# projects

application_id: 8111895
project_number: 5R01MH074865-05
project_title: BE-ACTIV: Treating Depression in Nursing Homes
administering_ic: NIMH
award_notice_date: 2011-06-03
application_type: 5
activity_code: R01
ic: MH
serial_number: 074865
program_official: ROWLAND, LAURA
project_start_date: 2007-07-14
project_end_date: 2013-06-30
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: 2011-07-01
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;Depressed mood;Depressive disorder;Diagnosis;Diagnostic;Discipline of Nursing;Elderly;Epidemiology;Evaluation;Event;Foundations;Goals;Health;Individual;Institution;Intervention;Interview;Interviewer;Link;Major Depressive Disorder;Manuals;Measures;Mediating;Mental Depression;Mental Health;Modeling;Moods;Nursing Homes;Outcome;Outcome Measure;Outpatients;Participant;Patient Self-Report;Phase;Population;Positive Reinforcements;Problem behavior;Process;Process Measure;Psyche structure;Randomized;Recovery;Research;Research Personnel;Risk;Social Functioning;Structure;Symptoms;Testing;Theoretical model;base;blind;depressive symptoms;design;effective therapy;efficacy testing;follow-up;geriatric depression;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: 8111845
project_number: 5R01EY013813-09
project_title: TNF-alpha in Cell Death & Neuroprotection in Glaucoma
administering_ic: NEI
award_notice_date: 2011-08-08
application_type: 5
activity_code: R01
ic: EY
serial_number: 013813
program_official: AGARWAL, NEERAJ
project_start_date: 2003-08-01
project_end_date: 2013-07-31
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 6803489
contact_pi: TEZEL, GULGUN
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-08-01
project_abstract:
DESCRIPTION (provided by applicant):  Only through a better understanding of the pathogenic mechanisms of glaucoma will improved treatments evolve. Ongoing studies during the original grant period have supported the involvement of tumor necrosis factor-alpha (TNF-a) signaling in glaucoma and illuminated many aspects of the TNF-a-mediated death of retinal ganglion cells (RGCs) during glaucomatous neurodegeneration. The proposed experiments in this renewal application are based on the hypothesis that an innovative analytical approach using proteomics technology can further elucidate TNF-a signaling in glaucoma by identifying time-dependent alterations in the protein complement. The specific aims that will address this hypothesis are: (1) To comparatively identify proteomic alterations in RGCs and glia exposed to TNF-a in vitro; and (2) To identify proteomic alterations associated with TNF-a signaling in RGCs during the course of glaucomatous neurodegeneration in vivo. For in vitro experiments RGCs and glial cells will be isolated from adult tissues. For large-scale identification of TNF-a-induced alterations in the protein complement differential proteomics will utilize protein lysates obtained from cultured cells. Time-dependent alterations in protein expression will be quantitatively evaluated by comparing the proteomic datasets obtained from RGCs and glial cells incubated in the presence and absence of TNF-a. Complementary approaches will be utilized to increase the sensitivity of protein identification. In addition phosphorylated proteins will be identified through targeted proteomics using tandem mass spectrometry. Findings of the proposed comparative analyses should provide comprehensive information about differential responses of RGCs and glia to TNF-a at the protein level. A better understanding of the cellular mechanisms associated with the relative protection of glial cells against glaucomatous injury can facilitate efforts to similarly improve RGC survival in glaucoma. The proposed in vivo experiments will utilize an experimental rat model of glaucoma in which intraocular pressure (IOP) elevation will be unilaterally induced by hypertonic saline injections into limbal veins. IOP exposure and axon loss will be determined for each rat sacrificed at different time points during a follow-up period of up to 12 weeks. RGC protein samples will be pooled from rat eyes matched for IOP exposure and axon loss. Interacting and phosphorylated RGC proteins in enriched multi-protein complexes will be identified using targeted proteomic approaches. The signaling complexes studied will include the TNF-a/TNF receptor complex and those associated with mitogen-activated protein kinase and nuclear factor-kappaB pathways (which are involved in TNF-a signaling and glaucomatous neurodegeneration). Due to diverse bioactivities of TNF-a which promote both cell death and survival signals specific inhibition of cell death signaling and/or the amplification of survival signaling (rather than the inhibition of receptor binding) should accomplish neuroprotection against TNF-a-mediated RGC death. An improved understanding of TNF-a signaling during glaucomatous neurodegeneration in a proteome-wide scale should therefore provide new and specific treatment targets for effective neuroprotective interventions in glaucoma a leading cause of blindness.

project_terms:
Address;Adult;Axon;Blindness;Cell Death;Cell Death Signaling Process;Cell Survival;Cells;Cessation of life;Complement;Complex;Cultured Cells;Data Set;Eye;Glaucoma;Grant;Immunohistochemistry;In Vitro;Incubated;Injection of therapeutic agent;Injury;Intervention;Mediating;Microglia;Mitogen-Activated Protein Kinases;Modeling;Nerve Degeneration;Neuroglia;Nuclear;Ocular Hypertension;Pathway interactions;Physiologic Intraocular Pressure;Predisposition;Proteins;Proteome;Proteomics;Rattus;Relative (related person);Research Personnel;Retina;Retinal;Retinal Ganglion Cells;Saline;Sampling;Signal Transduction;Technology;Time;Tissues;Tumor Necrosis Factor Receptor;Tumor Necrosis Factor-alpha;Veins;base;comparative;follow-up;human TNF protein;improved;in vivo;innovation;limbal;macroglia;neuronal survival;neuroprotection;prevent;programs;protein complex;protein expression;receptor binding;research study;response;tandem mass spectrometry


application_id: 8111204
project_number: 5R01GM083187-03
project_title: Regulation of alternative pre-mRNA processing by small nucleolar RNAs
administering_ic: NIGMS
award_notice_date: 2011-07-27
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 083187
program_official: BENDER, MICHAEL T
project_start_date: 2009-08-01
project_end_date: 2013-07-31
study_section: Molecular Genetics B Study Section[MGB]
contact_pi_person_id: 8899488
contact_pi: STAMM, STEFAN
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): There is a fundamental gap in understanding the function of small RNAs that constitute a large part of human gene expression. For example we do not know how the loss of small nucleolar RNA (snoRNA) expression contributes to the Prader-Willi syndrome the most frequent genetic cause for life-threatening obesity. Our long-term goal is to elucidate the regulation of alternative splicing by small RNAs that are estimated to comprise more than 40% of human gene expression. The objective of this application is to determine which alternative splicing patterns are influenced by the snoRNAs missing in individuals with Prader-Willi syndrome and to understand the molecular basis by which one of these snoRNAs HBII-52 influences alternative splicing patterns. The central hypothesis is that snoRNAs missing in individuals with Prader- Willi syndrome regulate alternative splicing by masking splicing regulatory elements on pre- mRNAs. Thus these snoRNAs regulate expression of numerous genes by changing their alternative splicing patterns. The rationale for the proposed research is that the genes regulated by these snoRNAs represent drug targets for treatment of the Prader-Willi syndrome. This proposal is therefore relevant to the NIH's mission that pertains to developing fundamental knowledge that will potentially help to reduce the burdens of human disease. Guided by our first published report that the snoRNA HBII-52 influences alternative splicing and additional strong preliminary data this hypothesis will be tested by pursuing two specific aims: 1) Identify the pre-mRNAs that are regulated by the snoRNAs missing in people with Prader-Willi syndrome; and 2) Determine how HBII-52 regulates alternative splice site usage and test alternatives for its expression. Under the first aim changes in pre-mRNA processing will be determined after ectopically expressing individual snoRNAs using bioinformatic predictions and splice-site sensitive DNA arrays. Under the second aim we will identify the repressor activity that competes with the snoRNA HBII-52 and determine its mode of action using an established in vitro system. The proposed work is innovative because it shows a complete new role for snoRNAs in the regulation of alternative pre-mRNA splicing. It may well change the current `textbook knowledge' that snoRNAs only regulate non-mRNAs. The proposed research is significant because it would show a novel role of snoRNAs identify the molecular defects in Prader-Willi syndrome and help to predict the influence of small RNAs on splice site selection.  
  
PUBLIC HEALTH RELEVANCE: The proposed studies delve into an under-investigated area of gene expression and have the potential applicability to understand the molecular cause of the Prader-Willi Syndrome and potentially other forms of inherited obesity. The proposed research is relevant for public health because it investigates a new mechanism of human gene expression. Understanding this mechanism is the basis to improve diagnostics and therapeutic options for human diseases caused by defects in pre-mRNA processing.

project_terms:
Affinity;Alternative Splicing;Area;Binding (Molecular Function);Biochemical;Bioinformatics;Biology;Boxing;Cell Culture Techniques;Code;Collaborations;Complex;DNA;Data;Defect;Diagnostic;Drug Delivery Systems;Exons;Failure (biologic function);Fostering;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Genome;Goals;Human;In Vitro;Individual;Inherited;Knockout Mice;Knowledge;Life;Link;Masks;Mass Spectrum Analysis;Messenger RNA;Methods;Mission;Molecular;Molecular Target;Obesity;Orphan;Outcome;Pattern;Peptide Nucleic Acids;Peptides;Prader-Willi Syndrome;Process;Property;Proteins;Publishing;RNA;RNA Sequences;RNA Splicing;Receptor Serotonin 5-HT2C;Regulation;Regulatory Element;Reporter Genes;Reporting;Research;Resources;Ribosomal RNA;Role;SNRPN;Science;Site;Small Nuclear RNA;Small Nucleolar RNA;Small Nucleolar Ribonucleoproteins;Small RNA;System;Techniques;Testing;Textbooks;Therapeutic;Transcript;Transfer RNA;Work;base;human disease;improved;in vivo;innovation;mRNA Precursor;novel;prevent;public health medicine (field);public health relevance;success

public_health_relevance:
Project narrativeThe proposed studies delve into an under-investigated area of gene expression and have thepotential applicability to understand the molecular cause of the Prader-Willi Syndrome andpotentially other forms of inherited obesity. The proposed research is relevant for public healthbecause it investigates a new mechanism of human gene expression. Understanding thismechanism is the basis to improve diagnostics and therapeutic options for human diseasescaused by defects in pre-mRNA processing.


application_id: 8111027
project_number: 1K23GM095859-01A1
project_title: Adjunctive Peritoneal Resuscitation in Hemorrhagic Shock
administering_ic: NIGMS
award_notice_date: 2011-03-14
opportunity_number: PA-10-060
application_type: 1
activity_code: K23
ic: GM
serial_number: 095859
suffix: A1
program_official: SOMERS, SCOTT D
project_start_date: 2011-04-01
project_end_date: 2015-03-31
study_section: Special Emphasis Panel[ZRG1 SBIB-E (02)]
contact_pi_person_id: 9885498
contact_pi: SMITH, JASON WAYNE
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
project_abstract:
DESCRIPTION (provided by applicant): This K23 proposal will enable Jason W. Smith MD to achieve his goal of becoming an independent investigator focusing on clinical and translational research in hemorrhagic shock and inflammation. Dr. Smith will conduct a prospective clinical study evaluating the effects of adjunctive direct peritoneal resuscitation (DPR) on patients undergoing damage control surgery and hemorrhagic shock. Highlights of Dr. Smith's career development plan include: (1) obtaining a PhD in Physiology and Biophysics focusing on microcirculation and hemorrhagic shock (2) experience running a prospective clinical trial at a large academic hospital and (3) technical laboratory training in experimental methods that can be applied across a wide range of future experiment subjects. These activities will occur in the setting of the University of Louisville and the University Of Louisville Hospital Trauma Institute and will be monitored quarterly by an advisory committee. An estimated 46 million Americans suffer a traumatic accident yearly. A number of those patients will suffer hemorrhagic shock and its sequelae as a result of their injury. Our preliminary data document (i) improvement in patient outcomes using adjunctive peritoneal resuscitation and (ii) improvement in liver blood flow after administration of DPR. Our hypothesis is that DPR therapy will result in improvement in mechanisms postulated to play a role in the development and progression of systemic inflammatory response due to hemorrhagic shock. To test this hypothesis we will perform a prospective randomized controlled mechanistic study of DPR administration in 100 patients undergoing damage control surgery for hemorrhagic shock over a 30 month period. The expected primary endpoints are an (i) increase in hepatic blood flow during resuscitation in patients treated with DPR  (ii) reduction in cellular edema and hepatocyte necrosis similar to our laboratory findings and (iii) a reduction inflammatory response and chemotactic mediators compared to the conventional resuscitation group. Additionally expected secondary clinical endpoints are (i) improved timeto abdominal closure (ii) decreased fluid resuscitation requirements with decreased vascular permeability and (iii) a reduction in post-operative complications following damage control surgery. These studies utilize state of-the art well validated techniques in a translational approach to develop an enhanced understanding of a potential innovativetherapy for hemorrhagic shock.  
  
PUBLIC HEALTH RELEVANCE: This K23 proposal will enable Jason W. Smith MD to achieve his goal of becoming an independent investigator focusing on clinical and translational research in hemorrhagic shock and inflammation. We will perform a randomized controlled study of adjunctive peritoneal resuscitation in patient suffering from hemorrhagic shock secondary to traumatic injury during the 30 month study period.

project_terms:
Abdomen;Accidents;Advisory Committees;American;Attenuated;Biophysics;Blood Circulation;Blood capillaries;Blood flow;Cause of Death;Cells;Cessation of life;Clinical;Clinical Research;Clinical Trials;Complex;Data;Development;Development Plans;Dialysis Solutions;Diffusion;Doctor of Philosophy;Edema;Future;Glucose;Goals;HMGB1 Protein;Health Benefit;Hemorrhage;Hemorrhagic Shock;Hepatic;Hepatocyte;Hospitals;Human;Inflammation;Inflammatory Response;Injury;Institutes;Intensive Care Units;Interleukin-6;Intravenous;Laboratories;Laboratory Finding;Laboratory Research;Liquid substance;Liver;Mediator of activation protein;Methodology;Methods;Microcirculation;Microcirculatory Bed;Monitor;Mortality Vital Statistics;Necrosis;Operative Surgical Procedures;Organ;Outcome;Patients;Perfusion;Peritoneal;Peritoneal Dialysis;Physiology;Play;Postoperative Period;Production;Publishing;Randomized;Randomized Controlled Trials;Reporting;Research Personnel;Resuscitation;Role;Running;Safety;Secondary to;Shock;Sodium Channel;Solutions;Surgical Intensive Care;TNF gene;Techniques;Testing;Time;Tissues;Training;Translational Research;Trauma;United States;Universities;Vascular Permeabilities;Vasodilation;Visceral;Water;Work;animal data;arm;base;capillary;career development;chemokine;clinical practice;crystalloid;experience;human study;hyaluronate;improved;innovation;interstitial;intrahepatic;prospective;research study;socioeconomics;translational approach

public_health_relevance:
This K23 proposal will enable Jason W. Smith MD to achieve his goal of becoming an independent investigator focusing on clinical and translational research in hemorrhagic shock and inflammation. We will perform a randomized controlled study of adjunctive peritoneal resuscitation in patient suffering from hemorrhagic shock secondary to traumatic injury during the 30 month study period.


application_id: 8110645
project_number: 5R01CA150947-03
project_title: Mechanisms of Immune Modulation Mediated by Yeast-derived Particulate Beta-Glucan
administering_ic: NCI
award_notice_date: 2011-07-13
opportunity_number: RFA-AT-08-003
application_type: 5
activity_code: R01
ic: CA
serial_number: 150947
program_official: KIM, YOUNG S
project_start_date: 2009-09-28
project_end_date: 2013-07-31
study_section: ZAT1-SM(13)
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The use of -glucans in complementary and alternative medicine (CAM) has prevailed for centuries in traditional Asian medicine. However their clinical use against malignancies in Western medicine has experienced an oscillating success due to a lack of understanding in their exact mechanisms of action. We have previously demonstrated that soluble yeast -glucan of low molecular weight is capable of binding to the lectin site of complement receptor 3 (CR3 CD11b/CD18) and priming CR3+ effector cells for cytotoxicity of iC3b-opsonized tumor cells. The work presented here shows that particulate yeast -glucan has more unique features than soluble -glucan. The objective of the proposed study is to elucidate the cellular and molecular mechanisms of action for particulate -glucan in tumor immunotherapy.   
Preliminary studies demonstrated that particulate -glucan not soluble -glucan stimulated macrophages and dendritic cells (DCs) for activation and proinflammatory cytokine production. Furthermore orally administered particulate -glucan stimulated DCs that captured apoptotic tumor cells for activation and maturation leading to the enhanced anti-tumor CD4 and CD8 T cell responses. Strikingly oral particulate -glucan treatment altered the tumor microenvironment toward Th1 response. Particulate -glucan was also shown to activate the complement system via an alternative pathway leading to C5a deposition on tumors. These preliminary data provide a strong basis for the current study.   
Aim 1 will dissect which signaling pathway(s) may be critical for particulate -glucan-mediated DC activation and cytokine release. Toll-like receptor pathway MyD-88- and TRIF-deficient mice CR3-deficient mice and dectin-1 pathway dectin-1- and CARD9-deficient mice will be used to address this issue. In addition T cell differentiation (Th1 Th2 and Th17) in the presence of particulate yeast -glucan stimulated DCs will be examined both in vitro and in vivo. Aim 2 will test the hypothesis that particulate -glucan modulates suppressive cells existing in the tumor microenvironment thereby promoting Th1 response. The function of myeloid-derived suppressive cells (MDSCs) dynamic interaction between regulatory T cells (Treg) and Th17 cells cross-talk between MDSCs and tumor-infiltrating macrophages will be examined. Lewis lung carcinoma transfected with surrogate antigen ovalbumin and tumor-associated antigen MUC1 will be used as the model systems to address those issues. Aim 3 will test the hypothesis that particulate -glucan stimulated complement activation may be partially contributed to the enhanced anti-tumor T cell responses. Furthermore the requirement for C3a and/or C5a and their receptors C3aR and C5aR as modulators of anti-tumor T cell responses will be determined. Further knowledge of the mechanisms involved in these effects of particulate -glucan will be of great value in the design of effective clinical applications.  
  
Public Health Relevance: This study will elucidate the cellular and molecular mechanisms of action of particulate yeast -glucan in tumor immunotherapy. The data generated in this study will allow for the rational design of immunotherapeutic protocols usable in clinical trials.

project_terms:
3-Dimensional;Address;Adjuvant;Affinity;Anti-Infective Agents;Antibodies;Antigens;Apoptotic;Asians;Bacteria;Barley (Food);Binding (Molecular Function);Biological Models;Biological Process;Biological Response Modifiers;Bone Marrow;C3bi;CD4 Positive T Lymphocytes;CD8B1 gene;Cell Maturation;Cells;Clinical;Clinical Trials;Complement;Complement 3a;Complement 5a;Complement Activation;Complementary and alternative medicine;Data;Dendritic Cells;Dendritic cell activation;Deposition;Effector Cell;Frequencies (time pattern);Glucans;Glucose;Helper-Inducer T-Lymphocyte;Host Defense Mechanism;Human;ITGAM gene;ITGB2 gene;Immune response;Immunity;Immunotherapeutic agent;Immunotherapy;In Vitro;Individual;Infection;Integrins;Interleukin-12;Knowledge;Lactosylceramides;Lectin;Lewis Lung Carcinoma;Ligands;Link;Macrophage-1 Antigen;Malignant Neoplasms;Mediating;Medicine;Modeling;Molecular Mechanisms of Action;Molecular Weight;Monoclonal Antibodies;Mucin-1 Staining Method;Mus;Myelogenous;Oral;Ovalbumin;Particulate;Pathway interactions;Production;Protocols documentation;Regulatory T-Lymphocyte;Reporting;Side;Signal Pathway;Site;Solubility;Structure;T cell differentiation;T cell response;T-Lymphocyte;Testing;Toll-Like Receptor Pathway;Treatment Efficacy;Tumor Antigens;Vertebral column;Work;Xenograft procedure;Yeasts;activation product;base;beta-Glucans;clinical application;complement system;cytokine;cytotoxic;cytotoxicity;dectin 1;design;experience;fungus;immunoregulation;in vivo;interest;macrophage;microbial;neoplastic cell;public health relevance;receptor;response;scavenger receptor;success;tool;tumor

public_health_relevance:
Project NarrativeThis study will elucidate the cellular and molecular mechanisms of action of particulate yeast -glucan in tumor immunotherapy. The data generated in this study will allow for the rationaldesign of immunotherapeutic protocols usable in clinical trials.


application_id: 8109937
project_number: 5R01CA118434-04
project_title: Biochemical Mechanisms of Se Anticancer Activity in Lung
administering_ic: NCI
award_notice_date: 2011-07-14
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 118434
program_official: PERLOFF, MARJORIE
project_start_date: 2008-09-01
project_end_date: 2013-07-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 7213583
contact_pi: FAN, TERESA WHEI-MEI
other_pis: Not Applicable
congressional_district: 03
department: CHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
  
The nutritionally essential element Se is also chemopreventive against prostate lung and several other leading human cancers when administered at supranutritional levels. The complex biochemical mechanism(s) underlying the anticancer action of Se compounds are not understood but they depend on Se metabolism in conjunction with multiple steps of redox regulation and antioxidation. Previously impractical such complexity can now be explored by combining the power of new molecular profiling tools. With metabolomics-edited transcriptomic analysis (META) to guide targeted proteomics we have recently discovered key changes in metabolic and regulatory pathways in Se-exposed lung cancer cells that control cell growth and migration. These preliminary results led to our current hypothesis: (a) the primary site(s) of Se action involve covalent modification(s) of key redox-sensitive proteins including thioredoxin reductase (TrxR) and NF:B; (b) their resultant dysfunctions lead to cell death and anti-metastasis. Here we propose to expand the approach to human Small Cell Lung Cancer cells with different metastatic potential for in vivo validation in a RAG1 null mice model. Our specific aims are: Aim 1: To define and correlate the biochemical pathway profiles with phenotypic changes of selected human lung cancer cell lines in response to treatments of different Se forms. The metabolomics data will be used to discern metabolic pathways related to growth apoptosis and metastatic potential (motility chemotaxis and adhesion); Aim 2: To acquire global and focused gene expression profiles of the treated cells for correlation to the metabolic profiles obtained from Aim 1. Using META gene expression profiles will be prioritized based on actual metabolic changes from Aim 1 to reveal Se action on regulatory pathways and key target proteins; Aim 3: To verify key working hypotheses in cell systems using a combination of immunochemical and proteomics analyses. [Potential key protein targets TrxR NF:B and IKK2] will be verified by relating their function to the modification state; Aim 4: To validate in vivo Se action on lung cancer cell metastasis in a RAG null mouse model. Emphasis will be on metastasis involving the chemokine SDF-1 and its receptor CXCR4 which is regulated by the NF:B-TrxR pathway. Altered metastasis and molecular signature of target mice tissues and blood in response to Se treatments will be related to the cell-based molecular signatures from Aims 1-3 for in vivo validation and for connection to ongoing human patient studies. This work is expected to accelerate the development of mechanistic biomarkers for lung cancer chemoprevention tumor diagnostics and anticancer efficacy. PUBLIC HEALTH RELEVANCE The nutritionally essential element Selenium (Se) has been shown to have anti-cancer properties against prostate lung and other cancers at supranutritional levels. The exact nature of this activity is presently unknown but is related to the metabolism of selenium and how it reduces the ability of cancer cells to survive oxidative damages generated by their overactive metabolism. Here we propose to use state-of-the-science "metabolomic" plus other "'omics" tools to determine the biochemical basis of Se action in lung cancers using cell cultures and mouse models. This work is expected to accelerate the development of more sensitive diagnostics for lung cancer chemoprevention tumor detection and anticancer treatment.

project_terms:
Adhesions;Anabolism;Antineoplastic Agents;Apoptosis;Biochemical;Biochemical Pathway;Biochemistry;Biological Availability;Blood;Bone Marrow;CXCR4 Receptors;CXCR4 gene;Cancer cell line;Cell Culture Techniques;Cell Cycle Arrest;Cell Death;Cell Proliferation;Cells;Chemicals;Chemopreventive Agent;Chemotaxis;Citric Acid Cycle;Clinical Trials;Complex;Data;Dependence;Detection;Development;Diagnostic;Dietary Supplements;Drug Formulations;Elements;Functional disorder;G-Protein-Coupled Receptors;Gene Expression;Gene Expression Profiling;Glycolysis;Growth;Health;Histocompatibility Testing;Human;Knockout Mice;Laboratories;Lead;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Metabolic;Metabolic Pathway;Metabolism;Modification;Molecular;Molecular Profiling;Mus;Nature;Neoplasm Metastasis;Organ;Oxidation-Reduction;Pathway interactions;Patients;Pattern;Pentosephosphate Pathway;Plasma;Play;Polyamines;Post-Translational Protein Processing;Process;Property;Prostate;Proteins;Proteomics;Regulation;Regulatory Pathway;Research;Role;Science;Selenium;Selenium Compounds;Selenomethionine;Site;System;Testing;Tissues;Trace Elements;Validation;Work;anticancer activity;anticancer treatment;base;biomarker;cancer cell;cancer chemoprevention;cancer prevention;cell growth;cell motility;chemokine;immunodeficient mouse model;in vivo;lipid metabolism;lung small cell carcinoma;lymph nodes;metabolomics;methylselenic acid;mouse model;neoplastic cell;nucleotide metabolism;oxidative damage;protein expression;response;thioredoxin reductase;tool;transcriptomics;tumor;urea cycle


application_id: 8109860
project_number: 5R01HL078663-06
project_title: Lysolipid Signaling in Cardiovascular Disease
administering_ic: NHLBI
award_notice_date: 2011-07-02
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 078663
program_official: HASAN, AHMED A K
project_start_date: 2004-09-24
project_end_date: 2014-06-30
study_section: Special Emphasis Panel[ZRG1-VH-E(02)M]
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are essential bioactive lysolipid mediators that regulate a range of developmental and physiological processes and are emerging as targets for a new class of molecular therapeutics. In the cardiovascular system LPA is poised to serve as a mediator of atherothrombotic disease: it is abundant in atherosclerotic plaque present in the blood produced by activated platelets triggers phenotypic responses in smooth muscle cells and potentiates platelet activation. Exposure of LPA during atherosclerotic plaque rupture/erosion has been proposed as a key modulator of platelet thrombosis. We report a novel pathway for regulation of platelet LPA responses that involves recruitment of the lysophospholipase D enzyme autotaxin responsible for LPA production to activated platelets. We have also found that LPA inhibits mouse platelet function and that approximately 20% of human volunteers also lack a stimulatory response to LPA. We have evidence that this inhibitory LPA-signaling pathway confers vascular protection from thrombosis in mice and potentially from atherosclerotic disease in humans. We suggest that a therapeutic strategy directed at blocking stimulatory platelet LPA responses while promoting inhibitory ones could result in beneficial anti-thrombotic effects. Implementation of this strategy requires the molecular characterization of platelet LPA responses and proof of a role for circulating or locally produced LPA in regulating hemostasis and thrombosis. The broad goal of this proposal is to provide mechanistic insight essential for establishing LPA signaling as a viable anti-thrombotic target. We will take advantage of the differences in murine and human platelet LPA responses to identify the receptor(s) responsible for LPA signaling in mice and humans and then generate a transgenic mouse with platelet-specific expression of a stimulatory LPA receptor that phenocopies the human LPA response so that processes of relevance to human disease can be studied in a small animal mode. We are uniquely well-prepared to achieve these goals based on our expertise in bioactive lipid signaling and the tools we have amassed to study LPA in the vasculature. Completion of these studies promises to provide valuable insight into regulation of platelet function and may have exciting implications for the development of novel anti-thrombotic strategies that target LPA signaling.  
  
PUBLIC HEALTH RELEVANCE: Atherothrombotic vascular disease is a leading cause of death in the United States. Blood platelets are essential for acute thrombotic events such as heart attacks and strokes and also contribute to local and systemic inflammation. This research project seeks to understand how the production of a class of pro-inflammatory lipid molecules is influenced by platelets and how the lipids affect platelet function. Completion of the work will provide new insights into pathways that could be targeted to prevent and treat arterial thrombosis.

project_terms:
Acute;Adenylate Cyclase;Affect;Agonist;Animal Model;Animals;Arterial Fatty Streak;Atherosclerosis;Binding (Molecular Function);Biological Models;Blood;Blood Platelets;Blood Pressure;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Cell physiology;Cell surface;Cells;Cyclic AMP;Data;Development;Developmental Process;Diagnosis;Dinoprostone;Disease;Dose;Enzymes;Event;Exposure to;Funding;G-Protein-Coupled Receptors;Genetic;Goals;Hemostatic function;Human;Human Volunteers;Hyperplasia;In Vitro;Inflammation;Inflammation Mediators;Inflammatory;Integrins;Investigation;Knowledge;Lipids;Lysophosphatidic Acid Receptors;Lysophospholipids;Mediator of activation protein;Molecular;Mortality Vital Statistics;Mus;Myocardial Infarction;Myocardial Ischemia;Nuclear Receptors;Pathway interactions;Peroxisome Proliferators;Phenocopy;Physiological;Physiological Processes;Physiology;Platelet Activation;Play;Positioning Attribute;Process;Production;Property;Prostaglandins;Regulation;Reporting;Research;Research Project Grants;Risk Factors;Role;Rupture;Signal Pathway;Signal Transduction;Smooth Muscle Myocytes;Surface;System;Testing;Therapeutic;Thrombosis;Transgenic Mice;United States;Vascular Diseases;Work;alkylglycerophosphoethanolamine phosphodiesterase;base;cell growth;cell motility;human disease;improved;in vitro Model;in vivo;innovation;insight;lysophosphatidic acid;novel;novel therapeutics;prevent;programs;prostaglandin EP3 receptor;public health relevance;receptor;receptor function;research study;response;sphingosine 1-phosphate;stroke;tool

public_health_relevance:
PROJECT NARRATIVEAtherothrombotic vascular disease is a leading cause of death in the United States. Blood platelets areessential for acute thrombotic events such as heart attacks and strokes and also contribute to localand systemic inflammation. This research project seeks to understand how the production of a class ofpro-inflammatory lipid molecules is influenced by platelets and how the lipids affect platelet function.Completion of the work will provide new insights into pathways that could be targeted to prevent andtreat arterial thrombosis.


application_id: 8109854
project_number: 5R01NS053470-05
project_title: Designer Proteoglycans for Central Nervous System Injury
administering_ic: NINDS
award_notice_date: 2011-06-20
application_type: 5
activity_code: R01
ic: NS
serial_number: 053470
program_official: JAKEMAN, LYN B
project_start_date: 2007-08-01
project_end_date: 2014-02-28
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 7875161
contact_pi: SNOW, DIANE M
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-08-01
project_abstract:
DESCRIPTION (provided by applicant): In the adult mammalian brain and spinal cord neuronal injury results in failed regeneration in part due to the upregulation of chondroitin sulfate proteoglycans (CSPGs). The majority of CSPGs originate from reactive astrocytes of the glial scar surrounding the lesion. The glial scar is beneficial for the recovering nervous system and should not be "excised" but axonal growth could be promoted if the expression of specific inhibitory portions of CSPGs could be targeted selectively. Our previous data indicate that neuronal inhibition is due to specific CSPG microheterogeneities and to the specific configurations of CSPGs predicted by their structure and by the molecules to which they bind. Our goal is to identify the most significant of the CSPG motifs with respect to neurite inhibition and regeneration and specifically to manipulate these moieties to promote regeneration. To this end we and our collaborators have engineered 1) an array of CSPG isoforms and mutants we call "Designer PCs" 2) a variety of unique bioassays to express CSPGs including a novel model of the glial scar in vitro and 3) imaging methods to measure subtle features of nerve responses to CSPGs. The hypothesis of this proposal is: Identification and manipulation of specific inhibitory CSPG motifs using designer PGs and novel models of the glial scar will promote plasticity and regeneration in vitro and in vivo. We propose three Specific Aims that represent independent but interrelated studies to test this hypothesis. One we will determine the expression and relative abundance of specific inhibitory CSPG types and posttranslational modifications or core protein domains by reactive astrocytes in vitro. Two we will determine the inhibitory potential for specific CSPG posttranslational modifications or core protein domains by establishing an inhibitory quotient to evaluate the responses of adult neurons in vitro. Three we will manipulate specific inhibitory moieties of CSPGs to promote neuronal regeneration of adult neurons in vivo. The long term goal of this study is to identify the mechanism(s) of CSPG-induced inhibition following brain and spinal cord injury. The significance of the studies lies in the tremendous potential for translational application through the manipulation of specific CSPG motifs in injured patients providing a therapeutic avenue to stimulate neuronal plasticity facilitate reconnectivity of injured neurons and accomplish restoration of function.

project_terms:
Adult;Astrocytes;Behavior;Binding (Molecular Function);Biological Assay;Brain;Chondroitin Sulfate Proteoglycan;Cicatrix;Core Protein;Cues;Data;Engineering;Family member;Goals;Growth;In Vitro;Injury;Knowledge;Lesion;Link;Measures;Modeling;Modification;Natural regeneration;Nerve;Nervous System Trauma;Nervous system structure;Neurites;Neuronal Injury;Neuronal Plasticity;Neurons;Patients;Pattern;Post-Translational Protein Processing;Protein Family;Protein Isoforms;Proteoglycan;Regulation;Relative (related person);Reporting;Site;Spinal Cord;Structure;Tertiary Protein Structure;Testing;Therapeutic;Up-Regulation (Physiology);axon growth;central nervous system injury;clinical application;glycosylation;imaging modality;in vivo;injured;innovation;mutant;novel;proteoglycan core protein;response;restoration;spinal cord and brain injury;sulfation


application_id: 8109407
project_number: 5R21AA019693-02
project_title: Autophagic Protection of Ethanol Neurotoxicity
administering_ic: NIAAA
award_notice_date: 2011-07-08
opportunity_number: PA-09-164
application_type: 5
activity_code: R21
ic: AA
serial_number: 019693
program_official: REGUNATHAN, SOUNDAR
project_start_date: 2010-07-10
project_end_date: 2013-06-30
study_section: Neuroscience and Behavior Study Section[AA-4]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Fetal alcohol spectrum disorder (FASD) is one of the leading causes of mental retardation and thus is a major public health concern. The developing central nervous system (CNS) is particularly sensitive to alcohol. One of the most deleterious effects of developmental alcohol exposure is the permanent loss of neurons in the CNS. The cellular/molecular mechanisms underlying ethanol-induced neuronal death remain unclear. During the last decade mitochondria damage and oxidative stress have been believed to play an important role in the pathogenesis of ethanol-associated CNS injury. However mitochondria damage does not fully explain ethanol neurotoxicity. The effects of ethanol on other cellular organelles receive little attention and the connection between mitochondria damage and other organelle dysfunction is poorly understood. This grant proposal attempts to fill this gap and investigate the effect of ethanol on the interaction between the endoplasmic reticulum (ER) and autophagy. ER stress is induced in various physiological and pathological conditions where the accumulation of unfolded proteins or disruption of ER Ca2+ homeostasis occurs. Autophagy a lysosomal pathway involved in the turnover of cellular macromolecules and organelles is induced to alleviate cytotoxicity during ER stress. We have demonstrated that ethanol induces ER stress in developing neurons. We hypothesize that ethanol neurotoxicity is partially caused by the induction of ER stress and the simultaneous impairment of the protective autophagic pathway. As a corollary we propose that activation of autophagy pathways during ethanol exposure can ameliorate ethanol cytotoxicity; contrarily inhibition of autophagy exacerbates the effect of ethanol. To test this hypothesis we will first determine whether ethanol inhibits ER stress- triggered autophagy. Next we will activate or inhibit the autophagic pathway by pharmacological or genetic approaches and determine whether the modulation of autophagic pathways ameliorates or exacerbates ethanol cytotoxicity.  Our hypothesis is novel and the proposed study is significant; it will offer new insight into the effect of ethanol on the endoplasmic reticulum and lysosomal degradation pathways. It will provide a potential avenue for alleviating ethanol cytotoxicity.  
  
PUBLIC HEALTH RELEVANCE:  Prenatal exposure to alcohol causes profound damages to the developing brain. Fetal alcohol syndrome is the leading cause of mental retardation. One of the most deleterious effects of developmental alcohol exposure is the permanent loss of neurons in the brain. However it remains unclear how alcohol kills immature neurons. The endoplasmic reticulum (ER) is an organelle that processes proteins and stores calcium. We have shown that ethanol causes ER injury. Autophagy a lysosomal pathway involved in the turnover of cellular macromolecules and organelles is induced to alleviate cytotoxicity during ER damage. Our study will test a novel hypothesis that alcohol neurotoxicity is partially caused by ER damage and simultaneous impairment of the protective autophagic pathway. Our study will offer novel insight into the effect of alcohol on the ER and lysosomal degradation pathways. It may provide a new therapeutic avenue.

project_terms:
Alcohols;Apoptosis;Applications Grants;Attention;Autophagocytosis;Behavioral;Brain;Calcium;Cell Survival;Cell surface;Cells;Cerebral cortex;Cessation of life;Client;Communities;Data;Degradation Pathway;Development;Endoplasmic Reticulum;Ethanol;Ethanol toxicity;Fetal Alcohol Spectrum Disorder;Fetal Alcohol Syndrome;Free Radicals;Functional disorder;Genetic;Homeostasis;Impairment;In Vitro;Injury;Killings;Liver;Mental Retardation;Mitochondria;Molecular;Molecular Chaperones;Mus;Neuraxis;Neurocognitive;Neurons;Organelles;Oxidative Stress;Pathogenesis;Pathway interactions;Physiological;Play;Process;Protein Biosynthesis;Proteins;Role;Signal Pathway;Source;Stress;Testing;alcohol consumption during pregnancy;alcohol effect;alcohol exposure;alcohol research;central nervous system injury;cytotoxicity;disability;endoplasmic reticulum stress;in vivo;inhibition of autophagy;insight;macromolecule;mouse model;neuron loss;neurotoxicity;novel;novel therapeutics;prenatal exposure;public health medicine (field);public health relevance;response

public_health_relevance:
Prenatal exposure to alcohol causes profound damages to the developing brain. Fetalalcohol syndrome is the leading cause of mental retardation. One of the most deleteriouseffects of developmental alcohol exposure is the permanent loss of neurons in the brain.However it remains unclear how alcohol kills immature neurons. The endoplasmic reticulum(ER) is an organelle that processes proteins and stores calcium. We have shown that ethanolcauses ER injury. Autophagy a lysosomal pathway involved in the turnover of cellularmacromolecules and organelles is induced to alleviate cytotoxicity during ER damage. Ourstudy will test a novel hypothesis that alcohol neurotoxicity is partially caused by ER damageand simultaneous impairment of the protective autophagic pathway. Our study will offer novelinsight into the effect of alcohol on the ER and lysosomal degradation pathways. It mayprovide a new therapeutic avenue.


application_id: 8109388
project_number: 5R01HL073085-08
project_title: Angiotensin: A Link Between Obesity and Hypertension
administering_ic: NHLBI
award_notice_date: 2011-06-23
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 073085
program_official: OH, YOUNGSUK
project_start_date: 2003-06-03
project_end_date: 2013-06-30
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Obesity is one of the most serious health problems in the United States and the most common cause of hypertension. Our laboratory demonstrated that adipocytes express components of the renin-angiotensin system (RAS) and that mice with diet-induced obesity and hypertension exhibit adipose-specific dysregulation of these components favoring an increase in blood pressure. Angiotensinogen (AGT) angiotensin type 1a receptors (AT1aR) and ACE2 are three components of the RAS that were regulated specifically in adipose tissue from mice with hypertension from diet-induced obesity. Preliminary data suggest that fatty acids enriched in the western high fat (HF) diet regulate specific RAS components in adipocytes serving as a mechanism for adipose-specific regulation of the RAS. We hypothesize that the RAS of adipocytes contributes to the development of obesity-induced hypertension. In aim 1 we hypothesize that adipose tissue is a predominant source for increased local and systemic angiotensin II (AngII) in obesity-hypertension. To test this hypothesis we will feed low fat (LF) or HF diets to mice with adipocyte-specific AGT deletion and determine the impact on the development of obesity-hypertension. In vitro studies will use adipose tissue from adipocyte AGT deficient mice to test the hypothesis that fatty acids regulate oxidative stress and proinflammatory adipokines through an AngII-dependent mechanism. In Aim 2 we hypothesize that adipocyte AT1aR mediate effects of local and/or systemic AngII to increase proinflammatory adipokine expression and promote obesity-hypertension. To test this hypothesis we will feed LF or HF diets to mice with adipocyte- specific AT1aR deficiency and determine the impact on the development of obesity-hypertension. In vitro studies will test the hypothesis that adipocyte AT1aR mediate effects of AngII to promote oxidative stress and adipokine expression. In Aim 3 we hypothesize that specific fatty acids regulate ACE2 expression and shedding to increase the development of obesity-hypertension. In vitro studies will define effects of specific fatty acids on ACE2 gene transcription and/or shedding in adipocytes and in vivo approaches will use ACE2 deficient mice to define their susceptibility to the development of obesity-hypertension. Results from these studies will identify dietary or pharmacologic sites for targeted reductions in the adipocyte RAS in the treatment of obesity-hypertension. PUBLIC HEALTH RELEVANCE: The relevance of this project to public health is the definition of mechanisms contributing to the development of hypertension in obese subjects. Given the epidemic of obesity in the US results from these studies will define whether an adipocyte renin-angiotensin system is a primary mechanism linking the epidemic of obesity to a growing prevalence of hypertension. Since the principal cause of death in obese patients is cardiovascular disease results from these studies are clinically significant.

project_terms:
Acids;Adipocytes;Adipose tissue;Adult;Angiotensin II;Angiotensin Type 1a Receptor;Angiotensinogen;Angiotensins;Blood Pressure;CCL2 gene;Cardiovascular Diseases;Cause of Death;Coupled;Data;Development;Diet;Epidemic;Exhibits;Fatty Acids;Fatty acid glycerol esters;Framingham Heart Study;Genetic Transcription;Health;Hypertension;In Vitro;Laboratories;Leptin;Link;Liver;Measures;Mediating;Mus;Obese Mice;Obesity;Overweight;Oxidative Stress;Patients;Predisposition;Prevalence;Production;Regulation;Relative (related person);Renin-Angiotensin System;Reporting;Site;Source;Testing;Therapeutic;Tissues;United States;Woman;Work;adipokines;clinically significant;feeding;in vivo;mRNA Expression;men;novel;obesity treatment;public health medicine (field);receptor coupling;resistin;response

public_health_relevance:
Project NarrativeThe relevance of this project to public health is the definition of mechanisms contributing to the development ofhypertension in obese subjects. Given the epidemic of obesity in the US results from these studies will definewhether an adipocyte renin-angiotensin system is a primary mechanism linking the epidemic of obesity to agrowing prevalence of hypertension. Since the principal cause of death in obese patients is cardiovasculardisease results from these studies are clinically significant.


application_id: 8109277
project_number: 5R01HD053509-04
project_title: Transcriptional Coactivators and Pregnancy Outcomes
administering_ic: NICHD
award_notice_date: 2011-07-25
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HD
serial_number: 053509
program_official: HENKEN, DEBORAH B
project_start_date: 2008-07-01
project_end_date: 2013-06-30
study_section: Pregnancy and Neonatology Study Section[PN]
contact_pi_person_id: 1861667
contact_pi: GREENE, ROBERT M
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Two major medical health care issues are inexorably intertwined: a woman's health and prenatal development of her unborn child. Maternal folate status is one condition that has a profound influence on development of the central nervous system (CNS) and the incidence and recurrence of certain developmental disorders of the CNS (neural tube defects NTDs). While NTDs are amongst the most common human malformations the mechanisms by which folate exerts its ameliorative effect on these malformations or its role in normal morphogenesis of the CNS is not well understood. Extant data argue for interactions between folate status and developmental pathways controlled by specific transcriptional regulators. This proposal explores the nature of such interactions and consists of five hypothesis-driven specific aims linked together in order to present a cohesive picture of the molecular mechanisms by which specific translational coactivators mediate signal transduction in and contribute to development of the developing CNS. The overall hypothesis to be tested by the proposed specific aims is that normal CNS development in the mammalian embryo requires folate-mediated activation of a transcriptional complex functionally dependent on proper expression and integration of specific transcriptional coactivators. Specifically we propose that not only is proper expression of Folbp and transcriptional coactivators such as CBP p300 Cited2 Cart1 and AP-2 requisite for CNS formation but the integration of these molecules into a functional regulon is critical to normal CNS morphogenesis. Investments in research designed to reveal the causes of congenital anomalies such as NT defects provide excellent opportunities to meet Public Health Service requirements that biomedical science must pay social dividends. Experiments proposed in the current application seek to identify genes genetic variations and molecular pathways associated with susceptibility to NT defects and to understand signaling mechanisms associated with such disorders.NARRATIVE: In the United States every three minutes a baby is born with a birth defect! While neural tube defects (NTDs) are amongst the most common human malformations the mechanisms by which folic acid exerts its ameliorative effect on these malformations or its role in normal development of the neural tube is not well understood. Studies proposed in the current application should provide a better understanding of prenatal factors influencing the nutritional/health status of pregnant women and their impact on the health of the developing fetus particularly as it relates to NTDs.

project_terms:
Complex;Congenital Abnormality;Data;Defect;Development;Disease;E1A-associated p300 protein;EP300 gene;Embryo;Fetus;Folate;Folic Acid;Folic Acid Deficiency;Genes;Genetic Polymorphism;Genetic Transcription;Health;Health Status;Healthcare;Human;Incidence;Investments;Link;Mediating;Medical;Molecular;Morphogenesis;Nature;Neural Tube Defects;Neural Tube Development;Neuraxis;Nuclear;Nutritional;Pathway interactions;Pattern;Predisposition;Pregnancy Outcome;Pregnant Women;Proteins;Recurrence;Regulon;Research Design;Risk;Role;Science;Signal Transduction;TFAP2A gene;Testing;Transcription Coactivator;Transcription Factor AP-2 Alpha;United States;United States Public Health Service;Variation (Genetics);Women's Health;developmental disease/disorder;genetic association;malformation;meetings;nervous system development;prenatal;research study;social;unborn child


application_id: 8108883
project_number: 2R37AG004542-22A1
project_title: Hippocampal Synaptic Structure
administering_ic: NIA
award_notice_date: 2011-03-03
opportunity_number: PA-10-067
application_type: 2
activity_code: R37
ic: AG
serial_number: 004542
suffix: A1
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 1998-01-01
project_end_date: 2016-02-29
study_section: Neurobiology of Learning and Memory Study Section[LAM]
contact_pi_person_id: 2405844
contact_pi: LANDFIELD, PHILIP W.
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  This is the resubmission of a renewal application for a longstanding project on dysregulation of calcium (Ca2+)-related processes in hippocampal neurons during aging and the consequences for altered neuronal function/vulnerability. The project initially derived from the finding that the Ca2+-dependent slow afterhyperpolarization (sAHP) that follows a burst of action potentials in hippocampal pyramidal neurons is larger in aged than in young-adult animals. Importantly larger sAHPs are correlated with reduced neuronal excitability and impaired learning and memory. Conversely smaller sAHPs are found in animals that learn a task. Since then we and others have determined that Ca2+ action potentials Ca2+ transients and L-type Ca2+ currents also are increased in aged neurons. These results led to a Ca2+ dysregulation hypothesis of brain aging in which increased activity of L-channels plays a key initiating role and the resulting larger sAHP reduces neuronal excitability. It also has become apparent that enhanced Ca2+-induced Ca2+ release (CICR) from ryanodine receptors (RyRs) modulates the magnitude of aging-related Ca2+ transients and sAHPs in pyramidal neurons. The major objective of this project is to fundamentally advance our understanding of the underlying molecular mechanisms of Ca2+ dysregulation that lead to unhealthy brain aging. Based on our new intriguing results we have formulated a novel working hypothesis of age-related Ca2+ dysregulation that suggests that downregulation of immunophilins particularly FK-506 binding protein 1b and/or 1a (FKBP1b/1a) leads to a cascade of RyR destabilization greater CICR and larger sAHPs. The resulting effect is impaired neuronal excitability and behavioral plasticity. These studies will manipulate hippocampal expression/function of FKBP1b/1a and other proteins in the FKBP- Ca2+ regulatory pathway in vivo using microinjection of viral vectors. Multiple outcomes will be assessed in the same animals using a multidisciplinary approach comprising extensive behavioral testing state-of-the-art intracellular electrophysiology with concomitant Ca2+ imaging immunohistochemistry and gene microarray analysis. These studies should substantially elucidate aging changes that depend on Ca2+ dysregulation and should clearly test the role of FKBPs in Ca2+ dysregulation and hippocampal function during aging. Chronic intervention studies are proposed that could have direct translational relevance and lead directly to novel preventative and therapeutic treatments against aging-related decline of brain function. Given the dramatic increase in the aging population it is becoming increasingly important to identify and develop such therapies to maintain cognitive function in the elderly.  
  
PUBLIC HEALTH RELEVANCE:   
The aging population of the United States is projected to increase at a dramatic rate with numbers that will undoubtedly impact our healthcare system (20% of the population will be >65 years of age by the year 2030). Cognitive decline frequently accompanies aging and depending on the severity can significantly affect quality of life. Our results indicate that a specific pathway (FKBP-Ca2+) that plays a major role in cardiac failure may also play a critical role in brain aging and cognitive decline; thus the goal of this project is to use gene therapy techniques to determine whether such interventions can prevent or slow the onset of age-related brain decline. The outcomes may have substantial therapeutic implications.

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

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


application_id: 8107647
project_number: 5R01DK071976-06
project_title: GKLF/Beta-catenin crosstalk in the intestine
administering_ic: NIDDK
award_notice_date: 2011-06-17
application_type: 5
activity_code: R01
ic: DK
serial_number: 071976
program_official: CARRINGTON, JILL L
project_start_date: 2007-09-01
project_end_date: 2013-06-30
study_section: Special Emphasis Panel[ZRG1-DIG-C(02)M]
contact_pi_person_id: 7013090
contact_pi: LIU, CHUNMING
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
budget_start_date: 2011-07-01
project_abstract:
DESCRIPTION (provided by applicant): The majority of colorectal cancers have mutations of the ARC (adenomatous polyposis coli) tumor supressor gene or the ?-catenin oncogene causing ?-catenin accumulation that activates other oncogenes. This project will investigate the interaction of ?-catenin and other signaling molecules in the intestine. Gut-enriched Krppel-like transcriptional factor (GKLF now called KLF4) is down-regulated in many colon cancer cells and considered to be a candidate tumor suppressor protein; it inhibits intestinal cell proliferation and induces cell differentiation. In contrast ?-catenin induces intestinal cell proliferation and inhibits differentiation. KLF4 expression is APC-dependent and its function and expression are inversely correlated with those of ?-catenin. The central hypothesis of this project is that KLF4 inhibits ?-catenin signaling in the differentiated cells; conversely ?-catenin inhibits KLF4 expression in proliferating cells so KLF4/??-catenin crosstalk defines the proliferating and differentiating compartments in the intestine. Up- regulation of ?-catenin and down-regulation of KLF4 together contribute to the initiation of colon cancers. To address this hypothesis we will pursue three Specific Aims to: 1) Delineate the mechanisms by which KLF4 inhibits ?-catenin signaling using cell-based assays or in vitro-binding assays; 2) Determine the mechanisms of APC-regulated KLF4 expression in colon cancer cells and in the intestines of APC-deleted mice; and 3) assess the functional effects of KLF4/??-catenin interactions in human colorectal cancers and in nude mice injected with colon cancer cells with altered KLF4/??-catenin signaling. These experiments should elucidate the role of this important signaling axis in the development and progression of colorectal cancers and eventually lead to new clinical markers and treatment approaches for this important class of cancers. Health Relevance: Colorectal cancer is the second leading cause of cancer-related deaths in the U.S. with -150000 new cases and 57000 deaths annually (about 10% of all cancer deaths) at an estimated annual economic cost greater than $3.5 billion. A better understanding of the signaling pathways contributing to colorectal cancer progression should provide targets for novel therapeutic agents to treat this disease.

project_terms:
Address;Adenomatous Polyposis Coli;Binding (Molecular Function);Binding Proteins;Biological Assay;C-terminal;Cancer Etiology;Casein Kinase Ialpha;Cell Adhesion;Cell Differentiation process;Cell Nucleus;Cell Proliferation;Cells;Cessation of life;Chromatin Structure;Clinical;Clinical Markers;Clinical Treatment;Colon Carcinoma;Colorectal Cancer;Complex;Cyclin D1;DNA;Data;Development;Disease;Down-Regulation;E-Cadherin;Epithelial Cells;Family;GKLF protein;Gene Targeting;Genes;Genetic Transcription;Glycogen Synthase Kinase 3;Health;Homeostasis;Human;In Vitro;Intestines;Kruppel-like transcription factors;Lead;Malignant Neoplasms;Mammalian Cell;Membrane;Messenger RNA;Methods;Molecular;Mus;Mutation;Natural regeneration;Neoplasm Metastasis;Nuclear Translocation;Nude Mice;Oncogenes;Pathway interactions;Phosphorylation;Process;Proliferating;Proteins;Proto-Oncogene Proteins c-myc;Publishing;Recruitment Activity;Repression;Research Personnel;Role;Sampling;Signal Pathway;Signal Transduction;Signaling Molecule;Stem cells;TCF Transcription Factor;Testing;Therapeutic Agents;Tissues;Transact;Transcription Coactivator;Tumor Suppressor Proteins;Up-Regulation (Physiology);base;beta catenin;c-myc Genes;cancer cell;colon cancer cell line;colon carcinogenesis;economic cost;gastrointestinal;insight;mouse model;multidisciplinary;novel;overexpression;programs;research study;tumor;tumor growth;tumor progression;tumor xenograft;tumorigenesis;ubiquitin ligase


application_id: 8107349
project_number: 1R01NS069633-01A1
project_title: Mitochondrial-Targeted Therapeutics for Treatment of Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2011-06-06
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: NS
serial_number: 069633
suffix: A1
program_official: KLEITMAN, NAOMI
project_start_date: 2011-06-15
project_end_date: 2015-04-30
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: RABCHEVSKY, ALEXANDER GEORGE
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 long-term health care problem in the United States and with the exception of the modestly effective methylprednisolone there is currently no neuroprotective intervention clinically available for treatment of acute SCI. Our published data and preliminary results demonstrate that oxidative damage to key mitochondrial enzymes and subsequent mitochondrial dysfunction is key to the neuropathological sequalae following SCI. This proposal focuses on directly targeting mitochondrial dysfunction as a novel therapeutic intervention for contusion SCI the fundamental concept being that SCI-induced excitotoxicity increases mitochondrial Ca2+ cycling/overload and the production of reactive oxygen species (ROS) ultimately leading to mitochondrial dysfunction and glutathione (GSH) depletion. Our approach is two-pronged aimed at reducing mitochondrial ROS production utilizing a novel cell-permeant antioxidant and GSH precursor NACA (the amide form of N-acetylcysteine) as well as an alternative biofuel substrate for energy production acetyl-l-carnitine (ALC) following SCI. Our published and preliminary data signify that both NACA and ALC improve mitochondrial bioenergetics following contusion SCI in rats and that prolonged NACA or ALC treatment increases tissue sparing following injury. The planned experiments are designed to test the novel hypothesis that reducing oxidative damage to key mitochondrial proteins will maintain mitochondrial bioenergetics thus leading to increased neuroprotection and improved functional recovery following contusion SCI. Specifically we will: 1) Characterize oxidative damage to specific mitochondrial proteins involved in bioenergetics and test the hypothesis that NACA treatment ameliorates mitochondrial oxidative damage following SCI 2) Test the hypothesis that a combinatorial treatment with NACA and ALC will act synergistically to preserve mitochondrial homeostasis following SCI and 3) Test the hypothesis that a combinatorial treatment with NACA and ALC will increase tissue sparing and promote long-term functional recovery following SCI. Critically this application is built around the utilization of several novel techniques we have developed for isolating synaptic (neuronal) and non-synaptic (soma and glia) mitochondria from the injured spinal cord as well as an L1/L2 contusion SCI paradigm that demonstrates a significant correlation between neuroprotection and remarkable improvements in recovery of hind limb function. Collectively the proposed experiments will pinpoint key mitochondrial events that could be potential novel targets for pharmacological interventions to more effectively treat SCI and perhaps other CNS injuries.  
  
PUBLIC HEALTH RELEVANCE: Spinal cord injury (SCI) is a serious health care problem in the United States. However with the exception of the modestly effective methylprednisolone no neuroprotective intervention is clinically available for treatment of acute SCI. This proposal focuses on directly targeting mitochondrial dysfunction as a novel therapeutic intervention following spinal cord injury (SCI).


application_id: 8106934
project_number: 3R01GM070662-06S1
project_title: COOPERATIVE INTERACTIONS IN DNA REPAIR
administering_ic: NIGMS
award_notice_date: 2010-07-26
application_type: 3
activity_code: R01
ic: GM
serial_number: 070662
suffix: S1
program_official: PREUSCH, PETER
project_start_date: 2004-04-01
project_end_date: 2012-08-31
study_section: Biophysics and Biophysical Chemistry A Study Section[BBCA]
contact_pi_person_id: 8344857
contact_pi: FRIED, MICHAEL G.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Our goal is to elucidate mechanisms by which DNA-repair proteins perform their essential biological functions. As immediate objectives we will investigate the interactions of human 0 6- alkylguanine-DNA alkyltransferase (AGT) with O6-alkylguanine (lesion)-containing and lesion-free DNAs. AGT repairs pro-mutagenic O -alkylguanine residues in DNA. It binds DNA with substantial cooperativity but little sequence or base composition dependence. These results argue against mechanisms of target recognition that depend strongly on sequence. An alternate possibility which comprises the central hypothesis of this application is that cooperative DNA binding and access to DNA modulate the binding distributions of AGT and its rate of DNA-repair. To test this hypothesis we will pursue three specific aims. These are: 1. To determine how binding cooperativity supercoiling and the presence of nucleosomes affect the equilibrium distribution of AGT among available DNA sites and between O6-alkylguanine - containing and lesion-free sequences. 2. To identify amino acids that are present at the protein-protein interface in the cooperative AGT-DNA complex. To test the consequences of mutation of these residues on DNA binding in vitro and on DNA repair in vitro and in vivo. 3. To identify the roles played by cooperative binding supercoiling and nucleosomes in the kinetic mechanisms of lesion-search by AGT and on its rate of DNA repatr. At the conclusion of this research we will have identified the role played by cooperative binding in lesion-search -binding and -repair and we will have tested the notion that the rate of lesion-search depends on the structure of the DNA template. Together these results will test the hypothesis that differences in DNA structure and accessibility determine the mechanism(s) by which AGT scans the genome for lesions and repairs them.

project_terms:
Active Sites;Affect;Affinity;Amino Acids;Base Composition;Binding (Molecular Function);Biological Process;Biology;Complex;DNA;DNA Binding;DNA Repair;DNA Structure;DNA alkyltransferase;DNA repair protein;DNA-Binding Proteins;Dependence;Equilibrium;Genome Scan;Goals;Homologous Gene;Human;In Vitro;Kinetics;Lesion;Modeling;Molecular;Mutation;Nucleosomes;O(6)-Methylguanine-DNA Methyltransferase;Play;Positioning Attribute;Protein Binding;Proteins;Research;Role;Site;Testing;Work;experience;in vivo;mutant;protein protein interaction;repaired


application_id: 8106684
project_number: 1R01AR059810-01A1
project_title: TAK1/TRAF6 Signaling in Skeletal Muscle
administering_ic: NIAMS
award_notice_date: 2011-06-17
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: AR
serial_number: 059810
suffix: A1
program_official: BOYCE, AMANDA T
project_start_date: 2011-07-01
project_end_date: 2016-06-30
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1917770
contact_pi: KUMAR, ASHOK
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Skeletal muscle atrophy/wasting is a devastating complication of a wide range of diseases and conditions such as aging disuse chronic obstructive pulmonary disease space travel chronic heart failure sepsis and cancer. Myogenesis is the process that is required not only for the embryonic development of skeletal muscle but it is also an important element of certain types of postnatal growth and repair of injured myofibers. Impairment in myogenesis is the critical determinant of skeletal muscle-wasting in several chronic diseases and also development of rhabdomyosarcoma in children. Although significant progress has been made to understanding the processes of skeletal muscle formation and wasting the upstream signaling events regulating skeletal muscle mass in various physiological and pathophysiological conditions remain poorly understood. We have accumulated strong evidence that supports a crucial role of TAK1/TRAF6 signaling complex in the acquisition and maintenance of skeletal muscle mass. Our preliminary studies have shown that both TRAF6 and TAK1 stimulate myogenic differentiation through novel Lysine-63-linked poly-ubiquitination mechanisms. TAK1 and TRAF6 are also required for MyoD-induced transformation of non-muscle cells into skeletal muscles. In adult skeletal muscle the activation of TAK1/TRAF6 leads to inflammation impairment in myofiber regeneration and atrophy. To clearly establish the role and delineate the mechanisms of action of TAK1/TRAF6 complex in skeletal muscle we will use genetic approaches including conditional knockout mice. Based on our preliminary data we hypothesize that signaling through TAK1 and TRAF6 is required for the development of skeletal muscle but not for maintaining differentiated phenotype. Under stress conditions the activation of TAK1 and TRAF6 stimulates catabolic pathways leading to skeletal muscle atrophy. To test this hypothesis we propose to address the following three specific aims: 1) Investigate the signaling mechanisms by which TAK1 and TRAF6 regulate myogenic differentiation in cultured myoblasts; 2) Investigate the role and cellular mechanisms by which TAK1 and TRAF6 regulate skeletal muscle development in vivo; and 3) Delineate the mechanisms by which TAK1 and TRAF6 regulates regeneration and atrophy in adult skeletal muscles. Successful completion of this project will provide critical insights into the signaling mechanisms and establish TAK1 and TRAF6 as novel molecular targets to prevent skeletal muscle loss in various muscular disorders.  
  
PUBLIC HEALTH RELEVANCE:  Skeletal muscle formation and wasting are well-orchestrated processes regulated by autocrine paracrine and endocrine factors via multiple signal transduction pathways. Our proposed studies are aimed to dissect the signaling mechanisms underlying the regulation of muscle differentiation with a focus on TAK1/TRAF6 complex. In addition to muscle formation our study will also delineate the signaling mechanisms responsible for accelerated protein degradation that causes rapid atrophy of mature skeletal muscles. Results of these studies will contribute to the understanding of skeletal muscle biology which will have a significant impact on health-related issues such as sarcopenia disease- induced muscle atrophy muscle regeneration and rhabdomyosarcoma.

project_terms:
Address;Adult;Affect;Aging;Apoptosis;Area;Atrophic;Biochemical;Biology;Calcineurin;Cell Culture Techniques;Cell Cycle Arrest;Cell Line;Cell Surface Proteins;Cells;Child;Chronic;Chronic Disease;Chronic Obstructive Airway Disease;Complex;Complication;Cytoplasmic Tail;Data;Denervation;Development;Disease;Drug Delivery Systems;Elements;Embryonic Development;Endocrine;Event;Family;Fiber;Genetic;Growth;Health;Heart failure;Human;Impairment;Inflammation;Knockout Mice;Laboratories;Lead;Link;Lysine;MAP Kinase Gene;MAP3K7 gene;MAPK14 gene;Maintenance;Malignant Neoplasms;Mediating;Methods;Molecular Target;Muscle;Muscle Development;Muscle Fibers;Muscular Atrophy;Myoblasts;Myopathy;Natural regeneration;Neonatal;Nude Mice;Pathway interactions;Perinatal;Phenotype;Phosphotransferases;Physiological;Play;Polyubiquitin;Process;Protein Biosynthesis;Proteins;Regulation;Rhabdomyosarcoma;Role;Sepsis;Signal Transduction;Signal Transduction Pathway;Skeletal muscle structure;Staging;Stem cells;Stimulus;Stress;System;TRAF6 gene;Testing;Transforming Growth Factors;Travel;Tumor Necrosis Factor Receptor;Ubiquitination;autocrine;base;human morbidity;human mortality;improved;in vivo;injured;insight;mouse model;muscle form;muscle regeneration;myogenesis;novel;paracrine;postnatal;prevent;protein degradation;repaired;response to injury;sarcopenia;satellite cell;skeletal muscle growth;skeletal muscle wasting;transcription factor NF-AT c3;ubiquitin-protein ligase;wasting


application_id: 8106571
project_number: 1R01HL103750-01A1
project_title: Respiratory motor control and blood pressure regulation after spinal cord injury
administering_ic: NHLBI
award_notice_date: 2011-06-06
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: HL
serial_number: 103750
suffix: A1
program_official: LAPOSKY, AARON D
project_start_date: 2011-06-07
project_end_date: 2015-05-31
study_section: Clinical and Integrative Cardiovascular Sciences Study Section[CICS]
contact_pi_person_id: 9348839
contact_pi: OVECHKIN, ALEXANDER VLADIMIROVICH
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
project_abstract:
DESCRIPTION (provided by applicant):   
Many individuals with chronic spinal cord injury (SCI) face the challenge of managing their unstable blood pressure which frequently results in persistent hypotension due to decreased cardiac output and autonomic nervous system dysfunction. In addition blood pooling in the lower body during upright posture leads to a further decrease in blood pressure known as orthostatic hypotension. These conditions severely impact the overall health of SCI individuals delay their participation in rehabilitative treatment limit the effectiveness of such treatment and significantly interfere with activities of daily living. In our clinic that utilizes activity-based therapy programs we have observed that one of the most common impediments to full participation in these programs was orthostatic hypotension. Further orthostatic intolerance increases the cost and decreases the efficacy of rehabilitative treatment. Another common impediment to rehabilitation after SCI is respiratory insufficiency due to paresis and paralysis of respiratory muscles. Physiologically these respiratory and cardiovascular dysfunctions are closely related. Data from our laboratory show that resting blood pressure correlates positively with pulmonary function outcomes and the location and severity of spinal cord lesion. These relationships could be due to better venous return to the heart as a result of higher negative intrapleural pressure and/or higher sympathetic tone due to better baroreflex response in individuals with better inspiratory and expiratory motor control. Our preliminary data showed that respiratory motor function after SCI can be improved by respiratory muscle training (RMT) a rehabilitative technique based on the breathing with resistance exercise. We observed that resting blood pressure and orthostatic tolerance were also improved after RMT in individuals with SCI. Therefore for the current proposal we hypothesize that RMT will improve blood pressure regulation in individuals with chronic SCI. We will examine the response of physiological regulatory mechanisms to RMT. Based on statistical power analysis forty five individuals who have chronic SCI will be recruited for this study over a four-year period. All subjects will have been diagnosed as having respiratory function deficits and orthostatic hypotension. We will evaluate pulmonary and cardiovascular function using spirometry respiratory muscle strength sympathetic skin response tests and surface electromyography of respiratory muscles. In addition we will use continuous beat-to-beat recording of systemic arterial blood pressure heart rate cardiac output and the measurements of blood catecholamines level during orthostatic stress test. Autonomic regulation outcomes will be calculated from beat-to-beat blood pressure and heart rate frequency composition analysis. We will also evaluate Spinal Cord Injury Independence (SCIM-III) and quality of life (CHART) measures. These outcomes will be obtained before a total of 20 RMT sessions lasting 45 minutes each / 5 days per week immediately after RMT and during 6-month follow-up period in 35 research participants forming the experimental group. Another 10 individuals serving as a control group will undergo the same procedures except the RMT intervention during the same time course. This technique as a therapeutic intervention in order to improve the blood pressure regulation and investigate its mechanisms in individuals with SCI has never been tested before. The results of this study will have direct effect on the SCI population by improving our understanding of the mechanisms of pulmonary function and blood pressure regulation and offering a pathophysiologically based rehabilitation strategy.  
  
PUBLIC HEALTH RELEVANCE:   
Spinal cord injury (SCI) is commonly associated with paralysis resulting in pulmonary and cardiovascular dysfunctions which are listed among the leading causes of death in SCI population. The overall goal of this project is use a respiratory to muscle training to enhance respiratory motor function improve blood pressure regulation and to investigate the mechanisms of such improvement in persons with chronic SCI. The results of this study will have direct effect on the SCI population by providing the opportunity to significantly improve the overall health in individuals with SCI using novel rehabilitative approaches.

project_terms:
Activities of Daily Living;Affect;Area;Autonomic nervous system;Baroreflex;Blood;Blood Pressure;Breathing;Cardiac Output;Cardiovascular Physiology;Cardiovascular system;Catecholamines;Cause of Death;Chronic;Clinic;Control Groups;Data;Diagnosis;Diastolic blood pressure;Educational Intervention;Effectiveness;Electromyography;Exercise;Face;Frequencies (time pattern);Functional disorder;Goals;Health;Heart;Heart Rate;Hypotension;Individual;Injury;Laboratories;Location;Lung;Measurement;Measures;Motor;Muscle;Muscle Weakness;Neurologic;Orthostatic Hypotension;Outcome;Outcome Measure;Paralysed;Paresis;Participant;Performance;Persons;Physiological;Play;Population;Posture;Procedures;Pulmonary Function Test/Forced Expiratory Volume 1;Quality of life;Recovery;Recruitment Activity;Regulation;Rehabilitation therapy;Research;Resistance;Respiration;Respiratory Insufficiency;Respiratory Muscles;Respiratory Paralysis;Respiratory physiology;Response Latencies;Rest;Role;Secondary to;Severities;Skin;Spinal Cord Lesions;Spinal cord injury;Spirometry;Stress;Stress Tests;Surface;Techniques;Testing;Therapeutic Intervention;Time;Training;Training Technics;Venous;Vital capacity;base;blood pressure regulation;cardiopulmonary system;clinically relevant;cost;density;experience;follow-up;functional outcomes;improved;improved functioning;motor control;muscle strength;novel;novel therapeutic intervention;pressure;programs;pulmonary function;rehabilitation strategy;respiratory;response


application_id: 8106301
project_number: 5R01HL072936-06
project_title: Regulation of Calcium Channel Function by the Rem GTPase
administering_ic: NHLBI
award_notice_date: 2011-06-14
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 072936
program_official: PRZYWARA, DENNIS
project_start_date: 2003-04-15
project_end_date: 2014-04-30
study_section: Electrical Signaling, Ion Transport, and Arrhythmias Study Section[ESTA]
contact_pi_person_id: 7875195
contact_pi: ANDRES, DOUGLAS ALLEN
other_pis: SATIN, JONATHAN
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:
Project Summary/Abstract:Voltage-activated Ca channels serve two critical functions: the regulation of cellular excitability and the regulation of Ca entry. Alterations in the density or function of L-type Ca channels are implicated in a variety of cardiovascular diseases. Thus elaborating the basic mechanisms that regulate Ca channels is important for understanding both fundamental channel physiology and for therapeutic intervention. During the past funding period we have identified the Rem GTPase as a novel modulator of l(Ca). It was originally thought that Rem association with CaVbeta subunits chronically regulated l(Ca) by inhibiting channel trafficking. Our studies have disproved this hypothesis demonstrating Rem-mediated Ca channel regulation without changes in surface density. Instead Rem seems to modulate Ca channel activity through interactions with both CaVbeta and the proximal CaV1.2 C-terminus near the CB/IQ domain. Two of the most physiologically relevant controls of l(Ca) are PKA-modulation and calmodulin (CaM)-modulation. Our most recent studies suggest that Rem modulates l(Ca) responses to each of these signaling pathways. Thus Rem appears to contribute to both beta-adrenergic and Ca-CaM control of l(Ca). The specific hypothesis to be tested is that Rem GTPase regulates Ca channel activity in cardiac muscle through interactions with both CaVb-subunits and the CaV1.2 C terminus. Three hypothesis driven aims focus our studies and advance knowledge of this novel regulatory mechanism. Aim 1 will explore the nature of Rem-mediated channel regulation by examining the effect of Rem loss on Ca channel regulation. Initial characterization of Rem knockout mice indicates that i) Rem functions in vivo to regulate l(Ca); ii) contributes to the cardiac response to pressure-overload; and iii) contributes to cardiac myocyte growth/maturation homeostasis. Aim 2 will determine whether interaction of Rem with CaVbeta or CB/IQ is critical for modulation of l(Ca). Aim 3 will investigate how Ca- calmodulin modulates Rem-mediated channel blockade and determine whether PKA phosphorylation alters Rem membrane trafficking or the interaction between Rem and its binding partners. RGK G-proteins function as modulators of Ca channel activity contributing to regulation of l(Ca) excitation contraction coupling and the cardiac response to pressure-overload. The goal of this research is to generate a deeper understanding of the physiological ramifications and molecular mechanism of RGK/Ca channel modulation to speed progress toward the therapeutic exploitation of RGKs in cardiovascular disease.

project_terms:
Adrenergic Agents;Animal Model;Atrial Fibrillation;Attenuated;Binding (Molecular Function);Biochemical;Calcium;Calcium Channel;Calmodulin;Cardiac;Cardiac Myocytes;Cardiovascular Diseases;Cell membrane;Chronic;Complex;Coupling;Critiques;Cyclic AMP-Dependent Protein Kinases;Echocardiography;Family;Funding;GTP-Binding Proteins;Goals;Grant;Growth;Guanosine Triphosphate Phosphohydrolases;Heart;Heart Diseases;Heart Hypertrophy;Heart failure;Histology;Homeostasis;Knock-out;Knockout Mice;Knowledge;L-Type Calcium Channels;Measurement;Mediating;Membrane Protein Traffic;Molecular;Monomeric GTP-Binding Proteins;Myocardial Contraction;Myocardial Ischemia;Myocardium;Nature;Performance;Phosphorylation;Physiological;Physiology;Process;Protein Family;Proteins;Regulation;Regulatory Pathway;Research;Role;Signal Pathway;Signal Transduction;Site-Directed Mutagenesis;Speed (motion);Surface;Testing;Therapeutic;Therapeutic Intervention;Transcriptional Regulation;Transgenic Organisms;adrenergic;cell growth regulation;density;heart function;in vivo;insight;member;mutant;novel;overexpression;pressure;protein function;public health relevance;response;stoichiometry;trafficking;voltage

public_health_relevance:
Project Narrative:Voltage-activated calciwn channels serve two critical functions: the regulation of calciwn entry and the control of heart contraction. Changes in the nwnber or function of L-type calcium channels are implicated in a vartety of cardiovascular diseases including atrial fibrillation heart failure and ischemic heart disease. Thus understanding the basic mechanisms that regulate calcium channels is important for understanding both fundamental heart muscle performance and for therapeutic intervention. We have identified a family of proteins that regulate calcium channels and the goal of this research is to speed progress toward the day when these proteins can be used to treat heart disease.


application_id: 8105492
project_number: 5T32ES011564-08
project_title: UofL Environmental Health Sciences Training Program
project_terms: Environmental Health;Training Programs
administering_ic: NIEHS
award_notice_date: 2011-07-04
opportunity_number: PA-06-468
application_type: 5
activity_code: T32
ic: ES
serial_number: 011564
program_official: SHREFFLER, CAROL A
project_start_date: 2004-07-01
project_end_date: 2014-06-30
study_section: Environmental Health Sciences Review Committee[EHS(T2)]
contact_pi_person_id: 1924912
contact_pi: HEIN, DAVID W
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant)  
  
The investigators have made strategic changes in their environmental health sciences training program in response to the announced restructuring and redirection of NIEHS training programs.  Participating Centers Institutes and Schools and the 43 members of the training faculty provide critical resources for cutting edge basic science clinical research computational sciences and public health.  Environmental health science partnerships have resulted in a very successful NIEHS Training Program in environmental health sciences and recently in the funding of a NIEHS P30 Center for Environmental Genomics and Integrative Biology (CEGIB). The renewal proposal incorporates and integrates several new Schools Centers and Institutes including CEGIB the Clinical and Translational Sciences Institute and the School of Public Health and Information Sciences.  The investigators propose a substantially improved pre-doctoral and postdoctoral training program that serves as an umbrella for interdisciplinary and integrated approaches to environmental health sciences. The training program will support six pre-doctoral and three postdoctoral trainees.  Initial student recruitment and funding for pre-doctoral trainees is provided by the University of Louisville Integrated Programs in the Biomedical Sciences recruitment gateway.  As in the first cycle pre-doctoral trainees will not be recruited directly into the environmental health sciences training program.  All faculty mentors are asked to nominate trainees who have completed an approved dissertation proposal with a defined focus in environmental health sciences research.  Faculty mentors will be asked to nominate either existing postdoctoral fellows (for example those already matriculated into the Clinical Chemistry and Toxicology Translational Sciences Program) or from trainees to be recruited.  Teams of mentors (basic and clinical scientists or basic and population-based scientists) will be particularly encouraged to emphasize the importance of multidisciplinary training and translation of basic science findings to the patient and/or community.  The training program facilitates multidisciplinary approaches for effective intervention and interfaces exceptionally well with the NIH Roadmap as well as with the strategic plans of the NIEHS and the University of Louisville.  
  
  
BACKGROUND  
  
This is the first competitive renewal of the University of Louisville Environmental Health Sciences Training Program.  The goal of this Training Program has been revised in this application to turn into a bigger umbrella for interdisciplinary and integrated approaches to environmental health sciences at the University of Louisville. The number of mentors has increased from 19 mentors and 13 associate mentors to 43 mentors.  Environmental health science partnerships have led to a recently funded NIEHS P30 Center for Environmental Genomics and Integrative Biology (CEGIB).  The training program will support 6 pre-doctoral and 3 postdoctoral trainees.


application_id: 8104120
project_number: 5R25GM083835-04
project_title: Appalachian Kentucky Bridges to Success
administering_ic: NIGMS
award_notice_date: 2011-06-16
opportunity_number: PAR-07-039
application_type: 5
activity_code: R25
ic: GM
serial_number: 083835
program_official: HAMLET, MICHELLE R
project_start_date: 2008-07-11
project_end_date: 2013-06-30
study_section: Special Emphasis Panel[ZRG1-IMM-A(50)R]
contact_pi_person_id: 8581205
contact_pi: KNOX, TAMARA L.
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Kentucky has set a goal of increasing the educational attainment level of the Commonwealth to the national average by 2020 and to do this Kentucky needs to double the number of baccalaureate degree holders over the next 14 years from roughly 400000 in 2000 to nearly 800000 by 2020. This goal is especially daunting for educational institutions serving the eastern (Appalachian) region of Kentucky. Recent research has shown that students entering the Kentucky Community and Technical College System (KCTCS) and 4-year universities that serve the regions with the greatest need (largely comprised of eastern Kentucky) were the least prepared for college study of all students in the state. To address this problem a collaboration between the Hazard Community and Technical College University of Kentucky Center for Excellence in Rural Health and University of Kentucky has been developed to propose a program to engage promising rural Appalachian community college students in academic research psychosocial and financial support networks to enable them to successfully complete their baccalaureate degree in the biomedical or behavioral sciences. This application proposes to: (a) recruit program participants from HCTC; (b) carefully assess participants' learning- related skills and deficits; (c) provide a program that includes mentoring instruction in skills necessary to be successful in 4-year institutions of higher learning structured experiences to expose participants to career options and group support; (d) facilitate participants' efforts to transfer from community college to 4-year institutions; (e) carefully evaluate each component of the program; and (f) track participants to document and assess participant experience at 4-year institutions. Program evaluation milestones will include the successful recruitment retention transfer and graduation of promising students in the biomedical and behavioral sciences; increased communication between faculty at community colleges and baccalaureate institutions; faculty participation in transfer initiatives and program development that promotes the seamless transition of students between participating institutions; development of programs that advance and improve science teaching and mentoring; and development of program resources.  
  
This project proposes to develop a comprehensive program for community college students in southeastern Kentucky a region with very low educational levels. The program will include instruction and experiences to increase participants' awareness of career options mentoring and support in applying to transfer from community college to 4-year educational institutions. The program will be evaluated rigorously and will include documentation of all activities assessment of participant progress and follow-up after transfer from the community college.

project_terms:
Address;Appalachian Region;Awareness;Bachelor's Degree;Behavioral Sciences;Biological Sciences;Collaborations;Collection;Communication;Communities;Data;Documentation;Educational Materials;Educational Status;Educational aspects;Educational process of instructing;Ensure;Faculty;Family;Financial Support;Goals;Grant;Health Hazards;Institution;Instruction;Joints;Kentucky;Learning;Mentors;Monitor;Natural Sciences;Pamphlets;Participant;Press Releases;Process;Program Development;Program Evaluation;Psychosocial Assessment and Care;Recruitment Activity;Research;Research Support;Resources;Rural;Rural Health;Scholarship;Science;Structure;Students;System;Time;Universities;Vocational Guidance;base;career;college;data management;experience;falls;follow-up;group support;hazard;improved;programs;skills;success;university student;web site


application_id: 8104112
project_number: 5R01GM079516-05
project_title: Structural and Functional Studies of the SMC5-6 Complex
administering_ic: NIGMS
award_notice_date: 2011-06-30
application_type: 5
activity_code: R01
ic: GM
serial_number: 079516
program_official: PREUSCH, PETER
project_start_date: 2007-07-01
project_end_date: 2013-10-31
study_section: Macromolecular Structure and Function C Study Section[MSFC]
contact_pi_person_id: 8139941
contact_pi: YE, HONG
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
DESCRIPTION (provided by applicant):  The structural maintenance of chromosomes (SMC) proteins which are evolutionarily conserved from prokaryotes to eukaryotes are essential for higher order chromosome organizations and functions. Six members of SMCs have been identified in eukaryotes which form three distinct complexes: cohesin condensin and the Smc5/6 complex. Each of the SMC complexes has a unique function. Cohesin is responsible for linking sister chromatids during mitosis and meiosis whereas condensin is required for condensation of chromosomes during mitosis and meiosis. The Smc5/6 holocomplex formed by a heterodimer of Smc5 and Smc6 in association with six non-SMC components in both Saccharomyces cerevisiae and Schizosaccharomyces pombe is localized on repetitive rDNA and telomere and is important for DNA replication and double stranded DNA damage repair through homologous recombination.  
  
SMC proteins are organized into five domains: an N-terminal head domain a long coiled-coil helix a hinge domain another long coiled-coil helix and a C-terminal head domain. The N- and C-terminal head domains associate together to form an ATPase head domain. The long coiled-coil helices associate together to form the coiled-coil arm. The hinge domain dimerizes to form the hinge of the complex. While the head appears to recognize DNA the hinge controls the spatial topology of the arms and the head and therefore the conformation of overall structure. In the Smc5/6 holocomplex the non-SMC component Mms21 a SUMO E3 ligase is important for Smc5/6-mediated DNA damage repair. The molecular mechanism of the function is unclear. In addition limited structural information is available on SMC complexes especially Smc5/6. To fill this gap we propose a series of comprehensive studies on several important aspects of this complex which will have tremendous impact on the molecular basis of Smc5/6 function as well as the functions of cohesin and condensin.

project_terms:
ATP phosphohydrolase;C-terminal;Cells;Characteristics;Chromosome Condensation;Chromosome Structures;Chromosomes;Complex;DNA;DNA Binding;DNA Repair;DNA biosynthesis;Eukaryota;Fingers;Fission Yeast;Head;Heterodimerization;In Vitro;Investigation;Length;Ligase;Link;Maintenance;Maps;Mediating;Meiosis;Mitosis;Molecular;Molecular Conformation;Mutation;N-terminal;Phenotype;Prokaryotic Cells;Proteins;Recombinant DNA;Recombinants;Research Personnel;Resolution;Saccharomyces cerevisiae;Series;Sister Chromatid;Site;Structure;Yeasts;arm;base;cohesin;condensin;ds-DNA;homologous recombination;in vivo;member;programs;telomere;ubiquitin-protein ligase


application_id: 8104095
project_number: 5T32ES007266-22
project_title: TRAINING GRANT IN MOLECULAR MECHANISMS OF TOXICITY.
project_terms: Grant;Molecular;Toxic effect;Training
administering_ic: NIEHS
award_notice_date: 2011-07-04
application_type: 5
activity_code: T32
ic: ES
serial_number: 007266
program_official: SHREFFLER, CAROL A
project_start_date: 1990-07-01
project_end_date: 2015-06-30
study_section: Environmental Health Sciences Review Committee[EHS(01)]
contact_pi_person_id: 1862358
contact_pi: VORE, MARY
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant)  
  
The objectives of the Molecular Mechanisms of Toxicity Training Program are to provide trainees with an education in the cellular and molecular mechanisms by which environmental agents induce human disease. The training program is based on an understanding of biochemistry molecular/cell biology pharmacology and toxicology and is coupled with in-depth laboratory research training. The Training Program is based in the Graduate Center for Toxicology (GCT) a basic science department in the College of Medicine that grants the Ph.D. in Toxicology and provides an administrative and teaching nucleus of 11 Core Faculty. Joint faculty from Medicine Pharmacy Agriculture and Arts & Sciences enrich the diversity of training opportunities; 25 of these Core and Joint Faculty with strong research programs make up the Training Grant Faculty. This competitive renewal application requests support for 4 pre- and 2 postdoctoral trainees; it is focused on three disease areas with an environmental basis: Cancer Cardiovascular Disease and Neurodegenerative Disease. Oxidative stress and DNA damage and repair are mechanistic themes that underlie many of the research programs providing opportunities for collaborations and multidisciplinary approaches that enrich the research training. The pre-doctoral training program requires biomedical (25 credits) and toxicology bases (13 credits) and an elective (2-4 credits). Pre-doctoral trainees will be supported for a maximum of 3 years (e.g. years 2-4 of doctoral training; Postdoctoral trainees will be supported for a minimum of 2 years.  Ph.D. fellows will be recruited within 3 years of their degree while M.D. fellows will be recruited upon completion of their residency training; the investigators anticipate a ratio of 2 Ph.D.s to 1 M.D. Postdoctoral trainees are required to enroll and participate in 2 credits of Environmental Exposure and Human Disease in addition to a rigorous laboratory experience.  Currently 28 students are enrolled in the Toxicology Ph.D. program including 6 minority students most of whom were recruited from the University of Puerto Rico and supported by summer research/education grants. The University provides strong support for the GCT in the form of student fellowships supplementation to this Training Grant and faculty lines space and equipment to enhance and sustain a strong toxicology program.   
  
Relevance: The Training Program in Molecular Mechanisms of Toxicity will provide pre- and postdoctoral fellows with a fundamental understanding of the molecular and cellular processes by which environmental agents impact human health and cause disease. The long-term goal is to prepare and inspire the next generation of scientists to address the ever-present environmental challenges to human health by the prevention of disease either by nutritional intervention or by otherwise exploiting human defense systems.


application_id: 8104036
project_number: 5T03OH008437-07
project_title: Occupational Safety and Health Program Improvement
administering_ic: NIOSH
award_notice_date: 2011-06-22
opportunity_number: PAR-06-484
application_type: 5
activity_code: T03
ic: OH
serial_number: 008437
program_official: NEWHALL, JIM
project_start_date: 2005-07-01
project_end_date: 2015-06-30
study_section: ZOH1-EEO(51)R
contact_pi_person_id: 8075543
contact_pi: KRAEMER, DAVID G
other_pis: Not Applicable
congressional_district: 01
department: OTHER HEALTH PROFESSIONS
primary_duns: 041980632
primary_uei: LHC2S92MXG63
duns_number: 041980632
uei: LHC2S92MXG63
fips: US
organization_id: 5591701
organization_name: MURRAY STATE UNIVERSITY
organization_city: MURRAY
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 420712393
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The purpose of this proposal is to strengthen the preparation of undergraduate and graduate level students in occupational safety and health. This will be accomplished by providing learning situations/activities designed to help students become more effective entry-level and advanced occupational safety and health professionals. The primary focus will be:  
  
1. Increased involvement of the internship supervisors in visiting intern sites to observe and improve employer-intern-university relationships.  
  
2. Development and enhancement of interdisciplinary/multidisciplinary concentrations and minors with the following programs: agriculture business and environmental/construction engineering technology.  
  
3. On-going faculty professional development to keep abreast of changes in the occupational safety and health field.  
  
4. Development of seminars and Occupational Safety and Health Training Center (OSHTC) courses designed to address current occupational safety and health issues.  
  
5. Support for graduate students in the form of travel and tuition and fees.  
  
Trainee fees for graduate students only are being requested.  
  
6. Improvement and upgrade of the laboratory and computer facilities and equipment within the OSH department.  
  
The OSH department had 279 students in the program during the 2008-2009 academic year which included 225 in the undergraduate program 54 in the graduate program and 35 students minoring in occupational safety and health. Additionally the department placed 73 interns during the 2008-2009 academic year and anticipates placing 75-90 interns in the upcoming academic year.


application_id: 8103961
project_number: 5T32DA007304-14
project_title: Research Training in Drug Abuse Behavior
project_terms: Behavior;Drug abuse;Research Training
administering_ic: NIDA
award_notice_date: 2011-06-22
opportunity_number: PA-06-468
application_type: 5
activity_code: T32
ic: DA
serial_number: 007304
program_official: KHALSA, JAGJITSINGH H
project_start_date: 1998-08-01
project_end_date: 2013-06-30
study_section: ZDA1-EXL-T(04)
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This training program co-directed by Thomas Garrity and Carl Leukefeld proposes to support three pre and three postdoctoral trainees with a training faculty of 24 drawn from six different academic and research units of the University. The environment is rich with opportunities for biobehavioral research in facilities such as the Center on Drug and Alcohol Research the Center for Drug and Alcohol Research and Translation and the Residential Research Facility. Trainees will be housed in offices and laboratories of their research supervisor with 24 hour/day access to laboratories and computer facilities. This program is designed to prepare trainees to assume research responsibilities in academic and other scientific organizations concerned with drug abuse and the behavioral aspects of health and medical care. Postdoctoral fellows will either have a doctorate in a behavioral science discipline and will be preparing for a research role in the drug abuse field or they will be health professionals who are seeking a behavioral science research orientation in drug abuse. Predoctoral trainees will concentrate in behavioral aspects of drug abuse as part of their program for a doctorate in a behavioral science discipline. Basic elements of the program include: (1) research training designed to provide experience in utilizing the basic building blocks of research (interviewing case study experimental design development and pretesting of instruments data analysis) and independent research competence; (2) an interdisciplinary orientation which takes students beyond their basic discipline and provides exposure to key theoretical concepts and methodological issues of the related behavioral sciences along with a biobehavioral'conceptualization; (3) a program of enculturation and orientation to drug abuse health and mental health settings; (4) opportunities to explore drug abuse topics from a medical behavioral perspective through courses offered by training faculty; and (5) opportunities for research around relevant questions in drug abuse behavior that can constitute significant learning experiences for postdoctoral fellows and a dissertation project for predoctoral trainees. The program for postdoctoral fellows will be individually geared to the objectives of the fellows and will build on their previous knowledge and experience.


application_id: 8103822
project_number: 5R01CA133171-02
project_title: The role of the Ras effector Nore1a in tumor suppression
administering_ic: NCI
award_notice_date: 2011-04-07
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 133171
program_official: WATSON, JOANNA M
project_start_date: 2010-07-01
project_end_date: 2015-04-30
study_section: Cancer Molecular Pathobiology Study Section[CAMP]
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:
DESCRIPTION (provided by applicant): Nore1a is a member of the RASSF family of tumor suppressors. It is frequently down- regulated in primary human tumors and is genetically linked to a familial human cancer syndrome. Over-expression of Nore1a can promote apoptosis cell cycle arrest and senescence. Restoration of Nore1a expression to physiological levels blocks the tumorigenic phenotype and shRNA mediated inactivation of Nore1a enhances the transformed phenotype. Thus the evidence that Nore1a is an important human tumor suppressor is strong. Nore1a also directly binds the Ras oncoprotein and appears to serve as a novel effector mediating some of the pro-apoptotic and pro-senescent effects of oncogenic Ras. Thus loss of function of Nore1a may be particularly important to Ras dependent tumors allowing oncogenic Ras to circumvent its apoptotic and senescent functions. However the signaling pathways controlled by Nore1a have not been defined and no animal model for Nore1a function has been investigated. Furthermore the effects of loss of Nore1a function on the transforming effects of oncogenic Ras have not been characterized.  Nore1a lacks obvious enzymatic activity and little is known about its mechanism of action. However it has been hypothesized that it may serve as a scaffolding protein to modulate the formation of tumor suppressor complexes. We have now identified two tumor suppressors in endogenous complex with Nore1a: the Homeodomain Interacting Protein Kinase 2 (HIPK2) protein and the Von Hippel-Lindau protein (VHL) a notorious tumor suppressor which plays a critical role in the development of the majority of Renal Cell Carcinomas (RCC). Both HIPK2 and VHL act in part by directly modulating the master tumor suppressor p53. Defects in p53 have been detected in approximately 50% of human tumors and it may be argued that p53 is the most critical tumor suppressor yet identified. Thus Nore1a may function by modulating p53 by dual pathways and could serve as part of the well known but poorly characterized link between Ras and p53.  We propose a series of experimental aims designed to determine the precise role of Nore1a loss of function in the development of the tumorigenic phenotype and in Ras mediated transformation. This includes a proposal to determine the role of the Nore1a/Ras interaction in vivo using a novel Nore1a knockout mouse model. We will then determine if the mechanism of action of Nore1a involves the modulation of the HIPK2 or VHL tumor suppressors and whether Nore1a acts to integrate their effects upon p53. We anticipate that these experiments will identify Nore1a as an important novel diagnostic and therapeutic target for cancer.  
  
PUBLIC HEALTH RELEVANCE: These studies will serve to define the role of a novel potential tumor suppressor Nore1a in human cancer. They will determine if Nore1a is an important diagnostic/prognostic marker for cancer. They will also determine if Nore1a may be a suitable candidate for the development of epigenetic therapy to restore its normal function in tumor cells.

public_health_relevance:
These studies will serve to define the role of a novel potential tumor suppressor Nore1ain human cancer. They will determine if Nore1a is an important diagnostic/prognosticmarker for cancer. They will also determine if Nore1a may be a suitable candidate forthe development of epigenetic therapy to restore its normal function in tumor cells.


application_id: 8103649
project_number: 2R01DC007176-07
project_title: Neurotrophin Regulation of Taste System Development
administering_ic: NIDCD
award_notice_date: 2011-04-25
opportunity_number: PA-10-067
application_type: 2
activity_code: R01
ic: DC
serial_number: 007176
program_official: SULLIVAN, SUSAN L
project_start_date: 2005-03-01
project_end_date: 2016-05-31
study_section: Special Emphasis Panel[ZRG1 IFCN-B (03)]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): During development gustatory innervation is a tightly regulated process in which specific numbers of primary taste afferents project to discrete regions of the oral cavity. Brain-derived neurotrophic factor (BDNF) regulates both the number and location of gustatory innervation during embryonic development. Our current research is designed to determine if and/or how these connections are important for central gustatory development or taste function and whether BDNF regulates development of the postnatal taste system. The proposed studies combine cell counting tract tracing immunohistochemistry electrophysiology and behavioral testing in conditional and inducible transgenic mice to: 1) determine if BDNF influences postnatal changes in geniculate ganglion and taste bud development 2) determine if embryonic or postnatal BDNF is important for central terminal field organization and 3) determine if embryonic or postnatal BDNF is important for adult gustatory function. Together these studies test the hypotheses that: 1) embryonic BDNF determines the number of neurons innervating a taste bud and taste buds increase in size to meet that number postnatally. 2) CNS terminal field formation is regulated by BDNF and the specificity of peripheral connections. 3) Gustatory sensitivity is reduced but that the taste system still functions despite wide-scale reorganization. These studies will determine how early peripheral innervation patterns influence continued development and function of the taste system. In addition we will determine whether BDNF is required for postnatal gustatory development. Because these experiments examine how neurotrophin regulation of sensory innervation influences continued development and adult function this project has important implications for the potential therapeutic use of these powerful signaling molecules in re-establishing gustatory function following neuronal impairment.  
  
PUBLIC HEALTH RELEVANCE: Taste disorders can have detrimental effects on a person's health and quality of life. According to NIDCD more than 200000 people visit a doctor each year for problems with their chemical senses including taste. The underlying mechanism of many gustatory disruptions is not well understood. As a result much emphasis has been placed on a basic understanding of the taste bud. However the neurons innervating taste buds receive little attention and are also required for normal gustatory function. Some adult gustatory disruptions may result from an alteration in factor(s) regulating gustatory system innervation both during development and as a part of normal adult homeostasis. Peripheral neuropathies are relatively common and frequently accompany other illnesses. A basic understanding of the factors that are required to promote innervation during development and possibly maintain it in adulthood may lead to therapeutic approaches that allow taste recovery following its loss.

project_terms:
Adult;Attention;Birth;Brain-Derived Neurotrophic Factor;Cell Count;Chemicals;Development;Electrophysiology (science);Embryo;Embryonic Development;Epithelium;Excision;Goals;Health;Homeostasis;Immunohistochemistry;Impairment;Individual;Lead;Location;Mus;National Institute on Deafness and Other Communication Disorders;Nerve;Neurons;Oral cavity;Pattern;Peripheral;Peripheral Nervous System Diseases;Persons;Physiological;Process;Quality of life;Recovery;Regulation;Research;Sensory;Signaling Molecule;Specificity;Stimulus;Structure of geniculate ganglion;System;Systems Development;Taste Buds;Taste Disorders;Taste Perception;Testing;Therapeutic;Therapeutic Uses;Tongue;Transgenic Mice;Visit;behavior test;chorda tympani;critical period;design;meetings;nerve supply;neurotrophic factor;overexpression;postnatal;preference;research study;response


application_id: 8103281
project_number: 5R01CA049797-20
project_title: Mechanisms of MnSOD expression in normal and tumor cells
administering_ic: NCI
award_notice_date: 2011-03-28
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 049797
program_official: MIETZ, JUDY
project_start_date: 1989-12-01
project_end_date: 2015-04-30
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this project is to identify novel redox base mechanisms that lead to the development of cancer. Our studies have identified the mitochondrial antioxidant enzyme manganese containing superoxide dismutase (MnSOD) as an important regulator that can both modulate the development of cancer and be modulated during the progression of cancer. Our studies in the previous funding period demonstrate that reduction of MnSOD levels occurs very early in the development of skin cancer and that the level of p53 regulates the expression of MnSOD. We also found that the level of the mitochondrial uncoupling protein 1 (UCP1) is significantly increased in skin tissues of MnSOD-deficient mice. We hypothesize that the activities of p53 MnSOD and UCP1 are regulated to minimize reactive oxygen species (ROS) production in mitochondria.  We propose that: 1) as a critical transcription factor p53 cooperates with transcriptional activators and suppressors to regulate MnSOD transcription (Aim 1) and 2) the reduction of MnSOD levels in mitochondria leads to UCP1 induction as a result of compromised mitochondrial function which induces transcriptional responses to reduce superoxide production from mitochondrial respiration (Aim 2). The positive and negative feedback loops between nuclei and mitochondria help to ensure that superoxide levels are minimized to prevent mitochondrial dysfunction and subsequent neoplastic transformation. We will use state-of-the-art molecular biology biochemistry and free radical biology approaches to address these specific aims.  Because mitochondria are major sites of cellular energy production and cellular ROS homeostasis and are integrators of apoptosis signaling that are altered in cancer cells understanding the regulation of mitochondrial ROS levels is important and will provide a unique opportunity to design novel interventions that maximize the benefits to normal tissues and prevent cancer development. Given that cellular redox status contributes to almost all aspects of biological function and that MnSOD and p53 are critical for normal cellular function and for cancer prevention the results from this study of cancer will have a broad impact on human health and the prevention of other diseases including obesity and metabolic disorders.  
  
PUBLIC HEALTH RELEVANCE: Skin cancer is the most common human malignancy in the United States. Many chemicals and Ultraviolet radiation (UV) are well-established agents that cause skin cancer. We have found that the mitochondrial antioxidant enzyme manganese containing superoxide dismutase (MnSOD) is an important regulator that can modulate the development of cancer as well as be modulated during the progression of cancer. Our studies demonstrate that reduction of MnSOD levels occurs very early in the development of skin cancer and that expression of MnSOD is regulated by p53. We also found that the levels of the mitochondrial uncoupling protein (UCPs) are altered in skin tissue of MnSOD-deficient mice. In this application we will extend from this novel finding to determine how UCPs acts to prevent skin cancer and will perform proof-of-concept experiments to verify the feasibility of using the knowledge to be learned to prevent the development of skin cancer resulting from exposure to UV and/or alteration of mitochondrial function.

project_terms:
Address;Antioxidants;Apoptosis;Binding (Molecular Function);Binding Sites;Biochemistry;Biogenesis;Biological Process;Biology;Cell Nucleus;Cell physiology;Cells;Chemicals;DNA Structure;Data;Development;Disease;Ensure;Enzymes;Exhibits;Family;Feedback;Free Radicals;Funding;Gene Expression;Genes;Genetic Transcription;Goals;Health;Homeostasis;Human;In Vitro;Intervention;Knowledge;Lead;Learning;Link;Luciferases;Malignant - descriptor;Malignant Neoplasms;Manganese;Mediating;Messenger RNA;Metabolic;Metabolic Diseases;Mitochondria;Mitochondrial Proteins;Molecular Biology;Monitor;Mus;Neoplastic Cell Transformation;Normal Cell;Normal tissue morphology;Obesity;Oxidation-Reduction;Oxidative Phosphorylation;Physiological;Prevention;Prevention strategy;Production;Promotor (Genetics);Proteins;RNA-Binding Proteins;Reactive Oxygen Species;Regulation;Regulatory Element;Reporter Genes;Reporting;Respiration;Ribonucleoproteins;Role;SOD2 gene;Signal Transduction;Site;Skin Cancer;Skin Carcinogenesis;Skin Tissue;Structure;Superoxide Dismutase;Superoxides;Testing;Transcription Coactivator;Transgenic Mice;Tumor Suppressor Proteins;UV Radiation Exposure;Ultraviolet Rays;United States;base;cancer cell;cancer prevention;design;disorder prevention;fascinate;in vivo;insight;link protein;liposarcoma;member;mitochondrial dysfunction;mitochondrial uncoupling protein;mouse model;neoplastic cell;novel;nucleophosmin;prevent;programs;public health relevance;research study;response;skin cancer prevention;transcription factor;tumor progression;uncoupling protein 1

public_health_relevance:
Program NarrativeSkin cancer is the most common human malignancy in the United States. Many chemicals andUltraviolet radiation (UV) are well-established agents that cause skin cancer. We have found that themitochondrial antioxidant enzyme manganese containing superoxide dismutase (MnSOD) is animportant regulator that can modulate the development of cancer as well as be modulated during theprogression of cancer. Our studies demonstrate that reduction of MnSOD levels occurs very early inthe development of skin cancer and that expression of MnSOD is regulated by p53. We also found thatthe levels of the mitochondrial uncoupling protein (UCPs) are altered in skin tissue of MnSOD-deficientmice. In this application we will extend from this novel finding to determine how UCPs acts to preventskin cancer and will perform proof-of-concept experiments to verify the feasibility of using theknowledge to be learned to prevent the development of skin cancer resulting from exposure to UVand/or alteration of mitochondrial function.


application_id: 8102093
project_number: 5R01CA035635-24
project_title: Specificity of Intercalation Reactions
administering_ic: NCI
award_notice_date: 2010-12-17
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 035635
program_official: LEES, ROBERT G
project_start_date: 1984-03-01
project_end_date: 2014-12-31
study_section: Macromolecular Structure and Function B Study Section[MSFB]
contact_pi_person_id: 1863983
contact_pi: CHAIRES, JONATHAN B.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): DNA is an underrepresented target for small molecule therapeutic agents. One reason for the dearth of DNA targeted drugs is that the fundamental molecular mechanisms that govern sequence- and structural-selective ligands to DNA remain poorly understood. In order to develop design principles for targeting specific DNA sites a thorough understanding of the binding mechanisms of existing compounds that bind to DNA with unique types of selectivity is needed. The long-range goal of this project is to understand the mechanism of DNA intercalation reactions with particular emphasis on the energetic basis of sequence- and structural-selective binding. Renewal is sought for a successful and highly productive basic science program that has produced several promising avenues for DNA-targeted drug development. Four-stranded G-quadruplex DNA structures have emerged as important functional elements within the genome and represent important new targets for therapeutic drugs. G-quadruplexes are functional elements that are important in telomere biology and are emerging as important control elements in the expression of many genes particularly oncogenes. Research in the next funding period will focus on biophysical studies of G-quadruplex structure folding and stability and on their selective interactions specific quadruplex structures with drug-like molecules. Specific aims include: 1. Determination of the structure of the 200 nt single-stranded DNA overhang that is a conserved feature of human telomeres. 2. Determination of the thermodynamic stability of higher-order quadruplex structures and the kinetics of the folding. 3. Determination of the thermodynamics and kinetics of drug binding to specific quadruplex structures including the higher-order structures in telomeric DNA and the G-quadruplex "silencer" element found in the c-myc promoter. The results of these proposed studies will deepen our understanding of the structure and stability of functionally important G-quadruplexes and will provide fundamental mechanistic information of use in the rational design of new small molecules to selectively target functionally important quadruplex structures.  
  
PUBLIC HEALTH RELEVANCE: G-quadruplexes are four-stranded DNA structures that are thought to be functionally import elements in the human genome. Quadruplexes have emerged as potential drug targets. The proposed project will use computational and biophysical methods to study the structure stability and drug binding of functionally significant quadruplex structures. The results will be of fundamental use for guiding the design of new drugs targeted toward quadruplexes.

project_terms:
Base Sequence;Basic Science;Beryllium;Binding (Molecular Function);Binding Proteins;Biology;Calorimetry;Cell Cycle;Coupled;Crystallography;DNA;DNA Intercalation;DNA Structure;Diffusion;Drug Delivery Systems;Drug Kinetics;Drug Stability;Elements;Fluorescence;Foundations;Funding;G-Quartets;Gene Expression;Genes;Genome;Goals;Higher Order Chromatin Structure;Human;Human Genome;In Vitro;Indium;Kinetics;Ligand Binding;Ligands;Methods;Molecular;New Agents;Oncogenes;Pharmaceutical Preparations;Process;Promotor (Genetics);Property;Proteins;Radial;Reaction;Refractory;Regulatory Element;Research;Research Design;Resolution;Sedimentation process;Single-Stranded DNA;Site;Specificity;Structural Models;Structure;Telomerase;Testing;Therapeutic Agents;Thermodynamics;Time;Transcriptional Silencer Elements;base;c-myc Genes;design;dimer;driving force;drug development;innovation;intercalation;light scattering;molecular dynamics;new therapeutic target;programs;public health relevance;sedimentation velocity;small molecule;telomere

public_health_relevance:
G-quadruplexes are four-stranded DNA structures that are thought to be functionallyimport elements in the human genome. Quadruplexes have emerged as potential drugtargets. The proposed project will use computational and biophysical methods to studythe structure stability and drug binding of functionally significant quadruplex structures.The results will be of fundamental use for guiding the design of new drugs targetedtoward quadruplexes.


application_id: 8101708
project_number: 2R15DA015351-03
project_title: Mechanisms of Amphetamine Withdrawal and Recovery
administering_ic: NIDA
award_notice_date: 2011-09-07
opportunity_number: PA-10-070
application_type: 2
activity_code: R15
ic: DA
serial_number: 015351
program_official: SU, SHELLEY
project_start_date: 2002-07-15
project_end_date: 2016-05-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 1885629
contact_pi: WHITE, WESLEY O
other_pis: Not Applicable
congressional_district: 05
department: PSYCHOLOGY
primary_duns: 041957010
primary_uei: MRGUP99ZAZ59
duns_number: 041957010
uei: MRGUP99ZAZ59
fips: US
organization_id: 569601
organization_name: MOREHEAD STATE UNIVERSITY
organization_city: MOREHEAD
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 403511684
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): In recreational drug use high but non toxic doses of a drug are occasionally administered. When rats are administered amphetamine according to this kind of regime an acute withdrawal syndrome occurs approximately 18 to 24 hours after drug receipt. Hypoactivity and hypophagia are among the symptoms observed. The overall research goal is to understand this amphetamine-induced acute withdrawal syndrome. As in past award periods basic information about the conditions that elicit different symptoms will be sought and hypotheses about mechanisms involved will be assessed. But in addition a new theory of how the symptoms of the acute withdrawal syndrome are organized will be explored. According to this theory the syndrome is organized into symptom clusters that is different groups of interrelated symptoms. In most of the proposed experiments rats will be housed in stations where either activity or food intake can be continuously monitored. In several of the proposed studies provisional criteria for grouping symptoms will be applied to hypoactivity and hypophagia in order to assess whether they are components of the same symptom cluster. For example if different doses of amphetamine produce comparable effects on hypoactivity and hypophagia then by one criterion the symptoms should be grouped. In other experiments some of the implications of conceiving of the withdrawal syndrome in this way will be assessed. In one study time-dependent changes in a putative symptom cluster will be used to guide the selection of times at which to look for potential molecular mediators. In a final study the methodology and conceptualizations will be applied to the acute withdrawal produced by a drug from another class morphine. The approach used in the proposed studies is consistent with initiatives to classify mental disorders on the basis of observable behaviors and neurobiological measures rather than on the basis of presenting symptoms. Because the theory under discussion views the fundamental unit of a syndrome as a cluster of symptoms it has significant implications for diagnosis and treatment.  
  
PUBLIC HEALTH RELEVANCE: Acute withdrawal is associated with personal distress decreased productivity and increased risk of drug relapse: Consequently preventing and ameliorating acute withdrawal is an important objective. Acute withdrawal can be managed only if the factors that give rise to the symptoms can be identified. The proposed research will provide an ethical well controlled and efficient means for identifying the brain and body factors that contribute to acute withdrawal and for evaluating potential treatments.

project_terms:
Acute;Affect;Amphetamines;Animal Housing;Award;Behavior;Brain;Development;Diagnosis;Distress;Dopamine Agonists;Dopamine Antagonists;Dose;Eating;Ethics;Gene Expression;Goals;Grouping;Hour;Housing;Measures;Mediating;Mediator of activation protein;Mental disorders;Methodology;Molecular;Monitor;Morphine;Neurobiology;Pharmaceutical Preparations;Productivity;Rattus;Recovery;Research;Risk;Substance Withdrawal Syndrome;Symptoms;Syndrome;Testing;Time;Time Study;Withdrawal;base;deficit syndrome;drug relapse;prevent;recreational drug use;research study;theories

public_health_relevance:
Acute withdrawal is associated with personal distress decreased productivity and increased risk of drug relapse: Consequently preventing and ameliorating acute withdrawal is an important objective. Acute withdrawal can be managed only if the factors that give rise to the symptoms can be identified. The proposed research will provide an ethical well controlled and efficient means for identifying the brain and body factors that contribute to acute withdrawal and for evaluating potential treatments.


application_id: 8101323
project_number: 5R01HD061996-03
project_title: The Combination of Cyclosporin and Choline Optimizes Outcomes In Focal and Diffus
administering_ic: NICHD
award_notice_date: 2011-07-12
opportunity_number: RFA-HD-08-003
application_type: 5
activity_code: R01
ic: HD
serial_number: 061996
program_official: ANSEL, BETH
project_start_date: 2009-08-05
project_end_date: 2013-06-30
study_section: ZHD1-RRG-K(03)
contact_pi_person_id: 1883820
contact_pi: PAULY, JAMES R
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The recent failure of several Phase III clinical trials (pharmacological and non-pharmacological) in patients with head injury underscores the need for improved therapeutic modalities. TBI in humans is a heterogeneous condition that differs substantially in severity location etiology clinical presentation and neuropathology. This differs from experimental TBI studies where multiple variables are carefully controlled. The acute and chronic molecular cellular biochemical and pathophysiological events that follow TBI are complex and multi-factorial. There may not be a single "magic bullet" drug that will be completely successful in preventing secondary damage following brain injury. Rather combinatorial drug treatments that target specific windows of secondary pathology may be more efficacious than treatment with a single drug. In the proposed experiments the PIs will evaluate cellular and functional outcomes following TBI and administration of Cyclosporin A (CsA) followed by dietary choline supplementation. The combination of CsA and choline was chosen based on the clinical utility of these drugs previously published work and preliminary data generated by the Pauly/Scheff/Sullivan labs. The overall hypothesis of this proposal is that a combinatorial approach will optimize outcome compared to single or dual treatment modalities. The experiments will advance the understanding of the neurobiological consequences of TBI and determine the efficacy of a combined pharmacological/behavioral approach to recovery in two different models of brain injury. The outcome measures proposed will provide important new information about neurobiological outcomes following TBI. Animal studies in TBI have generally not utilized combinatorial approaches to therapy. However given the variability and complexity of human brain injuries a treatment strategy that uses multiple agents targeted at specific neuropathological events seems to be a pragmatic approach that may optimize outcome. The studies proposed for this research are highly significant and could add to our understanding of the pathophysiology and therapeutic treatment of individuals with traumatic brain injuries. If the studies show benefit of combining CsA and choline the PIs will meet with clinical investigators to see if this could possibly be a new trial or an add-on to the CsA trial under consideration for funding. Although the pharmacological experiments proposed are not particularly mechanistic they are feasible and directly translatable into human patients. The NIH road map contends that if therapeutics are directly translatable to humans mechanistic studies are not the initial priority. Two different models of rat TBI will be used in these experiments the cortical contusion model of focal injury and the medial fluid percussion model of diffuse injury. The combined outcome measure the PIs will test may provide better characterization of recovery than previously used in either the CCI or MFPI model. Finally functional recovery in terms of cognition is a major focus of this grant. These studies are translational since both cyclosporin and choline are both approved for use in human patients. However the animal literature has gaps especially for the effects of CsA on cognitive recovery. Choline is readily available and could be administered to TBI patients outside of a critical care setting. Animal studies in TBI have generally not utilized combinatorial approaches to therapy. However given the variability and complexity of human brain injuries a treatment strategy that uses multiple agents targeted at specific neuropathological events seems to be a pragmatic approach that may optimize outcome.  
  
PUBLIC HEALTH RELEVANCE: The recent failure of several Phase III clinical trials (pharmacological and non-pharmacological) in patients with traumatic brain injury (TBI) underscores the need for improved therapeutic modalities. The overall hypothesis of this proposal is that a combinatorial approach with cyclosporin A (CsA) and dietary choline supplementation will optimize outcome compared to single treatment modalities. CsA and choline are both approved by the FDA and actively being pursued in NIH-sponsored trials as monotherapy for human TBI patients. The PIs' hypothesis will be evaluated in two different models of rat TBI that have different mechanisms and timing of neuropathology. These studies are a logical extension of current trials in TBI and will use a set of testable hypotheses to provide clinically relevant information about this drug combination.

project_terms:
Acute;Affect;Animal Model;Animals;Behavioral;Biochemical;Brain;Brain Injuries;Characteristics;Chemicals;Choline;Chronic;Chronic Phase;Clinical;Clinical Investigator;Clinical Trials;Cognition;Cognitive;Combination Drug Therapy;Combined Modality Therapy;Complex;Cortical Contusions;Craniocerebral Trauma;Critical Care;Cyclosporine;Cyclosporins;Cytidine Diphosphate Choline;Data;Development;Dietary Supplements;Diffuse;Diffuse Brain Injury;Dose;Drug Combinations;Drug Kinetics;Environment;Etiology;Event;FDA approved;Failure (biologic function);Functional disorder;Funding;Grant;Human;Individual;Injury;Liquid substance;Literature;Location;Magic;Maps;Measures;Medial;Modality;Modeling;Molecular;Nerve Degeneration;Neurobiology;Neurologic;Neuroprotective Agents;Outcome;Outcome Measure;Pathology;Patients;Percussion;Pharmaceutical Preparations;Pharmacodynamics;Pharmacotherapy;Phase;Phase III Clinical Trials;Publishing;Rattus;Recording of previous events;Recovery;Recovery of Function;Research;Safety;Severities;Staging;Supplementation;TBI Patients;Testing;Therapeutic;Time;Traumatic Brain Injury;United States National Institutes of Health;Work;base;clinically relevant;cognitive recovery;combinatorial;controlled cortical impact;drug efficacy;fluid percussion injury;functional outcomes;improved;innovation;meetings;neurochemistry;neuropathology;neuroprotection;prevent;public health relevance;research study;response;treatment strategy

public_health_relevance:
NarrativeThe recent failure of several Phase III clinical trials (pharmacological and non-pharmacological) in patients withtraumatic brain injury (TBI) underscores the need for improved therapeutic modalities. The overall hypothesisof this proposal is that a combinatorial approach with cyclosporin A (CsA) and dietary choline supplementationwill optimize outcome compared to single treatment modalities. CsA and choline are both approved by the FDAand actively being pursued in NIH-sponsored trials as monotherapy for human TBI patients. Our hypothesiswill be evaluated in two different models of rat TBI that have different mechanisms and timing ofneuropathology. These studies are a logical extension of current trials in TBI and will use a set of testablehypothesis to provide clinically relevant information about this drug combination.


application_id: 8101304
project_number: 5F31CA142317-03
project_title: Functional conversion of tumor associated macrophages via cytokine therapy
administering_ic: NCI
award_notice_date: 2011-06-29
opportunity_number: PA-07-106
application_type: 5
activity_code: F31
ic: CA
serial_number: 142317
program_official: MCNEIL FORD, NICOLE
project_start_date: 2009-07-10
project_end_date: 2014-07-09
study_section: Special Emphasis Panel[ZRG1-SBIB-V(29)L]
contact_pi_person_id: 9679618
contact_pi: MITCHELL, COURTNEY JETUN
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Breast cancer is the leading cancer diagnosis in women and second most common cause of women cancer deaths. Although mortality has decreased and incidence has remained steady persons diagnosed with late Stage disease have dismal survival rates. Hence the need for therapies with the ability to prevent cancer altogether. The objective of this project is to determine if IL-12 induced functional conversion of tumor associated macrophages from anti-inflammatory and tumor supportive to pro-immunogenic and anti- tumorigenic can be extended for therapeutic exploitation. The mice 4T1 mammary carcinoma with lung metastases model will be employed to accomplish the objective and achieve the specific aims of this project. Specific aim 1 will examine the immune cells and cytokines that contribute to the maintenance of the IL-12 induced pro-immunogenic functional conversion of the macrophages. Two approaches will be used in this aim. First the IL-12 response of scid mice which are T and B cell deficient will be compared with NK depleted scid mice. Secondly the role of IL-18 and IFN-y in the maintenance of the IL-12 induced conversion will be assessed by neutralizing these cytokines with anti-IFN-y or anti-IL-18. In specific aim 2 the ability of IL-15 and IL-18 to extend the pro-immunogenic status of tumor associated macrophages will be examined by injecting mice bearing 4T1 tumors with the encapsulated IL-12 alone and then injecting the mice subcutaneously with encapsulated IL-15 or IL-18 one to four days later. Specific aim 3 will determine if the extension of the IL-12 induced pro-immunogenic window enhances the efficacy of a tumor-dendritic cell vaccine via immunization of 4T1 bearing mice with a 4T1-dendritic cell fusion vaccine in combination with encapsulated buffer or encapsulated IL-12 alone or in combination with other cytokines as determined by specific aim 2. Analysis for each of our aims will include q-rt-PCR for various anti-inflammatory and tumor supportive as well as pro-immunogenic and anti-tumorigenc factors ELISA for serum IFN-gamma measurement of cytoplasmic levels of IFN-gamma perforin and granzyme B perfusion assisted weight and volume measurements for the primary tumor perfusion assisted quantification of lung metastases and anti- IFN-gamma and CD71 labeling for measurement of number of infiltrating leukocytes. By exploring the effects of IL-12 on tumor associated macrophages we may gain a better understanding of how cytokines and macrophages interact for tumor maintenance and progression.   
PUBLIC HEALTH RELEVANCE: This project will benefit public health by providing new information regarding potential cancer immunotherapy including including preventative vaccines for breast cancer.

project_terms:
Anti-Inflammatory Agents;Anti-inflammatory;B-Lymphocytes;Breast Carcinoma;Buffers;Cell fusion;Cells;Cessation of life;Dendritic Cell Vaccine;Dendritic Cells;Diagnosis;Disease;Encapsulated;Enzyme-Linked Immunosorbent Assay;Immune;Immunization;Incidence;Interferon Type II;Interferons;Interleukin-12;Interleukin-15;Interleukin-18;Label;Leukocytes;Lung;Maintenance;Malignant Neoplasms;Measurement;Modeling;Mortality Vital Statistics;Mus;Neoplasm Metastasis;Perfusion;Persons;Primary Neoplasm;Role;Serum;Staging;Survival Rate;T-Lymphocyte;TFRC gene;Therapeutic;Vaccines;Weight;Woman;breast cancer vaccine;cancer diagnosis;cancer immunotherapy;cytokine;cytokine therapy;granzyme B;immunogenic;macrophage;malignant breast neoplasm;perforin;prevent;public health medicine (field);public health relevance;response;tumor;tumorigenic


application_id: 8101170
project_number: 5R01AG027258-04
project_title: Telomeric dysfunction and the premature aging and cancer-prone disease Werner syn
administering_ic: NIA
award_notice_date: 2011-06-30
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AG
serial_number: 027258
program_official: GUO, MAX
project_start_date: 2008-08-01
project_end_date: 2013-12-31
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 7034221
contact_pi: ORREN, DAVID KEITH
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Telomeres are specialized structures on chromosome ends that are essential for genome stability and cellular replicative capacity. Maintenance of proper telomere structure and length allows continued cell division. However most replicating cells in the body do not express the maintenance enzyme telomerase and gradually lose telomeric DNA eventually reaching a critically short telomere length that triggers cellular senescence and/or apoptosis. Theoretically significant accumulation of senescent cells or loss of apoptotic cells in tissues occurs late in life and may underlie development of certain normal aging characteristics. However solid support for the relationship between telomere dysfunction cellular senescence and possible aging phenotypes in normal individuals is currently lacking. The premature aging disease Werner syndrome (WS) that shows early onset and increased frequency of many deleterious aging features (including cancer atherosclerosis osteoporosis cataracts diabetes and hypertension) is caused by loss of function of a single protein WRN. Cells derived from WS patients show telomeric abnormalities and a dramatic premature cellular senescence that is prevented by prior expression of telomerase. Investigations from several laboratories (including ours) indicate that WRN functions in telomere maintenance possibly in coordination with the telomeric protein TRF2. Thus WS is an excellent model for studying the relationships between telomere maintenance cellular senescence apoptosis and development of specific aging characteristics. This proposal will examine the biochemical activities of WRN (in conjunction with TRF2 and other telomeric factors) on relevant telomeric DNA structures and determine its protein partners during its function in telomere metabolism with specific emphasis on telomeric replication. In addition telomere dynamics (replication kinetics and length alterations) and cellular senescence in normal and WS cells will be examined during chronic treatment with selected DNA damaging agents. These studies will clarify the telomeric function of WRN and determine whether persistent DNA lesions in telomeric regions exacerbate telomere loss over time in WS cells compared to normal cells and provide further support to the role of telomere dysfunction in the development of specific age-related characteristics in WS as well as in normal aging. Thus this proposal will implicate and examine basic mechanisms at work in genome maintenance and suppression of certain aging phenotypes as well as cancer. PUBLIC HEALTH RELEVANCE: This proposal examines the role of a specific protein WRN in the maintenance of chromosome ends otherwise known as telomeres. When the function of human WRN is lost (in the hereditary disease Werner syndrome) the resulting telomeric abnormalities trigger cell senescence or cell death and in time cause early development of aging features and cancer in affected individuals. By investigating Werner syndrome and the role of WRN in telomere metabolism this proposal will help understand basic cellular mechanisms that act to suppress development of specific aging characteristics as well as cancer.

project_terms:
Affect;Aging;Apoptosis;Apoptotic;Atherosclerosis;Back;Binding (Molecular Function);Biochemical;Cataract;Cell Aging;Cell Death;Cell division;Cells;Characteristics;Chromosomal Instability;Chromosomes;Chronic;Cisplatin;DNA;DNA Damage;DNA Structure;DNA lesion;Development;Diabetes Mellitus;Disease;Dose;Ensure;Enzymes;Exonuclease;Fibroblasts;Frequencies (time pattern);Functional disorder;Genes;Genetic Recombination;Genome;Genome Stability;Health;Hereditary Disease;Human;Hypertension;Individual;Investigation;Kinetics;Knowledge;Laboratories;Length;Life;Link;Maintenance;Malignant Neoplasms;Mediating;Metabolic;Metabolism;Methods;Modeling;Monitor;Normal Cell;Osteoporosis;Oxidative Stress;Pathway interactions;Patients;Phenotype;Play;Premature aging syndrome;Process;Proteins;Reaction;Research;Resolution;Role;Solid;Structure;Study models;TERF1 gene;Telomerase;Telomere Maintenance;Telomeric Repeat Binding Protein 2;Time;Tissues;Werner Syndrome;Work;age related;early onset;helicase;human WRN protein;loss of function;normal aging;nuclease;premature;prevent;research study;senescence;telomere;tumor progression


application_id: 8101067
project_number: 5R01NS064247-02
project_title: Modulation of CNS Proinflammatory Cytokine Production
administering_ic: NINDS
award_notice_date: 2011-05-30
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 064247
program_official: CORRIVEAU, RODERICK A
project_start_date: 2010-07-01
project_end_date: 2014-06-30
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The serine/threonine protein kinase p381 MAPK is an established therapeutic target for a number of peripheral inflammatory diseases where increased proinflammatory cytokine production contributes to pathology. In contrast much less is known about the in vivo role of p381 MAPK in CNS dysfunction and its potential as a therapeutic target. Specifically little information is available on the quantitative contribution of microglial p381 MAPK signaling in vivo to up-regulation of proinflammatory molecules that lead to disease- relevant neuropathology the importance of p381 MAPK in the beneficial reparative and remodeling responses of activated microglia or the role of neuronal p381 MAPK in CNS dysfunction responses. We hypothesize that p381 (and not the closely related p382 MAPK isoform) is a key in vivo contributor to microglial inflammatory activation cascades that culminate in detrimental proinflammatory cytokine overproduction and subsequent neuronal/synaptic damage and that suppression of p38 MAPK signaling in the microglia and/or neuron can lead to selective beneficial outcomes. The field has been limited in its ability to pursue these questions because of the lack of CNS-penetrant selective small molecule p381 MAPK inhibitors. Our development of a novel orally bioavailable brain-penetrant selective small molecule p381 MAPK inhibitor (compound 069A) that attenuates hippocampal proinflammatory cytokine overproduction and leads to improved neurologic outcomes in a mouse CNS injury model now provides the opportunity to address these critical questions about p38 MAPK and CNS dysfunction in vivo as well as in vitro or in situ. We will use this unique chemical biology tool and novel knock-out (KO) and drug-resistant knock-in (KI) mice to pursue several important mechanistic investigations. First we will test the importance of p381 MAPK and p382 MAPK in vivo through the use of microglial p381 conditional KO and p382 global KO mouse models subjected to stressor stimuli. The temporal onset and profile of microglial activation and synaptic dysfunction responses will be determined. Second we will complement these in vivo studies by using cell culture models in order to explore in more detail the relative contributions of p38 MAPK isoforms in microglia and neurons. We will utilize microglial-neuronal co-cultures combined with pharmacological and genetic knock-down approaches to determine the importance of microglial and neuronal p38 MAPK isoforms to stressor-induced responses. Successful completion of this project will provide mechanistic insight into the role of the key regulatory protein p381 MAPK in microglial activation and neuronal damage caused by stressors that induce CNS pathophysiology and the contribution of microglial vs. neuronal p381 MAPK to the CNS dysfunction responses. In addition the studies will elucidate the potential role of the highly related p38 MAPK isoform p382 in the microglial and neuronal responses. Longer term the knowledge generated by the proposed studies will provide a firmer foundation for future development of new classes of disease-modifying therapeutics and fuller interpretation of disease progression investigations.  
  
PUBLIC HEALTH RELEVANCE: Successful completion of this project will provide mechanistic insight into how the key regulatory protein p381 MAPK is involved in brain pro-inflammatory responses and CNS dysfunction caused by disease- relevant stressors. In addition the results will delineate the relative importance of microglial versus neuronal p381 MAPK and p382 MAPK to the disease-relevant pathological responses. Longer term the insights and knowledge generated by the proposed studies will provide a firmer foundation for future development of new classes of disease-modifying therapeutics and fuller interpretation of disease progression investigations.

project_terms:
Address;Alzheimer's Disease;Attenuated;Bioavailable;Biology;Brain;Cell Culture Techniques;Chemicals;Chronic;Coculture Techniques;Complement;Cytokine Gene;Development;Disease;Disease Progression;Drug resistance;Embryo;Family;Foundations;Functional disorder;Future;Gene Expression;Genetic;Genetic Transcription;Hippocampus (Brain);Immune;In Situ;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Investigation;Knock-in Mouse;Knock-out;Knockout Mice;Knowledge;Lead;Link;MAP Kinase Gene;MAPK14 gene;Measurable;Microglia;Mitogen-Activated Protein Kinase Inhibitor;Modeling;Mus;Nature;Neurodegenerative Disorders;Neuroglia;Neurologic;Neurologic Dysfunctions;Neurological outcome;Neuronal Dysfunction;Neuronal Injury;Neurons;Outcome;Pathology;Pathway interactions;Peripheral;Phosphorylation;Physiological;Process;Production;Protein Isoforms;Protein-Serine-Threonine Kinases;Proteins;Recording of previous events;Regulation;Relative (related person);Rheumatoid Arthritis;Role;Signal Transduction;Stimulus;Synapses;Testing;Therapeutic;Tissues;Translations;Up-Regulation (Physiology);Work;age related;base;brain tissue;cell type;central nervous system injury;computerized data processing;cytokine;cytotoxicity;genetic regulatory protein;improved;in vivo;insight;interest;knock-down;macrophage;mouse model;neuropathology;novel;public health relevance;response;small molecule;stressor;therapeutic target;tool

public_health_relevance:
PROJECT NARRATIVE Successful completion of this project will provide mechanistic insight into how the key regulatoryprotein p38 MAPK is involved in brain pro-inflammatory responses and CNS dysfunction caused by disease-relevant stressors. In addition the results will delineate the relative importance of microglial versus neuronalp38 MAPK and p38 MAPK to the disease-relevant pathological responses. Longer term the insights andknowledge generated by the proposed studies will provide a firmer foundation for future development of newclasses of disease-modifying therapeutics and fuller interpretation of disease progression investigations.


application_id: 8100879
project_number: 1R15HL108192-01
project_title: Estrogen Mediated Regulation of miRNA in Cardiac Remodeling
administering_ic: NHLBI
award_notice_date: 2011-05-13
opportunity_number: PA-10-070
application_type: 1
activity_code: R15
ic: HL
serial_number: 108192
program_official: WANG, LAN-HSIANG
project_start_date: 2011-05-15
project_end_date: 2015-04-30
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 9528523
contact_pi: WAIKEL, REBEKAH
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 074051269
primary_uei: K69HFP3FKJ11
duns_number: 074051269
uei: K69HFP3FKJ11
fips: US
organization_id: 2274301
organization_name: EASTERN KENTUCKY UNIVERSITY
organization_city: RICHMOND
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 404753100
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal accomplishes the AREA program objectives: 1) supporting meritorious research; 2) exposing undergraduates to research; and 3) strengthening the research environment in non-research intensive universities. Approximately 80 million Americans have hypertension. Prolonged hypertension eventually leads to the development of left ventricular hypertrophy (LVH) which is a significant risk factor for cardiovascular death and heart failure (HF). Within the last few years research has shown that microRNAs (miRNAs) are highly regulated during cardiac hypertrophy and are capable of regulating cardiac remodeling. To date no comparison of sex dependent cardiac miRNAs have been described. Sex specific differences in the response of the heart to stressors such as hypertension have been well documented. Estrogen has been shown to play a protective role in this regard in both humans and rodent models. We have demonstrated in a pilot study that selected miRNAs are differentially regulated in male and female mice at baseline and in as a consequence of stimulation of cardiac hypertrophy. An understanding of sex specific regulation of miRNAs in the heart could have a far-reaching impact on the diagnosis and treatment of heart disease. This proposal will test the central hypothesis that male/female differences in susceptibility to adverse cardiac structural remodeling are due to estrogen mediated regulation of miRNAs. The specific aims of this research are 1) to identify miRNAs regulated by estrogen in cardiomyocytes during cardiac remodeling; 2) to determine the cell signaling mechanisms through which estrogen regulates miRNAs; and 3) to establish a functional role for miRNAs in estrogen mediated inhibition of cardiomyocyte hypertrophy. Ultimately the goal of this research is to improve our understanding of the sex specific regulation and downstream targets of miRNAs during cardiomyocyte hypertrophy to improve diagnosis and treatment of LVH. All the experiments outlined in this proposal are designed to engage undergraduates in research. Mentored by the PI undergraduates will perform experiments participate in weekly lab meetings present their research at scientific conferences and assist in the writing of manuscripts. Our research activities will be visible and shared with our department and university research community through scientific posters on the walls of the science building the university- wide Undergraduate Showcase and highlighting research student accomplishments in the EKU Today a monthly online newsletter. It is intended for this exposure to lead to increased excitement about scientific research and to stimulate EKU undergraduates to participate in research endeavors.  
  
PUBLIC HEALTH RELEVANCE: Approximately 80 million Americans have hypertension which can lead to a thickening of the heart muscle called left ventricular hypertrophy and eventually heart failure. The goal of this research is to identify markers (microRNAs) that are specific to males and females during cardiac hypertrophy in rodent models to ultimately aid in the diagnosis and treatment of heart failure. In addition this research should elucidate the signaling pathways that regulate these miRNAs as well as pathways that are themselves regulated by these miRNAs.

project_terms:
American;Cardiac;Cardiac Myocytes;Cessation of life;Communities;Development;Diagnosis;Doctor of Philosophy;Environment;Estrogen Receptors;Estrogens;Female;Goals;Heart;Heart Diseases;Heart Hypertrophy;Heart failure;Human;Hypertension;Hypertrophy;Lead;Left Ventricular Hypertrophy;Manuscripts;Mediating;Mentors;MicroRNAs;Molecular Profiling;Mus;Myocardium;Newsletter;Pathway interactions;Pilot Projects;Play;Predisposition;Rattus;Receptor Activation;Regulation;Research;Research Activity;Rodent Model;Role;Science;Signal Pathway;Signal Transduction;Students;Testing;Universities;Writing;cardiovascular risk factor;design;improved;lead exposure;male;meetings;posters;programs;research study;response;sex;stressor;symposium

public_health_relevance:
Approximately 80 million Americans have hypertension which can lead to a thickening of the heart muscle called left ventricular hypertrophy and eventually heart failure. The goal of this research is to identify markers (microRNAs) that are specific to males and females during cardiac hypertrophy in rodent models to ultimately aid in the diagnosis and treatment of heart failure. In addition this research should elucidate the signaling pathways that regulate these miRNAs as well as pathways that are themselves regulated by these miRNAs.


application_id: 8099724
project_number: 5R21HD062833-02
project_title: Parental Problem Drinking and Child Sleep: Family and Physiological Mechanisms of
administering_ic: NICHD
award_notice_date: 2011-07-07
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: HD
serial_number: 062833
program_official: HAVERKOS, LYNNE
project_start_date: 2010-07-01
project_end_date: 2013-06-30
study_section: Special Emphasis Panel[ZRG1-BBBP-C(02)M]
contact_pi_person_id: 9623914
contact_pi: KELLER, PEGGY S
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Alcohol problems are prevalent in the general population with an estimated 18.8 million Americans currently suffering from alcohol dependence or abuse (www.samhsa.gov) and 1 in 4 American children exposed to problem drinking in their family (Grant 2000). The consequences for children can be serious including emotional and behavioral problems but has been virtually no examination of the impact of parental problem drinking (PPD) on child sleep. Sleep is critical for healthy development and adaptive daytime functioning yet 20% to 40% of children experience clinically significant sleep disruptions. The objectives of the current study are to address these open scientific questions regarding the relation between PPD and child sleep within an exploratory and multidisciplinary framework. Specifically the goals are to (1) examine maternal and paternal PPD as a risk factor for children's shorter sleep duration lower sleep quality and erratic sleep schedule; (2) consider marital conflict and parenting as potential mediators of the association between PPD and child sleep; and (3) test whether vagal functioning (tone and withdrawal) moderates the association between PPD (and associated family dysfunction) and child sleep problems.  The study will include 250 children aged 6 to 11 and their married or cohabiting parents; children will be normally developing and drawn from the broader community. Children's sleep will be assessed over the course of one week using diary reports and actigraphy. PPD marital functioning and parent-child relations will be measured using multiple measures and reporters including collateral reports of drinking and conflict behavior permitting bias-free assessments of key constructs. Well-established procedures will assess vagal tone and withdrawal in response to laboratory procedures. A number of potentially important covariates will also be assessed and included in analyses such as parental depression parental antisocial behavior and child adjustment problems. Differences in relations based on parent and child gender will also be explored.  The proposed study will advance understanding of child outcomes associated with PPD and contribute to the small but growing literature that demonstrates the negative effects of family stress on child sleep (PA-07- 140 Research on Sleep and Sleep Disorders) by providing the first known examination of relations between PPD and child sleep amount quality or schedule. Further the proposed study will examine possible mechanisms of risk at both the interpersonal and physiological levels (PA-07-046 Research on Mind-Body Interactions and Health) providing initial evidence for processes accounting for the associations between PPD and child sleep and identifying those children who may be at greatest risk for sleep problems in the context of PPD. Findings will provide preliminary support for more focused R01 studies and ultimately will shed light on potential targets for intervention or prevention addressing the serious public health concerns of PPD and child sleep problems.  
  
PUBLIC HEALTH RELEVANCE: Alcohol problems are a serious public health concern yet their impact on family and child functioning are understudied. The proposed study is the first known examination between parental problem drinking (PPD) and child sleep parameters. Sleep disturbances in American children are highly prevalent and research increasingly demonstrates their harmful effects on child functioning. However little is known about how family stress may impact child sleep. Further research is needed to identify mechanisms of risk involved in these influences. The proposed study examines relations between maternal and paternal PPD and child sleep quality amount and schedule; it also tests family relationship problems (e.g. marital and parent-child conflict) and physiological stress response (e.g. vagal tone and withdrawal) as mechanisms of risk. Findings of the proposed study will illuminate specific forms of sleep disturbances that are associated with PPD help identify children and families at greatest risk and lay the foundation for a focused program of longitudinal research.

project_terms:
Accounting;Address;Alcohol abuse;Alcohol dependence;American;Attenuated;Behavior;Child;Child Behavior;Communities;Conflict (Psychology);Development;Emotional;Exhibits;Failure (biologic function);Family;Family Relationship;Foundations;Functional disorder;Gender;General Population;Goals;Government;Grant;Health;Individual Differences;Infant;Intervention;Knowledge;Laboratory Procedures;Light;Literature;Measures;Mediating;Mediator of activation protein;Mental Depression;Mental Health;Mind-Body Relationship (Physiology);Nervous System Physiology;Outcome;Parasympathetic Nervous System;Parent-Child Relations;Parenting behavior;Parents;Personal Satisfaction;Physiological;Polysomnography;Prevention;Problem behavior;Procedures;Process;Reporter;Reporting;Research;Risk;Risk Factors;Schedule;Sleep;Sleep Disorders;Sleep disturbances;Stress;Surveys;Testing;Withdrawal;actigraphy;aged;anti social;base;biological adaptation to stress;clinically significant;depressive symptoms;diaries;drinking;experience;multidisciplinary;programs;public health medicine (field);public health relevance;response

public_health_relevance:
Narrative Alcohol problems are a serious public health concern yet their impact on family and child functioning areunderstudied. The proposed study is the first known examination between parental problem drinking (PPD)and child sleep parameters. Sleep disturbances in American children are highly prevalent and researchincreasingly demonstrates their harmful effects on child functioning. However little is known about how familystress may impact child sleep. Further research is needed to identify mechanisms of risk involved in theseinfluences. The proposed study examines relations between maternal and paternal PPD and child sleepquality amount and schedule; it also tests family relationship problems (e.g. marital and parent-child conflict)and physiological stress response (e.g. vagal tone and withdrawal) as mechanisms of risk. Findings of theproposed study will illuminate specific forms of sleep disturbances that are associated with PPD help identifychildren and families at greatest risk and lay the foundation for a focused program of longitudinal research.


application_id: 8099417
project_number: 5R01AG029493-05
project_title: Targeting CNTF to increase adult forebrain neurogenesis
administering_ic: NIA
award_notice_date: 2011-06-24
opportunity_number: PAS-05-092
application_type: 5
activity_code: R01
ic: AG
serial_number: 029493
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 2007-09-01
project_end_date: 2013-03-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 6902570
contact_pi: HAGG, THEO
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:
DESCRIPTION (provided by applicant): Endogenous neural precursors in the adult brain might be useful in cell replacement therapies for neurological disorders. The development of treatments that would promote neurogenesis would be facilitated by identification of the endogenous regulators. We have shown that endogenous and injected ciliary neurotrophic factor (CNTF) promotes neurogenesis in the adult mouse subventricular zone in the adult mouse forebrain (SVZ). CNTF is produced mainly by astrocytes and Schwann cells making it a potentially nervous system-selective drug target. We have shown that CNTF expression is regulated by dopaminergic innervation and through D2 dopamine receptors which are present on GFAP+ SVZ cells and neural progenitors. We will determine which cells express which transmitter receptors which cells produce CNTF and which ones respond directly to CNTF. The extent to which glial-derived CNTF mediates D2 receptor-induced neurogenesis will be tested by administering D2 agonist while CNTF is blocked. These experiments may identify a regulation mechanism of neurogenesis that is readily amenable to pharmacological intervention with orally active and clinically approved drugs and does not rely on the presence of neurons that are lost in neurological disorders. The restricted neurogenesis and expression of CNTF in the SVZ and not the striatum may be determined by overlap between dopaminergic and serotonergic projections. Serotonin promotes neurogenesis through 5-HT1a receptors which are also found on SVZ astrocytes. We will determine whether a 5-HT1a receptor agonist also can increase CNTF expression and increases neurogenesis via CNTF. We will determine whether the D2 and 5-HT1a receptors together regulate this neurogenesis through CNTF. If so it might be possible that a combination of low doses of 5-HT1a and D2 agonists would robustly stimulate neurogenesis in the SVZ a strategy which ultimately would reduce side effects of regular doses. In addition we are targeting receptors that would not increase the CNTF production in the peripheral nerves and rest of the body which otherwise would result in systemic side effects. Finally this idea will be tested in a focal stroke model where neuron replacement in the neighboring neostriatum may be beneficial. This study may identify an important convergent neurogenesis-regulating mechanism that can selectively be manipulated with FDA-approved oral drugs.

project_terms:
8-Hydroxy-2-(di-n-propylamino)tetralin;Adult;Adverse effects;Affect;Agonist;Antibodies;Astrocytes;Brain;Cells;Ciliary Neurotrophic Factor;Clinical Trials;Corpus striatum structure;Cyclic AMP;Data;Denervation;Dopamine Agonists;Dopamine D2 Receptor;Dose;Drug Delivery Systems;FDA approved;Failure (biologic function);Glial Fibrillary Acidic Protein;Human;Injection of therapeutic agent;Intervention;Ischemia;Ischemic Stroke;Lateral;Mediating;Mediator of activation protein;Midbrain structure;Middle Cerebral Artery Occlusion;Modeling;Mus;Neostriatum;Nervous system structure;Neurons;Oral;Pathway interactions;Peripheral Nerves;Pharmaceutical Preparations;Production;Proliferating;Prosencephalon;Quinpirole;Regulation;Replacement Therapy;Rest;Rodent;Schwann Cells;Serotonin;Testing;Time;Transplantation;adult neurogenesis;cytokine;injured;nerve stem cell;nerve supply;nervous system disorder;neuroblast;neurogenesis;novel;receptor;relating to nervous system;repaired;research study;stroke;subventricular zone;therapy development


application_id: 8099047
project_number: 5P20RR021954-04
project_title: Center of Research in Obesity and Cardiovascular Disease (1P20 RR021954-01A1)
administering_ic: NCRR
award_notice_date: 2011-08-09
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
program_official: LIU, YANPING
project_start_date: 2008-09-08
project_end_date: 2013-06-30
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
Description (provided by applicant): The objective of this revised application is to create a Center of Biomedical Research Excellence in Obesity and Cardiovascular Disease (COCVD) to identify mechanisms linking the epidemic of obesity to the high incidence of cardiovascular diseases in the obese population and to use this focus as a platform to develop promising junior project investigators and enhance their success at competing for NIH grant support. We will achieve this objective by (1) assembling a group of established extramurally-supported scientists who will mentor faculty serving as principal project investigators on research projects that address timely and significant questions related to obesity and cardiovascular disease (2) providing a variety of mentoring approaches that will facilitate the development of research projects by project investigators leading to independent NIH-supported research (3) developing and supporting shared use core facilities that support and extend research methods critical to the study of obesity and cardiovascular disease (4) providing pilot grants for new projects focused on obesity and cardiovascular diseases (5) facilitating symposia seminars and meetings of participants researching obesity and cardiovascular diseases (6) focusing on the research of the center at retreats dedicated to evaluating progress by project investigators studying obesity and cardiovascular diseases (7) strategically hiring promising new faculty to develop a critical mass of productive physician and basic scientists studying obesity and cardiovascular diseases. Five project investigators representing both physician and basic scientists will serve as principal project investigators on research projects that address a central hypothesis and that utilize a common model of diet-induced obesity to study obesity-induced hypertension atherosclerosis and platelet dysfunction/vascular inflammation. The central hypothesis of this revised proposal is that obesity induces changes in the production and release of adipokinins and other inflammatory mediators to promote cardiovascular diseases. Each project addresses aspects of this hypothesis using a common model of diet-induced obesity and the projects synergize through their focus on adipokinesis inflammation and through coordinate development of multiple cardiovascular diseases. The proposed structure and mentoring mechanisms will meet the need of increasing NIH supported research and will develop a multi-disciplinary Center around the clinically significant area of obesity and cardiovascular disease.


application_id: 8098150
project_number: 5R01DE017921-02
project_title: Role of JAK2 in Innate Immunity
administering_ic: NIDCR
award_notice_date: 2011-05-27
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DE
serial_number: 017921
program_official: BURGOON, PENNY W
project_start_date: 2010-06-23
project_end_date: 2014-05-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
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): Porphyromonas gingivalis is considered to be one of the major etiologic agents of periodontal diseases. Studies assessing the host inflammatory response to P. gingivalis have demonstrated that the innate immune receptors TLR2 and TLR4 are the major TLRs involved in the recognition of both the LPS and various pathogen associated molecular patterns isolated from P. gingivalis. However as demonstrated from both in vitro and in vivo studies TLR2 has been documented to be the predominant TLR involved in regulating the innate immune response to the whole bacterium of P. gingivalis. Studies have shown that the absence of TLR2 results in abrogated or suppressed host inflammation enhanced bacterial clearance and attenuated bone loss. Thus the TLR2-mediated inflammatory response induced by P. gingivalis appears to be critical for its ability to exacerbate the disease process. Due to the primary importance of TLR2 in mediating the inflammatory response to whole-cell P. gingivalis we focused on the intracellular signaling pathways activated by TLR2 and have subsequently identified that the Janus Kinase 2 (JAK2) plays an essential role in controlling the innate inflammatory response. Our specific hypothesis is that JAK2 is a central kinase controlling TLR2- mediated inflammation by P. gingivalis-stimulated innate immune cells and thus plays an essential role in the disease process. This hypothesis is based on: 1) stimulation of innate immune cells [human gingival epithelial cells (EC) dendritic cells (DC) and macrophages] with P. gingivalis resulted in the TLR2-dependent activation of JAK2 and inhibition of JAK2 attenuated the inflammatory response; (2) stimulation of innate immune cells with P. gingivalis resulted in the association of activated JAK2 with the cytosolic domain of TLR2; (3) immunoprecipitation of TLR2 from P. gingivalis-stimulated cells demonstrated the association of JAK members JAK2 JAK3 and TYK2 with TLR2; (4) inhibition of JAK2 resulted in the loss of P. gingivalis-mediated tyrosine phosphorylation of TLR2 and loss of JAK2 JAK3 and TYK2 recruitment to TLR2; (5) inhibition of JAK2 resulted in the abrogated activation of the NF-:B p65 signaling pathway; (6) JAK2 was activated in mice challenged with P. gingivalis; and (7) in vivo inhibition of JAK2 abrogated the host inflammatory response in mice challenged with P. gingivalis. These preliminary findings are the first to characterize a functional cell- signaling pathway for JAK2 in regulating TLR2-mediated innate immune responses including how JAKs are activated and recruited to TLR2 and have identified that the ability of TLR2 to activate/recruit JAKs to TLR2 is a fundamental process involved in the inflammatory response to P. gingivalis. The Specific Aims will define the functional role the JAK2 pathway plays in regulating the host inflammatory response to P. gingivalis and assess the importance of targeting JAK2 in vivo by determining how JAK2 inhibition affects the ability of P. gingivalis to induce host inflammation and bone loss in a mouse model.  
  
PUBLIC HEALTH RELEVANCE:  Periodontitis is a chronic inflammatory disease. The host's immune response has been shown to play a fundamental role in the disease process by controlling the inflammatory response. Thus defining and characterizing the how the host controls the inflammatory response is critical for identifying potential therapeutic interventions.

project_terms:
1-Phosphatidylinositol 3-Kinase;Abscess;Acetylcysteine;Affect;Agonist;Alveolar Bone Loss;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Attenuated;Bacteria;Cell Nucleus;Cell surface;Cells;Chronic;Connective Tissue;Data;Dendritic Cells;Disease;Epithelial Cells;Event;Family;Family member;Gene Expression;Generations;Gingiva;Gram-Negative Anaerobic Bacteria;Host Defense;Human;Immune;Immune response;Immune system;Immunologic Receptors;Immunoprecipitation;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Invaded;JAK3 gene;Janus kinase 2;Life;Mediating;Modeling;Molecular;Mus;Natural Immunity;Nature;Pathogenesis;Pathway interactions;Pattern;Periodontal Diseases;Periodontitis;Phosphorylation;Phosphotransferases;Play;Porphyromonas gingivalis;Process;Production;Reactive Oxygen Species;Receptor Activation;Recruitment Activity;Role;Severity of illness;Signal Pathway;Signal Transduction;Signaling Molecule;TLR2 gene;TLR4 gene;TYK2;Therapeutic;Therapeutic Intervention;Toll-like receptors;Tooth structure;Tyrosine Phosphorylation;base;bone loss;cytokine;in vivo;macrophage;member;microbial;microorganism interaction;mouse model;p65;pathogen;prevent;public health relevance;receptor

public_health_relevance:
Project NarrativePeriodontitis is a chronic inflammatory disease. The host's immune response has beenshown to play a fundamental role in the disease process by controlling the inflammatoryresponse. Thus defining and characterizing the how the host controls the inflammatoryresponse is critical for identifying potential therapeutic interventions.


application_id: 8098105
project_number: 5K02DA019656-06
project_title: Neuropeptidergic Inhibition of Spinal Pain Transmission
administering_ic: NIDA
award_notice_date: 2011-06-15
opportunity_number: PA-00-020
application_type: 5
activity_code: K02
ic: DA
serial_number: 019656
program_official: THOMAS, DAVID A
project_start_date: 2007-07-01
project_end_date: 2012-06-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 1879170
contact_pi: TAYLOR, BRADLEY K.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The candidate for an Independent Scientist Award (K02) seeks five years of salary support to provide release time to study the role of neuropeptides in mediating inflammatory and neuropathic pain. His integrative approach includes pharmacologic behavioral and molecular studies. The candidate obtained a Ph.D. at UCSD worked with Allan Basbaum at UCSF and is now an Associate Professor of Pharmacology at Tulane University. He has published 28 original articles (25 as first/last author) plus 7 invited reviews and received NRSA FIRST (R29) R21 and R01 grants to study pain and analgesia. His broad career goals include: 1. Extension of his current R01 into a well-conceived long-term research program that yields a new pharmacotherapy for chronic pain (e.g. an NPY receptor agonist); 2. Continued interactions with mentors that will foster his deeper understanding of the physiological cellular and biochemical mechanisms of chronic pain and its inhibition by neuropeptides; and 3. Continued collaborations and training in the utilization of molecular biological viral transfection and conditional transgenic mouse technologies so as to develop precise and targeted approaches to important questions in chronic pain research. Tulane remains rich in educational opportunities for intellectual growth and independence and provides outstanding resources to Dr. Taylor including laboratory space equipment behavioral suites in the vivarium and internal research funding. Tulane considers Dr. Taylor to be an integral part of its strong commitment to research and granted him early tenure in 2004. Contingent upon K02 funding the institution provides assurances that 85% of Dr.Taylor's time will be set aside for research and career development activities. The Research Plan focuses on the overall hypothesis that inflammatory or sensory nerve injury decreases presynaptic and postsynaptic elements of NPY signaling at the dorsal horn thereby facilitating pronociceptive neurotransmission and ultimately increasing allodynia and hyperalgesia. Aim #1 will determine the contribution of Y1 or Y2 receptors to the actions of NPY using new receptor subtype- selective antagonists and deletion mutant mice. Aim #2 will correlate injury-induced changes in behavior with NPY release and Y1 receptor expression. Aim #3 will use microdialysis and immunohistochemistry to determine whether NPY inhibits substance P release and dorsal horn nociresponsive neurons.

project_terms:
Absence of pain sensation;Acute;Address;Affect;Agonist;Amino Acids;Animal Model;Animals;Arthritis;Behavior;Behavioral;Biochemical;Biological;Cell membrane;Cerebrospinal Fluid;Collaborations;Confocal Microscopy;Coupled;Cytoplasm;Data;Doctor of Philosophy;Dose;Elements;Equipment;Fluorescence;Formalin;Fostering;Freund's Adjuvant;Funding;Gene Expression;Genes;Goals;Grant;Growth;Hyperalgesia;Hypersensitivity;Immunohistochemistry;Independent Scientist Award;Inflammation;Inflammatory;Injection of therapeutic agent;Injury;Institution;Intrathecal Space;Laboratories;Mechanics;Mediating;Mediator of activation protein;Mentors;Microdialysis;Modeling;Molecular;Morphology;Mutant Strains Mice;National Research Service Awards;Nerve;Neurons;Neuropathy;Neuropeptide Receptor;Neuropeptide Y Receptor;Neuropeptides;Neurotransmitters;Nociception;Pain;Pain Research;Peripheral;Peripheral nerve injury;Persistent pain;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Physiological;Posterior Horn Cells;Publishing;Radioimmunoassay;Receptor Activation;Research;Research Design;Research Project Grants;Resources;Role;Signal Transduction;Spinal;Stimulus;Substance P;Substance P Receptor;Sum;Technology;Testing;Time;Training;Transfection;Transgenic Mice;Universities;Viral;Wages;Work;afferent nerve;allodynia;career;career development;chronic pain;dorsal horn;gamma-Aminobutyric Acid;immunoreactivity;in vivo;inflammatory neuropathic pain;inhibitor/antagonist;nerve injury;neuropeptide Y;neuropeptide Y-Y1 receptor;neurotransmission;neurotransmitter release;nociceptive response;painful neuropathy;postsynaptic;presynaptic;professor;programs;receptor;receptor expression;receptor internalization;research and development;response;sensory stimulus;transmission process


application_id: 8097343
project_number: 5R01MH083621-04
project_title: A Brief Clinic-Based HIV Prevention Program for African American Teen Males
administering_ic: NIMH
award_notice_date: 2011-05-24
opportunity_number: PAR-07-379
application_type: 5
activity_code: R01
ic: MH
serial_number: 083621
program_official: KAMATH, SUSANNAH M A
project_start_date: 2008-09-30
project_end_date: 2013-05-31
study_section: Special Emphasis Panel[ZRG1-RPHB-K(50)R]
contact_pi_person_id: 8234905
contact_pi: CROSBY, RICHARD A
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The Centers for Disease Control and Prevention has declared that AIDS is a "state of emergency" in the US relative to African Americans. Teen males attending STD clinics are one important yet often neglected population of African Americans at risk of HIV acquisition. Despite extremely high rates of STD acquisition (and subsequent infection) among this population effective clinic-based interventions specifically designed to reduce their sexual risk behavior for STD/HIV have not been developed/disseminated. A recent intervention trial (conducted by Dr. Crosby) demonstrated the efficacy of a brief clinic-based intervention designed to prevent subsequent STI acquisition among African American males 18 to 29 years of age. The proposed study will test the efficacy this intervention (in modified form) to reduce STI incidence among African American teen (15 to 20 years old). The primary hypothesis is that teens randomized to receive the intervention will have a lower incidence rate of laboratory-confirmed STIs at 2 and 6-month follow-up assessments (as well as 12-month follow-up conducted by a medical records review) compared to those receiving an attention-equivalent control condition. Teens (N = 840) will be recruited from a publicly-funded STD clinic located in an urban area of the South. After completing an A-CASI assessment teens will be rated on their ability to apply condoms to a penile model and then asked to donate a urine specimen for STI testing. Specimens will be tested for C. trachomatis N. gonorrhoeae and T. Vaginalis using nucleic acid amplification assays. Randomization will then be achieved by a concealment of allocation technique. Teens will be randomized to immediately receive: 1) a brief (60 minute) theory-based one-on-one interactive intervention delivered by a lay health advisor or 2) an attention equivalent control condition. The assessment battery will be repeated 2 months subsequent to enrollment and again 6 months after enrollment. A medical records review will be conducted 12 months after enrollment to compare clinic reported incidence rates between the randomized groups of teens. If incidence of STIs in this population of teens can be decreased as substantially as was found in the previous study of 18 to 29 year-old African American males (percent relative difference = 36.7) the public health significance for African American teen males will substantially contribute to rectify the racial disparity in HIV/STD experienced by African American teen males. By extension we suggest that their partners (typically African American teen females) will also benefit. Because our program is designed for ease of implementation the number of dissemination and translation issues will be greatly minimized thereby greatly facilitating the process of translating research into practice. PUBLIC HEALTH RELEVANCE: The proposed efficacy trial tests an innovative method of bridging the gap between research and practice. By providing a brief clinic-based HIV/STD prevention program to African American teen males attending an STD clinic the study will be the first to demonstrate that teen's sexual risk behavior can be reduced without excessive time and resources. The focus on African American teen males is also quite timely given the recent declaration by CDC that AIDS is a "state of emergency" for African Americans.

project_terms:
20 year old;Acquired Immunodeficiency Syndrome;African American;Age-Years;Attention;Biological Assay;Brothers;Caring;Centers for Disease Control and Prevention (U.S.);Chlamydia;Clinic;Emergency Situation;Enrollment;Female;Frequencies (time pattern);Funding;Future;Glare;Goals;Gonorrhea;HIV;Health;Health Educators;Hispanics;Incidence;Infection;Instruction;Intervention;Intervention Trial;Kentucky;Laboratories;Life;Low income;Medical Records;Methods;Modeling;Neisseria gonorrhoeae;Newly Diagnosed;Nucleic Acids;Perception;Population;Prevention program;Process;Randomized;Randomized Controlled Trials;Recruitment Activity;Relative (related person);Reporting;Research;Research Design;Resources;Risk;Science;Services;Sex Behavior;Sexual Partners;Specimen;Techniques;Teenagers;Testing;Time;Translating;Translational Research;Translations;Treatment Efficacy;Trichomonas Infections;Trichomonas vaginalis;Uncertainty;United States;Urine;Vagina;Woman;Work;arm;avoid sex;base;condoms;design;disorder prevention;effective intervention;efficacy testing;efficacy trial;experience;flexibility;follow-up;high risk men;improved;innovation;intervention effect;intervention program;male;man;medical specialties;men;neglect;post intervention;prevent;programs;public health medicine (field);research to practice;response;safer sex;sex;sex risk;theories;therapy design;urban area


application_id: 8097225
project_number: 5R01GM050388-18
project_title: Role of Lipid Phosphatases in Cholesterol and Triglyceride Synthesis
administering_ic: NIGMS
award_notice_date: 2011-06-13
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 050388
program_official: BARSKI, OLEG
project_start_date: 1994-08-01
project_end_date: 2014-06-30
study_section: Biochemistry and Biophysics of Membranes Study Section[BBM]
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cardiovascular and cerebrovascular diseases are the leading causes of death worldwide. Obesity elevations in circulating levels of cholesterol and triglycerides and alterations in the composition of circulating lipoproteins are major risk factors for cardiovascular and cerebrovascular disease. Obesity is a disorder of energy balance. When energy input exceeds energy output most of the excess calories consumed are converted to triglycerides and stored in adipose tissue. Similarly increases in circulating cholesterol leading to cholesterol deposition in the vasculature occur when the balance between de novo synthesis of cholesterol and provision of cholesterol from dietary sources exceeds normal cholesterol requirements and capacity to eliminate this essential sterol. Clinical management of obesity and its complications including hypercholesterolemia presently focuses on modifications of diet physical activity and behavior. Because these strategies are of limited effectiveness the prevalence of obesity continues to increase. Pharmacological inhibition of cholesterol synthesis is the primary and presently most effective strategy for the clinical management of hypercholesterolemia. Although to date efforts to develop pharmacological strategies for treatment of obesity focusing on appetite suppression and interference with lipid absorption have met with moderate success recent advances using mouse models suggest that inhibition of triglyceride synthesis may be a viable and effective treatment strategy. Identification of components of the pathways responsible for synthesis of triglycerides and cholesterol and development of a complete understanding of how these processes are regulated is therefore critical for the development of new or improved agents for treatment of obesity and hypercholesterolemia. Because of their pivotal position in cellular metabolism the pathways responsible for the de novo synthesis of cholesterol and triglycerides have been intensively studied but significant gaps in our knowledge remain. Two classes of lipid phosphate esters polyisoprenoid diphosphates and phosphatidic acid are critical intermediates in the synthesis of cholesterol and triglyceride but enzymes that dephosphorylate these intermediates have only recently been identified. The overall goal of this research is to address these gaps in our knowledge by investigating the regulation and function of two newly identified lipid phosphatases that play central roles in the synthesis of isoprenoids sterols and triglycerides. Our research uses techniques of biochemistry cell and molecular biology to study the regulation and function of these enzymes in vitro and in biomedically relevant model cell systems. In the first aim we will use these approaches to test the hypothesis that an integral membrane enzyme termed polyisoprenoid diphosphate phosphatase is a regulator of cholesterol synthesis and protein isoprenylation. In the second aim of the proposal we will test the hypothesis that activity of a phosphatidic acid phosphatase enzyme that catalyses a critical step in triglyceride synthesis is regulated by a novel membrane targeting motif. PUBLIC HEALTH RELEVANCE: Obesity and elevated cholesterol levels are major risk factors for Cardiovascular and Cerebrovascular disease which are the leading causes of death in this country. Obesity is a disorder of energy balance. When energy input exceeds energy output most of the excess calories consumed are converted to triglycerides and stored as body fat. Similarly increases in circulating cholesterol occur when the balance between cholesterol synthesis and provision of cholesterol from dietary sources exceeds normal cholesterol requirements and cholesterol excretion. In this research project we will test specific hypotheses about the regulation and function of newly identified enzymes that play central roles in the synthesis and metabolism of fat and cholesterol. Completion of our work will provide new insights into how synthesis of these lipids is regulated how this process may be altered in disease and the feasibility of targeting these processes to provide novel therapies for obesity and cardiovascular disease.

project_terms:
12-diacylglycerol;Address;Adipose tissue;Amplifiers;Anabolism;Basic Science;Behavior;Binding (Molecular Function);Biochemical;Biochemistry;Biological;Biological Assay;Body fat;Calories;Cardiovascular Diseases;Cause of Death;Cell Nucleus;Cell model;Cells;Cellular biology;Cerebrovascular Disorders;Cholesterol;Cholesterol Synthesis Inhibition;Clinical Management;Country;Data;Deposition;Desire for food;Detergents;Development;Diet;Diet Modification;Dietary Cholesterol;Diglycerides;Diphosphates;Disease;Drug Delivery Systems;Effectiveness;Endoplasmic Reticulum;Enzymatic Biochemistry;Enzymes;Equilibrium;Excretory function;Exhibits;Farnesol;Funding;Gene Family;Genes;Genetic;Glycerophospholipids;Goals;Health;In Vitro;Intervention;Intracellular Membranes;Isoprenoid Phosphates;Knowledge;Lecithin;Lipids;Lipoproteins;Malignant Neoplasms;Mediating;Membrane;Membrane Lipids;Membrane Proteins;Metabolic;Metabolic Diseases;Metabolism;Molecular;Molecular Biology;Mono-S;Morbidity - disease rate;Mortality Vital Statistics;Nuclear Envelope;Obesity;Output;Pathway interactions;Peripheral;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Phosphatidate Phosphatase;Phosphatidic Acid;Phospholipids;Phosphoric Monoester Hydrolases;Physical activity;Play;Positioning Attribute;Prevalence;Process;Protein Isoforms;Protein Isoprenylation;Proteins;Regulation;Research;Research Project Grants;Risk Factors;Role;Signal Transduction;Source;Specific qualifier value;Sphingolipids;Sterols;System;Techniques;Testing;Triglycerides;Viral Vector;Work;Yeasts;absorption;base;effective therapy;energy balance;enzyme activity;enzyme pathway;geranylgeraniol;human disease;hypercholesterolemia;improved;inorganic phosphate;insight;isoprenoid;lipid metabolism;lipine;meetings;member;membrane model;mevalonate;mouse model;novel;obesity management;obesity treatment;phosphate ester;preference;programs;prospective;success;therapeutic target;treatment strategy


application_id: 8096788
project_number: 5P50DA005312-21
project_title: CDART - Center for Drug Abuse Research Translation
administering_ic: NIDA
award_notice_date: 2011-06-24
application_type: 5
activity_code: P50
ic: DA
serial_number: 005312
program_official: LLOYD, JACQUELINE
project_start_date: 1992-09-30
project_end_date: 2012-07-14
study_section: ZDA1-RXL-E(29)
contact_pi_person_id: 1884463
contact_pi: BARDO, MICHAEL T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-01
project_abstract:
The current renewal application for the Center for Drug Abuse Research Translation (CDART) consists of a core and four projects. The central integrated theme of the Center is that reward seeking and inhibition are biologically-based personality constructs associated with drug abuse vulnerability and that these constructs are useful in the design of targeted drug abuse prevention messages. The Core will: (1) provide thematic scientific integration of the different projects around the constructs of reward seeking and inhibition; (2) create synergy across the four proposed projects and other ongoing projects on campus; (3) facilitate interdisciplinary collaboration among basic and prevention sciences using both neurobehavioral and psychosocial levels of analysis; and (4) oversee the long-range goal of translating our basic research into practice. In Project 1 (Bardo PI) a laboratory rat model will be used to determine if individual differences in reward seeking and inhibition are associated with stimulant drug self-administration and mesocorticolimbic cellular processes. In Project 2 (Kelly PI) human volunteers will be tested in a controlled laboratory environment to assess if individual differences in reward seeking and inhibition are associated with differences in drug reward and neural function as measured by functional magnetic resonance imaging (fMRI) and electroencephalography (EEC). In Project 3 (Lynam PI) a cohort of students transitioning from high school to college will be used to determine if individual differences in reward seeking and inhibition are associated with the initiation escalation and/or cessation of drug use in a longitudinal design. In Project 4 (Zimmerman PI) formative and experimental research will be conducted to determine if televised anti-drug public service announcements (PSAs) are differentially effective among individuals who vary in reward seeking and inhibition. Thus all of the critical elements are now in place to assess at multiple levels of discipline (biomedicine psychology and health communication) the role of reward seeking and inhibition in drug abuse vulnerability with the long-term goal of improving the efficacy of anti-drug televised PSAs that are tailored specifically for at-risk youth transitioning to adulthood.


application_id: 8096787
project_number: 5P50DA005312-20
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: 2010-07-01
budget_end_date: 2011-06-30
funding_mechanism: Research Centers
project_abstract:
The current renewal application for the Center for Drug Abuse Research Translation (CDART) consists of acore and four projects that are linked around the central theme that individual differences in personality areimportant predictors of drug abuse vulnerability during adolescence and young adulthood. Previous work inour center and other laboratories has identified sensation seeking as a critical personality constructassociated strongly with drug use especially use of illicit drugs. In the current proposal sensationseekingwill be divided into two separate constructs namely reward seeking and inhibition both of which are thoughtto be associatedwith drug use. In Project 1 (Bardo PI) a laboratory rat model will be used to determine ifindividual differences in reward seeking and inhibition are associated with stimulant drug self-administrationand mesocorticolimbic cellular processes. In Project 2 (Kelly PI) human volunteers will be used to assess ifindividual differences in reward seeking and inhibition are associated with differences in drug self-administration and neural function as measured by fMRI and EEC. In Project 3 (Lynam PI) a cohort ofstudents transitioning from high school to college will be used to determine if individual differences in rewardseeking and inhibition are associated with the initiation escalation and/or cessation of drug use in alongitudinal design. In Project 4 (Zimmerman PI) students will be used in experimental reserch designed toevaluate if individuals who vary in reward seeking and inhibition show a differential response to televisedanti-drug public service announcements. There are three specific aims in the Core: one scientific one organizational and one that involvescontinuing and expanding leadership in translating the prevention science and drug abuse researchcommunities. In relation to the four projects some key functions of the Core are to: (1) provide thematicscientific integration of the different projects around the constructs of reward seeking and inhibition; (2)create synergy across the four proposed projects and other ongoing projects on campus; (3) facilitateinterdisciplinary collaboration among basic and prevention sciences using both neurobehavioral andpsychosocial levels of analysis; and (4) oversee the long-range goal of translating our basic research intopractice by designing more effective anti-drug public service announements that target at-risk young adults.

project_terms:
Adolescence;Advocate;Basic Science;Cell physiology;Commit;Communities;Drug abuse;Drug usage;Educational workshop;Electroencephalography;Environment;Esthesia;Faculty;Functional Magnetic Resonance Imaging;Funding;Goals;Human Resources;Human Volunteers;Illicit Drugs;Individual;Individual Differences;Institution;International;Laboratories;Laboratory Rat;Leadership;Link;Measures;Modeling;Neurophysiology - biologic function;Personality;Pharmaceutical Preparations;Positioning Attribute;Prevention;Preventive Intervention;Process;Professional Organizations;Publications;Publishing;Research;Research Personnel;Resources;Rewards;Risk;Role;Science;Scientist;Self Administration;Series;Services;Structure;Students;Testing;Training;Translating;Translational Research;Translations;Work;base;cohort;college;design;drug abuse prevention;drug reward;evidence base;high school;implementation science;interdisciplinary collaboration;longitudinal design;neurobehavioral;next generation;outreach;programs;psychologic;psychosocial;relating to nervous system;research study;research to practice;response;social;symposium;trait;young adult


application_id: 8096786
project_number: 5P50DA005312-20
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: 2010-07-01
budget_end_date: 2011-06-30
funding_mechanism: Research Centers
project_abstract:
Interventions to prevent or reduce substance use or abuse among young adults are few and generallynot effective. This is unfortunate as young adults are among the most frequent users of a varietyofsubstances including marijuana alcohol and various illicit substances. Most substance abuse preventiveinterventions have largely ignored biologically-basedpredispositions that lead individuals both to engage inrisky behaviors including substance use and to attend and respond to certain kinds of interventionmessages. This project builds on our previous work using sensation seeking to target and tailor messagesaimed at reducing substance use and risky sexual behavior Specifically building on emerging research fromthe Center wedecompose sensation seeking into its component parts of reward-seeking and inhibition.Drawing on recent advances in message targeting and tailoring we move beyond our previous work onmessage sensation value to include consideration of the influence of message framing and fear on messageeffectiveness. The present proposal offers and tests a general model of message effectivenessthatconsiders the interaction between individual differences (i.e. reward seeking and inhibition) and messagecharacteristics (i.e. message sensation value framing and fear). The model is tested in three studies usingpublic service announcements (PSA) an intervention mode with which our team has extensive experience. There are four specific aims: 1) To examine the persuasive effects of high vs. low sensation value (HSVvs. LSV) substance abuse prevention messages on young adults varying in reward seeking and inhibition;2) To examine the persuasive effects of two emotion-based dimensions of substance abuse messages:message framing (gain vs. loss-framed [GF vs. LF]) and fear (high vs. low threat [HT vs. LT]) on youngadults varying in their levels of reward seeking and inhibition.; 3) To assess the extent to which thedifferential persuasive effects of HSV vs. LSV GF vs. LF and LT vs. HT substance abuse preventionmessages generalize to another high-risk behavior risky sex; and 4) Develop and pilot-test the effectivenessof substance abuse prevention public service announcements (PSAs) with young adults who are either highin reward seeking low in inhibition or both. We propose to accomplish these aims through three studies.The first examines the impact of message sensation value framing and fear on message effectiveness forPSAs aimed at reducing marijuana use as a function of reward seeking and inhibition; the second tests theboundaries of our model using PSAs aimed at reducing risky sexual behavior; the third begins the process ofdesigning optimally effective PSAs based on previous results. Outcomes from the experiments andqualitative studies proposed in this project may be immediately applied to an established body of workboth ours and others in the development of PSAs that are targeted at the reduction of marijuana use.

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;Marijuana Smoking;Modeling;Outcome;Personality;Predisposition;Prevention;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;high risk behavior;high risk sexual behavior;improved;member;novel;prevent;programs;reduce marijuana use;research study;sex;substance abuse prevention;success;trait;willingness;young adult


application_id: 8096785
project_number: 5P50DA005312-20
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: 2010-07-01
budget_end_date: 2011-06-30
funding_mechanism: Research Centers
project_abstract:
To optimally design targeted interventions aimed at reducing substance use one must know whichcharacteristics or traits are involved in substance use and how these characteristics lead to substanceuse;these relations are likely to be complex and to involve bi-directional influences. The present project focuseson two separable traits related to substance use: reward seeking defined as a tendency to enjoy and pursueexciting activities and new experiences and low inhibition defined as the tendency to act without thinking orreflection. The research primarily examines basic elemental processes (e.g. risk tolerance inhibitorycontrol delay discounting Behavioral Inhibition or Activation System functioning) that may mediate therelations between these traits and substance use. The elemental processes are hypothesized to reflect theactivity of two biological systems: an approach/reward seeking system and an inhibitory system. The rewardsystem is theorized to be responsive to reward and is responsible for activating approach behavior. Theinhibition system is theorized to be sensitive to punishment and is responsible for inhibiting ongoing behaviorand initiating active information processing. Several potential social variables are also examined as potentialmediators (i.e. substance use expectancies and peers). The research also allows for the possibility thatsubstance use itself changes the traits and the underlying elemental processes. Finally the project examinesthe interrelations among the elemental processes themselves. All of these issues are examined in thecontext of a three-year two cohort longitudinal study. There are four specific aims:1. To identify the mechanisms underlying the relations leading from reward seeking and inhibition tosubstance use. Inhibition and reward seeking are distinct traits with distinct outcomes including substanceuse and abuse. Little is known however about the processes that link these traits to their outcomes.2. To examine the effect of substance use on the processes associated with reward seeking and inhibition.Research has shown acute effects of drug exposure on the processes under study. For examplealcoholhas been shown to have acute effects on inhibitory control. Additionally a number of studies havedemonstrated process deficits in substance abusers. Thus it is possible that drug use influences theprocesses underlying reward seeking and inhibition although this has not been demonstrated longitudinally.3. To examine the relations among the underlying processes themselves. The processes examined in thepresent research come from a variety of levels and modes of assessment ranging from elementary inhibitorycontrol through Behavioral Inhibition System functioning assessed via psychophysiology. Although each taskand measure is related to substance use and has been designed to assess one of the two hypotheticalsystems these tasks have not been examined together previously.

project_terms:
Acute;Alcohol consumption;Alcohol or Other Drugs use;Alcohols;Behavior;Behavioral inhibition;Cardiac;Characteristics;Complex;Cues;Drug Exposure;Drug usage;Elements;Esthesia;Expectancy;Failure (biologic function);Galvanic Skin Response;Incentives;Intervention;Lead;Left;Link;Longitudinal Studies;Measures;Mediating;Mediator of activation protein;Motivation;Names;Outcome;Personality;Pharmaceutical Preparations;Process;Psychophysiology;Punishment;Reaction Time;Research;Research Personnel;Rewards;Risk;Risk Factors;Short-Term Memory;Signal Transduction;System;Thinking function;Time;Withdrawal;analog;approach behavior;biological systems;cognitive system;cohort;design;discount;discounting;experience;information processing;longitudinal design;peer;programs;response;social;substance abuser;trait


application_id: 8096783
project_number: 5P50DA005312-20
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: 2010-07-01
budget_end_date: 2011-06-30
funding_mechanism: Research Centers
project_abstract:
Recent theories describe drug abuse as a disorder involving not only positive incentive motivation but as adisorder also charactered by a loss of inhibitory control. In this project we will use a laboratory animalmodel to determine the critical neural mechanisms that underlie the association between risk-related traitsand drug abuse questions that cannot be addressed fully using human subjects. Our working hypothesis isthat individual differences in the risk-related traits reward seeking and inhibition play a role in drug abusevulnerability and that individual differences in these two behavioral constructs are mediated by dissociableneural systems. While reward seeking and inhibition undoubtedly involve complex and overlapping neuralcircuits our current knowledge suggests that reward seeking is subserved by ascending mesocorticolimbicdopamine (DA) systems whereas inhibition is subserved by frontal cortical regions involving both DA andserotonin (5-HT). Anatomical studies have also revealed that the medial prefrontal cortex (mPFC) isimplicated in both reward seeking and inhibition whereas the orbitofrontal cortex (OFC) is implicated ininhibition. These neural systems will be examined to determine their role in the association of rewardseeking and inhibition with drug reward. Rats will be assessedfor individual differences in reward seekingand inhibition using a variety of behavioral tests and then will assessed for amphetamine reward DA and 5-HT transporter function and neural activity assessed by in vivo voltammetry and electrophysiologicalstudies. We predict that rats that are high in reward seeking and low in inhibition will be most vulnerable tothe rewarding effect of amphetamine and related drugs. Also we predict that rats that are high in rewardseeking and low in inhibition will be most sensitive to nondrug alternative reinforcers that compete with drugreward which may have important translational implications for the design of effective drug abuse preventionintervention strategies in humans. Finally we predict that individual differences in reward seeking andinhibition will be associatedwith differences in DA and 5-HT systems within the nucleus accumbens mPFCand/or OFC. These results combined with the human behavioral pharmacology and neuroimaging results inProject 2 will provide a more comprehensive understanding the neural systems involved in risk-related traitsrelevant to the design of tailored anti-drug prevention intervention messages.

project_terms:
Address;Adolescent;Affect;Amphetamines;Animal Model;Behavioral;Clinical;Complex;Corpus striatum structure;Disease;Dopamine;Drug Formulations;Drug abuse;Drug usage;Esthesia;Exposure to;Human;Incentives;Individual Differences;Intervention;Investigation;Knowledge;Laboratory Animal Models;Medial;Mediating;Motivation;Neurophysiology - biologic function;Nucleus Accumbens;Pharmaceutical Preparations;Play;Population;Prefrontal Cortex;Preventive 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;neuronal patterning;non-drug;pre-clinical;reinforcer;relating to nervous system;response;theories;trait;young adult


application_id: 8096116
project_number: 1R21HD068844-01
project_title: Combating Produce Consumption Disparity: Appalachian Farm to School Intervention
administering_ic: NICHD
award_notice_date: 2011-03-18
opportunity_number: PA-07-391
application_type: 1
activity_code: R21
ic: HD
serial_number: 068844
program_official: RAITEN, DANIEL J
project_start_date: 2011-05-01
project_end_date: 2013-04-30
study_section: Health Disparities and Equity Promotion Study Section[HDEP]
contact_pi_person_id: 8931964
contact_pi: SWANSON, MARK
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Located in rural Appalachian Kentucky a region with significantly lower fruit and vegetable intake and higher rates of a range of diet related diseases than the US as a whole the proposed project in Lee County KY examines the feasibility of using a farm to school program which provides locally-raised produce to the school cafeteria as a health intervention. The proposed project will be sited in one of the two elementary schools in the county both of which have free and reduced lunch qualification rates exceeding 78 percent with the other school serving as a matched control site. Farm to school projects seek to increase student consumption of fruits and vegetables by linking local farms to school cafeterias; currently however there are no known empirically-based examinations of this promising ecologically oriented approach to improving child nutrition. A multidisciplinary team including an anthropologist a health communications specialist a biostatistician and a public health nutritionist will partner with school personnel students parents and farmers in a Community Based Participatory Research program designed to develop implement and assess a farm to school program in a low-income county in Central Appalachia. The Specific Aims of this project are 1) To tailor existing farm to school programs using formative research including the development of promotional media for use in a low-income high disparity Appalachian community; and (2) To implement and evaluate a pilot F2S program as a means of improving FandV consumption in a low-income Appalachian elementary school. During Phase I the developmental phase key informant interviews and focus groups will be conducted to gain insights into how to tailor existing farm to school programs from elsewhere in the US to the Central Appalachian setting. Formative research with school administrators and food service personnel teachers area farmers students and parents will guide modifications to model farm to school programs. Research team members will collaborate closely with community members in structuring key program components farmer recruitment and selection of produce. We will use social marketing techniques to design in-school promotional media based on student suggestions and feedback from pilot testing. During Phase II we will administer the intervention using a nonequivalent control group design with pre and post tests. The primary outcome measure is the level of consumption of fruits and vegetables measured using an innovative technique based on digital photographic assessment of cafeteria consumption. Outcome evaluation is complemented with extensive process evaluation. Upon project completion we will apply and expand the findings of this ecologically oriented CBPR project to create a large scale R01 project capable of reducing childhood obesity in a way enriching and acceptable to the community.  
  
PUBLIC HEALTH RELEVANCE: An important health risk faced by children in Appalachia is low intake of fruits and vegetables. This dietary deficiency can lead to a range of serious health consequences throughout life. Given the high levels of participation particularly in lower income schools the school lunch program is an important avenue to address this problem. The proposed project works with one Appalachian elementary school in Kentucky as well as its surrounding community to develop implement and assess a Farm to School program that brings locally grown produce into the cafeteria.

project_terms:
Achievement;Address;Administrator;Agriculture;American;Appalachian Region;Area;Attention;Behavior;Child;Child Nutrition;Communities;Complement;Complex;Consumption;Control Groups;County;Data;Development;Diet;Digital Photography;Disease;Eating;Effectiveness;Ensure;Evaluation;Farming environment;Feedback;Focus Groups;Food;Food Services;Funding;Grant;Health;Health Benefit;Health Communication;Housing;Human Resources;Intake;Intervention;Interview;Investments;Kentucky;Lead;Life;Light;Link;Low income;Malnutrition;Measurement;Measures;Modeling;Modification;North Carolina;Nutritionist;Outcome;Outcome Measure;Parents;Phase;Poverty;Pre-Post Tests;Price;Process;Program Effectiveness;Qualitative Methods;Qualitative Research;Reporting;Research;Research Design;Research Project Grants;Risk;Role;Rural;Schools;Site;Social Marketing;Specialist;Structure;Students;Suggestion;Techniques;Testing;Underrepresented Minority;Underserved Population;Vermont;Work;base;combat;community based participatory research;cost effectiveness;design;digital;elementary school;farmer;fruits and vegetables;health disparity;improved;informant;innovation;insight;member;multidisciplinary;obesity in children;primary outcome;programs;public health medicine (field);success;teacher;tool

public_health_relevance:
An important health risk faced by children in Appalachia is low intake of fruits and vegetables. This dietary deficiency can lead to a range of serious health consequences throughout life. Given the high levels of participation particularly in lower income schools the school lunch program is an important avenue to address this problem. The proposed project works with one Appalachian elementary school in Kentucky as well as its surrounding community to develop implement and assess a Farm to School program that brings locally grown produce into the cafeteria.


application_id: 8095486
project_number: 1R21HL108190-01
project_title: Exploring Culture Community Communication and F&V Intake in Black Kentuckians
administering_ic: NHLBI
award_notice_date: 2011-08-02
opportunity_number: PA-08-240
application_type: 1
activity_code: R21
ic: HL
serial_number: 108190
program_official: BOYINGTON, JOSEPHINE
project_start_date: 2011-08-02
project_end_date: 2013-02-28
study_section: Health Disparities and Equity Promotion Study Section[HDEP]
contact_pi_person_id: 10491209
contact_pi: DELLA, LINDSAY J
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): In the U.S. there is a higher prevalence of cardiovascular disease in minority communities and in particular African American (AA) communities than white communities. Additionally being overweight or obese has been scientifically linked to increased risk for cardiovascular disease (CVD). African Americans tend to weigh more on average than whites and other minorities groups and therefore are at increased risk for developing CVD. A healthy diet composed of high fiber foods such as fruit and vegetables has been shown (along with physical activity) to help manage weight and thereby decrease risk for CVD. Research has shown that environmental socio-cultural and psychological factors can affect diet. Given that Kentucky has the second highest prevalence rate of CVD in the nation current prevention efforts in African American communities need to be adapted to the culture geography and individual beliefs of the population. This study proposes a multi-level investigation of environmental community and individual level correlates of fruit and vegetable (F&V) consumption in two Kentucky cities with large African American populations - Louisville and Hopkinsville. Our transdisciplinary approach which leverages data collection and analysis techniques from sociology communication public health and marketing is grounded in the social-ecological model. As such our aims for this study include: 1) identifying documenting and exploring environmental community familial and intrapersonal-level determinants of F&V consumption 2) implementing a cross- sectional quantitative assessment based on data uncovered in Aim 1 to identify important audience segments and salient predictors of each segment and 3) designing a tailored intervention to positively impact F&V consumption in West Louisville and Hopkinsville. To achieve Aim 1 we will use an innovative combination of participatory inquiry (e.g. transect walks) and in- depth interviews interviewing 20 individuals in each city (N=40). Knowledge gained from these research activities will then be used to address Aim 2 and inform the development of the cross-sectional survey which will be collected from 150 individuals in each city (N = 300). These data will be used to identify important segments of the African American audiences in each city. Finally intervention design options will be tested using an approach borrowed from commercial marketing- Adaptive Conjoint Analysis (ACA). In the private- sector ACA is often deemed superior to focus group testing because it allows product/campaign designers to understand the relative importance of various product (or intervention) attributes. This study will be the first translation of ACA to a public health intervention development context.  
  
PUBLIC HEALTH RELEVANCE: The prevalence of cardiovascular disease (CVD) is higher in African Americans (AA) than other American populations. Therefore we need to better understand how the environment culture family and intrapersonal factors combine to impact behavior related to lessened cardiovascular disease risk - specifically increased fruit and vegetable (F&V) consumption. To that end the main purpose of this project is to use a formative research approach that incorporates participatory and qualitative research methods from sociology conceptual underpinnings from a cultural communication perspective and an intervention design method that borrows an analytic technique used by market researchers in the private sector in order to design a culturally congruent intervention to positively affect fruit and vegetable consumption among African American Kentuckians.

project_terms:
Achievement;Address;Adult;Affect;African American;American;Area;Behavior;Behavior Therapy;Belief;Cardiovascular Diseases;Cities;Communication;Communities;Comorbidity;Consumption;Cross-Sectional Studies;Data;Data Analyses;Data Collection;Development;Diet;Diet good;Discipline;Elements;Environment;European Economic Community;Family;Fiber;Focus Groups;Food;Geography;Goals;Health behavior;High Prevalence;Individual;Intake;Intervention;Interview;Investigation;Kentucky;Knowledge;Life;Life Style;Link;Location;Market Research;Marketing;Methodology;Methods;Minority;Minority Groups;Modeling;Motivation;Obesity;Overweight;Physical activity;Population;Population Density;Preparation;Prevalence;Prevention;Price;Private Sector;Psychological Factors;Publishing;Qualitative Research;Relative (related person);Reporting;Research;Research Activity;Research Methodology;Research Personnel;Risk;Rural;Social Marketing;Sociology;Taste Perception;Techniques;Testing;Translating;Translations;Walking;Weight;base;cardiovascular disorder risk;design;disorder risk;fruits and vegetables;innovation;metropolitan;preference;programs;public health medicine (field);social;therapy design;therapy development;tool

public_health_relevance:
The prevalence of cardiovascular disease (CVD) is higher in African Americans (AA) than other American populations. Therefore we need to better understand how the environment culture family and intrapersonal factors combine to impact behavior related to lessened cardiovascular disease risk - specifically increased fruit and vegetable (F&V) consumption. To that end the main purpose of this project is to use a formative research approach that incorporates participatory and qualitative research methods from sociology conceptual underpinnings from a cultural communication perspective and an intervention design method that borrows an analytic technique used by market researchers in the private sector in order to design a culturally congruent intervention to positively affect fruit and vegetable consumption among African American Kentuckians.


application_id: 8094276
project_number: 5R01OH009802-03
project_title: Effect of droplet size charge and presence of surfactants on coal dust capture
administering_ic: NIOSH
award_notice_date: 2011-07-12
opportunity_number: PA-07-318
application_type: 5
activity_code: R01
ic: OH
serial_number: 009802
program_official: FREDERICK, LINDA J
project_start_date: 2009-09-01
project_end_date: 2013-08-31
study_section: ZOH1-GGB(51)
contact_pi_person_id: 9966536
contact_pi: RAY, ASIT K
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
  
Prolonged exposure to respirable coal and silica dust particles in coal mine dust is the primary cause of Coal worker's pneumoconiosis (CWP). After a steady decline over the past years the prevalence of CWP is on the rise in recent years. The occurrence rate of CWP is directly related to the to the exposure level to respirable coal dust and a lowering of the coal-mine dust level standard from 2.0 to 1.0 mg/m3 has been proposed to reduce the rate. To achieve a lower dust level newer technologies are needed. Existing technologies based on plain water sprays are not effective for the removal of airborne small particles (i.e. size less than 10 <m or more specifically less than 2.5 <m) that pose the highest risk. This is because of large charge neutral droplets involved in the sprays and the hydrophobic nature of coal particles. We postulate that airborne coal particles carry significant amounts of charge and therefore these particles can be effectively captured by charged water droplets generated during spraying by the addition of ionic compounds. The objective of the proposed research is to understand the factors that control the capture of respirable coal particles in water droplets with an aim to develop an efficient water droplet based technology for the removal of coal mine dust. To achieve the objectives of the proposal we will (i) examine the effect of the presence of coal wetting agents in collecting droplets on the capture efficiency of coal particles (ii) measure charge distribution in airborne coal particles to establish whether the mechanism based on Coulombic attraction can be used to capture these particles (iii) examine whether spray droplets can be charged either negatively or positively by the addition of ionic surfactants or other ionic compounds (e.g. ionophores and ionic liquids) and (iv) measure capture efficiency of charged droplets exposed to charged coal particles. To obtain fundamental understanding of the mechanisms involved in the capture of particles by a droplet we propose to use an electrodynamic balance to examine the capture efficiency of single charged droplets suspended in a stream of well-characterized coal particles. In addition we will use linear streams of highly monodisperse droplets to measure the capture of coal particles with high temporal resolution. Such a system provides a unique space-time relation; thus by examining droplets at several distances from the generation point the capture of particles by a droplet with time can be deciphered.

public_health_relevance:
Project NarrativeProlonged exposure to coal mine dust causes incurable black lung disease which afflicts a large numberof people working in coal mines and its occurrence can be reduced significantly by lowering the dustlevel in coal mines. We will develop ways of improving the effectiveness of sprayed water droplets inremoving small coal dust particles that pose the greatest health risk. We will examine the effect ofthe use of additives and electrostatic charge in water droplets on the capture of small coal particlesby the droplets.


application_id: 8093146
project_number: 1R21EY021584-01
project_title: 14-3-3?? and epithelial differentiation in the eye and other tissues
administering_ic: NEI
award_notice_date: 2011-08-12
opportunity_number: PA-10-069
application_type: 1
activity_code: R21
ic: EY
serial_number: 021584
program_official: MCKIE, GEORGE ANN
project_start_date: 2011-09-01
project_end_date: 2013-08-31
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 8891723
contact_pi: LI, QIUTANG
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Epithelial differentiation has been widely studied and the process can be divided into two general steps: generation of proliferating progenitors from resident stem cells and the subsequent arrest and differentiation of these progenitors. Oscillation of the transcription factor TCF3 between activator and repressor is key to both maintaining a resident stem cell population and generating pulses of progenitor cells for these stem cells. These progenitors proliferate to fill the tissue field and then the Notch pathway triggers their cell cycle arrest and differentiation. Accordingly when Notch1 is mutated progenitors in the cornea meibomian gland and hair follicles fail to differentiate and they proliferate beyond the tissue fields leading to pathologic loss of function. The timing of Notch1 signal initiation in proliferating progenitors is critical to define the precise number of cells and thus tissue topology. Insight into to how Notch1 signaling is initiated in this process is only now emerging. Epithelial tissue fields are established by cell-cell contact inhibition as proliferating progenitors come in contact. Mutations in cell contact inhibition signaling lead to progenitor outgrowth beyond normal tissue fields (as with Notch1 mutation) loss of tissue function and ultimately cancer. But how might onset of Notch1 signaling be linked to such cell-cell contact? Cadherin-initiated junctional complexes not only mediate apical polarity in epithelial cells they also initiate a kinase cascade known as Hippo which phosphorylates a set of transcription factors that regulate both the cell cycle as well as differentiation programs. This phosphorylation provides a binding site for 14-3-3 which in turn sequesters the factors in an inactive form in the cytoplasm. Recent results demonstrate that mutations in components of the cell contact inhibition kinase cascade lead to loss of Notch 1 activity and likewise we have found that mutation of 14-3-3s in this pathway also leads to loss of Notch1 expression. Taken together such results imply that as progenitors expand in tissues their eventual cell contact signals 14-3-3s -dependent expression of Notch1 thereby signaling arrest and differentiation. In support of this hypothesis we have found that mutation of 14-3-3s in mice leads to accumulation of proliferating progenitor cells and a phenotype indistinguishable from that of Notch 1 in the cornea hair follicle and ductal structures such as those in the meibomian gland. This loss of 14-3-3s or Notch1 causes severe corneal defects ductal obstruction leading to loss of terminal ascini and abnormal hair follicles leading to hair loss. Importantly we demonstrate that expression of activated Notch1 rescues the differentiation defect in 14-3-3s mutant epithelial progenitors in culture. Here we propose a series of studies designed to further establish linkage between 14-3-3s and the Notch1 pathway in epithelial differentiation in the cornea meibomian gland and hair follicles and to development mouse model systems which can be used as a basis for a future R01 proposal examining the molecular details of the pathway through which 14-3-3s and Notch1 regulate the onset of epithelial differentiation.  
  
PUBLIC HEALTH RELEVANCE: The integrity of the cornea the most anterior part of the eye is indispensable for vision as evident by the facts that more than forty-five million individuals worldwide are bilaterally blind and another 135 million have severely impaired vision in both eyes because of the loss of corneal transparency. Our proposed experiments aim to uncover the essential role of 14-3-3s and the signaling network in controlling the corneal epithelial homeostasis. Our studies will elucidate the molecular mechanism underlying the corneal disease development such as corneal intraepithelial neoplasia and squamous cell carcinoma; and provide new strategies for detection and treatment.

project_terms:
Anterior;Apical;Binding Sites;Biological Models;Cadherins;Cell Count;Cell Cycle;Cell Cycle Arrest;Cell Cycle Regulation;Cell Differentiation process;Cells;Cellular Structures;Complex;Contact Inhibition;Cornea;Corneal Diseases;Corneal Intraepithelial Neoplasia;Cyclin E;Cytoplasm;Defect;Detection;Development;Ductal;Epithelial;Epithelial Cells;Epithelium;Eye;Eye Part;Future;Gene Expression;Generations;Genes;Genetic;Hair;Hair follicle structure;Histocompatibility Testing;Homeostasis;Individual;Intestines;Lead;Link;Malignant Neoplasms;Mediating;Microarray Analysis;Molecular;Mus;Mutate;Mutation;Normal tissue morphology;Obstruction;Pathologic;Pathway interactions;Phenotype;Phosphorylation;Phosphotransferases;Physiologic pulse;Process;Proliferating;Regulation;Research Design;Role;Series;Signal Pathway;Signal Transduction;Skin;Squamous cell carcinoma;Stem cells;Structure;TCF3 gene;Time;Tissues;Transcription Coactivator;Transgenes;Vision;base;blind;corneal epithelium;in vivo;insight;loss of function;meibomian gland;mouse model;mutant;notch protein;prevent;progenitor;programs;research study;stem cell population;transcription factor

public_health_relevance:
The integrity of the cornea the most anterior part of the eye is indispensable for vision as evident by the facts that more than forty-five million individuals worldwide are bilaterally blind and another 135 million have severely impaired vision in both eyes because of the loss of corneal transparency. Our proposed experiments aim to uncover the essential role of 14-3-3s and the signaling network in controlling the corneal epithelial homeostasis. Our studies will elucidate the molecular mechanism underlying the corneal disease development such as corneal intraepithelial neoplasia and squamous cell carcinoma; and provide new strategies for detection and treatment.


application_id: 8092773
project_number: 5R21HL104315-02
project_title: MG53 mediated myocardial repair for ischemic heart disease
administering_ic: NHLBI
award_notice_date: 2011-05-27
opportunity_number: PA-09-164
application_type: 5
activity_code: R21
ic: HL
serial_number: 104315
program_official: SCHWARTZ, LISA
project_start_date: 2010-06-17
project_end_date: 2013-05-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 10217681
contact_pi: CAI, CHUANXI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
Abstract  Ischemic heart disease remains as the single largest leading causes of death in the U.S.A. accounting for more than 1 in 3 deaths per annum. Acute ischemic injury and chronic cardiomyopathy lead to permanent loss of cardiac tissue and ultimately heart failure. Developing novel therapeutic approaches that can directly target the causes of cardiomyocyte death during Ischemia/Reperfusion (IR) injury will have broad translational potential. Our recent findings suggest that MG53 a novel muscle-specific member of the TRIM family of proteins (TRIM72) is essential for repair of muscle damage and also provide a therapeutic target for treatment of cardiovascular diseases. This application focuses on testing our hypothesis that "MG53 is an essential molecule for myocardial repair following ischemia-reperfusion injury and extracellular recombinant MG53 may promote myocardial repair and prevent ischemic heart disease". In specific aim 1 we will examine the mechanism underlying MG53-mediated myocardial repair under conditions of oxidative-stress ischemia or acute injury with isolated cardiomyocytes from neonatal mice. Aim 2 of this proposal will establish the efficacy of recombinant MG53 in protection against IR injury to the heart muscle using the wild type and mg53-/- animal models. Specifically we will determine if the application of MG53 protein prior to or after reperfusion can prevent or attenuate ischemia-reperfusion induced myocardial injury. Fulfillment of the proposed experiments may provide the essential proof-of-principle studies on the feasibility of targeting MG53 in treatment of ischemic heart disease.  
  
PUBLIC HEALTH RELEVANCE:   
Project Narrative  Ischemic heart disease is the most common cause of death in most Western countries. Developing novel therapeutic approaches that can directly target the causes of cardiomyocyte death during Ischemia/reperfusion (IR) injury will have broad translational potential. One pathway with great potential as a therapeutic target in regenerative medicine is the process by which individual cells repair their plasma membrane following injury. We recently found that MG53 is a novel muscle-specific member of the TRIM family of proteins (TRIM72) which contributes to the dynamic membrane repair process in skeletal muscle (1-3). However the role of MG53 in myocardial protection remains unknown. In this application we will conduct experiments to investigate the impacts of MG53 in myocardial repair following Ischemia/reperfusion injury. Initially we will use both wild type and MG53 knockout mice models to investigate the mechanism underlying MG53-mediated repair of membrane damage to cardiomyocytes under conditions of oxidative-stress ischemia or acute injury.  We will also assess the efficacy of recombinant MG53 protein in protection against IR injury to the heart muscle using comprehensive evaluation of myocardial performance including echocardiography immunohistochemistry and confocal microscopy with the wild type and MG53 knockout mice.  The results will provide novel insights into proof-of-principle studies to develop effective protein-based therapies for cardiac repair in patients with cardiovascular diseases.

project_terms:
Accounting;Acute;Acute myocardial infarction;Adenoviruses;Animal Model;Arteriosclerosis;Attenuated;Blood flow;Cardiac;Cardiac Myocytes;Cardiac Surgery procedures;Cardiomyopathies;Cardiovascular Diseases;Cause of Death;Cell Death;Cell membrane;Cells;Cessation of life;Chronic;Complex;Confocal Microscopy;Coronary Arteriosclerosis;Country;Data;Development;Echocardiography;Escherichia coli;Evaluation;Exploratory/Developmental Grant;Exposure to;Extracellular Space;Faculty;Future;Goals;Heart;Heart Diseases;Heart Injuries;Heart failure;Immunohistochemistry;Individual;Infarction;Injury;Intellectual Property;Ischemia;Knockout Mice;Lead;Mediating;Membrane;Membrane Protein Traffic;Metabolism;Molecular;Mortality Vital Statistics;Mus;Muscle;Muscle Cells;Myocardial;Myocardial Ischemia;Myocardium;Myopathy;NIH Program Announcements;Neonatal;Oxidative Stress;Pathway interactions;Patients;Performance;Physiological;Prevention;Process;Proteins;Recombinants;Regenerative Medicine;Reperfusion Injury;Reperfusion Therapy;Research;Research Project Grants;Role;Signal Transduction;Site;Skeletal muscle structure;Staging;Striated Muscles;TRIM Family;Testing;Therapeutic;Therapeutic Intervention;Tissues;Translating;United States National Institutes of Health;Vesicle;abstracting;anaerobic glycolysis;base;caveolin-3;efficacy testing;extracellular;human DYSF protein;human disease;injury and repair;insight;member;mouse model;novel;novel therapeutic intervention;oxidation;percutaneous coronary intervention;post-doctoral training;prevent;public health relevance;repaired;research and development;research study;restoration;sensor;therapeutic protein;therapeutic target;thrombolysis

public_health_relevance:
Project Narrative Ischemic heart disease is the most common cause of death in most Western countries.Developing novel therapeutic approaches that can directly target the causes of cardiomyocytedeath during Ischemia/reperfusion (IR) injury will have broad translational potential. Onepathway with great potential as a therapeutic target in regenerative medicine is the process bywhich individual cells repair their plasma membrane following injury. We recently found thatMG53 is a novel muscle-specific member of the TRIM family of proteins (TRIM72) whichcontributes to the dynamic membrane repair process in skeletal muscle (1-3). However the roleof MG53 in myocardial protection remains unknown. In this application we will conductexperiments to investigate the impacts of MG53 in myocardial repair followingIschemia/reperfusion injury. Initially we will use both wild type and MG53 knockout mice modelsto investigate the mechanism underlying MG53-mediated repair of membrane damage tocardiomyocytes under conditions of oxidative-stress ischemia or acute injury.  We will alsoassess the efficacy of recombinant MG53 protein in protection against IR injury to the heartmuscle using comprehensive evaluation of myocardial performance includingechocardiography immunohistochemistry and confocal microscopy with the wild type andMG53 knockout mice.  The results will provide novel insights into proof-of-principle studies todevelop effective protein-based therapies for cardiac repair in patients with cardiovasculardiseases.


application_id: 8092613
project_number: 5P30AG028383-05
project_title: CLINICAL CORE - SATELLITE
administering_ic: NIA
opportunity_number: RFA-AG-05-010
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1
subproject_number: 9005
contact_pi_person_id: 1896068
contact_pi: SMITH, CHARLES B
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
budget_end_date: 2011-06-30
funding_mechanism: Research Centers
project_abstract:
The Kentucky Clinic North Minority Satellite (KYCN) represents a renewed effort to recruit minorities
particularly African Americans into the University of Kentucky Alzheimer's Disease Center ( UK ADC)
clinical and research programs. This application integrates KYCN into a unique comprehensive model of
dementia-related services and research in the local African American community. Resources of the
Administration on Aging (AOA) the Kentucky Cabinet for Health Services the Alzheimer's Association and
the UK ADC are combined in a multidisciplinary partnership. These efforts include direct minority
participation in recruitment education administration care delivery dementia awareness in-home safety
assessment and transportation services. KYCN under the auspices of UK ADC maintains an independent
research function distinct from the service orientation of the AOA state agencies and the Alzheimer's
Association. The success of this clinic and our research efforts in this population is based on developing
trust between the UK ADC and the African American community nurtured through the provision of quality
medical care and the stable on-going presence of a local clinic staffed by well-trained dedicated
multicultural professionals. Over the last several years we have met program goals providing 97 initial
dementia evaluations recruiting 51 of these individuals into our longitudinal research programs and
obtaining autopsy consent in 6 of these subjects. For this proposal the initial success of this clinic will be
expanded in order to meet the following goals: (1) To provide dementia diagnoses for 30 new patients per
year and to follow a cohort of 100 primarily African American patients longitudinally. (2) To collect data
reportable to NACC as a Uniform Data Set (UDS) for normal controls MCI AD and other non-AD
dementias in a central Kentucky African American population. (3) In conjunction with the Education and
Information Transfer Core to educate the African American community about AD and other dementias the
importance of early diagnosis and treatment and participation in dementia research. (4) To increase
participation by African Americans in AD research with prearranged autopsy including the BRAINS and
Dementia Research programs.

project_terms:
Adult;African American;Age;Aging;Alzheimer's Disease;Autopsy;Awareness;Brain;Caring;Clinic;Clinical;Clinical Research;Communities;Consent;Control Groups;Data;Data Set;Dementia;Diagnosis;Early Diagnosis;Educational aspects;Ensure;Evaluation;Family;Goals;Health Services;Health Services Research;Home environment;Individual;Kentucky;Lead;Medical;Memory Disorders;Minority;Modeling;Neurologic;Patients;Population;Program Evaluation;Recruitment Activity;Reporting;Research;Resources;Safety;Services;Training;Training Support;Transportation;Trust;Universities;base;care delivery;clinical care;cohort;design;diagnosis evaluation;improved;meetings;multidisciplinary;neuropsychological;outreach;programs;success


application_id: 8092612
project_number: 5P30AG028383-05
project_title: EDUCATION AND INFORMATION CORE
administering_ic: NIA
opportunity_number: RFA-AG-05-010
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1
subproject_number: 9004
contact_pi_person_id: 8536107
contact_pi: WEKSTEIN, DAVID R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
budget_end_date: 2011-06-30
funding_mechanism: Research Centers
project_abstract:
The Education and Information Transfer Core (EITC) functions as a vital link between our Alzheimer's
Disease Center (ADC) and the local and state communities. Objectives for the EITC are: 1) to assist the
Clinical Core in the recruitment and retention of research subjects with a special emphasis on minorities; 2)
to enhance the development of AD-related research among faculty and students of the ADC and the
University; 3) to educate family caregivers and the local community about dementing disorders and to
increase the visibility of the ADC; 4) to provide training and educational opportunities on dementing illness to
health care and other professional audiences; and 5) to determine the needs of our target audiences and
evaluate the programs that we offer to them. To accomplish these goals the EITC will provide a range of
programs and services. Efforts developed at the Kentucky Clinic North Minority Satellite will be expanded so
that ADC research projects reflect greater participation by African Americans the largest minority group in
Kentucky. Programs for researchers will include a bibliographic service a scientific writing course seminars
and clinical research conferences. To increase disease awareness in the local community the EITC will offer
programs such as Alzheimer's Disease Awareness Day and Call the Doctor. The EITC participates in a
training grant on aging for family practice residents; an Administration on Aging grant focused on educating
African Americans about Alzheimer's disease and providing culturally sensitive dementia care; and a
Geriatric Education Center grant that provides training to health professionals in the geographic area. The
EITC and the local Alzheimer's Association jointly sponsor an annual community conference for family
members and others who provide care or support to AD families. In summary the EITC will work through
partnerships with national and statewide organizations to design and offer dementia-specific programs to
meet the needs of various target audiences. These offerings will be developed to promote improved health
and diversified services for patients and their family members suffering from dementia.

project_terms:
Adult;African American;Aging;Alzheimer's Disease;Attention;Awareness;Basic Science;Caring;Clinic;Clinical;Clinical Research;Collaborations;Communities;Community Health Education;Continuing Education;Dementia;Development;Discipline;Disease;Educational aspects;Elderly;Ensure;Evaluation;Faculty;Family;Family Caregiver;Family Practice;Family member;Fostering;Funding;General Population;Geographic Locations;Goals;Grant;Group Structure;Health;Health Personnel;Health Professional;Health Services;Healthcare;Kentucky;Link;Minority;Minority Groups;Neurodegenerative Disorders;Neurologic;Nurses;Participant;Patients;Population;Primary Care Physician;Program Effectiveness;Research;Research Activity;Research Personnel;Research Project Grants;Research Subjects;Research Support;Schedule;Services;Students;Surveys;Techniques;Training;Training Support;Underserved Population;Universities;Update;Work;Writing;community organizations;design;improved;informant;interest;meetings;mild cognitive impairment;multidisciplinary;outreach program;postdoctoral investigator;programs;research study;skills;symposium


application_id: 8092611
project_number: 5P30AG028383-05
project_title: NEUROPATHOLOGY CORE
administering_ic: NIA
opportunity_number: RFA-AG-05-010
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1
subproject_number: 9003
contact_pi_person_id: 1894359
contact_pi: MARKESBERY, WILLIAM R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
budget_end_date: 2011-06-30
funding_mechanism: Research Centers
project_abstract:
The overall objective of the Neuropathology Core of the University of Kentucky Alzheimer's Disease Center
is to support research on normal brain aging presymptomatic Alzheimer's disease (AD) mild cognitive
impairment (MCI) early and late AD mixed dementia syndromes and other dementing disorders. The core
will perform short postmortem interval (2-4 hr) autopsies by our Rapid Autopsy Team on longitudinally
followed subjects from our normal control BRAiNS Clinic Dementia Research Clinic and Kentucky Clinic
North Minority Satellite (KYCN) and provide brain specimens CSF and synaptosomes for investigators at
UK other ADCs and outside investigators. The core will also provide consensus conference determined
diagnoses quantitation of neurofibrillary tangles (NFT) neuritic plaques and diffuse plaques from 8 brain
regions Abeta 1-40 and 1-42 quantitation Braak staging CERAD and NIA-Reagan Institute staging on all
autopsied cases to investigators. The core will maintain a tissue bank of the above specimens and frozen
serum plasma buffy coats and CSF from living patients from the Dementia Research Clinic the normal
control BRAiNS Clinic and KYCN. Special emphasis will be placed on defining the neuropathological
findings in the brains of the oldest old (>85) and providing investigators with specimens from cognitively
normal control subjects with no Abeta and few NFT (Braak O-ll) (successful cerebral aging) and cognitively
normal control subjects with abundant Abeta and NFT. Monthly or more frequent consensus conferences will
be held with the Clinical Core to define clinical-pathological diagnoses on all autopsied subjects. Clinical-pathological
conferences will be held every two months and twice annually for the Ohio Valley Geriatric
Research Center. Support for the Nun Study the Honolulu Asian Aging study the UK Udall Parkinson's
Disease Research Center and the Georgia Centenarian Study will be provided by the Neuropathology Core.
This core's unique opportunity to conduct clinical-pathological correlative studies on longitudinally followed
subjects to better understand normal brain aging and the transition to dementia and the factors involved in
this transition could contribute to early interventions and possible preventive measures.

project_terms:
Age;Aged 80 and over;Aging;Alzheimer's Disease;Amygdaloid structure;Amyloid beta-Protein;Area;Asians;Autopsy;Biometry;Brain;Brain region;Centenarian;Cerebrospinal Fluid;Cerebrum;Clinic;Clinical;Consensus;Correlative Study;Data;Databases;Degenerative Disorder;Dementia;Deposition;Diagnosis;Disease;Early treatment;Educational aspects;Elderly;Evaluation;Faculty;Freezing;Funding;Hippocampus (Brain);Individual;Inferior;Institutes;Institution;Kentucky;Life;Lobule;Measures;Medical Students;Middle frontal gyrus structure;Minority;National Institute on Aging;Neurodegenerative Disorders;Neurofibrillary Tangles;Ohio;Parietal;Parkinson Disease;Participant;Pathologic;Pathology;Patients;Physicians;Plasma;Preparation;Preventive;Program Research Project Grants;Protocols documentation;Reporting;Research;Research Personnel;Research Support;Senile Plaques;Specimen;Staging;Structure of middle temporal gyrus;Synaptosomes;Syndrome;Technology;Tissue Banking;Tissue Banks;Universities;Visual;Work;age related;aging brain;association cortex;base;data management;entorhinal cortex;human very old age (85+);interest;mild cognitive impairment;neurofibrillary tangle formation;neuropathology;normal aging;peptide A;pre-clinical;symposium


application_id: 8092610
project_number: 5P30AG028383-05
project_title: BIOSTATISTICS AND DATA MANAGEMENT CORE
administering_ic: NIA
opportunity_number: RFA-AG-05-010
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1
subproject_number: 9002
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
budget_end_date: 2011-06-30
funding_mechanism: Research Centers
project_abstract:
The Biostatistics and Data Management Core (BDMC) has become a major part of the infrastructure of
the University of Kentucky Alzheimer's Disease Center (ADC). It plays an increasingly important role in data
management especially in reporting multiple data sets to NACC. This Core also provides an important
service in experimental design and statistical analysis to the ADC and affiliated AD research. The BDMC
has two specific aims one related to quality data management and the other related to effective statistical
consultation.
The first specific aim is to maintain a centralized database of the information collected by all ADC cores
pilot projects and affiliated AD and aging studies in an integrated manner. Relevant activities that support
this specific aim include: ensuring confidentiality at the subject level and security at the database level with
appropriate backup; assisting in the development of data collection forms and entering all data into the
centralized relational database in an accurate manner; training ADC personnel to practice quality data
collection procedures and to meet BDMC standards; providing expertise on data management procedures to
all ADC personnel and affiliated investigators; monitoring the flow of data in the longitudinal normal control
and AD cohorts and the minority satellite clinic; providing monthly summaries to the ADC Executive
Committee on subject recruitment retention and follow up; creating appropriate subsets of the database for
approved investigators and collaborative projects and archiving all such requests; and reporting accurate
and complete datasets to NACC.
The second specific aim is to provide expertise on experimental design and statistical analysis to ADC
cores pilot projects and affiliated AD projects. Relevant activities that support this specific aim include:
consultation for investigators in the early stages of all projects grant submissions presentations and
manuscripts; reviewing all ADC pilot projects for statistical content; collaborating with other Alzheimer's
Disease Centers on special projects of mutual interest such as periodic conferences on quantitative
methodologies in AD research; and incorporating advances in statistical methodology for interpreting and/or
analyzing data collected.
In addition this Core continues to contribute to the literature with innovative studies on statistical
methodology in AD research. It also participates in the training of graduate students postdoctoral
researchers and young investigators.

project_terms:
Aging;Alzheimer's Disease;Archives;Biometry;Biostatistics Core;Clinic;Clinical;Confidentiality;Consultations;Data;Data Analyses;Data Collection;Data Set;Databases;Dementia;Development;Ensure;Experimental Designs;Funding;Grant;Human Resources;Kentucky;Literature;Manuscripts;Methodology;Minority;Monitor;Participant;Pilot Projects;Play;Procedures;Program Research Project Grants;Reporting;Research;Research Infrastructure;Research Personnel;Research Project Grants;Role;Security;Services;Staging;Training;Universities;cohort;data management;follow-up;graduate student;innovation;interest;meetings;neuropathology;relational database;symposium


application_id: 8092609
project_number: 5P30AG028383-05
project_title: CLINICAL CORE
administering_ic: NIA
opportunity_number: RFA-AG-05-010
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1
subproject_number: 9001
contact_pi_person_id: 1896068
contact_pi: SMITH, CHARLES B
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
budget_end_date: 2011-06-30
funding_mechanism: Research Centers
project_abstract:
The overall goal of the Clinical Core of the University of Kentucky Alzheimer's Disease Center (UK ADC)
is to provide thoroughly evaluated longitudinally followed normal control subjects and Alzheimer's disease
(AD) and other non-AD dementing disorders patients for innovative research studies at UK other ADCs and
institutions studying AD and aging.
This Core will maintain a normal control population of 500 initially normal aged subjects who will be
followed longitudinally to autopsy (all have prearranged autopsies). The major emphases will be on studies
of normal aging and transition to preclinical AD mild cognitive impairment (MCI) and early AD. Control
participants will be evaluated annually with medical neurologic and neuropsychological tests to define
subtle changes in cognitive and neurologic functions. A developmental study will be carried out to attempt to
define the theoretical entity preclinical AD in this population.
This Core will maintain a Dementia Research Clinic of 200 subjects with dementing disorders who will be
followed longitudinally to autopsy (all have prearranged autopsies). Emphasis will be placed on recruiting
MCI early AD and mixed dementia (AD/vascular dementia AD/DLB Parkinson's Disease Dementia)
patients. Dementia Research Clinic patients undergo the same thorough annual evaluation as our control
subjects. The detailed evaluation of control and dementia subjects provides a database for use by UK
investigators associated with our Center and investigators at other ADCs and institutions. Longitudinally
followed control subjects and MCI and early AD patients will provide important data about the course and
progression of AD.
The Clinical Core will expand and maintain a satellite clinic for African Americans the Kentucky Clinic
North Minority Satellite in Lexington to provide longitudinal follow and broadening research opportunities for
an understudied population.
This Core will also obtain serum plasma buffy coats and CSF from normal control subjects MCI and
early AD patients for use by investigators. The Core will participate in the NIA AD neuroimaging initiative
NACC funded studies ADCS trials and industry sponsored drug trials. The uniform data set and the
minimum data set are collected by this Core and submitted to NACC in a timely fashion by the Biostatistics
and Data Management Core. The close relationship between the Clinical Core and the Neuropathology
Core allows for unique clinical-pathological correlation studies on longitudinally followed subjects to better
understand normal aging and transition to MCI and AD.

project_terms:
Adult;African American;Age-Years;Aging;Alzheimer's Disease;Autopsy;Biometry;Brain;Cessation of life;Characteristics;Clinic;Clinical;Clinical Data;Cognitive;Consent;Control Groups;Correlation Studies;Data;Data Set;Databases;Dementia;Development;Disease;Ensure;Evaluation;Funding;Goals;Grant;Guidelines;Image;Industry;Institution;International;Kentucky;Lewy Body Disease;Medical;Minority;Multicenter Studies;Names;Nervous System Physiology;Neurodegenerative Disorders;Neurologic;Neuropsychological Tests;Parkinson Disease;Parkinson's Dementia;Participant;Patients;Pharmaceutical Preparations;Pilot Projects;Plasma;Population;Population Control;Program Research Project Grants;Recruitment Activity;Research;Research Personnel;Research Project Grants;Staging;Techniques;Universities;Vascular Dementia;aged;cohort;data management;follow-up;innovation;mild cognitive impairment;neuroimaging;neuropathology;neuropsychological;normal aging;pre-clinical;research study;volunteer


application_id: 8092210
project_number: 1K08EY021521-01
project_title: Soluble VEGFR-2 as an endogenous inhibitor of retinal lymphatics
administering_ic: NEI
award_notice_date: 2011-09-05
opportunity_number: PA-10-059
application_type: 1
activity_code: K08
ic: EY
serial_number: 021521
program_official: SHEN, GRACE L
project_start_date: 2011-09-30
project_end_date: 2012-06-30
study_section: Special Emphasis Panel[ZEY1 VSN (10)]
contact_pi_person_id: 10500743
contact_pi: BAFFI, JUDIT ZSUZSANNA
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Abstract: The twin goals of this proposal are to (1) to define the mechanisms underlying the alymphatic nature of the retina by developing novel insights into the biology of the endogenous lymphangiogenesis inhibitor soluble vascular endothelial growth factor receptor-2 (sVEGFR-2); and (2) enable the principal investigator to develop the skills and experiences necessary to become an independent physician-scientist with a focus on studying ocular angiogenesis. Angiogenesis is fundamentally important for a vast array of physiological processes including development and wound healing and it comprises the intertwined growth and development of the blood (hemangiogenesis) and lymphatic (lymphangiogenesis) vasculatures. The retina is one of the very few tissues in the body that is served by blood vessels yet remains alymphatic. The mechanisms subserving this divergence in the vascular infrastructure of the retina are unknown. Recently our group reported the existence of a novel splice variant of VEGFR-2 that is the first described endogenous molecule that inhibits lymphangiogenesis but not hemangiogenesis (Albuquerque et al. Nat Med 2009). In new and exciting studies we found that sVEGFR-2 which is essential for the development of an alymphatic cornea is expressed in the human and mouse retina and that knockdown of sVEGFR-2 induced the development of lymphatic vessels in the retina. We will test the hypothesis that sVEGFR-2 is responsible for the alymphatic nature of the retina via the following 3 aims: (1) We will define the spatial and temporal expression and function of sVEGFR-2 in the mouse retina during development and in the adult; (2) We will define the molecular basis and cellular origin of lymphatics in the mouse retina after inhibition of sVEGFR-2 function; (3) We will define the mechanisms by which sVEGFR-2 and VEGF-C influence the function of cells that assume a lymphatic endothelial phenotype in the retina. This study will activate new concepts in sVEGFR-2 biology and yield novel insights into the mechanisms underlying the alymphatic nature of the retina and develop the career of the principal investigator as a clinician scientist.  
  
PUBLIC HEALTH RELEVANCE: Narrative: The retina is one of the very few tissues in the body that is served by blood vessels yet remains alymphatic. The mechanisms subserving this divergence in the vascular infrastructure of the retina are unknown. We discovered a naturally occurring molecule (sVEGFR-2) that selectively blocks lymphatic but not blood vessels. By molecularly uncoupling these intertwined processes we introduce a new research tool that can be used to specifically study lymphatic vascular biology in the retina.

project_terms:
Adult;Biological Assay;Biology;Birth;Blood;Blood Vessels;Cell physiology;Cornea;Development;Endothelial Cells;Gene Expression Profiling;Goals;Growth and Development function;Human;Lymphangiogenesis;Lymphatic;Lymphatic Endothelial Cells;Lymphatic vessel;Maintenance;Mediator of activation protein;Molecular;Mus;Nature;Phenotype;Physicians;Physiological Processes;Principal Investigator;Process;RNA Interference;RNA Splicing;Reporting;Research;Research Infrastructure;Retina;Retinal;Scientist;Signal Pathway;Source;Stem cells;Testing;Tissues;Transplantation;Twin Multiple Birth;Variant;Vascular Endothelial Growth Factor C;Vascular Endothelial Growth Factor D;Vascular Endothelial Growth Factor Receptor-2;Vascular Endothelial Growth Factor Receptor-3;Vascular Endothelial Growth Factors;Wound Healing;abstracting;allograft rejection;angiogenesis;base;career;corneal allograft;experience;inhibitor/antagonist;insight;macrophage;neovascularization;novel;ocular angiogenesis;research study;retina blood vessel structure;skills;tool;transdifferentiation

public_health_relevance:
Narrative: The retina is one of the very few tissues in the body that is served by blood vessels yet remains alymphatic. The mechanisms subserving this divergence in the vascular infrastructure of the retina are unknown. We discovered a naturally occurring molecule (sVEGFR-2) that selectively blocks lymphatic but not blood vessels. By molecularly uncoupling these intertwined processes we introduce a new research tool that can be used to specifically study lymphatic vascular biology in the retina.


application_id: 8091401
project_number: 5T32DA016176-08
project_title: Training in Drug Abuse Related Research
project_terms: Drug abuse;Research;Training
administering_ic: NIDA
award_notice_date: 2011-06-17
opportunity_number: PA-06-468
application_type: 5
activity_code: T32
ic: DA
serial_number: 016176
program_official: AVILA, ALBERT
project_start_date: 2004-07-01
project_end_date: 2014-06-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION ( provided by applicant):  This application is for renewal of a training program directed by Louis Hersh and co-directed by Linda Dwoskin and Sharon Walsh. We request continued support for four predoctoral and two postdoctoral trainees utilizing a training faculty of 15 housed in three colleges and 5 different departments within the University of Kentucky. All of the training faculty have been funded through NIDA or collaborate with NIDA funding training faculty with their research broadly focused on the molecular aspects of drug abuse. The University of Kentucky has a long history of involvement in drug abuse research and includes the Center on Drug and Alcohol Research and the Center for Drug and Alcohol Research and Translation. The goal of this training program continues to be the preparation of promising graduate students and postdoctoral fellows for careers in drug abuse research. The program provides broad-based training in modern aspects of drug abuse research with a particular emphasis on studying the cellular and molecular aspects of receptors involved in the response to drugs and the development of ligands which interact with these receptors as potential pharmacotherapy's for drug abuse. The training faculty share a common interest in understanding basic mechanisms related to drug abuse at the molecular level. The emphasis of the training faculty focus on the structure of opiate receptor ligands the effects of opiate receptor ligands on physiological processes and the structure and function of the proteins and ligands involved in opiate receptors. Trainees learn from a strong faculty who utilize state-of-the-art methodological approaches to drug abuse research. A unique aspect of this program is the interaction of trainees with other faculty and trainees involved in the behavioral aspects of drug abuse giving them a broad based understanding of drug abuse research. This unique training opportunity is hoped to fill the need for new investigators in drug abuse research who have a broad understanding of the field.   
PUBLIC HEALTH RELEVANCE: This program is designed to train graduate students and postdocs for a career in drug abuse research providing them with the tools to conduct research on the molecular aspects of drug abuse while at the same time endowing them with an understanding of the behavioral aspects of drug abuse.


application_id: 8091370
project_number: 5R01MH082762-02
project_title: 2/2-Computer-Assisted Cognitive-Behavior Therapy for Depression
administering_ic: NIMH
award_notice_date: 2011-03-02
opportunity_number: PAR-09-153
application_type: 5
activity_code: R01
ic: MH
serial_number: 082762
program_official: PEARSON, JANE L
project_start_date: 2010-06-16
project_end_date: 2014-01-31
study_section: Interventions Committee for Adult Disorders[ITVA]
contact_pi_person_id: 9075017
contact_pi: WRIGHT, JESSE H.
other_pis: Not Applicable
congressional_district: 03
department: PSYCHIATRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): We propose a two center randomized controlled trial evaluating the efficacy and cost-effectiveness of computer-assisted cognitive-behavior therapy (CCBT) for outpatients with major depressive disorder (MDD). Results of a preliminary study indicated that despite reducing the amount of therapist contact by about 50% CCBT was at least as effective as an 8 week course of conventional individual CBT on depression outcomes with greater effects on dysfunctional attitudes and knowledge about CBT. We now propose to conduct a more rigorous test of the therapeutic equivalence and cost-effectiveness of CCBT versus a full 16 week 20 session course of individual CBT which provides three times the amount of therapeutic contact. A total of 172 male and female outpatients (86 per site) meeting SCID/DSM-IV criteria for MDD will be randomized across five years. Outcomes will be assessed by independent evaluators without knowledge of the treatment received. The study is designed to have the statistical power to test the equivalence of CCBT and the full course of CBT at both the end of acute phase therapy and across 6 months of follow-up. In addition to effects on depressive symptoms and categorical outcomes (i.e. response and remission rates) dependent variables will include measures of dysfunctional attitudes social functioning quality of life and health care costs and utilization. It is predicted that: 1) CCBT will be equivalent to CBT at week 16 and across the 6 month follow-up; and 2) CCBT will be significantly more cost-effective than CBT. Secondary aims include testing potential moderators of treatment outcome and the predicted absence of site differences (as an indicator of disseminability). This trial has significant implications for the public health because it will provide a rigorous test the clinical utility of CCBT against a model of conventional individual therapy that offers three times as much clinical contact. If equivalence and cost- effectiveness are demonstrated the proposed research will set the stage for larger scale studies evaluating broader dissemination of CCBT.  
  
PUBLIC HEALTH RELEVANCE: Although Cognitive Behavior Therapy (CBT) is an effective treatment for major depressive disorder its utility is limited by cost and availability of trained therapists. Computer-assisted delivery of this therapy (CCBT) has shown promise and may offer similar benefits as CBT with as little as one third the amount of therapist time. The proposed study will test the therapeutic equivalence and cost-effectiveness of CCBT versus CBT across a 16 week acute phase and a 6 month follow-up.

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

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


application_id: 8090502
project_number: 5R21AT004544-03
project_title: CAM Referral and Outcomes: Chronic Low Back Pain in Urban and Rural Primary Care
administering_ic: NCCIH
award_notice_date: 2011-07-07
opportunity_number: PAR-07-291
application_type: 5
activity_code: R21
ic: AT
serial_number: 004544
program_official: WEBER, WENDY J
project_start_date: 2009-09-30
project_end_date: 2014-06-30
study_section: ZAT1-LD(30)
contact_pi_person_id: 7875359
contact_pi: ELDER, WILLIAM GIBBS
other_pis: LOVE, MARGARET M
congressional_district: 06
department: FAMILY 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): Kentucky ranks 2nd in disability among states with chronic low back pain (CLBP) as a major disability especially in our rural areas. In the last few years the medical use of opiate medications has significantly increased. Their use has complicated treatment greatly with addiction rates and misuse skyrocketing. Kentucky and U.S. health care providers need alternative and effective treatments. Following NCCAM strategic research recommendations this study will investigate health services outcomes of complementary and alternative medicine (CAM) therapies in an existing primary care practice-based research network (PBRN). The Kentucky Ambulatory Network (KAN) is the partnering PBRN. Patients with CLBP are often willing to try therapeutic options outside the conventional medical spectrum. Massage and relaxation therapies have demonstrated fairly good efficacy in controlled trials but their effectiveness in the "real world" of primary care is only beginning to be evaluated. The long-term goal of the proposed project builds on the foundation of these two established therapies to improve treatment of chronic low back pain (CLBP) in primary care practices. Two alternative (CAM) therapies progressive muscle relaxation (PMR) and clinical massage therapy (CMT) will be studied. The short-term objectives of the proposed project are to: (1) examine outcomes of CAM for patients with CLBP referred from primary care practices and (2) better understand physician decision-making to recommend CAM therapy for CLBP. Specific Aim 1 will evaluate improvement in health-related outcomes for patients with CLBP when referred to PMR or CMT from primary care. Specific Aim 2 will explore selected factors in primary care physicians' decisions to recommend CAM therapy to these patients. The proposed study is unique in that it addresses "real life" clinical situations and decision-making in both urban and rural clinical practices within an existing PBRN. Should such CAM referral prove successful for ameliorating CLBP it would provide relatively low cost non-addictive treatment options for inclusion in the repertoire of primary care physicians.  
  
PUBLIC HEALTH RELEVANCE: The "CAM Referral and Outcomes: Chronic Low Back Pain in Urban and Rural Primary Care" project will investigate clinical and patient-oriented outcomes of CAM therapies in an existing practice-based research network (PBRN). For patients with chronic low back pain we will examine the outcomes of clinical massage therapy and progressive muscle relaxation when referred by primary care physicians as well as selected factors in the physicians' decisions to recommend these therapies.

project_terms:
Address;Adoption;Back;Caring;Characteristics;Chronic low back pain;Client satisfaction;Clinical;Collaborations;Communication;Communities;Community Medicine;Complementary and alternative medicine;Decision Making;Educational aspects;Effectiveness;Family;Family Physicians;Family Practice;Foundations;Goals;Grant;Health;Health Personnel;Health Services;Kentucky;Licensing;Life;Massage;Medical;Methodology;Modality;Muscle relaxation phase;National Center for Complementary and Alternative Medicine;Opiates;Outcome;Pain;Pain Research;Patients;Pharmaceutical Preparations;Physicians;Practice based research;Preparation;Primary Care Physician;Primary Health Care;Recommendation;Relaxation Therapy;Reporting;Research;Rural;Students;Surveys;Testing;Therapeutic;Time;Training;Universities;addiction;alternative treatment;base;clinical practice;control trial;conventional therapy;cost;disability;effective therapy;health related quality of life;improved;lectures;member;patient oriented;practice-based research network;programs;public health relevance;rural area;willingness

public_health_relevance:
Project NarrativeThe "CAM Referral and Outcomes: Chronic Low Back Pain in Urban and Rural Primary Care"project will investigate clinical and patient-oriented outcomes of CAM therapies in an existingpractice-based research network (PBRN). For patients with chronic low back pain we willexamine the outcomes of clinical massage therapy and progressive muscle relaxation whenreferred by primary care physicians as well as selected factors in the physicians' decisions torecommend these therapies.


application_id: 8090451
project_number: 5R01CA125166-04
project_title: Transcriptional Repression of Sodium-Iodide Symporter in Thyroid Carcinoma
administering_ic: NCI
award_notice_date: 2011-06-29
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 125166
program_official: OKANO, PAUL
project_start_date: 2008-07-01
project_end_date: 2012-11-30
study_section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER]
contact_pi_person_id: 7875253
contact_pi: AIN, KENNETH BRUCE
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): Distantly metastatic dedifferentiated thyroid cancer is a fatal disease without effective treatment. This is from loss of ability to concentrate iodide rendering it unresponsive to radioactive iodine the only known systemic therapy. Iodide uptake requires expression of sodium-iodide symporter (hNIS). Hypermethylation of hNIS promoter region was thought to be a likely mechanism for loss of hNIS expression in thyroid cancer cells. hNIS expression and function is restored after treating these cells with demethylating and histone deacetylase-inhibiting agents. It was presumed that these agents permit transcriptional machinery access to the gene by relaxing chromatin compaction. 5-azacytidine (AzaC; DNA methyltransferase inhibitor) and sodium butyrate (NaB; putative histone deacetylase inhibitor) both singly and together restore hNIS expression and function to thyroid cancer cell lines. To show relaxed hNIS chromatin structures suggested by their presumed epigenetic effects we assessed DNAse I digestion rate of genomic hNIS regions when AzaC and NaB restored hNIS mRNA expression and hNIS function. Surprisingly these treatments did not produce enhanced DNAse I sensitivity suggesting the absence of effect on chromatin compaction. NaB-treated dedifferentiated thyroid cancer cells transfected with a luciferase reporter construct containing hNIS gene promoter stimulated both luciferase expression and native hNIS expression. Treating these cells with protein synthesis inhibitors (PSIs; cycloheximide anisomycin emetine) stimulated luciferase expression in a dose-dependent time course-dependent cell type-specific and promoter-specific fashion; as well as restored endogenous hNIS gene mRNA expression. This suggested presence of a trans-acting transcriptional inhibitor NIS-repressor responsible for loss of hNIS expression. We mapped the hNIS promoter sequence region responsible for this effect the NIS-repressor binding site (NRBS). NRBS used as a radiolabeled probe in electrophoretic mobility shift assays with thyroid cancer cell nuclear extract shows sequence-specific protein binding. These proteins were analyzed with liquid chromatography coupled to tandem mass spectrometry and revealed identity of a significant component of NIS-repressor. We hypothesize that loss of iodide transport activity in thyroid cancer results from loss of hNIS gene expression consequent to NIS-repressor binding to the hNIS promoter. This novel mechanism may underlie or be in addition to presumed epigenetic mechanisms of hNIS gene reactivation reported with various pharmacologic agents. Treatments directed to reduce or antagonize NIS- repressor components should restore hNIS gene expression responsible for iodide transport enabling I-131 therapy of dedifferentiated thyroid cancers. Our aims are to confirm our identification of NIS-repressor protein and identify other protein complex components discern its physiological and pathophysiological effects and develop strategies targeting it. This should result in treatments to restore NIS activity in dedifferentiated thyroid cancers restoring use of radioactive iodine to treat thyroid cancer metastases.  
  
Public Health Relevance Statement: Thyroid cancer for unknown reasons is the most rapidly increasing cancer in the United States in both men and women and it is the most common cancer in white women between 20 and 30 years of age. Although 75% of thyroid cancer patients respond adequately to radioactive iodine therapy 10% of patients lose response to this treatment and eventually die from disseminated tumor. Development of new methods of restoring clinical response to radioactive iodine could save lives.

project_terms:
ADP Ribose Transferases;Accounting;Affinity Chromatography;Age-Years;Anisomycin;Aortic Aneurysm;Azacitidine;Binding (Molecular Function);Binding Proteins;Binding Sites;Biological Assay;Butyrates;C-terminal;CREB1 gene;Calcium;Calmodulin;Cancer Patient;Cancer cell line;Catalytic Domain;Cattle;Cell Line;Cells;Chromatin;Chromatin Structure;Chromosomes;Clinical;Clinical Trials;Co-Immunoprecipitations;Complementary DNA;Complex;Consensus;Coupled;CpG Islands;Cross-Linking Reagents;Cycloheximide;DNA Binding;DNA Binding Domain;DNA Methylation;DNA Methyltransferase Inhibitor;DNA Repair;DNA ligase III;Data;Deoxyribonuclease I;Depsipeptides;Development;Digestion;Disease;Distal;Distant;Dominant-Negative Mutation;Dose;Drug usage;Effectiveness;Egtazic Acid;Electrophoretic Mobility Shift Assay;Elements;Emetine;Enhancers;Epigenetic Process;Fractionation;Functional disorder;Gel;Gel Chromatography;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genomics;Globulins;Goals;Grant;Histone Deacetylase;Histone Deacetylase Inhibitor;Human;Hypermethylation;I131 isotope;Immunoglobulin G;Immunohistochemistry;In Vitro;Incubated;Iodides;Iodine;Isotopically-Coded Affinity Tagging;Label;Ligands;Light;Liquid Chromatography;Luciferases;Lung;Malignant - descriptor;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of thyroid;Maps;Measures;Membrane;Messenger RNA;Methodology;Methods;Molecular Conformation;Molecular Weight;Mus;Neoplasm Metastasis;Nuclear;Nuclear Extract;Nude Mice;Oligonucleotides;Operative Surgical Procedures;Orphan Drugs;Pathway interactions;Patients;Peptides;Pharmaceutical Preparations;Physiological;Physiology;Plasmids;Poly(ADP-ribose) Polymerases;Precipitation;Probability;Production;Promoter Regions (Genetics);Promotor (Genetics);Protein Binding;Protein Structure Initiative;Protein Synthesis Inhibitors;Proteins;Publishing;Pulmonary Surfactant-Associated Protein B;Pulmonary Surfactant-Associated Proteins;Radiation;Radioactive;Radioactive Iodine;Radiolabeled;Rattus;Reagent;Recombinants;Regulatory Element;Relative (related person);Reporter;Reporting;Repressor Proteins;Reverse Transcriptase Polymerase Chain Reaction;Run-On Assays;Running;Site;Small Interfering RNA;Sodium Butyrate;Streptavidin;Systemic Therapy;TEV protease;TNFSF11 gene;Techniques;Testing;Thyroglobulin;Thyroid Gland;Thyroid carcinoma;Thyrotropin;Time;Tissues;Transcription Initiation Site;Transcription factor genes;Transfection;Translations;Treatment Failure;Tretinoin;Trichostatin A;Trypsin;Type I DNA Topoisomerases;United States;Upstream Enhancer;Validation;Valproic Acid;Vorinostat;Weight;Western Blotting;Woman;activating transcription factor;base;cancer cell;cell type;chelation;effective therapy;expectation;functional restoration;gene repression;human tissue;in vivo;inhibitor/antagonist;liquid chromatography mass spectrometry;mRNA Expression;men;mutant;novel;pre-clinical;preclinical study;protein complex;public health relevance;radiotracer;receptor;repaired;research study;response;restoration;sodium-iodide symporter;tandem mass spectrometry;therapeutic target;thyroid transcription factor 1;transcription factor;tumor;tumor xenograft;uptake


application_id: 8090442
project_number: 5R01GM079684-04
project_title: The Regulation of Smoothened in Hedgehog Signaling
administering_ic: NIGMS
award_notice_date: 2011-06-17
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 079684
program_official: HAYNES, SUSAN R
project_start_date: 2008-07-01
project_end_date: 2013-06-30
study_section: Development - 1 Study Section[DEV1]
contact_pi_person_id: 8575677
contact_pi: JIA, JIANHANG
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
  
The hedgehog (hh) family members control many aspects of development in both vertebrates and invertebrates. Hh signaling is associated with important biological phenomena such as patterning cell growth and morphogenesis. Abnormal activation of this pathway has been observed in several types of human cancers. The seven-pass transmembrane protein Smoothened (Smo) is required in both insects and mammals for transduction of the Hh signal. Our strategy is to use Drosophila as a simple and genetically tractable model system to explore the mechanisms of Hh signal transduction. The long-term goal of our research is to elucidate how Hh signals are sensed and transmitted to control downstream biological events that ultimately govern cell growth and patterning. We showed that Smo transduces the Hh signals by directly recruiting a Costal2-Fused (Cos2-Fu) complex. We also showed that Smo activation requires phosphorylation by protein kinase A (PKA) and casein kinase I (CKI) and that phosphorylation leads to increased Smo cell-surface levels and signaling activity. We recently uncovered a feedback mechanism by which Fu promotes Smo hyperphosphorylation and cell-surface accumulation by antagonizing Cos2. These findings provide new tools and hypotheses to investigate the mechanisms of Hh signaling at the cell membrane. In this project our central hypothesis is that Smo cell-surface accumulation and signaling activity are regulated by multiple kinases while phosphatase(s) act as inhibitory components to attenuate Smo activation. To test our hypothesis we will use a combination of genetic and biochemical approaches in three Specific Aims: 1) To further determine if differential Smo phosphorylation transduces gradient Hh activity; 2) to investigate the molecular mechanisms by which G protein-coupled receptor kinase 2 (GRK2) is involved in Hh signaling; and 3) to determine the role of phosphatase in Smo dephosphorylation and inactivation. HEALTH RELEVANCE Abnormal Smoothened (Smo) activation results cancers such as basal cell carcinoma (BCC) and medulloblastoma. Investigation of the Smo signaling mechanisms will provide both insights into fundamental developmental problems and new avenues for developing diagnostic tools and therapeutical treatments of cancers. PHS 398/2590 (Rev. 09/04 Reissued 4/2006) Page Project Narrative

project_terms:
Affect;Antibodies;Attenuated;Basal cell carcinoma;Beta-Adrenergic Receptor Kinase 1;Biochemical;Biological;Biological Assay;Biological Models;Biological Phenomena;Cell membrane;Cell surface;Cells;Cellular biology;Complex;Cyclic AMP-Dependent Protein Kinases;Cytoplasm;Data;Development;Diagnostic;Drosophila genus;Environment;Erinaceidae;Event;Family member;Feedback;Gene Transfer Techniques;Genes;Genetic;Goals;Health;Human;In Vitro;Individual;Insecta;Integral Membrane Protein;Integrase;Invertebrates;Investigation;Ligands;Malignant Neoplasms;Mammals;Mediating;Molecular;Morphogenesis;Mutation;Pathway interactions;Pattern;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphorylation Site;Phosphotransferases;Promotor (Genetics);Protein Dephosphorylation;Protein phosphatase;RNA Interference;Recruitment Activity;Regulation;Research;Residual state;Role;Signal Transduction;Site;System;Testing;Therapeutic;Tubulin;Variant;Vertebrates;Wing;Work;base;cancer cell;cancer therapy;casein kinase I;casein kinase II;cell growth;experience;hedgehog signal transduction;human SMO protein;in vivo;innovation;insight;loss of function;medulloblastoma;mutant;novel;overexpression;research study;response;smoothened signaling pathway;tool


application_id: 8089791
project_number: 3F31DA025424-02S1
project_title: Transdermal Delivery of Hydroxyphenylarachidonylamides
administering_ic: NIDA
award_notice_date: 2010-06-11
application_type: 3
activity_code: F31
ic: DA
serial_number: 025424
suffix: S1
program_official: PARK, MOO KWANG
project_start_date: 2008-07-17
project_end_date: 2011-01-16
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 9288396
contact_pi: SWADLEY, COURTNEY LEAH
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):  A patch for transdermal cannabinoid delivery could be therapeutically important in the reduction of chronic pain especially for patients who can't get pain relief from traditional treatments. Addition of a cannabinoid patch to a patient's standard pain-relief regimen could enhance analgesia because this class of drugs works by a different antinociceptive mechanism. Release of endocannabinoids (eCBs) such as anandamide (AEA) occurs in response to injury to relieve pain and inflammation. Inhibitors of eCB degradation mechanisms and transporters such as AM404 have been developed to induce and prolong the effects of the eCBs in situations of injury-induced pain and inflammation. Endocannabinoid and inhibitor compounds are clinically interesting because they initiate therapeutic effects via cannabinoid (CB) receptors without producing the side effects common to traditional cannabinoid agonist compounds such as THC. N-(4- hydroxyphenyl) arachidonoylamide (AM404) has been shown to relieve neuropathic pain and reduce alcohol consumption and anxiety in animals. N-arachidonoyl dopamine (NADA) is an eCB that acts at the CB receptor 1 which is associated with pain and emesis reduction. Transdermal delivery has numerous advantages over other drug delivery methods such as bypassing first-pass metabolism extended controlled drug release and the added ability for patients to self-administer the drug pain-free. NADA and AM404 present a challenge for transdermal delivery because of their high lipophilicity and enzymatic/chemical instability. The goal of this project is to improve the transdermal delivery of the hydroxyphenylarachidonylamides NADA and AM404. We propose to synthesize hydrophilic prodrugs of these compounds to promote their delivery across the skin barrier and possibly increase their stability. The additional phenolic hydroxyl in NADA will allow us to evaluate the effect of disubstituted prodrugs as compared to monosubstituted prodrugs of the AM404 structure. The proposed hydrophilic prodrugs will be useful in investigating quantitative-structure-permeability relationships (QSPR) of transdermal flux used to develop and improve delivery strategies for highly lipophilic compounds. The specific aims for this project are: (1) to study the diffusion and metabolism of NADA and AM404 across the skin barrier (2) to synthesize a series of prodrugs for transdermal flux optimization (3) to measure the penetration/concurrent bioconversion of the prodrugs through human skin in vitro and (4) to characterize the pharmacokinetics of the drugs in guinea pigs in vivo. Correlation of our in vitro data with the in vivo model will aid in developing a QSPR database for transdermal prodrugs.

project_terms:
AM404;Absence of pain sensation;Adverse effects;Agonist;Alcohol consumption;Animals;Anxiety;Blood Circulation;Bypass;Cannabinoids;Cavia;Chemical Structure;Chemicals;Data;Databases;Diffusion;Dopamine;Drug Controls;Drug Delivery Systems;Drug Kinetics;Endocannabinoids;Goals;Heating;Human;Hydrogen Bonding;Hydroxyl Radical;In Vitro;Inflammation;Injury;Knowledge;Measures;Metabolism;Methods;Molecular;Molecular Weight;Mono-S;Pain;Pain-Free;Patients;Penetration;Permeability;Pharmaceutical Preparations;Prodrugs;Property;Regimen;Research;Self-Administered;Series;Skin;Solubility;Solvents;Structure;System;Therapeutic Effect;Vomiting;Work;anandamide;cannabinoid receptor;chronic pain;design;hydroxyl group;improved;in vivo;in vivo Model;inhibitor/antagonist;interest;lipophilicity;melting;painful neuropathy;response to injury;tool


application_id: 8089565
project_number: 5R01AI069321-05
project_title: Modulation of apoptosis by Legionella Pneumophila
administering_ic: NIAID
award_notice_date: 2011-06-24
application_type: 5
activity_code: R01
ic: AI
serial_number: 069321
program_official: KORPELA, JUKKA K
project_start_date: 2007-07-15
project_end_date: 2014-06-30
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 1877865
contact_pi: ABU KWAIK, YOUSEF A
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
budget_start_date: 2011-07-01
project_abstract:
DESCRIPTION (provided by applicant):  Legionella pneumophila is an intracellular pathogen that evades endocytic fusion and hijacks ER-to-golgi vesicle traffic to remodel its phagosome into an ER-derived compartment permissive for intracellular replication. The Dot/lcm type IV secretion system of L. pneumophila is essential for both modulation of phagosome biogenesis and modulation of the macrophage apoptotic pathways through robust early and novel activation of caspase-3 independent of the intrinsic and extrinsic pathways of apoptosis. The Dot/lcm- mediated activation of caspase-3 results in cleavage of Rabaptin-5 which is an effector of the early endosome regulator Rab5. Inhibition of caspase-3 using caspase-3 peptide inhibitors blocks intracellular replication of L. pneumophila and results in trafficking of the organism to phagolysosomes similar to dot/icm mutants. Our hypothesis is: Caspase-3-meditaed cleavage of Rabaptin-5 is central to the arrested biogenesis of the Legionella-containing phagosome (LCP) and to intracellular replication. To test this hypothesis our specific aims are to examine the following: Specific aim I. Role of caspase-3 activation in biogenesis of the LCP; Specific aim II: Role of caspase-3-mediated cleavage of Rabaptin-5 in biogenesis of the LCP; Specific aim III. Identification of the L. pneumophila effector involved in caspase-3 activation. Significance: Our proposed studies are the crux of our understanding of the molecular and cellular mechanisms by which this pathogen commandeer the host cell and will she light on the cellular mechanism by which this pathogen engages a cross talk between the apoptotic pathways and vesicle traffic in the host cell to remodel it to its liking. The bacterial effector involved in this process is a potential target for therapy and prevention of the disease.

project_terms:
Abbreviations;Adenylate Cyclase;Apoptosis;Apoptotic;Biochemical;Biogenesis;Biological Models;Biological Preservation;Biology;Caspase Inhibitor;Cell physiology;Cells;Cellular biology;Co-Immunoprecipitations;Disease;Early Endosome;Endoplasmic Reticulum;Ensure;Golgi Apparatus;Human;Infection;Knowledge;Lead;Legionella;Legionella pneumophila;Life Style;Light;Mediating;Molecular;Nuclear;Organism;Pathway interactions;Peptides;Phagolysosome;Phagosomes;Prevention therapy;Process;Proteins;RNA Interference;Role;Small Interfering RNA;Staging;Testing;Type IV Secretion System Pathway;Vesicle;caspase-3;clinical application;disorder prevention;inhibitor/antagonist;macrophage;monocyte;mutant;novel;pathogen;programs;trafficking


application_id: 8089488
project_number: 5R01DE009761-19
project_title: BACTERIAL PROTEINASES IN PERIODONTAL DISEASE
administering_ic: NIDCR
award_notice_date: 2011-06-15
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DE
serial_number: 009761
program_official: LUNSFORD, DWAYNE
project_start_date: 1991-08-01
project_end_date: 2013-06-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6947603
contact_pi: POTEMPA, JAN S
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Periodontitis is classified as a microbiota shift disease whereby a very rich and diverse commensal flora characteristic for good oral health becomes dominated by several Gram-negative anaerobic bacterial species among which Porphyromonas gingivalis Tannerella forsythia and Treponema denticola constitute the so called "red complex" of microorganisms frequently associated with the development and progression of the disease. The common consequence of these three bacteria and a secondary periodontopathogen Prevotella intermedia is their production of proteolytic enzymes. Proteases of P. gingivalis and T. denticola are known to dysregulate tissue homeostasis and/or to frustrate defensive inflammatory responses thus significantly contributing to pathological changes in the infected periodontium. In contrast virtually nothing is known about proteases of T. forsythia and P. intermedia although it has been well documented that proteases from the former organism are produced in vivo and their activity correlates with periodontal destruction. Here we postulate that novel proteases produced by T. forsythia (forsypsin) and P. intermedia (interpains) promote periodontal tissue damage by deregulation of tightly controlled host proteolytic systems. Furthermore we suggest that the combined proteolytic activity produced locally by periodontopathogens may be a primary mechanism for synergistic periodontal tissue damage and contributes to mutual survival of the red complex bacteria. Most interestingly we have found that forsypsin and interpains as well as many other acknowledged virulence factors of P. gingivalis and T. forsythia share with gingipains a conserved C-terminal domain. We have shown that this domain together with a unique periplasmic protein and a unique outer membrane translocon protein conserved in these species is essential for gingipain secretion. This implies that a novel bacterial protein export system is employed by periodontopathogens to secrete a number of confirmed and putative virulence factors. For these reasons the specific aims of this project are as follows: 1) to use an array of biochemical and molecular biological methods to investigate the mechanism of gingipain translocation through the outer membrane of P. gingivalis and confirm the presence of this unique secretion pathway in both T. forsythia and P. intermedia; 2) to characterize novel proteases from T. forsythia and P. intermedia especially with regard to their ability to complement and/or synergize with the gingipain activity and 3) to determine the complementary or synergistic role of proteases from P. gingivalis T. forsythia and P. intermedia for in vivo proliferation and dissemination of bacteria in monomicrobial and mixed microbial infections using a murine chamber model.   
  
PUBLIC HEALTH RELEVANCE: The results of these proposed studies should not only illuminate the synergistic role of bacterial proteases in mixed infections but also shed light on a novel pathway for the secretion of virulence factors unique to P. gingivalis T. forsythia and P. intermedia. This insight may enable the design of antibodies or chemical compounds to block the export of multiple virulence factors from major periodontopathogens which in the long term may revolutionize treatment and prophylaxis of periodontal disease.

project_terms:
Affect;Albumins;Anti-Bacterial Agents;Antibodies;Bacteria;Bacterial Proteins;Bacteroidetes;Biochemical;Biological;Blood Circulation;C-terminal;Cell Surface Receptors;Cell surface;Characteristics;Chemicals;Coagulation Process;Complement;Complex;Cysteine Protease;Data;Development;Disease;Disease Progression;Elements;Enzymes;Extracellular Protein;Fibrinolysis;Forsythia;Foundations;Future;Goals;Gram-Negative Bacteria;Heavy-Chain Immunoglobulins;Homeostasis;Homologous Gene;Host Defense;Host Defense Mechanism;Human;Infection;Inflammatory Response;Injury;Kinins;Light;Link;Mediating;Membrane;Membrane Proteins;Methods;Modeling;Modus;Molecular;Mono-S;Mus;Nutrient;Oral health;Organism;Outcome;Pathway interactions;Peptide Hydrolases;Periodontal Diseases;Periodontal Infection;Periodontitis;Periodontium;Periplasmic Proteins;Plasma;Play;Porphyromonas gingivalis;Prevention;Preventive Intervention;Prevotella intermedia;Production;Progress Reports;Properdin;Property;Prophylactic treatment;Protein Export Pathway;Protein Secretion;Protein translocation;Proteins;Research;Role;Secretory Component;Seminal;Signal Transduction;Site;Solid;Structure;System;Testing;Therapeutic;Therapeutic Intervention;Tissues;Treponema denticola;Trypsin;Virulence;Virulence Factors;antibody inhibitor;arginyllysine;base;design;drug development;gingipain;human MADHIP protein;in vivo;inhibitor/antagonist;insight;microbial;microbial community;microorganism;mutant;neutrophil;novel;pathogen;periodontopathogen;proteinase In;public health relevance;streptopain


application_id: 8089481
project_number: 5P20RR017702-09
project_title: Molecular Determinants of Developmental Defects
administering_ic: NCRR
award_notice_date: 2011-05-26
opportunity_number: RFA-RR-07-001
application_type: 5
activity_code: P20
ic: RR
serial_number: 017702
program_official: DOUTHARD, REGINE
project_start_date: 2002-09-30
project_end_date: 2013-05-31
contact_pi_person_id: 1861667
contact_pi: GREENE, ROBERT M
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-06-01
project_abstract:
The present application represents a resubmission (01A1) of a COBRE application wherein we have addressed all concerns noted by reviewers (see "Introduction"). Revised individual project proposals are each preceded by an "Introduction" in which COBRE Investigators respond to Project Critiques provided by reviewers. The primary purpose of this renewal application continues to be fostering of health-related research and mentoring-enhanced competitiveness of junior unfunded investigators.   
In this renewal application we have included proposals from: 2 junior investigators who have not previously been a PI on a funded research project grant or program project grant; 2 early career investigators who were COBRE supported during our initial funding period and who were successful in obtaining independent funding from the NIH (R01 and K02); a senior investigator whose proposal will facilitate a mid-career research transition; and a pilot project from a clinical junior investigator seeking to redefine his academic career as a clinical research scientist. Two (2) new faculty lines representing sustained commitment from the university have been pledged as part of this competitive renewal application. Two junior faculty who complement the thematic scope of our COBRE will thus be recruited and will be COBRE-supported. Each of these investigators will be mentored by an established well-funded senior biomedical research scientist recognized for his/her scientific expertise in the area of the COBRE investigator's research proposal.  
The program continues to be led by Robert M. Greene Ph.D. an established biomedical research scientist well recognized for his extensive expertise central to the research theme of the proposal-molecular mechanisms underlying developmental defects. This renewal application if funded will 1) substantially enhance the research career development and research competitiveness of no less than five (5) junior investigators two early career investigators and one senior investigator and 2) promote the development and enhance the evolution of our Center such that it will be able to successfully compete for independent Center and/or program project funding. A detailed plan for each COBRE investigator's research career development has been formulated; expectations and objectives for achieving independent funding are clearly articulated; clear and tangible evidence of continuing and expanded institutional commitment is documented; excellent research resources and a supportive intellectual environment exists.


application_id: 8089297
project_number: 5P20NR010679-05
project_title: Center for biobehavioral research in self-management of cardipulmonary disease
administering_ic: NINR
award_notice_date: 2011-06-21
opportunity_number: RFA-NR-07-004
application_type: 5
activity_code: P20
ic: NR
serial_number: 010679
program_official: HUSS, KAREN
project_start_date: 2007-09-29
project_end_date: 2012-06-30
study_section: ZNR1-REV-B(04)R
contact_pi_person_id: 1906318
contact_pi: MOSER, DEBRA KAY
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): Cardiovascular and pulmonary diseases are the major chronic illnesses requiring life-long self- management; they also are the conditions in which self-management may be the most difficult to sustain. The improvements in outcomes to be gained by optimal self-management however suggest that a research focus on self-management of cardiovascular and pulmonary diseases should be a priority. In this application we propose to establish an exploratory research center the Center for Biobehavioral Research on Self- Management of Cardiopulmonary Disease at the University of Kentucky College of Nursing (UKCON). The purpose of the Center is to: 1) develop the research infrastructure at the UKCON to promote and support research on processes interventions and outcomes of self-management of cardiovascular and ' pulmonary diseases; 2) expand the quality and quantity of self-management research projects using biobehavioral methods by centralizing methodological resources; 3) expand the number of nurse investigators doing interdisciplinary self-management research by supporting interdisciplinary exchange and linkages; 4) contribute to the scientific foundation for self-management by promotion and dissemination of systematic investigations of self-management processes interventions and outcomes; and 5) plan for and develop sustainability of interdisciplinary self-management research programs by building active and growing partnerships inside and outside of the University of Kentucky. The proposed Center will consist of three Cores: an Administrative Core a Self-Management Pilot/Feasibility and Biobehavioral Outcomes Core and a Research Program Development Data Analysis and Dissemination Core. In addition three pilot studies are included that focus on testing self-management interventions. The Administrative Core will coordinate center activities guide development of new resources supporting research and facilitate interdisciplinary collaboration in the study of self-management in the context of cardiovascular and pulmonary disease management and prevention. The Self-Management Pilot/Feasibility and Biobehavioral Outcomes Core will provide training mentorship and expertise to investigators conducting studies aimed at improving self-management among patients with cardiovascular and pulmonary diseases that includes collection of biobehavioral outcomes data. The Research Program Development Data Analysis and Dissemination Core that will provide mentorship infrastructure and resources to support development and sustainability of interdisciplinary programs of research directed at improving self-management of patients with cardiovascular and pulmonary diseases. The proposed Center will provide the UKCON with the support needed to sustain a center of excellence to promote research programs that focus on self-management of cardiovascular and pulmonary disease.


application_id: 8089296
project_number: 5P20NR010679-04
project_title: Data Analysis Research Program Development and Dissemination Core
administering_ic: NINR
opportunity_number: RFA-NR-07-004
application_type: 5
activity_code: P20
ic: NR
serial_number: 010679
study_section: ZNR1
subproject_number: 9002
contact_pi_person_id: 1903848
contact_pi: HALL, LYNNE ANDERSON
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
budget_end_date: 2011-06-30
funding_mechanism: Research Centers
project_abstract:
Chronic cardiovascular and pulmonary diseases adversely affect the quality of life of millions of
Americans. Self-management is essential for disease management in those with these chronic conditions.
In order to move into a new area of research focused on improving self-management of cardiovascular and
pulmonary diseases and to support investigators in the development of extramural research proposals
junior as well as established investigators need training and mentoring with research program development
(e.g. establishing a research trajectory developing researchable problems conceptualizing theoretical
foundations for hypothesis formation proposal development) data analysis (e.g. selection of appropriate
statistical methods interpretation of statistical output presentation of statistical findings) and dissemination
of results via scientific presentations and publications in appropriate venues. The Research Program
Development Data Analysis and Dissemination Core will build on existing support services available in
the College of Nursing and extend services to support Center investigators in other ways.
The purposes of the Research Program Development Data Analysis and Dissemination Core
are to: (1) provide support services to assist faculty in developing a focused ongoing funded program of
research related to evidence-based interventions to promote self-management in patients with
cardiovascular and pulmonary diseases; (2) offer faculty development opportunities and mentoring in
research proposal development psychosocial instrumentation and surveys research design and sampling
data management and analysis and data-based presentation and manuscript preparation; and (3) through
collaboration with the Administrative Core the Self-management Pilot/Feasibility and Biobehavioral
Outcomes Core the Executive Committee and the Advisory Committee provide the infrastructure and
resources necessary for development of ongoing programs of research focused on improving selfmanagement
of patients with cardiovascular and pulmonary diseases.

project_terms:
Address;Advisory Committees;Affect;Age;American;Annual Reports;Applications Grants;Area;Award;Cardiovascular system;Chronic;Chronic Disease;Clinical Research;Collaborations;Consultations;Data;Data Analyses;Databases;Development;Discipline;Discipline of Nursing;Disease Management;Ensure;Equipment;Evaluation;Evidence based intervention;Extramural Activities;Faculty;Foundations;Funding;Goals;Grant;Health;Health Sciences;Housing;Institution;Link;Lung;Lung diseases;Manuscripts;Mentors;Monitor;Nature;Newsletter;Nurses;Outcome;Output;Paper;Patients;Persons;Pilot Projects;Preparation;Process;Program Development;Psychometrics;Publications;Quality of life;Questionnaires;Records;Research;Research Activity;Research Design;Research Infrastructure;Research Personnel;Research Proposals;Research Support;Resources;Sampling;Scholarship;Schools;Scientist;Self Management;Senior Scientist;Services;Statistical Methods;Surveys;Training;United States Office of Research Integrity;Universities;Work;Writing;base;biobehavior;college;data management;editorial;health disparity;improved;instrumentation;meetings;member;posters;programs;psychosocial;research and development;satisfaction;service utilization;statistics;web site


application_id: 8089295
project_number: 5P20NR010679-04
project_title: Self-Management Pilot/Feasibility and Biobehavioral Outcomes Core
administering_ic: NINR
opportunity_number: RFA-NR-07-004
application_type: 5
activity_code: P20
ic: NR
serial_number: 010679
study_section: ZNR1
subproject_number: 9001
contact_pi_person_id: 1906096
contact_pi: LENNIE, TERRY A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-07-01
budget_end_date: 2011-06-30
funding_mechanism: Research Centers
project_abstract:
Development of evidence-based strategies to improve self-management of cardiovascular and pulmonary diseases requires that investigators develop scientifically sound rigorous research studies. Measuring biobehavioral outcomes of self-management of cardiovascular and pulmonary diseases presents challenges to investigators entering this field of study. The University of Kentucky College of Nursing is doubling the size of the undergraduate program. Funding to hire eight additional faculty members who will have 50% release time for research has been approved by the Board of Regents. These new members who will be investigators early in their research careers will be hired over three years. Three of these members will start in the Fall of 2007. In addition we have junior faculty (Darlene Welsh and Misook Chung) and established investigators (Ann Peden and Lynne Hall) on our faculty who are planning to join our cardiovascular and pulmonary research team (RICH Heart Program). The proposed Center will be ideally suited to assist these faculty members to develop programs of research in self-management of cardiovascular and pulmonary diseases.

To meet the needs of current and future faculty members the proposed Core will assist project investigators in the development and conduct of pilot/feasibility studies aimed at improving self-management of cardiovascular and pulmonary diseases that include measurement of biobehavioral outcomes. Advice training and mentorship will be provided in research design as well as measurement and interpretation of three types of outcomes: 1) biobehavioral variables that demonstrate effectiveness of interventions (e.g. knowledge psychological status physiological status) 2) biobehavioral variables that demonstrate improvement in self-management behaviors (e.g. adherence nutritional status physiological status) and 3) biobehavioral
variables that demonstrate improvement in clinical outcomes (e.g. physiological status mortality morbidity and quality of life).

project_terms:
Adherence (attribute);Advisory Committees;Area;Behavior;Cardiovascular system;Clinical;Collaborations;Data Analyses;Development;Discipline of Nursing;Effectiveness of Interventions;Faculty;Feasibility Studies;Funding;Future;Heart;Interdisciplinary Study;Kentucky;Knowledge;Lung;Lung diseases;Measurement;Measures;Mentorship;Morbidity - disease rate;Mortality Vital Statistics;Nutritional status;Outcome;Patients;Physiological;Program Development;Quality of life;Research;Research Design;Research Infrastructure;Research Personnel;Resources;Self Management;Services;Time;Training;Universities;biobehavior;biobehavioral measurement;career;college;evidence base;falls;field study;improved;meetings;member;programs;psychologic;research study;sound


application_id: 8088186
project_number: 5U60OH008483-07
project_title: Kentucky Occupational Safety and Health Surveillance
administering_ic: NIOSH
award_notice_date: 2011-06-08
opportunity_number: PAR-09-184
application_type: 5
activity_code: U60
ic: OH
serial_number: 008483
program_official: INSERRA, STEVE
project_start_date: 2008-07-01
project_end_date: 2015-06-30
study_section: ZOH1-BSI(50)R
contact_pi_person_id: 7931539
contact_pi: BUNN, TERRY LEE
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Kentucky (KY) ranks as the 14th -worst state for fatal occupational injury rates in 2007 down from the 8th worst in 2004 and is the 8th worst state for nonfatal occupational injury and illness incidence rates. The objectives of the KY Occupational Safety and Health Surveillance (KOSHS) fundamental program are to 1) identify industry sectors occupations and worker populations at high risk for work injuries and illnesses; 2) identify potential risk factors trends and emerging issues; 3) develop and implement targeted strategies for occupational injury data dissemination utilizing a sector-based approach; 4) identify gaps within national occupational injury surveillance systems; and 5) advance the usefulness of surveillance data at the federal state and local levels. The specific aims for the study are to: 1) Establish and maintain partnerships and collaborations with state partners agencies organizations and other stakeholders (Seminars will be presented on the value of establishing a worker safety program; local state employee injury data will be analyzed. KOSHS personnel will participate in grantee meetings and conference calls); 2) Maintain the KOSHS program advisory committee; 3) Maintain comprehensive multi-source population-based  
surveillance of KY occupational injuries and illnesses using 26 occupational health indicators (OHIs) (One new KY-specific OHI to be established is work-related injuries among state employees and another KY-specific OHI will be work-related emergency department visits); 4) Enhance the KOSHS program through a) response to emerging issues; b) in-depth analyses interpretation and dissemination of occupational injury surveillance data through the use of spatial analysis to determine high risk collision areas involving commercial truck drivers; and c) an expanded web-based occupational injury data query system; 5) Provide targeted worker and employer groups with a sound evidence basis for improved worker safety by analyzing and disseminating data and research results through publications and web-based information for impact at both the state and national levels; and 6) Perform a process impact and outcome evaluation of the major activities conducted to assess effectiveness and impact of the KOSHS program.


application_id: 8086466
project_number: 2R01AA015407-07A1
project_title: GSK3beta a mediator of ethanol neurotoxicity
administering_ic: NIAAA
award_notice_date: 2011-03-07
opportunity_number: PA-10-067
application_type: 2
activity_code: R01
ic: AA
serial_number: 015407
suffix: A1
program_official: REGUNATHAN, SOUNDAR
project_start_date: 2005-08-01
project_end_date: 2016-02-29
study_section: Special Emphasis Panel[ZRG1 IFCN-C (02)]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
other_pis: SHI, XIANGLIN
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Alcohol is a neuroteratogen; alcohol consumption during pregnancy may cause Fetal Alcohol Spectrum Disorders (FASD) among which fetal alcohol syndrome (FAS) is the most severe form. The depletion of neurons in the developing CNS is the most deteriorating effect of ethanol. The loss of CNS neurons may underlie many of the behavioral deficits observed in FASD. Glycogen synthase kinase 3 (GSK3) a serine/threonine kinase is an important mediator of neuron degeneration. We have demonstrated that ethanol activates GSK3 and the activation of GSK3 leads to neuronal death. Oxidative stress is also considered an important contributor to ethanol-induced neurotoxicity. We have purified a potent antioxidant from blackberries cyanidin-3-glucoside (C3G). Our study indicates that C3G inhibits GSK3 activity and alleviates oxidative stress in cultured neuronal cells. In addition C3G protects neuronal cells against ethanol-induced cell death. C3G-mediated neuroprotection is much more potent than other antioxidants and GSK3 inhibitors. C3G can cross the blood brain barrier (BBB) and distribute in the brain. C3G diminishes ethanol-induced activation of caspase-3 and Bax in the developing brain. Pharmacologically relevant concentrations of C3G are achievable through oral administration or intravenous (iv) injection in animals and no adverse effect is observed. These findings suggest that C3G is a promising neuroprotective agent that may ameliorate/prevent ethanol-induced neuronal damage. We hypothesize that C3G's potent protection against ethanol-induced neuronal loss is mediated by the combined action of its antioxidant property and inhibition of pro-apoptotic signaling GSK3/Bax pathways. To test the hypothesis we will (1) investigate the antioxidant property of C3G and its metabolites and their effects on GSK3 activity; (2) determine whether C3G protection against ethanol- induced neuronal loss is mediated by the combined action of its antioxidant property and the inhibition of GSK3; (3) determine whether C3G ameliorates ethanol-induced behavioral deficits.  C3G is a potent natural antioxidant and has diverse potential benefits for human health. It is a promising neuroprotective agent against ethanol toxicity due to its dual functions as an antioxidant and a GSK3 inhibitor. As a unit the proposed experiments will elucidate the novel role of C3G and provide an important basis for future clinical trials to evaluate the feasibility of C3G to treat ethanol neurotoxicity. Our study will potentially offer a new therapeutic strategy.  
  
PUBLIC HEALTH RELEVANCE:  Alcohol consumption during pregnancy may cause Fetal Alcohol Spectrum Disorders (FASD) among which fetal alcohol syndrome (FAS) is the most severe form. The developing central nervous system (CNS) is particularly sensitive to ethanol. The loss of CNS neurons may underlie many of the behavioral deficits observed in FASD. Both glycogen synthase kinase 3 (GSK3) and oxidative stress contributes to ethanol neurotoxicity. We have purified a potent antioxidant from blackberries cyanidin-3-glucoside (C3G) which can also inhibit GSK3 and reduce oxidative stress. The current study is to determine whether C3G ameliorates ethanol-induced neuronal loss as well as behavioral deficits. The proposal will potentially develop a new therapeutic strategy.

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

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


application_id: 8085928
project_number: 5R13AI091316-02
project_title: Autumn Immunology Conference
administering_ic: NIAID
award_notice_date: 2011-07-05
opportunity_number: PA-08-149
application_type: 5
activity_code: R13
ic: AI
serial_number: 091316
program_official: COULTER, NANCY A
project_start_date: 2010-07-01
project_end_date: 2013-06-30
study_section: ZAI1-MMT-M(M1)
contact_pi_person_id: 1863468
contact_pi: WOODWARD, JEROLD G
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
  
Abstract  
PI: WOODWARD JEROLD G   Project:  1R13AI091316-01 Title:  Autumn Immunology Conference  Accession Number:  3256374  
==================  
NOTICE: THIS ABSTRACT WAS EXTRACTED FROM APPLICATION AND HAS NOT BEEN PROOFED BY AN SRA.WHEN THERE ARE PROBLEMS WITH THE APPLICATION SCANNING PROCESS THE EXTRACTED TEXT MAY BE INCORRECT OR INCOMPLETE.  
==================  
This proposal requests funds to support the annual Autumn Immunology Conference (AIC). The AIC was established in 1972 to promote Immunology research in the upper Midwest region of the United States. The conference provides a forum for the exchange of scientific data and ideas fosters collaborations between scientists at different institutions and provides career development and education opportunities to a diverse group of individuals with an interest in Immunology. The scientific focus of the meeting is intentionally broad; it includes basic Immunology and related biomedical fields such as cancer biology pathogenesis vaccine development inflammation and autoimmunity. Special emphasis is given to providing pre- and post-doctoral trainees with an opportunity to share their data participate in scientific and career discussions and to meet and exchange ideas with established investigators. We also seek to attract involve and promote the careers of women and racial/ethnic minorities that are underrepresented in science. These objectives are met by inviting a group of outstanding Immunology researchers (12-13 each year) from around the world to speak at the meeting. All presenters present both an oral and poster presentation and are designed to provide the greatest opportunity for feedback to the trainees. Finally scholarship programs career development workshops and mentoring luncheons promote the inclusion of minority scientists and seek to recruit undergraduates into the discipline of Immunology. High quality scientific conferences are vital to the public health mission of the NIH. This application requests funding for an annual scientific conference called the Autumn Immunology Conference. The purpose of this meeting is to exchange and disseminate information and to explore contemporary problems in the field of Immunology. Thus it is consistent with the fiscal and programmatic priorities of the National Institutes of Allergy and Infectious Diseases (NIAID) which is to conduct and support basic and applied research to better understand treat and ultimately prevent infectious immunologic and allergic diseases.

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

public_health_relevance:
Project NarrativeHigh quality scientific conferences are vital to the public health mission of theNIH. This application requests funding for an annual scientific conference calledthe Autumn Immunology Conference. The purpose of this meeting is toexchange and disseminate information and to explore contemporary problems inthe field of Immunology. Thus it is consistent with the fiscal and programmaticpriorities of the National Institutes of Allergy and Infectious Diseases (NIAID)which is to conduct and support basic and applied research to better understandtreat and ultimately prevent infectious immunologic and allergic diseases.


application_id: 8085897
project_number: 5R01HL059378-13
project_title: Cardiac Metabolism of Enals
administering_ic: NHLBI
award_notice_date: 2011-06-22
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 059378
program_official: WANG, LAN-HSIANG
project_start_date: 1998-12-01
project_end_date: 2014-06-30
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The overall aim of this proposal is to understand the mechanisms by which oxidative stress contributes to ischemic injury in the heart. Our working hypothesis is that reactive oxygen species (ROS) generated during ischemia-reperfusion initiate lipid peroxidation reactions and that unsaturated aldehydes (enals) generated from oxidized lipids trigger and sustain myocardial oxidative stress during ischemia-reperfusion. To asses the contribution of lipid oxidation derived enals we have in the past studied the biochemical pathways of enal metabolism. Our studies show that in the heart enals are metabolized by aldose reductase (AR) aldehyde reductase and glutathione-S-transferases. Metabolism via AR appears critical because the enzyme is activated during ischemia and inhibition of the enzyme abolishes the cardioprotective effects of ischemic preconditioning. Using AR to interrogate the role of enals in ischemia-reperfusion injury we now plan to test the hypothesis that accumulation of enals and their protein adducts in the ischemic heart triggers stress responses and cell death. We propose that these responses are mediated in part by endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) and that AR metabolism decreases myocardial injury by diminishing ER stress. The specific aims of the project are to: (1) delineate the contribution of UPR to enal- induced myocardial injury; (2) elucidate the role of AR in regulating enal-induced ER stress; and (3) to examine the role of AR in preventing ER stress and UPR in hearts subjected to coronary ligation and reperfusion in situ. To accomplish these aims we will examine specific components of the UPR triggered in isolated murine hearts and myocytes determine how pharmacological inhibition genetic ablation or transgenic over expression of AR modify enal-induced UPR. Using a murine model of coronary occlusion we also plan to study how AR activity and expression levels affect ER stress and UPR during ischemia and reperfusion. We expect that the results obtained from these studies will further our understanding of the nature of ischemic injury and may suggest new ways to prevent tissue injury and dysfunction associated with myocardial infarction. PUBLIC HEALTH RELEVANCE: The aim of this project is to elucidate how ischemia and subsequent reperfusion affects the heart. These studies are of relevance to the understanding of acute myocardial infarction and ischemic heart failure. These diseases are the major cause of death in the U.S. A better understanding of the molecular and cellular mechanisms by which oxidative stress contributes to tissue injury and dysfunction in the ischemic heart may lead to the development of more effective therapeutic interventions to treat heart disease.

project_terms:
Ablation;Acute myocardial infarction;Affect;Aging;Air;Aldehyde Reductase;Aldehydes;Asses;Atherosclerosis;Biochemical Pathway;Biochemical Process;Cardiac;Cardiac Myocytes;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Cell Death;Cell physiology;Characteristics;Coronary;Coronary Occlusions;Degradation Pathway;Development;Disease;Drug Metabolic Detoxication;Endoplasmic Reticulum;Enzyme Inhibition;Enzymes;Food;Functional disorder;Genetic;Glutathione S-Transferase;Health;Heart;Heart Diseases;Heart failure;In Situ;Inflammation;Inflammatory;Injury;Ischemia;Ischemic Preconditioning;Lead;Ligation;Lipid Peroxidation;Lipids;Mediating;Mediator of activation protein;Metabolism;Modeling;Molecular;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Nature;Neurodegenerative Disorders;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Phase;Proteins;Proteolysis;Reaction;Reactive Oxygen Species;Relative (related person);Reperfusion Injury;Reperfusion Therapy;Research;Role;Structure;Testing;Therapeutic Intervention;Tissues;Toxic effect;Transgenic Organisms;Water;Work;adduct;aldehyde dehydrogenases;base;biological adaptation to stress;endoplasmic reticulum stress;heart metabolism;insight;lipid metabolism;overexpression;oxidation;oxidized lipid;pollutant;prevent;response


application_id: 8082752
project_number: 5R01CA128903-02
project_title: Chemical Probes of Immunoproteasome Function in Cancer
administering_ic: NCI
award_notice_date: 2011-03-30
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 128903
program_official: LEES, ROBERT G
project_start_date: 2010-06-07
project_end_date: 2015-04-30
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 8152159
contact_pi: KIM, KYUNG BO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The essential roles of the ubiquitin-proteasome system (UPS) in many cellular processes are now well recognized. However many questions still remain unanswered. Intriguing yet not fully understood are the functions of the immunoproteasome an alternative form of the constitutive proteasome. It has been shown that the roles of the immunoproteasome in cells are not just limited to the generation of antigenic peptides but far more multifaceted. In this regard recent studies have shown that catalytic subunits of the immunoproteasome are implicated in various types of diseases including cancer. Despite these therapeutic implications the immunoproteasome remains largely untapped for cancer drug discovery. A better understanding of immunoproteasome functions would be crucial in developing the optimum LMP2 inhibitor(s). In our continuing efforts to better understand the role of the immunoproteasome in cells we have recently developed a small molecule probe ('UK-101') that specifically targets LMP2 a major catalytic subunit of the immunoproteasome. Further we found that LMP2 is highly expressed in several types of primary tumor tissues and cancer cell lines. Interestingly cancer cells that highly express LMP2 are markedly more sensitive to UK-101 than those expressing low level of LMP2. Consistent with these in vitro results UK-101 inhibits tumor growth in a mouse xenograft model of human prostate tumor that highly expresses LMP2 but not that of tumor that expresses low level of LMP2. These observations further support a potential role of LMP2 in cancer cell growth and survival. The goals of this application are to determine the roles of the immunoproteasome in prostate cancer and to investigate therapeutic potentials of the immunoproteasome-targeting approaches in cancer therapy. Towards this goal we propose to use innovative chemical probes that selectively target and visualize individual catalytic subunits of the immunoproteasome. In order to accomplish this goal four specific aims are proposed: 1) To validate the immunoproteasome as the major pharmacological target of UK-101 2) To determine dynamic cellular distribution of the catalytically active immunoproteasome and 3) To determine the unique functions of the immunoproteasome compared to the constitutive proteasome and 4) To develop an optimum LMP2 inhibitor(s) by generating a structurally diversified small molecule library. The proposed work integrates both chemical and biological approaches. Successful completion of the project will significantly expand our knowledge on the role of the immunoproteasome. In addition the study will yield critical information in developing immunoproteasome-specific inhibitors as a potential therapeutic agent. Finally small molecule probes that will be used in this application will provide valuable research tools for the ubiquitin-proteasome biology community.   
  
PUBLIC HEALTH RELEVANCE: Small molecule probes are valuable tools in deciphering protein functions. We have developed a novel cell permeable small molecule that selectively targets the immunoproteasome. Using this small molecule and other molecular tools we will investigate the roles of the immunoproteasome in cancer cells and therapeutic potentials of the immunoproteasome-targeting approaches in cancer therapy.

project_terms:
Affinity;Antineoplastic Agents;Attention;Binding Proteins;Biological;Biology;Bortezomib;Cancer Cell Growth;Cancer cell line;Catalytic Domain;Cell Death;Cell Line;Cell Survival;Cell physiology;Cells;Chemicals;Clinical;Communities;Complex;Data;Development;Disease;Dominant-Negative Mutation;Down-Regulation;Generations;Goals;Human;In Vitro;Individual;Inflammatory;Inflammatory Bowel Diseases;Interferon Type II;Investigation;Knowledge;Libraries;Malignant Neoplasms;Malignant neoplasm of prostate;Molecular;Multiple Myeloma;Mus;Normal Cell;Organ;Peptide Library;Peptides;Pharmaceutical Preparations;Play;Primary Neoplasm;Prostatic Neoplasms;Proteasome Inhibitor;Proteomics;Publications;Refractory;Research;Role;Screening procedure;Signal Pathway;Small Interfering RNA;Solid Neoplasm;System;Therapeutic;Therapeutic Agents;Toxic effect;Tumor Tissue;Ubiquitin;Up-Regulation (Physiology);Work;Xenograft Model;cancer cell;cancer therapy;drug discovery;imaging probe;in vivo;inhibitor/antagonist;innovation;multicatalytic endopeptidase complex;neoplastic cell;novel;overexpression;protein function;public health relevance;small molecule;small molecule libraries;tool;tumor;tumor growth

public_health_relevance:
Project Narrative:Small molecule probes are valuable tools in deciphering protein functions. We havedeveloped a novel cell permeable small molecule that selectively targets theimmunoproteasome. Using this small molecule and other molecular tools we willinvestigate the roles of the immunoproteasome in cancer cells and therapeutic potentialsof the immunoproteasome-targeting approaches in cancer therapy.


application_id: 8082706
project_number: 5R21CA143676-02
project_title: Identification and synergism of bioactive components of pomegranate juice in pros
administering_ic: NCI
award_notice_date: 2011-07-14
opportunity_number: PA-07-362
application_type: 5
activity_code: R21
ic: CA
serial_number: 143676
program_official: KIM, YOUNG S
project_start_date: 2010-09-01
project_end_date: 2013-08-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 9772485
contact_pi: VADHANAM, MANICKA V
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This project is developed in response to the Program Announcement PA-07-362 [Exploratory Cancer Prevention Studies Involving Molecular Targets for Bioactive Food Components (R21)] to identify novel bioactive compounds in pomegranate juice that may act synergistically with the ellagitannins.  There is growing evidence to suggest that approximately one third of all cancer deaths can be prevented by changes in diet and lifestyle and/or through the use of preventive drug therapy. Identification of novel agents capable of modulating molecules responsible for cancer cell survival and metastasis is warranted. Available methodologies limit the detection to known compounds with potential chemopreventive properties. Unrecognized minor components that may be more potent remain untested which limits the exploitation of the power of chemoprevention. Pomegranate which comprises of ellagitannins including punicalagins and ellagic acids has gained attention due to its superior antioxidant properties. The metabolites of ellagitannins accumulate the most in prostate tissue when administered orally and bioavailability studies have focused on measuring ellagic acid in plasma. However in vitro studies have shown that pomegranate juice has lower IC50 values than individual components. Minor components of pomegranate include phenolic acids flavanoids and tannins besides others known widely for their protective effects. We hypothesize that the minor components of pomegranate juice act synergistically with the ellagitannins and is more efficacious in modulating molecules involved in preventing prostate cancer. Support to our hypothesis lies in the fact that ellagic acid when tested in a mammary tumor model was not as efficacious as black raspberry powder which contains 150-fold less ellagic acid. Further analysis of pomegranate extract detected several components apart from the major ellagitannins which were not reported previously. We used hybrid mass spectrometer (MS-filtered Fourier- transform Ion Cyclotron Resonance MS) with a nanospray autosampler that has the advantage of high mass measurement accuracy wit high resolving poser and a large dynamic range. The other advantage of this instrument is the identification of compounds in mixtures with ultra-high resolution and accuracy without need for chromatographic separation. Data mining identified several polyphenols not reported so far in pomegranate juice which are shown to have antiviral and anti-inflammatory properties among others. We will therefore pursue the following specific aims: 1) Identification of minor polyphenols bioavailability and toxicity of major and minor polyphenols from pomegranate extract using FTICR-MS; and 2) Efficacy of various fractions of pomegranate extract in modulating the tumor growth in a xenograft model. These studies will identify the components of juice other than the well studied ellagitannins and determine the synergistic effects. Based on the information on bioavailability and efficacy future studies will focus on isolation of minor components and identification of molecular targets and mechanisms.  
  
PUBLIC HEALTH RELEVANCE: Pomegranate contains multiple compounds with varied biological activities. Most of the studies focus on major components such as ellagitannins while the total juice seems more protective. This project will identify the minor bioactive components in pomegranate that might work synergistically to elicit their efficacy. The data derived from this project will form the basis to understand the mechanisms of action of pomegranate juice components in prostate cancer prevention.

project_terms:
Anthocyanins;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Antiviral Agents;Attention;Berry;Biological;Biological Availability;Breast Cancer Model;Cell Survival;Cessation of life;Chemoprevention;Chemopreventive Agent;Column Chromatography;Data;Detection;Development;Diet;Dose;Drug or chemical Tissue Distribution;Ellagi-Tannins;Ellagic Acid;Fourier transform ion cyclotron resonance;Future;High Pressure Liquid Chromatography;Hybrids;In Vitro;Individual;Ingestion;Inhibitory Concentration 50;Juice;LNCaP;Lead;Life Style;Malignant Neoplasms;Malignant neoplasm of prostate;Mass Spectrum Analysis;Measurement;Measures;Methodology;Methods;Minor;Molecular Target;Mus;NIH Program Announcements;Neoplasm Metastasis;Oxidative Stress;PC3 cell line;Pharmacotherapy;Plasma;Pomegranate;Pomegranate Juice;Powder dose form;Preventive;Property;Prostate;Raspberries;Reporting;Solvents;Tannic Acid;Testing;Tissues;Toxic effect;Tumor Burden;Wit;Work;Xenograft Model;base;bioactive food component;cancer cell;cancer prevention;data mining;flavanoid;instrument;mass spectrometer;nano;novel;phenolic acid;polyphenol;prevent;prostate cancer prevention;protective effect;public health relevance;punicalagin;response;synergism;tumor growth;ultra high resolution

public_health_relevance:
Project NarrativePomegranate contains multiple compounds with varied biological activities. Most of the studies focus on majorcomponents such as ellagitannins while the total juice seems more protective. This project will identify theminor bioactive components in pomegranate that might work synergistically to elicit their efficacy. The dataderived from this project will form the basis to understand the mechanisms of action of pomegranate juicecomponents in prostate cancer prevention.


application_id: 8082139
project_number: 1R56DC010171-01A1
project_title: Genomic Mechanisms of Gustatory Palatability
administering_ic: NIDCD
award_notice_date: 2010-06-08
opportunity_number: PA-07-094
application_type: 1
activity_code: R56
ic: DC
serial_number: 010171
suffix: A1
program_official: SULLIVAN, SUSAN L
project_start_date: 2010-06-10
project_end_date: 2011-05-31
study_section: Neurobiology of Motivated Behavior Study Section[NMB]
contact_pi_person_id: 2239737
contact_pi: LUNDY, ROBERT F
other_pis: PANGULURI, SIVA KUMAR
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
project_abstract:
In large part food consumption is driven by pleasure not just by the need for calories. According to the NIH strategic plan for obesity research one reason for rising obesity rates may lie in abundant choices of relatively inexpensive calorically-dense foods that are convenient and taste good. That is many people prefer this type of food stuff as is evidenced by the nearly 2/3 of adults in the United States that are overweight or obese. Overweight and obesity are leading causes of hypertension stroke heart disease chronic musculoskeletal problems and type 2- diabetes. A well-known fact is that learning plays an important role in the establishment and strengthening of food preferences. Even in adults though neural mechanisms exist to dynamically modulate gustatory preference. The objective of this project is to understand changes in gene expression in central gustatory/visceral nuclei that are associated with altered taste preference. The long-term objective is to elucidate neural mechanisms by which the brain integrates orosensory and postingestive signals critical for the establishment of taste preference/aversion behavior. We already know that the gustatory parabrachial nucleus (PBN) is obligate for the expression of learned and some forms of unlearned control of taste preference. Accumulating evidence suggests further that the axons necessary for altering taste preference relay through direct projections from the PBN to ventral forebrain regions like the lateral hypothalamus (LH) and amygdala. The first goal of the current proposal will use DNA microarray analyses to identify genes in the PBN LH and amygdala that are up- or downregulated following acquisition of a learned taste preference and learned taste aversion. Thus new information will be provided concerning genomic correlates of a learned preference that increases consumption and a learned aversion that decreases consumption. The second goal of the current proposal will validate and further quantify changes in gene expression using quantitative real-time polymerase chain reaction (qRT-PCR) as well as Western blot to determine whether changes in mRNA levels are translated into altered protein levels. The third goal will use in situ hybridization to demonstrate that mRNA identified by microarray analysis and validated by qRT-PCR and Western blot is indeed expressed in the brain regions of interest.

project_terms:
Accounting;Adaptive Behaviors;Address;Adult;Altered Taste;Amygdaloid structure;Animals;Area;Axon;Behavior;Brain;Brain Stem;Brain region;Calories;Cell Nucleus;Chronic;Consumption;DNA Microarray Chip;Development;Fatty acid glycerol esters;Flavoring;Food;Food Preferences;Gene Expression;Genes;Genomics;Goals;Heart Diseases;Human;Hyperphagia;Hypertension;Hypothalamic structure;In Situ Hybridization;Ingestion;Intake;Lateral;Lateral Hypothalamic Nucleus;Learning;Malaise;Messenger RNA;Microarray Analysis;Minority;Modeling;Musculoskeletal;Mutation;Nausea;Non-Insulin-Dependent Diabetes Mellitus;Nutrient;Nutritional status;Obesity;Oligonucleotides;Overweight;Pattern;Play;Polymerase Chain Reaction;Population;Process;Prosencephalon;Proteins;RNA;Regulation;Research;Reverse Transcriptase Polymerase Chain Reaction;Role;Signal Transduction;Strategic Planning;Taste Perception;Technology;Time;Tissues;Translating;United States;United States National Institutes of Health;Visceral;Visual Cortex;Western Blotting;Woman;classical conditioning;food consumption;innovation;interest;long term memory;mRNA Expression;neuromechanism;parabrachial nucleus;pleasure;preference;prevent;rat genome;stroke;sugar

public_health_relevance:
Nearly 2/3 of adults in the U.S. are overweight (35%) or obese (30%) with women minorities and the poor accounting for a disproportionate share of this population. This research is important because the learning process through which foods often high in fat and sugar come to be preferred can promote overeating and contribute to obesity. This research is innovative because it will utilize cutting-edge technology to address the underlying genetic alterations associated with altered taste preference.


application_id: 8081746
project_number: 5R21AG036875-02
project_title: Novel assay identifies all microRNA targets in Alzheimer and normal aged brains
administering_ic: NIA
award_notice_date: 2011-06-20
opportunity_number: PA-09-164
application_type: 5
activity_code: R21
ic: AG
serial_number: 036875
program_official: REFOLO, LORENZO
project_start_date: 2010-06-15
project_end_date: 2013-05-31
study_section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: 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
project_abstract:
DESCRIPTION (provided by applicant): We hypothesize that microRNAs (miRNAs) play important roles in the human brain during healthy aging and in Alzheimer's disease (AD). MiRNAs are small RNAs that regulate gene expression. Most miRNAs act through hybridization with "target" mRNAs. We and others have observed an altered pattern of miRNA expression in AD brain tissue. In various models where miRNAs are reduced neurodegeneration ensues quickly. The mechanisms of miRNA-mediated neuroprotection and neurodegeneration are poorly understood partly because most of the mRNA targets of miRNAs are still unknown. Unfortunately there has been no suitable technique to indicate experimentally which mRNAs are miRNA targets. We developed a high-throughput assay to identify miRNA targets in human brain tissue. Here we propose to use this novel assay to better understand the neurochemistry of AD. Our research program has the following Specific Aims: 1. Obtain brain tissue from the University of Kentucky Alzheimer's Disease Center Brain Bank that is thoroughly characterized including clinical evaluations near death short post-mortem intervals and state-of-the-art neuropathology. Clinical cohorts will include brain tissue of non- demented controls mild cognitive impairment controls AD and non-AD dementia controls. 2. Optimize a novel biochemical assay for accurate specific and direct miRNA target identification. This assay the Co-immunoprecipitation MicroRNA Assay Procedure (CoMAP) has been optimized in cell culture and preliminarily in brain tissue. CoMAP will be performed on the brain tissue described in Specific Aim #1. 3. Analyses of CoMAP data will incorporate data from mRNA microarray miRNA microarray clinical data and pathological data referent to the same specimens. These analyses will focus on discovering miRNA targets relevant to AD treatment and diagnosis and on elucidating the mRNA targets that subserve the neuroprotective functions of miRNA. The raw and analyzed datasets and the CoMAP assay itself will be shared freely with other investigators. These Specific Aims are intended to answer the following fundamental questions: 7 What mRNAs are miRNA targets in healthy brain aging? 7 What mRNAs are miRNA targets in Alzheimer's disease and other altered brain states? 7 How do changes in mRNA targets correlate with changes in expression of miRNAs?  
  
PUBLIC HEALTH RELEVANCE: The objective of this project is to use a novel technique to better understand the causes of Alzheimer's disease and why some people remain Alzheimer's disease-free during aging. We will characterize in human brains a newly-discovered high impact level of gene regulation which are called microRNAs using a method called a Co-immunoprecipitation MicroRNA Assay Procedure (CoMAP). We think that we can produce information that directly or indirectly contributes to diagnostics and therapeutics for Alzheimer's disease patients.

project_terms:
Aging;Alzheimer's Disease;Biochemical;Biological Assay;Biology;Brain;Cell Culture Techniques;Cessation of life;Clinical;Clinical Data;Co-Immunoprecipitations;Data;Data Set;Dementia;Diagnosis;Diagnostic;Evaluation;Future;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Human;Investigation;Journals;Kentucky;Link;Mediating;Medicine;Messenger RNA;Methods;MicroRNAs;Modeling;Nerve Degeneration;Nobel Prize;Patients;Pattern;Physiology;Play;Prize;Procedures;Research;Research Personnel;Role;Sampling;Science;Small RNA;Specimen;Techniques;Therapeutic;Tissues;Universities;aging brain;brain tissue;cohort;healthy aging;high throughput screening;mild cognitive impairment;neurochemistry;neuropathology;neuroprotection;normal aging;novel;programs;public health relevance;research clinical testing

public_health_relevance:
PROJECT SUMMARY / PROJECT NARRATIVE The objective of this project is to use a novel technique to better understand the causes of Alzheimer's disease and why some people remain Alzheimer's disease-free during aging.  We will characterize in human brains a newly-discovered high impact level of gene regulation which are called microRNAs using a method called a Co-immunoprecipitation MicroRNA Assay Procedure (CoMAP).  We think that we can produce information that directly or indirectly contributes to diagnostics and therapeutics for Alzheimer's disease patients.


application_id: 8081723
project_number: 5R01CA125152-05
project_title: Breast Cancer Chemoprevention Potential of Common Spices
administering_ic: NCI
award_notice_date: 2011-05-26
application_type: 5
activity_code: R01
ic: CA
serial_number: 125152
program_official: RISCUTA, GABRIELA
project_start_date: 2007-07-01
project_end_date: 2014-05-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 8240457
contact_pi: GUPTA, RAMESH C
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-06-01
project_abstract:
DESCRIPTION (provided by applicant):  The female hormone 1715-estradiol (E2) and its metabolites particularly 4-hydroxy-E2 (4E2) have been implicated in breast cancer. It is proposed that excessive estrogen exposure causes cell proliferation and oxidative DNA damage which may lead to gene mutations and ultimately breast cancer. It has become increasingly clear that the problem of breast cancer mortality cannot be solved by treatment alone. Therefore attention has rightfully turned to the detection of early markers of exposure and disease prevention. Unlike the current trend this application focuses on common spices belonging to one plant family for their potential against estrogen-mediated breast cancer. We hypothesize that phytochemicals present in common spices belonging to the Apiaceae family (anise caraway coriander cumin dill and fennel) will favorably alter estrogen metabolism oxidative DNA damage and cell proliferation and ultimately diminish the mammary tumorigenesis. Results obtained from extracts of all the six spices have shown drastic reduction of estrogen-mediated oxidative DNA damage by inhibiting P450 activity and/or scavenging hydroxy radicals as well as antiproliferative activity in vivo supporting our working hypothesis. Our major objectives are to identify efficacious spices based on their modes of action to inhibit estrogen-mediated mammary tumorigenesis and to correlate early markers with tumor indices. Specifically i) determine potential of the spices in short-term in vivo assays to favorably modulate estrogen metabolism oxidative DNA adduction and cell proliferation; ii) determine efficacy of test spices to inhibit estrogen-mediated mammary tumorigenesis and correlate modulation of early markers with tumor indices; and iii) determine potential of extracts of two selected spices against estrogen-mediated mammary cancer. Data resulting from this project will identify spices with the potential to inhibit breast cancer and establish an association of early biomarkers with tumor indices. Efficacious extracts will in future be fractionated and active subfractions and purified component(s) will be tested for their efficacy against estrogen carcinogenicity and their effects on early biomarkers. Thus the early biomarkers may identify women who may be at the higher risk of developing breast cancer much before the onset of pathologically detectable lesions and prevent the disease by intervention with common house-hold spices.

project_terms:
17p;American Cancer Society;Anise Seed;Antioxidants;Apiaceae;Attention;Binding (Molecular Function);Biological Assay;Breast Cancer Model;Breast Cancer Prevention;Caraway;Cell Proliferation;Chemoprevention;Chemopreventive Agent;Coriander (Spice);Cumin (spice);Cytochrome P450;DNA Adduction;DNA Adducts;DNA Damage;Data;Development;Dill;Disease;Dose;Early Diagnosis;Enzymes;Epidemiology;Estradiol;Estrogen Metabolism;Estrogen Receptors;Estrogen Replacement Therapy;Estrogens;Family;Female;Fennel - dietary;Free Radicals;Future;Gene Mutation;Goals;Hormones;Housing;Human;Immunohistochemistry;Implant;In Vitro;Inbred ACI Rats;Intervention;Laboratories;Lead;Lesion;Malignant Neoplasms;Mammary Gland Parenchyma;Mammary Neoplasms;Mammary Tumorigenesis;Measures;Mediating;Modeling;Molecular;Mortality Vital Statistics;Nutritionist;Oxidation-Reduction;Pathology;Phytochemical;Plants;Rattus;Risk;Route;Silastic;Site;Spices;Subgroup;System;Testing;Time;Tissues;United States;Western Blotting;Woman;Work;base;biomarker;cancer chemoprevention;carcinogenicity;disorder prevention;efficacy testing;high risk;improved;in vivo;indexing;malignant breast neoplasm;meetings;multidisciplinary;oxidative DNA damage;prevent;subcutaneous;trend;tumor


application_id: 8080960
project_number: 5F32AG037280-02
project_title: Harnessing microglia towards repair vs. damage: Does p38 MAPK hold the reins?
administering_ic: NIA
award_notice_date: 2011-02-21
opportunity_number: PA-09-210
application_type: 5
activity_code: F32
ic: AG
serial_number: 037280
program_official: REFOLO, LORENZO
project_start_date: 2010-04-15
project_end_date: 2012-09-14
study_section: Special Emphasis Panel[ZRG1-F01-L(20)L]
contact_pi_person_id: 10095513
contact_pi: BACHSTETTER, ADAM D
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
A primary pathological component of Alzheimer's disease (AD) is brain inflammation. Activation of microglia the "macrophages of the brain" is known to occur in AD and believed to contribute to the neuronal damage. Studies of peripheral macrophages have determined that multiple distinct activation states of macrophages exist and recent studies have confirmed these findings in microglia. Macrophages/microglia can be broadly defined as being classically activated or alternatively activated. Classically activated macrophages are typified by the release of proinflammatory cytokines (e.g. IL-12 TNF-1) and reactive oxygen and nitrogen species which are components of the inflammatory response that is known to cause neuronal damage. However not all forms of microglia activation are detrimental. Some forms of microglia activation are beneficial such as alternative activation responses that lead to removal or clearance of amyloid beta (A2). This proposal will test the hypothesis that the p381 MAP kinase signaling cascade leads to the detrimental forms of microglia activation and that blocking the p381 pathway will decrease the detrimental responses of activated microglia without affecting the beneficial responses. Aim 1 will test the hypothesis that activation of the p381 MAP kinase signaling cascade occurs in microglia during the early phase of pathogenesis in an AD-relevant transgenic mouse model (the Tg6799 mouse). Aim 2 will use a novel brain-penetrant small molecule inhibitor of p381 to test the hypothesis that suppression of p381 activity will slow the pathology in the Tg6799 mouse. This aim will provide training in the use of pharmacological tools transgenic models of neurodegenerative disease and therapeutic target validation. Aim 3 will evaluate the relative contribution of p381 in microglia vs. other neural cell types in the damage produced by A2. To test this aim we will use an A2 infusion AD-relevant model in a mouse with a genetic deletion of p381 only in the microglia. This aim will provide training in the use of conditional knockout mouse models using the cre/lox system and stereotaxic surgery in mice. Successful completion of this project will provide mechanistic insight into how the key regulatory protein p381 is involved in CNS pathophysiology mechanisms and intervention responses and will form the foundation for follow-on CNS therapeutic development campaigns targeting this important protein kinase. A Career Development Plan has been formalized and includes a combination of formal classroom and specialty workshop participation regular presentations of proposed research plans and results at the laboratory and research group level presentation of independent research results in seminar format participation in national and international scientific meetings preparation of research proposals and publications and development of additional career- enhancing skills. An experienced mentor a rich scientific environment and an organized educational and training plan will assure that the applicant has optimal opportunities for scientific growth career enhancement and development into an independent academic investigator.  
  
PUBLIC HEALTH RELEVANCE:   
Neuroinflammation is increasingly being recognized as a contributor to pathology in many neurodegenerative diseases such as Alzheimer's disease a devastating disease of aging with no effective treatment or cure. Successful completion of this project will provide mechanistic insight into how the key regulatory protein p381 MAPK is involved in brain pro-inflammatory responses and CNS dysfunction caused by disease-relevant stressors. In addition the results will delineate the relative importance of microglial p381 MAPK to the disease-relevant pathological responses. Longer term the insights and knowledge generated by the proposed studies will provide a firmer foundation for future development of new classes of disease- modifying therapeutics and fuller interpretation of disease progression investigations.

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

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Neuroinflammation is increasingly being recognized as a contributor to pathology in many neurodegenerative diseases such as Alzheimer's disease a devastating disease of aging with no effective treatment or cure. Successful completion of this project will provide mechanistic insight into how the key regulatory protein p381 MAPK is involved in brain pro-inflammatory responses and CNS dysfunction caused by disease-relevant stressors. In addition the results will delineate the relative importance of microglial p381 MAPK to the disease-relevant pathological responses. Longer term the insights and knowledge generated by the proposed studies will provide a firmer foundation for future development of new classes of disease- modifying therapeutics and fuller interpretation of disease progression investigations.


