;Cloning;Development;Equipment and supply inventories;Gene Transfer;Genes;Genes LacZ;Green Fluorescent Proteins;Mediating;Mitochondria;Mus;Myocardial Ischemia;Preparation;Reperfusion Injury;Running;Services;System;Technology;Virus;design;experience;gene cloning;gene therapy;in vivo;interest;plasmid DNA;recombinant virus;therapeutic gene;vector


application_id: 7618279
project_number: 5P01HL078825-04
project_title: CORE--Surgery and Transgenic Mouse Core
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 9001
contact_pi_person_id: 8251726
contact_pi: GUO, YIRU
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The Surgery and Transgenic Mouse Core (Core B) will provide state-of-the-art support to all four Projects with studies involving surgical procedures in murine models and use of transgenic/knockout mice. The Core will consist of two Units the Surgery Unit which will be responsible for all surgical procedures and the Transgenic Mouse Unit which will beresponsible for generating breeding and genotyping the various lines of transgenic and knockout mice. These two Units will be inextricably intertwined as the Transgenic Unit will produce the mice operated on by the Surgery Unit while the Surgery Unit will phenotype the mice generated by the Transgenic Unit. Dr. Yiro Guo an expert surgeon will be Leader of Core B and will be specifically responsible for all operations in the Surgery Unit. Dr. Gregg Rokosh an expert molecular biologist will be Co-Leader of Core B and will be specifically responsible for the functions of the Transgenic Mouse Unit. The complementarity of their backgrounds coupled with their collegial nature provides a strong foundation for productive synergy. The Surgical Unit of Core B will perform coronary artery occlusion/reperfusion studies measurements of infarct size gene transfer procedures administrationof pharmacologicagents perfusion fixation ofcardiac tissue and noninvasive and hemodynamic studies. It will also generate myocardial tissue samples as well as cardiomyocytes to be used for molecular studies. State-of-the-art facilities and equipment are available. All Core personnel have extensive experience with the murine models of myocardialinfarctionand gene therapy to be used in the four Projects. These procedures have been performed in over 9000 mice and are associated with  minimal complications. The postmortem perfusion technique to measure infarct size results in accurate delineation of the infarcted area area at risk and nonischemic area such that measurements of infarct size are highly reproducible. Meticulous attention is paid to maintaining fundamental physiologic parameters (heart rate arterial blood pressure arterial blood pH hematocrit and body temperature) within normal limits throughout the coronary occlusion/reperfusionstudies. The protocol for gene delivery (i.v. infusion of viral vectors with distal aortic clamping under whole-body hypothermia) results in widespread highly efficient transduction (70-90%) of cardiomyocytes throughout the left ventricle. The Core is equipped with fully functional echocardiography and invasive hemodynamic laboratories for accurate assessment of LV function in vivo. The Transgenic Mouse Unit of Core B will provide 14 transgenic or knockout mouse lines to be used by the four Projects. The Unit has already created several transgenic mouse lines with cardiac-specific gene expression including a novelinducible knockout of STAT3 and will create new genetically-engineered models that will allow temporal control of transgenic expression. The Unit will also be responsible for breeding genotyping and handling all of the transgenic and knockout mice to be used in the four Projects. For knockout mice controls will consist of wild-type littermates generated by Het x Het inbreeding; similarly wild-type littermates will be used as controls for transgenic mice. Insummary Core B will provide a strong backbone for this Program Project. The extensive experience of the personnel the superb facilities available and the strong collegiality of the investigators will provide the four Projects with an outstanding experimental resource to undertake physiologically-relevant studies pertaining to the protection of ischemic myocardium.

project_terms:
Area;Arts;Attention;Autopsy;Blood;Blood Pressure;Body Temperature;Breeding;Cardiac;Coronary artery;Coupled;Distal;Echocardiography;Engineering;Equipment;Foundations;Gene Delivery;Gene Expression;Genotype;Heart Rate;Hematocrit procedure;Human Resources;Inbreeding;Infarction;Infusion procedures;Invasive;Knock-out;Laboratories;Left ventricular structure;Measurement;Measures;Mice Knockout;Mice Transgenic;Modeling;Molecular;Mus;Myocardial Ischemia;Myocardial tissue;Myocytes Cardiac;Nature;Occlusions Coronary;Operative Surgical Procedures;Perfusion;Phenotype;Physiological;Physiological reperfusion;Procedures;Protocols documentation;Reperfusion Therapy;Research Personnel;Resources;Risk;STAT3 gene;Surgeon;Techniques;Tissue Sample;Tissues;Transgenic Organisms;Vertebral column;Viral Vector;artery occlusion;experience;gene therapy;hemodynamics;hypothermia natural;in vivo;novel;programs;sample fixation;size


application_id: 7618278
project_number: 5P01HL078825-04
project_title: Metabolic Basis of Preconditioning
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0004
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The long-term goal of this project is to understand the fundamental molecular mechanisms ofcardioprotection Our central hypothesis is that inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1) protect the heart from ischemia-reperfusion (I-R)injury by partially inhibiting mitochondrial electron transport which decreases the generation of free radicals and prevents mitochondrial permeability transition (MPT). We propose that these changes prevent ischemic cell death and are responsible for the cardioprotective effects of the late phase of preconditioning (PC). We will use electron paramagnetic resonance measurements to quantify the generation of oxygen-derived free radicals and nitric oxide and determine whether free radicals generation and oxidative stress are attenuated in preconditioned hearts subjected to I-R (Aim 1). To test the antioxidant role of iNOS and HO-1 we will measure free radical generation and oxidative stress in hearts transduced with recombinant adeno-associated virus (rAAV) carrying the iNOS or HO-1 gene. Conversely we will determine whether I-R-induced oxidative stress and radical generation are exacerbated in the hearts of iNOS or HO-1 null mice (Aim 2). To examine whether the cardioprotective effects of late PC are derived from inhibition of MPT we will measure permeability transition and the activity of respiratory complexes in mitochondria isolated from naive and preconditioned hearts and test whether PC decreases I-R-induced MPT in isolated perfused hearts (Aim 3). To determine the role of iNOS and HO-1 we will examine whether inhibition or the lack of these proteins abolishes the effects of PC on MPT and conversely whether hearts of mice transduced with rAAV/iNOS or rAAV/HO-1 are resistant to I-R-induced MPT. We will determine whether iNOS and HO-1 prevent mitochondrial injury by associating withthe mitochondria and whether localization of these proteins to the mitochondria (by using mitochondria-specific leader sequence) is sufficient to confer cardioprotection (Aim 4).

project_terms:
Affect;Aldehydes;Antioxidants;Apoptosis;Attenuated;Cell Death;Collaborations;Complex;Development;Electron Spin Resonance Spectroscopy;Electron Transport;Enzyme Inhibition;Enzymes;Free Radicals;Generations;Genes;Goals;Heart;Heme Oxygenase (Decyclizing);Injury;Investigation;Ischemia;Ischemic Preconditioning;Late Effects;Lead;Lipid Peroxidation;Localized;Measurement;Measures;Mediating;Mediator of activation protein;Metabolic;Metabolism;Mice Knockout;Mitochondria;Mitochondrial Proteins;Modification;Molecular;Mus;Myocardial;Myocardial Ischemia;NOS2A protein human;Nature;Necrosis;Nitric Oxide;Nitric Oxide Donors;Oxidative Stress;Oxygen;Pathway interactions;Permeability;Phase;Phenotype;Physiological reperfusion;Proteins;Recombinant adeno-associated virus (rAAV);Reperfusion Injury;Reperfusion Therapy;Resistance;Respiration;Respiratory Chain;Role;Signal Transduction;Testing;Transcription Genetic;Work;base;clinically relevant;indexing;insight;intracellular protein transport;preconditioning;prevent;protective effect;protein localization location;respiratory


application_id: 7618277
project_number: 5P01HL078825-04
project_title: Delayed Cardioprotection Induced by NO and CO
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0003
contact_pi_person_id: 1964532
contact_pi: XUAN, YU-TING
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Previous work from our laboratory indicates that NO and CO two functionally-coupled molecules confer robust and sustained protection against ischemia/reperfusion injury via mechanisms that are unknown. NO donors are widely used clinically; CO donors have recently been developed by our collaborator Dr. Motterlini and may become a new class of anti-ischemic agents. The overall objective of Project 3 is to illuminate the molecular mechanisms that underlie the long-lasting infarct-sparing and anti-apoptotic effects observed after exposure of the heart to NO and CO. We propose that the NO-CO axis plays a critical role in the cardiac adaptation tostress by virtue of its ability to genetically reprogram the heart. Our fundamenta/hypothesis is that NO and CO act synergistically to induce a sustained cardioprotected phenotype by activating pro-survival signaling pathways via the recruitment of a cluster of stress-responsive transcription factors (STAT1 STAT3 and NF-kappaB) leading to the upregu/ation of anti-apoptotic proteins that inhibit both the death receptor- and the mitochondria-dependentpathways of apoptosis. In Aim 1 we will determine whether the sustained cardioprotective effects of NO and CO are due to inhibition of apoptosis vs. necrosis which will be discerned with state-of-the-art techniques including hairpin-1/caspase-3 and hairpin-2/caspase-3 dual-labeling assays. The influence of NO and CO donors on the extrinsic and intrinsic pathways of apoptosis will be elucidated by examining their effects on the release of cytochrome c and Smac the activation of caspase-3 8 and 9 and the expression of pro-apoptotic proteins (Bax Bak Bid Bad) and anti-apoptotic proteins (Bcl-2 Bcl-XL McI-1 c-FLIPL c-FLIPs ARC XlAP clAP-1 clAP-2). Aims 2 and 3 will establish whether the delayed anti-apoptotic and anti-necrotic actions of NO and CO are mediated by STAT1 and/or STAT3; this will be accomplished by knockout of the STAT1 gene and by genetic inhibition of STAT3 via constitutive cardiac-specific STAT3 knockout or via a novel inducible cardiac-specific STAT3 knockout. Aim 4 will determine whether the cardioprotective effects of the NO-CO axisrequire both Tyr-705 (via JAKs) and Ser-727 (via the PKCepsilon-Raf-1-MEK-1/2-p44/42 MAPK cascade) phosphorylation of STAT3 which will be interrogated by using a Tyr-705 dominant negative mutant of STAT3 and a Ser-727 mutant of STAT3 respectively. The role of PKCepsilon in the activation of the Raf-1-MEK1/2-p44/42 MAPK cascade will be interrogated with targeted deletion of PKCepsilon (PKCepsilon-/- mice). Using I-kappa-B-alpha dominant negativemutant (l-kappa-B-alpha-S32AS36A mice) in Aim 5 we will determine whether (and the mechanism by which) NF-kappaB mediates the sustained cardioprotective effects of NO and CO. These studies will elucidate the specific roles of STAT1 vs. STAT3 and of NF-kappaB in myocardial ischemia/reperfusion injury. The results of this project will provide novelinsights into the mechanism whereby the NO-CO axis genetically reprograms the heart and will also have therapeutic implications for patients with coronary artery disease.

project_terms:
Apoptosis;Apoptotic;Arts;Biological Assay;CASP8 and FADD-like apoptosis regulating protein;Cardiac;Cessation of life;Class;Coronary Arteriosclerosis;Dominant-Negative Mutation;Genetic;Heart;I Kappa B-Alpha;Infarction;Inhibition of Apoptosis;Knock-out;Label;Laboratories;MAP Kinase Gene;MEKs;Mediating;Mitochondria;Molecular;Mus;Myocardial Ischemia;NF-kappa B;Necrosis;Patients;Phenotype;Phosphorylation;Play;Proteins;Reperfusion Injury;Role;STAT1 gene;STAT3 gene;Signal Pathway;Stress;Techniques;Therapeutic;Work;caspase-3;cytochrome c;insight;mutant;novel;pro-apoptotic protein;receptor;transcription factor


application_id: 7618276
project_number: 5P01HL078825-04
project_title: Cardioprotective Genes and Postinfarction Left Ventricular Remodeling
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0002
contact_pi_person_id: 1914941
contact_pi: PRABHU, SUMANTH D
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
Heme oxygenase-1 (HO-1) extracellular superoxide dismutase (ecSOD) and inducible nitric oxide synthase (iNOS) are interrelated stress-responsive proteins that are cardioprotective against acute ischemia/reperfusion injury. However their role in chronic heart failure (HF) is not clear. The central objective of this Project is to unravel the pathophysiologic roles of HO-1 ecSOD and iNOS in post-infarction HF using genetically modulated mice and to determine whether these systems can be therapeutically manipulated for long-term benefit. Based on our preliminary studies our central hypothesis is that in HF Iong-term HO-1 and ecSOD induction are important beneficial adaptations that mitigate left ventricular (LV) remodeling. We further hypothesize that the effects of iNOS induction in HF depend on its cellular source i.e. whereas myocyte iNOS is cardioprotective inflammatory cell iNOS is detrimental. To test this hypothesis we will perform four Specific Aims. In Aim 1 we will define the cardiac expression of HO-1 and ecSOD in murine post-infarction HF and its relationship to LV remodeling. We will then determine the effects of HO-1 loss- or gain-of function on LV remodeling via studies in HO-1 null mice and cardiac-specific HO-1 transgenic (TG) mice. Given the antioxidant and anti-apoptotic properties of HO-1 we will evaluate the effects of HO-1 modulation on oxidative stress ecSOD expression and apoptosis. In Aim 2 we will evaluate the role of ecSOD in post-infarction LV remodeling using ecSOD null mice and cardiac-specific ecSOD TG mice. As alterations in ecSOD would primarily impact extracellular free radicals we will carefully examine in addition to oxidative stress the relationship between ecSOD modulation matrix metalloproteinase activation and dysregulation of the cardiac extracellular matrix. In Aim 3 we will determine whether iNOS is beneficial or detrimental in HF and establish the importance of the cellular source of iNOS. We will spatially and temporally define iNOS expression in post-infarction HF and then evaluate the impact of iNOS loss- or gain-of-function on the HF phenotype using iNOS null and cardiac-specific iNOS TG mice. We will then examine mice with iNOS overexpression in the heart but with loss of iNOS in the periphery to determine the role of myocyte versusinflammatory cell iNOS in HF. Finally in Aim 4 we will determine whether the protective effects of HO-1 ecSOD and iNOS in post-infarction HF can be exploited therapeutically by the use of recombinant adeno-associated virus-mediated gene transfer. We will also evaluate whether the benefits of HO-1 gene therapy are lost in ecSOD null mice thereby defining whether ecSOD is necessary for HO-1-mediated cardioprotection. Collectively these studies will provide novelinsights into the pathophysiologic roles of HO-1 ecSOD and iNOS in HF and will establish the mechanistic link between this cardioprotective system and oxidative/nitrative stress apoptosis and chamber remodeling post-infarction.

project_terms:
Ablation;Acute;Address;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Apoptosis;Apoptotic;Biliverdine;Biological;Carbon Monoxide;Cardiac;Cardiomyopathies;Catecholamines;Cells;Cellular Stress Response;Chronic;Classification;Clinical;Collaborations;Coronary;Coupled;Cytoprotection;Dilatation - action;Doctor of Medicine;Enzyme Activation;Enzymes;Extracellular Matrix;Financial compensation;Free Radicals;Functional disorder;Gene Delivery;Gene Transfer;Genes;Genetic;Heart;Heart failure;Heme;Heme Oxygenase (Decyclizing);Homeostasis;Hypertrophy;Infarction;Inflammatory;Injury;Investigation;Iron;Left;Left Ventricular Remodeling;Link;Matrix Metalloproteinases;Mediating;Mediator of activation protein;Mice Knockout;Mice Transgenic;Mus;Muscle Cells;Myocardial;Myocardial Ischemia;Myocardium;NOS2A protein human;Operative Surgical Procedures;Oxidative Stress;Oxygenases;Pathological Dilatation;Pathology;Patients;Peripheral;Phase;Phenotype;Physiological reperfusion;Play;Process;Property;Protein Isoforms;Protein Overexpression;Proteins;Rate;Recombinant adeno-associated virus (rAAV);Relative (related person);Reperfusion Injury;Reperfusion Therapy;Role;Source;Stress;Superoxide Dismutase;System;Testing;Therapeutic;Time;Tissues;Transgenes;Transgenic Organisms;Translations;Up-Regulation (Physiology);Ventricular;Ventricular Remodeling;Wild Type Mouse;base;biological adaptation to stress;cytokine;extracellular;gain of function;gene therapy;genetic manipulation;improved;insight;novel;protective effect;research study;transgene expression;vector


application_id: 7618275
project_number: 5P01HL078825-04
project_title: Gene Therapy to Achieve Permanent Cardioprotection
administering_ic: NHLBI
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 0001
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-04-01
budget_end_date: 2009-03-31
funding_mechanism: Non-SBIR/STTR
project_abstract:
The heart has evolved an adaptive response to stress termed late preconditioning (PC) that confers powerful and sustained protection against ischemiaJreperfusion injury. Previous work by us and others has shown that late PC is mediated by the upregulation of a cluster of stress-responsive cardioprotective proteins namely iNOS HO-1 and ecSOD. Our preliminary data indicate that these proteins are organized hierarchically and are inextricably linked forming a functionally inter-related module. Building upon this previous work we will determine the feasibility of transferring these genes to the heart to achieve a permanent preconditioned-likestate. We will also determine the mechanism by which the respective proteins interact. All studies will be performed in a well-established murine model of myocardial infarction using recombinant adeno-associated virus (rAAV) vectors. In Aim 1 we will determine whether rAAV-mediated transfer of the genes that form the iNOS-HO-1-ecSOD module produces chronic cardioprotection and whether this is due to prevention of apoptosis necrosis or both. Mice will undergo iNOS HO-1 or ecSOD gene transfer and then will be subjected to myocardial infarction 1 6 or 12 months later to determine the presence of a protective phenotype. In Aim 2we will decipher the interplay between iNOS and HO-I. Using both a loss-of-function (HO-1-/-) and a gain-of-function (HO-1 TG) approach we will determine whether the infarct-sparing effects of iNOS gene therapy depend on the presence of HO-1 and whether HO-1 modulate iNOS and thus limits oxidative and nitrative stress after iNOS gene therapy. The specific role of CO (one of the by-products of HO-1 ) will be elucidated by using novel CO-releasing agents. In Aim 3 we will use ecSOD-/- mice to test the hypothesis that ecSOD is obligatorily required for iNOS-dependent HO-1-dependent and CO-dependent protection. We will also test thenovel idea that HO-1 augments cardiac NO levels by upregulating ecSOD. Finally in Aim 4 we will use Nrf2 -/- mice to test the hypothesis that Nrf2 a pleiotropic stress-responsive transcription factor mediates iNOS-dependent upregulation of HO-1 and iNOS- and HO-l-dependent upregulation of ecSOD. These studies will test the hypothesis that Nrf2 is a critical "switch" that links iNOS HO-1 and ecSOD. Throughout this Project evidence for or against a functional role of specific proteins will be obtained by using genetic manipulations inintact animals (gene transfer transgenic mice or KO mice). This molecular physiologic strategy will make it possible to arrive at conclusions that are definitive and at the same time physiologically relevant. These studies will be the first to test the novel idea that gene therapy can be used to achieve chronic prophylactic cardioprotection. The results will provide a framework for translating cardioprotective gene therapy to the clinical arena and will have broad pathophysiological implications for numerous biologic processes in which NO and CO are known to serve an important regulatory function.

project_terms:
Acute myocardial infarction;Adenoviruses;Adverse effects;American;Animal Model;Animals;Antioxidants;Apoptosis;Area;Arts;Binding Sites;Cardiac;Chloride Ion;Chlorides;Chronic;Clinical;Complement Factor B;Coronary Arteriosclerosis;Country;DNA Nucleotidylexotransferase;DNTT gene;Data;Doctor of Medicine;EFRAC;EMSA;Effectiveness;Electrophoretic Mobility Shift Assay;Endoplasmic Reticulum;Enzyme Immunoassay;Failure (biologic function);Forecast of outcome;Gene Transfer;Genes;Heart;Heme Oxygenase (Decyclizing);I-kappa B Proteins;In Situ Nick-End Labeling;Infarction;Injury;Ischemia;Janus kinase;Label;Laboratories;Left ventricular structure;Link;Measures;Mediating;Mice Transgenic;Modeling;Models Experimental;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Mus;Myocardial Infarction;Myocytes Cardiac;Myosin Heavy Chains;N-acetylpenicillamine;NF-kappa B;NOS2A protein human;Nature;Necrosis;Nitric Oxide;Nitric Oxide Donors;Nitric Oxide Synthase;Nuclear;Occlusions Coronary;Oxides;PTGS2 gene;Pancreas;Patients;Pharmaceutical Preparations;Phenotype;Phosphotransferases;Physiological;Physiological reperfusion;Play;Polymerase Chain Reaction;Prevention;Procedures;Process;Promotor (Genetics);Protein Kinase C;Proteins;Reactive Oxygen Species;Recombinant adeno-associated virus (rAAV);Recombinants;Relative (related person);Reperfusion Injury;Reperfusion Therapy;Research Personnel;Response Elements;Role;S-nitro-N-acetylpenicillamine;Stress;Superoxide Dismutase;TNF gene;TNFRSF5 gene;Techniques;Testing;Therapeutic;Time;Tissues;Transgenic Organisms;Translating;Tumor Necrosis Factor-alpha;Up-Regulation (Physiology);Ventricular Cardiac alpha-Myosin;Work;adeno-associated viral vector;caspase;coronary angioplasty;cyclooxygenase 2;experience;extracellular;gain of function;gene therapy;genetic manipulation;inhibitor/antagonist;limitin;loss of function;myocardial infarct sizing;novel;preconditioning;prevent;programs;prophylactic;protective effect;response;size;thrombolysis;transcription factor;triphenyltetrazolium


application_id: 7617853
project_number: 5R01CA116658-05
project_title: Regulation of Cell Survival and Tumor Progression by Akt
administering_ic: NCI
award_notice_date: 2009-04-21
application_type: 5
activity_code: R01
ic: CA
serial_number: 116658
program_official: JHAPPAN, CHAMELLI
project_start_date: 2005-08-01
project_end_date: 2011-05-31
study_section: Tumor Cell Biology Study Section[TCB]
contact_pi_person_id: 1883986
contact_pi: RANGNEKAR, VIVEK M
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-06-01
project_abstract:
DESCRIPTION (provided by applicant): Akt is the focal point of a number of signaling pathways that regulate cell survival and tumor progression. Akt interacts with and modifies via phosphorylation many substrates involved in these cellular events. Owing to its anti-apoptotic properties Akt plays a key role in promoting human cancer. Thus the identification of molecules that interact with Akt may lead to a better understanding of the role of Akt in various local signaling networks and enable the development of strategies for specifically blocking signaling pathways involved in cancer development and progression.   Par-4 is a leucine zipper domain protein that when ectopically expressed induces apoptosis in cancer cells but not in normal or immortalized cells. Apoptosis by ectopic Par-4 occurs by inhibition of NF-kappaB activity. As cancer cells contain reasonable levels of endogenous Par-4 we sought to determine whether Par-4 exists in an inactive form. Our Preliminary Studies reveal that Akt1 binds and inactivates endogenous Par-4 rendering it ineffective in apoptosis-induction. Moreover inactivation of Akt1 releases Par-4 to induce apoptosis implying that endogenous Par-4 is functionally active in the absence of Akt1. In view of the pro-survival functions of Akt1 and the pro-apoptotic functions of Par-4 the objective of this proposal is to study the molecular basis and functional relevance of the interaction between Akt1 and Par-4 in prostate cancer cell survival and tumor progression. Toward this end we propose the following specific aims: Aim 1 elucidate the molecular basis for the isoform-specific effects of Akt on Par-4; Aim 2 determine the mechanism for cytoplasmic retention and inactivation of Par-4 by Akt1; and Aim 3 determine the downstream effects and functional relevance of Par-4 inhibition by Akt1 in tumor growth. Because PTEN loss is a well defined genetic lesion that elevates Akt activity and neutralizes the apoptotic pathway in the prostate and contributes to prostate tumors in mouse models this study will focus on the prostate cancer cell background to study the Akt1-Par-4 interaction. However as the Akt1-Par-4 interaction occurs in diverse tumor cell types we anticipate that the findings of this study will have broad implications in cancer. The findings will be further developed in future studies to design therapeutic strategies that can prevent Par-4 binding to Akt1 and induce apoptosis and tumor growth regression.

project_terms:
Address;Apoptosis;Apoptotic;BCL2 gene;BIRC4 gene;Binding (Molecular Function);Biological;Cell Nucleus;Cell Proliferation;Cell Survival;Cell membrane;Cell model;Cell physiology;Cells;Clinical;Cytoplasm;Development;Epithelial Cells;Event;Future;Gene Proteins;Genetic;Genetic Transcription;Human;Induction of Apoptosis;Inhibition of Apoptosis;Ionizing radiation;Lead;Lesion;Leucine Zippers;Malignant Neoplasms;Malignant neoplasm of prostate;Molecular;NF-kappa B;Nuclear;Nuclear Translocation;PAWR gene;PTEN gene;Pathway interactions;Phosphorylation;Phosphorylation Site;Play;Principal Investigator;Property;Prostate;Prostatic Neoplasms;Protein Isoforms;Proteins;Reading;Regulation;Resistance;Role;Signal Pathway;Signal Transduction;Small Interfering RNA;Specimen;Tertiary Protein Structure;Testing;Therapeutic;Tissues;Tumor Suppressor Proteins;angiogenesis;base;cancer cell;cell motility;cell type;chemotherapeutic agent;cytokine;design;glucose metabolism;immortalized cell;mouse model;neoplastic cell;novel;prevent;pro-apoptotic protein;research study;small hairpin RNA;trafficking;tumor;tumor growth;tumor progression


application_id: 7617659
project_number: 5R21CA120693-02
project_title: Cryopreparation of PBMC for Immunotherapy and Immune Assessment Studies.
administering_ic: NCI
award_notice_date: 2009-04-07
opportunity_number: RFA-CA-07-037
application_type: 5
activity_code: R21
ic: CA
serial_number: 120693
program_official: CHUAQUI, RODRIGO F
project_start_date: 2008-05-01
project_end_date: 2011-04-30
study_section: ZCA1-SRRB-3(O1)
contact_pi_person_id: 1870178
contact_pi: YANNELLI, JOHN R.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  There are many immunotherapy trials being conducted throughout the world ranging from vaccines to T cell transfer and antibody studies. In these trials aside from the obvious need to assess clinical responses Investigators must analyze changes in immune responsiveness which results from the immune intervention. Thus there is a need to collect PBMC from patients at regular intervals both before and following the therapy. These PBMC are cryopreserved to save the PBMC phenotype and function until a later time point when the PBMC can be thawed and assessed to determine if the immunotherapy was effective. In addition preparation of subsequent doses benefits from a source of readily obtainable PBMC which will respond to in vitro manipulation similar to the day the product was received by the lab. There are few standardized techniques available for cell cryopreservation as it relates to immunotherapy. Most labs have their own protocols which themselves often provide inconsistencies in cell viability and function upon thawing. It is also difficult to evaluate results of immunotherapy trials and make comparisons from lab to lab. The current proposal will focus on cryopreservation medium and compare static vs. controlled rate freezing techniques. In 4 Specific aims we will examine: 1) optimum medium for cryopreservation. Human serum + DMSO will be compared to Plasmalyte-A an FDA approved commercial serum free electroyte or rehydration fluid. The comparison of Plasmalyte A to serum is important because if it works significant cost reduction will occur since the cost per liter is less than 1% of the cost of serum. In addition this is an FDA approved product which is consistent from batch to batch. The second specific aim will evaluate different methods of thaw. Specific Aim 3 will compare static freeze techniques to controlled rate freezing. The fourth specific aim will monitor Specific aims 1 and 3 by comparing PBMC subset function at various time intervals using assays of cellular immunity. The goal of the proposal will be to develop a strategy for peripheral blood mononuclear cell (PBMC) cryopreservation which can be more universally applied. A more standardized approach will allow a more accurate assessment of immne responsivenss which can be compared between studies in different centers. In addition other clinical studies utilizing PBMC can also benefit from such a study (studies of HIV and transplantation for instance). The 4 specific aims will be done over a two year period of time.

project_terms:
Acute;Address;Aftercare;Antibodies;Area;Biological Assay;Blood;Boxing;Cell Survival;Cell physiology;Cells;Cellular Immunity;Clinical;Clinical Research;Clinical Trials;Cryopreservation;Dendritic Cells;Dimethyl Sulfoxide;Dose;Effector Cell;Electrolytes;Ensure;FDA approved;Freezing;Gases;Glucose;Goals;HIV;Histology;Human;Immune;Immune response;Immunologics;Immunotherapy;In Vitro;Intervention;Investigation;Kentucky;Laboratories;Learning;Leukapheresis;Licensing;Liquid substance;Lymphokine-Activated Killer Cells;Malignant Neoplasms;Measures;Mechanics;Methodology;Methods;Monitor;Natural Killer Cells;Nitrogen;Patients;Peripheral;Peripheral Blood Mononuclear Cell;Phase;Phenotype;Plasmalyte A;Preparation;Procedures;Process;Property;Protocols documentation;Reagent;Rehydrations;Reliability of Results;Research Personnel;Running;Sampling;Serum;Serum-Free Culture Media;Site;Solutions;Source;T-Lymphocyte;Techniques;Temperature;Testing;Therapeutic;Time;Transplantation;Treatment Protocols;United States;Universities;Vaccines;Variant;Viral;Work;cell preparation;clinical research site;cost;crystalloid;in vivo;innovation;insight;melanoma;precursor cell;research clinical testing;research study;response;standard measure;time interval;tumor


application_id: 7616600
project_number: 1F32NS063744-01A1
project_title: Therapeutic Strategies for Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2008-09-13
opportunity_number: PA-07-107
application_type: 1
activity_code: F32
ic: NS
serial_number: 063744
suffix: A1
program_official: KLEITMAN, NAOMI
project_start_date: 2008-09-15
project_end_date: 2010-04-14
study_section: Special Emphasis Panel[ZRG1 F01-V (20)]
contact_pi_person_id: 8477680
contact_pi: VAISHNAV, RADHIKA ANAND
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
project_abstract:
DESCRIPTION (provided by applicant): Spinal cord injury (SCI) is a devastating condition that affects active individuals of all ages for whom treatment options remain inadequate. Two well-established injury mechanisms are reactive oxygen species (ROS)-mediated oxidative damage to lipids and proteins; and the activation of calcium-dependent proteases (calpains) and consequent breakdown of a number of proteins including cytoskeletal proteins. Despite the progress made in understanding the cellular and molecular mechanisms of neurodegeneration following acute SCI treatment of this condition has remained a challenge. Therapeutic intervention against ROS mediated oxidative damage using the antioxidant compound Tempol at short time points following acute SCI has been shown to be at least partially neuroprotective. To achieve a greater protective effect following SCI it would be advantageous to combine more than one therapeutic approach. The overall aim is to systematically block post-traumatic neurodegeneration following SCI by scavenging ROS and inhibiting calpain-mediated proteolytic degradation of the neuronal cytoskeleton. Aim 1 will test the hypothesis that inhibition of calpain using a novel drug with high cell permeability and blood-brain barrier penetrability will decrease cytoskeletal damage to the neurons and promote neuroprotection in acute SCI. The rat PSI T10 spinal cord contusion injury model will be used in Aims 1 and 2. Shams injured rats with vehicle and injured rats treated with critically selected doses of the calpain inhibitor will be compared at specific time points following injury. Calpain-mediated cytoskeletal breakdown will be assessed using an immunochemical spectrin breakdown assay as an indirect measure of calpain activity. Tissue sparing functional and locomotor recovery will also be compared among the treatment and control groups. Aim 2 will test the hypothesis that a combination of antioxidant therapy with calpain inhibition will produce an additive and/or synergistic protective effect after SCI. The optimal dosing paradigm for the antioxidant Tempol as previously determined and for the novel calpain inhibitor as determined in Aim 1 will be used in this combinatorial approach. In addition to the methodology used in Aim 1 oxidative damage will be assessed using immunochemical approaches including slot blots Western blots and immunohistochemistry. The objective of this project is to develop a combinatorial therapeutic strategy for the treatment of SCI in a rat model. The findings of this study will provide a foundation for the design of future translational studies in human SCI.

project_terms:
2266-tetramethyl-4-piperidinol-N-oxyl;3-nitrotyrosine;Acute;Affect;Age;Animal Model;Animals;Antioxidants;Biological Assay;Blood - brain barrier anatomy;Blotting Western;Calcium;Calpain;Cells;Clinical Trials;Condition;Control Groups;Contusions;Cysteine Protease;Cytoskeletal Proteins;Cytoskeleton;Data;Dose;Drug Kinetics;Endopeptidases;Event;Female;Figs - dietary;Foundations;Functional disorder;Future;Gender;Human;Immunohistochemistry;Individual;Injury;Intervention;Laboratories;Life;Lipids;Locomotor Recovery;Measures;Mechanics;Mediating;Methodology;Methods;Mitochondria;Modeling;Molecular;Nerve Degeneration;Neurologic;Neurons;Oxidative Stress;Peptide Hydrolases;Permeability;Peroxonitrite;Pharmaceutical Preparations;Pharmacologic Substance;Property;Protein Structure Initiative;Proteins;Proteolysis;Rattus;Reactive Oxygen Species;Recovery;Role playing therapy;Spectrin;Spinal Cord;Spinal Cord Contusions;Spinal Cord transection injury;Spinal cord injury;Stretching;Testing;Therapeutic;Therapeutic Intervention;Time;Tissues;Translating;Translations;Trauma Nervous System;United States;antioxidant therapy;base;behavior test;calpain inhibitor;combinatorial;design;improved;injured;neuroprotection;novel;numb protein;pre-clinical;prevent;protective effect;protein activation;research clinical testing;sham surgery;translational study;treatment duration;young adult


application_id: 7615488
project_number: 5K08NS050110-06
project_title: Alpha-synuclein mRNA is a putative microRNA target
administering_ic: NINDS
award_notice_date: 2009-05-28
application_type: 5
activity_code: K08
ic: NS
serial_number: 050110
program_official: SUTHERLAND, MARGARET L
project_start_date: 2005-05-01
project_end_date: 2010-04-30
study_section: Neurological Sciences Training Initial Review Group[NST]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-05-01
project_abstract:
Small regulatory RNAs participate in many eukaryotic cell functions microRNAs (miRNAs) the major subclass of small regulatory RNAs in animal species regulate gene expression post-transcriptionally by destabilizing and/or reducing the translation of specific 'target' mRNAs. Post-transcriptional gene regulation has revolutionary implications yet very little is known of the roles played by miRNAs in neurons or neurodegenerative disease. AIM 1: CHARACTERIZE THE POLYRIBOSOMAL miRNP IN NEURON-LIKE CELLS. miRNA-related biochemistry is poorly understood. We hypothesize that miRNA-containing polyribosomal ribonucleoprotein complexes (miRNPs) represent the biochemical substrate for miRNA:mRNA regulation. We will partially purify the polyribosomal miRNP from Weri retinoblastoma cells to characterize the biochemical properties and the protein components of this important particle. AiM 2: IDENTIFY AND CHARACTERIZE miRNA:mRNA PAIRS. Although hundreds of human miRNAs are known most mRNA targets are unknown. We discerned "rules" that govern miRNA:target mRNA interaction. Using these guidelines our bioinformatician collaborators predict mRNA targets regulated by human miRNAs. We will use cell biological tools to verify hypothesized miRNA-mRNA partners relevant to human neurological diseases. AIM 3: CHARACTERIZE A miRNA INTERACTION THAT MAY REGULATE THE EXPRESSION OF ALPHA-SYNUCLEIN (A-SN). On the basis of preliminary evidence we hypothesize that an evolutionarily conserved sequence element in the 3'-untranslated region of A-SN mRNA is recognized by a specific miRNA (miR-93). A-SN protein plays a central role in some neurodegenerative diseases and itsregulation by a miRNA would have important implications in neurobiology neurodegenerative disease and RNA biology. We will study this interaction using neuronal cell lines as a prototype of miRNA:mRNA validation. We will also extend the analyses to human brain tissue in health and disease.

project_terms:
3' Untranslated Regions;Amyotrophic Lateral Sclerosis;Animals;Biochemical;Biochemistry;Bioinformatics;Biological;Biological Assay;Biology;Cell Line;Cell physiology;Cells;Co-Immunoprecipitations;Complex;Computational algorithm;Conserved Sequence;Disease;Eukaryotic Cell;Fragile X Syndrome;Gene Expression;Gene Expression Regulation;Guidelines;Health;Human;Immunohistochemistry;In Situ;In Situ Hybridization;Indium;Journals;Medical;Mental Retardation;Messenger RNA;MicroRNAs;Nerve Degeneration;Neurobiology;Neurodegenerative Disorders;Neurons;Neurosciences;Northern Blotting;Paper;Parkinson Disease;Physiological;Play;Polyribosomes;Process;Property;Proteins;RNA;Regulation;Research;Retinoblastoma;Ribonucleoproteins;Role;Science;Specificity;Techniques;Testing;Translations;Tuberous Sclerosis;Tumor Cell Line;Validation;alpha synuclein;base;biological systems;brain tissue;human TSC1 protein;nervous system disorder;novel;particle;protein expression;prototype;synuclein;tool


application_id: 7615157
project_number: 5P30NS051220-04
project_title: Core--Pharmacokinetics and Biomarker
administering_ic: NINDS
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: National Institute of Neurological Disorders and Stroke Initial Review Group[NSD]
subproject_number: 9005
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-05-01
budget_end_date: 2009-04-30
funding_mechanism: Research Centers
project_abstract:
The proposed core facility will include a single large room . It will be used for the analysis of the levels of experimental compounds in various biofluids (plasma CSF urine) and tissues (brain spinal cord) in normal or injured rats or mice. For this purpose we will transfer the Shimadzu HPLC with ESA Coulichem electrochemical detector to the Core. However a new state of the art HPLC system with autosampler and electrochemical UV/Vis fluorescence and light scattering detectors is requested in the grant budget for year 4. Secondly the core will be used for carrying out the bioanalytical work associated with exploration of various pathophysiological biomarkers. A major focus will be on the measurement of isoprostanes using GC-MS.The recently purchased Shimadzu GC-MS will be moved to this facility. A microplate reader for protein assays and ELISAs that will be moved to this core. In addition we will continue working on the potential of CSF alpha-spectrin measurements carried out by immunoblot or ELISA. Most of the latter will take place in Dr. Hall's laboratory space outside of the core. In addition all animal surgeries injury procedures and sample collection will take place in the Animal Surgery and TBI/SCI Model Core facility. The Pharmacokinetics & Biomarker Core will only be used for bioanalytical work.

project_terms:
Acute;Affect;Animal Model;Animals;Arachidonic Acids;Arts;Biological Assay;Biological Markers;Budgets;Cerebrospinal Fluid;Chromatography High Pressure Liquid;Clinical;Clinical Trials;Core Facility;Cytoskeletal Proteins;Detection;Doctor of Philosophy;Dose;Drug Kinetics;Enzyme-Linked Immunosorbent Assay;Evaluation;Faculty;Family;Fluorescence;Free Radicals;Funding;Gas Chromatography;Grant;Immunoblotting;Injury;Intervention;Investigation;Isoprostanes;Laboratories;Lipid Peroxidation;Measurable;Measurement;Measures;Modeling;Monitor;Mus;Neuroprotective Agents;Operative Surgical Procedures;Plasma;Postdoctoral Fellow;Procedures;Process;Proteins;Protocols documentation;Purpose;Rattus;Reader;Research;Research Personnel;Spectrin;Spinal Cord;System;Techniques;Technology;Testing;Time;Tissues;Translations;Urine;Work;alpha Spectrin;brain tissue;detector;injured;light scattering;member;neuroprotection;sample collection;urinary;veterinary science


application_id: 7615156
project_number: 5P30NS051220-04
project_title: Core--Microscopy Image Analysis and Stereology
administering_ic: NINDS
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: National Institute of Neurological Disorders and Stroke Initial Review Group[NSD]
subproject_number: 9004
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-05-01
budget_end_date: 2009-04-30
funding_mechanism: Research Centers
project_abstract:
As proposed the Microscopy Image Analysis & Stereology Core would be created as an independent core completely separated from the existing Microscopy Facility at this institution. The core would however be equipped with current in-house equipment made available by SCoBIRC faculty including two Olympus Provis AX70 Fluorescence Microscopes (Image Pro interfaced via MagnaFire Digital Camera) Olympus BX 41 with Video Camera Olympus BX 50 Epifluorescent Microscope (Bioquant Stereology package + 3D topographer interfaced with MagnaFire Digital Camera & Optronics Video Camera) Nikon E400 teaching microscopy with DAGE Video Camera. Specifically the proposed Microscopy Image Analysis & Stereology Core will combine the existing equipment which is currently scattered among various NINDS-funded investigators' laboratories with the additional new equipment and dedicated technical oversight. It would also place all these facilities under one administrative structure. Accordingly the proposed core requests the provision of a senior technician who will oversee the use of the image analysis and stereology equipment as well as the desired confocal microscope.

project_terms:
Calendar;Date/Time;Educational process of instructing;Equipment;Faculty;Funding;Grant;Guidelines;Housing;Image;Image Analysis;Institution;Laboratories;Microscope;Microscopy;Research Personnel;Schedule;Specific qualifier value;Structure;Supervision;Time;Training;desire;digital;fluorescence microscope


application_id: 7615155
project_number: 5P30NS051220-04
project_title: Core-Behavioral Testing
administering_ic: NINDS
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: National Institute of Neurological Disorders and Stroke Initial Review Group[NSD]
subproject_number: 9003
contact_pi_person_id: 7875165
contact_pi: SPRINGER, JOE E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-05-01
budget_end_date: 2009-04-30
funding_mechanism: Research Centers
project_abstract:
SCI Testing Paradigms: Gross locomotor skill will be assessed during open field walking with the 21-point Basso Beattie and Bresnahan (BBB) locomotor recovery scale. The horizontal ladder (Columbus Instruments) will be used to examine hindlimb locomotor function and interlimb coordination. Specific kinetic and kinematic parameters of overground locomotion will be studied and analyzed using a runway device previously described (Muir et al. 1996; Muir and Whishaw 1999). For assessment of sensory function animals will be examined using von Frey hairs for testing tactile sensation and Hargreaves' test for nociception (Stoelting Instruments). The grip strength meter (TSE Systems) is a recently developed apparatus that measures the gripping strength of the front or hind paw of either rats or mice. Blood pressure monitors (Columbus Instruments) will also be required in order to study changes in blood pressure and heart rate in a model of autonomic dysreflexia. TBI Testing Paradigms: The Morris water maze is a well accepted procedure for studying functional deficits and recovery of function following TBI and one room of the Core will be dedicated. Animals will also be tested on additional paradigms including the rotarod test (Columbus Instruments) balance beam and the grip strength meter.

project_terms:
Animals;Area;Autonomic Dysreflexia;Blood Pressure;Blood Pressure Monitors;Calendar;Core Facility;Daily;Date/Time;Devices;Electronics;Ensure;Equilibrium;Esthesia;Evaluation;Funding;Future;Guidelines;Hair;Heart Rate;Hindlimb;Human Resources;IACUC;Individual;Injury of central nervous system;Kinetics;Laboratories;Letters;Locomotion;Locomotor Recovery;Measures;Modeling;Mus;Neurologic;Operative Surgical Procedures;Pain Measurement;Procedures;Protocols documentation;Qualifying;Rattus;Recovery of Function;Reporting;Research Personnel;Rotarod Performance Test;Schedule;Sensory;Surgical Injuries;System;Tactile;Testing;Time;United States National Institutes of Health;Walking;Work;Writing;animal care;base;behavior test;grasp;instrument;kinematics;meter;morris water maze;research study;skills


application_id: 7615154
project_number: 5P30NS051220-04
project_title: Core--Animal surgery and TBI /SCI model
administering_ic: NINDS
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: National Institute of Neurological Disorders and Stroke Initial Review Group[NSD]
subproject_number: 9002
contact_pi_person_id: 1884283
contact_pi: SCHEFF, STEPHEN W
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-05-01
budget_end_date: 2009-04-30
funding_mechanism: Research Centers
project_abstract:
The Animal Surgery & TBI/SCI Model Core will be available to all members of the center and theirstudents and technicians. Services provided by this core will include: assistance in performing 1) traumatic brain injury using one of the standard closed head injury models (controlled cortical impact fluid percussion Marmarou diffuse impact-acceleration); 2) spinal cord injury (NYU device IH 0400 device OSU device). The facility will be designed to handle both rats and mice with the stipulation that only one species will be present at any given surgery appointment. The core facility will also provided assistance in post-injury animal welfare and care including bladder expression following SCI.

project_terms:
Acceleration;Animal Welfare;Animals;Appointment;Bladder;Caring;Closed head injuries;Core Facility;Devices;Diffuse;Injury;Liquid substance;Modeling;Mus;Operative Surgical Procedures;Percussion;Rattus;Services;Spinal cord injury;Standards of Weights and Measures;Students;Traumatic Brain Injury;controlled cortical impact;design;member


application_id: 7615153
project_number: 5P30NS051220-04
project_title: Core--Bioinformatics
administering_ic: NINDS
application_type: 5
activity_code: P30
ic: NS
serial_number: 051220
study_section: National Institute of Neurological Disorders and Stroke Initial Review Group[NSD]
subproject_number: 9001
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-05-01
budget_end_date: 2009-04-30
funding_mechanism: Research Centers
project_abstract:
The Bioinformatics Center Core facility will provide an administrative and organizationalframework to support and coordinate Center research cores and related activities and to facilitate increased collaboration among investigators. In addition the Core will maintain a secure server to store and archive scientific data from each of the Center cores and investigators and will provide ongoing support and further development of the existing SCIgenes database.

project_terms:
Archives;Bioinformatics;Collaborations;Core Facility;Data;Databases;Development;Reporting;Research;Research Personnel;Secure


application_id: 7615130
project_number: 5R44HD055019-03
project_title: Adaptive High Intensity Electrical Stimulation for Post-Surgical Rehabilitation
administering_ic: NICHD
award_notice_date: 2009-04-01
opportunity_number: PA-06-120
application_type: 5
activity_code: R44
ic: HD
serial_number: 055019
program_official: SHINOWARA, NANCY
project_start_date: 2008-04-15
project_end_date: 2012-03-31
study_section: Special Emphasis Panel[ZRG1-MOSS-L(10)B]
contact_pi_person_id: 7771781
contact_pi: HARTMAN, ERIC C
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 129360637
duns_number: 129360637
fips: US
organization_id: 4168101
organization_name: CUSTOMKYNETICS, INC.
organization_city: NICHOLASVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403401290
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-04-01
budget_end_date: 2012-03-31
project_abstract:
DESCRIPTION (provided by applicant): Recovery of quadriceps muscle force following post-surgical knee immobilization is a significant therapeutic aim which is associated with quality of gait and the ability to perform activities of daily living. Several studies from various research groups have shown that neuromuscular electrical stimulation (NMES) used in conjunction with a comprehensive post-surgical rehabilitation program is a safe and highly effective method for achieving quadriceps strengthening. The most profound results have been demonstrated with use of high intensity NMES technique in which a few very strong isometric contractions of the quadriceps muscle were performed several times per week during a physical therapy session in which the patient was seated on a biomechanical dynamometer. Efficacy of this technique has been demonstrated for individuals undergoing rehabilitation following surgical reconstruction of the anterior cruciate ligament (ACLR); however widespread clinical acceptance of the technique has been limited. We assert that this high intensity electrical stimulation technique would be more widely practiced: 1) if a low cost practical cohesive system were available to replace costly and loosely connected research-based apparatus and 2) if the system involved an NMES unit that controlled stimulation automatically using an outcome-based paradigm that did not require incessant involvement of the therapist. We propose a novel rehabilitation system indicated for quadriceps strengthening during post-surgical knee immobilization in which the knee joint will be stabilized using an instrumented post-surgical knee brace and stimulation is delivered by a high output portable NMES unit with autonomous adaptive stimulation control capabilities. The target markets for this device would be clinics who serve patients undergoing rehabilitation following ACLR or total knee arthroplasty (TKA). The target price for the system will be $4000. The goals of this FastTrack SBIR project are therefore to demonstrate feasibility of the adaptive stimulation control approach in Phase I using laboratory-based apparatus. We will interface our adaptive stimulator to the KinCom dynamometer and show that the stimulator can elicit a contraction of sufficient strength that function outcomes could be expected and demonstrate that the adaptive controller can develop appropriate stimulation patterns for use in this low-cycle count application. The Phase II goals will be: 1) to develop an instrumented knee brace capable of stabilizing the knee during near maximal isometric contractions and obtaining measurements of the resulting torque; 2) to implement a rapid training version of our adaptive stimulation controller that is suited for use in this low cycle count application; 3) to implement an alternate fundamental stimulation waveform that may be more comfortable to some users; and 4) to demonstrate efficacy of the proposed system for quadriceps strengthening following ACLR or TKA. / Relevance The proposed work may benefit public health through development of an electrical stimulation exercise device indicated for quadriceps strengthening during post-surgical immobilization following surgical repair of the anterior cruciate ligament (ACLR) or total knee arthroplasty (TKA). Quadriceps strengthening has been shown to improve gait and improve performance of activities of daily living (ADLs). There are approximately 100000 ACLR and 400000 TKA surgeries per year in the United States.

project_terms:
Activities of Daily Living;Algorithms;Arthroplasty Replacement Knee;Biomechanics;Braces-Orthopedic appliances;Client;Clinic;Clinical;Databases;Degenerative polyarthritis;Delaware;Development;Devices;Electric Stimulation;Exercise;Gait;Goals;Immobilization;Individual;Isometric Contraction;Isometric Exercise;Knee;Knee joint;Laboratories;Lead;Leg;Marketing;Measurement;Methods;Muscle;Operative Surgical Procedures;Outcome;Output;Patients;Pattern;Performance;Phase;Physical therapy;Pilot Projects;Postoperative Period;Price;Protocols documentation;Ramp;Recovery;Recruitment Activity;Regulation;Rehabilitation therapy;Reporting;Research;Safety;Signal Transduction;Small Business Innovation Research Grant;Speed (motion);Staging;System;Techniques;Therapeutic;Time;Torque;Training;Transducers;United States;Universities;Work;analog;anterior cruciate ligament reconstruction;base;cost;improved;instrument;neuromuscular;novel;programs;prototype;public health medicine (field);tool


application_id: 7615079
project_number: 5R01HL089939-02
project_title: Organ protection during cardiopulmonary arrest
administering_ic: NHLBI
award_notice_date: 2009-03-18
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 089939
program_official: LIANG, ISABELLA Y
project_start_date: 2008-05-01
project_end_date: 2009-08-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 7035773
contact_pi: DAWN, BUDDHADEB
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  No intervention is currently available to prevent the consequences of organ damage associated with cardiopulmonary arrest. While the protective effects of preconditioning (PC) during regional ischemic injury to several organs have been well-documented it remains unknown whether this phenomenon can be utilized to improve the outcome following cardiac arrest. The overall objective of this proposal is to evaluate the efficacy of physiologic and pharmacologic late PC-mimetic interventions in preventing cardiac and neuronal injury during cardiopulmonary arrest. Our fundamental hypothesis is that the heart and brain can be preconditioned to tolerate the ischemic injury during cardiac arrest by using clinically-feasible PC-mimetic interventions that can be given prophylactically to patients at risk for cardiopulmonary arrest. Specifically we will test the hypothesis that exposure to exercise adenosine A1 receptor agonists opioid ?1 receptor agonists and NO donors induces delayed antistunning and antiapoptotic effects that result in improved outcome following cardiopulmonary arrest and that these salubrious effects are mediated by a coordinated upregulation of iNOS COX-2 and HO-1. This study will utilize a broad multidisciplinary approach that will involve integrative physiology protein chemistry molecular biology and gene targeting. All studies will be carried out in a well-characterized mouse model of cardiac arrest using genetically-engineered animals which will provide conclusive information. In Aim 1 the efficacy of exercise CCPA TAN-67 and DETA/NO in conferring protection during cardiac arrest will be carefully characterized and the mechanism of the antiapoptotic effects will be elucidated. Aim 2 will investigate the role of iNOS in organ protection during cardiopulmonary arrest. Both iNOS-/- and iNOS transgenic mice will be used to determine whether iNOS is necessary and sufficient to confer protection. In Aim 3 the beneficial role of COX-2 will be conclusively established by genetic ablation and pharmacologic inhibition. Aim 4 will elucidate the role of HO-1 as a co-mediator of protection using HO-1-/- mice and HO-1 transgenic mice. Aim 5 will determine the utility of adenovirus-mediated gene transfer of iNOS COX-2 and HO-1 in recapitulating the beneficial effects. This proposal will yield new and important information regarding the role of clinically-relevant agents in inducing protection against a devastating and common health problem. This information may eventually lead to the development of novel therapeutic strategies to save human lives.  PUBLIC HEALTH RELEVANCE Approximately 500000 Americans are affected by cardiopulmonary arrest every year. Despite decades of research the survival and prognosis after cardiac arrest remain dismal. Although the phenomenon of preconditioning (PC) has been shown to protect various organs during ischemic injury its role in cardiac arrest remains unclear. The primary goal of this proposal is to examine whether PC-mimetic physiologic and pharmacologic interventions can protect against cardiac and neurologic injury sustained during cardiac arrest. These results would have enormous therapeutic implications for patients with cardiac arrest. The results of the proposed studies will therefore be highly relevant for improving public health and improving the length and quality of life of thousands of patients with cardiac arrest.

project_terms:
Abbreviations;Ablation;Adenosine;Adenosine A1 Receptor;Adenoviruses;Affect;Agonist;American;Animals;Apoptosis;Blood Circulation;Brain;Cardiac;Cardiac Myocytes;Cardiopulmonary;Cardiopulmonary Arrest;Clinical Research;Congestive Heart Failure;Development;Dose;Endothelial Cells;Engineering;Exercise;Exposure to;Female;Gene Targeting;Gene Transfer;Genetic;Goals;Health;Heart;Heart Arrest;Heme Oxygenase (Decyclizing);Human;Inhibition of Apoptosis;Injury;Intervention;Intestines;Ischemia;Ischemic Preconditioning;Kidney;Lead;Left;Length;Life;Mediating;Mediator of activation protein;Molecular Biology;Mortality Vital Statistics;Mus;Muscle;Myocardial;Myocardial Ischemia;Myocardium;NS-398;Neurologic;Neuronal Injury;Nitric Oxide;Opioid;Organ;Outcome;PTGS2 gene;Pathology;Patients;Phase;Physiological;Physiology;Protein Chemistry;Quality of life;Reactive Oxygen Species;Recovery;Research;Risk;Role;Stress;Testing;Therapeutic;Time;Transgenic Mice;Transgenic Organisms;Up-Regulation (Physiology);Ventricular;Ventricular Fibrillation;celecoxib;clinically relevant;cyclooxygenase 2;experience;gene therapy;human NOS2A protein;improved;inhibitor/antagonist;interdisciplinary approach;intervention effect;mimetics;mouse model;neuron apoptosis;novel;novel therapeutics;outcome forecast;overexpression;preconditioning;pressure;prevent;protective effect;public health medicine (field);public health relevance;receptor;response


application_id: 7614215
project_number: 5P01NS058484-02
project_title: Proteomics and biomarker
administering_ic: NINDS
application_type: 5
activity_code: P01
ic: NS
serial_number: 058484
study_section: ZNS1
subproject_number: 9002
contact_pi_person_id: 3079616
contact_pi: GUTTMANN, RODNEY P
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-05-01
budget_end_date: 2009-04-30
funding_mechanism: Non-SBIR/STTR
project_terms:
4 hydroxynonenal;Address;Alzheimer's Disease;American;Amyotrophic Lateral Sclerosis;Animal Model;Area;Astrocytes;Behavioral;Biological Assay;Biological Markers;Biological Models;Blotting Western;Brain Injuries;Calcium;Calpain;Cell Death;Cells;Cerebral Ischemia;Cerebrospinal Fluid;Cessation of life;Cleaved cell;Collaborations;Condition;Cultured Cells;Data;Digestion;Disease;Effectiveness;Electrophoresis Gel Two-Dimensional;Endopeptidases;Enzymes;Functional disorder;Future;Goals;Huntington Disease;In Vitro;Individual;Injury;Ionophores;Link;Lipid Peroxidation;Measurement;Measures;Mediating;Methods;Mice Knockout;Microglia;Mitochondria;Modeling;Monitor;Nature;Nerve Degeneration;Neuroglia;Neuronal Dysfunction;Neurons;Numbers;Oligodendroglia;Outcome;Oxidation-Reduction;Oxidative Stress;Parkinson Disease;Pathway interactions;Peptide Hydrolases;Population;Primary Cell Cultures;Prions;Protein Isoforms;Proteins;Proteolysis;Proteomics;Publishing;Role;Serum;Spectrin;Spectrum Analysis Mass;Spinal cord injury;System;Testing;Therapeutic;Therapeutic Intervention;Time;Traumatic Brain Injury;Treatment Efficacy;Work;attenuation;base;brain tissue;calpastatin;cell injury;cell type;disability;functional outcomes;improved;in vivo;inhibitor/antagonist;insight;m-calpain;neurofilament;novel;oxidation;prevent;programs;small molecule;therapeutic effectiveness;tool


application_id: 7614214
project_number: 5P01NS058484-02
project_title: Animal
administering_ic: NINDS
application_type: 5
activity_code: P01
ic: NS
serial_number: 058484
study_section: ZNS1
subproject_number: 9001
contact_pi_person_id: 6875991
contact_pi: SAATMAN, KATHRYN E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-05-01
budget_end_date: 2009-04-30
funding_mechanism: Non-SBIR/STTR
project_terms:
Adult;Animals;Behavior assessment;Behavioral;Blinded;Brain;Brain Injuries;Breeding;Calpain;Cognitive;Condition;Craniocerebral Trauma;Cultured Cells;Data;Diffuse;Drops;Efficiency Program;Evaluation;Female;Generations;Genotype;Goals;Human;Human Resources;I Calpain;Individual;Injury;Investigation;Knock-out;Life;Literature;Maintenance;Mediating;Mice Knockout;Mice Transgenic;Modeling;Monitor;Motor;Mus;Nerve Degeneration;Neurologic Dysfunctions;Operative Surgical Procedures;Pathway interactions;Patient currently pregnant;Performance;Procedures;Process;Protein Isoforms;Protein Overexpression;Reagent;Research Personnel;Resources;Schedule;Survivors;Testing;Therapeutic;Time;Tissue Harvesting;Training;Transgenic Organisms;Traumatic Brain Injury;Weight;brain pathway;calpastatin;cellular targeting;cognitive function;cohort;controlled cortical impact;cyclophilin D;functional outcomes;grasp;in vivo;inhibitor/antagonist;injured;insight;interest;memory retention;morris water maze;mouse model;neuropathology;novel;novel strategies;pre-clinical;programs;research study;small molecule


application_id: 7614213
project_number: 5P01NS058484-02
project_title: Is u-calpain a pathologic isoform?
administering_ic: NINDS
application_type: 5
activity_code: P01
ic: NS
serial_number: 058484
study_section: ZNS1
subproject_number: 0003
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-05-01
budget_end_date: 2009-04-30
funding_mechanism: Non-SBIR/STTR
project_terms:
Animals;Atractyloside;Attenuated;Behavior;Biological Markers;Calpain;Cell Death;Cell Nucleus;Cells;Cessation of life;Cleaved cell;Cognitive;Cyclosporine;Cytosol;Data;Diffuse;Digitonin;Disease;Drops;Endopeptidases;Exhibits;Family;Functional disorder;Glycine;Injury;Knock-out;Knowledge;Localized;Methods;Mice Knockout;Mitochondria;Modeling;Motor;Mus;N-Methylaspartate;Nerve Degeneration;Neurons;Nuclear Translocation;Pathologic;Peptide Hydrolases;Protein Isoforms;Protein Overexpression;Proteolysis;Proteomics;Research Personnel;Resistance;Role;Signal Transduction;System;Tissues;Traumatic Brain Injury;Weight;Work;apoptosis inducing factor;base;calpain inhibitor;calpastatin;caspase;cell motility;controlled cortical impact;cyclophilin D;functional disability;m-calpain;mitochondrial membrane;mitochondrial permeability transition pore;neuroprotection;novel;research study;small molecule


application_id: 7614212
project_number: 5P01NS058484-02
project_title: Newer small molecule calpain inhibitors for TBI
administering_ic: NINDS
application_type: 5
activity_code: P01
ic: NS
serial_number: 058484
study_section: ZNS1
subproject_number: 0002
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-05-01
budget_end_date: 2009-04-30
funding_mechanism: Non-SBIR/STTR
project_terms:
AK 295;Acute;Address;Animals;Antioxidants;Attenuated;Behavioral;Biological Markers;Brain;Brain Injuries;Calcium;Calpain;Cathepsins;Cell Death;Cells;Cessation of life;Classification;Clinical;Clinical Trials;Collaborations;Conceptions;Cultured Cells;Cysteine Protease;Cytoskeletal Proteins;Data;Development;Diffuse;Dose;Early treatment;End Point;Enzymes;Evaluation;Excision;Failure (biologic function);Free Radicals;Functional disorder;Future;Goals;Hand;Hour;Human Resources;I Calpain;Impairment;Infarction;Injury;Intravenous;Knock-out;Laboratories;Lead;Lipid Peroxidation;Lipids;Measures;Mediating;Mitochondria;Modeling;Mus;Nerve Degeneration;Neurologic;Neurons;Outcome;Oxygen;Papain;Patients;Peptides;Pharmaceutical Preparations;Pharmacodynamics;Phosphatidylethanolamine Binding Protein;Plasma;Play;Preparation;Principal Investigator;Process;Promotor (Genetics);Property;Protein Overexpression;Proteins;Proteolysis;Proteomics;Protocols Treatment;Recovery;Relative (related person);Reporting;Research;Research Personnel;Research Laboratory;Rodent;Role;Running;Sampling;Screening procedure;Series;Solubility;Spectrin;Testing;Therapeutic;Time;Tissues;Transgenic Organisms;Translations;Traumatic Brain Injury;Treatment Efficacy;Work;apoptosis inducing factor;base;brain tissue;calpain inhibitor;calpastatin;caspase;comparative;design;improved;in vivo;inhibitor/antagonist;injured;innovation;intraperitoneal;knockout animal;lipid peroxidation inhibitor;mitochondrial dysfunction;mouse model;neuroprotection;novel;prevent;programs;protective effect;research study;response;small molecule;therapeutic target;treatment duration;water solubility


application_id: 7614211
project_number: 5P01NS058484-02
project_title: Role of calpastatin in modulating function following TBI
administering_ic: NINDS
application_type: 5
activity_code: P01
ic: NS
serial_number: 058484
study_section: ZNS1
subproject_number: 0001
contact_pi_person_id: 6875991
contact_pi: SAATMAN, KATHRYN E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-05-01
budget_end_date: 2009-04-30
funding_mechanism: Non-SBIR/STTR
project_terms:
Acute;Address;Attenuated;Behavioral;Biological Availability;Brain;Brain Injuries;Calcium;Calpain;Cell Count;Cell Death;Cell Death Signaling Process;Cell Survival;Cells;Cerebrospinal Fluid;Cessation of life;Cognitive;Condition;Cytoskeletal Proteins;Data;Diffuse;Disease;Disinhibition;Disruption;Dose;Drops;Evaluation;Event;Functional disorder;Genetic;Glutamate Receptor;Goals;Hippocampus (Brain);Human;Immunoblotting;Immunohistochemistry;Impairment;In Vitro;Injury;Injury Diffuse Brain;Knock-out;Maintenance;Mediating;Membrane Proteins;Mice Knockout;Mitochondria;Modeling;Molecular;Morbidity - disease rate;Motor;Mus;Nerve Degeneration;Neurons;Nuclear;Numbers;Operative Surgical Procedures;Outcome;Outcome Measure;Pathology;Pathway interactions;Play;Principal Investigator;Property;Protein Overexpression;Proteins;Proteolysis;Proteomics;Recovery;Relative (related person);Research Personnel;Rodent;Role;Serum;Signal Pathway;Signaling Protein;Silver Staining;Solubility;Specificity;Spectrin;Staining method;Stains;Standardization;Structure of dentate gyrus;System;Techniques;Testing;Therapeutic;Time;Tissue Sample;Tissues;Transgenes;Translating;Translations;Trauma;Traumatic Brain Injury;Weight;apoptosis inducing factor;base;brain tissue;calpain inhibitor;calpastatin;clinically relevant;controlled cortical impact;endonuclease G;functional disability;functional improvement;improved;in vivo;inhibitor/antagonist;injured;innovation;insight;memory retention;neurofilament;neuron loss;neuronal survival;neuroprotection;novel;novel therapeutics;pre-clinical;prevent;programs;research study;response;small molecule;tau Proteins;therapeutic target;tool


application_id: 7613336
project_number: 7R01DK080327-02
project_title: Effects of fish oil on inflammation and metabolic syndrome
administering_ic: NIDDK
award_notice_date: 2009-05-01
opportunity_number: PA-07-070
application_type: 7
activity_code: R01
ic: DK
serial_number: 080327
program_official: STATEN, MYRLENE A
project_start_date: 2008-05-01
project_end_date: 2013-04-30
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
24-thiazolidinedione;Adipocytes;Adipose tissue;Affect;Aftercare;Agonist;Animal Feed;Anti-Inflammatory Agents;Anti-inflammatory;Apoptosis;Arachidonic Acids;Biopsy;Blood specimen;Cardiovascular system;Cell Adhesion Molecules;Chronic;Complex;Coronary;Coronary heart disease;Development;Diabetes Mellitus;Disease Progression;Epidemic;Event;Fasting;Fatty Acids;Fish Oils;Generations;Genes;Health Benefit;Heart Diseases;Human;Hyperglycemia;In Vitro;Incidence;Inflammation;Inflammatory;Insulin;Insulin Resistance;Interleukin-6;Life;Lipids;Literature;Measures;Mediating;Mediator of activation protein;Membrane;Metabolic syndrome;Molecular Weight;Muscle;Muscle Cells;Non-Insulin-Dependent Diabetes Mellitus;Nuclear Hormone Receptors;Obesity;Omega-3 Fatty Acids;Organ;PPAR gamma;Parents;Peripheral;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Process;Production;Property;Protein Isoforms;Proteins;Rattus;Reactive Oxygen Species;Research;Risk Factors;Series;Serum;Signal Transduction;Source;Syndrome;TNF gene;Thiazolidinediones;Translational Research;Triglycerides;Tumor Necrosis Factor-alpha;Tumor Necrosis Factors;Western World;adiponectin;carbohydrate metabolism;cytokine;feeding;high risk;immunoregulation;improved;inflammatory marker;inhibitor/antagonist;insulin secretion;insulin sensitivity;insulin signaling;macrophage;oxidation;receptor;research study;response;toll-like receptor 4


application_id: 7611813
project_number: 1R43DA026266-01
project_title: Transdermal Delivery of Buprenorphine Prodrugs
administering_ic: NIDA
award_notice_date: 2009-06-01
opportunity_number: PA-08-050
application_type: 1
activity_code: R43
ic: DA
serial_number: 026266
program_official: PARK, MOO KWANG
project_start_date: 2009-06-01
project_end_date: 2010-03-31
study_section: Special Emphasis Panel[ZRG1 BST-Z (10)]
contact_pi_person_id: 1866585
contact_pi: STINCHCOMB, AUDRA L.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178031683
primary_uei: EKBZRSBPS8A3
duns_number: 178031683
uei: EKBZRSBPS8A3
fips: US
organization_id: 10006751
organization_name: ALLTRANZ, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Currently buprenorphine (BUP) is used in the treatment of opioid abuse and for pain management. It can also be used improperly and abused as an opioid. In the United States buprenorphine is marketed in sublingual and injectable forms. While the drug provides effective treatment these forms of drug delivery are not desirable because of their peak plasma level related side effects and short duration of action. Transdermal delivery of drugs decreases peak-related side effects and is ideal for chronic therapies as one patch can deliver a constant rate of drug for up to one week. Initial positive preliminary data has encouraged AllTranz to seek funding to develop new buprenorphine prodrugs and optimize their use through a transdermal patch or gel drug delivery system. Prodrugs are chemically modified parent drugs that are more skin permeable than the parent and once they cross the stratum corneum quickly separate back into the parent drug and prodrug moiety. We will also create formulations for abuse deterrence for this opioid delivery system. Transdermal delivery systems patches and gels offer a number of improvements over other delivery systems. Patches and gels do not require swallowing eliminating oral side effects and bitter opioid taste concerns; nor do they require skin puncture by needles eliminating pain and patient visits to a physician. Permeation through the skin allows the drug to directly enter the systemic circulation and avoid the first pass effect decreasing gastric side effects and liver damage effects in hepatocompromised drug abusers and critically ill patients. The transdermal BUP system that is available in Europe could benefit from a higher skin permeation rate improvement in adhesion an abuse deterrent mechanism a smaller patch size less residual drug remaining in the patch after use and the ultimate dosing flexibility of a transdermal gel. Less drug needed in the formulation means less drug for potential abuse when the patch is removed as currently the European marketed patches still contain fifty percent of their drug load at the end of treatment. To make abuse more difficult still we will create an abuse deterrent formulation with opioid antagonist non-permeating prodrug and/or coated particles. The altered antagonist will remain in the patch or gel and not enter the body at a therapeutic rate but will block the euphoria effect of BUP if abuse is attempted via the injectable or buccal routes. Specifically we aim to synthesize prodrugs of BUP and create an abuse deterrent component with naltrexone. We then aim to assess their in vitro human skin permeation for optimum flux. The optimal drugs will be combined and reassessed to see that the formulation provides increased permeation of BUP from prodrug during transdermal transport while the delivery of altered naltrexone is prevented. In further studies we will develop the prototype product and apply for an IND and begin Phase I clinical trials. We will create a marketable transdermal drug that will significantly ai in the treatment of heroin abuse and chronic pain.  
  
Public Health Relevance: AllTranz is seeking funding to create a transdermal prodrug gel and improved patch of buprenorphine for treatment of opioid dependence and chronic pain. These transdermal systems would be abuse deterrent and more effective than currently marketed products of the controlled substance buprenorphine. The gel would be a non-invasive non-oral dosage form with ultimate dosing flexibility without the need for patch cutting. The patches will be designed to have less residual drug content after use making them more appealing from a regulatory perspective they could have better adhesion properties if less of a more permeable drug could be used and when higher delivery rates are desirable in terminal pain the patient would benefit from the increased drug loading possible with the faster prodrug permeation allowing a smaller patch size to be used.

project_terms:
Adhesions;Adverse effects;Back;Blood Circulation;Buprenorphine;Chronic;Chronically Ill;Critical Illness;Data;Deglutition;Diffusion;Dosage Forms;Dose;Dose-Rate;Drug Delivery Systems;Drug Formulations;Drug abuser;Euphoria;Europe;European;Funding;Gel;Heroin Abuse;Human;In Vitro;Injectable;Injection of therapeutic agent;Liver;Marketing;Mastication;Naltrexone;Narcotic Antagonists;Nausea and Vomiting;Needles;Opiate Addiction;Opioid;Oral;Pain;Pain management;Parents;Patients;Pharmaceutical Preparations;Phase I Clinical Trials;Physicians;Plasma;Prodrugs;Property;Puncture procedure;Research;Residual state;Route;Skin;Stomach;Stratum corneum;Subutex;System;Taste Perception;Therapeutic;Transdermal substance administration;United States;Visit;buprenorphine abuse;chronic pain;design;effective therapy;flexibility;improved;opioid abuse;particle;prevent;prototype;public health relevance

public_health_relevance:
Narrative:AllTranz is seeking funding to create a transdermal prodrug gel and improvedpatch of buprenorphine for treatment of opioid dependence and chronic pain.These transdermal systems would be abuse deterrent and more effective thancurrently marketed products of the controlled substance buprenorphine. The gelwould be a non-invasive non-oral dosage form with ultimate dosing flexibilitywithout the need for patch cutting. The patches will be designed to have lessresidual drug content after use making them more appealing from a regulatoryperspective they could have better adhesion properties if less of a morepermeable drug could be used and when higher delivery rates are desirable interminal pain the patient would benefit from the increased drug loading possiblewith the faster prodrug permeation allowing a smaller patch size to be used.


application_id: 7611436
project_number: 1R43CA136017-01A1
project_title: SapC-DOPS Nanovesicles for Treating Glioblastoma Multiforme
administering_ic: NCI
award_notice_date: 2008-09-25
opportunity_number: PA-08-050
application_type: 1
activity_code: R43
ic: CA
serial_number: 136017
suffix: A1
program_official: HAIM, TODD E
project_start_date: 2008-09-25
project_end_date: 2010-06-24
study_section: Special Emphasis Panel[ZRG1 ETTN-C (11)]
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
project_abstract:
DESCRIPTION (provided by applicant): We are proposing to develop a new treatment 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. GBM tumors have proven to be resistant to existing anti-cancer therapies. Complete surgical ablation is nearly impossible because invasive cells remain hidden in the brain. The tumor returns rapidly. There is an urgent demand and a growing market for an efficacious anti-glioma drug. To address this need we are planning to determine the feasibility of using novel proteolipid nanovesicles to target and destroy glioma tumor cells. Composed of the small lysosomal 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 which are common in many types of tumor cells. To check whether the nanovesicles could be used for targeting and attacking tumor cells we conducted preliminary in vitro and in vivo assays and discovered that indeed the nanovesicles have high propensity to accumulate in tumors and very importantly in gliomas. Upon repeated SapC-DOPS injection in tumor-bearing mice we noticed a reduction in tumor size and improved survival. These intriguing observations prompted us to explore the use of SapC-DOPS as a potentially therapeutic drug for treating aggressive brain tumors. In Phase I of this proposal our specific aims are: (1) Confirm that Saposin C (SapC) is necessary for delivery of nanovesicles to intracranial gliomas and evaluate the biodistribution of the nanovesicles in vivo (2) Using a bioluminescent glioma xenograft model determine the dose-dependent elimination of tumor cells by SapC-DOPS nanovesicles and (3) Evaluate the anti-tumor activity of SapC-DOPS nanovesicles against a second type of glioma with aggressive and invasive growth properties. Tissues from treated mice will be analyzed to confirm that the nanovesicles are relatively nontoxic at useful doses. Neurological evaluation will be performed monitoring for evidence of toxicity. Upon the completion of these studies we expect to have compelling evidence to support further development of SapC-DOPS nanovesicles as a first-line anti-glioma therapeutic. In Phase II detailed optimization efficacy distribution pharmacokinetics scale-up and safety studies will be conducted while in Phase III the emphasis will be on IND-enabling studies to move the product toward clinical testing. This research is innovative because SapC-DOPS nanovesicles offer a unique approach for imaging and eliminating hidden brain tumors. Eventually 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 treatment for glioblastoma multiforme a deadly form of brain tumor that kills over 90% of afflicted patients. Current treatment methods 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:
Ablation;Address;Adverse effects;Affinity;American;Animal Model;Animals;Antibodies;Autopsy;Benchmarking;Binding (Molecular Function);Biodistribution;Biological Assay;Biological Sciences;Bone Marrow;Brain;Brain Neoplasms;C-Peptide;Catabolism;Cell Line;Cell surface;Cells;Characteristics;Clinical Trials Phase II;Colon;Data;Development;Devices;Diagnosis;Diagnostic;Dose;Drug Kinetics;Drug resistance;Duodenum;Engineering;Evaluation;Excision;Fluorescence;Formulations Drug;Frozen Sections;Genus Cola;Glioblastoma;Glioma;Glucosylceramides;Growth;Head;Health behavior;Heart;Human;Image;Imaging Techniques;Implant;In Vitro;Injection of therapeutic agent;Intracranial Neoplasms;Invasive;Kidney;Killings;Label;Life;Liver;Luciferases;Lung;Magnetic Resonance Imaging;Malignant Glioma;Malignant Neoplasms;Marketing;Measures;Mediating;Membrane;Methods;Mice Nude;Microscopic;Modeling;Monitor;Morbidity - disease rate;Mus;Muscle;Neurologic;Normal Cell;Normal tissue morphology;Ohio;Operative Surgical Procedures;Organ;Output;Pathology;Patients;Pharmaceutical Preparations;Phase;Phosphatidylserines;Phospholipids;Preparation;Procedures;Property;Proteins;Proteolipids;Quality Control;Radiation therapy;Radiosurgery;Range;Research;Resistance;Resolution;Route;Safety;Saline;Small Business Funding Mechanisms;Small Business Innovation Research Grant;Speed (motion);Spleen;Staining method;Stains;Stomach;Strikes Employee;Surface;Technology;Testing;Therapeutic;Time;Tissues;Toxic effect;Tumor-Derived;Universities;Variant;Vesicle;Vimentin;Water consumption;Week;Weights and Measures;Xenograft Model;base;beta-Glucosidase Stimulating Protein;brain tissue;cancer cell;cancer therapy;chemotherapy;commercialization;day;digital imaging;drug development;drug testing;expectation;fluorophore;food surveillance;improved;in vivo;innovation;iron oxide;luciferin;luminescence;lysosomal proteins;mouse model;neoplastic cell;neurobehavior;novel;novel therapeutics;public health medicine (field);red fluorescent protein;research clinical testing;research study;scale up;size;success;tool;tumor;tumor growth;whole body imaging

public_health_relevance:
PROJECT NARRATIVEWe are developing a new treatment for glioblastoma multiforme a deadly form of brain tumor that killsover 90% of afflicted patients. Current treatment methods consisting of surgery radiation andchemotherapy have not been effective in significantly reducing morbidity. Our strategy involves usingnew proteolipid nanovesicles that can penetrate the tumors and selectively destroy malignant cellswithout harming normal cells. Success in the proposed animal models will enable us to test the product inhumans.3


application_id: 7610717
project_number: 5P20RR020171-04
project_title: STUDIES OF RILP AND RILP-BINDING PROTEIN DYNACTIN P150GLUED AND HUNTINGTIN
administering_ic: NCRR
award_notice_date: 2007-08-05
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2007-08-01
project_end_date: 2008-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7720
contact_pi_person_id: 7875223
contact_pi: SHIMOJO, MASAHITO
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.Huntingtons disease (HD) is a dominantly inherited neurodegenerative disorder caused by a polyglutamine repeat expansion in the huntingtin protein.  It was suggested that the longer polyglutamine domain induce conformational changes causing it to form intracellular aggregates as nuclear inclusions in most cases.  HD is characterized by disturbances in motor cognitive and psychiatric function.  It has been postulated that the expanded polyglutamine repeat causes huntingtin to interact abnormally with other cellular proteins.  Wild-type huntingtin was found to interact with the transcriptional regulator REST which represses most neuronal gene expression in non-neuronal cells.  The interaction between huntingtin and REST kept REST in the cytosol thereby preventing REST target genes repression.  It was shown that wild-type and mutant huntingtin mediate REST dependent neuronal gene expression of BDNF through its regulatory DNA element RE1.  We have cloned another REST interacting protein we called RILP for REST/NRSF-Interacting LIM domain Protein.  RILP is a novel protein which is required for the nuclear targeting and function of REST.  We have preliminarily identified another RILP-interacting protein which is dynactin p150Glued and have shown that huntingtin and dynactin p150Glued copurify with RILP.  Dynactin p150Glued is an accessory protein for the microtubule motor protein dynein which is thought to be involved in trafficking steroid receptors and some other transcription factors between the cytoplasm and nucleus in a dynactin dependent process.  We thus postulate that RILP dynactin p150Glued and huntingtin are involved in targeting cytoplasmically synthesized REST through the dynein-microtubule pathway to the nucleus.  Disruption of this function could contribute to the neuronal dysfunction and death seen in diseases such as Huntingtons disease (HD).

project_terms:
Binding Proteins;Brain-Derived Neurotrophic Factor;Cell Nucleus;Cessation of life;Cognitive;Computer Retrieval of Information on Scientific Projects Database;Cytoplasm;Cytosol;DNA;Disease;Disruption;Dynein ATPase;Elements;Funding;Gene Expression;Grant;Huntingtin protein human;Huntington Disease;Inherited;Institution;LIM Domain Protein;Mediating;Microtubule Proteins;Microtubules;Motor;Neurodegenerative Disorders;Neuroglia;Neuronal Dysfunction;Neurons;Nuclear;Nuclear Inclusion;Pathway interactions;Process;Proteins;Receptors Steroid;Research;Research Personnel;Resources;Source;Thinking function;United States National Institutes of Health;dynactin;gene repression;mutant;novel;polyglutamine;prevent;trafficking;transcription factor


application_id: 7610716
project_number: 5P20RR020171-04
project_title: INTERFERENCE OF PROTEIN-PROTEIN INTERACTION DURING PRION CONVERSION; DEVELOPING
administering_ic: NCRR
award_notice_date: 2007-08-05
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2007-08-01
project_end_date: 2008-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7719
contact_pi_person_id: 9338717
contact_pi: CHONGSUCK, RYOU
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.Prion diseases also referred to as the transmissible spongiform encephalopathies are a group of fatal neurological disorders that manifest unique clinical symptoms and pathological changes in brain tissue. The diseases include Creutzfeldt-Jakob disease  in humans bovine spongiform encephalopathy ("mad cow" disease) in cattle scrapie in sheep and chronic wasting disease in deer elk and moose. The diseases are caused by unconventional pathogens termed prions which are composed of an aberrantly folded form of the normal cellular prion protein. Despite many studies and investigations approached from various angles much about prion diseases remains to be discovered. Similarly in prion therapeutics there is no known way to treat prion diseases although numerous drugs and other pharmacologically active chemicals have been tested. In the prion conversion event formation of nascent PrPSc (disease-associated conformationally misfolded prion protein) appears to require an initial interaction between PrPC (cellular prion protein with normal physiological function) and protein X (an auxiliary factor that assists prion conversion). Thus a systematic approach based on a mechanistic aspect of prion conversion appears to be more important and worth consideration. In this grant application  with a purpose of developing treatments for prion diseases we propose to test the anti-prion activity of the compounds that block the interaction between proteins involved in prion conversion process.

project_terms:
Cattle;Chemicals;Classification;Clinical;Computer Retrieval of Information on Scientific Projects Database;Creutzfeldt-Jakob Syndrome;Deer;Disease;Encephalopathy Bovine Spongiform;Event;Funding;Grant;Grants Applications;Human;Institution;Investigation;Pharmaceutical Preparations;Physiological;PrPSc Proteins;Prion Diseases;Prions;Process;Proteins;Purpose;Research;Research Personnel;Resources;Scrapie;Sheep;Source;Symptoms;Testing;Therapeutic;United States National Institutes of Health;Wasting Disease Chronic;base;brain tissue;nervous system disorder;pathogen;protein function;protein protein interaction


application_id: 7610715
project_number: 5P20RR020171-04
project_title: MECHANISMS OF RENAL LIPID RETENTION IN DIABETIC NEPHROPATHY
administering_ic: NCRR
award_notice_date: 2007-08-05
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2007-08-01
project_end_date: 2008-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7718
contact_pi_person_id: 3123430
contact_pi: TANNOCK, LISA R
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.Nephropathy is a major complication of diabetes. Renal lipid and lipoprotein accumulation accelerates the progression of nephropathy. The mechanism leading to renal lipoprotein accumulation is unknown. Glomerulosclerosis the characteristic lesion of diabetic nephropathy is caused by increased deposition of mesangial matrix including proteoglycans. There are numerous commonalities between the development of glomerulosclerosis and atherosclerosis. Proteoglycans have been shown to play a critical role in the initiation of atherosclerosis due to their ability to bind and retain lipoproteins. We have recently shown that renal proteoglycans demonstrate high lipoprotein binding affinity and that TGF-b increases their LDL binding affinity. TGF-b is clearly shown to play a critical role in the development of diabetic nephropathy and TGF-b levels are increased in diabetes. TGF-b stimulates the synthesis of extracellular matrix including stimulation of the small proteoglycan biglycan. Thus the increased TGF-b in diabetes may stimulate renal biglycan synthesis which can mediate renal lipid accumulation and exacerbate progression of diabetic nephropathy.  The overall goal of this grant is to test the hypothesis that renal lipid accumulation is mediated through interactions of lipoproteins with renal proteoglycans especially biglycan. To determine if renal lipid accumulation is mediated via retention of LDL by proteoglycans diabetic nephropathy will be compared between mice expressing proteoglycan-binding defective LDL and mice expressing wildtype LDL. To determine if biglycan is the key proteoglycan responsible diabetic nephropathy will be compared between biglycan deficient and wildtype mice.

project_terms:
Affinity;Atherosclerosis;Binding (Molecular Function);Characteristics;Complications of Diabetes Mellitus;Computer Retrieval of Information on Scientific Projects Database;Deposition;Development;Diabetes Mellitus;Diabetic Nephropathy;Extracellular Matrix;Funding;Goals;Grant;Institution;Kidney;Kidney Diseases;Lesion;Lipids;Lipoprotein Binding;Lipoproteins;Low-Density Lipoproteins;Mediating;Mus;Play;Proteoglycan;Research;Research Personnel;Resources;Role;Source;Testing;United States National Institutes of Health;biglycan;glomerulosclerosis


application_id: 7610714
project_number: 5P20RR020171-04
project_title: ROLE OF CALCINEURIN IN ASTROCYTE ACTIVATION ASSOCIATED WITH ALZHEIMER?S DISEASE
administering_ic: NCRR
award_notice_date: 2007-08-05
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2007-08-01
project_end_date: 2008-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7717
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
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.Alzheimer?s Disease (AD) and other neurodegenerative syndromes are accompanied by a pronounced immune/inflammatory response (e.g. activated neuroglia and elevated cytokine levels) that could contribute significantly to widespread neuronal death and deterioration. In lymphocytes and other cell types the Ca2+/calmodulin dependent protein phosphatase calcineurin along with its target transcription factor NFAT (nuclear factor of activated T cells) have long been recognized to induce numerous immune/inflammatory signaling cascades.  As such it is somewhat surprising that the calcineurin/NFAT pathway has not been investigated extensively for a similar role in neuro-immune/inflammatory signaling. Recently we showed that calcineurin immunostaining is markedly upregulated in activated astrocytes in hippocampus and neocortex of transgenic AD model mice (Norris et al. J Neurosci 25:4649 2005). Moreover overexpression of activated calcineurin in mixed (neuronal and glial) hippocampal cultures induced ?activation-like? changes in astrocytes (i.e. pronounced hypertrophy of soma and processes) and also triggered the expression of most  genetic markers for the activated phenotype including numerous immune/inflammatory factors. The results suggest that similar to its well-known role in lymphocytes calcineurin also may serve as a critical upstream regulator of immune/inflammatory signaling cascades associated with astrocyte activation and AD. 

Using astrocyte-enriched cell cultures and viral-mediated gene transfer the proposed research will extend our earlier work by determining whether endogenous inflammatory mediators recruit the calcineurin/NFAT pathway in astrocytes en route to the expression of a panel of molecular markers for the activated astrocyte phenotype. Furthermore adeno-associated viruses encoding an astrocyte-specific promoter will be used to determine if calcineurin/NFAT activity in astrocytes contributes significantly to the neuropathological changes and cognitive deficits found in amyloid-bearing AD model mice.

project_terms:
Alzheimer's Disease;Alzheimer's disease model;Amyloid;Astrocytes;Biological Markers;Biological Response Modifiers;Calcineurin;Calmodulin;Cessation of life;Cognitive deficits;Computer Retrieval of Information on Scientific Projects Database;Cultured Cells;Dependovirus;Deterioration;Funding;Gene Transfer;Genetic Markers;Grant;Hippocampus (Brain);Hypertrophy;Immune;Inflammatory;Inflammatory Response;Institution;Lymphocyte;Mediating;Mediator of activation protein;Mus;NF-AT;Neocortex;Nerve Degeneration;Neuroglia;Neurons;Pathway interactions;Phenotype;Process;Promotor (Genetics);Protein Overexpression;Protein phosphatase;Recruitment Activity;Research;Research Personnel;Resources;Role;Route;Signal Transduction;Source;Syndrome;United States National Institutes of Health;Viral;Work;cell body (neuron);cell type;cytokine;nuclear factors of activated T-cells;transcription factor;transgenic model of alzheimer disease


application_id: 7610708
project_number: 5P20RR020171-04
project_title: KY COBRE: PDGF SIGNAL TRANSDUCTION ROLE FOR ABI FAMILY KINASES IN CELL MIGRATIO
administering_ic: NCRR
award_notice_date: 2007-08-05
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2007-08-01
project_end_date: 2008-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7711
contact_pi_person_id: 1918859
contact_pi: PLATTNER, RINA
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.Growth factors induce cell proliferation differentiation migration apoptosis and angiogenesis. Regulation of these processes is extremely important as deregulation contributes to the induction and progression of malignancy. In particular cell motility is critical for tumor invasion and metastasis hallmarks of aggressive cancers. Growth factors control cellular events by activating proteins in a complex web of signaling pathways. Previously we found that c-Abl a kinase involved in the development of leukemia is activated by platelet-derived growth factor (PDGF) and is required for mitogenesis cytoskeletal reorganization and migration downstream of PDGF. Signaling pathways that control cell migration are beginning to be identified however the pathways are not completely characterized and cross-talk between the pathways is only beginning to be elucidated. The overall goal of this proposal is to define Abl kinase-dependent PDGF signaling pathways that control cell migration. We aim to: 1) Determine the functional significance of PDGFR-Abl kinase bidirectional signaling. 2) Identify downstream targets of Abl kinases involved in PDGFinduced cell motility. 3) Determine whether Abl kinase activity is upregulated in non-hematopoeitic cancer cell lines and whether Abl kinases function to promote motility and/or invasion in these ce_ls. Results from these experiments will provide us with mechanistic insight into how Abl kinase deregulation contributes to cancer formation/progression which will aid in the discovery of new drug combinations for cancer treatment.

project_terms:
ABL1 gene;Apoptosis;Cancer cell line;Cell Proliferation;Cells;Centers of Research Excellence;Complex;Computer Retrieval of Information on Scientific Projects Database;Cytoskeletal Modeling;Development;Drug Combinations;Event;Family;Funding;Goals;Grant;Growth Factor;Institution;Internet;Malignant Neoplasms;Neoplasm Metastasis;Pathway interactions;Phosphotransferases;Platelet-Derived Growth Factor;Process;Proteins;Regulation;Research;Research Personnel;Resources;Role;Signal Pathway;Signal Transduction;Source;Stimulation of Cell Proliferation;Tumor Cell Invasion;United States National Institutes of Health;angiogenesis;c-abl Proto-Oncogenes;cancer therapy;cell motility;insight;leukemia;migration;research study


application_id: 7610707
project_number: 5P20RR020171-04
project_title: KY COBRE: TALIN-1 METASTISIS SUPPRESSOR IN LUNG CANCER
administering_ic: NCRR
award_notice_date: 2007-08-05
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2007-08-01
project_end_date: 2008-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7710
contact_pi_person_id: 8345406
contact_pi: MCCANN, RICHARD O.
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.Lung cancer is a multifactorial disease caused by a cascade of genetic events including changes in cell cycle checkpoint and progression cell proliferation and chromosome stability which leads to the development of a primary carcinoma. After establishment of the primary tumor changes in normal cell adhesion and motility subsequently allow these tumor cells to escape from the original tumor migrate to secondary sites and grow anew. The acquisition of this capacity in the primary tumor frequently results in clinically incurable disease and these secondary tumors or metastases are a significant contributor to mortality and morbidity in lung cancer patients. Several genetic lesions on chromosome 9 at position 9p21 have been associated with lung cancer. Among these is the focal adhesion protein Talin-1 which is involved in cell adhesion and motility. Talin-1 levels are decreased in certain lung cancer cells.
The HYPOTHESIS to be evaluated is that dysregulation of Talin-1 leads to altered cell adhesion leading to anchorage-independent growth of cells in the primary tumor. Acquisition of this phenotype then increases the invasiveness of these cells and results in the development of metastatic lung cancer.
SPECIFIC AIMS. This hypothesis will be addressed by (1) determining the molecular basis for the Talin-1 deficiency at the gene mRNA and protein levels in lung cancer cells; (2) determining the role of Talin-1 in lung cancer cell adhesion migration and invasion with particular emphasis on the behavior of lung cancer cells in three-dimensional culture matrices that mimic the cellular environment in vivo; and (3) extending these studies to a broad panel of lung cancer cell lines representing each histological class of lung cancer so that previously unknown general features of metastatic lung cancer will be identified.
SIGNIFICANCE. These studies will provide insight into the molecular and cellular mechanisms of lung cancer progression and determine whether Talin-1 is a suppressor of metastasis in lung cancer. These studies will also lead to the development of new prognostic indicators and therapeutic strategies for treatment of metastatic lung cancer.

project_terms:
9p21;Address;Anchorage-Independent Growth;Behavior;Cancer Patient;Cancer cell line;Cell Adhesion;Cell Cycle Checkpoint;Cell Proliferation;Cells;Chromosomal Stability;Chromosomes Human Pair 9;Class;Computer Retrieval of Information on Scientific Projects Database;Development;Disease;Environment;Event;Focal Adhesions;Funding;Genes;Genetic;Grant;Institution;Lead;Lesion;Malignant neoplasm of lung;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Neoplasm Metastasis;Normal Cell;Phenotype;Positioning Attribute;Primary Carcinoma;Primary Neoplasm;Proteins;RNA Messenger;Research;Research Personnel;Resources;Role;Secondary to;Site;Source;Talin;Therapeutic;United States National Institutes of Health;base;cancer cell;cell motility;in vivo;insight;migration;neoplastic cell;prognostic;tumor;tumor progression


application_id: 7610657
project_number: 5P20RR020145-04
project_title: UKY DENTAL COBRE: INFLAMMATORY MEDIATORS LEVELS FULL MOUTH EXTRACTIONS
administering_ic: NCRR
award_notice_date: 2007-09-01
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2007-08-01
project_end_date: 2008-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7667
contact_pi_person_id: 2045756
contact_pi: CUNNINGHAM, LARRY 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.Hypothesis:  Full mouth tooth extraction in patients with advanced periodontal disease will lead to significantly decreased systemic inflammation determined by levels of C-reactive protein IL-6 and serum amyloid A.
The aims will be studied using a prospective longitudinal design to model the loss of systemic inflammatory risk factors related to dental therapy resulting in an edentate patient.  Patients (ages 18-80) who selected treatment plans that include extraction of all remaining teeth will be eligible for the study.  In this pilot study to provide preliminary data for proof of concept we will enroll approximately 40 patients with 20 in each group (eg. generalized periodontitis dental caries).  Patients who have elected to have all their teeth removed and to have dentures made will be recruited.  On the day of their surgery blood will be drawn for baseline levels of CRP IL-6 and SAA.  Extractions will then be completed as normal with separate standard surgical informed consent.  Post-surgery visits at 1 3 6 and 12 months will be scheduled coordinated with routine denture follow-up appointments for collection of blood and analysis of changes in CRP IL-6 and SAA.  The analysis of the mediators will be accomplished through the Core Translational Diagnostic Laboratory of the CBBOSD.
The two patient groups will be compared in terms of the profile of their CRP values IL-6 values and SAA values across visits.  A linear mixed model (LMM) will be used for this repeated-measures experiment. Statistical significance will be determined at the level of 0.05.  We have recruited 58 patients thus far and 37 have concluded the 12 month study interval.  Levels of selected analytes demonstrated noticeable trends following tooth extraction and elimination of periodontitis.  IgG antibody to all 7 of the periodontal pathogens decreased over time with lowest levels by 12 months. Acute phase markers CRP (30%) serum amyloid P (35%) and haptoglobin (32%) also decreased. The chemokines RANTES (30%) and IP-10 (35%) involved in T cells recruitment and activation decreased post-extraction. However no significant changes occurred in numerous other analytes suggesting a reasonably specific response alteration. This prospective longitudinal study examined the contribution of periodontitis to systemic inflammatory responses and developed a unique approach to study the elimination of periodontitis focusing on patients that become edentulous. The results support previous data suggesting that chronic periodontal disease may contribute to elevations in systemic inflammatory mediators. The evidence suggests that successful treatment of periodontitis would be expected decrease systemic biomolecules.

project_terms:
Acute;Age;Amyloid;Antibodies;Appointment;Blood;C-reactive protein;CXCL10 gene;Chronic;Collection;Computer Retrieval of Information on Scientific Projects Database;Data;Dental;Dental caries;Dentures;Diagnostic;Elevation;Enrollment;Funding;Grant;Haptoglobins;Immunoglobulin G;Inflammation;Inflammatory;Inflammatory Response;Informed Consent;Institution;Interleukin-6;Laboratories;Lead;Longitudinal Studies;Measures;Mediator of activation protein;Modeling;Mouth Edentulous;Operative Surgical Procedures;Oral cavity;Patients;Periodontal Diseases;Periodontitis;Phase;Pilot Projects;RANTES;Recruitment Activity;Research;Research Personnel;Resources;Risk Factors;Schedule;Serum;Serum amyloid A protein;Source;Standards of Weights and Measures;T-Lymphocyte;Time;Tooth Extraction;Tooth structure;United States National Institutes of Health;Visit;chemokine;concept;cysteine rich protein;day;design;follow-up;pathogen;prospective;research study;response;treatment planning;trend


application_id: 7610656
project_number: 5P20RR020145-04
project_title: SMOKING: EFFECTS OF GENOTYPE ON PERIODONTITIS
administering_ic: NCRR
award_notice_date: 2007-09-01
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2007-08-01
project_end_date: 2008-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7666
contact_pi_person_id: 8534338
contact_pi: AL-SABBAGH, MOHANAD
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.Smoking: Effect of Genotype on Periodontitis; Mohanad Al-Sabbagh DDS MS (Division of Periodontics College of Dentistry); Mentors: Mark V. Thomas DMD MS (Associate Professor & Chief Division of Periodontics Peter Wedlund PhD Associate Professor Department of Pharmaceutical Sciences College of Pharmacy)
Periodontitis is a polygenic multifactorial disease which is the result of complex interactions between oral bacteria and host response. Bacteria are necessary but not sufficient to cause the soft and hard tissue destruction that is the hallmark of periodontal disease(s).  Genetic background diabetes age and smoking have been demonstrated to increase susceptibility to periodontal diseases with smoking being an especially strong risk. Genetic factors have also been identified to confer risk with some studies estimating the heritable risk at nearly 50%. After sequencing of the human genome the data indicates that the genome of the population is nearly 99.9% identical across individuals which allows for ~3 million bp differences between individuals; nearly 90% of the variation is determined by single nucleotide polymorphisms (SNPs).  Interestingly certain polymorphisms have been associated with severe periodontitis eg. genes that code for inflammatory mediators/cytokines and/or produce cell receptors for innate/immune signaling. Although smoking is a strong risk factor for periodontitis not all smokers are equally susceptible to periodontal tissue destruction as noted by the extent of disease variation in the smoking population. This suggests that other factors including genetic polymorphisms may alter risk in response to smoking and result in differential susceptibility and/or disease expression. The objective of this proposal is that for more effective management of periodontitis it would be desirable to identify subsets of individuals at greatest risk for developing smoking-related periodontitis. Identification of genetic markers that confer increased risk to periodontitis in smokers would permit more effective allocation of healthcare resources and permit targeted interventions. It would also contribute to our general understanding of the mechanisms by which smoking confers risk.  The hypotheses tested include: (1) SNP that increase production of select pro-inflammatory mediators would be related to periodontitis; (2) SNP that decrease production of anti-inflammtory biomolecules would be related to periodontitis; and (3) SNP that affect the production of enzymes required for detoxification of various noxious products of smoking would be related to periodontitis.  We propose to conduct a case-control study of 500 smokers with or without periodontitis. We will compare these groups with regard to certain genetic polymorphisms that may be associated with increased risk for periodontitis.

This project originally was initiated as a potential YIP pilot project; however with the graduation of Dr. Kesavalu?s Project #3 from the CBBO/SD we solicited the ability of Dr. Al-Sabbagh and his mentors to develop a full project.  This has been accomplished during the 01 year.  The proposal has been submitted to the SAC for review and the reviews are currently be gathered to submit to NCRR for a start time within the next 3 months.

project_terms:
Affect;Age;Bacteria;Case-Control Studies;Code;Complex;Computer Retrieval of Information on Scientific Projects Database;Data;Dentistry;Diabetes Mellitus;Disease;Doctor of Philosophy;Enzymes;Funding;Genes;Genetic;Genetic Markers;Genome;Genome Human;Genotype;Grant;Healthcare;Immune;Immune response;Individual;Inflammatory;Institution;Intervention;Mediator of activation protein;Mentors;Metabolic Detoxication Drug;National Center for Research Resources;Periodontal Diseases;Periodontic specialty;Periodontitis;Pharmacologic Substance;Pharmacy facility;Pilot Projects;Polymorphism Genetic;Population;Predisposition;Production;Receptor Cell;Research;Research Personnel;Resources;Risk;Risk Factors;Science;Signal Transduction;Single Nucleotide Polymorphism;Smoke;Smoker;Smoking;Source;Testing;Time;Tissues;United States National Institutes of Health;Variant;college;cytokine;oral bacteria;professor;response


application_id: 7610655
project_number: 5P20RR020145-04
project_title: ALZHEIMERS DISEASE: EFFECTS OF ORAL INFECTION INFLAMMATION AND DISEASE
administering_ic: NCRR
award_notice_date: 2007-09-01
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2007-08-01
project_end_date: 2008-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7665
contact_pi_person_id: 8536079
contact_pi: STEIN, PAM
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.Alzheimer?s Disease: Effects of Oral Infection Inflammation and Disease
Pamela Stein DMD (Anatomy & Neurobiology College of Medicine); Mentors: M. John Novak David Wekstein PhD (Associate Director Sanders-Brown Aging Center)
The characteristics of periodontal disease are a Gram negative infection a local and systemic inflammatory response involving neutrophils monocytes/macrophages and lymphocytes cytokine mediated regulation of the inflammatory response and cellular and extracellular pathology that results in loss of function of the affected area. Current research suggests that many of the same mechanisms are apparent in pathologically affected sites in AD. A Gram negative infection with Chlamydia pneumoniae has been implicated in the etiology of AD and activation of the resident macrophages of the brain microglia is a feature. Recent pilot prospective studies have indicated that patients with AD who have other systemic infections demonstrate cognitive impairment that continues for at least 2 months after resolution of the infection and that the impairment is preceded by elevated serum levels of IL-1? ?. In addition significant evidence is accruing to implicate cytokines in the etiology of brain pathology. The ability of circulating Gram negative organisms to activate inflammatory systems in the brain that may lead to pathologic changes has been highlighted recently by the identification of specific receptors for formylated peptides on monocytes and microglia. These receptors are specific for Gram negative organisms and support the concept that Gram negative infection can initiate inflammatory and pathologic changes in the brain.  In the current study we are working with The Sanders Brown Center on Aging to recruit subjects to test our hypothesis that older adults with a life history of exposure to extensive oral infection are at higher risk for developing Alzheimer?s disease than older adults who have maintained minimal levels of oral infection.  Methods for testing our hypothesis include  (1) characterizing the prevalence extent and severity of periodontal disease in a population of patients with Alzheimer?s disease (AD) when compared to age race and sex matched controls (2) characterizing the subgingival microbial ecology in patients with AD and controls to determine if specific microbial characteristics are associated with adverse outcomes and  (3) determining if patients with AD and periodontitis have elevated levels of circulating inflammatory mediators compared to patients with AD and no periodontitis and non-AD controls. Since the approval and funding of this pilot project we have made considerable progress in obtaining IRB approval establishing collaborative arrangements with the Sanders Brown investigators and developing case report forms.  We are now ready to enroll our first subject in June 2005.

project_terms:
Affect;Age;Aging;Alzheimer's Disease;Area;Brain;Brain Pathology;Case Report Form;Characteristics;Chlamydophila pneumoniae;Computer Retrieval of Information on Scientific Projects Database;Disease;Doctor of Philosophy;Ecology;Elderly;Enrollment;Ethics Committees Research;Etiology;Exposure to;Funding;Grant;Impaired cognition;Impairment;Infection;Inflammation;Inflammatory;Inflammatory Response;Institution;Interleukin-1;Lead;Lymphocyte;Mediating;Mediator of activation protein;Medicine;Mentors;Methods;Microglia;Neurobiology;Organism;Outcome;Pathologic;Pathology;Patients;Peptides;Periodontal Diseases;Periodontitis;Pilot Projects;Population;Prevalence;Prospective Studies;Race;Recruitment Activity;Regulation;Research;Research Personnel;Resolution;Resources;Risk;Science of Anatomy;Serum;Severities;Site;Source;System;Systemic infection;Testing;United States National Institutes of Health;Work;college;concept;cytokine;disorder control;extracellular;life history;loss of function;macrophage;microbial;monocyte;neutrophil;oral infection;receptor;sex


application_id: 7610654
project_number: 5P20RR020145-04
project_title: UKY DENTAL COBRE: ORAL INFECTIONS: VIRAL INFECTIONS IN CHRONIC ORAL DISEASES
administering_ic: NCRR
award_notice_date: 2007-09-01
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2007-08-01
project_end_date: 2008-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7664
contact_pi_person_id: 9185054
contact_pi: LI, MENGTAO
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.Although bacteria are the primary pathogens in periodontitis human herpesviruses have a purported relationship with inflamed periodontal tissues. This could be important because herpesviruses modulate host immune responses through a variety of mechanisms.  The goal of this research was to test the hypothesis that herpesviruses enhance the pathogenesis of periodontal diseases.  Our hypothesis is being examined using three approaches:  1) determine the role of herpesviruses in periodontitis by  analyzing clinical samples from patients with and without periodontal disease 2) investigating the ability of herpesvirus to enhance the progression of periodontitis in the rat model;  and 3) define mechanisms of immunomodulation by cytomegalovirus (CMV).  We have initiated a plan to recruit 100 patients with periodontal disease and collect dental plaques and saliva samples.  Real-time PCR will be used to detect DNA of human herpesvirus in plaque from healthy and diseased sites and parallel saliva samples.  This method that has been successfully used to identify all 8 HHVs in saliva is being optimized to detect viral DNA in plaque.  In the second project we have obtained rat CMV (RCMV) Maastricht strain propagated lab stocks and obtained titers on the virus.  Animal inoculation(s) with P. gingivalis and/or RCMV will be initiated in early summer 2005.  In the study of molecular mechanisms of immunomodulation by CMV we have successfully constructed and purified a recombinant CMV that expresses GFP (green fluorescence protein).  In addition we cloned CMV vIL-10 gene.  We discovered 5 previously unidentified vIL-10 isoforms.  We are in the process of characterizing 8 different vIL-10 isoforms in vitro and analyzing their amino acid sequences using bioinformatics methods.  Because CMV vIL-10 is a potent immune suppressor we are initiating study to determine its roles in modulating the host response of oral epithelia and gingival fibroblasts against bacterial invasion.

project_terms:
Amino Acid Sequence;Animals;Bacteria;Bioinformatics;Chronic;Clinical;Computer Retrieval of Information on Scientific Projects Database;Cytomegalovirus;DNA;DNA Viral;Dental;Dental Plaque;Fibroblasts;Fluorescence;Funding;Genes;Gingiva;Goals;Grant;Herpesviridae;Human;Immune;Immune response;In Vitro;Institution;Methods;Modeling;Molecular;Mouth Diseases;Pathogenesis;Patients;Periodontal Diseases;Periodontitis;Polymerase Chain Reaction;Porphyromonas gingivalis;Process;Protein Isoforms;Proteins;Rat Cytomegalovirus;Rattus;Recombinants;Recruitment Activity;Research;Research Personnel;Resources;Role;Saliva;Sampling;Simplexvirus;Site;Source;Testing;Time;Tissues;United States National Institutes of Health;Virus;Virus Diseases;immunoregulation;oral cavity epithelium;oral infection;pathogen


application_id: 7610652
project_number: 5P20RR020145-04
project_title: UKY DENTAL COBRE: ORAL INFECTIONS: IMPACT ON GESTATIONAL DIABETES
administering_ic: NCRR
award_notice_date: 2007-09-01
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2007-08-01
project_end_date: 2008-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7662
contact_pi_person_id: 1880406
contact_pi: NOVAK, KAREN F.
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.Gestational Diabetes Mellitus (GDM) occurs in approximately 5% of pregnant women with onset during pregnancy and subsiding after parturition.  Importantly nearly 50% of women with GDM will eventually develop type 2 diabetes mellitus within 3-5 years post-partum.  Moreover acute and chronic neonatal morbidity and mortality have been described in neonates delivered by women with GDM.  Substantial evidence is available documenting that the severity of periodontal disease is increased in patients with type 2 diabetes but no data are available on the effects of GDM on periodontal health.  In addition substantial data is accruing to support earlier observations that the infection and inflammation associated with periodontal disease may have a negative impact on the period of gestation and on fetal growth leading to the birth of preterm low birth weight infants.  Our GENERAL HYPOTHESIS is that women with GDM are at higher risk for developing more severe periodontal disease than women without GDM and that the combination of GDM and periodontal disease will be associated with an increased negative impact on maternal and fetal health.  This hypothesis will be tested by collecting (a) clinical oral health data on periodontal status as well as maternal and fetal outcomes data (Specific Aim 1) (b) microbial dental plaque samples (Specific Aim 2) and (c) serum samples in women with GDM and in non-GDM controls (Specific Aim 3).  These prospective clinical data will be correlated with basic science laboratory evaluations of the microflora and host response to provide insight into the pathogenic mechanisms contributing to negative maternal and fetal outcomes associated with inflammatory periodontal disease and GDM.  To date 25 subjects have enrolled in the study.  The appropriate data have been collected on all subjects.  Enrollment will continue in the coming year.  Collected data will be subjected to statistical analyses at the mid-point and at the end of the study.

project_terms:
Acute;Basic Science;Birth;Chronic;Clinical;Clinical Data;Computer Retrieval of Information on Scientific Projects Database;Data;Dental;Dental Plaque;Diabetes Mellitus Non-Insulin-Dependent;Diabetes Gestational;Enrollment;Evaluation;Funding;Grant;Growth Fetal;Health;Immune response;Infection;Inflammation;Inflammatory;Institution;Laboratories;Low Birth Weight Infant;Mortality Vital Statistics;Oral health;Outcome;Patients;Periodontal Diseases;Pregnancy;Pregnant Women;Premature Birth;Research;Research Personnel;Resources;Risk;Sampling;Serum;Severities;Source;Testing;United States National Institutes of Health;Woman;fetal;insight;microbial;neonatal morbidity;neonate;oral infection;prospective


application_id: 7610651
project_number: 5P20RR020145-04
project_title: UKY DENTAL COBRE: ORAL INFECTIONS: COX-2
administering_ic: NCRR
award_notice_date: 2007-09-01
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2007-08-01
project_end_date: 2008-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7661
contact_pi_person_id: 8351945
contact_pi: LOFTIN, CHARLES DAVID
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.Specific Aim 1. Determine the role of COX-2 in P. gingivalis-induced periodontal disease and atherosclerosis.  Periodontitis is a chronic inflammatory disease resulting from microbial infection of the oral cavity. The disease is initiated by gram-negative anaerobic species including Porphyromonas gingivalis. P. gingivalis infection may produce inflammation localized within the oral cavity which results in alveolar bone resorption and may produce a systemic inflammatory response resulting from bacteremia. The systemic inflammatory response is thought to account for the increased risk of developing complications of cardiovascular disease in patients with periodontitis. Prostaglandins are a class of inflammatory mediators that are significantly increased in diseased periodontal tissues. The synthesis of prostaglandins requires the activity of a cyclooxygenase and cyclooxygenase-2 (COX-2) is the isoform that is highly induced by gram-negative bacterial products and is increased in atherosclerotic lesions.  The current studies utilized an established mouse model of P. gingivalis-induced periodontitis to examine the role of COX-2-derived prostaglandins in alveolar bone resorption and atherosclerosis. Alveolar bone resorption and cardiovascular disease resulting from P. gingivalis requires chronic infection to be established in the oral cavity of the mice. Therefore the mice are inoculated with P. gingivalis 4 days a week every 3rd week over a 12 week course. We have optimized the PCR technique to confirm that chronic infection with P. gingivalis is established in the mice. We have also utilized the highly sensitive technique real-time PCR to examine the expression of COX-2 as well as downstream prostaglandin synthases in aortic tissue. Furthermore we have optimized immunohistochemical analysis for detection of COX-2 protein expression in the aortas of mice. These procedures will allow us to examine the effects of P. gingivalis infection on the expression of COX-2 and downstream prostaglandin synthases. Studies are in progress to examine the effectiveness of genetic or pharmacological inactivation of COX-2 in reducing P. gingivalis-induced alveolar bone resorption and atherosclerosis in mice. 

Specific Aim 2.  Define the role of 12/15-lipoxygenase in P. gingivalis-induced periodontal disease and  atherosclerosis.  Angiotensin II (AngII) markedly accelerates atherogenesis in hyperlipidemic mice.  Moreover AngII increases the expression of 12/15-lipoxygenase (12/15-LO).  Deficiency of 12/15-LO markedly attenuates atherosclerosis in hyperlipidemic mice.   Therefore we sought to determine if 12/15-LO plays a role in AngII-induced vascular disease.  Age matched male apolipoproteinE deficient (apoE-/-)  mice or 12/15-LO deficient apoE-/- mice were infused with AngII (1000 ng/kg/min) for 28 days.  Total serum cholesterol or lipoprotein profile was not altered in 12/15-LO deficient mice following AngII infusion compared to control. 12/15-LO modestly decreased AngII-induced atherosclerotic lesion formation (12/15-LO+/+: 1.26% vs 12/15-LO-/-: 1.99%; P = 0.12) on the intimal surface of the aortic arch however this decrease did not reach statistical significance.  Additionally 12/15-LO deficiency decreased the incidence of AngII-induced abdominal aortic aneurysm formation (12/15-LO+/+: 42% vs 12/15-LO-/-: 17%; P = 0.12) and the abdominal aortic diameter (12/15-LO+/+: 1.6 mm vs 12/15-LO-/-: 1.1 mm; P = 0.11) however the reduction in both of these parameters did not reach statistical significance.  While these results suggest 12/15-LO does not significantly alter AngII-induced atherosclerosis and AAA formation the number of mice utilized in these studies did not result in a power of 0.08.  This coupled with the trend toward a decrease in both atherosclerosis and AAA formation suggest that additional studies are required to define the effect of 12/15-LO on AngII-induced vascular disease.

project_terms:
Abdomen;Accounting;Age;Angiotensin II;Aorta;Aortic Aneurysm Abdominal;Aortic arch structure;Apolipoprotein E;Arachidonate 15-Lipoxygenase;Arterial Fatty Streak;Atherosclerosis;Attenuated;Bacteremia;Bone Resorption;Caliber;Cardiovascular Diseases;Centers of Research Excellence;Cholesterol;Chronic;Class;Computer Retrieval of Information on Scientific Projects Database;Coupled;Dental;Detection;Disease;Effectiveness;Funding;Genetic;Grant;Incidence;Infection;Inflammation;Inflammatory;Inflammatory Response;Infusion procedures;Institution;Lipoproteins;Localized;Mediator of activation protein;Mus;Numbers;Oral;Oral cavity;Patients;Periodontal Diseases;Periodontitis;Play;Polymerase Chain Reaction;Porphyromonas gingivalis;Procedures;Prostaglandin-Endoperoxide Synthase;Prostaglandins;Protein Isoforms;Research;Research Personnel;Resources;Risk;Role;Serum;Source;Surface;Techniques;Thinking function;Time;Tissues;United States National Institutes of Health;Vascular Diseases;Week;alveolar bone;atherogenesis;cyclooxygenase 1;cyclooxygenase 2;day;male;microbial;mouse model;protein expression;trend


application_id: 7610650
project_number: 5P20RR020145-04
project_title: UKY DENTAL COBRE: DENTAL CLINICAL RESEARCH CENTER
administering_ic: NCRR
award_notice_date: 2007-09-01
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2007-08-01
project_end_date: 2008-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7660
contact_pi_person_id: 7875071
contact_pi: NOVAK, MICHAEL JOHN
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.A primary focus of the DDKCRC is to create a research infrastructure to: 1) develop and train clinical research professionals research coordinators and research staff and 2) define and impact oral health disparities in rural communities of Kentucky.  An initial emphasis will be on investigations to determine oral-systemic disease linkages in these rural populations and to define biological genetic and socio-behavioral factors contributing to these disparities.  The DDKCRC personnel have focused on the preparation and submission of forms for IRB approval for Projects 4 5 and 6 for the center.  These have all been obtained and the projects initiated.  The personnel have contributed to the recruitment of patients for these same projects as well as collecting biological specimens for the projects.  In addition the DDKCRC will be supporting the clinical research needs of the Pilot Project on Alzheimer?s Disease (Dr. Stein) and the new full project on Smoking Genotypes (Dr. Al-Sabbagh).  Finally the laboratory personnel in the DDKCRC have provided support for evaluation of host analytes for Projects 2 4 5 and 6.  In addition the laboratory has developed a real-time quantitative PCR methodology for assessment of target microorganisms in the subgingival plaque allowing improved evaluation of microbial changes in Projects 4 5 and 6.

project_terms:
Alzheimer's Disease;Behavioral;Biological;Clinical Research;Computer Retrieval of Information on Scientific Projects Database;Dental;Ethics Committees Research;Evaluation;Funding;Genetic;Genotype;Grant;Human Resources;Institution;Investigation;Kentucky;Laboratories;Laboratory Personnel;Methodology;Oral;Oral health;Pilot Projects;Polymerase Chain Reaction;Preparation;Recruitments Patient;Research;Research Infrastructure;Research Personnel;Resources;Rural Community;Rural Population;Smoking;Source;Specimen;Systemic disease;Time;Training;United States National Institutes of Health;health disparity;improved;microbial;microorganism


application_id: 7610648
project_number: 5P20RR020145-04
project_title: UKY DENTAL COBRE: ADMINISTRATIVE AND EDUCATIONAL CORE
administering_ic: NCRR
award_notice_date: 2007-09-01
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2007-08-01
project_end_date: 2008-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7658
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 during this initial funding period 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.  During this year the A/E Core has initiated a monthly seminar series in collaboration with the College of Dentistry and the regional chapter of the American Association for Dental Research. This has enabled invited speakers monthly beginning Nov. 2004.  We have hired a full-time Administrative Officer to manage the COBRE grant as well as working with investigators across the College of Dentistry to enhance grant submission and the quality of grants management.  We have organized a review of both the YIP/OHP (pilot) Grants by the SAC as well as a replacement project for Project #3 that was funded via an R01.  The A/E Core is also developing a solicitation for a second round of YIP/OHP and currently hast 3 new junior faculty preparing applications for these pilot grants.  The A/E Core has also developed with the junior investigators and mentors tools for assessment of needs and expectations relative to the maturation of the investigators as academic faculty.  These tools have been administered to obtain initial information from the group so as to provide yearly monitoring of changing needs.  The A/E Core has also begun work with the UK K30 award group to develop training and career development opportunities with shared resources and interacting groups of faculty and fellows particularly as related to clinical research and faculty development.

project_terms:
Accounting;Advisory Committees;American;Award;Centers of Research Excellence;Clinical Research;Collaborations;Computer Retrieval of Information on Scientific Projects Database;Dental;Dental Research;Dentistry;Development;Faculty;Funding;Goals;Grant;Institution;Mentors;Monitor;Needs Assessment;Outcome Assessment (Health Care);Participant;Pilot Projects;Relative (related person);Reporting;Research;Research Personnel;Research Training;Resource Sharing;Resources;Schedule;Series;Source;Time;Training;United States National Institutes of Health;Work;career;college;expectation;tool


application_id: 7610647
project_number: 5P20RR020145-04
project_title: UKY DENTAL COBRE: ORAL INFECTIONS AND HIV RECRUDESCENCE
administering_ic: NCRR
award_notice_date: 2007-09-01
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2007-08-01
project_end_date: 2008-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7657
contact_pi_person_id: 8367053
contact_pi: HUANG, CHIFU BRAD
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 introduction of HAART regimens (Highly Active Antiretroviral Therapy) has significantly modified the course of HIV disease with longer survival rates and improvement of life quality in HIV-infected individuals. However complete eradication of HIV infection cannot be achieved with currently available antiretroviral regimens.  This primarily results from the establishment of a pool of latently infected CD4+ T cells macrophages and other host cells (eg. dendritic cells mast cells) during the very earliest stages of acute HIV infection that persists with an extremely long half-life.  This persistence of HIV-1 within various host immune cells including macrophages constitutes a major obstacle in the control of HIV-1 infection.  We are using model T cell and macrophage systems to evaluate the capacity of the oral microbial challenges to reactivate HIV.  Our initial studies have used the BF24 cell line a human macrophage transfected with the HIV LTR promoter driving a chloramphenicol acetyltransferase (CAT) gene. Specific Aim 1 was to examine the alteration of these cells were challenged with oral bacteria (Pg Sm Cr Fn) or sonicates to assess variations in HIV promoter activation related to species dose and time. We also evaluated the ability of a polymicrobial challenge to synergize in this activation. The outcome was measured using a CAT ELISA. Differences were noted in the ability of the various oral bacteria and bacterial sonicates to activate HIV supporting that the characteristics of oral infection in periodontitis patients could variably impact reactivation of HIV.  We also noted that a polybacterial challenge of the BF24 cells demonstrated an additive reactivation when compared to either bacterium alone.  Specific Aim 2 focuses on the ability of host induced molecules to reactivate HIV.  In these studies we have challenged human gingival fibroblast (HGF) cultures with various bacterial sonicates.  The resulting supernatants were then used to stimulate HIV reactivation in the BF24 cells.  The findings indicated a dose and time responsiveness for the HGF supernatants to stimulate the BF24 cells.  However these reactions appeared substantially less that direct bacterial stimulation of the macrophages.  Finally we have initiated some co-culture experiments in which the HGF macrophages and bacterial challenge take place in the same milieu.  Initial results suggest that factors in these cultures may actually modulate the ability to activate the HIV promoter.  Thus the data demonstrate that oral bacteria have the capacity to activate HIV in latently infected macrophages. There appeared some specificity to the magnitude of this activation and a polybacterial challenge of these infected cells can enhance HIV reactivation. The results suggest chronic oral infections provide a risk to treatment success in HIV infected patients.

project_terms:
Acute;Anti-Retroviral Agents;Antiretroviral Therapy Highly Active;Automobile Driving;Bacteria;CD4 Positive T Lymphocytes;Cell Line;Cells;Characteristics;Chloramphenicol O-Acetyltransferase;Chronic;Coculture Techniques;Computer Retrieval of Information on Scientific Projects Database;Data;Dendritic Cells;Dental;Disease;Dose;Enzyme-Linked Immunosorbent Assay;Fibroblasts;Funding;Genes;Gingiva;Grant;HIV;HIV Infections;HIV-1;Half-Life;Human;Immune;Individual;Infection;Institution;Measures;Modeling;Oral;Outcome;Patients;Periodontitis;Promotor (Genetics);Protocols Treatment;Quality of life;Reaction;Recrudescences;Research;Research Personnel;Resources;Risk;Source;Specificity;Staging;Survival Rate;System;T-Lymphocyte;Time;United States National Institutes of Health;Variant;macrophage;mast cell;microbial;oral bacteria;oral infection;research study;success


application_id: 7610543
project_number: 5P20RR018733-05
project_title: COBRE PROJ 10: VSEL AND BRAIN REGENERATION IN A MURINE MODEL OF SLEEP APNEA
administering_ic: NCRR
award_notice_date: 2007-08-14
opportunity_number: RFA-RR-02-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2007-07-01
project_end_date: 2008-06-30
study_section: ZRR1-RI-8(01)
subproject_number: 7554
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
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.     Stem cells provide a novel potential source to replace dead neurons and supporting tissue in brain damaged by chronic ischemia as seen for example in sleep apnea (SA). Some investigations of animals and short-term human bone marrow 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. 
      Recently we have purified from adult murine bone marrow (BM) a homogenous population of rare (~0.01% of BMMNC) CXCR4+ Oct-4+ SSEA-1+ Sca-1+ lin- CD45- very small embryonic-like (VSEL) stem cells.  Direct electron microscopical analysis revealed that these cells are small (~2-4 mm) possess large nuclei surrounded by a narrow rim of cytoplasm and contain open-type chromatin (euchromatin) that is typical for embryonic stem cells.  Based on our preliminary data a novel hypothesis is presented that the pool of CXCR4+ epiblast derived VSEL 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 VSEL may contribute to aging of the central nervous system (CNS) resulting in less effective repair.  To investigate these issues four specific aims are proposed (see Progress Section for aims).

project_terms:
Adult;Aging;Animals;Antigens CD15;Bone Marrow;Bone Marrow Cells;Bone Marrow Transplantation;Brain;Brain Damage Chronic;Brain Injuries;CXCR4 gene;Cell Nucleus;Cells;Centers of Research Excellence;Chromatin;Computer Retrieval of Information on Scientific Projects Database;Cytoplasm;Data;Deposition;Development;Disease;Effectiveness;Electrons;Embryo;Epiblast;Euchromatin;Funding;Grant;Human;Hypoxia;Institution;Investigation;Ischemia;Longevity;Marrow;Methodology;Modeling;Mus;Natural regeneration;Neuraxis;Neurons;PTPRC gene;Patients;Play;Population;Research;Research Personnel;Resources;Role;Sleep Apnea Syndromes;Source;Stem cells;Stromal Cell-Derived Factor 1;Therapy Cell;Tissues;United States National Institutes of Health;age related;base;embryonic stem cell;functional improvement;novel;peripheral blood;repaired;stroke;tissue regeneration


application_id: 7610542
project_number: 5P20RR018733-05
project_title: COBRE PROJ 9: STRUCTURE-ACTIVITY ANALYSIS OF TISSUE-SPECIFIC CARCINOGENS
administering_ic: NCRR
award_notice_date: 2007-08-14
opportunity_number: RFA-RR-02-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2007-07-01
project_end_date: 2008-06-30
study_section: ZRR1-RI-8(01)
subproject_number: 7553
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
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.Progress Report Summary:  Dr. Albert Cunningham who arrived on April 1 2007 is finalizing his project description which has the specific aims of discovering molecular targets of chemical carcinogens that (1) can be used to study the etiology of tissue-specific chemical carcinogenesis and (2) can also serve as potentially new therapeutic targets for drug discovery.  He will concurrently employ computational structure-activity relationship modeling and proteomic/genomic analyses to look at chemical carcinogens with differing tissue specificity in order to first identify structural attributes of chemical carcinogens associated with tissue-specific carcinogenesis and then using these attributes as chemical probes to search for tissue specific molecular targets associated with chemical carcinogenesis.

project_terms:
Attributes of Chemicals;Carcinogens;Chemicals;Computer Retrieval of Information on Scientific Projects Database;Etiology;Funding;Genomics;Grant;Institution;Modeling;Molecular Target;Proteomics;Reports Progress;Research;Research Personnel;Resources;Source;Specificity;Structure;Structure-Activity Relationship;Summary Reports;Tissues;United States National Institutes of Health;carcinogenesis;chemical carcinogen;chemical carcinogenesis;drug discovery;novel therapeutics;therapeutic target


application_id: 7610541
project_number: 5P20RR018733-05
project_title: COBRE PROJ 8: ROLES OF IKK ?LPHA IN SKIN DEVELOPMENT AND DYSPLASIA
administering_ic: NCRR
award_notice_date: 2007-08-14
opportunity_number: RFA-RR-02-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2007-07-01
project_end_date: 2008-06-30
study_section: ZRR1-RI-8(01)
subproject_number: 7552
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
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 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 NF-kappa B signaling pathway. IKKalpha knockout mice die at birth with the skin defects associated with increased proliferation and impaired terminal differentiation in keratinocytes.  The function of the IKKalpha in keratinocyte is independent from its kinase activity and NF-kappa B signaling pathway. The mechanism under 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 and how do those interacting proteins participate in the IKKalpha signaling in the keratinocytes? (3) Does IKKalpha function as a tumor suppressor in skin? The cell cycle analysis and functional study 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;Knowledge;Loss of Heterozygosity;Mice Knockout;Molecular;Mus;NF-kappa B;Phosphotransferases;Predisposition;Proteins;Regulation;Research;Research Personnel;Resources;Role;Signal Pathway;Signal Transduction;Skin;Skin Cancer;Skin Neoplasms;Source;Spectrum Analysis Mass;Testing;Tumor Suppressor Genes;Tumor Suppressor Proteins;United States National Institutes of Health;clinically relevant;day;keratinocyte;tumor


application_id: 7610540
project_number: 5P20RR018733-05
project_title: COBRE PROJ 7: CONTROL OF TUMOR GROWTH BY RAS-RELATED PROTEINS
administering_ic: NCRR
award_notice_date: 2007-08-14
opportunity_number: RFA-RR-02-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2007-07-01
project_end_date: 2008-06-30
study_section: ZRR1-RI-8(01)
subproject_number: 7551
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
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.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.

Studies and Results
1.  Allen et al Oncogene 2007 in press (epub April 2007).  In this paper we have identified and characterized a novel member of the RASSF family designated RASSF6.  We show that RASSF6 exhibits the characteristics of a Ras effector/tumor suppressor but that it has several unique features compared to other family members.  These include the ability to negatively modulate the NFkB pathway.  This may provide a mechanistic explanation for the genetic link that has recently been demonstrated between RASSF6 and sensitivity to severe Respiratory Syncytial Virus infection.
2.  We have shown that the RASSF2 family member is frequently down-regulated in prostate cancer and that knockdown of RASSF2 enhances the tumorigenic phenotype of prostate tumor cell lines.  Moreover we have shown that RASSF2 forms an endogenous complex with the tumor suppressor PAR-4 (Prostate apoptosis response gene 4).  Thus we appear to have identified a role and a novel mechanism for the involvement of RASSF2 in prostate cancer.
3.  We have identified the novel protein Salvador as a binding partner for RASSF1A and have shown that Salvador exhibits tumor suppressor properties.  We have developed evidence that RASSF1A uses Salvador to promote the activation of the LATs tumor suppressors. 
4.  We have used micro array analysis to demonstrate that RASSF5 (Nore1a) activates the p21 cdk inhibitor.  We have confirmed this by Western analysis and shown that p21 -/- MEFs are resistant to Nore1a mediated growth inhibition.
5.  We have initiated a virtual screen for inhibitors of the Ras/RalGDS interaction with the Molecular Modeling Core.

Significance: We were the first to identify and characterize RASSF6 as a novel tumor suppressor.  Moreover  we have demonstrated a potential mechanism by which it modulates both tumor suppression and contributes to the pathogenicity of Respiratory Syncytial Virus infection.  We have identified three distinct novel signaling pathways utilized by different RASSF family members.  These are the Salvador tumor suppressor for RASSF1A the PAR-4 tumor suppressor for RASSF2 and the p21 WAF/CIP cdk inhibitor for Nore1a.  In each case the pathway is deeply implicated in the development of the transformed phenotype.  These findings begin to explain the mechanisms that RASSF family members use to impede transformation.

project_terms:
Apoptosis;Binding (Molecular Function);CDKN1A gene;Cell Line;Cells;Characteristics;Complex;Computer Retrieval of Information on Scientific Projects Database;Development;Exhibits;Family;Family member;Farnesyl Transferase Inhibitor;Funding;Genes;Genetic;Grant;Growth;Growth and Development function;HRAS gene;Human;Institution;Investigation;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Mus;Oncogene Proteins;Oncogenes;Paper;Pathogenicity;Pathway interactions;Phenotype;Process;Property;Prostate;Prostatic Neoplasms;Proteins;RALGDS gene;RAS Superfamily Proteins;Ras Inhibitor;Research;Research Personnel;Resistance;Resources;Respiratory Syncytial Virus Infections;Role;Series;Signal Pathway;Source;System;Tumor Suppression;Tumor Suppressor Proteins;Tumorigenicity;United States National Institutes of Health;Work;cancer therapy;inhibitor/antagonist;member;molecular modeling;neoplastic cell;novel;oncoprotein p21;ral Guanine Nucleotide Exchange Factor;ras Oncogene;ras Proteins;response;small molecule;tumor growth;tumorigenic;virtual


application_id: 7610539
project_number: 5P20RR018733-05
project_title: COBRE PROJ 6: PROGRAMMED DEATH PATHWAY INITIATED FROM THE ENDOPLASMIC RETICULUM
administering_ic: NCRR
award_notice_date: 2007-08-14
opportunity_number: RFA-RR-02-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2007-07-01
project_end_date: 2008-06-30
study_section: ZRR1-RI-8(01)
subproject_number: 7550
contact_pi_person_id: 6950638
contact_pi: LI, CHI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
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

The aims of this proposal 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 a lot of 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;Stress;United States National Institutes of Health;design;programs


application_id: 7610538
project_number: 5P20RR018733-05
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE E: PROTEOMICS FACILITY
administering_ic: NCRR
award_notice_date: 2007-08-14
opportunity_number: RFA-RR-02-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2007-07-01
project_end_date: 2008-06-30
study_section: ZRR1-RI-8(01)
subproject_number: 7549
contact_pi_person_id: 2105319
contact_pi: KLEIN, JON
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
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 Core Proteomics Laboratory is uniquely equipped with robotic workstations that increase gel throughput image analysis spot excision in-gel peptide digestion and MALDI-MS sample preparation.  The automated workstations include a  Propic gel spot picker that visualizes and excises spots from fluorescence-stained gels and a ProGest station that automates in-gel trypsin digestion in a 96- or 384-well format.  The laboratory also contains a ProMS robot that automates desalting concentrating and spotting of peptide samples onto MALDI targets allowing fully integrated high-throughput analysis of protein samples.  MALDI-MS analysis is performed using a Micromass Inc. TOF-Spec 2E.  The lab recently instituted automated analysis of high-resolution 2D gels using Progenesis software significantly decreasing analysis time of 2D gels accelerating throughput. The CPL maintains active collaborations and provides instruction to COBRE-affiliated faculty and graduate students.

project_terms:
Collaborations;Computer Retrieval of Information on Scientific Projects Database;Computer software;Digestion;Excision;Faculty;Fluorescence;Funding;Gel;Grant;Image Analysis;Institutes;Institution;Instruction;Laboratories;Peptides;Preparation;Progest;Proteins;Proteomics;Research;Research Personnel;Resolution;Resources;Robot;Robotics;Sampling;Source;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Spottings;Staining method;Stains;Students;Time;Trypsin;United States National Institutes of Health;high throughput analysis


application_id: 7610537
project_number: 5P20RR018733-05
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE D: NMR & PROTEIN PURIFICATION FACILITIES
administering_ic: NCRR
award_notice_date: 2007-08-14
opportunity_number: RFA-RR-02-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2007-07-01
project_end_date: 2008-06-30
study_section: ZRR1-RI-8(01)
subproject_number: 7548
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
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 seeing 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 above). 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 interested in using metabolomics approaches for understanding metabolic consequences of apoptotic proteins on isolated mitochondria. 
      Dr. Hong Ye (Project 5) makes use of the expression core facilities for protein production advice and analysis and will need the NMR capabilites for some functional analyses of the proteins whose structures she has solved by X-ray diffraction methods.
      Dr. J. 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 is 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. B. 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:
Apoptotic;Bacteria;Biophysics;Calmodulin;Cells;Centers of Research Excellence;Chromatography Affinity;Computer Retrieval of Information on Scientific Projects Database;Core Facility;Crystallography;Crystallography X-Ray;Data Collection;Ensure;Enzymes;Escherichia coli;Fibroblasts;Funding;Goals;Grant;Inclusion Bodies;Insecta;Institution;Jurkat Cells;Label;Laboratories;Large T Antigen;Ligand Binding;Manuscripts;Metabolic;Metabolic Pathway;Methods;Mitochondria;Numbers;Peptides;Preparation;Production;Property;Proteins;Publishing;RNA Interference;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Resources;Scheme;Solutions;Source;Stable Isotope Labeling;Structure;Tissues;United States National Institutes of Health;Work;X ray diffraction analysis;X-Ray Diffraction;base;bronchial epithelium;cancer cell;cell type;interest;metabolomics;programs;protein expression;protein purification;sphingosine kinase


application_id: 7610536
project_number: 5P20RR018733-05
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE C: MOLECULAR MODELING FACILITY
administering_ic: NCRR
award_notice_date: 2007-08-14
opportunity_number: RFA-RR-02-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2007-07-01
project_end_date: 2008-06-30
study_section: ZRR1-RI-8(01)
subproject_number: 7547
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
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 I II III and IV.  Using homology modeling and virtual screening of potential inhibitors Dr. Trent has made very important contributions on a collaborative basis to members of each MT-COBRE 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;Extrasensory Perception;Funding;Goals;Grant;Homology Modeling;Institution;Modeling;Molecular Target;Pharmaceutical Preparations;Rate;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: 7610534
project_number: 5P20RR018733-05
project_title: COBRE: LOUISVILLE RES FOUND INC: CORE A:ADMINISTRATIVE CORE
administering_ic: NCRR
award_notice_date: 2007-08-14
opportunity_number: RFA-RR-02-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 018733
project_start_date: 2007-07-01
project_end_date: 2008-06-30
study_section: ZRR1-RI-8(01)
subproject_number: 7545
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
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 operation 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 Nancy Roseberry the Administrative Assistant Drs. Miller and Eaton are responsible for oversight of all administrative aspects of the COBRE.  Several important changes have been made during the first four years of the MT-COBRE.  Four of the five original investigators have received NIH funding during that period with the fifth original member  Dr. Kozlowski - retiring from the program to pursue other interests.  Dr. Robert Mitchell Dr. Jason Chesney Dr. Binks Wattenberg and Dr. Hong Ye have all received NIH R01 grants.

project_terms:
Centers of Research Excellence;Collaborations;Computer Retrieval of Information on Scientific Projects Database;Funding;Grant;Institution;Molecular Target;Operative Surgical Procedures;Research;Research Personnel;Resources;Source;United States National Institutes of Health;day;interest;member;programs


application_id: 7610397
project_number: 5P20RR016481-07
project_title: DEVELOPMENT OF NOVEL HYDROQUINONE-BASED SERCA INHIBITORS
administering_ic: NCRR
award_notice_date: 2007-05-11
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2007-05-01
project_end_date: 2008-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 7412
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.The overall goal of the proposed research is to initiate the development of novel inhibitors of the enzyme sarco-endoplasmic reticulum calcium ATPase (SERCA) using a combination of experimental and computational techniques. Not only are SERCA inhibitors powerful tools for the study of the enzyme's function but they are also believed to be of potential medicinal value for cancer chemotherapy.

project_terms:
Ca(2+)-Transporting ATPase;Chemotherapy-Oncologic Procedure;Computational Technique;Computer Retrieval of Information on Scientific Projects Database;Development;Endoplasmic Reticulum;Enzyme Inhibitor Drugs;Enzyme Inhibitors;Enzymes;Funding;Goals;Grant;Hydroquinones;Institution;Research;Research Personnel;Resources;Source;United States National Institutes of Health;base;hydroquinone;inhibitor/antagonist;novel;tool


application_id: 7610395
project_number: 5P20RR016481-07
project_title: WKU LEAD FACULTY
administering_ic: NCRR
award_notice_date: 2007-05-11
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2007-05-01
project_end_date: 2008-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 7410
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 Lead Faculty Representative for the Western Kentucky University (WKU) INBRE program my role is primarily administrative.

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


application_id: 7610394
project_number: 5P20RR016481-07
project_title: FUNCTIONAL & MOLECULAR ANALYSIS OF LONG-TERM SLEEP DISRUPTION BY ETHANOL
administering_ic: NCRR
award_notice_date: 2007-05-11
opportunity_number: RFA-RR-03-108
application_type: 5
activity_code: P20
ic: RR
serial_number: 016481
project_start_date: 2007-05-01
project_end_date: 2008-04-30
study_section: ZRR1-RI-7(01)
subproject_number: 7409
contact_pi_person_id: 7024822
contact_pi: CARDEN, WILLIAMS B
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.Sleep perturbations by ethanol play a key role in the progression of alcoholism and are predictive of relapse. For some insomniacs the sedative effects of ethanol are the pathway to bedtime alcohol consumption and eventual abuse. Continued abuse of ethanol leads to long-term changes in neuronal sleep circuitry that last well beyond the cessation of ethanol administration. The overall goal of this project is to determine key molecular events that underlie cellular adaptation of sleep circuitry to alcohol and to correlate them with functional changes in sleep physiology. The thalamus is an integral participant in the generation of sleep/wake cycles and the brain rhythms that occur during sleep. One of the best understood of these rhythms is the thalamic spindle oscillation associated with Stage II sleep. In alcoholics spindle waves are diminished and are replaced with less-restful random eye movement (REM) sleep. Understanding the fate of spindle wave sleep is thus a vital question that directly relates to the reinforcement effects of ethanol since some alcoholics return to drinking in an effort to improve the quality of their sleep. The spindle waves generated by thalamocortical relay cells are the output of a complex network oscillation that is propagated throughout the brain. The engine that allows spindle waves to flow through the brain is a low threshold calcium current mediated by T-type calcium channels. Based on our previous studies thalamic T-type calcium channels appear particularly sensitive to ethanol exposure and the disruption of their function and/or availability may provide a cellular mechanism to explain why the sleep of alcoholics is disrupted. To test this hypothesis we are examining whether the electrophysiological properties and/or the relative expression of the thalamic T channels are affected in Long-Evans rats undergoing chronic ethanol self-administration.

project_terms:
Affect;Alcohol abuse;Alcohol consumption;Alcoholism;Alcohols;Brain;Calcium;Calcium Channels T-Type;Cells;Chronic;Complex;Computer Retrieval of Information on Scientific Projects Database;Disruption;Ethanol;Event;Eye Movements;Funding;Generations;Goals;Grant;Institution;Mediating;Molecular;Molecular Analysis;Neurons;Output;Participant;Pathway interactions;Physiology;Play;Property;Psychological reinforcement;Rats Long-Evans;Relapse;Relative (related person);Research;Research Personnel;Resources;Role;Self Administration;Sleep;Sleep Wake Cycle;Source;Stage II Sleep;Testing;Thalamic structure;United States National Institutes of Health;alcohol effect;alcohol exposure;base;drinking;improved;problem drinker;sedative


